LYMPHATIC SYSTEM-DIRECTING LIPID PRODRUGS

Information

  • Patent Application
  • 20220001015
  • Publication Number
    20220001015
  • Date Filed
    August 29, 2018
    5 years ago
  • Date Published
    January 06, 2022
    2 years ago
Abstract
The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a provided lipid prodrug or a pharmaceutical composition thereof.
Description
TECHNICAL FIELD

The present invention relates to compounds in the form of prodrugs, in particular, compounds that promote transport of a pharmaceutical agent to the lymphatic system and subsequently enhance release of the parent drug. The present invention also relates to compositions and methods of using such prodrugs.


CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Patent Application Nos. 62/551,627, filed on Aug. 29, 2017; 62/607,700, filed on Dec. 19, 2017; 62/607,749, filed on Dec. 19, 2017; 62/714,029, filed on Aug. 2, 2018; 62/724,274, filed on Aug. 29, 2018; and 62/724,440, filed on Aug. 29, 2018; the entirety of each of which is hereby incorporated by reference.


BACKGROUND OF THE INVENTION

The lymphatic system consists of a specialized network of vessels, nodes and lymphoid tissues that are distributed throughout the body in close proximity to the vascular system. The lymphatic system plays a number of key roles in immune response, fluid balance, nutrient absorption, lipid homeostasis, and tumor metastasis. Due to the unique anatomical and physiological characteristics of the lymphatic system, targeted drug delivery to and through the lymphatic system has been suggested as a means to improve both pharmacokinetic and pharmacodynamic profiles.


Lymphatic drug transport has the potential to enhance oral bioavailability through avoidance of first pass metabolism, to alter systemic drug disposition, and to enhance efficacy against lymph or lymphocyte mediated pathologies such as lymphoma, leukemia, lymphatic tumor metastasis, autoimmune disease, lymph resident infections and transplant rejection. In order for drugs to access the intestinal lymph, they must first associate with intestinal lymph lipoproteins that are assembled in intestinal absorptive cells (enterocytes) in response to lipid absorption. Association with these lipoproteins subsequently promotes drug transport into the lymph since their size precludes ready diffusion across the vascular endothelium lining the blood capillaries that drain the small intestine. Instead, these large colloidal structures enter the lymphatic capillaries since the lymphatic endothelium is considerably more permeable than that of the vascular endothelium.


Historically, drugs with high lymphatic transport have been highly lipophilic in order to promote physical association with lipoproteins (usually, but not exclusively, log D>5 and solubility in long chain triglyceride of >50 mg/g). Therefore, highly lipophilic analogues of drugs have been envisaged as one way to promote lymphatic drug transport. However, chemical modification of a parent drug can result in a reduction in potency and in many cases, significant increases in lipophilicity have been correlated with increases in toxicity.


Compounds in the form of lipophilic prodrugs provide a means to temporarily increase lipophilicity and lipoprotein affinity of a pharmaceutical compound, thereby increasing lymphatic targeting. Having been transported via the lymphatic system, the prodrug is cleaved, thereby releasing the parent drug in order to be active at its target site.


Lipophilic esters of drugs have been explored as more bioavailable versions of existing drugs. For example, testosterone undecanoate is a marketed drug for hypogonadism and other conditions. Oral administration of testosterone itself is problematic because of its extensive first pass metabolism in the liver and resulting very low bioavailability. The undecanoate ester of testosterone redirects a small proportion of the absorbed dose into the lymphatic system, thereby avoiding hepatic first pass metabolism and increasing the oral bioavailability of testosterone. However, this process is still very inefficient, and the bioavailability of testosterone after oral administration of the undecanoate ester is thought to be <5%.


Accordingly, there exists a need to develop novel lipid-pharmaceutical agent conjugates that facilitate stable transport of the pharmaceutical agent to the intestinal lymph and that readily revert to the parent active agent in order to be active.


SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of Formula VI:




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or a pharmaceutically acceptable salt thereof, wherein each variable is as defined herein.


In another aspect, the present invention provides a method of treating a disease, disorder, or condition such as one of those disclosed herein, comprising administering to a patient in need thereof an effective amount of a disclosed compound, such as a compound of Formula VI, or a pharmaceutically acceptable salt thereof.





BRIEF DESCRIPTION OF THE DRAWINGS


FIG. 1 shows lymphatic transport data for mycophenolic acid prodrug MPA-I-17 in rats.



FIG. 2 shows lymphatic transport data for mycophenolic acid prodrug MPA-I-18 in rats.



FIG. 3 shows lymphatic transport data for mycophenolic acid prodrug MPA-I-19 in rats.



FIG. 4 shows lymphatic transport data for mycophenolic acid prodrug MPA-I-20 in rats.



FIG. 5 shows lymphatic transport data for mycophenolic acid prodrug MPA-I-21 in rats.



FIG. 6 shows lymphatic transport of phenol-conjugated mycophenolic acid prodrugs (mean±SD when n≥3 or as mean±range when n=2).



FIG. 7 shows lymphatic transport of mycophenolic acid (MPA) and mycophenolate mofetil (MMF) (mean±SD). MPA (0.13%) and MMF (0.17%) had similar, very low lymphatic transport values in rats. Both compounds were administered as an intraduodenal infusion of 2 mg compound in 5.6 mL of a lipid formulation.



FIG. 8A and FIG. 8B show measured concentrations of free mycophenolic acid (MPA) in mouse mesenteric and peripheral lymph nodes after oral administration of MPA-I-34 or MPA.



FIG. 9 shows measured concentrations of the monoglyceride form of MPA-I-20 (in which both palmitic acid groups are cleaved) and free MPA released from the monoglyceride over time in rat plasma supplemented with LPL.



FIG. 10 shows conversion of MPA-I-22 into its monoglyceride form (in which both palmitic acid groups are cleaved) and release of MPA from the monoglyceride followed over time in rat plasma supplemented with LPL.



FIG. 11 shows lymphatic transport data for MMF prodrug compound MPA-I-32. The compound was administered as an intraduodenal infusion of 2 mg compound in 5.6 mL of a lipid formulation. Lymphatic transport of approximately 40% was observed.



FIG. 12 shows lymphatic transport data for mycophenolic acid prodrug MPA-I-43 in rats (plot of cumulative dose into lymph vs. time for each rat).



FIG. 13 shows lymphatic transport data for mycophenolic acid prodrug MPA-I-44 in rats.



FIG. 14 shows lymphatic transport data for mycophenolic acid prodrug MPA-I-46 in rats.



FIG. 15 shows lymphatic transport data for mycophenolic acid prodrug MPA-I-47 in rats.



FIG. 16 shows lymphatic transport data for mycophenolic acid prodrug MPA-I-48 in rats.



FIG. 17 shows lymphatic transport data for mycophenolic acid prodrug MPA-I-50 in rats.



FIG. 18 shows lymphatic transport data for several mycophenolic acid prodrugs (mycophenolic acid (MPA) and mycophenolate mofetil (MMF) shown for comparison).



FIG. 19 depicts the lymphatic transport of TAC-I-18 (TAC-C10-TG (32OH)) and TAC-I-20 (TAC-C12α′MeβME-TG (32OH)) as the concentration of total tacrolimus related compounds detected in the mesenteric lymph following intraduodenal infusion. In comparison, detected total tacrolimus-related compounds following administration of tacrolimus (TAC) alone was about 0.2%, below the limit of quantitation.



FIG. 20 depicts the results of in vitro release of tacrolimus from TAC-I-18 over time in rate plasma. “TAC” is tacrolimus; “MG” is the monoglyceride form of TAC-I-18; and “acid” is the released lipid prodrug moiety.



FIG. 21 depicts the in vitro release of tacrolimus from TAC-I-20 over time in rate plasma. “TAC” is tacrolimus; “MG” is the monoglyceride form of TAC-I-20; and “acid” is the released lipid prodrug moiety.





DETAILED DESCRIPTION OF THE INVENTION
1. General Description of Certain Aspects of the Invention
Lymphatic System Directing Prodrugs

Compounds of the present invention, and compositions thereof, are useful in promoting transport of a therapeutic agent to the lymphatic system and in subsequently enhancing release of the parent drug, i.e. the therapeutic agent.


In one aspect, the present invention provides a compound of Formula I:




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or a pharmaceutically acceptable salt thereof, wherein:

  • R1 and R2 are each independently hydrogen, a lipid, or —C(O)R3;
  • each R3 is independently a saturated or unsaturated, straight or branched C2-37 hydrocarbon chain;
  • X is —O—, —NR—, or —S—;
  • each R is independently hydrogen or an optionally substituted C1-4 aliphatic;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-20 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,




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wherein:

  • each -Cy- is independently an optionally substituted 5-6 membered bivalent aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
  • L is




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wherein:

  • R4 and R5 are each independently hydrogen or C1-4 aliphatic;
  • M is a self-immolative group;
  • n is 0-18;
  • R6 is hydrogen or C1-4 aliphatic; and
  • A is a therapeutic agent.


In one aspect, the present invention provides a compound of Formula VI:




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or a pharmaceutically acceptable salt thereof, wherein:

    • R1 and R2 are each independently hydrogen, an acid-labile group, a lipid, or —C(O)R3;
    • each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-37 hydrocarbon chain;
    • X is —O—, —NR—, —S—, —O(C1-6 aliphatic)-O—, —O(C1-6 aliphatic)-S—, —O(C1-6 aliphatic)-NR—, —S(C1-6 aliphatic)-O—, —S(C1-6 aliphatic)-S—, —S(C1-6 aliphatic)-NR—, —NR(C1-6 aliphatic)-O—, —NR(C1-6 aliphatic)-S—, or —NR(C1-6 aliphatic)-NR—, wherein 0-2 methylene units of the C1-6 aliphatic group are independently and optionally replaced with —O—, —NR—, or —S— and the C1-6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms;
    • each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
    • Y is absent or is —C(O)—, —C(NR)—, or —C(S)—;
    • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —C(S)—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-; or
    • L is




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wherein either the right-hand side or left-hand side of L is attached to A;

    • each -Cy- is independently an optionally substituted 3-6 membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
    • each R4 and R5 is independently hydrogen, deuterium, halogen, —CN, —OR, —NR2, —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C1-6 aliphatic group optionally substituted with —CN, —OR, —NR2, —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the C1-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R4 or R5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered saturated monocyclic carbocyclic ring or 3-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
    • -M- is a self-immolative group;
    • n is 0-18;
    • each m is independently 0-6; and
    • A is a therapeutic agent.


In one aspect, the present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof, comprising administering to the patient a disclosed lipid prodrug, such as a compound of Formula I or VI, or a pharmaceutically acceptable salt thereof.


It is understood that a disclosed lipid prodrug may exist in the form of a pharmaceutically acceptable salt. Thus, a reference to a “lipid prodrug” is also a disclosure of “lipid prodrug or a pharmaceutically acceptable salt thereof” It follows that such a lipid prodrug or pharmaceutically acceptable salt thereof may be used in a pharmaceutical composition and a method of use, such as those disclosed herein.


One approach to directing drugs into the lymphatic transport system is to employ prodrugs that participate in endogenous pathways that control the absorption, transport (including passive transport), and metabolism of dietary lipids. In one aspect, the present invention provides a lipid prodrug comprising a therapeutic agent conjugated to a glycerol-based moiety comprising up to two fatty acids or other lipids. Without wishing to be bound by theory, it is believed that such a prodrug mimics a dietary triglyercide, such that it participates in triglyceride processing and metabolism in the GI tract. Where appropriate, certain lipid prodrug scaffolds may be modified from the literature for use in accordance with the present disclosure. For example, certain drug-lipid conjugates and lipid prodrug scaffolds are disclosed in WO 2017/041139 and WO 2016/023082, each of which is hereby incorporated by reference in its entirety. Further examples of drug-lipid conjugates where the parent drug contains an available carboxylic acid group and has been directly conjugated to a glyceride backbone are described in Paris, G. Y. et al., J. Med. Chem. 1979, 22, (6), 683-687; Garzon Aburbeh, A. et al., J. Med. Chem. 1983, 26, (8), 1200-1203; Deverre, J. R.; et al., J. Pharm. Pharmacol. 1989, 41, (3), 191-193; Mergen, F. et al, J. Pharm. Pharmacol. 1991, 43, (11), 815-816; Garzon Aburbeh, A. et al, J. Med. Chem. 1986, 29, (5), 687-69; and Han, S. et al. J. Control. Release 2014, 177, 1-10.


Further examples have used a short linker where the drug does not contain an available carboxylic acid (Scriba, G. K. E., Arch. Pharm. (Weinheim) 1995, 328, (3), 271-276; and Scriba, G. K. E. et al, J. Pharm. Pharmacol. 1995, 47, (11), 945-948). Other examples have utilized an ester linkage to the drug and an ether linkage to the glyceride (Sugihara, J. et al., J. Pharmacobiodyn. 1988, 11, (5), 369-376; and Sugihara, J. et al., J. Pharmacobiodyn. 1988, 11, (8), 555-562).


Typical use of prodrug strategies to improve a therapeutic agent's (active pharmaceutical agent's) pharmacokinetic properties relies on cleavage in vivo to the parent agent via non-specific degradation or enzymatic cleavage, thus allowing the agent to exert its biological activity. The present invention, in one aspect, provides modified glyceride-based compounds (lipid prodrugs) that direct lymphatic transport of a therapeutic agent and improve cleavage of the lipid prodrug to the therapeutic agent.


Dietary lipids, including triglycerides, follow a particular metabolic pathway to gain access to the lymph (and ultimately the systemic circulation) that is entirely distinct from that of other nutrients such as proteins and carbohydrates. After ingestion, dietary triglycerides are hydrolyzed by lipases in the lumen to release one monoglyceride and two fatty acids for each molecule of triglyceride. The monoglyceride and two fatty acids are subsequently absorbed into enterocytes and re-esterified to triglycerides.


Resynthesised triglycerides are assembled into intestinal lipoproteins, primarily chylomicrons. After formation, chylomicrons are exocytosed from enterocytes and subsequently gain preferential access to the intestinal lymphatics. Once within the lymphatic system, chylomicrons containing packaged triglycerides drain through a series of capillaries, nodes and ducts to join the systemic circulation at the junction of the left subclavian vein and internal jugular vein. Following entry into blood circulation, triglycerides in chylomicrons are preferentially and efficiently taken up by tissues with high expression levels of lipoprotein lipases, such as adipose tissue, the liver, and potentially certain types of tumor tissues.


Lipid prodrugs are expected to behave similarly to natural triglycerides and to be transported to and through the lymphatic system to reach the systemic circulation without interacting with the liver. In some embodiments, the lipid prodrugs are cleaved, releasing the therapeutic agent, after the prodrugs have reached the systemic circulation, or after reaching a target tissue. In some embodiments, the lipid prodrugs release the therapeutic agent by destruction of a self-immolative linker that attaches the therapeutic agent to the glyercol-derived group, or by enzymatic cleavage of a linker. In this way, the pharmacokinetic and pharmacodynamic profiles of the parent therapeutic agent may be manipulated to enhance access to the lymph and lymphoid tissues, thereby promoting oral bioavailability via avoidance of first-pass metabolism (and potentially intestinal efflux). Accordingly, in some embodiments, the disclosed lipid prodrug has improved oral bioavailability, reduced first-pass metabolism, reduced liver toxicity, or improved other pharmacokinetic properties as compared with the parent therapeutic agent. In some embodiments, the disclosed lipid prodrug has increased drug targeting (as compared with the parent therapeutic agent) to sites within the lymph, lymph nodes and lymphoid tissues, and to sites of high lipid utilization and lipoprotein lipase expression such as adipose tissue, liver and some tumours.


In certain aspects, the present invention provides methods of modulating the delivery, distribution, or other properties of a therapeutic agent. In one aspect, the present invention provides a method of delivering a therapeutic agent to the systemic circulation of a patient in need thereof, wherein the therapeutic agent partially, substantially, or completely bypasses first-pass liver metabolism in the patient, comprising the step of administering to the patient a disclosed lipid prodrug of the therapeutic agent. In another aspect, the present invention provides a method of modifying a therapeutic agent to partially, substantially, or completely bypass first-pass liver metabolism in a patient after administration of the therapeutic agent, comprising the step of preparing a disclosed lipid prodrug of the therapeutic agent. In some embodiments, the lipid prodrug is administered orally. In some embodiments, preparing the lipid prodrug comprises the step of conjugating a therapeutic agent to a glycerol-based scaffold comprising two fatty acids or other lipids, thereby providing the lipid prodrug.


In another aspect, the present invention provides a method of improving oral bioavailability of a therapeutic agent, enhancing gut absorption of a therapeutic agent, or decreasing metabolism, decomposition, or efflux in the gut of a therapeutic agent, comprising the step of preparing a disclosed lipid prodrug of the therapeutic agent.


In another aspect, the present invention provides a method of modifying, e.g., improving, delivery of a therapeutic agent to a target tissue, comprising the step of preparing a disclosed lipid prodrug of the therapeutic agent. In some embodiments, the target tissue is the lymph, a lymph node (such as a mesenteric lymph node), adipose tissue, liver, or a tumor, such as a lymph node site of metastasis.


Lipid prodrugs that readily convert to parent therapeutic agent after transport via the systemic circulation have reduced free drug concentrations in the gastrointestinal (GI) tract, which may provide benefits in reducing gastrointestinal irritation or toxicity, and/or in increased drug solubility in intestinal bile salt micelles (due to similarities to endogenous monoglycerides). Disclosed lipid prodrugs may also in certain embodiments have increased passive membrane permeability (due to greater lipophilicity compared with the parent therapeutic agent). In some embodiments, the lipid prodrug has greater solubility in lipid formulations or vehicles comprising either lipids alone or mixtures of lipids with surfactants and/or cosolvents, allowing for the use of lipophilic formulations for otherwise highly hydrophilic therapeutic agents.


In one aspect, the present invention provides a compound of Formula I:




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or a pharmaceutically acceptable salt thereof, wherein:

  • R1 and R2 are each independently hydrogen, a lipid, or —C(O)R3;
  • each R3 is independently a saturated or unsaturated, straight or branched C2-37 hydrocarbon chain; X is —O—, —NR—, or —S—;
  • each R is independently hydrogen or an optionally substituted C1-4 aliphatic;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-20 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,




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wherein:

  • each -Cy- is independently an optionally substituted 5-6 membered bivalent aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
  • L is wherein:




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  • R4 and R5 are each independently hydrogen or C1-4 aliphatic;

  • M is a self-immolative group;

  • n is 0-18;

  • R6 is hydrogen or C1-4 aliphatic; and

  • A is a therapeutic agent.



As defined above and described herein, R1 and R2 are each independently hydrogen, a lipid such as a fatty acid, or —C(O)R3.


In some embodiments, R1 is hydrogen. In some embodiments, R1 is a lipid. In some embodiments, R1 is a fatty acid. In some embodiments, R1 is —C(O)R3.


In some embodiments, R1 is selected from those depicted in Table A, below.


In some embodiments, R2 is hydrogen. In some embodiments, R2 is a lipid. In some embodiments, R2 is a fatty acid. In some embodiments, R2 is —C(O)R3.


In some embodiments, R2 is selected from those depicted in Table A, below.


As defined above and described herein, each R3 is independently a saturated or unsaturated, straight or branched C2-37 hydrocarbon chain.


In some embodiments, R3 is a saturated, straight C2-37 hydrocarbon chain. In some embodiments, R3 is an unsaturated, straight C2-37 hydrocarbon chain. In some embodiments, R3 is a saturated, branched C2-37 hydrocarbon chain. In some embodiments, R3 is an unsaturated, branched C2-37 hydrocarbon chain.


In some embodiments, R3 is selected from those depicted in Table A, below.


As defined above and described herein, X is —O—, —NR—, or —S—.


In some embodiments, X is —O—. In some embodiments, X is —NR—. In some embodiments, X is —S—.


In some embodiments, X is selected from those depicted in Table A, below.


As defined above and described herein, each R is independently hydrogen or an optionally substituted C1-4 aliphatic.


In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C1-4 aliphatic.


In some embodiments, R is selected from those depicted in Table A, below.


As defined above and described herein, L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-20 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,




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In some embodiments, L is a covalent bond. In some embodiments, L is a bivalent, saturated, straight C1-20 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,




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In some embodiments, L is a bivalent, saturated, branched C1-20 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,




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In some embodiments, L is a bivalent, unsaturated, straight C1-20 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,




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In some embodiments, L is a bivalent, unsaturated, branched C1-20 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, or —NRC(O)O—.


In some embodiments, L comprises




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In some embodiments, L comprises




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In some embodiments, L comprises




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In some embodiments, L comprises




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In some embodiments, L comprises




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In some embodiments, L comprises




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In some embodiments, L comprises




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In some embodiments, L comprises




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In some embodiments, L is selected from those depicted in Table A, below.


As defined above and described herein, each -Cy- is independently an optionally substituted 5-6 membered bivalent aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.


In some embodiments, -Cy- is an optionally substituted 5-6 membered bivalent aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is an optionally substituted 5 membered bivalent aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is an optionally substituted 6 membered bivalent aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.


In some embodiments, -Cy- is selected from those depicted in Table A, below.


As defined above and described herein, L is




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In some embodiments, L is




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In some embodiments, L is




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In some embodiments, L is




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In some embodiments, L is selected from those depicted in Table A, below.


As defined above and described herein, R4 and R5 are each independently hydrogen or C1-4 aliphatic.


In some embodiments, R4 is hydrogen. In some embodiments, R4 is C1-4 aliphatic. In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl. In some embodiments, R4 is n-propyl. In some embodiments, R4 is isopropyl. In some embodiments, R4 is cyclopropyl or cyclobutyl. In some embodiments, R4 is n-butyl. In some embodiments, R4 is sec-butyl. In some embodiments, R4 is isobutyl. In some embodiments, R4 is tert-butyl. In some embodiments, R4 is selected from those depicted in Table A, below.


In some embodiments, R5 is hydrogen. In some embodiments, R5 is C1-4 aliphatic. In some embodiments, R5 is methyl. In some embodiments, R5 is ethyl. In some embodiments, R5 is n-propyl. In some embodiments, R5 is isopropyl. In some embodiments, R5 is cyclopropyl or cyclobutyl. In some embodiments, R5 is n-butyl. In some embodiments, R5 is sec-butyl. In some embodiments, R5 is isobutyl. In some embodiments, R5 is tert-butyl. In some embodiments, R4 is selected from those depicted in Table 1, below. In some embodiments, R5 is selected from those depicted in Table A, below.


As defined above and described herein, M is a self-immolative group.


In some embodiments, M is a self-immolative group.


In some embodiments, M is




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In some embodiments, M is




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In some embodiments, M is




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In some embodiments, M is




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In some embodiments, M is




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In some embodiments, M is




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In some embodiments, M is selected from those depicted in Table A, below.


As defined above and described herein, n is 0-18.


In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17. In some embodiments, n is 18.


In some embodiments, n is selected from those depicted in Table A, below.


As defined above and described herein, R6 is hydrogen or C1-4 aliphatic.


In some embodiments, R6 is hydrogen. In some embodiments, R6 is C1-4 aliphatic. In some embodiments, R6 is methyl. In some embodiments, R6 is ethyl. In some embodiments, R6 is n-propyl. In some embodiments, R6 is isopropyl. In some embodiments, R6 is n-butyl. In some embodiments, R6 is isobutyl. In some embodiments, R6 is tert-butyl.


In some embodiments, R6 is selected from those depicted in Table A, below.


As defined above and described herein, A is a therapeutic agent.


In some embodiments, A is a therapeutic agent.


In some embodiments, A is a therapeutic agent selected from any of those set forth in Tables 1-7, or a derivative thereof, below.


One of ordinary skill in the art will appreciate that certain therapeutic agents listed in Tables 1-7 are in the form of prodrugs. For example, mycophenolate mofetil is a prodrug of a mycophenolic acid. Thus, it will be appreciated that a lipid prodrug moiety of the present invention is attached to the therapeutic agent or the active form thereof. For the purpose of clarity, and by way of example, it will be understood that a provided lipid prodrug moiety is attached at any modifiable oxygen, sulfur, or nitrogen atom of the therapeutic agent, e.g. either mycophenolate mofetil or mycophenolic acid.


In some embodiments, A is selected from those depicted in Table A, below.


In one aspect, the present invention provides a compound of Formula VI:




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or a pharmaceutically acceptable salt thereof, wherein:

  • R1 and R2 are each independently hydrogen, an acid-labile group, a lipid, or —C(O)R3;
  • each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-37 hydrocarbon chain;
  • X is —O—, —NR—, —S—, —O(C1-6 aliphatic)-O—, —O(C1-6 aliphatic)-S—, —O(C1-6 aliphatic)-NR—, —S(C1-6 aliphatic)-O—, —S(C1-6 aliphatic)-S—, —S(C1-6 aliphatic)-NR—, —NR(C1-6 aliphatic)-O—, —NR(C1-6 aliphatic)-S—, or —NR(C1-6 aliphatic)-NR—, wherein 0-2 methylene units of the C1-6 aliphatic group are independently and optionally replaced with —O—, —NR—, or —S— and the C1-6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms;
  • each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • Y is absent or is —C(O)—, —C(NR)—, or —C(S)—;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —C(S)—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-; or
  • L is




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wherein either the right-hand side or left-hand side of L is attached to A;

  • each -Cy- is independently an optionally substituted 3-6 membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • each R4 and R5 is independently hydrogen, deuterium, halogen, —CN, —OR, —NR2, —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C1-6 aliphatic group optionally substituted with —CN, —OR, —NR2, —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the C1-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or
    • two instances of R4 or R5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered saturated monocyclic carbocyclic ring or 3-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;


      -M- is a self-immolative group;


      n is 0-18;


      each m is independently 0-6; and


      A is a therapeutic agent.


As defined above and described herein, R1 and R2 are each independently hydrogen, an acid-labile group, a lipid such as a fatty acid, or —C(O)R3.


In some embodiments, R1 is hydrogen. In some embodiments, R1 is an acid-labile group. In some embodiments, R1 is a lipid. In some embodiments, R1 is a fatty acid. In some embodiments, R1 is —C(O)R3. In some embodiments, R1 is selected from those depicted in Table A, below.


In some embodiments, R2 is hydrogen. In some embodiments, R2 is an acid-labile group. In some embodiments, R2 is a lipid. In some embodiments, R2 is a fatty acid. In some embodiments, R2 is —C(O)R3. In some embodiments, R2 is selected from those depicted in Table A, below.


In some embodiments, each of R1 and R2 is independently a fatty acid, phosphatide, phospholipid, or analogue thereof, such as those described in detail below. In some embodiments, each fatty acid is independently a saturated or unsaturated medium-chain or long-chain fatty acid. In some embodiments, each fatty acid independently has a C2-C40 chain. In some embodiments, each fatty acid independently has a C6-C20, C8-C20, C10-C20, C10-C18, C12-C18, C14-C18, C16-C18, or C10-C16 chain. In some embodiments, each fatty acid is independently selected from oleic acid, palmitic acid, EPA, or DHA.


In some embodiments, R1 and R2 are each independently selected from an acid labile group such as tert-butoxycarbonyl (Boc), an amino acid, PEG group, —C(O)OR, —C(O)NR2, —CH2OR, —C(NR)R, or —P(O)2OR.


As defined above and described herein, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-37 hydrocarbon chain.


In some embodiments, R3 is a saturated, straight, optionally substituted C1-37 hydrocarbon chain. In some embodiments, R3 is an unsaturated, straight, optionally substituted C1-37 hydrocarbon chain. In some embodiments, R3 is a saturated, branched, optionally substituted C1-37 hydrocarbon chain. In some embodiments, R3 is an unsaturated, branched, optionally substituted C1-37 hydrocarbon chain. In some embodiments, R3 is selected from those depicted in Table A, below.


As defined above and described herein, X is —O—, —NR—, —S—, —O (C1-6 aliphatic)-O—, —O(C1-6 aliphatic)-S—, —O(C1-6 aliphatic)-NR—, —S(C1-6 aliphatic)-O—, —S(C1-6 aliphatic)-S—, —S(C1-6 aliphatic)-NR—, —NR(C1-6 aliphatic)-O—, —NR(C1-6 aliphatic)-S—, or —NR(C1-6 aliphatic)-NR—, wherein 0-2 methylene units of the C1-6 aliphatic group are independently and optionally replaced with —O—, —NR—, or —S— and the C1-6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms.


In some embodiments, X is —O—. In some embodiments, X is —NR—. In some embodiments, X is —S—. In some embodiments, X is —O(C1-6 aliphatic)-O—. In some embodiments, X is —O(C1-6 aliphatic)-S—. In some embodiments, X is —O(C1-6 aliphatic)-NR—. In some embodiments, X is —S(C1-6 aliphatic)-O—. In some embodiments, X is —S(C1-6 aliphatic)-S—. In some embodiments, X is —S(C1-6 aliphatic)-NR—. In some embodiments, X is —NR(C1-6 aliphatic)-O—. In some embodiments, X is —NR(C1-6 aliphatic)-S—. In some embodiments, X is —NR(C1-6 aliphatic)-NR—. In any of the foregoing embodiments, 0-2 methylene units of the bivalent C1-6 aliphatic group are independently and optionally replaced with —O—, —NR—, or —S— and the bivalent C1-6 aliphatic group is independently and optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, X is selected from those depicted in Table A, below.


As defined above and described herein, Y is absent or is —C(O)—, —C(NR)—, or —C(S)—.


In some embodiments, Y is absent. In some embodiments, Y is —C(O)—. In some embodiments, Y is —C(NR)—. In some embodiments, Y is —C(S)—. In some embodiments, Y is selected from those depicted in Table A, below.


As defined above and described herein, L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 hydrocarbon chain, wherein 0-8 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —C(S)—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-; or L is




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wherein either the right-hand side or left-hand side of L is attached to A.


In some embodiments, L is a covalent bond. In some embodiments, L is a bivalent, saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 (e.g., C3-30, C5-30, C7-30, C3-25, C5-25, C7-25, C3-20, C5-20, C7-20, C8-18, C6-18, C7-17, C8-16, C8-15, C8-14, C7-13, C6-12, etc.) hydrocarbon chain, wherein 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —C(S)—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or an amino acid; and wherein 1 methylene unit of L is optionally replaced with -M-. In some embodiments, L is




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wherein either the right-hand side or left-hand side of L is attached to A.


In some embodiments, L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched, optionally substituted bivalent C1-30 (e.g., C3-30, C5-30, C7-30, C3-25, C5-25, C7-25, C3-20, C5-20, C7-20, C8-18, C6-18, C7-17, C8-16, C8-15, C8-14, C7-13, C6-12, etc.) hydrocarbon chain, wherein 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —C(S)—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or an amino acid selected from




embedded image


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and wherein 1 methylene unit of L is optionally replaced with -M-; or


L is




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wherein either the right-hand side or left-hand side of L is attached to A.


In some embodiments, L is a bivalent, saturated or unsaturated, straight or branched, optionally substituted bivalent C1-20 (e.g., C3-20, C5-20, C7-20, C8-18, C6-18, C7-17, C8-16, C8-15, C8-14, C7-13, C6-12, etc.) hydrocarbon chain, wherein 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8) methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —C(S)—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—, or a naturally-occurring amino acid such as




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and wherein 1 methylene unit of L is optionally replaced with -M-. In some embodiments, L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C3-16, C5-12, C8-16 or C6-16 hydrocarbon chain, wherein 0-6, 0-4, 0-3, or 0-1 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —C(S)—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,




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and 1 methylene unit of L is optionally replaced with -M-. In some embodiments, L is a bivalent, saturated, straight C3-20, C5-16, C6-12, C7-20, C5-20, C8-18, C6-18, C7-17, C8-16, C8-15, C8-14, C7-13, or C6-12 hydrocarbon chain, wherein 0-6, 0-4, 0-3, or 0-1 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, or —NRC(O)O—; and 1 methylene unit of L is optionally replaced with -M-. In some embodiments, L is a bivalent, saturated, straight C3-20, C5-16, C6-12, C5-20, C7-20, C8-18, C6-18, C7-17, C8-16, C8-15, C8-14, C7-13, or C6-12 hydrocarbon chain, wherein 0-6, 0-4, 0-3, or 0-1 methylene units of L are independently replaced by —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, or —C(S)—; and 1 methylene unit of L is optionally replaced with -M-.


In some embodiments, L is a bivalent, saturated C3-30, C5-25, C6-20, C8-20, C10-18, C5-20, C7-20, C8-18, C6-18, C7-17, C8-16, C8-15, C8-14, C7-13, or C6-12 hydrocarbon chain optionally substituted with 1, 2, 3, or 4 R4 groups, wherein 0-4 methylene units of L are independently replaced by —O—, —OC(O)—, —C(O)O—, or —C(O)—; and 1 methylene unit of L is optionally replaced with -M-.


In some embodiments, L is a bivalent, saturated C1-25, C5-25, C5-20, C7-20, C8-18, C6-18, C7-17, C8-16, C8-15, C8-14, C7-13, or C6-12 hydrocarbon chain optionally substituted with 1, 2, 3, or 4 groups selected from deuterium, halogen, —CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C1-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; wherein 0-4 methylene units of L are independently replaced by —O—, —OC(O)—, —C(O)O—, or —C(O)—; and 1 methylene unit of L is optionally replaced with -M-.


In some embodiments, L comprises (—OCH2CH2-)1-8 (i.e., 1-8 polyethylene glycol (PEG) units). In some embodiments, L comprises 1, 2, 3, 4, 5, 6, 7, or 8 PEG units.


In some embodiments, 0-6 units of L are independently replaced by —O—, —S—, —OC(O)—, —C(O)O—, —C(O)—, or —C(S)—; and 1 methylene unit of L is optionally replaced with -M-.


In some embodiments, L comprises




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In some embodiments, L comprises




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In some embodiments, L comprises




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In some embodiments, L comprises




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In some embodiments, L comprises




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In some embodiments, L comprises




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In some embodiments, L comprises




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In some embodiments, L comprises




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In some embodiments, 1 methylene unit of L is replaced with -M-.


In some embodiments, 1, 2, 3, or 4 available hydrogen atoms of L are replaced with an R4 group, i.e., L is optionally substituted with 1, 2, 3, or 4 R4 groups.


In some embodiments, a methylene unit of L is replaced with an amino acid. The amino acid may be naturally-occurring or non-naturally occurring. In some embodiments, the amino acid is selected from a non-polar or branched chain amino acid (BCAA). In some embodiments, the amino acid is selected from valine, isoleucine, leucine, methionine, alanine, proline, glycine, phenylalanine, tyrosine, tryptophan, histidine, asparagine, glutamine, serine threonine, lysine, arginine, histidine, aspartic acid, glutamic acid, cysteine, selenocysteine, or tyrosine. In some embodiments, the amino acid is an L-amino acid. In some embodiments, the amino acid is a D-amino acid.


In some embodiments, L is selected from those depicted in Table A, below.


As defined above and described herein, each -Cy- is independently an optionally substituted 3-6 membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.


In some embodiments, -Cy- is an optionally substituted 3-6 membered bivalent saturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is an optionally substituted 5-membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is an optionally substituted 6-membered bivalent saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, -Cy- is selected from those depicted in Table A, below.


As defined above and described herein, each R4 and R5 is independently hydrogen, deuterium, halogen, —CN, —OR, —NR2, —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C1-6 aliphatic group optionally substituted with —CN, —OR, —NR2, —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the C1-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R4 or R5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered saturated monocyclic carbocyclic ring or 3-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.


In some embodiments, R4 is hydrogen. In some embodiments, R4 is deuterium. In some embodiments, R4 is halogen. In some embodiments, R4 is —CN. In some embodiments, R4 is —OR. In some embodiments, R4 is —NR2. In some embodiments, R4 is —SR. In some embodiments, R4 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R4 is phenyl. In some embodiments, R4 is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R4 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4 is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4 is a C1-6 aliphatic group optionally substituted with —CN, —OR, —NR2, —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4 is a C1-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, two instances of R4 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered saturated monocyclic carbocyclic ring or 3-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.


In some embodiments, each R4 is independently hydrogen, deuterium, halogen, —CN, or C1-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R4 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered saturated monocyclic carbocyclic ring or 3-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.


In some embodiments, at least one instance of R4 is not hydrogen.


In some embodiments, R4 is C1-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, R4 is C1-4 alkyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R4 is methyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R4 is ethyl. In some embodiments, R4 is n-propyl. In some embodiments, R4 is isopropyl. In some embodiments, R4 is n-butyl. In some embodiments, R4 is isobutyl. In some embodiments, R4 is tert-butyl. In some embodiments, R4 is selected from those depicted in Table A, below.


In some embodiments, R5 is hydrogen. In some embodiments, R5 is deuterium. In some embodiments, R5 is halogen. In some embodiments, R5 is —CN. In some embodiments, R5 is —OR. In some embodiments, R5 is —NR2. In some embodiments, R5 is —SR. In some embodiments, R5 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R5 is phenyl. In some embodiments, R5 is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R5 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5 is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5 is a C1-6 aliphatic group optionally substituted with —CN, —OR, —NR2, —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5 is a C1-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, two instances of R5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered saturated monocyclic carbocyclic ring or 3-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.


In some embodiments, each R5 is independently hydrogen, deuterium, halogen, —CN, or C1-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered saturated monocyclic carbocyclic ring or 3-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.


In some embodiments, at least one instance of R5 is not hydrogen.


In some embodiments, R5 is C1-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, R5 is methyl optionally substituted with 1, 2, or 3 deuterium or halogen atoms. In some embodiments, R5 is ethyl. In some embodiments, R5 is n-propyl. In some embodiments, R5 is isopropyl. In some embodiments, R5 is n-butyl. In some embodiments, R5 is isobutyl. In some embodiments, R5 is tert-butyl. In some embodiments, R5 is selected from those depicted in Table A, below.


As defined above and described herein, -M- is a self-immolative group.


In some embodiments, -M- is an acetal, an o-benzylalcohol, a p-benzylalcohol, a styryl group, a coumarin, or a group that self-immolates via a cyclization reaction. In some embodiments, -M- is selected from a disulfide, hydrazone, acetal self-immolative group, carboxyacetal self-immolative group, carboxy(methylacetal) self-immolative group, para-hydroxyb enzyl self-immolative group, para-hydroxybenzyl carbonyl self-immolative group, flipped ester self-immolative group, trimethyl lock self-immolative group, or 2-hydroxyphenyl carbamate (2-HPC) self-immolative group.


In some embodiments, -M- is selected from one of the following:




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  • wherein each R6 is independently selected from hydrogen, deuterium, C1-10 aliphatic, halogen, or —CN;

  • each R7 is independently selected from hydrogen, deuterium, halogen, —CN, —OR, —NR2, —NO2, —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C1-6 aliphatic group optionally substituted with —CN, —OR, —NR2, —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the C1-6 aliphatic is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms;



each Z1 is independently selected from —O—, —NR—, or —S—;


each Z2 is independently selected from —O—, —NR—, —S—, —OC(O)—, —NRC(O)O—, or —OC(O)NR—;


each Z3 is independently selected from ═N— or ═C(R7)—; and


each Z4 is independently selected from —O—, —NR—, —S—, —C(R6)2—, or a covalent bond.


As defined generally above and described herein, each R6 is independently selected from hydrogen, deuterium, C1-10 aliphatic, halogen, or —CN. In some embodiments, R6 is hydrogen. In some embodiments, R6 is deuterium. In some embodiments, R6 is C1-10 aliphatic. In some embodiments, R6 is halogen. In some embodiments, R6 is —CN.


In some embodiments, R6 is hydrogen, C1-5 alkyl, halogen, or —CN. In some embodiments, R6 is hydrogen or C1-3 alkyl. In some embodiments, R6 is hydrogen or methyl.


In some embodiments, each instance of R6 in the above formulae is the same. In some embodiments, each R6 is different. In some embodiments, one R6 is hydrogen. In some embodiments, one R6 is C1-5 aliphatic. In some embodiments, each R6 is hydrogen. In some embodiments, each R6 is C1-5 aliphatic. In some embodiments, R6 is selected from those depicted in Table A, below.


As defined generally above and described herein, each R7 is independently selected from hydrogen, deuterium, halogen, —CN, —OR, —NR2, —NO2, —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C1-6 aliphatic group optionally substituted with —CN, —OR, —NR2, —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the C1-6 aliphatic group is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.


In some embodiments, R7 is hydrogen. In some embodiments, R7 is deuterium. In some embodiments, R7 is halogen. In some embodiments, R7 is —CN. In some embodiments, R7 is —OR. In some embodiments, R7 is —NR2. In some embodiments, R7 is —NO2. In some embodiments, R7 is —SR. In some embodiments, R7 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R7 is phenyl. In some embodiments, R7 is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R7 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7 is or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7 is or a C1-6 aliphatic group optionally substituted with —CN, —OR, —NR2, —SR, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7 is a C1-6 aliphatic group optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms.


In some embodiments, R7 is hydrogen, deuterium, halogen, —CN, —OR, —NR2, —NO2, —SR, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C1-6 aliphatic group optionally substituted with —CN, —OR, —NR2, —SR, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the C1-6 aliphatic group is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, R7 is hydrogen, deuterium, halogen, —CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a C1-4 alkyl group optionally substituted with —CN, a 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or the C1-4 alkyl group is optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, R7 is hydrogen, halogen, —CN, —OR, or C1-4 alkyl.


In some embodiments, R is hydrogen or C1-4 alkyl.


In some embodiments, R7 is selected from those depicted in Table A, below.


As defined generally above and described herein, each Z1 is independently selected from —O—, —NR—, or —S—. In some embodiments, Z1 is —O—. In some embodiments, Z1 is —NR—. In some embodiments, Z1 is —S. In some embodiments, Z1 is —NH— or —NMe-.


In some embodiments, Z1 is selected from those depicted in Table A, below.


As defined generally above and described herein, each Z2 is independently selected from —O—, —NR—, —S—, —OC(O)—, —NRC(O)O—, or —OC(O)NR—.


In some embodiments, Z2 is —O—. In some embodiments, Z2 is —NR—. In some embodiments, Z2 is -5-. In some embodiments, Z2 is —OC(O)—. In some embodiments, Z2 is —NRC(O)O—. In some embodiments, Z2 is —OC(O)NR—.


In some embodiments, each Z2 is independently selected from —O—, —NH—, —NMe-, —S—, —OC(O)—, —NHC(O)O—, —NMeC(O)O—, —OC(O)NH—, or —OC(O)NMe-.


In some embodiments, Z2 is covalently bound to A. In some embodiments, Z2 is —O— or —OC(O)O—.


In some embodiments, Z2 is selected from those depicted in Table A, below.


In some embodiments, Z1 is —O— and Z2 is —O— or —OC(O)O—.


As defined generally above and described herein, each Z3 is independently selected from ═N— or ═C(R7)—. In some embodiments, Z3 is ═N—. In some embodiments, Z3 is ═C(R7)—.


In some embodiments, Z3 is selected from those depicted in Table A, below.


As defined generally above and described herein, each Z4 is independently selected from —O—, —NR—, —S—, —C(R6)2—, or a covalent bond. In some embodiments, Z4 is —O—. In some embodiments, Z4 is —NR—. In some embodiments, Z4 is —S—. In some embodiments, Z4 is —C(R6)2—. In some embodiments, Z4 is a covalent bond.


In some embodiments, Z4 is selected from those depicted in Table A, below.


In some embodiments, -M- is selected from one of the following:




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In some embodiments, -M- is selected from




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In some embodiments, -M- is selected from




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In some embodiments, -M- is selected from those depicted in Table A, below.


As defined above and described herein, n is 0-18.


In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17. In some embodiments, n is 18. In some embodiments, n is 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-3, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, 3-12, 3-8, 3-6, 4-10, 4-8, 4-6, 5-10, 5-8, 5-6, 6-18, 6-10, 6-8, 8-12, 5-18, 5-13, 8-18, 8-17, 8-16, 8-15, 8-16, or 6-16.


As defined above and described herein, each m is independently 0-6. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, each m is independently 0, 1, or 2. In some embodiments, each m is independently 1, 2, 3, or 4.


As defined above and described herein, A is a therapeutic agent.


In some embodiments, A is a therapeutic agent selected from any of those set forth in Tables 1-7, or a derivative thereof, below.


One of ordinary skill in the art will appreciate that certain therapeutic agents listed in Tables 1-7 are in the form of prodrugs. For example, mycophenolate mofetil is a prodrug of a mycophenolic acid. Thus, it will be appreciated that a lipid prodrug moiety of the present invention is attached to the prodrug of the therapeutic agent or the active form of the prodrug. For the purpose of clarity, and by way of example, it will be understood that a provided lipid prodrug moiety is attached at any modifiable oxygen, sulfur, or nitrogen atom of the therapeutic agent, e.g. either mycophenolate mofetil or mycophenolic acid.


In some embodiments, a disclosed lipid prodrug comprises one or two lipids covalently bound to one or two of the hydroxyl groups of the glyceride-based group shown in, e.g. Formula I or VI.


In some embodiments, a disclosed lipid prodrug further comprises a lipid covalently bound to the therapeutic agent. In some embodiments, such a lipid increases the lipophilicity or other desirable property of the lipid prodrug, e.g. to increase lymphatic uptake and transport. In some embodiments, the lipid is conjugated to the therapeutic agent at an available at an available nitrogen, sulfur, or oxygen atom, such as a carboxylic acid, amine, hydroxyl, or amide. In some embodiments, the lipid is selected from those described below. In some embodiments, the lipid forms an ester of the therapeutic agent.




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As used herein, depiction of brackets around a therapeutic agent, A, means that the




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moiety is covalently attached to A at any available modifiable nitrogen, oxygen, or sulfur atom. For purposes of clarity and by way of example, such available modifiable nitrogen, oxygen, or sulfur atoms in the following therapeutic agent compound structure are depicted below, wherein each wavy bond defines the point of attachment to said




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In certain embodiments, the present invention provides a compound of formula I, wherein L is




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thereby forming a compound of formula II:




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or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R4, X, M and A is as defined above and described in embodiments herein, both singly and in combination.


In certain embodiments, the present invention provides a compound of formula I, wherein L is




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thereby forming a compound of formula III:




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or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R4, R5, X, M and A is as defined above and described in embodiments herein, both singly and in combination.


In certain embodiments, the present invention provides a compound of formula I, wherein L is




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and M is



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thereby forming a compound of formula IV:




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or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R4, R5, R6, X, and A is as defined above and described in embodiments herein, both singly and in combination.


In some embodiments, the present invention provides a compound of Formula VI-a:




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or a pharmaceutically acceptable salt thereof, wherein each of L, R2, R, X, and A is as defined above and described in embodiments herein, both singly and in combination.


In some embodiments, the present invention provides a compound of Formula VII-a or VII-b:




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or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R4, R5, X, M, and A is as defined above and described in embodiments herein, both singly and in combination.


In some embodiments, the present invention provides a compound of Formula VIII-a or VIII-b:




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or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R4, R5, X, n, and A is as defined above and described in embodiments herein, both singly and in combination.


In some embodiments, the present invention provides a compound of Formula IX-a, IX-b, IX-c, or IX-d:




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or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both singly and in combination.


In some embodiments, the present invention provides a compound of Formula X-a, X-b, X-c, X-d, X-e, X-f, X-g, or X-h:




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or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both singly and in combination.


In some embodiments, the present invention provides a compound of Formula XI-a or XI-b:




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or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both singly and in combination.


In the above formulae, when a range of numbers, such as 0-4 or 1-18, is disclosed, individual integers within the range are also specifically disclosed. Thus, the above range of 0-4 includes 0, 1, 2, 3, and 4. The range 1-18 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18 as well as ranges in between such as 6-18 and 8-18. The range 0-1 includes 0 and 1, i.e. the group is optionally present. Where more than one range is disclosed in a formula, each range is independently and optionally selected from the disclosed range. For example, in Formula X-c above, each 0-4 and 0-1 range is varied independently of the others.


In some embodiments, the lipid prodrug is one of those described in U.S. Ser. No. 62/724,274, filed on Aug. 29, 2018, the entirety of which is hereby incorporated by reference.


In some embodiments, the lipid prodrug is one of those described in U.S. Ser. No. 62/724,440, filed on Aug. 29, 2018, the entirety of which is hereby incorporated by reference.


In other embodiments, the present invention provides a compound of Formula V:




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or a pharmaceutically acceptable salt thereof, wherein:

  • R1 and R2 are each independently hydrogen or —C(O)R3;
  • each R3 is independently a saturated or unsaturated, straight or branched C2-37 hydrocarbon chain;
  • X is —O—, —NR—, or —S—;
  • each R is independently hydrogen or an optionally substituted C1-4 aliphatic;
  • L1 is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-20 hydrocarbon chain, wherein 0-6 methylene units of L1 are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, or —NRC(O)O—, wherein:
  • each -Cy- is independently an optionally substituted 5-6 membered bivalent aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
  • R7 is a moiety suitable for click chemistry or metal-free click chemistry.


R1, R2, R3, X, R, and -Cy- are as defined above and described herein. Embodiments of R1, R2, R3, X, R, and -Cy- are as defined above and described herein.


As defined above and described herein, L1 is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-20 hydrocarbon chain, wherein 0-6 methylene units of L1 are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, or —NRC(O)O—.


In some embodiments, L1 is a covalent bond. In some embodiments, L1 is a bivalent, saturated, straight C1-20 hydrocarbon chain, wherein 0-6 methylene units of L1 are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, or —NRC(O)O—. In some embodiments, L1 is a bivalent, saturated, branched C1-20 hydrocarbon chain, wherein 0-6 methylene units of L1 are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, or —NRC(O)O—. In some embodiments, L1 is a bivalent, unsaturated, straight C1-20 hydrocarbon chain, wherein 0-6 methylene units of L1 are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, or —NRC(O)O—. In some embodiments, L1 is a bivalent, unsaturated, branched C1-20 hydrocarbon chain, wherein 0-6 methylene units of L1 are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —NRS(O)2—, —S(O)2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, or —NRC(O)O—.


In some embodiments, L1 is selected from those depicted in Table A, below.


As defined above and described herein, R7 is a moiety suitable for click chemistry or metal-free click chemistry.


In some embodiments, R7 is a moiety suitable for click chemistry. In some embodiments, R7 is a moiety suitable for metal-free click chemistry.


In some embodiments, R7 is —N3. In some embodiments, R7 is




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In some embodiments, R7 is




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In some embodiments, R7 is




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In some embodiments, R7 is




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In some embodiments, R7 is




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In some embodiments, R7 is




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In some embodiments, R7 is




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In some embodiments, R7 is




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In some embodiments, R7 is




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In some embodiments, R7 is




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In some embodiments, R7 is




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In some embodiments, R7 is




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In some embodiments, R7 is




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In some embodiments, R7 is




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In one aspect, the present invention provides a lipid prodrug compound, or pharmaceutically acceptable salt thereof, shown in Table A:









TABLE A





Exemplary Compounds


















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I-1







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I-2







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I-3







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I-4







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I-5







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I-6







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I-7







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I-8







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I-9







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I-10







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I-11







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I-12







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I-13







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I-14







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I-15







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I-16







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I-17







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I-18







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I-19







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I-20







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I-21







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I-22







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I-23







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I-24







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I-25







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I-26







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I-27







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I-28







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I-29







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I-30







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I-31







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I-32







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I-33







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I-34







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I-35







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I-36







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I-37







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I-38







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I-39







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I-40







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I-41







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I-42







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I-43







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I-44







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I-45







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I-46







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I-47







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I-48







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I-49







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I-50







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I-51







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I-52







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I-53







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I-54







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I-55







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I-56







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MPA- MPA- I-1







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MPA- MPA- I-2







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MPA- MPA- I-3







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MPA- MPA- I-4







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MPA- MPA- I-5







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MPA- MPA- I-6







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MPA- MPA- I-7







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MPA- MPA- I-8







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MPA- MPA- I-8′







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MPA- MPA- I-9







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MPA- MPA- I-10







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MPA- MPA- I-11







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MPA- MPA- I-12







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MPA- MPA- I-13







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MPA- MPA- I-14







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MPA- MPA- I-15







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MPA- MPA- I-16







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MPA- MPA- I-17







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MPA- MPA- I-18







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MPA- MPA- I-19







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MPA- MPA- I-20







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MPA- MPA- I-21







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MPA- MPA- I-22







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MPA- MPA- I-23







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MPA- MPA- I-24







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MPA- MPA- I-25







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MPA- MPA- I-26







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MPA- MPA- I-27







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MPA- MPA- I-28







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MPA- MPA- I-29







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MPA- I-30







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MPA- I-31







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MPA- I-32







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MPA- I-33







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MPA- I-34







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MPA- I-35







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MPA- I-36







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MPA- I-37







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MPA- I-38







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MPA- I-39







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MPA- I-40







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MPA- I-41







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MPA- I-42







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MPA- I-43







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MPA- I-44







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MPA- I-45







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MPA- I-46







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MPA- I-47







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MPA- I-48







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MPA- I-49







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MPA- I-50







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MPA- I-51







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MPA- I-52







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MPA- I-53







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MPA- I-54







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TAC- I-1







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TAC- I-2







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TAC- I-3







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TAC- I-4







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TAC- I-5







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TAC- I-6







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TAC- I-7







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TAC- I-8







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TAC- I-9







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TAC- I-10







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TAC- I-11







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TAC- I-12







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TAC- I-13







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TAC- I-14







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TAC- I-15







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TAC- I-16







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TAC- I-17







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TAC- I-18







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TAC- I-19







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TAC- I-20







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TAC- I-21







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TAC- I-22







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TAC- I-23







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TAC- I-24







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TAC- I-25







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TAC- I-26







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TAC- I-27







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TAC- I-28







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TAC- I-29









Lipids, Including Fatty Acids, Phospholipids, Lipid-Processing Mimetics, and Mixtures Thereof for Use in Disclosed Lipid Prodrugs

Lipid prodrugs according to the present disclosure mimic the lipid processing that takes place in the human body. In some embodiments, a disclosed lipid prodrug comprises one or two lipids covalently bound to one or two of the hydroxyl groups of the glyceride-based group shown in, e.g. Formula I or VI.


In some embodiments, a disclosed lipid prodrug further comprises a lipid covalently bound to the therapeutic agent. In some embodiments, such a lipid increases the lipophilicity or other desirable property of the lipid prodrug, e.g. to increase lymphatic uptake and transport. In some embodiments, the lipid is conjugated to the therapeutic agent at an available nitrogen, sulfur, or oxygen atom, such as a carboxylic acid, amine, hydroxyl, or amide. In some embodiments, the lipid is selected from those described below. In some embodiments, the lipid forms an ester of the therapeutic agent.


A variety of lipids are suitable for use in lipid prodrugs of the present disclosure. In some embodiments, the lipid prodrug comprises a fatty acid, phosphatide, phospholipid, or analogue thereof (e.g. phophatidylcholine, lecithin, phosphatidylethanolamine, cephalin, or phosphatidylserine or analogue or portion thereof, such as a partially hydrolyzed portion thereof), or other lipid-processing mimetic (e.g., a group cleaved by lipases, other digestive enzymes, or other mechanisms in the GI tract that enables the lipid prodrug to mimic dietary lipid processing). In some embodiments, the fatty acid is a short-chain, medium-chain, or long-chain fatty acid. In some embodiments, the fatty acid is a saturated fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid. In some embodiments, the fatty acid is a monounsaturated fatty acid. In some embodiments, the fatty acid is a polyunsaturated fatty acid, such as an ω-3 (omega-3) or ω-6 (omega-6) fatty acid. In some embodiments, the lipid, e.g., fatty acid, has a C2-C60 chain. In some embodiments, the lipid, e.g., fatty acid, has a C2-C28 chain. In some embodiments, the lipid, e.g., fatty acid, has a C2-C40 chain. In some embodiments, the lipid, e.g., fatty acid, has a C2-C12 or C4-C12 chain. In some embodiments, the lipid, e.g., fatty acid, has a C4-C40 chain. In some embodiments, the lipid, e.g., fatty acid, has a C4-C40, C2-C38, C2-C36, C2-C34, C2-C32, C2-C30, C4-C30, C2-C28, C4-C28, C2-C26, C4-C26, C2-C24, C4-C24, C6-C24, C8-C24, C10-C24, C2-C22, C4-C22, C6-C22, C8-C22, C10-C22, C2-C20, C4-C20, C6-C20, C8-C20, C10-C20, C2-C18, C4-C18, C6-C18, C8-C18, C10-C18, C12-C18, C14-C18, C16-C18, C2-C16, C4-C16, C6-C16, C8-C16, C10-C16, C12-C16, C14- C16, C2-C15, C4-C15, C6-C15, C8-C15, C9-C15, C10-C15, C11-C15, C12-C15, C13-C15, C2-C14, C4-C14, C6-C14, C8-C14, C9-C14, C10-C14, C11-C14, C12-C14, C2-C13, C4-C13, C6-C13, C7-C13, C8-C13, C9-C13, C10-C13, C10-C13, C11-C13, C2-C12, C4-C12, C6-C12, C7-C12, C8-C12, C9-C12, C10-C12, C2-C11, C4-C11, C6-C11, C7-C11, C8-C11, C9-C11, C2-C10, C2-C9, C4-C9, C2-C8, C4-C8, C2-C7, C4-C7, C2-C6, or C4- C6, chain. In some embodiments, the lipid, e.g., fatty acid, has a C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, or C60 chain. In some embodiments, the lipid prodrug comprises two fatty acids, each of which is independently selected from a fatty acid having a chain with any one of the foregoing ranges or numbers of carbon atoms. In some embodiments, one of the fatty acids is independently a fatty acid with a C6-C21 chain and one is independently a fatty acid with a C12-C36 chain. In some embodiments, each fatty acid independently has a chain of 11, 12, 13, 14, 15, 16, or 17 carbon atoms.


In some embodiments, the lipid prodrug comprises two lipids. In some embodiments, the two lipids, e.g. fatty acids, taken together have 6-80 carbon atoms (an equivalent carbon number (ECN) of 6-80). In some embodiments, the lipids, e.g., fatty acids, have an ECN of 6-80, 8-80, 10-80, 12-80, 14-80, 16-80, 18-80, 20-80, 22-80, 24-80, 26-80, 28-80, 30-80, 4-76, 6-76, 8-76, 10-76, 12-76, 14-76, 16-76, 18-76, 20-76, 22-76, 24-76, 26-76, 28-76, 30-76, 6-72, 8-72, 10-72, 12-72, 14-72, 16-72, 18-72, 20-72, 22-72, 24-72, 26-72, 28-72, 30-72, 6-68, 8-68, 10-68, 12-68, 14-68, 16-68, 18-68, 20-68, 22-68, 24-68, 26-68, 28-68, 30-68, 6-64, 8-64, 10-64, 12-64, 14-64, 16-64, 18-64, 20-64, 22-64, 24-64, 26-64, 28-64, 30-64, 6-60, 8-60, 10-60, 12-56, 14-56, 16-56, 18-56, 20-56, 22-56, 24-56, 26-56, 28-56, 30-56, 6-52, 8-52, 10-52, 12-52, 14-52, 16-52, 18-52, 20-52, 22-52, 24-52, 26-52, 28-52, 30-52, 6-48, 8-48, 10-48, 12-48, 14-48, 16-48, 18-48, 20-48, 22-48, 24-48, 26-48, 28-48, 30-48, 6-44, 8-44, 10-44, 12-44, 14-44, 16-44, 18-44, 20-44, 22-44, 24-44, 26-44, 28-44, 30-44, 6-40, 8-40, 10-40, 12-40, 14-40, 16-40, 18-40, 20-40, 22-40, 24-40, 26-40, 28-40, 30-40, 6-36, 8-36, 10-36, 12-36, 14-36, 16-36, 18-36, 20-36, 22-36, 24-36, 26-36, 28-36, 30-36, 6-32, 8-32, 10-32, 12-32, 14-32, 16-32, 18-32, 20-32, 22-32, 24-32, 26-32, 28-32, or 30-32.


Suitable fatty acids include saturated straight-chain fatty acids, saturated branched fatty acids, unsaturated fatty acids, hydroxy fatty acids, and polycarboxylic acids. In some embodiments, such fatty acids have up to 32 carbon atoms.


Examples of useful saturated straight-chain fatty acids include those having an even number of carbon atoms, such as butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachic acid, behenic acid, lignoceric acid, hexacosanoic acid, octacosanoic acid, triacontanoic acid and n-dotriacontanoic acid, and those having an odd number of carbon atoms, such as propionic acid, n-valeric acid, enanthic acid, pelargonic acid, hendecanoic acid, tridecanoic acid, pentadecanoic acid, heptadecanoic acid, nonadecanoic acid, heneicosanoic acid, tricosanoic acid, pentacosanoic acid, and heptacosanoic acid.


Examples of suitable saturated branched fatty acids include isobutyric acid, isocaproic acid, isocaprylic acid, isocapric acid, isolauric acid, 11-methyldodecanoic acid, isomyristic acid, 13-methyl-tetradecanoic acid, isopalmitic acid, 15-methyl-hexadecanoic acid, isostearic acid, 17-methyloctadecanoic acid, isoarachic acid, 19-methyl-eicosanoic acid, α-ethyl-hexanoic acid, α-hexyldecanoic acid, α-heptylundecanoic acid, 2-decyltetradecanoic acid, 2-undecyltetradecanoic acid, 2-decylpentadecanoic acid, 2-undecylpentadecanoic acid, and Fine oxocol 1800 acid (product of Nissan Chemical Industries, Ltd.). Suitable saturated odd-carbon branched fatty acids include anteiso fatty acids terminating with an isobutyl group, such as 6-methyl-octanoic acid, 8-methyl-decanoic acid, 10-methyl-dodecanoic acid, 12-methyl-tetradecanoic acid, 14-methyl-hexadecanoic acid, 16-methyl-octadecanoic acid, 18-methyl-eicosanoic acid, 20-methyl-docosanoic acid, 22-methyl-tetracosanoic acid, 24-methyl-hexacosanoic acid, and 26-methyloctacosanoic acid.


Examples of suitable unsaturated fatty acids include 4-decenoic acid, caproleic acid, 4-dodecenoic acid, 5-dodecenoic acid, lauroleic acid, 4-tetradecenoic acid, 5-tetradecenoic acid, 9-tetradecenoic acid, palmitoleic acid, 6-octadecenoic acid, oleic acid, 9-octadecenoic acid, 11-octadecenoic acid, 9-eicosenoic acid, cis-11-eicosenoic acid, cetoleic acid, 13-docosenoic acid, 15-tetracosenoic acid, 17-hexacosenoic acid, 6,9,12,15-hexadecatetraenoic acid, linoleic acid, linolenic acid, α-eleostearic acid, β-eleostearic acid, punicic acid, 6,9,12,15-octadecatetraenoic acid, parinaric acid, 5,8,11,14-eicosatetraenoic acid, 5,8,11,14,17-eicosapentaenoic acid, 7,10,13,16,19-docosapentaenoic acid, 4,7,10,13,16,19-docosahexaenoic acid, and the like.


Examples of suitable hydroxy fatty acids include α-hydroxylauric acid, α-hydroxymyristic acid, α-hydroxypalmitic acid, α-hydroxystearic acid, w-hydroxylauric acid, α-hydroxyarachic acid, 9-hydroxy-12-octadecenoic acid, ricinoleic acid, α-hydroxybehenic acid, 9-hydroxy-trans-10,12-octadecadienic acid, kamolenic acid, ipurolic acid, 9,10-dihydroxystearic acid, 12-hydroxystearic acid and the like.


Examples of suitable polycarboxylic acids include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, D,L-malic acid, and the like.


In some embodiments, each fatty acid is independently selected from Propionic acid, Butyric acid, Valeric acid, Caproic acid, Enanthic acid, Caprylic acid, Pelargonic acid, Capric acid, Undecylic acid, Lauric acid, Tridecylic acid, Myristic acid, Pentadecylic acid, Palmitic acid, Margaric acid, Stearic acid, Nonadecylic acid, arachidic acid, Heneicosylic acid, Behenic acid, Tricosylic acid, Lignoceric acid, Pentacosylic acid, Cerotic acid, Heptacosylic acid, Montanic acid, Nonacosylic acid, Melissic acid, Henatriacontylic acid, Lacceroic acid, Psyllic acid, geddic acid, ceroplastic acid, hexatriacontylic acid, heptatriacontanoic acid, or octatriacontanoic acid.


In some embodiments, each fatty acid is independently selected from α-linolenic acid, stearidonic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, gamma-linoleic acid, dihomo-gamma-linoleic acid, arachidonic acid, docosatetraenoic acid, palmitoleic acid, vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic acid, eurcic acid, nervonic acid, mead acid, adrenic acid, bosseopentaenoic acid, ozubondo acid, sardine acid, herring acid, docosahexaenoic acid, or tetracosanolpentaenoic acid, or another monounsaturated or polyunsaturated fatty acid.


In some embodiments, one or both of the fatty acids is an essential fatty acid. In view of the beneficial health effects of certain essential fatty acids, the therapeutic benefits of disclosed lipid prodrugs may be increased by including such fatty acids in the lipid prodrug. In some embodiments, the essential fatty acid is an n-6 or n-3 essential fatty acid selected from the group consisting of linolenic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, adrenic acid, docosapentaenoic n-6 acid, alpha-linolenic acid, stearidonic acid, the 20:4n-3 acid, eicosapentaenoic acid, docosapentaenoic n-3 acid, or docosahexaenoic acid.


In some embodiments, each fatty acid is independently selected from all-cis-7,10,13-hexadecatrienoic acid, α-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, docosahexaenoic acid (DHA), tetracosapentaenoic acid, tetracosahexaenoic acid, or lipoic acid. In other embodiments, the fatty acid is selected from eicosapentaenoic acid, docosahexaenoic acid, or lipoic acid. Other examples of fatty acids include all-cis-7,10,13-hexadecatrienoic acid, α-linolenic acid (ALA or all-cis-9,12,15-octadecatrienoic acid), stearidonic acid (STD or all-cis-6,9,12,15-octadecatetraenoic acid), eicosatrienoic acid (ETE or all-cis-11,14,17-eicosatrienoic acid), eicosatetraenoic acid (ETA or all-cis-8,11,14,17-eicosatetraenoic acid), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA, clupanodonic acid or all-cis-7,10,13,16,19-docosapentaenoic acid), docosahexaenoic acid (DHA or all-cis-4,7,10,13,16,19-docosahexaenoic acid), tetracosapentaenoic acid (all-cis-9,12,15,18,21-docosahexaenoic acid), or tetracosahexaenoic acid (nisinic acid or all-cis-6,9,12,15,18,21-tetracosenoic acid). In some embodiments, the fatty acid is a medium-chain fatty acid such as lipoic acid.


Fatty acid chains differ greatly in the length of their chains and may be categorized aaccording to chain length, e.g. as short to very long.


Short-chain fatty acids (SCFA) are fatty acids with chains of about five or less carbons (e.g. butyric acid). In some embodiments, each of the fatty acids is independently a SCFA. In some embodiments, one of the fatty acids is independently a SCFA.


Medium-chain fatty acids (MCFA) include fatty acids with chains of about 6-12 carbons, which can form medium-chain triglycerides. In some embodiments, each of the fatty acids is independently a MCFA. In some embodiments, one of the fatty acids is independently a MCFA.


Long-chain fatty acids (LCFA) include fatty acids with chains of 13-21 carbons. In some embodiments, each of the fatty acids is independently a LCFA. In some embodiments, one of the fatty acids is independently a LCFA.


Very long chain fatty acids (VLCFA) include fatty acids with chains of 22 or more carbons, such as 22-60, 22-50, or 22-40 carbons. In some embodiments, each of the fatty acids is independently a VLCFA. In some embodiments, one of the fatty acids is independently a VLCFA.


In some embodiments, one of the fatty acids is independently a MCFA and one is independently a LCFA.


Use of Click Chemistry to Attach Therapeutic Agent to the Lymphatic Drug-Release Moiety

In some embodiments, the therapeutic agent is covalently attached to the lymphatic drug-release moiety (i.e., the remaining portion of the lipid prodrug besides the therapeutic agent) by the use of “click” chemistry. The term “click-ready group” refers to a chemical moiety capable of undergoing a click reaction, such as an azide or alkyne.


Click reactions tend to involve high-energy (“spring-loaded”) reagents with well-defined reaction coordinates that give rise to selective bond-forming events of wide scope. Examples include nucleophilic trapping of strained-ring electrophiles (epoxide, aziridines, aziridinium ions, episulfonium ions), certain carbonyl reactivity (e.g., the reaction between aldehydes and hydrazines or hydroxylamines), and several cycloaddition reactions. The azide-alkyne 1,3-dipolar cycloaddition and the Diels-Alder cycloaddition are two such reactions.


Such click reactions (i.e., dipolar cycloadditions) are associated with a high activation energy and therefore require heat or a catalyst. Indeed, use of a copper catalyst is routinely employed in click reactions. However, in certain instances where click chemistry is particularly useful (e.g., in bioconjugation reactions), the presence of copper can be detrimental (See Wolbers, F. et al.; Electrophoresis 2006, 27, 5073). Accordingly, methods of performing dipolar cycloaddition reactions were developed without the use of metal catalysis. Such “metal free” click reactions utilize activated moieties in order to facilitate cycloaddition. Therefore, the present invention provides click-ready groups suitable for metal-free click chemistry.


Certain metal-free click moieties are known in the literature. Examples include 4-dibenzocyclooctynol (DIBO)




embedded image


(from Ning et al; Angew Chem Int Ed, 2008, 47, 2253); gem-difluorinated cyclooctynes (DIFO or DFO)




embedded image


(from Codelli, et al.; J. Am. Chem. Soc. 2008, 130, 11486-11493.); biarylazacyclooctynone (BARAC)




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(from Jewett et al.; J. Am. Chem. Soc. 2010, 132, 3688.); or bicyclononyne (BCN) (From Dommerholt, et al.; Angew Chem Int Ed, 2010, 49, 9422-9425).


As used herein, the phrase “a moiety suitable for metal-free click chemistry” refers to a functional group capable of dipolar cycloaddition without use of a metal catalyst. Such moieties include an activated alkyne (such as a strained cyclooctyne), an oxime (such as a nitrile oxide precursor), or oxanorbornadiene, for coupling to an azide to form a cycloaddition product (e.g., triazole or isoxazole).


Therapeutic Agents and Exemplary Associated Diseases

In accordance with the present invention, a variety of therapeutic agents may be covalently conjugated to the lymphatic system-directing lipids, e.g. triglyceride scaffolds, described herein. In some embodiments, by conjugating a therapeutic agent to a lymphatic system-directing lipid, the present invention enhances desirable properties of the therapeutic agent such as improving oral bioavailability, minimizing destruction of the agent in the gut, avoiding liver first-pass effect, improving therapeutic agent delivery to a target tissue, or increasing the solubility and stability of the therapeutic agents, including the solubility and stability of the agents in vivo.


The present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof comprising administering to said patient a disclosed lipid prodrug. In some embodiments, a disclosed lipid prodrug is useful in treating a disease, disorder, or condition for which the parent therapeutic agent is known to be used. Furthermore, because of the improved delivery and other properties of the disclosed lipid prodrugs, in some embodiments, a disclosed lipid prodrug is useful also for treating or preventing a disease, disorder, or condition for which the parent therapeutic agent is not suitable because of insufficient lymphatic transport, undesired metabolism, off-target toxicity, or the like.


In one aspect, the present invention provides a lipid prodrug of an immunomodulatory therapeutic agent.


In some embodiments, the present invention provides a method of treating an autoimmune disease, disorder, or condition in a patient in need thereof comprising administering to the patient a disclosed lipid prodrug. In some embodiments, the autoimmune disease, disorder, or condition is selected from Behcet's disease, pemphigus vulgaris, refractory incomplete systemic lupus erythematosus, immunoglobulin A nephropathy, small vessel vasculitis, or psoriasis.


In some embodiments, the present invention provides a method of preventing organ transplant rejection in a patient in need thereof, comprising administering a disclosed lipid prodrug to a patient in need thereof.


In some embodiments, a disclosed lipid prodrug modulates the immune system of a patient after administration by increased exposure of the active agent to the lymphatic system of the patient. In some embodiments, a disclosed lipid prodrug is taken up selectively into the lymphatic system of the patient after oral administration. In some embodiments, once in the lymphatic system, the lipid prodrug interacts with immune cells in the lymphatic system. In some embodiments, a disclosed lipid prodrug is delivered selectively to B or T lymphocytes. In some embodiments, a disclosed lipid prodrug modulates the activity of B or T lymphocytes. In some embodiments, a disclosed lipid prodrug modulates the activity of one or more of B cells, dendritic cells, granulocytes, innate lymphoid cells (ILCs), megakaryocytes, monocytes/macrophages, myeloid-derived suppressor cells (MDSC), natural killer (NK) cells, platelets, red blood cells (RBCs), T cells, or thymocytes. In some embodiments, a disclosed lipid prodrug exhibits increased delivery at a given dose or more selective delivery at a given dose to B or T lymphocytes as compared with a corresponding dose of a non-lipid prodrug form of the active agent. In some embodiments, a given dose of a disclosed lipid prodrug more effectively modulates the activity of one or more of B cells, dendritic cells, granulocytes, innate lymphoid cells (ILCs), megakaryocytes, monocytes/macrophages, myeloid-derived suppressor cells (MDSC), natural killer (NK) cells, platelets, red blood cells (RBCs), T cells, or thymocytes, as compared with a corresponding dose of a non-lipid prodrug form of the parent therapeutic agent.


In some embodiments, the present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof, comprising administering to the patient a disclosed lipid prodrug, or a pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition is selected from Inflammatory disease, Abdominal cavity inflammation, Peritonitis, Mesenteritis, Perihepatitis, Salpingoperitonitis, Autoinflammatory disease, Cryopyrin associated periodic syndrome, CINCA syndrome, Familial cold autoinflammatory syndrome, Muckle Wells syndrome, Cardiovascular inflammation, Carditis, Endocarditis, Bacterial endocarditis, Infectious endocarditis, Non infectious endocarditis, Thromboendocarditis, Pericarditis, Chylopericarditis, Dressler syndrome, Pleuropericarditis, Vasculitis, Arteritis, Aortitis, Takayasus arteritis, Endarteritis, HIV associated arteritis, Kawasaki disease, Periarteritis, Polyarteritis nodosa, Temporal arteritis, Extracranial temporal arteritis, Intracranial temporal arteritis, Churg-Strauss syndrome, Cutaneous vasculitis, Perivasculitis, Phlebitis, Lymphangiophlebitis, Thrombophlebitis, Mondor disease, Thromboangiitis, Thromboangiitis obliterans, Thrombophlebitis, Mondor disease, Dermatitis, Acrodermatitis, Angiodermatitis, Drug eruption, Erythema multiforme, Serum sickness, Stevens Johnson syndrome, Toxic epidermal necrolysis, Intertrigo, Skin allergy, Atopic dermatitis, Contact dermatitis, Eczema, Fibrosis, Cicatrix, Tissue adhesions, Pulmonary fibrosis, Idiopathic pulmonary fibrosis, Renal fibrosis, Gastrointestinal inflammation, Anusitis, Biliary tract inflammation, Hepatocholangitis, Cholecystiti s, Esophagiti s, Eosinophilic esophagiti s, Gastriti s, Gastroduodeniti s, Gastroenteriti s, Hypertrophic gastritis, Hepatitis, Enterohepatitis, Hepatitis virus infection, Hepatitis A virus infection, Hepatitis B virus infection, Hepatitis C virus infection, Hepatitis D virus infection, Hepatitis E virus infection, Hepatitis F virus infection, Hepatitis G virus infection, Hepatocholangitis, Non-viral hepatitis, Alcoholic hepatitis, Autoimmune hepatitis, Perihepatitis, Steatohepatitis, Non-alcoholic steatohepatitis, Inflammatory bowel disease, Colitis, Diverticulitis, Meckel's diverticulitis, Enterocolitis, Acute enterocolitis, Necrotizing enterocolitis, Ileocecitis, Pseudomembranous colitis, Sigmoiditis, Rectosigmoiditis, Ulcerative colitis, Crohns disease, Enteritis, Enterocolitis, Acute enterocolitis, Necrotizing enterocolitis, Enterohepatitis, Hemorrhagic enteritis, Ileitis, Ileocecitis, Pouchitis, Jejunitis, Mucositis, Pancreatitis, Balser necrosis, Necrotizing acute pancreatitis, Peritonitis, Mesenteritis, Perihepatitis, Salpingoperitonitis, Proctitis, Rectosigmoiditis, Ulcerative proctitis, Genitourinary tract inflammation, Genital tract inflammation, Female genital tract inflammation, Endometriosis, Parametritis, Pelvic inflammatory disease, Salpingitis, Vaginitis, Atrophic vaginitis, Bartholinitis, Vulvovaginitis, Vulvitis, Vulvovaginitis, Male genital tract inflammation, Balanitis, Epididymitis, Epididymo-orchiti s, Orchiti s, Epididymo-orchiti s, Periorchiti s, Prostatitis, Urinary tract inflammation, Nephritis, Alport syndrome, Glomerulonephritis, Focal segmental glomerulosclerosi s, IgA nephropathy, Membranoproliferative glomerulonephritis, Membranous glomerulonephritis, Wegener granulomatosis, Lupus nephritis, Pyelitis, Pyelocystitis, Pyelonephriti s, Granulomatosi s, Allergic granulomatosis, Sarcoidosis, Wegener granulomatosi s, Mastitis, Mouth inflammation, Gingivitis, Pericoroniti s, Pharyngiti s, Rhinopharyngiti s, Sialadenitis, Musculoskeletal system inflammation, Arthritis, Behcets disease, Chondrocalcinosis, Gout, Infectious arthritis, Osteoarthritis, Periarthritis, Psoriatic arthritis, Reiter syndrome, Rheumatoid arthritis, Adult onset Stills disease, Felty syndrome, Juvenile rheumatoid arthritis, Bursitis, Dactylitis, Myositis, Dermatomyositis, Inclusion body myositis, Hereditary inclusion body myositis, Sporadic inclusion body myositis, Polymyositis, Pyomyositis, Nervous system inflammation, Meningitis, Arachnoiditi s, Aseptic meningitis, Infectious meningitis, Bacterial meningitis, Neisseria meningitidis meningitis, Fungal meningitis, Cryptococcus neoformans meningitis, Parasitic meningitis, Viral meningitis, Neoplastic meningitis, Pachymeningitis, Neuritis, Neuromyelitis optica, Poliovirus infection, Postpoliomyelitis syndrome, Ocular and orbital inflammation, Ocular inflammation, Chorioretinitis, Conjunctivitis, Allergic conjunctivitis, Blepharoconjunctivitis, Keratoconjunctivitis, Infectious keratoconjunctivitis, Ophthalmia neonatorum, Trachoma, Uveitis, Intermediate uveitis, Pars planitis, Orbital inflammatory disease, Idiopathic orbital inflammation, Respiratory tract inflammation, Lower respiratory tract inflammation, Bronchitis, Lung inflammation, Asthma, Asthma attack, Exercise induced asthma, Nocturnal asthma, Occupational asthma, Status asthmaticus, Pleurisy, Upper respiratory tract inflammation, Pharyngiti s, Rhinopharyngiti s, Rhinitis, Allergic rhiniti s, Perennial allergic rhiniti s, Seasonal allergic rhinitis, Rhinopharyngitis, Sinusitis, Acute sinusitis, Chronic sinusitis, Ethmoiditis, Kartagener syndrome, Pansinusitis, Serositis, Familial mediterranean fever, Systemic inflammatory response syndrome, Immune disorder, Allergy, Delayed hypersensitivity, Contact dermatitis, Hypersensitivity, Immediate hypersensitivity, Food hypersensitivity, Egg hypersensitivity, Milk hypersensitivity, Oral allergy syndrome, Peanut hypersensitivity, Wheat hypersensitivity, Fungal allergy, Immune complex disease, Arthus reaction, Immediate type hypersensitivity, Atopic dermatitis, Respiratory tract allergy, Allergic rhinitis, Perennial allergic rhinitis, Seasonal allergic rhinitis, Asthma, Asthma attack, Exercise induced asthma, Nocturnal asthma, Occupational asthma, Status asthmaticus, Skin allergy, Atopic dermatitis, Contact dermatitis, Eczema, Autoimmune disease, Antiphospholipid syndrome, Autoimmune hemolytic anemia, Cold agglutinin disease, Autoimmune hepatitis, Autoimmune nervous system disease, Autoimmune demyelinating nervous system disease, Stiff person syndrome, Lambert-Eaton syndrome, Behcets disease, Crohns disease, Cutaneous lupus erythematosus, Discoid lupus erythematosus, Evans syndrome, Goodpasture syndrome, Graves disease, Guillain Barre syndrome, Hashimotos disease, Henoch Schonlein purpura, Lupus nephritis, Multiple sclerosis, Myasthenia gravis, Paroxysmal nocturnal hemoglobinuria, Primary biliary cirrhosis, Psoriasis, Parapsoriasis, Psoriatic arthritis, Rheumatoid arthritis, Adult onset Stills disease, Felty syndrome, Juvenile rheumatoid arthritis, Sjoegrens syndrome, Systemic lupus erythematosus, Temporal arteritis, Extracranial temporal arteritis, Intracranial temporal arteritis, Ulcerative colitis, Vitiligo, Non segmental vitiligo, Segmental vitiligo, Wegener granulomatosis, Graft versus host disease, Transplant rejection, Bone marrow transplant rejection, Cell transplant rejection, Corneal transplant rejection, Heart transplant rejection, Kidney transplant rejection, Liver transplant rejection, Lung transplant rejection, Organ transplant rejection, Intestine transplantation, Large intestine transplantation, Small intestine transplantation, Pancreas transplant rejection, Islet cell transplant rejection, Skin transplant rejection, Tissue transplant rejection, Immune deficiency, Agammaglobulinemia, Brutons disease, Combined immunodeficiency, Acquired immune deficiency syndrome, AIDS related complex, Nezelof syndrome, Severe combined immunodeficiency syndrome, Adenosine deaminase deficiency, Common variable immunodeficiency, DiGeorge syndrome, Dysgammaglobulinemia, Immunoglobulin A deficiency, Immunoglobulin G deficiency, Phagocyte bactericidal disorder, Chediak Higashi syndrome, Chronic granulomatous disease, Job syndrome, Wiskott-Aldrich syndrome, Immunoadsorption, Lymphatic system disease, Adenoid disease, Adenoid hypertrophy, Adenoid tumor, Adenoiditis, Lymphadenopathy, Kawasaki disease, Lymphadenitis, Lymphangiophlebitis, Lymphangitis, Lymphatic system tumor, Adenoid tumor, Castleman's disease, Lymphangioma, Cystic hygroma, or Lymphangiomyoma.


In some embodiments, the autoimmune disease, disorder, or condition is selected from Behcet's disease, pemphigus vulgaris, refractory incomplete systemic lupus erythematosus, retroperitoneal fibrosis, idiopathic thrombocytopenic purpura (ITP), scleroderma (systemic sclerosis or SSc), pemphigus vulgaris, granulomatosis with polyangiitis, immunoglobulin A nephropathy, small vessel vasculitis, retroperitoneal fibrosis, and psoriasis.


In some embodiments, the present invention provides a method of treating or preventing organ transplant rejection, graft-versus-host disease, or implant rejection, comprising administering to a patient in need thereof an effective amount of a disclosed lipid prodrug. In some embodiments, the organ transplant is selected from a skin, liver, heart, kidney, pancreas, thymus, small intestine, large intestine, uterus, a vascularized composite allograft (VCA) such as face or hand, bone marrow, allogenic blood and marrow transplant (BMT), cornea, and lung transplant. In some embodiments, the organ transplant rejection is acute or chronic transplant rejection.


In some embodiments, the present invention provides a lipid prodrug for use in the treatment or prevention of a disease or disorder in which increased testosterone levels are beneficial, or a disease or disorder caused by a testosterone deficiency. Such diseases and disorders include, but are not limited to, hypogonadism, anemia due to bone marrow failure, anemia due to renal failure, chronic respiratory failure, chronic cardiac failure, steroid-dependent autoimmune disorders, AIDS wasting, hereditary angioedema or urticaria, terminal breast cancer, or menopause.


In some embodiments, the present invention provides a method of modulating an immune response, comprising administering to a patient in need thereof an effective amount of a disclosed lipid prodrug that comprises an immunomodulatory therapeutic agent. In some embodiments, the immune response includes one or more immune responses mediated by the lymphatic system, or mediated by immune cells in the lymphatic system. In some embodiments, the patient is suffering from a hyperproliferative disease, disorder, or condition such as cancer. In some embodiments, the patient is suffering from an autoimmune disease, disorder, or condition.


Various therapeutic agents are suitable for use in the present invention. Examples of suitable therapeutic agents include, but are not limited to, testosterone, mycophenolic acid (MPA), buprenorphine, oestrogens (estrogen), opiates such as morphine, tetrahydrocannabinol (THC), cannabidiol, metoprolol, raloxifene, alphaxolone, statins such as atorvastatin, pentazocine, propranolol, L-DOPA, lidocaine, chlorpromazine, sertraline, amitriptyline, nortriptyline, pentazocine, glyceryl trinitrate, oxprenolol, labetalol, salbutamol, epitiostanol, melphalan, lovastatin, non-steroidal antiinflammatory medications (NSAIDS, such as aspirin, ibuprofen, and naproxen), COX-2 inhibitors (such as celecoxib), corticosteroid anti-inflammatory medications (such as prednisolone, prednisone, or dexamethasone), anti-malarial medications (such as hydroxychloroquine), nitrosoureas, methotrexate, dactinomycin, anthracyclines (such as daunorubicin), mitomycin C, bleomycin, mithramycin, drugs acting on immunophilins (such as cyclosporin, tacrolimus, sirolimus), sulfasalazine, leflunomide, mycophenolate, opioids, fingolimod, myriocin, chlorambucil, doxorubicin, nelarabine, cortisone, dexamethasone, prednisone, pralatrexate, vinblastine, bortezomib, nelarabine, daunorubicin hydrochloride, clofarabine, cytarabine, dasatinib, imatinibmesylate, ponatinib hydrochloride, vincristine sulfate, bendamustine hydrochloride, fludarabine phosphate, bosutinib, nilotinib, omacetaxine mepesuccinate, capecitabine, paclitaxel, gemcitabine, fulvestrant, tamoxifen, lapatinib, toremifene, ixabepilone, eribulin, albendazole, ivermectin, diethylcarbamazine, albendazole, doxycycline, closantel, maraviroc, enfuvirtide, deoxythymidine, zidovudine, stavudine, didanosine, zalcitabine, abacavir, lamivudine, emtricitabine, tenofovir, delavirdine, rilpivirine, raltegravir, elvitegravir, lopinavir, indinavir, nelfinavir, amprenavir, ritonavir, or acyclovir, or a pharmaceutically acceptable salt thereof.


In some embodiments, the therapeutic agent is an NSAID or pharmaceutically acceptable salt thereof. Exemplary NSAIDs fall into a number of categories, including: 1) salicylates and various derivatives thereof, including acetyl salicylic acid, salicylic acid, methyl salicylate, diflunisal, and salsalate; 2) the pyrazolone derivatives, including phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, dipyrone, and apazone; 3) the para-aminophenol derivatives, including acetaminophen (paracetamol), phenacetin and related compounds; 4) indomethacin, sulindac and related compounds; 5) the fenamates, including; mefenamic, meclofenamic, flufenamic, tolfenamic, and etofenamic acids, and related compounds; 6) the proprionic acid derivatives including ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen and related compounds; 7) the oxicam derivatives such as piroxicam and related compounds; 8) the phenylacetic acid derivatives such as diclofenac and related compounds; and 9) other NSAIDs such as tolmetin, etodolac and nabumetone.


In some embodiments, the NSAID is selected from acetyl salicylic acid, salicylic acid, methyl salicylate, diflunisal, salsalate, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, dipyrone, apozone, acetaminophen, phenacetin, indomethacin, sulindac, mefenamic, meclofenamic, flufenamic, tolfenamic, etofenamic acid, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, prioxicam, diclofenac, tolmetin, etodolac, or nabumetone.


In some embodiments, the therapeutic agent is a 5-amino salicylate (5-ASA) compound, sulfasalazine, balsalazide, or olsalazine.


Examples of suitable imaging agents include, but are not limited to, fluorophores such as the Alexa Fluor series of optical imaging probes for fluorescence microscopy or where the fluorophore has emission spectra in the infra-red range, for in vivo imaging; gamma emitters that can be used for positron emission tomography (PET), such as fluorodeoxyglucose, or chelating agents in order to chelate magnetic resonance imaging probes such as gadolinium or iron.


In some embodiments, the therapeutic agent is selected from non-steroidal anti-inflammatory medications (NSAIDS, such as aspirin, ibuprofen, or naproxen), COX-2 inhibitors (such as celecoxib), corticosteroid anti-inflammatory medications (such as prednisolone, or dexamethasone), anti-malarial medications (such as hydroxychloroquine), cyclophosphamide, PPAR agonists (such as the fibrates), nitrosoureas, platinum, methotrexate, azathioprine, mercaptopurine, fluorouracil, dactinomycin, anthracyclines, mitomycin C, bleomycin, mithramycin, drugs acting on immunophilins (such as ciclosporin, tacrolimus, or sirolimus), sulfasalazine, leflunomide, mycophenolate, opioids, fingolimod, myriocin, chlorambucil, doxorubicin, nelarabine, cortisone, pralatrexate, vinblastine, bortezomib, thiotepa, nelarabine, daunorubicin hydrochloride, clofarabine, cytarabine, dasatinib, imatinibmesylate, ponatinib hydrochloride, vincristine sulfate, bendamustine hydrochloride, fludarabine phosphate, bosutinib, nilotinib, omacetaxine, mepesuccinate, anastrozole, capecitabine, letrozole, paclitaxel, gemcitabine, fulvestrant, tamoxifen, lapatinib, toremifene, ixabepilone, eribulin, albendazole, ivermectin, diethylcarbamazine, doxycycline, closantel, maraviroc, enfuvirtide, deoxythymidine, zidovudine, stavudine, didanosine, zalcitabine, abacavir, lamivudine, emtricitabine, tenofovir, nevirapine, delavirdine, efavirenz, rilpivirine, raltegravir, elvitegravir, lopinavir, indinavir, nelfinavir, amprenavir, ritonavir, acyclovir and immunosuppressants such as mycophenolic acid, cyclosporine, tacrolimus, or sirolimus.


In some embodiments, the therapeutic agent is selected from acetaminophen, buprenorphine, rivastigmine, allopregnanolone (for use in treating, e.g., post-partum depression, Niemann-Pick disease, or Status Epilecticus), brivarectam, tegretol, levetiracetam or brivaracetam or other anticonvulsant (for use in treating, e.g., epilepsy and/or as an anticonvulsant), fosphenytoin, propranolol, tenofivir, a small-molecule chemotherapeutic agent for treating lymphoma, an analgesic such as an NSAID, an oral contraceptive, a therapeutic agent for treating a parasitic disease, a mercaptopurine such as azathioprine or 6-mercaptopurine (for treating inflammatory bowel disease), a corticosteroid, silymarin, paclitaxel, oxaliplatin, docetaxel, gemcitabine, irinotecan, zoledronic acid or other bisphosphonate anticancer agent, cladribine, pralatrexate, romidepsin, bexarotene, bortezomib, bendamustine, chlormethine, nelarabine, belinostat, prednisolone, cyclophosphamide, guperimus, dexanabinol, mitoxantrone, verteporfin, methotrexate, fosbretabulin, pentostatin, or dexamethasone.


In one embodiment, the therapeutic agent is testosterone or a derivative or analogue thereof. Testosterone replacement therapy (TRT) is commonly used for patients with hypogonadism (a disorder characterised by abnormally low serum testosterone levels) to restore their serum testosterone levels to the normal range and thus relieve many of the symptoms of hypogonadism such as mood disturbance and sexual dysfunction.


In some embodiments, the therapeutic agent is a proteasome inhibitor such as bortezomib, carfilzomib, KZR-616, delanzomib, marizomib, ixazomib, LC-530110, TP-110, FV-214, FV-162, or the like.


In some embodiments, the therapeutic agent is a BTK inhibitor such as ibrutinib, ONO-WG-307, ML-319, ZYBT-1, X-022, spebrutinib, or the like.


In some embodiments, the therapeutic agent is a ROR-γt inhibitor or modulator. Exemplary ROR-γt inhibitors and modulators include LYC-55716, digoxin, ursolic acid, SR2211, ML 209, TMP778, TMP920, GSK805, ARN-6039, GNE-3500, MRL-299, JTE-151, VTP-43742, and compounds disclosed in WO2015116904, which is hereby incorporated by reference; see, e.g. Bioorganic & Medicinal Chemistry Letters, Volume 26, Issue 18, 15 Sep. 2016, Pages 4387-4393, hereby incorporated by reference.


In some embodiments, the therapeutic agent is selected from an immunomodulatory imide drug (IMiD) such as thalidomide, lenalidomide, pomalidomide, or apremilast.


In some embodiments, the therapeutic agent is selected from purine synthesis inhibitors (e.g. Azathioprine, Mycophenolic acid), pyrimidine synthesis inhibitors (Leflunomide, Teriflunomide), antifolate (Methotrexate), Macrolides/other IL-2 inhibitors, FKBP/Cyclophilin/Calcineurin (Tacrolimus, Ciclosporin, Pimecrolimus) Abetimus, or Gusperimus.


In some embodiments, the immunomodulatory therapeutic agent is selected from thalidomide, lenalidomide, pomalidomide, apremilast, azathioprine, mycophenolic acid, leflunomide, teriflunomide, methotrexate, a macrolide IL-2 inhibitor, tacrolimus, sirolimus (Rapamune®), everolimus (Certican™), CCI-779, ABT578, temsirolimus, TAFA-93, vistusertib, ciclosporin, pimecrolimus, abetimus, or gusperimus.


In some embodiments, the therapeutic agent is one of those in Table 1, below; or a pharmaceutically acceptable salt thereof.









TABLE 1







Exemplary Therapeutic Agents and Associated Diseases and Disorders










Abbreviated


Mechanism Of


Drug Name
Drug Name
Indication
Action





abacavir
abacavir
HIV-1 Infection, HIV-2 Infection



Acetylcysteine
Acetylcysteine

Antioxidants, Free



injection -

radical inhibitors


Acitretin
Acitretin
Psoriasis, Dermatitis, Cancer
Retinoic acid receptor





agonists


acyclovir
acyclovir
Herpes Labialis (Oral Herpes), Genital





Herpes, Herpes Simplex Virus (HSV)





Infections, Varicella Zoster (HHV-3)





Infections, Herpes Zoster (Shingles),





Fever Blisters, Chicken Pox



Adefovir
Adefovir
HIV infections, Cancer, Hepatitis B,
DNA-directed DNA




Rheumatic disorders, Graft-versus-
polymerase inhibitors,




host disease
Cell differentiation





stimulants,





Immunomodulators,





Immunosuppressants


Adefovir
Adefovir
Hepatitis B, HIV infections, Rheumatic
DNA-directed DNA


dipivoxil
dipivoxil
disorders
polymerase inhibitors,





Hepatitis B virus





replication inhibitors,





Nucleotide reverse





transcriptase inhibitors


Alatrofloxacin
Alatrofloxacin




Albendazole
Albendazole
Helminthic Infestations, Cysticercosis
Tubulin inhibitors,




(Taeniasis), Giardiasis, Nematodal
Vascular endothelial




(Round Worm) Infections, Tape Worm
growth factors




Infections, Ascariasis, Alveolar
inhibitors




Echinococcosis (Alveolar Hydatid





Disease), Ancylostomiasis (Hookworm





Infections), Cystic Echinococcosis





(Alveolar Hydatid Disease),





Echinococcosis (Hydatid Disease),





Neurocysticercosis, Strongyloidiasis,





Trichuriasis



albuterol sulfate
albuterol sulfate
Asthma, Bronchospasm, Obstructive
Beta 2 Adrenergic




Pulmonary Disease, Chronic
Receptor (Beta 2




Obstructive Pulmonary Disease
Adrenoreceptor or




(COPD), Chronic
ADRB2) Agonist




Bronchitis, Emphysema, Exercise-





Induced Bronchoconstriction (EBI),





Premature Labor (Tocolysis),





Pulmonary Tuberculosis, Status





Asthmaticus



Alendronic acid
Alendronic acid
Postmenopausal osteoporosis, Male
Osteoclast inhibitors




osteoporosis, Fracture, Osteitis





deformans, Osteoporosis,





Corticosteroid-induced osteoporosis,





Malignant hypercalcaemia, Bone





resorption



Alitretinoin
Alitretinoin




Alitretinoin
Alitretinoin oral
Acute promyelocytic leukaemia,
Retinoic acid receptor




Multiple myeloma, Ovarian cancer,
agonists, Retinoid X




Psoriasis, Non-Hodgkin's lymphoma,
receptor agonists,




Lung cancer, Preleukaemia, Renal
Protein synthesis




cancer, Cancer, Retinal disorders,
inhibitors, Retinoic




Prostate cancer, Kaposi's sarcoma,
acid receptor




Head and neck cancer
antagonists


Alovudine
Alovudine
HIV infections
Nucleoside reverse





transcriptase inhibitors


Ambrisentan
Ambrisentan




Amifloxacin
Amifloxacin
Gram-negative infections, Septic
Type II DNA




shock, Urinary tract infections
topoisomerase





inhibitors


Amifostine
Amifostine




Aminolevulinic
Aminolevulinic
Actinic keratosis, Brain cancer, Warts,
Photosensitisers


acid
acid
Barrett's oesophagus, Photodamage,





Skin cancer, Acne vulgaris,





Oesophageal cancer, Leucoplakia,





Psoriasis



Aminopterin
Aminopterin
Leukaemia, Endometrial cancer
Antimetabolites,





Tetrahydrofolate





dehydrogenase





inhibitors


Aminosalicylic
Aminosalicylic




acid
acid




Amiodarone
Amiodarone





Cosolvent-free




Amisulpride
Amisulpride

Dopamine D2 receptor





antagonists,





Dopamine D3 receptor





antagonists


amitriptyline
amitriptyline
Anxiety Disorders, Depression



amprenavir
amprenavir
HIV-1 Infection



Anagrelide
Anagrelide




anastrozole
anastrozole
Breast Cancer, Metastatic Breast





Cancer, Hormone Sensitive Breast





Cancer



Aphidicolin
Aphidicolin
Cancer, Herpesvirus infections
DNA-directed DNA





polymerase inhibitors


Apomorphine
Apomorphine

Dopamine D2 receptor





agonists


apremilast
apremilast
Psoriatic Arthritis, Plaque Psoriasis
Phosphodiesterase 4




(Psoriasis Vulgaris)
(PDE4 or EC 3.1.4.53)





Inhibitor


Arbutamine
Arbutamine




Argatroban
Argatroban




aripiprazole
aripiprazole




aspirin
aspirin
Cardiovascular Disease, Angina





(Angina Pectoris), Myocardial





Infarction, Migraine, Pain, Post-





Operative Pain, Osteoarthritis Pain,





Dysmenorrhea, Stroke, Cerebral





Infarction (Brain Infarction), Back Pain,





Pharyngitis, Gouty Arthritis (Gout),





Nasopharyngitis (Common Cold),





Unstable Angina, Ankylosing





Spondylitis (Bekhterev's Disease),





Ischemic Cerebral Stroke, Ischemic





Stroke, Ischemia, Bronchitis, Arthritis





Pain, Cardiovascular Risk Factors,





Cerebrovascular Disease, Chronic





Stable Angina, Dental Pain, Infectious





Fever, Joint Pain, Low Back Pain, Mild





Pain, Moderate Pain, Musculoskeletal





Pain, Neuralgia, Rheumatoid Arthritis





Pain, Sciatic Pain, Stable Angina,





Tension -Type Headache,





Thromboembolism



Atazanavir/
Atazanavir/
HIV-1 infections
Cytochrome P 450


cobicistat
cobicistat

enzyme system





inhibitors, HIV





protease inhibitors


Atorvastatin
Atorvastatin
Hyperlipoproteinaemia type IIa,
HMG-CoA reductase




Hypercholesterolaemia, Low HDL
inhibitors




cholesterol, Hypertriglyceridaemia,





Cardiovascular disorders, Heart failure,





Hyperlipoproteinaemia type III,





Alzheimer's disease, Neurological





disorders



Atovaquone
Atovaquone




Avibactam/
Avibactam/




ceftazidime
ceftazidime




Azacitidine
Azacitidine

Antimetabolites, DNA





methylation inhibitors


azathioprine
azathioprine
Liver Transplantation, Heart





Transplantation, Polymyositis,





Idiopathic Thrombocytopenic Purpura





(Immune Thrombocytopenic Purpura),





Dermatomyositis, Ulcerative Colitis,





Transplantation, Rheumatoid Arthritis,





Crohn's Disease (Regional Enteritis),





Systemic Lupus Erythematosus,





Kidney Transplantation, Acquired





(Autoimmune) Hemolytic Anemia,





Arteritis, Autoimmune Hepatitis,





Pemphigus Vulgaris



Azithromycin
Azithromycin
antibiotic
Protein synthesis





inhibitor


Aztreonam
Aztreonam




Baclofen
Baclofen




Balsalazide
Balsalazide





disodium




Bedaquiline
Bedaquiline




Belinostat
Belinostat




bendamustine
bendamustine
Anaplastic Astrocytoma, Glioblastoma




hydrochloride
Multiforme (GBM), Non-Hodgkin





Lymphoma, Diffuse Large B-Cell





Lymphoma, High Grade Non-Hodgkin





Lymphoma, High-Grade Glioma,





Indolent Lymphoma, Intermidiate Non-





Hodgkin Lymphoma, Mantle Cell





Lymphoma, Refractory Multiple





Myeloma, Relapsed Multiple Myeloma



Benzoate and
Benzoate and




phenylacetate
phenylacetate




Betaine
Betaine




Bexarotene
Bexarotene oral
Cutaneous T cell lymphoma, Non-
Peroxisome




small cell lung cancer, Thyroid cancer
proliferator-activated





receptor agonists,





Protein synthesis





inhibitors, Retinoid X





receptor agonists


Biapenem
Biapenem
Bacterial infections
Cell wall inhibitors


Bicalutamide
Bicalutamide
Prostate cancer
Testosterone





congener inhibitors


Bortezomib
Bortezomib
Mantle-cell lymphoma; Multiple
Apoptosis stimulants,




myeloma
Proteasome inhibitors,





Immunomodulators


Bosentan
Bosentan
Skin ulcer, Pulmonary arterial
Endothelin A receptor




hypertension, Diabetic foot ulcer,
antagonists,




Pulmonary fibrosis, Heart failure,
Endothelin B receptor




Malignant melanoma, Asthma,
antagonists




Ischaemic heart disorders, Transplant





rejection, Inflammatory bowel





diseases, Kidney disorders, Myocardial





infarction, Reperfusion injury



bosutinib
Bosutinib
Bile Duct Cancer





(Cholangiocarcinoma), Colorectal





Cancer, Polycystic Kidney Disease,





Acute Lymphocytic Leukemia (ALL,





Acute Lymphoblastic Leukemia),





Chronic Myelocytic Leukemia (CML,





Chronic Myeloid Leukemia),





Pancreatic Cancer, Metastatic Breast





Cancer, Recurrent Glioblastoma





Multiforme (GBM)



Bromfenac
Bromfenac
Ocular inflammation, Ocular pain, Age-
Cyclooxygenase




related macular degeneration,
inhibitors




Postoperative pain, Osteoarthritis, Dry





eyes, Dysmenorrhoea



Bropirimine
Bropirimine
Bladder cancer, Lymphoma, Herpes
Interferon alpha




simplex virus infections
stimulants


Broxuridine
Broxuridine
Breast cancer, Brain cancer
Antimetabolites, DNA





modulators


Buprenorphine
Buprenorphine
Neuropathic Pain, Pain, Cancer Pain,
Nociceptin receptor



transdermal
Chronic Pain, Post-Operative Pain,
agonists, Opioid delta




Osteoarthritis Pain, Back Pain,
receptor antagonists,




Fibromyalgia, Diabetic Neuropathic
Opioid kappa receptor




Pain, Low Back Pain, Moderate Pain,
antagonists, Opioid




Musculoskeletal Pain, Rheumatoid
mu receptor agonists




Arthritis Pain, Opium addiction



Bupropion
Bupropion
Seasonal affective disorder, Major
Adrenergic receptor




depressive disorder, Smoking
antagonists,




withdrawal, Obesity, Social phobia,
Dopamine uptake




Post-traumatic stress disorders
inhibitors


Cabazitaxel
Cabazitaxel




Cabozantinib
Cabozantinib




Calcitonin
Calcitonin





human for





injection




Calcium
Calcium




levofolinate
levofolinate




Cangrelor
Cangrelor




capecitabine
capecitabine
Breast Cancer, Esophageal Cancer,





Colorectal Cancer, Gastric Cancer,





Metastatic Breast Cancer, Colon





Cancer, Metastatic Colorectal Cancer



Capsaicin
Capsaicin

TRPV1 receptor



dermal patch

agonists, Substance P





inhibitors


Carfilzomib
Carfilzomib
Refractory Multiple Myeloma,
Proteasome inhibitors




Relapsed Multiple Myeloma



Carvedilol
Carvedilol
Hypertension, Heart failure, Angina
Alpha 1 adrenergic




pectoris, Atrial fibrillation, Myocardial
receptor antagonists,




infarction, Post-traumatic stress
Beta-adrenergic




disorders, Reperfusion injury,
receptor antagonists,




Arrhythmias, Ischaemic heart disorders
Calcium channel





antagonists,





Antioxidants


Cefepime
Cefepime




Ceftaroline
Ceftaroline




fosamil
fosamil




Ceftazidime
Ceftazidime

Cell wall inhibitors


Ceftibuten
Ceftibuten
Otorhinolaryngological infections,
Cell wall inhibitors




Bacterial infections, Respiratory tract





infections



Ceftolozane/
Ceftolozane/




tazobactam
tazobactam




celecoxib
celecoxib
Acute Pain, Post-Operative Pain,





Osteoarthritis Pain, Juvenile





Rheumatoid Arthritis, Back Pain,





Ankylosing Spondylitis (Bekhterev's





Disease), Dental Pain, Familial





Adenomatous Polyposis, Joint Pain,





Low Back Pain, Musculoskeletal Pain,





Primary Dysmenorrhea, Rheumatoid





Arthritis Pain, Tenosynovitis



Celgosivir
Celgosivir
Dengue, HIV infections, Hepatitis C
Alpha-glucosidase





inhibitors


Ceramide
Ceramide





trihexosidase/





alpha-





galactosidase A




ceritinib
ceritinib




chlorambucil
chlorambucil
Breast Cancer, Ovarian Cancer,





Follicular Lymphoma, Waldenstrom





Macroglobulinemia, Lymphoma, Non-





Hodgkin Lymphoma, Chronic





Lymphocytic Leukemia (CLL), Hodgkin





Lymphoma, Indolent Lymphoma,





Mantle Cell Lymphoma, Metastatic





Ovarian Cancer, Pediatric Cancer



cholic acid
cholic acid




ciclosporin
ciclosporin
Keratoconjunctivitis sicca (Dry Eye),





Corneal Graft Rejection, Vernal





Keratoconjunctivitis, Breast Cancer,





Lung Cancer, Uveitis, Liver





Transplantation, Heart Transplantation,





Bone Marrow Transplantation, Lung





Transplantation, Psoriasis,





Transplantation, Rheumatoid Arthritis,





Graft Versus Host Disease (GVHD),





Kidney Transplantation, Atopic





Dermatitis, Intermediate Uveitis,





Posterior Uveitis



Cidofovir
Cidofovir




Cinacalcet
Cinacalcet




Ciprofloxacin
Ciprofloxacin
Anthrax, Nosocomial pneumonia,
DNA gyrase inhibitors,




Respiratory tract infections, Intestinal
DNA topoisomerase




infections, Acute sinusitis, Typhoid,
inhibitors




Intra-abdominal infections, Urinary





tract infections, Skin and soft tissue





infections, Gonorrhoea



Cladribine
Cladribine




Clazosentan
Clazosentan

Endothelin A receptor





antagonists


Clevidipine
Clevidipine




Clofarabine
Clofarabine
Acute lymphoblastic leukaemia,
Apoptosis stimulants,




Histiocytosis, Haematological
DNA synthesis




malignancies, Acute myeloid
inhibitors




leukaemia, Myelodysplastic





syndromes, Chronic lymphocytic





leukaemia, Non-Hodgkin's lymphoma,





Psoriasis, Solid tumours, B cell





lymphoma



Clofazimine
Clofazimine




closantel
closantel




Colchicine
Colchicine




Colfosceril
Colfosceril





palmitate, cetyl





alcohol,





tyloxapol




Conivaptan
Conivaptan




cortisone
cortisone
Arthritis, Osteoarthritis, Asthma,





Seborrhea, Proteinuria, Juvenile





Rheumatoid Arthritis, Retinitis





Pigmentosa (Retinitis), Serum





Sickness, Polymyositis, Tuberculous





Meningitis, Keratitis, Ankylosing





Spondylitis (Bekhterev's Disease),





Idiopathic Thrombocytopenic Purpura





(Immune Thrombocytopenic Purpura),





Psoriatic Arthritis, Humoral





Hypercalcemia of Malignancy,





Psoriasis, Ulcerative Colitis,





Rheumatoid Arthritis, Crohn's Disease





(Regional Enteritis), Systemic Lupus





Erythematosus, Lymphoma, Acute





Lymphocytic Leukemia (ALL, Acute





Lymphoblastic Leukemia), Allergic





Conjunctivitis, Leukemias, Dermatitis,





Eczema, Thrombocytopenia, Acquired





(Autoimmune) Hemolytic Anemia,





Acute and Sub-Acute Bursitis, Acute





Nonspecific Tenosynovitis, Acute





Rheumatic Heart Disease, Allergic





Corneal Marginal Ulcers, Anterior





Segment Inflammation, Aspiration





Pneumonitis, Atopic Dermatitis,





Bacterial Infections, Berylliosis





(Chronic Beryllium Disease), Bullous





Pemphigoid, Chorioretinitis,





Choroiditis, Congenital Adrenal





Hyperplasia (Adrenogenital





Syndrome), Congenital Hypoplastic





Anemia, Contact Dermatitis, Dermatitis





Herpetiformis (Duhring's Disease),





Diffuse Posterior Uveitis, Drug





Hypersensitivity Reactions, Edema,





Epicondylitis, Erythema Multiforme,





Erythroblastopenia (RBC Anemia),





Herpes Zoster Ophthalmicus, Iritis,





Juvenile Arthritis, Loeffler Syndrome





(Pulmonary Eosinophilia), Mycosis





Fungoides, Nonsuppurative Thyroiditis,





Optic Neuritis, Pemphigus, Perennial





Allergic Rhinitis, Pulmonary





Tuberculosis, Seasonal Allergic





Rhinitis, Sympathetic Ophthalmia,





Symptomatic Sarcoidosis,





Trichomonas Vaginitis



Crizotinib
Crizotinib




Cromolyn
Cromolyn





sodium




cyclophosphamide
cyclophosphamide
Breast Cancer, Lung Cancer, Ovarian





Cancer, Burkitt Lymphoma, Testicular





Cancer, Throat Cancer,





Retinoblastoma, Follicular Lymphoma,





Rhabdomyosarcoma, Hematopoietic





Stem Cell Transplantation, Vasculitis,





Polymyositis, Lupus Erythematosus,





Rheumatoid Arthritis, Systemic Lupus





Erythematosus, Cervical Cancer,





Lymphoma, Melanoma, Multiple





Myeloma (Kahler Disease), Non-





Hodgkin Lymphoma, Acute





Lymphocytic Leukemia (ALL, Acute





Lymphoblastic Leukemia), Acute





Myelocytic Leukemia (AML, Acute





Myeloblastic Leukemia), Chronic





Lymphocytic Leukemia (CLL), Chronic





Myelocytic Leukemia (CML, Chronic





Myeloid Leukemia), Hodgkin





Lymphoma, Liver Cancer, Pancreatic





Cancer, Gastric Cancer, Bladder





Cancer, Leukemias, Systemic





Sclerosis (Scleroderma), Metastatic





Breast Cancer, Small-Cell Lung





Cancer, Sarcomas, Solid Tumor,





Polycythemia Vera, Endometrial





Cancer, Acute Lymphoblastic





Lymphoma, Adenocarcinoma, Bone





Tumor, Choriocarcinoma (Gestational





Trophoblastic Neoplasia), Colon





Cancer, Hydatidiform Mole, Kidney





Disease, Lymphoblastic Lymphoma,





Malignant Neoplasms, Metastatic





Melanoma, Mycosis Fungoides,





Nephrotic Syndrome, Neuroblastoma,





Pediatric Cancer, Pheochromocytoma,





Wegener Polyangiitis



Cysteamine
Cysteamine




cytarabine
cytarabine
Leptomeningeal Disease (Neoplastic





Meningitis, Leptomeningeal





Carcinomatosis), Non-Hodgkin





Lymphoma, Acute Lymphocytic





Leukemia (ALL, Acute Lymphoblastic





Leukemia), Acute Myelocytic Leukemia





(AML, Acute Myeloblastic Leukemia),





Chronic Myelocytic Leukemia (CML,





Chronic Myeloid Leukemia), Meningeal





Leukemia, Pediatric Cancer,





Refractory Leukemia



Dabrafenib
Dabrafenib




dactinomycin
dactinomycin
Ewing Sarcoma, Testicular Cancer,





Uterine Cancer, Rhabdomyosarcoma,





Childhood Rhabdomyosarcoma,





Melanoma, Solid Tumor, Endometrial





Cancer, Choriocarcinoma (Gestational





Trophoblastic Neoplasia), Gestational





Trophoblastic Disease, Hydatidiform





Mole, Kaposi Sarcoma, Locally





Recurrent Or Locoregional Solid





Malignancies, Metastatic Melanoma,





Metastatic Nonseminomatous





Testicular Cancer, Metastatic Renal





Cell Carcinoma, Pediatric Cancer,





Wilms' Tumor (Nephroblastoma)



Dalbavancin
Dalbavancin




Dalfampridine
Dalfampridine




danazol
danazol
Endometriosis, Hereditary
Follicle Stimulating




Angioedema (HAE) (C1 Esterase
Hormone Receptor




Inhibitor [C1-INH] Deficiency),
(Follitropin Receptor




Fibrocystic Breast Disease
or FSHR) Antagonist;





Lutropin





Choriogonadotropic





Hormone Receptor





(Luteinizing Hormone





Receptor or LHCGR)





Antagonist


Dantrolene
Dantrolene low-





volume




Daptomycin
Daptomycin
Bacteraemia, Bacterial endocarditis,
Cell wall inhibitors



intravenous
Gram-positive infections, Skin and soft





tissue infections, Staphylococcal





infections, Osteomyelitis, Urinary tract





infections, Community-acquired





pneumonia, Burns, Gram-Positive





Bacterial Infections, Sepsis, Methicillin-





Resistant Staphylococcus aureus





(MRSA) Infections, Bacteremia,





Bacterial Endocarditis, Complicated





Skin And Skin Structure Infections





(cSSSI), Hospital Acquired Methicillin-





Resistant Staphylococcus aureus (HA-





MRSA) Infections, Skin And Soft





Tissue Infections, Skin Infections,





Surgical Wound Infections



Darunavir
Darunavir
HIV-1 infections
HIV protease inhibitors


dasatinib
dasatinib
Bile Duct Cancer





(Cholangiocarcinoma),





Oligodendroglioma, Non-Small Cell





Lung Cancer, Myelofibrosis,





Gliosarcoma, Acute Myelocytic





Leukemia (AML, Acute Myeloblastic





Leukemia), Pancreatic





Cancer, Myelodysplastic Syndrome,





Systemic Sclerosis (Scleroderma),





Metastatic Breast Cancer, Diffuse





Large B-Cell Lymphoma, Polycythemia





Vera, Hypereosinophilic Syndrome,





Interstitial Lung Fibrosis, Metastatic





Hormone Refractory (Castration





Resistant, Androgen-Independent)





Prostate Cancer, Myeloid Metaplasia,





Recurrent Glioblastoma Multiforme





(GBM), Refractory Multiple Myeloma,





Relapsed Multiple Myeloma, Systemic





Mastocytosis



Daunorubicin
Daunorubicin





citrate liposome





injection




Decitabine
Decitabine




Deferiprone
Deferiprone
Iron overload, Pantothenate kinase-
Chelating agents




associated neurodegeneration,





Parkinson's disease, HIV infections,





Friedreich's ataxia, Kidney disorders



Defibrotide
Defibrotide




delavirdine
delavirdine
HIV-1 Infection



Deoxycholic
Deoxycholic

Cell membrane


acid
acid

modulators,





Membrane lipid





modulators


deoxythymidine
deoxythymidine




Desmopressin
Desmopressin





acetate




Dexamethasone
Dexamethasone
Bacterial Conjunctivitis, Uveitis,




Intravitreal
Keratitis, Blepharitis, Conjunctivitis,




Implant
Allergic Conjunctivitis, Anterior





Segment Inflammation, Anterior





Uveitis, Blepharoconjunctivitis, Corneal





Ulcers, Herpes Zoster Ophthalmicus,





Iritis, Keratoconjunctivitis, Ocular





Inflammation, Scleritis



Dexmedetomidine
Dexmedetomidine




Dexrazoxane
Dexrazoxane




Dextran sulfate
Dextran sulfate
Ovarian cancer, Cancer metastases,
Platelet-derived




HIV infections
growth factor inhibitors


DHAC
DHAC
Mesothelioma, Prostate cancer,
RNA methylation




Cancer
inhibitors, RNA





synthesis inhibitors


Dichlorphenamide
Dichlorphenamide




Diclofenac
Diclofenac

Cyclooxygenase



transdermal

inhibitors



second





generation




Didanosine
Didanosine
HIV infections, Toxoplasmosis
Nucleoside reverse





transcriptase inhibitors


Didox
Didox
Cancer, Psoriasis, Cytomegalovirus
Ribonucleoside




infections, HIV infections
triphosphate





reductase inhibitors,





Ribonucleotide





reductase inhibitors


Difluprednate
Difluprednate




Docetaxel
Docetaxel
Breast Cancer, Lung Cancer, Ovarian
Tubulin Inhibitor




Cancer, Prostate Cancer, Non-Small





Cell Lung Cancer, Esophageal Cancer,





Head And Neck Cancer, Gastric





Cancer, Metastatic Breast Cancer,





Endometrial Cancer, Adenocarcinoma





Of The Gastroesophageal Junction,





Adenocarcinoma, Head And Neck





Cancer Squamous Cell Carcinoma,





Hormone Refractory (Castration





Resistant, Androgen-Independent)





Prostate Cancer, Hormone-Sensitive





Prostate Cancer, Metastatic Ovarian





Cancer, Metastatic Prostate Cancer,





Recurrent Head And Neck Cancer





Squamous Cell Carcinoma



Dolasetron
Dolasetron
Nausea and vomiting, Psychotic
Serotonin 3 receptor




disorders
antagonists


Doripenem
Doripenem

Cell wall inhibitors


Doxercalciferol
Doxercalciferol

Calcitriol receptor





agonists


Doxorubicin
Doxorubicin
Breast Cancer, Lung Cancer, Ovarian
DNA intercalators,



liposomal
Cancer, Thyroid Cancer, Soft Tissue
Type II DNA




Sarcoma, Lymphoma, Acute
topoisomerase




Lymphocytic Leukemia (ALL, Acute
inhibitors




Lymphoblastic Leukemia), Acute





Myelocytic Leukemia (AML, Acute





Myeloblastic Leukemia), Hodgkin





Lymphoma, Gastric Cancer, Bladder





Cancer, Metastatic Breast Cancer,





Sarcomas, Kaposi Sarcoma,





Neuroblastoma, Wilms' Tumor





(Nephroblastoma)



doxycycline
doxycycline
Urinary Tract Infections, Malaria,





Bacterial Conjunctivitis, Gonorrhea,





Rocky Mountain Spotted Fever,





Syphilis, Cholera, Upper Respiratory





Tract Infections, Lower Respiratory





Tract Infections, Acne Vulgaris,





Actinomycosis, Anthrax, Bartonellosis,





Brucellosis, Chancroid, Extraintestinal





Amebiasis, Granuloma Inguinale,





Listeriosis, Nongonococcal Urethritis,





Plague, Q Fever, Tick-Borne





Relapsing Fever, Typhus Fever,





Uncomplicated Urethral, Endocervical,





or Rectal Infections in Adults, Yaws



droxidopa
droxidopa




Edatrexate
Edatrexate
Cancer, Rheumatoid arthritis
Tetrahydrofolate





dehydrogenase





inhibitors


Efavirenz
Efavirenz
HIV-1 infections
Non-nucleoside





reverse transcriptase





inhibitors


Eflapegrastim
Eflapegrastim

Granulocyte colony





stimulating factor





stimulants


Eflornithine HCl
Eflornithine HCl




elvitegravir
elvitegravir
HIV-1 Infection



emtricitabine
emtricitabine
HIV-1 Infection



Enalapril
Enalapril




maleate
maleate (powder





for oral solution)




Entacapone
Entacapone
Parkinson's disease, Restless legs
Catechol-O-




syndrome
methyltransferase





inhibitors


Epacadostat
Epacadostat
Malignant melanoma, Ovarian cancer,
Indoleamine-pyrrole




Fallopian tube cancer, Peritoneal
2,3-dioxygenase




cancer, Solid tumours, Non-small cell
inhibitors




lung cancer



Epinephrine
Epinephrine
Asthma, Anaphylaxis, Type I
Adrenergic receptor



injection
Hypersensitivity, Anaphylactic Shock
agonists


epitiostanol
epitiostanol




Epoprostenol
Epoprostenol





intravenous




ergotamine
ergotamine
Migraine
5-Hydroxytryptamine





Receptor 1A (5 HT1A





or G 21 or Serotonin





Receptor 1A or





HTR1A) Agonist; 5-





Hydroxytryptamine





Receptor 1B (5 HT1B





or S12 or Serotonin





1D Beta Receptor or





Serotonin Receptor 1B





or HTR1B) Agonist; 5-





Hydroxytryptamine





Receptor 1D (5 HT1D





or Serotonin 1D Alpha





Receptor or Serotonin





Receptor 1D or





HTR1D) Agonist;





Alpha 1 Adrenergic





Receptor (ADRA1)





Antagonist


Eribulin
Eribulin
Breast Cancer, Prostate Cancer, Non-





Small Cell Lung Cancer, Soft Tissue





Sarcoma, Lymphoma, Bladder Cancer,





Metastatic Breast Cancer, Solid





Tumor, Metastatic Hormone Refractory





(Castration Resistant, Androgen-





Independent) Prostate Cancer,





Transitional Cell Cancer (Urothelial





Cell Cancer), Ureter Cancer, Urethral





Cancer



Esomeprazole
Esomeprazole
Bleeding ulcer; Gastro-oesophageal
Proton pump inhibitors




reflux; Heartburn; Helicobacter





infections; NSAID-induced ulcer;





Peptic ulcer; Reflux oesophagitis;





Zollinger-Ellison syndrome



Esperamicin
Esperamicin-A1
Cancer
DNA inhibitors


Estradiol
Estradiol

Estrogen receptor



transdermal

agonists


estrogen
estrogen
Hormonal Contraception
Estrogen Receptor



(ethinylestradiol +

(ESR) Agonist;



norethindrone)

Progesterone





Receptor (Nuclear





Receptor Subfamily 3





Group C Member 3 or





NR3C3 or PGR)





Agonist


Ethanolamine
Ethanolamine




oleate
oleate




Ethinylestradiol/
Ethinylestradiol/

Estrogen receptor


norelgestromin
norelgestromin

agonists,



transdermal

Progesterone receptor





agonists


ethiodized oil
ethiodized oil





injection




etonogestrel
etonogestrel
Hormonal Contraception
Progesterone





Receptor (Nuclear





Receptor Subfamily 3





Group C Member 3 or





NR3C3 or PGR)





Agonist


everolimus
everolimus




Exisulind
Exisulind
Familial adenomatous polyposis, Non-
Apoptosis stimulants,




small cell lung cancer, Prostate
Cyclic GMP




cancer, Breast cancer, Small cell lung
phosphodiesterase




cancer
inhibitors,





Angiogenesis





inhibitors


Ezetimibe
Ezetimibe
Sitosterolaemia,
Cholesterol absorption




Hypercholesterolaemia,
inhibitors




Hyperlipoproteinaemia type II, Acute





coronary syndromes



Ezetimibe/
Ezetimibe/
Hypercholesterolaemia, Acute
Cholesterol absorption


simvastatin
simvastatin
coronary syndromes, Hyperlipidaemia,
inhibitors, HMG-CoA




Aortic valve stenosis
reductase inhibitors


Faldaprevir
Faldaprevir
Hepatitis C
Hepatitis C virus NS3





protein inhibitors


Fasudil
Fasudil
Cerebral vasospasm, Cerebral
Calcium channel




ischaemia, Pulmonary arterial
antagonists, Protein




hypertension, Intracranial thrombosis,
kinase C inhibitors,




Angina pectoris, Atherosclerosis, HIV-
Rho-associated kinase




1 infections
inhibitors


Felbamate
Felbamate




Fenoldopam
Fenoldopam




Fenretinide
Fenretinide
Breast cancer, Dry age-related
Plasma retinol-binding




macular degeneration, Glioma,
protein inhibitors




Prostate cancer, Neuroblastoma,





Rheumatoid arthritis, Basal cell cancer,





Bladder cancer



Ferric
Ferric

Iron replacements


carboxymaltose
carboxymaltose




Ferumoxytol
Ferumoxytol

Iron replacements


Fialuridine
Fialuridine
Hepatitis B
DNA-directed DNA





polymerase inhibitors


Finasteride
Finasteride
Benign prostatic hyperplasia, Alopecia,
Cholestenone 5-alpha




Prostate cancer
reductase inhibitors


Fingolimod
Fingolimod
Multiple sclerosis, Chronic
Apoptosis stimulants,




inflammatory demyelinating
Immunosuppressants,




polyradiculoneuropathy, Amyotrophic
Sphingosine 1




lateral sclerosis, Renal transplant
phosphate receptor




rejection, Optic neuritis, Type 1
modulators




diabetes mellitus, Rheumatoid arthritis,





Graft-versus-host disease, Myocarditis



Florbenazine
Florbenazine

Vesicular monoamine


F18
F18

transporter 2 inhibitors


Florbetaben F18
Florbetaben F18

Positron-emission





tomography





enhancers


Florbetapir F 18
Florbetapir F 18

Emission-computed





tomography





enhancers


Fludarabine
Fludarabine
Follicular Lymphoma, B-Cell Chronic
DNA synthesis




Lymphocytic Leukemia, Refractory
inhibitors,




Chronic Lymphocytic Leukemia (CLL),
Immunosuppressants




Chronic Lymphocytic Leukemia (CLL),





B-Cell Non-Hodgkin Lymphoma,





Mantle Cell Lymphoma



Fluorine 18 AV
Fluorine 18 AV

Positron-emission


1451
1451

tomography





enhancers


fluorouracil
fluorouracil
Breast Cancer, Ovarian Cancer,





Prostate Cancer, Colorectal Cancer,





Cervical Cancer, Liver Cancer, Head





And Neck Cancer, Pancreatic Cancer,





Gastric Cancer, Actinic (Solar)





Keratosis, Endometrial Cancer, Basal





Cell Carcinoma (Basal Cell





Epithelioma), Paget Disease of Bone,





Human Papillomavirus Infections,





Kidney Cancer (Renal Cell Cancer),





Squamous Cell Carcinoma,





Esophageal Cancer, Colorectal





Cancer, Cervical Cancer, Liver





Cancer, Head And Neck Cancer,





Pancreatic Cancer, Gastric Cancer,





Adenocarcinoma, Colon Cancer,





Gastrointestinal Tract Cancer, Genital





Warts (Condylomata Acuminata),





Keratoacanthoma, Pediatric Cancer,





Rectal Cancer



Fluoxymesterone
Fluoxymesterone
Breast cancer, Delayed puberty,
Testosterone agonists




Hypogonadism



Flutafuranol F
Flutafuranol F

Positron-emission


18
18

tomography





enhancers


Flutemetamol F
Flutemetamol F

Positron-emission


18
18

tomography





enhancers


Fomepizole
Fomepizole




Fosaprepitant
Fosaprepitant




Fosphenytoin
Fosphenytoin

Sodium channel





antagonists


Fospropofol
Fospropofol

Undefined mechanism


fulvestrant
fulvestrant
Breast Cancer, Metastatic Breast





Cancer, Hormone Sensitive Breast





Cancer



Furosemide
Furosemide

Loop diuretics



controlled





release




Gadobenic acid
Gadobenic acid

Magnetic resonance





imaging enhancers


Gadobutrol
Gadobutrol




Gadoversetamide
Gadoversetamide

Undefined mechanism


Gadoxetate
Gadoxetate

Magnetic resonance


disodium
disodium

imaging enhancers


Ganciclovir
Ganciclovir





intravitreal





implant




gemcitabine
Gemcitabine
Breast Cancer, Lung Cancer, Ovarian
DNA synthesis




Cancer, Bile Duct Cancer
inhibitors




(Cholangiocarcinoma), Non-Small Cell





Lung Cancer, Epithelial Ovarian





Cancer, Cervical Cancer, Non-Hodgkin





Lymphoma, Hodgkin





Lymphoma, Pancreatic Cancer,





Bladder Cancer, Metastatic Breast





Cancer, Small-Cell Lung Cancer,





Metastatic Pancreatic Cancer, Biliary





Tumor, Metastatic Adenocarcinoma of





The Pancreas, Metastatic Ovarian





Cancer, Non-Small Cell Lung





Carcinoma, Renal Cell Carcinoma,





Transitional Cell Cancer (Urothelial





Cell Cancer), Ureter Cancer, Urethral





Cancer



Glimepiride
Glimepiride
Type 2 diabetes mellitus
Potassium channel





agonists


Glycerol
Glycerol





phenylbutyrate




Gonadorelin
Gonadorelin




acetate
acetate




Granisetron
Granisetron

Serotonin 3 receptor



transdermal

antagonists


Guadecitabine
Guadecitabine

Antimetabolites, DNA





cytosine 5





methyltransferase 1





inhibitors


Halofantrine
Halofantrine




Heparin
Heparin
Disseminated intravascular
Thrombin inhibitors




coagulation; Peripheral arterial





occlusive disorders; Pulmonary





embolism; Thromboembolism; Venous





thrombosis



hydroxychloroquine
hydroxychloroquine
Malaria, Rheumatoid Arthritis,





Systemic Lupus Erythematosus



Hydroxyurea
Hydroxyurea




Ibandronic acid
Ibandronic acid

Dimethylallyltranstrans-





ferase inhibitors


ibrutinib
ibrutinib




ibuprofen
ibuprofen
Osteoarthritis Pain, Gastric Ulcers,
Cyclooxygenase




Duodenal Ulcer, Ankylosing
inhibitors




Spondylitis (Bekhterev's Disease),





Musculoskeletal Inflammation,





Myalgia, Rheumatoid Arthritis Pain



Idarubicin
Idarubicin




idelalisib
idelalisib




Idoxuridine
Idoxuridine
Colorectal cancer, Glioma
DNA synthesis





inhibitors


Ifosfamide
Ifosfamide




Iloprost
Iloprost solution





for infusion




imatinib
imatinib
Soft Tissue Sarcoma, Acute




mesylate
Lymphocytic Leukemia (ALL, Acute





Lymphoblastic Leukemia), Chronic





Myelocytic Leukemia (CML, Chronic





Myeloid Leukemia), Myelodysplastic





Syndrome, Gastrointestinal Stromal





Tumor (GIST), Myeloproliferative





Disorders, Hypereosinophilic





Syndrome, Pediatric Cancer, Systemic





Mastocytosis



Imiquimod
Imiquimod
Actinic keratosis, Basal cell cancer,
Immunostimulants,




Genital warts, Herpes simplex virus
Toll-like receptor 7




infections, Cervical intraepithelial
agonists




neoplasia, Warts, Molluscum





contagiosum, Tinea pedis, Vulvar





intraepithelial neoplasia,





Photodamage, Hepatitis C, Hepatitis B,





HIV infections



Indinavir
Indinavir
HIV-1 Infection, HIV-2 Infection
HIV protease inhibitors


Intoplicine
Intoplicine
Cancer, Solid tumours, Cancer
DNA topoisomerase I




metastases
inhibitors, Type II DNA





topoisomerase





inhibitors


Iobenguane I-
Iobenguane I-

Enzyme inhibitors,


123
123

Diagnostic imaging





enhancers


Iobenguane
Iobenguane




sulfate 131
sulfate I 131




Ioxilan
Ioxilan

Radiography





enhancers


Irinotecan
Irinotecan




Iron
Iron

Iron replacements


isomaltoside
isomaltoside




1000
1000




Iron sucrose
Iron sucrose

Iron replacements


Isavuconazonium
Isavuconazonium




Ivacaftor
Lumacaftor/





ivacaftor




ivermectin
ivermectin
Scabies, Elephantiasis (Lymphatic





Filariasis), Onchocerciasis (River





Blindness), Strongyloidiasis, Rosecea,





Head Lice



ixabepilone
ixabepilone
Prostate Cancer, Non-Small Cell Lung





Cancer, Esophageal Cancer, Gastric





Cancer, Metastatic Breast Cancer,





Metastatic Pancreatic Cancer, Solid





Tumor, Endometrial Cancer,





Adenocarcinoma



Ixazomib citrate
Ixazomib citrate




labelalol
labelalol
Hypertension



Lacosamide
Lacosamide
Male osteoporosis; Osteoporosis;





Postmenopausal osteoporosis



lamivudine
lamivudine
HIV/AIDS, HIV-1 Infection, Hepatitis





B



Lamotrigine
Lamotrigine
Bipolar disorders, Lennox-Gastaut
Sodium channel




syndrome, Partial epilepsies, Tonic-
antagonists




clonic epilepsy, Absence epilepsy,





Epilepsy, Neuropathic pain, Diabetic





neuropathies, Schizophrenia



Lansoprazole
Lansoprazole




Lapatinib
Lapatinib
Breast Cancer, Non-Small Cell Lung
Epidermal growth




Cancer, Esophageal Cancer, Gastric
factor receptor




Cancer, Metastatic Pancreatic Cancer,
antagonists, ERBB 2




Adenocarcinoma Of The
receptor antagonists




Gastroesophageal Junction, Head And





Neck Cancer Squamous Cell





Carcinoma, Metastatic Colorectal





Cancer, Non-Neoplastic Neuromas,





Vestibular Schwannoma (Acoustic





Neuroma)



Lazabemide
Lazabemide
Parkinson's disease, Alzheimer's
Monoamine oxidase B




disease, Smoking withdrawal
inhibitors, Antioxidants


L-dopa
L-dopa
Parkinson's Disease
Aromatic L Amino Acid





Decarboxylase (AADC





or Dopa





Decarboxylase or





DDC or EC 4.1.1.28)





Inhibitor; Catechol O





Methyltransferase





(Epididymis Secretory





Sperm Binding Protein





Li 98n or COMT or EC





2.1.1.6) Inhibitor;





Dopamine Receptor





(DRD) Agonist


leflunomide
leflunomide
Rheumatoid Arthritis



Lenalidomide
Lenalidomide




lenvatinib
lenvatinib




Letermovir
Letermovir

Cytomegalovirus





replication inhibitors


Leucovorin
Leucovorin




Leuprolide
Leuprolide





acetate




Levetiracetam
Levetiracetam

SV2A protein





modulators


Levocarnitine
Levocarnitine




Levofloxacin
Levofloxacin

DNA gyrase inhibitors,





Type II DNA





topoisomerase





inhibitors


Levoleucovorin
Levoleucovorin




Levothyroxine
Levothyroxine
Thyroid Cancer, Goiter,
Thyroid hormone



sodium
Hypothyroidism, Hashimoto Thyroiditis
receptor agonists


Lidocaine
Lidocaine

Sodium channel



transdermal

antagonists



patch




lidocane
lidocane
Postherpetic Neuralgia
Voltage Gated Sodium





Channel (SCN)





Blocker


Linezolid
Linezolid

Protein 30S ribosomal





subunit inhibitors


Lobaplatin
Lobaplatin
Small cell lung cancer, Chronic
Alkylating agents




myeloid leukaemia, Breast cancer,





Cancer



Lodoxamide
Lodoxamide





tromethamine




Lomitapide
Lomitapide
Hyperlipoproteinaemia type IIa
Microsomal





triglyceride transfer





protein inhibitors


lopinavir
lopinavir
HIV-1 Infection



lovastatin
lovastatin
Myocardial Infarction,





Hypercholesterolemia, Atherosclerosis,





Unstable Angina, Dyslipidemia,





Hyperlipidemia, Coronary Disease,





Familial Hypercholesterolemia (Type II





Hyperlipoproteinemia)



Lumacaftor
Lumacaftor/





ivacaftor




macitentan
macitentan




maraviroc
maraviroc
HIV-1 Infection



Mefloquine HCl
Mefloquine HCl




Meloxicam
Meloxicam

Cyclo-oxygenase 2



injection

inhibitors


melphalan
melphalan
Breast Cancer, Ovarian Cancer,





Retinoblastoma, Soft Tissue Sarcoma,





Bone Marrow Transplantation,





Melanoma, Multiple Myeloma (Kahler





Disease), Metastatic Breast





Cancer, Polycythemia Vera,





Adenocarcinoma, Metastatic Ovarian





Cancer, Neuroblastoma



mercaptopurine
mercaptopurine
Acute Lymphocytic Leukemia (ALL,




oral solution
Acute Lymphoblastic Leukemia), Acute





Myelocytic Leukemia (AML, Acute





Myeloblastic Leukemia), Chronic





Myelocytic Leukemia (CML, Chronic





Myeloid Leukemia), Leukemias,





Pediatric Cancer



Meropenem
Meropenem
Febrile neutropenia, Bacterial
Cell wall inhibitors




infections, Community-acquired





pneumonia, Skin and soft tissue





infections



Mesna
Mesna

Undefined mechanism


methotrexate
methotrexate
Psoriasis, Rheumatoid Arthritis,
Tetrahydrofolate




Polyarticular Juvenile Idiopathic
dehydrogenase




Arthritis (PJIA)
inhibitors, Thymidylate





synthase inhibitors


Methylnaltrexone
Methylnaltrexone

Opioid mu receptor



bromide

antagonists


Methylphenidate
Methylphenidate

Adrenergic receptor



transdermal

modulators, Dopamine





release stimulants


metoprolol
metoprolol
Angina (Angina Pectoris),
Beta 1 Adrenergic




Hypertension, Myocardial Infarction,
Receptor (Beta 1




Migraine
Adrenoreceptor or





ADRB1) Antagonist


Mifepristone
Mifepristone




Miglustat
Miglustat




Miltefosine
Miltefosine
Visceral leishmaniasis, Cutaneous
Signal transduction




leishmaniasis, Cancer metastases,
pathway inhibitors




Leishmaniasis, Chagas disease,





Malignant melanoma



Minocycline
Minocycline IV

Glial cell inhibitors,





Protein 30S ribosomal





subunit inhibitors


mitomycin C
mitomycin C
Breast Cancer, Lung Cancer, Prostate





Cancer, Anal Cancer, Bone Cancer,





Non-Small Cell Lung Cancer,





Squamous Cell Carcinoma, Uterine





Cancer, Malignant Mesothelioma,





Colorectal Cancer, Cervical Cancer,





Chronic Lymphocytic Leukemia (CLL),





Chronic Myelocytic Leukemia (CML,





Chronic Myeloid Leukemia), Liver





Cancer, Head And Neck Cancer,





Pancreatic Cancer, Gastric Cancer,





Bladder Cancer, Leukemias, Metastatic





Breast Cancer, Sarcomas, Solid





Tumor, Adenocarcinoma Of The





Gastroesophageal Junction, Colon





Cancer, Metastatic Adenocarcinoma of





The Pancreas, Non Muscle Invasive





Bladder Cancer (NMIBC) (Superficial





Bladder Cancer), Skin Cancer



Mitoxantrone
Mitoxantrone

DNA inhibitors, DNA





topoisomerase





inhibitors, Type II DNA





topoisomerase





inhibitors,





Immunosuppressants


Modafinil
Modafinil




Morphine
Morphine
Acute Pain, Chronic Pain, Dyspnea
Mu Type Opioid





Receptor (MOR1 or





Mu Opiate Receptor or





Mu Opioid Receptor or





OPRM1) Agonist


Motexafin
Motexafin
Brain cancer, Non-small cell lung
Thioredoxin reductase


gadolinium
gadolinium
cancer, Glioma, Lymphoma, Chronic
inhibitors




lymphocytic leukaemia, Glioblastoma,





Multiple myeloma, Non-Hodgkin's





lymphoma, Renal cancer,





Cardiovascular disorders, Head and





neck cancer, Solid tumours,





Amyotrophic lateral sclerosis



Moxifloxacin
Moxifloxacin
Intra-abdominal infections, Acute
Type II DNA




exacerbations of chronic bronchitis,
topoisomerase




Community-acquired pneumonia, Skin
inhibitors




and soft tissue infections, Acute





sinusitis, Bacterial infections,





Respiratory tract infections, Pelvic





inflammatory disorders, Plague,





Tuberculosis



Mycophenolate
Mycophenolate
Liver Transplantation, Heart
Immunosuppressants,


mofetil
mofetil
Transplantation, Kidney
Inosine




Transplantation
monophosphate





dehydrogenase





inhibitors


Nafarelin
Nafarelin





acetate




Naloxone
Naloxone

Opioid receptor



injection

antagonists


naproxen
naproxen
Osteoarthritis Pain, Gastric Ulcers,





Ankylosing Spondylitis (Bekhterev's





Disease), Rheumatoid Arthritis Pain,





Migraine



nelarabine
nelarabine
Acute Lymphocytic Leukemia (ALL,





Acute Lymphoblastic Leukemia), Acute





Lymphoblastic Lymphoma



nelfinavir
nelfinavir
HIV-1 Infection



Neostigmine
Neostigmine




Nevirapine
Nevirapine
HIV-1 infections
Non-nucleoside





reverse transcriptase





inhibitors


nilotinib
Nilotinib
Anaplastic Astrocytoma,





Oligodendroglioma, Colorectal Cancer,





Pulmonary Arterial Hypertension,





Acute Lymphocytic Leukemia (ALL,





Acute Lymphoblastic Leukemia), Acute





Myelocytic Leukemia (AML, Acute





Myeloblastic Leukemia), Chronic





Myelocytic Leukemia (CML, Chronic





Myeloid Leukemia), Systemic Sclerosis





(Scleroderma), Graft Versus Host





Disease (GVHD), Gastrointestinal





Stromal Tumor (GIST), Anaplastic





Oligoastrocytoma, Head And Neck





Cancer Squamous Cell Carcinoma,





Metastatic Melanoma, Pigmented





Villonodular Synovitis, Recurrent





Glioblastoma Multiforme (GBM),





Tenosynovitis, Vestibular





Schwannoma (Acoustic Neuroma)



Nilutamide
Nilutamide
Prostate cancer
Testosterone





congener inhibitors


nintedanib
nintedanib




Nitazoxanide
Nitazoxanide




Nitisinone
Nitisinone




nitrosoureas
nitrosoureas
Astrocytoma, Glioblastoma Multiforme





(GBM), Metastatic Brain Tumor,





Glioma, Ependymoma, Lymphoma,





Melanoma, Multiple Myeloma (Kahler





Disease), Non-Hodgkin Lymphoma,





Hodgkin Lymphoma, Solid Tumor,





Brain Tumor, Gastrointestinal Tract





Cancer, Medulloblastoma



nortriptyline
nortriptyline
Depression



NSC 361456
NSC 361456
Cancer
Undefined mechanism


obeticholic acid
obeticholic acid




olaparib
olaparib




Omacetaxine
Omacetaxine
Chronic Myelocytic Leukemia (CML,
Apoptosis stimulants,


mepesuccinate
mepesuccinate
Chronic Myeloid Leukemia)
Cyclin D1 inhibitors,





MCL1 protein





inhibitors, Protein





synthesis inhibitors,





Proto oncogene





protein c-myc





inhibitors


Omadacycline
Omadacycline

Protein synthesis





inhibitors


Omeprazole
Omeprazole
Peptic ulcer, Helicobacter infections,
Proton pump inhibitors




Duodenal ulcer, Gastric ulcer, Gastro-





oesophageal reflux, Zollinger-Ellison





syndrome, Gastritis, Dyspepsia



opioids
opioids
Pain



Oritavancin
Oritavancin




Orlistat
Orlistat
Obesity
Lipase inhibitors


Oxaliplatin
Oxaliplatin

DNA cross linking





agents, DNA synthesis





inhibitors


oxprenolol
oxprenolol
Hypertension



Oxybate
Oxybate




Oxybutynin
Oxybutynin

Cholinergic receptor





antagonists,





Muscarinic receptor





antagonists


Oxymetholone
Oxymetholone
Anaemia, Cachexia
Protein synthesis





stimulants, Stem cell





stimulants,





Testosterone





congener stimulants


Paclitaxel
Paclitaxel
Ovarian cancer, Breast cancer, Gastric
Mitosis inhibitors,




cancer, Kaposi's sarcoma, Non-small
Proto-oncogene




cell lung cancer, Cervical cancer,
protein c-bcl-2




Multiple myeloma, Head and neck
inhibitors, Tubulin




cancer, Prostate cancer, Cancer
polymerisation




metastases, Bladder cancer, Testicular
promoters




cancer, Endometrial cancer, Non-





Hodgkin's lymphoma, Sarcoma, Lung





cancer, Mesothelioma, Leukaemia,





Pleural effusion, Small cell lung cancer



Hemin
Hemin




Pantoprazole
Pantoprazole




Paracetamol
Paracetamol
Fever; Pain




intravenous




Paricalcitol
Paricalcitol

Calcitriol receptor





agonists, Parathyroid





hormone receptor





antagonists


Pazopanib
Pazopanib




Pemetrexed
Pemetrexed
Non-small cell lung cancer,
Antimetabolites,




Mesothelioma, Breast cancer, Non-
Tetrahydrofolate




Hodgkin's lymphoma, Head and neck
dehydrogenase




cancer, Ovarian cancer,
inhibitors, Thymidylate




Osteosarcoma, Renal cancer, Small
synthase inhibitors




cell lung cancer



Pentamidine
Pentamidine




isethionate
isethionate




pentazocine
pentazocine
Pain, Moderate Pain




(acetaminophen +





pentazocine





hydrochloride)




Pentosan
Pentosan





polysulfate





sodium




Pentostatin
Pentostatin
Hairy cell leukaemia, Cutaneous T cell
Adenosine deaminase




lymphoma, Graft-versus-host disease,
inhibitors,




Non-Hodgkin's lymphoma, Rheumatoid
Immunomodulators




arthritis



Peramivir
Peramivir




Perflexane
Perflexane




Perflutren
Perflutren

Undefined mechanism


Phenylephrine
Phenylephrine





intravenous




Piperacillin/
Piperacillin/

Beta lactamase


tazobactam
tazobactam

inhibitors, Cell wall





inhibitors


Pirmenol
Pirmenol
Ventricular arrhythmias
Calcium channel





antagonists,





Muscarinic M2





receptor antagonists,





Potassium channel





antagonists, Sodium





channel antagonists


Plazomicin
Plazomicin

Protein synthesis





inhibitors


Plerixafor
Plerixafor

CXCR4 receptor





antagonists


Polidocanol
Polidocanol




Pomalidomide
Pomalidomide




ponatinib
ponatinib
Glioblastoma Multiforme (GBM), Non-




hydrochloride
Small Cell Lung Cancer, Acute





Lymphocytic Leukemia (ALL, Acute





Lymphoblastic Leukemia), Acute





Myelocytic Leukemia (AML, Acute





Myeloblastic Leukemia), Chronic





Myelocytic Leukemia (CML, Chronic





Myeloid Leukemia), Gastrointestinal





Stromal Tumor (GIST), Biliary Tumor,





Medullary Thyroid Cancer



Posaconazole
Posaconazole




pralatrexate
Pralatrexate
Non-Small Cell Lung Cancer,
Antimetabolites,




Esophageal Cancer, Cutaneous T-Cell
Tetrahydrofolate




Lymphoma, Hodgkin Lymphoma,
dehydrogenase




Gastric Cancer, Bladder Cancer, Oral
inhibitors




Mucositis, Metastatic Breast Cancer,





B-Cell Non-Hodgkin Lymphoma,





Peripheral T-Cell Lymphomas (PTCL),





Transitional Cell Cancer (Urothelial





Cell Cancer)



prednisolone
prednisolone
Burns, Keratitis, Blepharitis,





Conjunctivitis, Anterior Uveitis,





Herpetic Keratitis, Ocular





Inflammation, Scleritis



prednisone
predisone
Multiple Sclerosis, Asthma, Sicca





Syndrome (Sjogren), Proteinuria,





Uveitis, Juvenile Rheumatoid Arthritis,





Vasculitis, Chronic Obstructive





Pulmonary Disease (COPD), Idiopathic





Pulmonary Fibrosis, Hypoxemia,





Serum Sickness, Polymyositis,





Tuberculous Meningitis, Gouty Arthritis





(Gout), Ankylosing Spondylitis





(Bekhterev's Disease), Idiopathic





Thrombocytopenic Purpura (Immune





Thrombocytopenic Purpura), Psoriatic





Arthritis, Polymyalgia Rheumatica,





Dermatomyositis, Ulcerative Colitis,





Transplantation, Rheumatoid Arthritis,





Crohn's Disease (Regional Enteritis),





Systemic Lupus Erythematosus,





Dermatitis, Thrombocytopenia,





Acquired (Autoimmune) Hemolytic





Anemia, Adrenal Insufficiency, Allergic





Bronchopulmonary Aspergillosis,





Aspiration Pneumonitis, Atopic





Dermatitis, Bronchiolitis Obliterans,





Congenital Adrenal Hyperplasia





(Adrenogenital Syndrome), Contact





Dermatitis, Dermatitis Herpetiformis





(Duhring's Disease), Drug





Hypersensitivity Reactions, Edema,





Erythema Multiforme, Idiopathic





Eosinophilic Pneumonia, Idiopathic





Interstitial Pneumonia (IIP),





Nonsuppurative Thyroiditis, Ocular





Inflammation, Pemphigus, Perennial





Allergic Rhinitis, Pneumocystis carinii





Pneumonia, Pulmonary Tuberculosis,





Respiratory Hypersensitivity, Seasonal





Allergic Rhinitis, Sympathetic





Ophthalmia, Symptomatic Sarcoidosis



Propofol
Propofol

GABA receptor





agonists


propranolol
propranolol
Angina (Angina Pectoris),
Beta 1 Adrenergic




Hypertension, Myocardial Infarction,
Receptor (Beta 1




Migraine, Atrial Fibrillation, Essential
Adrenoreceptor or




Tremor, Pheochromocytoma,
ADRB1) Antagonist;




Tachycardia (Tachyarrhythmias),
Beta 2 Adrenergic




Hyperthyroidism, Ventricular
Receptor (Beta 2




Arrhythmia, Wolff-Parkinson-White
Adrenoreceptor or




Syndrome
ADRB2) Antagonist


Quinapril
Quinapril

ACE inhibitors


Quinine sulfate
Quinine sulfate




Quinupristin/
Quinupristin/
Enterococcal infections, Gram-positive
Protein synthesis


dalfopristin
dalfopristin
infections, Skin and soft tissue
inhibitors




infections, Nosocomial pneumonia



Raloxifene
Raloxifene
Postmenopausal osteoporosis, Breast
Selective estrogen




cancer, Fracture, Cardiovascular
receptor modulators




disorders, Endometriosis, Vasomotor





symptoms, Hypercholesterolaemia,





Leiomyoma



raltegravir
raltegravir
HIV/AIDS, HIV-1 Infection



Raltitrexed
Raltitrexed
Colorectal cancer, Mesothelioma
Thymidylate synthase





inhibitors


Ramatroban
Ramatroban
Allergic rhinitis, Asthma, Ischaemic
Thromboxane A2




heart disorders, Thrombosis
receptor antagonists


Regadenoson
Regadenoson
Coronary disorders
Adenosine A2





receptor agonists


Regorafenib
Regorafenib




Remacemide
Remacemide
Huntington's disease, Epilepsy, Stroke,
Glutamate receptor




Neurological disorders, Parkinson's
antagonists, NMDA




disease, Neuropathic pain
receptor antagonists


riboflavin
riboflavin





ophthalmic





solution &





ultraviolet A




Rifabutin
Rifabutin




Rifampin
Rifampin




Rifapentine
Rifapentine
Tuberculosis, Mycobacterium avium
Protein 50S ribosomal




complex infections
subunit inhibitors


Rifaximin
Rifaximin




rilpivirine
rilpivirine
HIV-1 Infection



Riluzole
Riluzole




Riociguat
Riociguat




Ritonavir
Ritonavir
Hepatitis C, HIV-1 Infection
HIV protease inhibitors


RO 316840
RO 316840
Hepatitis B, HIV infections
RNA-directed DNA





polymerase inhibitors


Romidepsin
Romidepsin




Ropeginterferon
Ropeginterferon

Interferon alpha 2b


alfa-2b
alfa-2b

stimulants


rosuvastatin
rosuvastatin




Rotigotine
Rotigotine

Dopamine D2 receptor





agonists


Rufinamide
Rufinamide




Ruxolitinib
Ruxolitinib





Phosphate




Sabril
Sabril




salbutamol
salbutamol
Asthma, Bronchospasm, Obstructive





Pulmonary Disease, Chronic





Obstructive Pulmonary Disease





(COPD), Chronic Bronchitis,





Emphysema, Exercise-Induced





Bronchoconstriction (EBI), Premature





Labor (Tocolysis), Pulmonary





Tuberculosis, Status Asthmaticus



Salmeterol
Salmeterol

Arachidonic acid



injection

inhibitors, Beta 2





adrenergic receptor





agonists


Samarium 153
Samarium 153

Ionising radiation


lexidronam
lexidronam

emitters, Reactive





oxygen species





stimulants


Sapropterin
Sapropterin




saquinavir
saquinavir
HIV-1 Infection
HIV 1 Retropepsin





(HIV Aspartyl





Protease or HIV





Proteinase or





Retroproteinase or





Gag Protease or HIV





Aspartyl Protease or





EC 3.4.23.16)





Inhibitor; HIV 2





Retropepsin (HIV 2





Protease or EC





3.4.23.47) Inhibitor


Satraplatin
Satraplatin
Squamous cell cancer, Prostate
DNA cross linking




cancer, Non-small cell lung cancer,
agents, DNA synthesis




Breast cancer, Solid tumours
inhibitors


Sedoxantrone
Sedoxantrone
Prostate cancer, Colorectal cancer,
DNA helicase




Solid tumours
inhibitors, DNA





inhibitors


Selexipag
Selexipag




Semaxanib
Semaxanib
Kaposi's sarcoma, Colorectal cancer,
Angiogenesis




Non-small cell lung cancer, Acute
inhibitors, Protein




myeloid leukaemia, Solid tumours,
tyrosine kinase




Cancer metastases
inhibitors, Vascular





endothelial growth





factor receptor-2





antagonists


Sertraline
Sertraline
Major depressive disorder, Panic
Serotonin uptake




disorder, Post-traumatic stress
inhibitors




disorders, Social phobia, Obsessive-





compulsive disorders, Premenstrual





dysphoric disorder, Generalised





anxiety disorder, Premature





ejaculation, Obesity



Sildenafil
Sildenafil




Simvastatin
Simvastatin
Hypertriglyceridaemia,
HMG-CoA reductase




Hypercholesterolaemia, Low HDL
inhibitors, Nitric oxide




cholesterol, Hyperlipoproteinaemias,
synthase type II




Diabetic cardiomyopathy, Cystic
inhibitors




fibrosis, Multiple sclerosis, Alzheimer's





disease, Bone resorption, Rheumatoid





arthritis



sirolimus
sirolimus
Arteriovenous Fistula, Benign





Cardiovascular Tumor, Dermatological





Disorders, Kidney Transplantation,





Choroidal Neovascularization, Diabetic





Macular Edema, Keratoconjunctivitis





sicca (Dry Eye), Dry (Atrophic) Macular





Degeneration, Posterior Uveitis, Wet





(Neovascular/Exudative) Macular





Degeneration



Sodium ferric
Sodium ferric

Iron replacements


gluconate
gluconate





complex




Sodium nitrite-
Sodium nitrite-




sodium
sodium




thiosulfate
thiosulfate




combination
combination




therapy
therapy




Sodium
Sodium

Ammonia scavengers


phenylacetate/
phenylacetate/




sodium
sodium




benzoate
benzoate




Sodium
Sodium




phenylbutyrate
phenylbutyrate




Sorafenib
Sorafenib




Sorivudine
Sorivudine
Herpes zoster
RNA-directed DNA





polymerase inhibitors


Sotalol
IV Sotalol




Stavudine
Stavudine
HIV-1 infections
Nucleoside reverse





transcriptase inhibitors


sulfasalazine
sulfasalazine
Colitis, Ulcerative Colitis, Crohn's





Disease (Regional Enteritis), Proctitis



Sumatriptan
Sumatriptan

Serotonin 1D receptor



transdermal

agonists


Sunitinib
Sunitinib
Pancreatic cancer, Gastrointestinal
Colony stimulating




stromal tumours, Renal cancer,
factor receptor




Prostate cancer, Oesophageal cancer,
antagonists, Fms-like




Thyroid cancer, Bladder cancer,
tyrosine kinase 3




Malignant melanoma, Soft tissue
inhibitors, Platelet




sarcoma, Hepatocellular carcinoma,
derived growth factor




Germ cell and embryonal neoplasms,
alpha receptor




Non-small cell lung cancer, Breast
antagonists, Platelet-




cancer, Colorectal cancer, Gastric
derived growth factor




cancer, Urogenital cancer, Acute
beta receptor




myeloid leukaemia
antagonists, Proto





oncogene protein c ret





inhibitors, Proto





oncogene protein c-kit





inhibitors, Vascular





endothelial growth





factor receptor 3





antagonists, Vascular





endothelial growth





factor receptor-1





antagonists, Vascular





endothelial growth





factor receptor-2





antagonists


Tacrine
Tacrine
Alzheimer's disease, HIV infections
Acetylcholinesterase





inhibitors


Tacrolimus
Tacrolimus
Transplant rejection, Atopic dermatitis,
Calcineurin inhibitors,




Ulcerative colitis, Myasthenia gravis,
Cytokine inhibitors,




Intestinal transplant rejection, Graft-
Immunosuppressants,




versus-host disease, Interstitial lung
T cell activation




diseases, Lupus nephritis, Allergic
inhibitors




conjunctivitis, Rheumatoid arthritis,





Coronary artery restenosis, Open-





angle glaucoma, Psoriasis, Eye





disorders, Dry eyes, Lupus Nephritis,





Myasthenia Gravis, Pneumonia, Liver





Transplantation, Heart Transplantation,





Bone Marrow Transplantation, Lung





Transplantation, Ulcerative Colitis,





Rheumatoid Arthritis, Crohn's Disease





(Regional Enteritis), Eczema, Kidney





Transplantation, Atopic Dermatitis



Tanomastat
Tanomastat
Non-small cell lung cancer, Ovarian
Angiogenesis




cancer, Pancreatic cancer, Small cell
inhibitors, Matrix




lung cancer, Osteoarthritis
metalloproteinase





inhibitors


tasimelteon
tasimelteon




Tc 99m apcitide
Tc 99m apcitide

Radionuclide imaging





enhancers


Tc 99m
Tc 99m

Single-photon


ethylenedicysteine
ethylenedicysteine

emission-computed


deoxyglucose
deoxyglucose

tomography





enhancers


Tedizolid
Tedizolid




Teicoplanin
Teicoplanin
Gram-positive infections, Bacterial
Cell wall inhibitors




infections



Telavancin
Telavancin

Cell membrane





permeability





enhancers, Cell wall





inhibitors


Telithromycin
Telithromycin
Acute sinusitis, Gram-positive
Protein 50S ribosomal




infections, Community-acquired
subunit inhibitors




pneumonia, Tonsillitis, Acute





exacerbations of chronic bronchitis,





Pharyngitis, Respiratory tract





infections, Obstetric and





gynaecological infections, Pelvic





inflammatory disorders, Skin and soft





tissue infections, Toxoplasmosis



Temafloxacin
Temafloxacin
Bacterial infections
Type II DNA





topoisomerase





inhibitors


Temozolomide
Temozolomide




Temsirolimus
Temsirolimus
Mantle-cell lymphoma, Renal cancer,
MTOR protein




Glioblastoma, Hodgkin's disease,
inhibitors




Glioma, Non-Hodgkin's lymphoma,





Head and neck cancer, Follicular





lymphoma, Lymphoma, Acute





lymphoblastic leukaemia, Colorectal





cancer, Solid tumours, Prostate





cancer, Multiple myeloma, Breast





cancer, Soft tissue sarcoma,





Pancreatic cancer



Teniposide
Teniposide




tenofovir
tenofovir
HIV-1 Infection



Terbinafine
Terbinafine
Mycoses, Tinea cruris, Pityriasis
Squalene




versicolor, Tinea pedis, Tinea corporis,
monooxygenase




Tinea capitis
inhibitors


Testosterone
Testosterone
Breast cancer, Delayed puberty,
Androgen Receptor


propionate
propionate
Hypogonadism, Menopausal
(Dihydrotestosterone




syndrome, Decreased libido, Male
Receptor or Nuclear




Hypogonadism, Secondary
Receptor Subfamily 3




(Hypogonadotropic) Hypogonadism,
Group C Member 4 or




Testicular (Primary) Hypogonadism,
DHTR or NR3C4 or




Testicular Diseases
AR) Agonist


Thalidomide
Thalidomide




Tianeptine
Tianeptine
Anxiety disorders, Major depressive
Serotonin uptake




disorder, Alcoholism, Irritable bowel
stimulants




syndrome, Asthma



Tigecycline
Tigecycline




Tinzaparin
Tinzaparin

Factor Xa inhibitors,


sodium
sodium

Thrombin inhibitors


Tiopronin
Tiopronin




Tizanidine
Tizanidine
Muscle spasticity, Migraine,
Alpha 2 adrenergic




Fibromyalgia
receptor agonists


Tobramycin
Tobramycin for





inhalation




Tolcapone
Tolcapone
Parkinson's disease
Catechol-O-





methyltransferase





inhibitors


Tolrestat
Tolrestat
Diabetic complications
Aldehyde reductase





inhibitors


Tolvaptan
Tolvaptan
Oedema, Hyponatraemia, Cardiac
Vasopressin V2




oedema, Autosomal dominant
receptor antagonists




polycystic kidney disease, Renal





failure, Ascites



Topiramate
Topiramate
Epilepsy, Migraine, Lennox-Gastaut
AMPA receptor




syndrome, Obesity, Post-traumatic
antagonists, Carbonic




stress disorders, Diabetic
anhydrase inhibitors,




neuropathies, Bipolar disorders
GABA-A receptor





antagonists, Kainic





acid receptor





antagonists, Sodium





channel antagonists,





GABA A receptor





agonists


Topotecan
Topotecan
Small cell lung cancer, Ovarian cancer,
DNA topoisomerase I




Cervical cancer, Brain cancer
inhibitors


Trabectedin
Trabectedin




Trametinib
Trametinib




Treprostinil
Treprostinil
Pulmonary Arterial Hypertension
Prostacyclin Receptor





(Prostaglandin I2





Receptor or





Prostanoid IP





Receptor or PTGIR)





Agonist


Tretinoin
Tretinoin




Triciribine
Triciribine
Ovarian cancer, Breast cancer, Acute
DNA synthesis




myeloid leukaemia, Solid tumours,
inhibitors, Protein




Haematological malignancies,
kinase inhibitors, Proto




Pancreatic cancer, HIV infections,
oncogene protein c-




Cancer
akt inhibitors


Trientine
Trientine HCl




Trimetrexate
Trimetrexate
Pneumocystis pneumonia, Colorectal
Tetrahydrofolate




cancer, Bladder cancer, Lung cancer,
dehydrogenase




Cancer, Pancreatic cancer, Cervical
inhibitors




cancer, Non-small cell lung cancer,





Breast cancer, Gastric cancer,





Psoriasis, Leukaemia, Rheumatoid





arthritis



Trovafloxacin
Trovafloxacin
Bacterial infections, Genital tract
Type II DNA




infections, Respiratory tract infections,
topoisomerase




Toxoplasmosis
inhibitors


Uridine
Uridine




triacetate
triacetate




Ursodiol
Ursodiol




Vandetanib
Vandetanib




venetoclax
venetoclax




verapamil
verapamil
Angina (Angina Pectoris),





Hypertension, Unstable Angina, Renal





(Renovascular) Hypertension, Atrial





Fibrillation, Ischemia, Atrial Flutter,





Chronic Stable Angina, Idiopathic





(Essential) Hypertension, Paroxysmal





Ventricular Tachycardia,





Supraventricular Tachycardia,





Vasospastic Angina, Wolff-Parkinson-





White Syndrome



Verteporfin
Verteporfin




vinblastine
vinblastine
Breast Cancer, Testicular Cancer,





Lymphoma, Hodgkin Lymphoma,





Carcinomas, Gestational Trophoblastic





Disease, Kaposi Sarcoma, Letterer-





Siwe Disease (Multifocal and





multisystemic (disseminated)





Langerhans-cell histiocytosis), Mycosis





Fungoides



vincristine
vincristine
Metastatic Uveal Melanoma, Non-
Tubulin polymerisation


sulfate
sulfate
Hodgkin Lymphoma, Acute
inhibitors




Lymphocytic Leukemia (ALL, Acute





Lymphoblastic Leukemia)



Vinorelbine
Vinorelbine
Non-small cell lung cancer, Breast
Mitosis inhibitors,




cancer, Ovarian cancer, Head and
Tubulin polymerisation




neck cancer, Prostate cancer, Small
inhibitors




cell lung cancer, Cervical cancer,





Malignant melanoma, Multiple





myeloma



Vismodegib
Vismodegib
Basal cell cancer, Pancreatic cancer,
Hedgehog cell-




Basal cell nevus syndrome, Gastric
signalling pathway




cancer, Small cell lung cancer,
inhibitors




Medulloblastoma, Breast cancer,





Chondrosarcoma, Myelofibrosis,





Idiopathic pulmonary fibrosis,





Glioblastoma, Colorectal cancer,





Chronic lymphocytic leukaemia,





Ovarian cancer, B cell lymphoma,





Myelodysplastic syndromes, Acute





myeloid leukaemia, Prostate cancer,





Sarcoma



Vitamin B12
Vitamin B12




fluorescent-
fluorescent-




analogues
analogues




Voglibose
Voglibose
Type 2 diabetes mellitus
Alpha-glucosidase





inhibitors, Glucagon-





like peptide 1





stimulants


Voriconazole
Voriconazole




Zafirlukast
Zafirlukast
Asthma
Leukotriene D4





receptor antagonists,





Leukotriene E4





receptor antagonists


zalcitabine
zalcitabine
HIV/AIDS



zidovudine
zidovudine
HIV-1 Infection, HIV-2 Infection



Zileuton
Zileuton
Asthma, Ulcerative colitis, Chronic
5-lipoxygenase




obstructive pulmonary disease, Acute
inhibitors




asthma, Acne, Atopic dermatitis,





Rheumatoid arthritis, Cancer, Allergic





rhinitis, Atherosclerosis, Nasal polyps



Zoledronic acid
Zoledronic acid
Osteitis deformans, Bone metastases,
Bone resorption factor




Malignant hypercalcaemia,
inhibitors,




Postmenopausal osteoporosis,
Geranyltranstransferase




Corticosteroid-induced osteoporosis,
inhibitors,




Multiple myeloma, Male osteoporosis,
Osteoclast inhibitors




Fracture, Mesothelioma, Osteoporosis,





Breast cancer, Osteogenesis





imperfecta, Osteosarcoma,





Rheumatoid arthritis









In some embodiments, the therapeutic agent is an antimicrobial, antiviral, antiparasitic, anticancer agent, or other therapeutic agent selected from those in Table 2, below; or a pharmaceutically acceptable salt thereof.









TABLE 2







Exemplary Therapeutic Agents and Associated Diseases and Disorders










Therapeutic





Agent Name
Indication
Mechanism of Action
Therapeutic Area





Amikacin liposomal
Cystic fibrosis-associated respiratory tract infections,
Protein 30S ribosomal
Bacterial Infections, Drug


inhaled - Insmed
Mycobacterial infections, Bronchiectasis
subunit inhibitors
Delivery Systems


Azithromycin
Community-acquired pneumonia, Bacterial infections, Acute
Protein 50S ribosomal
Bacterial Infections, Digestive



sinusitis, Pelvic inflammatory disorders, Otitis media,
subunit inhibitors
System Disorders, Ischaemic



Sexually transmitted infections, Cystic fibrosis-associated

Heart Disease, Obstructive



respiratory tract infections, Cholera, Asthma, Pertussis,

Airways Disease



Typhoid, Gastroparesis, Acute coronary syndromes


Cefepime
Intra-abdominal infections, Bacterial infections, Skin
Cell wall inhibitors
Bacterial Infections



and soft tissue infections, Urinary tract infections,



Respiratory tract infections, Febrile neutropenia


Ceftaroline
Community-acquired pneumonia, Skin and soft tissue
Cell wall inhibitors,
Bacterial Infections


fosamil
infections, Methicillin-resistant Staphylococcus aureus
Penicillin-binding



infections, Bacteraemia, Sepsis, Bacterial infections,
protein inhibitors



Osteomyelitis


Ceftazidime - B
CNS infections, Skin and soft tissue infections,
Cell wall inhibitors
Bacterial Infections


Braun Medical
Bacteraemia, Intra-abdominal infections, Gynaecological



infections, Bone and joint infections, Respiratory tract



infections


Ceftolozane/
Intra-abdominal infections, Gram-negative infections,
Beta lactamase inhibitors,
Bacterial Infections


tazobactam
Urinary tract infections, Pyelonephritis, Nosocomial
Cell wall inhibitors



pneumonia


Ceftriaxone
Pelvic inflammatory disorders, Respiratory tract
Cell wall inhibitors
Bacterial Infections


injectable
infections, Skin and soft tissue infections, Otitis



media, Gonorrhoea, Bone and joint infections,



Epididymitis, Urinary tract infections, Meningococcal



infections


Cidofovir
Cytomegalovirus retinitis, Cystitis, Polyomavirus
DNA-directed DNA
Cancer, Genitourinary



infections, Herpes simplex virus infections, Human
polymerase inhibitors,
Disorders, Rheumatic



papillomavirus infections, Kaposi's sarcoma, Viral
Immunomodulators
Disease, Viral Infections



infections, Molluscum contagiosum, Cancer, Rheumatic



disorders


Delafloxacin
Skin and soft tissue infections, Community-acquired
DNA gyrase inhibitors,
Bacterial Infections



pneumonia, Nosocomial pneumonia, Urinary tract
DNA topoisomerase



infections, Intra-abdominal infections, Gonorrhoea,
IV inhibitors



Acute exacerbations of chronic bronchitis, Anthrax


Doripenem
Gram-positive infections, Gram-negative infections,
Cell wall inhibitors
Bacterial Infections



Paediatric infections, Intra-abdominal infections,



Urinary tract infections, Meningococcal infections,



Nosocomial pneumonia, Respiratory tract infections,



Pneumonia, Bacterial infections


Eravacycline
Urinary tract infections, Intra-abdominal infections,
Protein 30S ribosomal
Bacterial Infections



Respiratory tract infections
subunit inhibitors


Fosfomycin
Urinary tract infections, Intra-abdominal infections,
Cell wall inhibitors,
Bacterial Infections


intravenous -
Skin and soft tissue infections, Pseudomonal infections
Peptidoglycan inhibitors


Zavante


Therapeutics


Gentamicin
Postoperative infections, Diabetic foot ulcer
Protein 30S ribosomal
Bacterial Infections,


implant -

subunit inhibitors
Drug Delivery Systems,


Innocoll


Skin Disorders


Iclaprim
Skin and soft tissue infections, Nosocomial infections,
Tetrahydrofolate
Bacterial Infections,



Nosocomial pneumonia, Gonorrhoea, Chlamydial infections
dehydrogenase inhibitors
Mycoses


Isavuconazonium
Aspergillosis, Zygomycosis, Candidiasis, Mycoses
14-alpha demethylase
Mycoses




inhibitors


Lefamulin
Community-acquired pneumonia, Skin and soft tissue
Peptidyltransferase
Bacterial Infections



infections, Bone and joint infections,
modulators, Protein



Osteomyelitis, Sexually transmitted infections,
50S ribosomal subunit



Nosocomial pneumonia
modulators


Letermovir
Cytomegalovirus infections
Cytomegalovirus
Viral Infections




replication inhibitors


Levofloxacin
Respiratory tract infections, Skin and soft tissue
DNA gyrase
Bacterial Infections,



infections, Prostatitis, Bacterial infections, Urinary
inhibitors, Type
Viral Infections



tract infections, Acute sinusitis, Acute exacerbations
II DNA topoisomerase



of chronic bronchitis, Community-acquired pneumonia,
inhibitors



Anthrax, Nosocomial pneumonia, Sinusitis, Pneumonia,



Pyelonephritis, Postoperative infections, Tuberculosis,



Gynaecological infections


Linezolid
Vancomycin-resistant enterococcal infections, Nosocomial
Protein 30S ribosomal
Bacterial Infections



pneumonia, Nosocomial infections, Diabetic foot ulcer,
subunit inhibitors



Gram-positive infections, Methicillin-resistant




Staphylococcus aureus infections, Community-acquired




pneumonia, Skin and soft tissue infections, Bacterial



infections


Meropenem
Febrile neutropenia, Bacterial infections, Community-
Cell wall inhibitors
Bacterial Infections



acquired pneumonia, Skin and soft tissue infections


Meropenem - B
Skin and soft tissue infections, Intra-abdominal
Cell wall inhibitors
Bacterial Infections


Braun Medical
infections, Bacterial meningitis


Meropenem/
Pyelonephritis, Bacteraemia, Gram-negative infections,
Beta lactamase
Bacterial Infections,


vaborbactam
Urinary tract infections, Pneumonia
inhibitors, Cell
Genitourinary Disorders




wall inhibitors


Minocycline IV -
Gram-positive infections, Gram-negative infections
Glial cell inhibitors,
Bacterial Infections


Rempex

Protein 30S ribosomal


Pharmaceuticals

subunit inhibitors


Moxifloxacin
Intra-abdominal infections, Acute exacerbations of
Type II DNA
Bacterial Infections



chronic bronchitis, Community-acquired pneumonia,
topoisomerase



Skin and soft tissue infections, Acute sinusitis,
inhibitors



Bacterial infections, Respiratory tract infections,



Pelvic inflammatory disorders, Plague, Tuberculosis


Moxifloxacin
Community-acquired pneumonia, Intra-abdominal
Type II DNA
Bacterial Infections


injection
infections, Acute exacerbations of chronic bronchitis,
topoisomerase



Skin and soft tissue infections, Acute sinusitis
inhibitors


Omadacycline
Skin and soft tissue infections, Community-acquired
Protein synthesis
Bacterial Infections



pneumonia, Urinary tract infections, Nosocomial
inhibitors



infections, Acute sinusitis, Anthrax, Plague


Oseltamivir
Influenza virus infections
Neuraminidase inhibitors
Viral Infections


Peramivir
Influenza A virus H1N1 subtype, Influenza virus
Neuraminidase inhibitors
Viral Infections



infections


Plazomicin
Urinary tract infections, Bacteraemia, Pyelonephritis,
Protein synthesis
Bacterial Infections



Nosocomial pneumonia, Gram-negative infections,
inhibitors



Respiratory tract infections, Yersinia infections,



Tularaemia


Ropeginterferon
Polycythaemia vera, Essential thrombocythaemia,
Interferon alpha 2b
Cancer, Haematological


alfa-2b
Hepatitis B, Hepatitis C, Myelofibrosis, Chronic
stimulants
Disorders, Viral



myeloid leukaemia, Cancer

Infections


Rose bengal
Malignant melanoma, Psoriasis, Atopic dermatitis,
Cell death stimulants,
Cancer, Skin Disorders


sodium
Liver metastases, Hepatocellular carcinoma, Breast
Cell membrane modulators,



cancer, Neuroendocrine tumours, Acne vulgaris
Immunostimulants


Solithromycin
Community-acquired pneumonia, Chlamydial infections,
Protein 50S ribosomal
Bacterial Infections,



Gonorrhoea, Urethritis, Chronic obstructive pulmonary
subunit inhibitors
Liver Disorders,



disease, Non-alcoholic steatohepatitis,

Parasitic Infections,



Otorhinolaryngological infections, Tularaemia,

Respiratory Tract



Bacterial infections, Anthrax, Obstetric and

Disorders



gynaecological infections, Otitis media, Cystic



fibrosis, Mycoplasma infections, Legionella infections,



Enterococcal infections, Mycobacterium avium complex



infections, Malaria


Tedizolid
Skin and soft tissue infections, Nosocomial pneumonia,
Ribosomal protein
Bacterial Infections



Bacteraemia, Gram-positive infections
inhibitors









In some embodiments, the therapeutic agent is selected from Gentamicin, Tobramycin, Amikacin, Kanamycin, Neomycin, Netilmicin, Paromomycin, Spectinomycin, Ampicillin, Ampicillin-sulbactam, Azithromycin, Aztreonam, Benzathine Penicillin, Cefotaxime, Ceftaroline, Fosamil, Ceftriaxone, Ciprofloxacin, Clindamycin, Doxycycline, Ertapenem, Imipenem-cistlastin, Levofloxacin, Merropenem, Metronidazole, Moxifloxacin, Rifampin, Tigecycline, Vancomycin, Oritavancin, Tedizolid, Telavancin Nafcillin, or Oxacillin; or a pharmaceutically acceptable salt thereof.


In some embodiments, the therapeutic agent is one of those in Table 3, below; or a pharmaceutically acceptable salt thereof.









TABLE 3







Exemplary Therapeutic Agents and Associated Diseases and Disorders











Active
Target-based



Drug Name
Indications
Actions
Structure





immunosuppressant,





Panax





IC-101

Cell adhesion





molecule inhibitor



P-21





WF-10917





reblastatin





CKD-461





sulfircin analogs, GPC

Hydrolase inhibitor; Protein phosphatase inhibitor


embedded image







AZD-2315





curdlan sulfate





SCH-204698

CD80 antagonist;





T cell surface





glycoprotein CD28





inhibitor



TAK-603








terprenin derivatives, Shionogi




embedded image







microcolins, RCT




embedded image







IMPDH inhibitors

Inosine



(transplant

monophosphate



rejection/rheumatoid

dehydrogenase



athritis), c-a-i-r

inhibitor



biosciences





PMI-001

Cyclooxygenase 2





inhibitor; IL-2





antagonist;





Inducible nitric





oxide synthase





inhibitor;





Interleukin-1 beta





ligand inhibitor;





TNF alpha ligand





inhibitor



APS-2010





alkaloidal





immunosuppresants,





C-TRI





kanglemycin C





(immune diasease),





Henan Topfond





Pharmaceutical





kirenol (rheumatoid
Rheumatoid




arthritis), Peking
arthritis




University Health





Science Center





glucocorticoid/rIL-2
Immune disorder;
Glucocorticoid



(inflammation/immune-
Inflammatory
agonist; IL-2



mediated
disease;
agonise;



disorders/transplant
Transplant
Interleukin-2 ligand



rejection), NCI
rejection




T-cell targeted anti-

Lck tyrosine



Lck SH2 agents

kinase inhibitor



(rheumatoid





arthritis), Mogam





tacrolimus
Atopic dermatitis
Calcineurin



(transdermal

inhibitor



nanoscale lipid





emulsion





ointment/Nanoaqualip,





atopic dermatitis),





Jina





Pharmaceutical/Intas





Pharmaceuticals





tacrolimus
Organ
Calcineurin



(intravenous
transplantation
inhibitor



nanosomal lipid





suspension/Nanoaqua-





lip, organ





transplantation),





Jina





Pharmaceuticals/Intas





Pharmaceuticals





GPCR modulators
Autoimmune
Unspecified GPCR



(neurodegenerative
disease;
modulator



disease/autoimmune
Metabolie




disease/metabolic
disorder;




disease),
Neurodegenerative




GinkgoPharma
diasease




thiopalmitoylated





peptides





(autoimmune





disease), University





of Queensland





mometasone furoate
Atopic dermatitis;




(topical foam,
Dermatological




psoriasis/atopic
disease;




dermatitis), Foamix
Psoriasis







vioprolides (inflammatory/auto- immune disease), HZI




embedded image







triptolide
Autoimmune





disease




MDX-3
Systemic lupus





erythematosus




low molecular
Islet cell




weight dextran
transplant




sulfate (intravenous,
rejection




islet cell transplant





rejection), TikoMed





tacrolimus
Organ
Calcineurin



(oral/nanosomal/lipid
transplantation
inhibitor



suspension/Nanoaqua-





lip, transplantation),





Jina





Pharmaceuticals/Intas





Pharmaceuticals








higher fatty acids (cancer/transplantation on rejection), Xiamen University/Guangxi Normal University
Cancer; Transplant rejection



embedded image







REC-200

Glucocorticoid





antagonist



ciclosporin +

Calcineurin



prednisolone

inhibitor;



(allergic

Glucocorticoid



conjunctivitis),

agonist



CombinaoRx/Fovea





oxfenmino

Cannabinoid



hydrochloric acid

receptor





antagonist;





Sphingosine-1-





phosphate





receptor-1 agonist



RDP-58

IL12 gene





inhibitor; Interferon





gamma receptor





antagonist; p38





MAP kinase





inhibitor



PBI-1308

Immunoglobulin G



(dermatological,

modulator



dermatological





diseases),





Darier/ProMetic





EndoS
Autoimmune
Unspecified




disease;
enzyme stimulator




Transplant





rejection




prednisone (oral,
Inflammatory
Glucocorticoid



delayed release),
disease;
agonist



Horizon/Mundiphar-
Rheumatoid




ma
arthritis; Systemic





lupus





erythematosus




cannabidiol (graft
Graft versus host




versus host
disease




disease), Kalytera





Therapeutics





ciclosporin (lipid
Brain injury;
Calcineurin



emulsion, brain
Myocardial
inhibitor; Peptidyl-



injury/myocardial
infarction;
prolyl cis-trans



infarction),
Traumatic brain
isomerase D



NeuroVive
injury
inhibitor



Ampion
Chronic
Stem cell antigen-




obstructive
1 inhibitor




pulmonary





disease; Crohns





disease;





Osteroarthritis




LLDT-8
HIV infection;





Rheumatoid





arthritis




tacrolimus
Bone marrow
Calcineurin




transplantation;
inhibitor




Heart





transplantation;





IgA nephropathy;





Kidney





transplantation;





Liver





transplantation;





Lung





transplantation;





Lupus nephritis;





Myasthenia





gravis;





Pneumonia;





Rheumatoid





arthritis;





Transplant





rejection;





Ulcerative colitis




voclosporin
Autoimmune
Calcineurin




disease; Kidney
inhibitor; IL-2




transplant
antagonist




rejection; Lupus





nephritis;





Psoriasis; Renal





disease;





Transplant





rejection; Uveitis







text missing or illegible when filed








In some embodiments, the therapeutic agent is one of those in Table 4, below; or a pharmaceutically acceptable salt thereof.









TABLE 4







Exemplary Therapeutic Agents and Associated Diseases and Disorders











Active
Target-based



Drug Name
Indications
Actions
Structure





YM-13650





L-683742








ruthenium complexes, Procept




embedded image







PIC-060 analogs





SC-114





oligomycin-F,





Boehringer





Mannheim





L-755860

Potassium





channel inhibitor



NP-2214





pyrazole





immunosuppressants,





Abbott





TAN-2178

IL-1 antagonist



mycophenolic acid





derivatives, Abbott





L-732531





purine nucleoside

Purine nucleoside



phosphorylase

phosphorylase



inhibitors, Merrell

inhibitor



Dow








p56Ick inhibitors (phenylaminopyrimidines), Celltech

Zap70 tyrosine kinase inhibitor


embedded image







T-cell modulators,





Lund Research





Center





NE-501





cathepsin C

Dipeptidyl



inhibitors, Axys

peptidase I





inhibitor



PIC-060





IML-1, Incyte
Autoimmune





disease; Multiple





sclerosis;





Transplant





rejection




Bi-51013





Fas delta therapy,





LXR Biotechnology





WF-10917





LXR-015-2

Carnitine





palmitoyltransferase





modulator



CT-3578





ISP-I-55





interleukin-12

JAK tyrosine



modulators

kinase inhibitor



(transplant





rejection/autoimmune





disease), Ligand





DHODH inhibitors,

Dehydrogenase



Procept

inhibitor



SKF-105685





AlloMune





Win-17317-3

Potassium





channel inhibitor



MC-1288

Vitamin D3





receptor agonist






MC-1301

Vitamin D3 receptor agonist


embedded image







specific HLA binding





inhibitors, Avidex





CKD-461





TAN-2451 analogs,





Takeda





IR-1116








TNFalpha-induced apoptosis inhibitors, Genzyme

TNF alpha ligand inhibitor


embedded image







roquinimex analogs, Fujisawa




embedded image







B-975

TNF antagonist






Lck kinase inhibitors, Boehringer

Lck tyrosine kinase inhibitor


embedded image







Xenocarb





KF-20444

Dihydroorotate





dehydrogenase





inhibitor



immune system





regulator, Hollis-





Eden








Lck tyrosine kinase inhibitors, AstraZeneca

Lck tyrosine kinase inhibitor


embedded image







CD45 inhibitors, AstraZeneca

CD45 antagonist; Protein tyrosine phosphatase inhibitor


embedded image







LG293 inhibitors,

Unspecified



Lexicon

enzyme inhibitor



rapamycin

mTOR inhibitor



derivatives, SB





ICAM-3 antibodies,

Cell adhesion



ICOS

molecule inhibitor






mRNA modulating agents, PTC Therapeutics




embedded image







ZAP inhibitors,

Zap70 tyrosine



ARIAD

kinase inhibitor






NFAT transcription factor regulator, Abbott

IL2 gene inhibitor; IL4 gene inhibitor; IL5 gene inhibitor; IL8 gene inhibitor


embedded image







NIBR-0071

IL-2 antagonist; IL-





2 receptor alpha





subunit inhibitor;





TNF alpha ligand





inhibitor



SCH-204698

CD80 antagonist;





T cell surface





glycoprotein CD28





inhibitor



ISP-1/myriocin





analogs, Yoshitomi





VLA-4 inhibitors,

Integrin alpha-



Novartis

4/beta-1





antagonist






B7-1 inhibitors, Wyeth

CD80 antagonist; Cytotoxic T- lymphocyte protein-4 inhibitor; T cell surface glycoprotein CD28 inhibitor


embedded image







FR-901483








B-cell immunosuppressants (transplant rejection), Novartis




embedded image







B-220




embedded image







oral





immunomodulators,





Enzo








radicicol derivatives, Kyowa

Hsp 90 modulator


embedded image







NSC-651016

CCR1 chemokine





antagonist; CCR3





chemokine





antagonist; CCR5





chemokine





antagonist;





CXCR4





chemokine





antagonist



IPL-423 series,





Inflazyme





transplantation





therapy, 4SC





CD46 cofactor,

Complement



Austin Research

cascade inhibitor;





Membrane





cofactor protein





modulator



CXCR3 antagonist

CXCR3



(transplant

chemokine



rejection), Merck &

antagonist



Co





tyrosine

Protein



phosphatase

phosphatase



modulators

modulator



(allergy/autoimmune





disease/cancer/trans-





plant rejection),





Cerylid








Ick inhibitors, Abbott

Lck tyrosine kinase inhibitor


embedded image







Lck tyrosine kinase inhibitors, BMS

Lck tyrosine kinase inhibitor


embedded image







delta opioid

Opioid receptor



antagonists

delta antagonist



(immunosuppression),





Adolor








toxin based therapeutics, BRI

Calcium channel inhibitor; Potassium channel inhibitor


embedded image







TJU-103





interleukin-17

IL-17 receptor



receptor, Immunex

modulator



KB-R7785

Matrix





metalloprotease





inhibitor



VLA-4/VCAM

Integrin alpha-



antagonists

4/beta-1



(inflammation),

antagonist;



Elan/Wyeth

Vascular cell





adhesion protein 1





modulator



VLA-4 inhibitors,

Selectin



Cytel

antagonist



T-cell receptor,

CD3 agonist



Procept





CD4/CD2 inhibitors,





Procept/Sandoz





alpha-Gal PEG





conjugates, Nextran





Xenoject





Allotrap-2702





4AZA-IS





anti-inflammatories,

Cell adhesion



Genetics Institute

molecule inhibitor;





Phospholipase A2





inhibitor



KRX-211

Jak3 tyrosine





kinase inhibitor



LFA-1 inhibitors

CD11a antagonist;



(autoimmune

Integrin antagonist



diseases),





Tanabe/Novartis





TSK-204





protein kinase C

Protein kinase C



modulators, Terrapin

modulator



ACEA-1021

NMDA glycine





antagonist



HMR-1279

Dihydroorotate





dehydrogenase





inhibitor



immunosuppressant

CD95 agonist;



(CD95), CERES

PARP inhibitor



immunotherapy, ML





Laboratories








CCR5 antagonists (HIV/Transplant Rejection), Merck & Co

CCR5 chemokine antagonist; CXCR5 chemokine antagonist


embedded image







NP-005





FTA-2062

EP4 prostanoid





receptor agonist



TG-4








IMPDH II inhibitors, UCB Celltech

Inosine monophosphate dehydrogenase 2 inhibitor


embedded image







sirolimus (oral,

mTOR inhibitor



controlled-release,





transplant rejection),





LifeCycle Pharma








PDE 7 inhibitors (autoimmune disease), BMS

PDE 7 inhibitor


embedded image







NK-10958P





FR-260330

Inducible nitric





oxide synthase





inhibitor



elsibucol

Vascular cell





adhesion protein 1





antagonist



LJP-920





Genz-29155

TNF alpha ligand





inhibitor



zolimomab aritox








podofilox derivatives, PharmaMar




embedded image







AZ-4175





Prosorba
Rheumatoid





arthritis;





Thrombocytopenic





purpura




IMPDH inhibitors

Inosine



(transplant

monophosphate



rejection/rheumatoid

dehydrogenase



athritis), c-a-i-r

inhibitor



biosciences





monocarboxylate-1

Monocarboxylate



transporter (MCT1)

transporter-1



inhibitor (transplant

inhibitor



rejection),





AstraZeneca








apoptosis stimulators, Hughes Institute

Jak3 tyrosine kinase inhibitor


embedded image







JWH-015

Cannabinoid CB2





receptor agonist



JWH-051

Cannabinoid CB2





receptor agonist;





Cannabinoid





receptor agonist



O-823

Cannabinoid





receptor agonist



O-585

Cannabinoid





receptor agonist;





Cell adhesion





molecule inhibitor



O-689

Cannabinoid





receptor agonist



TKB-662





immunosuppressants





(bone marrow-





derived engineered





veto cells, allogenic





transplant rejection),





Isogenis





PD-184352

MEK-1 protein





kinase inhibitor



ZK-203278

Vitamin D3





receptor agonist



ZK-261991

Kit tyrosine kinase





inhibitor; VEGF-2





receptor





antagonist; VEGF-





3 receptor





antagonist






interleukin-2 antagonists (graft- versus-host disease), Sunesis

IL-2 antagonist






EGS-21

Insulin sensitizer



CCR5 antagonists,

CCR5 chemokine



Novartis

antagonist



alkaloidal





immunosuppresants,





C-TRI





AD-412

Jak3 tyrosine





kinase inhibitor



JNKK modulators,

Protein kinase



Celgene

inhibitor



multimeric cell-

Cell adhesion



binding compounds

molecule



(cardiovascular

stimulator



disease/transplant





rejection/renal





failure/stroke),





Repair Technologies





BXL-01-0029

CXCL10 gene





inhibitor



BLNP-007





TAFA-93

mTOR inhibitor



PG-140

CD86 antagonist



PTL-101

TGF beta





antagonist



VR-909





azathioprine (oral





liquid, rheumatoid





arthritis/GVHD),





DOR BioPharma





R-524

Protein kinase C





theta inhibitor



AS-2643361

Inosine





monophosphate





dehydrogenase





inhibitor



mycophenolate
Kidney transplant
Inosine



sodium (modified
rejection
monophosphate



release tablets,

dehydrogenase



Kidney transplant

inhibitor



rejection), Panacea





Biotec





small molecule





therapy (transplant





rejection), SEEK





Aom-0871





IKappaB kinase

I-kappa B kinase



(IKK) inhibitors,

beta inhibitor



BMS





HPH-116
Allergy; Genital
HIV p7




tract infection;
nucleocapsid




HIV infection;
protein inhibitor; T-




Inflammatory
cell surface




disease;
glycoprotein CD8




Transplant
modulator




rejection




CS-0777

Sphingosine-1-





phosphate





receptor-1





modulator



NK-026680
Graft versus host





disease




immunomodulators,





T Cell/Repligen





TAQ-588

IL-4 antagonist;





TNF alpha ligand





inhibitor



immunomodulators,





Mycosearch/T Cell





Sciences








enisoprost

Prostanoid receptor agonist


embedded image







CWF-0808
Transplant





rejection




c-Rel inhibitors
Autoimmune
C-Rel proto-



(cancer/inflammatory
disease; Cancer;
oncogene protein



disease/autoimmune
Inflammatory
inhibitor



diseases/transplantation
disease;




rejection),
Transplant




Cornell University
rejection




ciclosporin

Calcineurin



(aerosolized

inhibitor



liposomes,





transplant rejection),





Alulim





tacrolimus





(oral/FDT),





Samyang Corp








transmethylator inhibitor (oral, MS/transplant rejection) Digna

Methyltransferase inhibitor


embedded image







protein kinase C inhibitors (autoimmune disease/allograft injection), Novartis Institutes for BioMedical Research

Protein kinase C delta inhibitor; Protein kinase C epsilon inhibitor; Protein kinase C eta inhibitor; Protein kinase C theta inhibitor


embedded image







ETR-001

Complement





cascade inhibitor



AS-1896596

Histone





deacetylase





inhibitor



SHIP inhibitors

SH2 domain



(GVHD/transplant

inositol



rejection), H Lee

phosphatase



Moffitt Cancer

inhibitor



Center and





Research Institute





KAR-2581

Histone





deacetylase





inhibitor



NOX-100
Hypotension;





Respiratory





distress





syndrome;





Sepsis; Septic





shock




leflunomide (oral
BK virus
Dihydroorotate



tablet, rheumatoid
infection; Kidney
dehydrogenase



arthritis/lupus
transplant
inhibitor



nerphritis/kidney
rejection; Lupus




transplant rejection),
nephritis;




Suzhou
Rheumatoid




Changzheng-Xinkai
arthritis




Pharmaceutical





FFP-106

CD40 ligand





inhibitor; CD40





ligand receptor





antagonist



AS-2521780

Protein kinase C





theta inhibitor



low molecular
Islet cell




weight dextran
transplant




sulfate (intravenous,
rejection




islet cell transplant





rejection), TikoMed





HS-378
Atopic dermatitis;
Calcineurin




Psoriasis;
inhibitor; Opioid




Rheumatoid
receptor delta




arthritis
antagonist



vasoactive intestinal
Graft versus host
VIP antagonist



peptide antagonist
disease




(graft-vs-host





disease), Emory





University





VEGFR3/VLA-1
Corneal
CD49a antagonist;



inhibitors (corneal
transplant
VEGF-3 receptor



transplant rejection),
rejection
antagonist



University of





California at





Berkeley





BLHP-008
Erythema
Glucocorticoid





agonist



p-ATT (type 1/2

Alpha 1 antitrypsin



diabetes/influenza/

modulator;



tuberculosis/anthrax/

Caspase-3



HIV

inhibitor; Elastase



infection/transplant

inhibitor;



rejection/GVHD),

Interleukin-1



Omni Bio

converting





enzyme inhibitor;





Serine protease





inhibitor; Trypsin





inhibitor



immunomodulator





(graft versus host





disease/solid organ





transplantation),





Destum Partners Inc








CXCR3 antagonists (autoimmune diseases), Ligand Pharmaceuticals/ Merck Research Laboratories

CXCR3 chemokine antagonist


embedded image







NYK-1341
Kidney transplant
Hsp 70 stimulator




rejection; Renal





injury







NF-kappaB subunit c-Rel inhibitors, ImmuneTarget
Chronic lymphocytic leukemia; Diffuse large B-cell lymphoma; Graft versus host disease; Multiple myeloma; Multiple sclerosis; Organ transplantation
C-Rel proto- oncogene protein inhibitor


embedded image







mucosa-associated
B-cell lymphoma;
MALT protein 1



lymphoid tissue
Cancer
inhibitor; MALT



lymphoma

protein 1



translocation protein

modulator



1 inhibitor (B-cell





lymphoma),





University of





Lausanne/MRC





Technology





Jak-STAT signal

JAK tyrosine



transduction

kinase inhibitor;



pathway inhibitors

STAT inhibitor



(transplant





rejection/autoimmune





diseases), NHLBI





tacrolimus
Transplant
Calcineurin



(sustained release
rejection
inhibitor



subcutaneous





suspension, Plexis,





graft rejection),





Auritec





eritoran

TLR-4 antagonist






Kv1.3 potassium channel blockers, AstraZeneca

Potassium channel inhibitor


embedded image







RTU-009, graft-
Graft versus host
Membrane copper



versus-host disease
disease
amine oxidase





inhibitor






higher fatty acids (cancer/transplantation rejection), Xiamen University/Guangxi Normal University
Cancer; Transplant rejection



embedded image







dihydroorotate

Dihydroorotate



dehydrogenase

dehydrogenase



(DHODH) inhibitors

inhibitor



(oral, autoimmune





disease/transplant





rejection), H





Lundbeck A/S





IB-08C175
Multiple sclerosis




LT-1945





BX-471

CCR1 chemokine





antagonist






synthetic cyclic AMP derivatives (immune disorders), Immune Modulation

cAMP modulator


embedded image







LT-1951

Graft versus host





disease



Iadarixin
Insulin dependent
CXCR1




diabetes
chemokine





antagonist;





CXCR2





chemokine





antagonist; IL-8





antagonist



AER-270
Transplant
Aquaporin 4




rejection
inhibitor






immunoproteasome inhibitor (transplant rejection), Harvard Medical School/Weill Cornell Medicine
Transplant rejection
Proteasome beta- 5 subunit inhibitor


embedded image







MALT1 inhibitors

MALT protein 1



(cancer/inflammation/

inhibitor; NF



transplant

kappa B activating



rejection/autoimmune

protein stimulator



diseases), KU





Leuven/Catholic





University of





Leuven/AstraZeneca





R-548
Dermatological
Jak3 tyrosine




disease
kinase inhibitor



ulodesine

Purine nucleoside





phosphorylase





inhibitor



MRx-109
Rheumatoid





arthritis;





Transplantation




KZR-616
Autoimmune
Proteasome




disease
inhibitor






JAK3 tyrosine kinase inhibitors (autoimmune disease, transplant rejection), Cytopia/Novartis

Jak3 tyrosine kinase inhibitor


embedded image







compound A (graft versus host disease), Theralogics

IKK complex associated protein inhibitor






NF-kB/AP-1 inhibitor, Tanabe

AP1 transcription factor inhibitor; Nuclear factor kappa B inhibitor


embedded image







RDP-58

IL12 gene





inhibitor; Interferon





gamma receptor





antagonist; p38





MAP kinase





inhibitor



MRx-108

Transcription





factor inhibitor



bardoxolone (iv;

Transcription



inflammation,

factor modulator;



cancer), Reata

Unspecified





growth factor





receptor





modulator



SUDCA,





Axcan/CHRF





elocalcitol

Unspecified





growth factor





antagonist;





Vitamin D3





receptor agonist



transplant rejection





therapy, Praxis





XE-9





vidofludimus
Autoimmune
AKT1 gene




disease; Crohns
inhibitor;




disease;
Dihydroorotate




Inflammatory
dehydrogenase




bowel disease;
inhibitor; IL-17




Rheumatoid
antagonist; JAK2




arthritis; Systemic
gene inhibitor;




lupus
STAT3 gene




erythematosus;
inhibitor




Transplant





rejection;





Ulcerative colitis




autoimmune disease





therapy, BEXEL





Pharmaceuticals





brequinar

Dehydrogenase





inhibitor






brequinar analogs




embedded image







Improx





tresperimus





cyclophosphamide





(high dose,





autoimmune





disorders), Accentia





tacrolimus (oral
Graft versus host
Calcineurin



sustained-release),
disease; Intestine
inhibitor



Astellas
transplantation;





Kidney transplant





rejection; Liver





transplant





rejection;





Transplant





rejection




C-87
Graft versus host
TNF alpha ligand




disease
inhibitor



GB-301
Corneal





transplant





rejection




sotrastaurin
Diffuse large B-
Protein kinase C




cell lymphoma;
alpha inhibitor;




Uveal melanoma
Protein kinase C





beta inhibitor;





Protein kinase C





delta inhibitor;





Protein kinase C





epsilon inhibitor;





Protein kinase C





eta inhibitor;





Protein kinase C





theta inhibitor



APH-703 (iv,
Alzheimers
Protein kinase C



Alzheimer's
disease
stimulator



disease), Aphios





NADPH oxidase
Age related
NADPH oxidase



inhibitors (dry AMD),
macular
inhibitor



Alimera
degeneration




mizoribine
Lupus nephritis;
Inosine




Nephrotic
monophosphate




syndrome;
dehydrogenase




Rheumatoid
inhibitor




arthritis;





Transplant





rejection




GCS-100 (iv, end

Cell adhesion



stage renal

molecule inhibitor;



disease/renal

Galectin-3 inhibitor



transplantation/cancer),





La Jolla





Pharmaceutical





mocravimod
Crohns disease;
Sphingosine-1-



dihydrochloride
Graft versus host
phosphate




disease;
receptor-1 agonist




Transplant





rejection




RGI-2001
Graft versus host





disease;





Hemophilia;





Lysosome





storage disease




reparixin
Breast tumor;
CXCR1




Cancer; Islet cell
chemokine




transplant
antagonist;




rejection; Kidney
CXCR2




transplant
chemokine




rejection; Liver
antagonist; IL-8




transplant
antagonist




rejection; Lung





transplant





rejection;





Metastatic breast





cancer




TM-5509
Obesity; Stem





cell





transplantation;





Transplant





rejection





lactobacillus

Graft versus host





plantarum strain

disease




299v (GvHD),





National Cancer





Institute






Lactobacillus

Graft versus host





plantarum strain 299

disease




(graft versus host





disease), National





Cancer Institute





CRAC inhibitors
Autoimmune
Ca2+ release



(transplant
disease;
activated Ca2+



rejection/autoimmune
Transplant
channel 1 inhibitor



disease), Johns
rejection




Hopkins University





triciribine (iv,
Acute
AKT protein



breast/ovarian
myelogenous
kinase inhibitor



cancer/AML),
leukemia; Breast




Prescient
tumor; Leukemia;





Ovary tumor;





Solid tumor




gusperimus
Lupus nephritis;
Hsp 70 family



trihydrochloride
Transplant
inhibitor




rejection;





Wegener





granulomatosis




tacrolimus
Kidney transplant
Calcineurin



(improved tablet
rejection; Liver
inhibitor



formulation),
transplant




Veloxis/Chiesi
rejection




fingolimod
Multiple sclerosis;
Cannabinoid




Optic neuritis;
receptor




Rett syndrome;
antagonist;




Uveitis
Sphingosine-1-





phosphate





receptor-1





modulator



KD-025
Graft versus host
IL-17 antagonist;




disease;
Rho associated




Hepatocellular
protein kinase 2




carcinoma;
inhibitor




Idiopathic





pulmonary





fibrosis; Lupus





nephritis; Non-





alcoholic





steatohepatitis;





Psoriasis;





Rheumatoid





arthritis; Spinal





cord injury;





Systemic lupus





erythematosus




peficitinib
Dermatological
JAK tyrosine




disease;
kinase inhibitor;




Rheumatoid
Jak1 tyrosine




arthritis
kinase inhibitor;





Jak3 tyrosine





kinase inhibitor



cenicriviroc
HIV associated
CCR2 chemokine




dementia; Liver
antagonist; CCR5




fibrosis; Liver
chemokine




injury; Non
antagonist




alcoholic fatty





liver disease;





Non-alcoholic





steatohepatitis;





Primary





sclerosing





cholangitis




beclomethasone
Crohns disease;
Glucocorticoid



dipropionate (oral,
Enteritis;
agonist



acute radiation
Gastrointestinal




syndrome/Crohn's
inflammation;




Disease/radiation
Radiation




enteritis), Soligenix
sickness;





Ulcerative colitis




dual aurora kinase
Graft versus host
Aurora protein



A/JAK2 inhibitors
disease
kinase 2 inhibitor;



(GvHD), H Lee

Jak2 tyrosine



Moffitt Cancer

kinase inhibitor



Center and





Research Institute





2-Se-Cl
Graft versus host
P-Glycoprotein




disease
stimulator



cannabidiol (graft
Graft versus host




versus host
disease




disease), Kalytera





Therapeutics





echinomycin
Acute
Hypoxia inducible



(AML/GVHD),
myelogenous
factor inhibitor



Oncolmmune
leukemia; Graft





versus host





disease




PKX-001
Dermatitis;
Cell adhesion




Inflammatory
molecule inhibitor




disease; Insulin





dependent





diabetes; Islet





cell transplant





rejection; Ocular





inflammation




peldesine

Purine nucleoside





phosphorylase





inhibitor



budesonide
Colitis; Crohns
Glucocorticoid



(gastroresistant
disease;
agonist



capsule, Crohn's
Ulcerative colitis




disease/ulcerative





colitis), Dr Falk





Pharma/Salix





manitimus

Dihydroorotate





dehydrogenase





inhibitor



telmisartan (graft
Graft versus host




versus host
disease




disease),





Hackensack





University Medical





Center





arsenic trioxide
Graft versus host




(intravenous,
disease;




autoimmune
Systemic lupus




disease), Medsenic
erythematosus




HBI-002
Ischemic stroke;





Kidney transplant





rejection; Sickle





cell anemia;





Traumatic brain





injury




NFATc1
Graft versus host
T-cell transcription



SUMOylation
disease
factor NFAT1



blockers (GvHD),

modulator



Pfizer/Würzburg





University/New York





University School of





Medicine





pentostatin
Chronic
Adenosine




lymphocytic
deaminase




leukemia; Hairy
inhibitor




cell leukemia




emricasan (oral, islet
Alcoholic
Caspase inhibitor



transplant
hepatitis;




rejection/liver
Idiopathic




disease), Novartis
pulmonary





fibrosis; Liver





cirrhosis; Liver





failure; Non-





alcoholic





steatohepatitis;





Portal





hypertension;





Renal failure




entospletinib
Acute
Syk tyrosine




myelogenous
kinase inhibitor




leukemia; B-cell





acute





lymphoblastic





leukemia;





Chronic





lymphocytic





leukemia; Diffuse





large B-cell





lymphoma; Graft





versus host





disease;





Macroglobulinemia;





Mantle cell





lymphoma;





Non-Hodgkin





lymphoma




everolimus
Acute
mTOR complex 1




lymphoblastic
inhibitor; mTOR




leukemia;
inhibitor




Advanced solid





tumor;





Angiomyolipoma;





Astrocytoma;





Bladder cancer;





Breast tumor;





Colorectal tumor;





Cutaneous T-cell





lymphoma;





Diffuse large B-





cell lymphoma;





Endometrioid





carcinoma;





Epilepsy;





Esophagus





tumor; Glioma;





Head and neck





tumor; Heart





transplant





rejection; Kidney





transplant





rejection; Liver





transplant





rejection; Lung





transplant





rejection;





Macroglobulinemia;





Medullary





thyroid cancer;





Metastatic breast





cancer;





Metastatic renal





cancer; Multiple





hamartoma





sydrome;





Neuroendocrine





tumor;





Neurofibromatosis





type I; Non-





Hodgkin





lymphoma; Non-





small-cell lung





cancer;





Pancreatic





endocrine tumor;





Renal cell





carcinoma; Solid





tumor; Stomach





tumor; Thyroid





tumor; Transplant





rejection; Uveal





melanoma




IRX-4204
Alzheimers
Beta amyloid




disease;
antagonist;




Autoimmune
Retinoid X




encephalomyelitis;
receptor agonist;




Cancer; Graft
Synuclein alpha




versus host
inhibitor; Tau




disease; Multiple
aggregation




sclerosis; Non-
inhibitor




small-cell lung





cancer;





Parkinsons





disease; Prostate





tumor




enteric-coated
Kidney transplant
Inosine



mycophenolate
rejection; Lupus
monophosphate



sodium, Novartis
nephritis;
dehydrogenase




Nephrotic
inhibitor




syndrome




pacritinib
Acute
CSF-1 antagonist;




myelogenous
Cytochrome P450




leukemia;
reductase




Chronic
inhibitor; Flt3




lymphocytic
tyrosine kinase




leukemia; Graft
inhibitor; IRAK-1




versus host
protein kinase




disease;
inhibitor; Jak2




Myelofibrosis;
tyrosine kinase




Thrombocytopenia
inhibitor



momelotinib

Jak1 tyrosine





kinase inhibitor;





Jak2 tyrosine





kinase inhibitor;





Serine threonine





protein kinase





TBK1 modulator



panobinostat (oral),
Advanced solid
Cytochrome P450



Novartis
tumor; Cancer;
2D6 inhibitor;




Glioma; Graft
Histone




versus host
deacetylase




disease; HIV-1
inhibitor; Histone




infection;
deacetylase-1




Hormone
inhibitor; Histone




refractory
deacetylase-2




prostate cancer;
inhibitor; Histone




Macroglobulinemia;
deacetylase-3




Multiple
inhibitor; Histone




myeloma;
deacetylase-6




Myelofibrosis;
inhibitor; JAK2




Neuroendocrine
gene inhibitor;




tumor; Non-
Orphan nuclear




small-cell lung
hormone receptor




cancer; Sickle
NR4A1 agonist




cell anemia;





Stage IV





melanoma




panobinostat
Breast tumor;
Histone



(intravenous),
Cancer; Graft
deacetylase



Novartis
versus host
inhibitor




disease;





Hormone





refractory





prostate cancer;





Small-cell lung





cancer




itacitinib
Advanced solid
Jak1 tyrosine




tumor; B-cell
kinase inhibitor




lymphoma;





Diffuse large B-





cell lymphoma;





Graft versus host





disease;





Hodgkins





disease;





Myelofibrosis;





Non-small-cell





lung cancer;





Pancreas tumor





Acute
Btk tyrosine




myelogenous
kinase inhibitor




leukemia; Allergic





rhinitis;





Autoimmune





disease; B-cell





acute





lymphoblastic





leukemia; B-cell





lymphoma;





Breast tumor;





Carcinoid tumor;





Chronic





lymphocytic





leukemia;





Colorectal tumor;





Diffuse large B-





cell lymphoma;





Follicle center





lymphoma; Graft





versus host





disease; Hairy





cell leukemia;





Lymphoplasmacy





toid lymphoma;





Macroglobulinemia;





Mantle cell





lymphoma;





Marginal zone B-





cell lymphoma;





Metastatic non





small cell lung





cancer;





Metastatic renal





cancer; Multiple





myeloma;





Neuroendocrine





tumor; Non-





Hodgkin





lymphoma;





Pancreas tumor;





Renal cell





carcinoma; Solid





tumor; Stomach





tumor; Systemic





mastocytosis; T-





cell lymphoma;





Transitional cell





carcinoma




ruxolitinib (oral,
Acute
Jak1 tyrosine



myeloproliferative
lymphoblastic
kinase inhibitor;



disorders),
leukemia; Acute
Jak2 tyrosine



Incyte/Novartis
myelogenous
kinase inhibitor




leukemia; B-cell





lymphoma;





Breast disease;





Cachexia;





Chronic





lymphocytic





leukemia;





Chronic





myelocytic





leukemia; Graft





versus host





disease; Head





and neck tumor;





Hodgkins





disease;





Leukemia;





Metastatic breast





cancer;





Myelofibrosis;





Polycythemia





vera;





Splenomegaly; T-





cell lymphoma;





Thalassemia





major;





Thrombocythemia




nilotinib
Acute
Abl tyrosine




lymphoblastic
kinase inhibitor;




leukemia; Acute
Bcr protein




myelogenous
inhibitor; DDR




leukemia;
tyrosine kinase




Alzheimers
receptor inhibitor;




disease; Cancer;
Kit tyrosine kinase




Chronic
inhibitor; PDGF




myelocytic
receptor




leukemia; Giant
antagonist




cell bone tumor;





Glioma; Graft





versus host





disease; Lewy





body dementia;





Parkinsons





disease;





Pigmented





villonodular





synovitis




pomalidomide
AL amyloidosis;





Cancer; Multiple





myeloma;





Myelofibrosis;





Scleroderma




bortezomib
Acute
26S proteasome




lymphoblastic
complex inhibitor;




leukemia; Acute
Proteasome




myelogenous
inhibitor




leukemia; Breast





tumor; Chronic





lymphocytic





leukemia; Diffuse





large B-cell





lymphoma; Graft





versus host





disease; Head





and neck tumor;





Hormone





refractory





prostate cancer;





Kidney transplant





rejection;





Macroglo-





bulinemia;





Mantle cell





lymphoma;





Multiple





myeloma;





Myelodysplastic





syndrome; Non-





Hodgkin





lymphoma; Non-





small-cell lung





cancer; Ovary





tumor; Peripheral





T-cell lymphoma;





Solid tumor;





Squamous cell





carcinoma; Stage





IV melanoma




imatinib
Acute
Abl tyrosine




lymphoblastic
kinase inhibitor;




leukemia;
Bcr protein




Aggressive
inhibitor; Kit




fibromatosis;
tyrosine kinase




Asthma; Chronic
inhibitor; PDGF




myelocytic
receptor




leukemia;
antagonist; Signal




Dermatofibro-
transduction




sarcoma;





Gastrointestinal
inhibitor




stromal tumor;





Hypereosinophilic





syndrome;





Myelodysplastic





syndrome;





Myeloid





leukemia;





Myeloproliferative





disorder;





Systemic





mastocytosis




tacrolimus
Bone marrow
Calcineurin




transplantation;
inhibitor




Heart





transplantation;





IgA nephropathy;





Kidney





transplantation;





Liver





transplantation;





Lung





transplantation;





Lupus nephritis;





Myasthenia





gravis;





Pneumonia;





Rheumatoid





arthritis;





Transplant





rejection;





Ulcerative colitis




ponesimod
Graft versus host
Sphingosine-1-




disease; Multiple
phosphate




sclerosis
receptor-1 agonist



tofacitinib citrate
Discoid lupus
JAK tyrosine



(oral, inflammation),
erythematosus;
kinase inhibitor;



Pfizer
Juvenile
Jak1 tyrosine




rheumatoid
kinase inhibitor;




arthritis;
Jak3 tyrosine




Psoriasis;
kinase inhibitor




Psoriatic arthritis;





Rheumatoid





arthritis; Systemic





lupus





erythematosus;





Ulcerative colitis




sirolimus
Chondrosarcoma;
mTOR inhibitor




Graft versus





host disease;





Kidney transplant





rejection;





Liposarcoma;





Lymphangioleio-





myomatosis;





Systemic lupus





erythematosus;





Tuberous





sclerosis




mycophenolate
Heart transplant
Inosine



mofetil
rejection; IgA
monophosphate




nephropathy;
dehydrogenase




Interstitial lung
inhibitor; PurH




disease; Kidney
purine




transplant
biosynthesis




rejection; Liver
protein inhibitor




transplant





rejection; Lung





transplant





rejection; Lupus





nephritis;





Pancreas





transplant





rejection;





Pemphigus;





Scleroderma;





Transplant





rejection




Ozanimod
Multiple sclerosis,





Ulcerative colitis,





Crohn's disease




Piclidenoson
Psoriasis,





Rheumatoid





arthritis,





Glaucoma,





Uveitis,





Osteoarthritis,





Dry eyes,





Colorectal





cancer, Solid





tumours




ABT 494
Rheumatoid





arthritis, Crohn's





disease,





Ulcerative colitis,





Atopic dermatitis




Desoximetasone
Plaque psoriasis,





Atopic dermatitis




Siponimod
Multiple sclerosis,





Polymyositis,





Dermatomyositis,





Renal failure,





Liver failure




Calcipotriol/betamet
Plaque psoriasis,




hasone dipropionate
Psoriasis




Forigerimod
Systemic lupus





erythematosus




Masitinib
Amyotrophic





lateral sclerosis,





Mastocytosis,





Prostate cancer,





Alzheimer's





disease,





Colorectal





cancer, Malignant





melanoma,





Pancreatic





cancer,





Gastrointestinal





stromal tumours,





Multiple





myeloma,





Asthma,





Peripheral T-cell





lymphoma,





Multiple sclerosis,





Crohn's disease,





Ovarian cancer,





Progressive





supranuclear





palsy, Breast





cancer, Chronic





obstructive





pulmonary





disease, Non-





small cell lung





cancer, Mood





disorders, Head





and neck cancer,





Glioblastoma,





Hepatocellular





carcinoma,





Gastric cancer,





Oesophageal





cancer, Stroke,





Psoriasis,





Rheumatoid





arthritis




Filgotinib
Rheumatoid





arthritis, Crohn's





disease,





Ulcerative colitis




Laquinimod
Multiple sclerosis,





Huntington's





disease, Crohn's





disease, Lupus





nephritis,





Systemic lupus





erythematosus




Baricitinib
Rheumatoid





arthritis, Systemic





lupus





erythematosus,





Diabetic





nephropathies,





Atopic dermatitis,





Psoriasis




DFD 06
Plaque psoriasis




Tazarotene/
Plaque psoriasis




Ulobetasol





Calcipotriol
Plaque psoriasis,





Psoriasis




Clobetasol
Atopic dermatitis,




propionate
Psoriasis, Skin





disorders




DFD 01
Plaque psoriasis




Pefcalcitol
Plaque psoriasis,





Palmoplantar





keratoderma




ALKS 8700
Multiple sclerosis




Calcitriol
Plaque psoriasis







text missing or illegible when filed








In some embodiments, the therapeutic agent is one of those in Table 5, below; or a pharmaceutically acceptable salt thereof.









TABLE 5







Exemplary Therapeutic Agents and Associated Diseases and Disorders










Drug Name
Active Indications
Target-based Actions
Structure












HS-026




fomitellan A


immunostimulant, InKine


sizofiran
Uterine cervix tumor


Jenact


ANA-971

TLR-7 modulator


acemannan
HIV infection; Wound healing
Interferon gamma receptor




agonist


ANA-975

TLR-7 modulator


MNLP-24


Phellinus linteus derivative


(cancer), Il-Yang


icadamine B (viral infection/


cancer/immune diseases), Cornell


Phytomix-40

Interferon agonist


KLH (bladder tumor), Intracel


MM-15-01


OM-294-DP

TLR-4 agonist


OM-197-MP-AC

TLR-4 agonist


Dendrigen

SL cytokine ligand


beta glucan/lectin combination


drug (cancer), Metabolic Research


CMP-1


SMT-14400


KLH/IMG
Vaccination


BCG polysaccharide and nucleic
Asthma; Chronic bronchitis; Common cold


acid, Zhejiang Wanma


Pharmaceutical Chemical


KLH/SUBUNIT
Vaccination


BCG polysaccharide and nucleic
Allergy; Asthma; Cancer; Chronic bronchitis;


acid, Jilin Yatai
Common cold; Immune complex disease;


Bio-Pharmaceutical
Infectious disease


polysaccharide vaccine
Pneumonia


(antigen-specific immune


cell activation technolotgy,


pneumonia), Haikou


BCV-01


oglufanide disodium
Bacterial infection; Viral infection


(intranasal, infectious


diseases), Implicit Bioscience


AMZ-0026-H


plant-derived immunostimulators


(vaccination), BioStrategies


Ochrobactrum intermedium
Sepsis
TLR-2 agonist; TLR-4


LPS (sepsis), Diomune

agonist


S4 (peptides, immune


diseases), Entopharm


picroliv
Liver disease


VSSP (adjuvant/HIV/
HIV infection; Renal tumor; Vaccination


cancer), Center of Molecular


Immunology


BLI-1301
Myelodysplastic syndrome


CEL-1000
Cancer; Immune disorder; Infectious disease


ISCOMATRIX
Vaccination


JVRS-100
Leukemia; Radiation sickness;
TLR modulator



Reperfusion injury; Vaccination


P-MAPA
Bladder cancer; Mycobacterium tuberculosis
TLR-2 agonist; TLR-4



infection; Zika virus infection
agonist


Arthrobotrys oligospora
Cancer


derived nanoparticles


(cancer), University of


Tennessee


AMZ-0026


AS-210


Mycobacterium brumae
Bladder cancer


immunotherapy (bladder


cancer), Universitat


Autonoma de Barcelona


TR-987
Diabetic foot ulcer; Skin burns; Varicosis
C-type lectin domain



ulcer; Wound healing
protein 7A modulator;




TLR-2 modulator


beta-1,3/1,6-glucan,
Allergy; Breast tumor; Inflammatory bowel


Biotec Pharmacon
disease; Neuroblastoma; Non-Hodgkin lymphoma


EG-Vac
Infectious disease; Vaccination


AF-122
Cancer
Liver X receptor




modulator


lentinan (stabilized powder
Cancer; Infectious disease; Non-small-cell
Integrin alpha-M/beta-2


formulation), GlycaNova
lung cancer
modulator


QS-21
Vaccination


MPL-containing Pollinex
Allergy


allergy desensitization


sublingual vaccine (grass),


Allergy Therapeutics


Acarovac Plus
Allergy


Ragweed MATA MPL
Allergy
TLR agonist


AS-01 adjuvant
Vaccination


AGI-134
Cancer


selumetinib + durvalumab
Solid tumor
MEK-1 protein kinase


(solid tumors), AstraZeneca

inhibitor; MEK-2 protein




kinase inhibitor;




Programmed cell death




ligand 1 inhibitor


inarigivir soproxil
Hepatitis B virus infection; Hepatitis D virus
NOD2 gene stimulator;



infection
Retinoic acid-inducible




gene 1 stimulator


TLR2 agonist (infection),
Infectious disease
TLR-2 agonist


Innavac


Poly-ICLC
Cancer; Glioma; Metastatic colon cancer;
Interferon agonist;



Metastatic pancreas cancer; Non-Hodgkin lymphoma;
TLR-3 agonist



Solid tumor; Stroke; Viral infection


trabectedin + durvalumab (iv,
Ovary tumor; Soft tissue sarcoma
Programmed cell death


ovarian cancer/soft tissue

ligand 1 inhibitor


sarcoma), AstraZeneca/


PharmaMar


IMM-60, iOx Therapeutics/
Cancer


University of Oxford/Ludwig


Institute For Cancer Researc


docetaxel
Breast tumor; Cancer; Endometrioid carcinoma;



Esophagus tumor; Head and neck tumor; Hormone



refractory prostate cancer; Metastatic breast



cancer; Metastatic non small cell lung cancer;



Metastatic stomach cancer; Nasopharyngeal



carcinoma; Non-small-cell lung cancer; Ovary



tumor; Paranasal sinus disease; Prostate tumor;



Squamous cell carcinoma; Stomach tumor


plinabulin
Cancer; Febrile neutropenia; Non-small-cell
Guanine nucleotide



lung cancer
exchange factor stimulator;




Tubulin antagonist


NANT Ovarian Cancer Vaccine
Ovary tumor
Acyltransferase inhibitor;




Brachyury protein modulator;




CD66 modulator; Erbb2




tyrosine kinase receptor




modulator; Estrogen receptor




antagonist; IL-15 agonist;




IL-15 receptor modulator;




Mucin 1 modulator;




Programmed cell death ligand




1 inhibitor; Ras GTPase




modulator; Thymidylate




synthase inhibitor; VEGF




ligand inhibitor


NANT Non-small Cell Lung
Non-small-cell lung cancer
Acyltransferase inhibitor;


Cancer Vaccine

Brachyury protein




modulator; CD66 modulator;




Erbb2 tyrosine kinase




receptor modulator; Estrogen




receptor antagonist;




IL-15 agonist; Mucin 1




modulator; Programmed




cell death ligand 1




inhibitor; Programmed




cell death protein 1




inhibitor; Ras GTPase




modulator; Thymidylate




synthase inhibitor; VEGF




ligand inhibitor


Pollinex Quattro Birch
Allergy


Grass MATA MPL
Allergy









In some embodiments, the therapeutic agent is one of those in Table 6, below; or a pharmaceutically acceptable salt thereof.









TABLE 6







Exemplary Therapeutic Agents and Associated Diseases and Disorders











Active
Target-based



Drug Name
Indications
Actions
Structure





FR-111142





1069C85





purine nucleoside

Purine nucleoside



phosphorylase

phosphorylase



inhibitors, Merrell

inhibitor



Dow





SA-450

Glucocorticoid





agonist






retinoid receptor agonists, Chinese Academy of Sciences




embedded image







enloplatin





MC-1288

Vitamin D3





receptor agonist



lexacalcitol

Vitamin D3





receptor agonist



MM-014





CC-394





KT-5720

Protein kinase A





inhibitor



SA-47








N,N-disubstituted alanine, Ortho McNeil

Sphingomyelinase inhibitor


embedded image







PSK-3668

Estrogen receptor





antagonist



tyrosine kinase

Btk tyrosine



inhibitor, Hughes

kinase inhibitor



Institute





TXU-PAP, Hughes





Institute





sobuzoxane
Leukemia; Non-
DNA gyrase




Hodgkin
inhibitor;




lymphoma
Topoisomerase II





inhibitor



ALRT-1455

Retinoic acid





receptor alpha





agonist



ALRT-792

Retinoic acid





receptor agonist;





Retinoid X





receptor agonist



JAK tyrosine kinase

JAK tyrosine



inhibitors (cancer),

kinase inhibitor



Cephalon





anticancer therapy,





SuperGen





IL-6 trap, Regeneron

IL-6 antagonist



SR-271425

DNA gyrase





inhibitor;





Topoisomerase II





inhibitor



SDX-101

Beta-catenin





inhibitor; Nuclear





factor kappa B





inhibitor; PPAR





gamma agonist



phosphonate

Phospholipase C





inhibitor



menogaril





skeletal targeted





radiotherapy, NeoRx





CT-32228

Lysophosphatidic





acid





actyltransferase





inhibitor



adenosine deaminase inhibitors, Astellas

Adenosine deaminase inhibitor


embedded image







farnesyl transferase inhibitos (multiple myeloma), University of South Florida/H Lee Moffitt Cancer Center

Protein farnesyltransferase inhibitor; Ras GTPase inhibitor


embedded image







phorboxaole A





(acute lymphoblastic





leukamia/multiple





myelome), Hughes





Institute








phenylmorphans, NIH

Sigma opioid receptor agonist


embedded image







Ki-4, dgA





semaxanib

Aryl hydrocarbon





receptor agonist;





MAP kinase





inhibitor; VEGF-2





receptor





antagonist



galarubicin

Metalloprotease-2





inhibitor;





Metalloprotease-9





inhibitor;





Metalloproteinase





inhibitor-1





inhibitor;





Metalloproteinase





inhibitor-2 inhibitor



AE-941

Metalloprotease-





12 inhibitor;





Metalloprotease-2





inhibitor;





Metalloprotease-9





inhibitor; Tissue





plasminogen





activator





modulator; VEGF





receptor





antagonist



sardomozide

S-





adenosylmethionine





decarboxylase





inhibitor



imexon (injectable,





Enhanced Prodrug),





Heidelberg Pharma





PS-031291

CCR1 chemokine





antagonist



mitoguazone





epirubicin





(Biotransport),





Supratek





eheofazine





AR-623





SR-45023A

ACAT inhhibitor;





Farnesoid X





receptor agonist



T-607

Tubuline binding





agent



L-OddU





GSK-461364

Polo-like kinase 1





inhibitor; Polo-like





kinase 3 inhibitor



didemnin B





talmapimod

p38 MAP kinase





inhibitor



AEW-541

Insulin-like growth





factor 1 antagonist



PPI-2458

Aminopeptidase





inhibitor



TAE-684

ALK tyrosine





kinase receptor





family inhibitor



UCL-67022

Histone





deacetylase-6





inhibitor



JNKK modulators,

Protein kinase



Celgene

inhibitor



lestaurtinib

Flt3 tyrosine





kinase inhibitor;





Jak2 tyrosine





kinase inhibitor;





TrkA receptor





antagonist



VEGF-D inhibitors

VEGF-D ligand



(lumphangioleiomyo-

inhibitor



matosis), Circadian





Technologies





SCIO-323

p38 MAP kinase





inhibitor



fluphenazine

5-HT 1b receptor



(multiple

antagonist



myeloma/psoriasis),





Corridor





Pharmaceuticals





[(CD20)2xCD16]

B-lymphocyte





antigen CD20





modulator;





Immunoglobulin





gamma Fc





receptor IIIA





modulator



interleukin-2

Itk tyrosine kinase



inducible tyrosine

inhibitor



kinase inhibitors (T-





cell lymphoma),





MannKind





GDC-0349

mTOR inhibitor



CCX-721

CCR1 chemokine





antagonist



lexibulin (iv infusion,

Tubulin binding



cancer), YM

agent



BioSciences





etoposide

Topoisomerase II



(Biotransport),

inhibitor



Supratek





Entelon
Lymphatic





system disease;





Osteoarthritis







PBOX apoptosis inducers, Trinity College/University of Siena




embedded image







PI3K delta kinase

Phosphoinositide-



inhibitors (B-cell

3 kinase delta



lymphomas/

inhibitor



rheumatoid





arthritis/asthma/





COPD),





Incozen





Therapeutics








ITK inhibitors (cancer), University of California Davis

Itk tyrosine kinase inhibitor


embedded image







CYB5B modulators

Cytochrome B5



(lymphoma), BC

modulator



Cancer Agency





valspodar





lexibulin (oral

Tubulin binding



capsule, cancer),

agent



YM Biosciences





XL-228

Abl tyrosine





kinase inhibitor;





Aurora protein





kinase inhibitor;





Insulin-like growth





factor 1





antagonist;





Insulin-like growth





factor 1 recptor





moculator; Src





tyrosine kinase





inhibitor



tasisulam





TP-1149





alitretinoin
Kaposis sarcoma
Retinoid X





receptor





modulator



immunotoxin
Adult T-cell




(autoimmune
lymphoma;




diseases/leukemias/
Autoimmune




lymphomas),
disease;




NIMH/NIH OTT
Cutaneous T-cell





lymphoma




combination therapy

Adenosine A2a



with evodenoson

receptor agonist



(anticancer, multiple





myeloma),





CombinatoRx





SOM-0350





litonesib

Kinesin-like





protein KIF11





inhibitor



small molecule





therapeutics





(multiple myeloma),





Array BioPharma





cathepsin K

Cathepsin K



inhibitors (multiple

inhibitor



myeloma/bone





disease), ONO





Pharmaceuticals





ONO-WG-307

Btk tyrosine





kinase inhibitor



next generation EVB

Thymidine kinase



TK gene expression

stimulator



stimulators (cancer),





Phoenicia





Biosciences





MLN-0905

Polo-like kinase 1





inhibitor



ridaforolimus

mTOR inhibitor



(intravenous), Merck





& Co





deuterated





lenalidomide,





Deuteria





Pharmaceuticals








ALK inhibitors (anaplastic large cell lymphoma), Cephalon

Anaplastic lymphoma kinase receptor inhibitor


embedded image







OTJ
Hypercalcemia;





Multiple





myeloma;





Ostealgia;





Osteoporosis;





Pagets bone





disease




KW-2478
Hematological
Hsp 90 inhibitor




neoplasm;





Multiple





myeloma




SOM-0666

DHFR inhibitor;





Folate antagonist



rabacfosadine

DNA polymerase





inhibitor



motexafin

Thioredoxin



gadolinium

reductase





modulator



small molecule





compounds (multiple





myeloma),





University of





Technology Sydney





Epstein-Barr virus
Infectious
Complement



targeting program
mononucleosis
receptor 2



(infectious

modulator



mononucleosis),





Molplex





Pharmaceuticals





delta-opioid receptor
Multiple
Opioid receptor



ligands (cancer),
myeloma
delta modulator



Rutgers university








Pim kinase inhibitors (cancer), Genentech
Multiple myeloma
PIM protein kinase inhibitor


embedded image







AKR-302





repurposed
Epstein Barr virus
NKG2D ligand



pamidronic acid
infection;
modulator



(EBV-induced B cell
Lymphopro-




lymphoproliferative
liferative




disorders), The
diasease




University of Hong





Kong





canfosfamide
Breast tumor;
Glutathione S-




Colon tumor;
transferase P




Diffuse large B-
modulator




cell lymphoma;





Lung tumor;





Mantle cell





lymphoma;





Multiple





myeloma; Non-





small-cell lung





cancer; Ovary





tumor




QIN-1

Nuclear factor





kappa B inhibitor



SB-743921

Kinesin-like





protein KIF11





inhibitor



cutaneous T cell





lymphoma





therapeutics, BC





Cancer Agency





silicon





phthalocyanine





4 + photodynamic





therapy (T-cell non-





Hodgkin lymphoma),





NCI





DNX-5000 series

Focal adhesion





kinase inhibitor;





Focal adhesion





kinase-2 inhibitor



BI-2536

Polo-like kinase 1





inhibitor



tyrosine kinase

Protein tyrosine



inhibitors (non-

kinase inhibitor



Hodgkins





lymphoma), Hospital





Clinic of





Barcelona/Fundacio





Clinic








proteasome inhibitors (multiple myeloma), Evestra

Proteasome inhibitor


embedded image







GRK6 inhibitors

GRK6 protein



(multiple myeloma),

kinase inhibitor



Mayo Clinic





small molecule





therapeutic (oral,





Castleman's





disease/Kaposi's





sarcoma/primary





effusion lymphoma),





Ascepion





Pharmaceuticals





A-1014907

Aurora protein





kinase inhibitor;





VEGF receptor





antagonist



microtubule
T-cell lymphoma




depolymerization





inducer (T-cell





lymphoma), Inje





University





epigenetic





monoclonal





induction therapy





(cancer), Nimble





Epitech





P-276-00

Cyclin D1 inhibitor;





Cyclin T inhibitor;





Cyclin-dependent





kinase inhibitor 1B





inhibitor; Cyclin-





dependent kinase-





4 inhibitor; Cyclin-





dependent kinase-





9 inhibitor



delanzomib

Immunoglobulin G





antagonist;





Proteasome





inhibitor



LC-530110
Multiple myeloma
Proteasome





inhibitor



TP-110, Microbial

Proteasome



Chemistry Research

inhibitor



Foundation





thalidomide (multiple
Erythema




myeloma), Fujimoto
nodosum leprae;





Multiple





myeloma;





POEMS





syndrome




gallium nitrate
Hypercalcemia




PM-00104/50

P-Glycoprotein 1





inhibitor;





Transcription





factor inhibitor



CVXL-0102

Jak3 tyrosine





kinase inhibitor;





Syk tyrosine





kinase inhibitor



EDE-1206
Elephantiasis




PRT-2607
Allergy; Cancer;
Syk tyrosine




Chronic
kinase inhibitor




lymphocytic





leukemia;





Inflammatory





disease; Non-





Hodgkin





lymphoma;





Rheumatoid





arthritis; Systemic





lupus





erythematosus







PKC-theta inhibitors (inflammatory/auto- immune disease/cancer), CompleGen
Autoimmune disease; HIV infection; Inflammatory disease; T-cell lymphoma
Protein kinase C theta inhibitor


embedded image







perk kinase
Multiple myeloma
Proline rich



inhibitors (multiple

receptor like



myeloma), New

kinase PERK



York University

inhibitor



EP-009

Jak3 tyrosine





kinase inhibitor



immunoglobulin

Immunoglobulin G



heavy chain gene

antagonist



enhancer inhibitors





(multiple myeloma),





Leukogene





Therapeutics





ASP-4132
Advanced solid





tumor;





Lymphoma




NFkB inhibitors
Diffuse large B-
Nuclear factor



(diffuse large B-cell
cell lymphoma
kappa B inhibitor



lymphoma),





University of





Rochester





SHIP-1 inhibitors
Multiple myeloma
INPP5D gene



(multiple myeloma),

inhibitor



Upstate Medical





University





MKC-204
Multiple
IRE1 protein




myeloma
kinase inhibitor



boanmycin
Liver tumor;




hydrochloride (im/iv,
Lymphoma;




esophageal
Metastatic




cancer/liver
esophageal




cancer/lymphoma),
cancer




Liaoyuan Dikang





Pharmaceutical





fluorinonide
Atopic dermatitis;




(topical), Medicis
Contact





dermatitis;





Mycosis





fungoides;





Pruritus;





Psoriasis




hybrid compounds





(multiple myeloma),





Virginia





Commonwealth





University





BLHP-007
Head and neck





tumor; Hodgkins





disease




BLHP-001








CSA-92




embedded image







Btk covalent irreversible inhibitors (lymphoma), Peking University
Lymphoma
Btk tyrosine kinase inhibitor


embedded image







SOM-0558





STK-405759
Multiple myeloma




SRI-31277
Fibrosis; Multiple
Thrombospondin-




myeloma
1 ligand inhibitor



S-6810





DS-3078

mTOR complex 1





inhibitor; mTOR





complex 2 inhibitor



BEBT-908
Cancer; Chronic
Histone




lymphocytic
deacetylase




leukemia;
inhibitor;




Lymphoma;
Phosphoinositide




Multiple myeloma
3-kinase inhibitor



JAK2 inhibitors
Lymphoma
Jak2 tyrosine



(lymphoma),

kinase inhibitor



University of Iowa





DRX-254
Multiple myeloma




Btk inhibitors (B-cell
B-cell lymphoma
Btk tyrosine



lymphoma), National

kinase inhibitor



Health Research





Institutes








NF-kappaB subunit c-Rel inhibitors, Immune Target
Chronic lymphocytic leukemia; Diffuse large B-cell lymphoma; Graft versus host disease; Multiple myeloma; Multiple sclerosis; Organ transplantation
C-Rel proto- oncogene protein inhibitor


embedded image







IL-6 inhibitors (oral,
Cachexia;
IL-6 antagonist



inflammation/Castle-
Castlemans




mans
disease;




disease/cachexia),
Inflammatory




Interprotein/RIKEN
disease




prednisolone
Lymphoma




(malignant





lymphoma),





Shionogi





MI-2
Diffuse large B-
MALT protein 1




cell lymphoma
inhibitor






Btk inhibitors (autoimmune diseases), Genentech/Gilead
Autoimmune disease; B-cell lymphoma
Btk tyrosine kinase Inhibitor


embedded image







HDAC inhibitor

Hemoglobin



(hemoglobinopathy),

modulator;



Italfarmaco

Histone





deacetylase-1





inhibitor; Histone





deacetylase-2





inhibitor; Histone





deacetylase-4





inhibitor



TAS-5567

Syk tyrosine





kinase inhibitor



mucosa-associated
B-cell lymphoma;
MALT protein 1



lymphoid tissue
Cancer
inhibitor; MALT



lymphoma

protein 1



translocation protein

modulator



1 inhibitor (B-cell





lymphoma),





University of





Lausanne/MRC





Technology





JNJ-40646527

CSF-1 antagonist



Q-203, QUE





Oncology





ML-319
Chronic
Btk tyrosine




lymphocytic
kinase inhibitor




leukemia; Mantle





cell lymphoma;





Non-Hodgkin





lymphoma




CCX-354
Bone
CCR1 chemokine




metastases;
antagonist




Multiple





myeloma;





Rheumatoid





arthritis




ZYBT-1
Arthritis; Diffuse
Btk tyrosine




large B-cell
kinase inhibitor




lymphoma




daniquidone

Topoisomerase I





inhibitor;





Topoisomerase II





inhibitor



bone targeted





epigenetic drugs





(multiple myeloma),





Episynesis





X-022
Autoimmune
Btk tyrosine




disease; B-cell
kinase inhibitor




lymphome




second generation
Multiple myeloma
Extracellular



program, Kesios

signal related



Therapeutics

kinase-5 inhibitor;





GADD45B gene





inhibitor



linsitinib

Insulin receptor





antagonist;





Insulin-like growth





factor 1 antagonist



canavanine, Multiple
Multiple myeloma




Myeloma





muparfostat sodium
Hepatocellular
FGF receptor




carcinoma
antagonist; FGF-1





ligand inhibitor;





FGF-2 ligand





inhibitor;





Heparanase





inhibitor; VEGF





receptor





antagonist



CU-042
Diffuse large B-
Nuclear factor




cell lymphoma
kappa B inhibitor



immunomodulators
Lymphoma; Solid




(lymphoma/solid
tumor




tumor), Alligator





bioscience/Stanford





University





obatoclax

Bcl-2 protein





inhibitor; Mcl-1





differentiation





protein inhibitor



FV-214
Macroglobulinemia;
Chymotrypsin




Multiple
inhibitor;




myeloma
Proteasome





inhibitor



FV-162
Macroglo-
Chymotrypsin




bulinemia;
inhibitor;




Multiple
Proteasome




myeloma
inhibitor



luminespib
Cancer
ATPase inhibitor;





Hsp 90 inhibitor



dexamethasone
Multiple myeloma
Glucocorticoid



acetate (high-dose

agonist



formulation, multiple





myeloma),





Laboratories CTRS





NK-012
Breast tumor;
Topoisomerase I




Colorectal tumor;
inhibitor




Multiple





myeloma; Small-





cell lung cancer




CYF-2-11
B-cell lymphoma




imexon (injectable),

Hypoxia inducible



AmpliMed

factor-1 alpha





inhibitor;





Ribonucleotide





reductase inhibitor



CXCR5 inhibitors (T-
Angioimmuno-
CXCR5



cell lymphoma),
blastic T-cell
chemokine



Yale University
lymphoma
antagonist



CCX-9588
Cancer
CCR1 chemokine





antagonist



SCFV-based
Leukemia;




chimeric antigen
Lymphoma




receptors





(leukemia/ lymphoma),





Lentigen





Technology





SG-2000
Lymphoma




curcumin-ND
Mantle cell




(mantle cell
lymphoma




lymphoma), Lypro





HDAC 6/8 inhibitors

Histone



(multiple

deacetylase-6



myeloma/neuro-

inhibitor; Histone



blastoma),

deacetylase-8



Kancera AB

inhibitor






diazeniumdiolate NO releasing compounds (cancer), JSK Therapeutics




embedded image







4SC-205
Cancer;
Kinesin-like




Lymphoma; Solid
protein KIF11




tumor
inhibitor



TORC2 inhibitors
Multiple myeloma
mTOR complex 2



(multiple myeloma),

inhibitor



VA Greater Los





Angeles





DRGT-54





JAK1 kinase
Lymphoma
Jak1 tyrosine



inhibitors, Cloud

kinase inhibitor



Pharmaceuticals





HDAC8 inhibitor (T
T-cell-lymphoma
Histone



cell lymphoma),

deacetylase-8



Cloud

inhibitor



Pharmaceuticals





antielephantiasis





therapy, Anacor





RG-7602

Checkpoint kinase





1 inhibitor



VDA-1102
Cutaneous T-cell
Hexokinase 2




lymphoma;
modulator;




Keratosis;
Voltage




Squamous cell
dependent anion




carcinoma
channel modulator



SIRT2 inhibitors (B-
B-cell lymphoma
NAD-dependent



cell lymphoma),

deacetylase



Fred Hutchinson

sirtuin-2 inhibitor



Cancer Research





Center





SPARC-147709





sepantronium

Survivin protein



bromide

inhibitor



modified formulation

Proteasome



of bortezomib

inhibitor



(solution for





injection, multiple





myeloma),





InnoPharma





pictilisib

NOTCH1 gene





inhibitor;





Phosphoinositide-





3 kinase alpha





inhibitor



darinaparsin (oral,
Cancer




cancer), Solasia





Pharma





palifosfamide
Cancer




acadesine

AMP activated



(intravenous,

protein kinase



prodrug, B-

stimulator



CLL/MM/MCL),





Advancell





2-methoxyestradiol,
Multiple sclerosis;
Hypoxia inducible



CASI
Rheumatoid
factor-1 inhibitor;



Pharmaceuticals
arthritis
VEGF receptor





antagonist



leukotriene B4
Lymphedema;




inhibitor
Pulmonary artery




(PAH/lymphedema),
hypertension




Eiger





BioPharmaceuticals





IRAK4 inhibitors
Autoimmune
IRAK-4 protein



(lymphoma/
disease; Diffuse




inflammatory
large B-cell




disorders),





Genentech
lymphoma;





Inflammatory





disease




GT-1036

Apoliproprotein E





agonist; Retinold





X receptor agonist



noscapine (cancer),

Tubulin binding



Cougar

agent



rHuEPO (multiple
Multiple myeloma
Erythropoietin



myeloma), XTL

receptor agonist



avicin D (multiple
Mantle cell




myeloma), Avicin
lymphoma;




Therapeutics
Multiple myeloma




perifosine
Cancer;
AKT protein




Colorectal tumor;
kinase inhibitor;




Glioma; Multiple
Phosphoinositide




myeloma
3-kinase inhibitor



elsamitrucin

DNA gyrase





inhibitor;





Topoisomerase I





inhibitor;





Topoisomerase II





inhibitor



CUDC-427
Lymphoma; Solid
X-linked inhibitor




tumor
of apoptosis





protein inhibitor



cladribine
Chronic
Adenosine




lymphocytic
deaminase




leukemia; Hairy
inhibitor




cell leukemia




AT-101
Chronic
Bcl-xL Bcl-2




lymphocytic
associated death




leukemia;
promotor inhibitor;




Esophagus
Mcl-1




tumor; Glioma;
differentiation




Hormone
protein inhibitor




refractory





prostate cancer;





Larynx tumor;





Multiple





myeloma; Non-





Hodgkin





lymphoma; Non-





small-cell lung





cancer; Small-cell





lung cancer




banoxantrone

Topoisomerase II





inhibitor



CX-1001 +

Serotonin



undisclosed

transporter



anticancer therapy

stimulator



(B-cell cancer),





Celentyx





CX-1001

Serotonin





transporter





stimulator



safingol
Lymphoma; Solid
Protein kinase C




tumor
inhibitor



DTRMWXHS-12
lymphoma
Btk tyrosine





kinase inhibitor



dinaciclib

Cyclin-dependent





kinase-1 inhibitor;





Cyclin-dependent





kinase-2 inhibitor;





Cyclin-dependent





kinase-5- inhibitor;





Cyclin-dependent





kinase-9 inhibitor



SNS-032

Cyclin-dependent





kinase-2 inhibitor;





Cyclin-dependent





kinase-7 inhibitor;





Cyclin-dependent





kinase-9 inhibitor



IPH-1101





talabostat
Chronic
Dipeptidyl




Lymphocytic
peptidase IV




leukemia;
inhibitor;




Hematological
Dipeptidyl




disease;
peptidase IX




Melanoma;
inhibitor;




Neutropenia;
Dipeptidyl




Non-Hodgkin
peptidase VIII




lymphoma; Non-
inhibitor; Seprase




small-cell lung
inhibitor




cancer; Pancreas





tumor; Renal





tumor




RH-1





thymocartin





AR-726

DNA binding





protein modulator



STF-083010

ERN1 gene





modulator



tanespimycin
Cancer; Thyroid
Hsp 90 inhibitor;




tumor
MET tyrosine





kinase receptor





family inhibitor



JNJ-40346527

CSF-1 antagonist



doxorubicin
Breast tumor;
DNA polymerase



hydrochloride
Cancer; Kaposis
inhibitor;



(liposomal
sarcoma; Multiple
Topoisomerase II



formulation, cancer),
myeloma; Ovary
inhibitor



TTY Biopharm
tumor




IQS-019
Non-Hodgkin
Bcr protein




lymphoma
inhibitor



MCLA-114

CD3 modulator



BET inhibitors

Bromodomain



(cancer), Zenith

containing protein



Epigenetics

inhibitor; MYC





gene inhibitor



daporinad

Nicotinamide





phosphoribosyltrans-





ferase inhibitor



cefotiam
Abscess; Acute





bronchitis;





Bacterial





infection;





Bacterial





meningitis;





Bacterial





pneumonia;





Bacterial





respiratory tract





infection;





Bacterial skin





infection;





Cholangitis;





Cholecystitis;





Corneal ulcer;





Cystitis;





Dacryocystitis;





Empyema;





Female genital





tract infection;





Infectious





arthritis; Keratitis;





Laryngo- pharyngitis;





Lympha- denopathy;





Mastitis;





Ocular infection;





Osteomyelitis;





Otitis media;





Peritonitis;





Prostatitis;





Pyelonephritis;





Sepsis; Sinusitis;





Tonsillitis;





Urethritis




BAY-1862864
Non-Hodgkin
B-lymphocyte cell




lymphoma
adhesion molecule





inhibitor



FAB-114
Chronic





lymphocytic





leukemia; Non-





Hodgkin





lymphoma




sonidegib (oral),
Acute
Hedgehog protein



Novartis
myelogenous
inhibitor;




leukemia; Basal
Smoothened




cell carcinoma;
receptor




Basal cell nevus
antagonist




syndrome;





Chronic





myelocytic





leukemia;





Hematological





neoplasm;





Multiple





myeloma;





Myelodysplastic





syndrome;





Myelofibrosis;





Pancreas tumor




PERK-selective

Proline rich



kinase inhibitors

receptor like



(multiple

kinase PERK



myeloma/B-cell

inhibitor



lymphoma), Janssen





Research and





Development





samarium(153Sm)
Cancer; Pain




lexidronam





BNV-215





beta-1,3/1,6-glucan,
Allergy; Breast




Biotec Pharmacon
tumor;





Inflammatory





bowel disease;





Neuroblastoma;





Non-Hodgkin





lymphoma




KRX-0402
Cancer;
O-methylguanine




Cutaneous T-cell
DNA




lymphoma
methyltransferase





inhibitor



entasobulin

Topoisomerase II





inhibitor; Tubulin





beta inhibitor



BTK inhibitors (B-
Autoimmune
Btk tyrosine



cell
disease; B-cell
kinase inhibitor



lymphomas/
lymphoma




autoimmune





disease),





Eternity Bioscience





reformulated
Elephantiasis;




flubendazole
Onchocerciasis




(elephantiasis/river





blindness), J&J/





Drugs for Neglected





Diseases initiative





GDC-0575
Lymphoma; Solid
Checkpoint kinase




tumor
1 inhibitor



radiolabeled
Multiple myeloma
CXCR4 gene



pentixather (multiple

modulator



myeloma),





University of





Wurzburg/Technical





University of Munich





spebrutinib
Autoimmune
Btk tyrosine




disease; Chronic
kinase inhibitor




lymphocytic





leukemia; Diffuse





large B-cell





lymphoma;





Multiple





myeloma; Non-





Hodgkin





lymphoma;





Rheumatoid





arthritis




CC-223

mTOR complex 1





inhibitor; mTOR





complex 2 inhibitor



doxorubicin

DNA polymerase



(liposome-

inhibitor;



encapsulated),

Topoisomerase II



NeoPharm

inhibitor



CPI-0610
Acute leukemia;
Bromodomain




Autoimmune
containing protein




disease; Cystic
4 inhibitor;




fibrosis;
Bromodomain




Lymphoma;
containing protein




Mantle cell
inhibitor; Myc




lymphoma;
proto-oncogene




Multiple
protein inhibitor




myeloma;





Myelodysplastic





syndrome




voxtalisib

Phosphoinositide





3-kinase inhibitor;





mTOR inhibitor



sotrastaurin
Diffuse large B-
Protein kinase C




cell lymphoma;
alpha inhibitor;




Uveal melanoma
Protein kinase C





beta inhibitor;





Protein kinase C





delta inhibitor;





Protein kinase C





epsilon inhibitor;





Protein kinase C





eta inhibitor;





Protein kinase C





theta inhibitor



REM-1086
Multiple
Nuclear factor




myeloma;
kappa B




Rheumatoid
modulator;




arthritis; Spinal
Nuclear factor




cord disease
keppa B p105





inhibitor;





Transcription





factor RelB





inhibitor;





Transcription





factor p65 inhibitor



clofarabine (oral),





Genzyme





SH-7113
B-cell lymphoma;
Unspecified




Leukemia
receptor





modulator



SH-7133
B-cell lymphoma;
Unspecified




Leukemia
receptor





modulator



FROST-600
Mantel cell





lymphoma




GS-9820

Phosphoinositide-





3 kinase beta





inhibitor;





Phosphoinositide-





3 kinase delta





inhibitor



voruciclib
Cancer
Cyclin dependent





kinase 4 inhibitor





D inhibitor; Cyclin-





dependent kinase





inhibitor 1B





inhibitor; Cyclin-





dependent kinase-





4 inhibitor; Cyclin-





dependent kinase-





9 inhibitor



filanesib
Multiple myeloma
Kinesin-like





protein KIF11





inhibitor



apitolisib

Phosphoinositide





3-kinase inhibitor;





mTOR complex 1





inhibitor; mTOR





complex 2 inhibitor



TACE inhibitors
Inflammatory
TACE inhibitor



(inflammatory
disease




diseases), Allosterix





GS-5829
Advanced solid
Bromodomain




tumor; Hormone
containing protein




refractory
inhibitor




prostate cancer;





Lymphoma;





Metastatic breast





cancer




GCS-100 (iv, end

Cell adhesion



stage renal

molecule inhibitor;



disease/renal

Galectin-3 inhibitor



transplantation/cancer),





La Jolia





Pharmaceutical





ASTX-660
Advanced solid
Inhibitor of




tumor; Cancer;
apoptosis protein




Lymphoma
2 inhibitor; X-





linked inhibitor of





apoptosis protein





inhibitor



clofarabine
Acute
DNA polymerase




lymphoblastic
inhibitor;




leukemia; Diffuse
Ribonucleotide




large B-cell
reductase inhibitor




lymphoma;





Histiocytosis;





Myelodysplastic





syndrome; Non-





Hodgkin





lymphoma




galectin-3 inhibitor
Multiple myeloma
Galectin-3 inhibitor



(multiple myeloma),





Kiromic, LLC/Texas





Tech University





Health Sciences





Center/Universita





degli Studi di Milano





KM-301
Non-Hodgkin
Enhancer of zeste




lymphoma
homolog 2





inhibitor



490-PXN

Bcl-6 protein





inhibitor



enzastaurin
Diffuse large B-
Protein kinase C




cell lymphoma
beta inhibitor



mitoxantrone
Acute
Topoisomerase II




myelogenous
modulator




leukemia; Breast





tumor; Cancer;





Hormone





refractory





prostate cancer;





Liver tumor;





Multiple sclerosis;





Non-Hodgkin





lymphoma




CB-5083
Multiple
AAA ATPase




myeloma; Solid
inhibitor;




tumor
Transitional





endoplasmic





ATPase inhibitor



LCL-161
Breast tumor;
SMAC protein




Leukemia;
modulator; X-




Multiple
linked inhibitor of




myeloma; Solid
apoptosis protein




tumor
inhibitor



trifarotene
Acne vulgaris;
Retinoic acid




Cutaneous T-cell
receptor gamma




lymphoma;
agonist




Ichthyosis




AMG-224
Multiple myeloma




OXS-4235
Multiple
Sequestosome 1




myeloma; Pagets
inhibitor




bone disease




dovitinib

CSF-1 antogonist;





FGF1 receptor





antagonist; FGF2





receptor





antagonist; FGF3





receptor





antagonist; Flt3





tyrosine kinase





inhibitor; Kit





tyrosine kinase





inhibitor; PDGF





receptor





antagonist; Ret





tyrosine kinase





receptor inhibitor;





SL cytokine ligand





inhibitor; TrkA





receptor





antagonist; VEGF-





1 receptor





antagonist; VEGF-





2 receptor





antagonist; VEGF-





3 receptor





antagonist



danusertib
Chronic
Abl tyrosine




myelocytic
kinase inhibitor;




leukemia; Solid
Aurora protein




tumor
kinase inhibitor;





FGF1 receptor





antagonist; Ret





tyrosine kinase





receptor inhibitor;





TrkA receptor





antagonist



CEP-8983
Advanced solid
Poly ADP ribose




tumor; Mantle cell
polymerase 1




lymphoma; Non-
inhibitor; Poly ADP




small-cell lung
ribose polymerase




cancer; Solid
2 inhibitor




tumor




evofosfamide
Astrocytoma;
Topoisomerase II




Biliary cancer;
inhibitor




Multiple





myeloma;





Pancreas tumor;





Soft tissue





sarcoma; Solid





tumor




bromocriptine,
Galactorrhea;
Dopamine D2



Novartis
Parkinsons
receptor agonist




disease




apilimod mesylate
Non-Hodgkin
IL-12 antagonist;



(capsule, B-cell non-
lymphoma
IL-23 antagonist;



Hodgkins

PIKFYVE gene



lymphoma), Lam

inhibitor



Therapeutics





VRx-3996
Cancer; Multiple
Histone




myeloma
deacetylase-1





inhibitor; Histone





deacetylase-2





inhibitor; Histone





deacetylase-3





inhibitor



mocetinostat
Acute
Caspase-3



dihydrobromide
myelogenous
stimulator;




leukemia; B-cell
Caspase-7




lymphoma;
stimulator; Histone




Cancer; Chronic
deacetylase-1




lymphocytic
inhibitor; Histone




leukemia;
deacetylase-11




Hodgkins
inhibitor; Histone




disease;
deacetylase-2




Leukemia; Non-
inhibitor; Histone




small-cell lung
deacetylase-3




cancer; Pancreas
inhibitor; Histone




tumor; Solid
deacetylase-4




tumor;
inhibitor




Transitional cell





carcinoma




TG-02
Chronic
Brachyury protein




lymphocytic
inhibitor; Cyclin-




leukemia;
dependent kinase-




Hematological
1 inhibitor; Cyclin-




neoplasm;
dependent kinase-




Hepatocellular
2 inhibitor; Cyclin-




carcinoma;
dependent kinase-




Multiple
5 inhibitor; Cyclin-




myeloma; Solid
dependent kinase-




tumor
7 inhibitor; Cyclin-





dependent kinase-





9 inhibitor;





cytochrome P450





reductase





inhibitor;





Extracellular





signal related





kinase-5 inhibitor;





Flt3 tyrosine





kinase inhibitor;





Jak2 tyrosine





kinase inhibitor;





Mcl-1





differentiation





protein inhibitor;





RNA polymerase





II modulator;





STAT5A gene





modulator; p38





MAP kinase





inhibitor



VGC-001
T-cell lymphoma




histone lysine
Multiple myeloma
Histone lysine



methyltransferase

methyltransferase



NSD2 inhibitors

NSD2 inhibitor



(cancer), Inventiva





IRAK-4 modulators

IRAK-4 protein



(inflammation),

kinase modulator



Aurigene





CB-988
B-cell lymphoma
Btk tyrosine





kinase inhibitor



DCDS-0780A
Non-Hodgkin





lymphoma




dexamethasone
Hormone
Glucocorticoid



(liposome
refractory
agonist;



formulation,
prostate cancer;
Phospholipase A2



castration resistant
Multiple myeloma
inhibitor



prostate





carcinoma/multiple





myeloma),





Enceladus





TRC-694
Hematological
Nuclear factor




neoplasm;
kappa B inducing




Multiple myeloma
kinase inhibitor



BCN-004
Non-Hodgkin
Phosphoinositide




lymphome
3-kinase inhibitor



ixabepilone
Breast tumor;
Tubulin modulator




Fallopian tube





cancer;





Metastatic breast





cancer; Ovary





tumor; Peritoneal





tumor




TC-11
Multiplet myeloma




CPI-1205
Lymophoma
Enhancer of zeste





homolog 2





inhibitor



NMS-E194
Multiple myeloma
Proline rich





receptor like





kinase, PERK





inhibitor



minocycline

Acinetobacter





hydrochloride
infection;




(intravenous,

Actinomyces





bacterial infections),

israelli infection;





Rempex

Bacillus anthracis





Pharmaceuticals
infection;





Bacterial





infection;






Bartonella







bacilliformis






infection;






Bartonellaceae






infection; Borrelia






recurrentis






infection; Brucella





infection;






Campylobacter







fetus infection;






Cervix infection;






Chlamydia







trachomatis






infection;






Clostridium






infection;





Complicated skin





and skin structure





infection;






Enterobacter







aerogenes






infection;






Escherichia coli






infection;






Francisella







tularensis






infection;






Fusobacterium






infection;





Granuloma;






Haemophilus







influenzae






infection;






Klebsiella







granulomatis






infection;






Klebsiella






infection; Listeria






monocytogenes






infection;






Lymphogranulom







a venereum;







Meningitis;







Mycoplasma







pneumoniae






infection;






Neisseria







meningitidis






infection; Q fever;





Respiratory tract





infection;






Rickettsia







infection; Rocky






mountain spotted





fever; Scrub





typhus; Shigella





infection;






Staphylococcus







aureus infection;







Streptococccus







pneumoniae






infection;





Trachoma;






Treponema







pallidum






infection;






Ureaplasma







urealyticum






infection;





Urethritis; Urinary





tract infection;






Vibrio cholerae






infection; Yersinia






pestis infection





eltanexor
Multiple myeloma
Exportin 1 inhibitor






EZH2 inhibitors (diffuse large B-cell lymphoma), Pfizer
Diffuse large B-cell lymphoma
Enhancer of zeste homolog 2 inhibitor


embedded image







PIM-447
Acute
PIM protein kinase




myelogenous
inhibitor; PIM-1




leukemia;
protein kinase




Multiple
inhibitor; PIM-2




myeloma;
protein kinase




Myelodys- plastic
inhibitor; PIM-3




syndrome;
protein kinase




Myelofibrosis
inhibitor



romidepsin (topical,

Histone



cancer), Gloucester

deacetylase



Pharmaceuticals

inhibitor



belinostat (oral,
Cancer
Histone



cancer), Onxeo

deacetylase





inhibitor



navitoclax

Apoptosis





regulator Bcl w





inhibitor; Bcl-2





protein inhibitor;





Bcl-xL Bcl-2





associated death





promotor inhibitor



barasertib
Diffuse large
Aurora protein




B-cell
kinase 1 inhibitor;




lymphoma
Aurora protein





kinase 2 inhibitor



SCM-02-138
Diffuse large
MALT protein 1




B-cell
inhibitor



AZD-1208
lymphoma
PIM protein kinase





inhibitor



CC-95821
Muleiple myeloma
Protein cereblon





modulator;





Ubiquitin ligase





modulator






BET PROTAC
Burkitts lymphoma; Cancer
Bromodomain containing protein 4 inhibitor; C-myc binding protein inhibitor; E3 ubiquitin protein ligase CBL modulator; VHL gene modulator


embedded image







cyclophosphamide
Lymphoma




monohydrate





AMG-176
Multiple myeloma
Mcl-1





differentiation





protein inhibitor



deubiquitinating
Diffuse large B-
Unspecified



enzyme inhibitor (B-
cell lymphoma
enzyme inhibitor



Cell lymphoma),





University of





Leicester





veliparib
Breast tumor;
PARP inhibitor;




Cancer;
Poly ADP ribose




Colorectal tumor;
polymerase 1




Fallopian tube
inhibitor; Poly ADP




cancer;
ribose polymerase




Glioblastoma;
2 inhibitor




Glioma;





Gliosarcoma;





Liver disease;





Lymphoma;





Metastasis;





Metastatic breast





cancer;





Metastatic





colorectal cancer;





Metastatic head





and neck cancer;





Metastatic non





small cell lung





cancer;





Metastatic





pancrease cancer;





Metastatic rectal





cancer; Multiple





myeloma;





Neuroendocrine





tumor; Ovary





tumor; Peritoneal





tumor; Prostate





tumor; Renal





disease; Small-





cell lung cancer;





Solid tumor;





Stage IV





melanoma




RP-323
Acute
Protein kinase C




myelogenous
stimulator




leukemia;





Hodgkins





disease;





Myelodysplastic





syndrome




plerixafor
Bone marrow
CXCR4




transplantation;
chemokine




Chronic
antagonist;




lymphocytic
Neuroplastin




leukemia;
inhibitor




Diabetic foor





ulcer; Glioma;





Neutropenia;





Non-Hodgkin





lymphoma; Sickle





cell anemia




melphalan
AL amyloidosis;




(intravenous/Captisol,
Multiple myeloma




multiple myeloma),





Spectrum/CASI





Pharmaceuticals





fotemustine
Melanoma; Uveal





melanoma




amoxicillin +
Abdominal
Beta lactamase



clavulanate
abscess; Acute
inhibitor



potassium GSK
bronchitis;





Bacterial





infection;





Bacterial





pneumonia;





Bacterial





respiratory tract





infection;





Bacterial skin





infection;





Bacterial urinary





tract infection;





Bone and joint





infection;





Bronchitis;





Cellulitis; Cystitis;






Enterobacter






infection;






Escherichia coli






infection; Female





genital tract





infection;






Haemophilus







influenzae






infection;





Haemophilus





parainfluenzae





infection;





infectious





disease;






Klebsiella






infection;






Klebsiella







pneumoniae






infection;





Laryngitis; Lower





respiratory tract





infection;





Lymphangitis;





Mastoiditis;






Moraxella







catarrhalis






infection;






Neisseria







gonorrhoeae






infection;





Osteomyelitis;





Otitis media;





Pelvic





inflammatory





disease;





Pharyngitis;





Prophylaxis;





Pyelonephritis;





Sinusitits;






Staphylococcus







aureus infection;






Tonsillitis




belinostat (iv,
Colorectal tumor;
Histone



cancer),
Hepatocellular
deacetylase



Onxeo/Spectrum
carcinoma; Non-
inhibitor




small-cell lung





cancer; Ovary





tumor; Peripheral





T-cell lymphoma;





Solid tumor




GSK-2126458
Idiopathic
Phosphoinositide




pulmonary
3-kinase inhibitor;




fibrosis;
mTOR complex 1




Lymphoma;
inhibitor; mTOR




Metastatic
complex 2 inhibitor




prostate cancer;





Solid tumor




picibanil
Carcinoma;





Cystic hygroma;





Ranula




anti-wolbachia
Elephantiasis;




therapy
Filariasis;




(onchocerciasis/lym-
Onchocerciasis




phatic filariasis),





LSTM





melphalan
Cancer; Multiple
Caspase-3



flufenamide
myeloma; Ovary
stimulator;



hydrochloride
tumor
Peptidase





modulator



quisinostat
Cutaneous T-cell
Androgen receptor




lymphoma;
antagonist;




Fallopian tube
Histone H3




cancer;
modulator;




Metastatic ovary
Histone




cancer; Multiple
deacetylase-1




myeloma;
inhibitor; Histone




Peritoneal tumor;
deacetylase-2




Solid tumor
inhibitor; Prostate





specific antigen





inhibitor



Decuprate
Motor neurone
Superoxide




disease; Wilson
dismutase inhibitor




disease







next-generation BET bromodomain inhibitors (multiple myeloma), Dana- Farber Cancer Institute
Multiple myeloma
Bromodomain containing protein inhibitor


embedded image







komaroviquinone
Multiple myeloma




derivatives (cancer),





Keio University





AZ-1495
Central nervous
IRAK-1 protein




system tumor;
kinase inhibitor;




Lymphoma
IRAK-2 protein





kinase inhibitor



TAS-4464
Cancer;
Amyloid protein




Lymphoma;
binding protein-1




Multiple myeloma
inhibitor



FF-10502-01
Lymphoma; Solid





tumor




doxorubicin
Cancer; Kaposis
DNA polymerase



(liposomal,
sarcoma;
inhibitor;



STEALTH), Alza
Metastatic breast
Topoisomerase II




cancer; Multiple
inhibitor




myeloma; Ovary





tumor; T-cell





lymphoma




SGX-301
Cutaneous T-cell





lymphoma;





Psoriasis




pixantrone
Breast tumor;
DNA gyrase




Lymphoma;
inhibitor




Metastasis; Non-





Hodgkin





lymphoma; Solid





tumor




tosedostat
Acute
Aminopeptidase




myelogenous
inhibitor;




leukemia;
Leukotriene A4




Myelodysplastic
hydrolase inhibitor




syndrome




eprodisate
Sarcoidosis
Amyloid protein





deposition inhibitor



CC-90011
Advanced solid
Lysine specific




tumor; Non-
histone




Hodgkin
demethylase 1




lymphoma; Solid
inhibitor




tumor




DS-3201b
Acute
Enhancer of zeste




lymphoblastic
homolog 2




leukemia; Acute
inhibitor




myelogenous





leukemia; Adult





T-cell lymphoma;





Non-Hodgkin





lymphoma




citarinostat
Advanced solid
Histone




tumor; Mantle cell
deacetylase-6




lymphoma;
inhibitor




Melanoma;





Multiple myeloma




ubenimex
Acute
Aminopeptidase




myelogenous
inhibitor;




leukemia;
Leukotriene A4




Carcinoma;
hydrolase




Lymphedema;
inhibitor;




Pulmonary artery
Leukotriene BLT




hypertension
receptor





antagonist



RGX-104
Glioblastoma;
Liver X receptor




Lymphoma;
agonist




Melanoma; Solid





tumor




TAK-659
Acute
Flt3 tyrosine




myelogenous
kinase inhibitor;




leukemia;
Syk tyrosine




Chronic
kinase inhibitor




lymphocytic





leukemia; Diffuse





large B-cell





lymphoma;





Lymphoma; Solid





tumor




RG-6146
Acute
Bromodomain




myelogenous
containing protein




leukemia;
inhibitor




Multiple





myeloma;





Myelodysplastic





syndrome; Solid





tumor




dezapelisib
B-cell lymphoma;
Phosphoinositide-




Hodgkins disease
3 kinase delta





inhibitor



DS-3032
Advanced solid
E3 ubiquitin




tumor; Cancer;
protein ligase




hematological
MDM2 inhibitor




neoplasm;





Liposarcoma;





Lymphoma;





Multiple





myeloma; Soft





tissue sarcoma




valproic acid +
Diffuse large B-
Glucocorticoid



prednisone (oral,
cell lymphoma
agonist; Histone



diffuse large B-cell

deacetylase



lymphoma),

inhibitor



Valcuria/





Respiratorius





VLX-1570
Cancer; Multiple
Proteasome




myeloma
inhibitor; Ubiquitin





carboxyl hydrolase





isozyme L5





inhibitor; Ubiquitin





thioesterase-14





inhibitor



CC-115
Chronic
DNA dependent




lymphocytic
protein kinase




leukemia;
inhibitor; mTOR




Glioblastoma;





Non-Hodgkin





lymphoma; Solid





tumor




vincristine sulfate





(liposome injection,





cancer), Shanghai





Fudan-Zhangijang





Bio-





Pharmaceutical/





Shanghai





Pharmaceuticals





NS-018
Multiple
Jak2 tyrosine




myeloma;
kinase inhibitor;




Myelodysplastic
Src tyrosine




syndrome;
kinase inhibitor




Myelofibrosis




naloxone (topical
Mycosis
Opioid receptor



lotion, CTCL-
fungoides;
antagonist



associated pruritus),
Pruritus




Elorac





peldesine

Purine nucleoside





phosphorylase





inhibitor



atiprimod





CS-2164
Cancer; Non-
Aurora protein




Hodgkin
kinase 1 inhibitor;




lymphoma; Ovary
PDGF receptor




tumor
antagonist; VEGF-





1 receptor





antagonist; VEGF-





2 receptor





antagonist; VEGF-





3 receptor





antagonist



pexidartinib
Glioblastoma;
CSF-1 antagonist;




Gliosarcoma;
Fit3 tyrosine




Metastatic breast
kinase inhibitor;




cancer;
Kit tyrosine kinase




Pigmented
inhibitor; SL




villonodular
cytokine ligand




synovitis; Solid
inhibitor




tumor; Stage III





melanoma; Stage





IV melanoma




roneparstat
Multiple myeloma
Heparanase





inhibitor



volasertib

Polo-like kinase 1





inhibitor



resminostat
Biliary tumor;
Arginase-I




Colorectal tumor;
inhibitor; Histone




Cutaneous T-cell
deacetylase




lymphoma;
inhibitor; Histone




Hepatocellular
deacetylase-1




carcinoma;
inhibitor; Histone




Hodgkins
deacetylase-2




disease; Non-
inhibitor; Histone




small-cell lung
deacetylase-3




cancer; Pancreas
inhibitor; Histone




tumor; Solid
deacetylase-6




tumor
inhibitor



miltefosine (topical,





cutaneous T-cell





lymphoma),





ExperGen





amrubicin
Bladder tumor;
DNA gyrase




Metastatic breast
inhibitor;




cancer; Multiple
Topoisomerase II




myeloma; Non-
inhibitor




small-cell lung





cancer; Small-cell





lung cancer;





Thymus





neoplasm




silmitasertib
Cancer;
Casein kinase II




Cholangiocarcino-
inhibitor




ma; Multiple





myeloma




fenretinide
Cutaneous T-cell
FGF receptor



(intravenous
lymphoma;
antagonist; VEGF



emulsion,
Leukemia;
receptor



lymphoma/solid
Lymphoma;
antagonist



tumors/pediatric
Neuroblastoma;




neuroblastomas/
Peripheral T-cell




pediatric leukemia),
lymphoma; Solid




CerRx
tumor




doxorubicin
Metastatic breast
DNA polymerase



hydrochloride
cancer;
inhibitor;



(liposomal,
Metastatic ovary
Topoisomerase II



chromane-6
cancer; Multiple
inhibitor



antioxidant),
myeloma




Lipotec/GP Pharm
Sarcoma; Soft





tissue sarcoma




firtecan pegol
Breast tumor;
Hypoxia inducible




Cancer;
factor-1 alpha




Colorectal tumor;
modulator;




Solid tumor
Topoisomerase I





inhibitor



ENMD-2076
Breast tumor;
Aurora protein




Hepatocellular
kinase 1 inhibitor;




carcinoma;
Aurora protein




Leukemia;
kinase 2 inhibitor,




Multiple
FGF1 receptor




myeloma;
antagonist; FGF3




Ovarian clear cell
receptor




carcinoma; Ovary
antagonist; Flt3




tumor; Soft tissue
tyrosine kinase




sarcoma; Solid
inhibitor; Jak2




tumor
tyrosine kinase





inhibitor; VEGF-1





receptor





antagonist; VEGF-





2 receptor





antagonist; X-





linked inhibitor of





apoptosis protein





inhibitor



AT-9283 (iv,

Abl tyrosine



cancer), Astex

kinase inhibitor;





Aurora protein





kinase 1 inhibitor;





Aurora protein





kinase 2 inhibitor;





Bcr protein





inhibitor; Flt3





tyrosine kinase





inhibitor; Jak2





tyrosine kinase





inhibitor



forodesine (oral,
Peripheral T-cell
Purine nucleoside



cancer),
lymphoma
phosphorylase



BioCryst/

inhibitor



Mundipharma





minodronic acid
Osteroporosis




abexinostat
Breast tumor;
Histone




Follicle center
deacetylase




lymphoma;
inhibitor




Hematological





neoplasm;





Lymphoma;





Mantle cell





lymphoma;





Nasopharyngeal





carcinoma; Non-





Hodgkin





lymphoma; Renal





cell carcinoma;





Sarcoma; Solid





tumor




darinaparsin (iv,
Peripheral T-cell




cancer), Solasia
lymphoma




Pharma





cefcapene
Abscess; Acute
Penicillin binding




bronchitis;
protein inhibitor




Bacterial eye





infection;





Bacterial





infection;





Bacterial





pneumonia;





Bacterial





respiratory tract





infection;





Bacterial skin





infection;





Bacterial urinary





tract infection;






Bacteroides






infection;





Bartholinitis;





Cervicitis;





Cholangitis;





Cholecystitis;





Citrobacter





infection; Cystitis;





Dacryocystitis;






Enterobacter






infection;






Escherichia coli






infection;






Haemophilus







influenzae






infection; Jaw





disease;






Klebsiella






infection;





Laryngitis;





Lymphangitis;





Mastitis;






Moraxella







catarrhalis






infection;






Morganella







morganii






infection;






Neisseria







gonorrhoeae






infection; Otitis






externa; Otitis






media; Pelvic





inflammatory





disease;






Peptostreptococcus







infection;






Pericoronitis;





Periodontal





disease;





Pharyngitis;






Prevotella






infection;






Propionibacterium







acnes






infection; Proteus





infection;






Providencia







infection;






Pyelonephritis;





Respiratory





disease; Serratia





infection;





Sinusitis;






Staphylococcus






infection;






Streptococcus






infection;






Streptococcus






pneumoniae





infection;





Tonsillitis;





Urethritis; Uterus





infection




tasquinimod
Hepatocellular
S100 calcium




carcinoma;
binding protein A9




Multiple myeloma
modulator



forodesine
B-cell acute
Purine nucleoside



(intravenous,
lymphoblastic
phosphorylase



cancer), BioCryst/
leukemia;
inhibitor



Mundipharma
Chronic





lymphocytic





leukemia;





Leukemia; T-cell





lymphoma




arsenic trioxide, CTI
Acute




BioPharma Corp
myelogenous





leukemia; Acute





promyelocytic





leukemia;





Bladder tumor;





Brain tumor;





Chronic





myelocytic





leukemia;





Chronic





myelomonocytic





leukemia;





Esophagus





tumor; Glioma;





Hodgkins





disease;





Lymphoid





leukemia;





Lymphoma;





Melanoma;





Multiple





myeloma;





Myelodysplastic





syndrome; Non-





Hodgkin





lymphoma;





Prostate tumor;





Renal cell





carcinoma;





Uterine cervix





tumor




sapacitabine
Acute
DNA polymerase




myelogenous
inhibitor




Leukemia; B-cell





lymphoma;





Chronic





lymphocytic





leukemia;





Myelodysplastic





syndrome; Non-





small-cell lung





cancer; Ovary





tumor; Solid





tumor




RO-6870810
Multiple myeloma
Bromodomain





containing protein





inhibitor



nelfinavir (multiple
Multiple myeloma




myeloma), Swiss





Group for Clinical





Cancer Research





para-
Adenoid tumor;




toluenesulfonamide
Cancer




(adenoid cystic





carcinoma), PTS





International





MK-1454
Advanced solid
Stimulator of




tumor;
interferon genes




Lymphoma
protein stimulator



vitalethine





resiquimod (topical
Cutaneous T-cell
IL2 gene



gel, cutaneous T cell
lymphoma
stimulator; TLR-7



lymphoma)

agonist; TLR-8



Galderma/University

agonist



of Pennsylvania





sirolimus (inhaled,
Lymphangioleio-
mTOR inhibitor



lymphangioleiomyo-
myomatosis;




matosis/pulmonary
Pulmonary artery




artery hypertension),
hypertension




LAM Therapeutics





M-2951
Diffuse large B-
Btk tyrosine




cell lymphoma;
kinase inhibitor




Multiple sclerosis;





Rheumatoid





arthritis; Systemic





lupus





erythematosus




RG-7845
Autoimmune
Btk tyrosine




disease;
kinase inhibitor




Rheumatoid





arthritis; Systemic





lupus





erythematosus;





Urticaria




ME-401
Chronic
Phosphoinositide-




lymphocytic
3 kinase delta




leukemia; Follicle
inhibitor




center





lymphoma;





Hematological





neoplasm




AR-42
Acoustic
Histone




neuroma;
deacetylase




Hematological
inhibitor




neoplasm;





Meningioma;





Multiple





myeloma;





Neurofibromatosis





type II; Solid





tumor




SP-2-59
Multiple myeloma
Histone





deacetylase-6





inhibitor



bimiralisib
Cancer; Central
Phosphoinositide




nervous system
3-kinase inhibitor;




tumor; Diffuse
mTOR complex 1




large B-cell
inhibitor; mTOR




lymphoma;
complex 2 inhibitor




Glioblastoma;





Lymphoma;





Metastatic breast





cancer; Non-





Hodgkin





lymphoma; Solid





tumor




taselisib
Breast tumor;
Phosphoinositide




Metastatic breast
3-kinase inhibitor




cancer; Non-





Hodgkin





lymphoma; Solid





tumor




MBC-11
Bone





metastases;





multiple





myeloma;





Prostate tumor




DaunoXome
Acute





myelogenous





leukemia;





Kaposis sarcoma




eFT-508
Lymphoma;
MNK1 protein




Metastatic
kinase inhibitor;




colorectal cancer;
MNK2 protein




Solid tumor
kinase inhibitor



sapanisertib
Anaplastic thyroid
mTOR complex 1




cancer; Breast
inhibitor; mTOR




tumor;
complex 2 inhibitor




Endometrioid





carcinoma;





Hepatocellular





carcinoma;





Lymphoma;





Macroglobulinemia;





Merkel cell





carcinoma;





Metastatic renal





cancer; Multiple





myeloma;





Prostate tumor;





Renal tumor;





Solid tumor;





Transitional cell





carcinoma




zoledronic acid
Bone





metastases;





Bone resorption;





Breast tumor;





Hypercalcemia;





Male





osteoporosis;





Mesothelioma;





Metastasis;





Multiple





myeloma;





Osteoarthritis;





Osteogenesis





imperfecta;





Osteoporosis;





Pagets bone





disease;





Postmenopausal





osteoporosis




mechlorethamine
Cutaneous T-cell




hydrochloride
lymphoma;




(topical gel,
Mycosis




CTCL/mycosis
fungoides




fungoides), Yaupon





irinotecan
Brain tumor;
Topoisomerase I




Breast tumor;
inhibitor




Colorectal tumor;





Lung tumor;





Metastatic





colorectal cancer;





Metastatic





pancreas cancer;





Non-Hodgkin





lymphoma; Ovary





tumor; Solid





tumor; Squamous





cell carcinoma;





Stomach tumor;





Uterus tumor




clarithromycin
Abscess; Acute





bronchitis; Acute





sinusitis;





Bacterial





infection;





Bacterial





pneumonia;





Bacterial





respiratory tract





infection;





Bacterial skin





infection;






Bordetella







pertussis






infection;






Campylobacter






infection;





Cervicitis;






Chlamydia






infection;






Chlamydia







pneumoniae






infection; Chronic





bronchitis;





Enterocolitis;






Haemophilus







influenzae






infection;






Haemophilus







parainfluenzae






infection;






Helicobacter







pylori infection;






Laryngitis;






Legionella






infection;





Lymphadenitis;





Lymphangitis;






Moraxella







catarrhalis






infection;






Mycobacterium






infection;





Mycoplasma





infection; Otitis






media;







Peptostreptococcus






infection;





Pericoronitis;





Periodontitis;





Pharyngitis;





Prophylaxis;





Sinusitis;






Staphylococcus







aureus infection;







Staphylococcus






infection;






Streptococcus






infection;






Streptococcus







pneumoniae






infection;






Streptococcus







pyogenes






infection;





Tonsillitis;





Urethritis




bexarotene (oral
Cutaneous T-cell
Insulin sensitizer;



formulation), Eisai
lymphoma
Retinoid X





receptor





modulator



bexarotene (gel
Cutaneous T-cell
Retinoid X



formulation),
lymphoma
receptor



Eisai/Minophagen

modulator



OXS-3550
B-cell lymphoma




acalabrutinib
B-cell lymphoma;
Btk tyrosine




Chronic
kinase inhibitor




lymphocytic





leukemia;





Glioblastoma;





Macroglobulinemia;





Mantle cell





lymphoma;





Metastatic





bladder cancer;





Metastatic head





and neck cancer;





Metastatic





pancreas cancer;





Non-small-cell





lung cancer;





Ovary tumor;





Rheumatoid





arthritis




RRx-001
Cholangiocarcino-
DNA




ma; Colorectal
methyltransferase




tumor; Multiple
inhibitor; Epigen




myeloma;
modulator




Neuroendocrine





tumor; Non-





small-cell lung





cancer; Ovary





tumor; Small-cell





lung cancer




topotecan
Lung tumor;
Topoisomerase I




Ovary tumor;
inhibitor




Small-cell lung





cancer; Solid





tumor; Uterine





cervix tumor




ricolinostat
Cancer;
Histone




Cholangiocarcino-
deacetylase-1




ma; Cilia disease;
inhibitor; Histone




Diabetic
deacetylase-2




neuropathy;
inhibitor; Histone




Lymphoma;
deacetylase-6




Multiple
inhibitor




myeloma;





Neuropathy;





Polycystic kidney





disease




mitoxantrone
Lymphoma;
Topoisomerase II



hydrochloride
Metastatic breast
modulator



(liposome,
cancer; Non-




lymphoma), CSPC
Hodgkin




Zhongqi
lymphoma; Solid




Pharmaceutical
tumor




Technology





(Shijiazhuang) Co





Ltd





bendamustine
Chronic
PARP modulator



hydrochloride
lymphocytic




(ready-to-dilute, iv,
leukemia; Non-




chronic lymphocytic
Hodgkin




leukemia/non-
lymphoma




Hodgkin's





lymphoma), Eagle





Pharmaceuticals





idasanutlin
Acute
Mdm2 p53-binding




myelogenous
protein inhibitor




leukemia;





Hematological





neoplasm; Non-





Hodgkin





lymphoma;





Polycythemia





vera; Solid tumor;





Thrombocythemia




Poly-ICLC
Cancer; Glioma;
Interferon agonist;




Metastatic colon
TLR-3 agonist




cancer;





Metastatic





pancreas cancer;





Non-Hodgkin





lymphoma; Solid





tumor; Stroke;





Viral infection




vorinostat (oral),
Acute
Histone



Merck & Co
myelogenous
deacetylase




leukemia; B-cell
inhibitor; Histone




lymphoma;
deacetylase-1




Breast tumor;
inhibitor; Histone




Chronic
deacetylase-2




lymphocytic
inhibitor; Histone




leukemia;
deacetylase-3




Colorectal tumor;
inhibitor; Histone




Cutaneous T-cell
deacetylase-6




lymphoma;
inhibitor




Diffuse large B-





cell lymphoma;





Follicle center





lymphoma; HIV





infection;





Leukemia;





Lymphoma;





Mantle cell





lymphoma;





Marginal zone B-





cell lymphoma;





Metastasis;





Metastatic non





small cell lung





cancer;





Metastatic renal





cancer; Multiple





myeloma;





Myelodysplastic





syndrome; Non-





Hodgkin





lymphoma;





Prostate tumor;





Renal tumor;





Sarcoma; Small-





cell lung cancer;





Solid tumor




pentostatin
Chronic
Adenosine




lymphocytic
deaminase




leukemia; Hairy
inhibitor




cell leukemia




retinoic acid
Adenoid tumor
MYB gene



agonists (adenoid

inhibitor; Retinoic



cystic carcinoma),

acid receptor



Boston Children's

agonist



Hospital





KA-2237
B-cell lymphoma;
Phosphoinositide-




Inflammatory
3 kinase beta




disease; Solid
inhibitor;




tumor
Phosphoinositide-





3 kinase delta





inhibitor



motolimod
B-cell lymphoma;
TLR-8 agonist




Fallopian tube





cancer; Head and





neck tumor;





Ovary tumor;





Peritoneal tumor




entinostat
Acute
Histone




myelogenous
deacetylase




leukemia; Breast
inhibitor




tumor; Colorectal





tumor;





Lymphoma;





Melanoma;





Metastatic breast





cancer;





Metastatic non





small cell lung





cancer;





Metastatic renal





cancer;





Myelodysplastic





syndrome; Non-





small-cell lung





cancer; Ovary





tumor; Uveal





melanoma




CLR-131
Glioma; Head





and neck tumor;





Hematological





neoplasm;





Multiple





myeloma; Solid





tumor; Uterus





tumor




afuresertib

AKT protein





kinase inhibitor



SNX-5422 (oral,
Cancer, Chronic
Hsp 90 inhibitor



cancer), Esanex
lymphocytic





leukemia;





Hematological





neoplasm; Non-





Hodgkin





lymphoma; Solid





tumor




AT-7519
Chronic
Cyclin-dependent




lymphocytic
kinase-1 inhibitor;




leukemia;
Cyclin-dependent




Hematological
kinase-2 inhibitor;




neoplasm; Mantle
Cyclin-dependent




cell lymphoma;
kinase-3 inhibitor;




Multiple
Cyclin-dependent




myeloma; Non-
kinase-4 inhibitor;




Hodgkin
Cyclin-dependent




lymphoma; Solid
kinase-5 inhibitor;




tumor
Cyclin-dependent





kinase-6 inhibitor;





Cyclin-dependent





kinase-7 inhibitor;





Cyclin-dependent





kinase-9 inhibitor;





Glycogen





synthase kinase-3





beta inhibitor;





RNA polymerase





II inhibitor



CKD-581 (iv,
Lymphoma;
Caspase-3



cancer), Chong
Multiple myeloma
stimulator;



Kun Dang

Caspase-7





stimulator;





Caspase-9





stimulator; Histone





deacetylase





inhibitor



pralatrexate
B-cell lymphoma;
DHFR inhibitor;




Bladder tumor;
Folate antagonist;




Breast tumor;
Folate transporter




Cutaneous T-cell
1-modulator




lymphoma;





Esophagus





tumor; Fallopian





tube cancer;





Head and neck





tumor; Multiple





myeloma; Non-





small-cell lung





cancer; Ovary





tumor; Peripheral





T-cell lymphoma;





Peritoneal tumor;





Stomach tumor




retaspimycin (iv,

Flt3 tyrosine



cancer), Infinity

kinase modulator;





Hsp 90 inhibitor;





Kit tyrosine kinase





modulator



RP-4010
Non-Hodgkin
Ca2+ release




lymphoma
activated Ca2+





channel inhibitor



opaganib
Cholangiocarcino-
Dihydroceramide




ma; Diffuse large
delta 4 desaturase




B-cell lymphoma;
inhibitor;




Hepatocellular
Sphingosine




carcinoma;
kinase 2 inhibitor




Multiple





myeloma;





Prostate tumor;





Radiation





sickness




thalidomide, TTY
Erythema
TNF alpha ligand



Biopharm
nodosum leprae;
inhibitor




Hepatocellular





carcinoma;





Multiple





myeloma;





Myelodysplastic





syndrome




mometasone
Allergic rhinitis;




furoate (nasal),
Nasal polyps;




Merck & Co
Perennial allergic





rhinitis; Seasonal





allergic rhinitis




GSK-3326595
Non-Hodgkin
Protein arginine N-




lymphoma
methyltransferase





5 inhibitor



tirabrutinib
B-cell lymphoma;
Btk tyrosine



hydrochloride
Chronic
kinase inhibitor




lymphocytic





leukemia; Non-





Hodgkin





lymphoma;





Rheumatoid





arthritis;





Sjoegrens





syndrome;





Systemic lupus





erythematosus




entospletinib
Acute
Syk tyrosine




myelogenous
kinase inhibitor




leukemia; B-cell





acute





lymphoblastic





leukemia;





Chronic





lymphocytic





leukemia; Diffuse





large B-cell





lymphoma; Graft





versus host





disease;





Macroglobulinemi-





a; Mantle cell





lymphoma; Non-





Hodgkin





lymphoma




alpelisib
Metastatic breast
Phosphoinositide-




cancer; Multiple
3 kinase alpha




myeloma
inhibitor



vinorelbine
Breast tumor;





Mesothelioma;





Metastatic breast





cancer;





Metastatic non





small cell lung





cancer; Multiple





myeloma; Non-





small-cell lung





cancer




CWP-291
Acute
Beta-catenin




myelogenous
inhibitor




leukemia;





Cancer; Chronic





myelomonocytic





leukemia;





Multiple





myeloma;





Myelodysplastic





syndrome




vemurafenib
Colorectal tumor;
Raf B protein




Hairy cell
kinase inhibitor




leukemia;





Histiocytosis;





Multiple





myeloma; Non-





small-cell lung





cancer; Solid





tumor; Stage IV





melanoma




saracatinib
Alcoholism;
Abl tyrosine




Alzheimers
kinase inhibitor;




disease;
Fyn tyrosine




Lymphangioleio-
kinase inhibitor;




myomatosis;
Src tyrosine




Ostealgia; Otitis
kinase inhibitor




media;





Psychiatric





disorder




temsirolimus
Acute
FK506 binding




lymphoblastic
protein-12




leukemia;
modulator; mTOR




Adrenal cortical
inhibitor




carcinoma;





Angiosarcoma;





Bladder cancer;





Blastoma;





Central nervous





system tumor;





Endometrioid





carcinoma;





Glioma; Head





and neck tumor;





Hemangiopericy-





toma;





Hemangiosarco-





ma; Hepatocellular





carcinoma;





Hodgkins





disease;





Lymphoblastic





leukemia; Mantle





cell lymphoma;





Myelodysplastic





syndrome; Non-





Hodgkin





lymphoma;





Ovarian clear cell





carcinoma;





Paraganglioma;





Peripheral T-cell





lymphoma;





Pheochromocyto-





ma; Renal cell





carcinoma;





Rhabdomyosarco-





ma; Thymus





neoplasm;





Thyroid tumor




everolimus
Acute
mTOR complex 1




lymphoblastic
inhibitor; mTOR




leukemia;
inhibitor




Advanced solid





tumor;





Angiomyolipoma;





Astrocytoma;





Bladder cancer;





Breast tumor;





Colorectal tumor;





Cutaneous T-cell





lymphoma;





Diffuse large B-





cell lymphoma;





Endometrioid





carcinoma;





Epilepsy;





Esophagus





tumor; Glioma;





Head and neck





tumor; Heart





transplant





rejection; Kidney





transplant





rejection; Liver





transplant





rejection; Lung





transplant





rejection;





Macroglobulinemi-





a; Medullary





thyroid cancer;





Metastatic breast





cancer;





Metastatic renal





cancer; Multiple





hamartoma





sydrome;





Neuroendocrine





tumor;





Neurofibromatosis





type I; Non-





Hodgkin





lymphoma; Non-





small-cell lung





cancer;





Pancreatic





endocrine tumor;





Renal cell





carcinoma; Solid





tumor; Stomach





tumor; Thyroid





tumor; Transplant





rejection; Uveal





melanoma




sunitinib
Adrenal cortical
CSF-1 antagonist;




carcinoma;
Flt3 tyrosine




Anaplastic
kinase inhibitor;




astrocytoma;
Kit tyrosine kinase




Angiosarcoma;
inhibitor; PDGF




Blastoma;
receptor alpha




Central nervous
antagonist; PDGF




system tumor;
receptor beta




Chondrosarcoma;
antagonist; RET




Endometrioid
tyrosine kinase




carcinoma;
receptor family




Gastrointestinal
inhibitor; VEGF-1




stromal tumor;
receptor




Genitourinary
antagonist; VEGF-




tract tumor;
2 receptor




Glioblastoma;
antagonist; VEGF-




Glioma;
3 receptor




Hemangiopericytoma;
antagonist




Hemangiosarcoma;





Hepatocellular





carcinoma;





Hippel Lindau





syndrome;





Mesothelioma;





Neuroendocrine





tumor;





Neurofibromatosis





type I; Ovarian





clear cell





carcinoma; Ovary





tumor; Pancreatic





endocrine tumor;





Paraganglioma;





Pheochromocyto-





ma; Pulmonary





hypertension;





Renal cell





carcinoma; Stage





IV melanoma;





Testis tumor;





Thymus





neoplasm;





Thyroid tumor;





Transitional cell





carcinoma;





Uterine cervix





tumor




G-100
Follicle center
TLR-4 agonist




lymphoma;





Merkel cell





cardinoma; Soft





tissue sarcoma




CKI-27
Multiple
BRAF gene




myeloma; Solid
inhibitor; MEK-1




tumor
protein kinase





inhibitor; Raf 1





protein kinase





inhibitor; Raf B





protein kinase





inhibitor



buparlisib
Diffuse large B-
Phosphoinositide




cell lymphoma;
3-kinase inhibitor




Follicle center





lymphoma;





Hematological





neoplasm; Mantle





cell lymphoma;





Myelofibrosis




MAK-683
Diffuse large B-
Polycomb protein




cell lymphoma;
EED inhbitor




Nasopharyngeal





carcinoma




givinostat
Acute
Bradykinin




myelogenous
receptor




leukemia; Becker
modulator;




muscular
Histone




dystrophy;
deacetylase




Crohns disease;
inhibitor; P2X7




Duchenne
purinoceptor




dystrophy;
agonist;




Hodgkins
Unspecified




disease; Juvenile
cytokine receptor




rheumatoid
antagonist




arthritis; Multiple





myeloma;





Myeloproliferative





disorder;





Polycythemia





vera




ONC-201,
Acute
AKT protein



Oncoceutics
lymphoblastic
kinase inhibitor;




leukemia; Acute
Dopamine D2




myelogenous
receptor




leukemia; Breast
antagonist; TRAIL




tumor; Diffuse
receptor agonist;




large B-cell
Unspecified




lymphoma;
GPCR antagonist




Endometrioid





carcinoma;





Glioblastoma;





Mantle cell





lymphoma;





Metastatic breast





cancer; Multiple





myeloma;





Myelodysplastic





syndrome; Non-





Hodgkin





lymphoma; Solid





tumor




crenigacestat
Solid tumor; T-
Gamma-secretase




cell acute
inhibitor; Notch




lymphoblastic
antagonist; Notch




leukemia; T-cell
receptor




lymphoma
modulator



vistusertib
Advanced solid
mTOR complex 1




tumor; Diffuse
inhibitor; mTOR




large B-cell
complex 2 inhibitor




lymphoma;





Meningioma;





Metastatic breast





cancer; Non-





small-cell lung





cancer; Prostate





tumor; Small-cell





lung cancer;





Stomach tumor




pacritinib
Acute
CSF-1 antagonist;




myelogenous
Cytochrome P450




Leukemia;
reductase




Chronic
inhibitor; Flt3




lymphocytic
tyrosine kinase




leukemia; Graft
inhibitor; IRAK-1




versus host
protein kinase




disease;
inhibitor; Jak2




Myelofibrosis;
tyrosine kinase




Thrombocytopenia
inhibitor



vismodegib
B-cell lymphoma;
Hedgehog protein




Basal cell
inhibitor;




carcinoma; Basal
Smoothened




cell nevus
receptor




syndrome;
antagonist




Chronic





lymphocytic





leukemia; Head





and neck tumor;





Idiopathic





pulmonary





fibrosis;





Meningioma;





Metastatic





prostate cancer;





Myelodysplastic





syndrome;





Myelofibrosis;





Odontogenic





tumor; Pancreatic





ductal





adenocarcinoma;





Sarcoma;





Stomach tumor




gemcitabine
Biliary cancer;





Bladder tumor;





Breast tumor;





Cancer;





Carcinoma;





Hepatobiliary





system tumor;





Lymphoma;





Metastatic breast





cancer;





Metastatic non





small cell lung





cancer;





Metastatic





pancrease cancer;





Non-small-cell





lung cancer;





Ovary tumor;





Pancrease tumor;





Renal cell





carcinoma




SHR-1459
B-cell lymphoma;





Rheumatoid





arthritis




palbociclib
Acute
Cyclin-dependent




lymphoblastic
kinase-4 inhibitor;




leukemia; Acute
Cyclin-dependent




myelogenous
kinase-6 inhibitor;




leukemia; Breast
Retinoblastoma




tumor;
associated protein




Carcinoma; Head
modulator




and neck tumor;





Hormone





refractory





prostate cancer;





Mantle cell





lymphoma;





Metastatic breast





cancer;





Metastatic





prostate cancer;





Multiple





myeloma; Non-





small-cell lung





cancer;





Pancreatic ductal





adenocarcinoma;





Renal failure;





Solid tumor;





Squamous cell





carcinoma; Stage





IV melanoma




BCL-201
Acute
Bcl-2 protein




myelogenous
inhibitor




leukemia;





Chronic





lymphocytic





leukemia; Follicle





center





lymphoma;





Mantle cell





lymphoma;





Myelodysplastic





syndrome; Non-





Hodgkin





lymphoma




dasatinib
Acute
Abl tyrosine




lymphoblastic
kinase inhibitor;




leukemia; Acute
Bcr protein




myelogenous
inhibitor; EPH




leukemia; Breast
family tyrosine




tumor;
kinase inhibitor;




Cholangiocarcino-
Fyn tyrosine




ma; Chronic
kinase inhibitor;




myelocytic
Kit tyrosine kinase




leukemia;
inhibitor; Lck




Colorectal tumor;
tyrosine kinase




Glioblastoma;
inhibitor; PDGF-B




Head and neck
ligand inhibitor;




tumor;
Src tyrosine




Metastasis;
kinase inhibitor;




Sarcoma; Solid
Yes tyrosine




tumor
kinase inhibitor



idelalisib
AL amyloidosis;
Phosphoinositide-




Chronic
3 kinase delta




lymphocytic
inhibitor




leukemia; Follicle





center





lymphoma;





Macroglobulinemi-





a; Mantle cell





lymphoma;





Myelofibrosis;





Non-Hodgkin





lymphoma;





Pancreatic ductal





adenocarcinoma




doxorubicin
Breast tumor;
DNA polymerase



(liposome
Non-Hodgkin
inhibitor;



formulation),
lymphoma; Ovary
Topoisomerase II



Cephalon
tumor
inhibitor



cytarabine-
Acute




asparagine
lymphoblastic




conjugate
leukemia; Acute




(leukemia),
myelogenous




BioSight
leukemia;





Chronic





myelocytic





leukemia; Non-





Hodgkin





lymphoma




panobinostat (oral),
Advanced solid
Cytochrome P450



Novartis
tumor; Cancer;
2D6 inhibitor;




Glioma; Graft
Histone




versus host
deacetylase




disease; HIV-1
inhibitor; Histone




infection;
deacetylase-1




Hormone
inhibitor; Histone




refractory
deacetylase-2




prostate cancer;
inhibitor; Histone




Macroglobulinemi-
deacetylase-3




a; Multiple
inhibitor; Histone




myeloma;
deacetylase-6




Myelofibrosis;
inhibitor; JAK2




Neuroendocrine
gene inhibitor;




tumor; Non-
Orphan nuclear




small-cell lung
hormone receptor




cancer; Sickle
NR4A1 agonist




cell anemia;





Stage IV





melanoma




azacitidine
Acute
DNA




myelogenous
methyltransferase




leukemia;
inhibitor




Chronic





lymphocytic





leukemia;





Chronic





myelocytic





leukemia;





Colorectal tumor;





Follicle center





lymphoma;





Glioma; Hormone





refractory





prostate cancer;





Marginal zone B-





cell lymphoma;





Metastatic breast





cancer; Multiple





myeloma;





Myelodysplastic





syndrome; Ovary





tumor; Renal cell





carcinoma




ARQ-531
Chronic
Btk tyrosine




lymphocytic
kinase inhibitor




leukemia; Diffuse





large B-cell





lymphoma;





Hematological





neoplasm




MOL-4249
Cutaneous T-cell
STAT-3 inhibitor




lymphoma;





Psoriasis




leukemia therapy,
B-cell lymphoma;
Btk tyrosine



Centaurus
Chronic
kinase inhibitor



Biopharma
lymphocytic





leukemia;





Macroglobulinemia




selinexor
Acute
Abl tyrosine




myelogenous
kinase inhibitor;




leukemia; B-cell
Bcr protein




lymphoma;
inhibitor; Cyclin-




Cancer; Chronic
dependent kinase




lymphocytic
inhibitor 1B




leukemia;
stimulator;




Cutaneous T-cell
Exportin 1 inhibitor




lymphoma;





Diffuse large B-





cell lymphoma;





Endometrioid





carcinoma;





Female genital





tract tumor;





Gastrointestinal





tumor;





Glioblastoma;





Hematological





neoplasm;





Hormone





refractory





prostate cancer;





Liposarcoma;





Lung tumor;





Metastatic breast





cancer; Multiple





myeloma;





Myelodysplastic





syndrome;





Neuroendocrine





tumor; Non-





Hodgkin





lymphoma; Non-





small-cell lung





cancer; Ovary





tumor; Pancreas





tumor; Peripheral





T-cell lymphoma;





Rectal tumor;





Sarcoma; Small-





cell lung cancer;





Spina bifida;





Squamous cell





carcinoma;





Systemic lupus





erythematosus;





Thymoma;





Uterine cervis





tumor; Viral





infection




TGR-1202
B-cell lymphoma;
Phosphoinositide-




Chronic
3 kinase delta




lymphocytic
inhibitor




leukemia; Diffuse





large B-cell





lymphoma;





Follicle center





lymphoma;





Hematological





neoplasm;





Hodgkins





disease;





Myelofibrosis;





Non-Hodgkin





lymphoma;





Polycythemia





vera; Solid tumor




cerdulatinib
Chronic
JAK tyrosine




lymphocytic
kinase inhibitor;




leukemia; Non-
Syk tyrosine




Hodgkin
kinase inhibitor




lymphoma;





Rheumatoid





arthritis




duvelisib
Chronic
Phosphoinostide-




lymphocytic
3 kinase delta




leukemia; Follicle
inhibitor;




center
Phosphoinositide-




lymphoma;
3 kinase gamma




Hematological
inhibitor




neoplasm;





Lymphoma; Non-





Hodgkin





lymphoma; T-cell





lymphoma




avadomide
Chronic
Pleiotropic drug




lymphocytic
resistance




leukemia; Diffuse
transporter




large B-cell
modulator; Protein




lymphoma;
cereblon




Hepatocellular
modulator




carcinoma;





Multiple





myeloma; Non-





Hodgkin





lymphoma; Solid





tumor




tucidinostat
Acute
Histone




myelogenous
deacetylase-1




leukemia; Breast
inhibitor; Histone




tumor; Cancer;
deacetylase-10




Cutaneous T-cell
inhibitor; Histone




lymphoma;
deacetylase-2




Diffuse large B-
inhibitor; Histone




cell lymphoma;
deacetylase-3




Non-Hodgkin
inhibitor




lymphoma; Non-





small-cell lung





cancer;





Peripheral T-cell





lymphoma; Solid





tumor




fostamatinib
Autoimmune
Syk tyrosine



disodium
hemolytic
kinase inhibitor




anemia; IgA





nephropathy;





Immune





thrombocytopenic





purpura;





Systemic lupus





erythematosus




celecoxib
Ankylosing
Cyclooxygenase 2




spondylitis; Back
inhibitor




pain; Breast





tumor;





Dysmenorrhea;





Familial





adenomatous





polyposis;





Osteoarthritis;





Pain; Periarthritis;





Rheumatoid





arthritis;





Tenosynovitis




S-64315
Acute
Mcl-1




myelogenous
differentiation




leukemia; Diffuse
protein inhibitor




large B-cell





lymphoma;





Multiple





myeloma;





Myelodysplastic





syndrome




itacitinib
Advanced solid
Jak1 tyrosine




tumor; B-cell
kinase inhibitor




lymphoma;





Diffuse large B-





cell lymphoma;





Graft versus host





disease;





Hodgkins





disease;





Myelofibrosis;





Non-small-cell





lung cancer;





Pancrease tumor




BGB-3111
B-cell lymphoma;
Btk tyrosine




Chronic
kinase inhibitor




lymphoctyic





leukemia; Diffuse





large B-cell





lymphoma;





Hematological





neoplasm;





Macroglobulinemi-





a; Mantle cell





lymphoma; Solid





tumor




encorafenib
Advanced solid
Raf B protein




tumor;
kinase inhibitor




Melanoma;





Metastatic





colorectal cancer;





Multiple





myeloma; Non-





small-cell lung





cancer; Stage IV





melanoma




venetoclax
Acute
Bcl-2 protein




myelogenous
inhibitor




leukemia;





Cancer; Chronic





lymphocytic





leukemia; Diffuse





large B-cell





lymphoma;





Follicle center





lymphoma;





Hematological





neoplasm; Mantle





cell lymphoma;





Metastatic breast





cancer; Multiple





myeloma;





Myelodysplastic





syndrome; Non-





Hodgkin





lymphoma;





Systemic lupus





erythematosus




copanlisib
Advanced solid
Phosphoinositide




tumor; Breast
3-kinase inhibitor




tumor;





Cholangiocarcino-





ma; Diffuse large





B-cell lymphoma;





Endometrioid





carcinoma;





Follicle center





lymphoma;





Marginal zone B-





cell lymphoma;





Non-Hodgkin





lymphoma;





Peripheral T-cell





lymphoma;





Splenic marginal





zone lymphoma




GMI-1271
Acute
E-Selectin




myelogenous
antagonist




leukemia; Deep





vein thrombosis;





Metastasis;





Multiple





myeloma;





Myocardial





infarction;





Pancrease tumor;





Solid tumor;





Thromboembolism




binimetinib
Acute
BRAF gene




myelogenous
inhibitor; MEK




leukemia;
protein kinase




Adenocacinoma;
inhibitor; MEK-1




Advanced solid
protein kinase




tumor; Biliary
inhibitor; MEK-2




cancer; Cancer;
protein kinase




Chronic
inhibitor; PERK




myelocytic
gene inhibitor




leukemia;





Colorectal tumor;





Liver disease;





Melanoma;





Metastatic





colorectal cancer;





Multiple





myeloma;





Neurofibromatosis





type I; Noonan





syndrome;





Prostate tumor;





Stage IV





melanoma; Uveal





melanoma




trametinib
Acute
MEK-1 protein




myelogenous
kinase inhibitor;




leukemia; Biliary
MEK-2 protein




cancer;
kinase inhibitor




Colorectal tumor;





Endometrioid





carcinoma;





Leukemia;





Melanoma;





Metastatic non





small cell lung





cancer;





Metastatic rectal





cancer; Non-





small-cell lung





cancer; Pancreas





tumor; Solid





tumor; Stage III





melanoma; Stage





IV melanoma;





Thyroid tumor;





Uterine cervix





tumor




ibrutinib
Acute
Btk tyrosine




myelogenous
kinase inhibitor




leukemia; Allergic





rhinitis;





Autoimmune





disease; B-cell





acute





lymphoblastic





leukemia; B-cell





lymphoma;





Breast tumor;





Carcinoid tumor;





Chronic





lymphocytic





leukemia;





Colorectal tumor;





Diffuse large B-





cell lymphoma;





Follicle center





lymphoma; Graft





versus host





disease; Hairy





cell leukemia;





Lymphoplasmacy-





toid lymphoma;





Macroglobulinemi-





a; Mantle cell





lymphoma;





Marginal zone B-





cell lymphoma;





Metastatic non





small cell lung





cancer;





Metastatic renal





cancer; Multiple





myeloma;





Neuroendocrine





tumor; Non-





Hodgkin





lymphoma;





Pancreas tumor;





Renal cell





carcinoma; Solid





tumor; Stomach





tumor; Systemic





mastocytosis; T-





cell lymphoma;





Transitional cell





carcinoma




ruxolitinib (oral,
Acute
Jak1 tyrosine



myeloproliferative
lymphoblastic
kinase inhibitor;



disorders),
leukemia; Acute
Jak2 tyrosine



Incyte/Novartis
myelogenous
kinase inhibitor




leukemia; B-cell





lymphoma;





Breast disease;





Cachexia;





Chronic





lymphocytic





leukemia;





Chronic





myelocytic





leukemia; Graft





versus host





disease; Head





and neck tumor;





Hodgkins





disease;





Leukemia;





Metastatic breast





cancer;





Myelofibrosis;





Polycythemia





vera;





Splenomegaly; T-





cell lymphoma;





Thalassemia





major;





Thrombocythemia




cabozantinib S-
Acute
Axl tyrosine kinase



malate
myelogenous
receptor inhibitor;




leukemia;
Flt3 tyrosine




Advanced solid
kinase inhibitor;




tumor; Bladder
Hepatocyte growth




cancer; Bone
factor antagonist;




metastases;
Kit tyrosine kinase




Breast tumor;
inhibitor; MET




Cancer;
tyrosine kinase




Colorectal tumor;
receptor family




Endometrioid
inhibitor; RET




carcinoma;
tyrosine kinase




Gastrointestinal
receptor family




stromal tumor;
inhibitor; Tek




Glioblastoma;
tyrosine kinase




Hepatocellular
receptor inhibitor;




carcinoma;
TrkB receptor




Medullary thyroid
antagonist; VEGF




cancer; Merkel
receptor




cell carcinoma;
antagonist; VEGF-




Metastatic renal
1 receptor




cancer; Multiple
antagonist; VEGF-




myeloma;
2 receptor




Neuroendocrine
antagonist; VEGF-




tumor; Non-
3 receptor




small-cell lung
antagonist




cancer; Ovary





tumor; Pancreas





tumor; Papillary





thyroid tumor;





Renal cell





carcinoma; Soft





tissue sarcoma




bosutinib
Acute
Abl tyrosine




lymphoblastic
kinase inhibitor;




leukemia;
DNA gyrase




Advanced solid
inhibitor; Src




tumor; Chronic
tyrosine kinase




myelocytic
inhibitor




leukemia;





Dementia;





Multiple





myeloma; Non-





Hodgkin





lymphoma




pomalidomide
AL amyloidosis;





Cancer; Multiple





myeloma;





Myelofibrosis;





Scleroderma




bortezomib
Acute
26S proteasome
proteasome



lymphoblastic
complex inhibitor;




leukemia; Acute
Proteasome




myelogenous
inhibitor




leukemia; Breast





tumor; Chronic





lymphocytic





leukemia; Diffuse





large B-cell





lymphoma; Graft





versus host





disease; Head





and neck tumor;





Hormone





refractory





prostate cancer;





Kidney transplant





rejection;





Macroglobulinemi-





a; Mantle cell





lymphoma;





Multiple





myeloma;





Myelodysplastic





syndrome; Non-





Hodgkin





lymphoma; Non-





small-cell lung





cancer; Ovary





tumor; Peripheral





T-cell lymphoma;





Solid tumor;





Squamous cell





carcinoma; Stage





IV melanoma




MOL-4239,
Cutaneous T-cell
STAT-3 inhibitor



Moleculin Biotech
lymphoma;





Psioriasis




febuxostat
Gout;
Xanthine oxidase




Hyperuricemia;
inhibitor




Tumor lysis





syndrome




milciclib
Breast tumor;
Cyclin dependent




Hepatocellular
kinase inhibitor;




carcinoma; Liver
Cyclin-dependent




tumor; Thymus
kinase-1 inhibitor;




neoplasm
Cyclin-dependent





kinase-4 inhibitor;





Cyclin-dependent





kinase-5 inhibitor;





Cyclin-dependent





kinase-7 inhibitor



alisertib

Aurora protein





kinase 2 inhibitor



vinorelbine
Cutaneous T-cell




(intravenous/
lymphoma; Non-




liposome
Hodgkin




encapsulated,
lymphoma;




cancer), Taiwan
Rhabdomyosarco-




Liposome
ma; Soft tissue





sarcoma




pazopanib
Bladder cancer;
FGF1 receptor




Merkel cell
antagonist; FGF3




carcinoma;
receptor




Prostate tumor;
antagonist; Itk




Renal cell
tyrosine kinase




carcinoma; Soft
inhibitor; Kit




tissue sarcoma
tyrosine kinase





inhibitor; Lck





tyrosine kinase





inhibitor; Ltk





tyrosine kinase





receptor inhibitor;





PDGF receptor





alpha antagonist;





PDGF receptor





beta antagonist;





Protein tyrosine





kinase inhibitor;





VEGF-1 receptor





antagonist; VEGF-





2 receptor





antagonist; VEGF-





3 receptor





antagonist



axitinib
Advanced solid
Bcr protein




tumor; Carcinoid
inhibitor; CD79




tumor; Chronic
antagonist; CSF-1




myelocytic
antagonist; PDGF




leukemia;
receptor




Glioblastoma;
antagonist; Protein




Hepatocellular
tyrosine kinase




carcinoma;
inhibitor; Tyrosine




Melanoma;
protein kinase




Multiple
ABL1 inhibitor;




myeloma;
VEGF receptor




Nasopharyngeal
antagonist; VEGF-




carcinoma; Non-
1 receptor




Hodgkin
antagonist; VEGF-




lymphoma;
2 receptor




Prostate tumor;
antagonist; VEGF-




Renal cell
3 receptor




carcinoma
antagonist



thalidomide,
Multiple




Celgene
myeloma;





Mycobacterium





leprae infection




imiquimod
Basal cell
TLR-7 agonist




carcinoma;





Condyloma;





Keratosis;





Molluscum





contagiosum





infection; Mycosis





fungoides;





Verruca vulgaris




masitinib
Alzheimers
CSF-1 antagonist;




disease; Asthma;
FGF3 receptor




Breast tumor;
antagonist; Fyn




Chronic
tyrosine kinase




obstructive
inhibitor; Kit




pulmonary
tyrosine kinase




disease;
inhibitor; Lyn




Gastrointestinal
tyrosine kinase




tumor;
inhibitor; NK cell




Glioblastoma;
receptor




Hormone
modulator; PDGF




refractory
receptor




prostate cancer;
antagonist; Protein




Ischemic stroke;
tyrosine kinase




Mastocytosis;
inhibitor




Melanoma;





Metastatic breast





cancer;





Metastatic





colorectal cancer;





Metastatic head





and neck cancer;





Metastatic liver





cancer;





Metastatic non





small cell lung





cancer;





Metastatic ovary





cancer;





Metastatic





pancreas cancer;





Metastatic





stomach cancer;





Motor neurone





disease; Multiple





myeloma;





Multiple sclerosis;





Pancreas tumor;





Peripheral T-cell





lymphoma;





Progressive





supranuclear





palsy;





Rheumatoid





arthritis




nintedanib
Acute
FGF receptor




myelogenous
antagonist; FGF1




leukemia;
receptor




Advanced solid
antagonist; FGF2




tumor; Bladder
receptor




cancer; Breast
antagonist; FGF3




tumor;
receptor




Endometrioid
antagonist; PDGF




carcinoma;
receptor alpha




Glioblastoma;
antagonist; PDGF




Hepatic
receptor




insufficiency;
antagonist; PDGF




Hepatocellular
receptor beta




carcinoma;
antagonist; VEGF




Hormone
receptor




refractory
antagonist; VEGF-




prostate cancer;
1 receptor




Idiopathic
antagonist; VEGF-




pulmonary
2 receptor




fibrosis;
antagonist; VEGF-




Inflammatory
3 receptor




breast cancer;
antagonist




Interstitial lung





disease;





Lymphangioleio-





myomatosis;





Mesothelioma;





Metastatic





colorectal cancer;





Metastatic non





small cell lung





cancer;





Neuroendocrine





tumor; Ovarian





clear cell





carcinoma; Ovary





tumor; Renal cell





carcinoma;





Scleroderma;





Soft tissue





sarcoma; Stage





IV melanoma;





Thyroid tumor




fluticasone
Allergic rhinitis;




propionate
Asthma




etoposide
Acute
Topoisomerase II



phosphate
myelogenous
inhibitor




leukemia;





Choriocarcinoma;





Germ cell and





embryonic





cancer; Hodgkins





disease;





Hormone





refractory





prostate cancer;





Lung tumor; Non-





hodgkin





lymphoma;





Small-cell lung





cancer




vandetanib
Biliary cancer;
EGFR family




Brain tumor;
tyrosine kinase




Breast tumor;
receptor inhibitor;




Colorectal tumor;
EPH family




Glioblastoma;
tyrosine kinase




Medullary thyroid
inhibitor;




cancer;
Epidermal growth




Metastatic breast
factor antagonist;




cancer; Non-
Protein tyrosine




small-cell lung
kinase 6 inhibitor;




cancer; Papillary
RET tyrosine




thyroid tumor;
kinase receptor




Solid tumor;
family inhibitor;




Squamous cell
Src tyrosine




carcinoma;
kinase inhibitor;




Thyroid tumor;
Tek tyrosine




Transitional cell
kinase receptor




carcinoma
inhibitor; VEGF





receptor





antagonist; VEGF-





2 receptor





antagonist



tazemetostat
Advanced solid
Enhancer of zeste




tumor; Diffuse
homolog 2




large B-cell
inhibitor; Histone




lymphoma;
lysine




Follicle center
methyltransferase




lymphoma;
inhibitor




Mesothelioma;





Neuroblastoma;





Non-Hodgkin





lymphoma; Non-





small-cell lung





cancer; Ovary





tumor; Renal cell





carcinoma;





Sarcoma




regorafenib
Adenoid tumor;
Caspase-3




Biliary cancer;
stimulator;




Cholangiocarcino-
Caspase-9




ma; Esophagus
stimulator; FGF




tumor;
receptor




Gastrointestinal
antagonist; Kit




stromal tumor;
tyrosine kinase




Hepatocellular
inhibitor; PDGF




carcinoma;
receptor beta




Metastatic
modulator; RET




colorectal cancer;
tyrosine kinase




Pancreas tumor;
receptor family




Soft tissue
inhibitor; Raf 1




sarcoma; Solid
protein kinase




tumor; Stomach
inhibitor; Raf B




tumor
protein kinase





inhibitor; TIE





tyrosine kinase





receptor inhibitor;





Tek tyrosine





kinase receptor





inhibitor; VEGF-1





receptor





antagonist; VEGF-





2 receptor





antagonist; VEGF-





3 receptor





antagonist



marizomib (iv,
Glioma; Multiple
Proteasome



cancer), Celgene
myeloma
inhibitor



bendamustine
Amyloidosis; B-
PARP modulator




cell lymphoma;





Chronic





lymphocytic





leukemia; Diffuse





large B-cell





lymphoma;





Glioma; Mantle





cell lymphoma;





Metastatic ovary





cancer; Multiple





myeloma; Non-





Hodgkin





lymphoma




lenvatinib mesylate
Adenocarcinoma;
FGF1 receptor




Adenoid tumor;
antagonist; FGF2




Anaplastic thyroid
receptor




cancer; Biliary
antagonist; FGF3




cancer; Breast
receptor




tumor;
antagonist; FGF4




Endometrioid
receptor




carcinoma;
antagonist; Kit




Fallopian tube
tyrosine kinase




cancer;
inhibitor; PDGF




Hepatocellular
receptor alpha




carcinoma;
antagonist; PDGF




Medullary thyroid
receptor beta




cancer;
antagonist; Ret




Metastatic breast
tyrosine kinase




cancer;
receptor inhibitor;




Metastatic
VEGF-1 receptor




colorectal cancer;
antagonist; VEGF-




Neuroendocrine
2 receptor




tumor; Non-
antagonist; VEGF-




small-cell lung
3 receptor




cancer; Ovary
antagonist




tumor; Peritoneal





tumor; Renal cell





carcinoma;





Sarcoma; Solid





tumor; Thyroid





tumor




tamibarotene
Acute
Retinoic acid




myelogenous
receptor alpha




leukemia; Acute
agonist; Retinoic




promyelocytic
acid receptor beta




leukemia;
agonist; Retinoid




Fibrosis;
receptor agonist




Hepatocellular





carcinoma;





Myelodysplastic





syndrome;





Neutropenia




carboplatin
Breast tumor;





Esophagus





tumor; Head and





neck tumor;





Lymphoma; Non-





small-cell lung





cancer; Ovary





tumor; Small-cell





lung cancer;





solid tumor;





Stomach tumor;





Testis tumor;





Uterine cervix





tumor




INCB-50465
B-cell lymphoma;
Phosphoinositide-




Follicle center
3 kinase delta




lymphoma;
inhibitor




Myelofibrosis




INCB-054828
Cholangiocarcino-
FGF receptor




ma;
antagonist




Hematological





neoplasm;





Lymphoma;





Multiple





myeloma; Solid





tumor;





Transitional cell





carcinoma




crizotinib
Anaplastic large
ALK tyrosine




cell lymphoma;
kinase receptor




Cancer;
family inhibitor;




Glioblastoma;
Anaplastic




Hormone
lymphoma kinase




refractory
receptor inhibitor;




prostate cancer;
Echinoderm




Metastasis;
microtubule like




Metastatic non
protein 4 inhibitor;




small cell lung
Hepatocyte growth




cancer;
factor antagonist;




Neuroblastoma;
MET tyrosine




Non-small-cell
kinase receptor




lung cancer;
family inhibitor;




Renal cell
Ros1 tyrosine




carcinoma;
kinase receptor




Rhabdomyosarco-
inhibitor




ma; Soft tissue





sarcoma;





Transitional cell





carcinoma; Uveal





melanoma




carfilzomib
AL amyloidosis;
Proteasome




Acute
inhibitor; Ubiquitin




lymphoblastic
inhibitor




leukemia;





Chronic





lymphocytic





leukemia;





Cutaneous T-cell





lymphoma;





Hormone





refractory





prostate cancer;





Macroglobulinemi-





a; Mantle cell





lymphoma;





Multiple





myeloma;





Neuroendocrine





tumor; Non-





Hodgkin





lymphoma;





Peripheral T-cell





lymphoma; Renal





cell cardinoma;





Small-cell lung





cancer; Solid





tumor




tipifamib
Chronic
Protein




myelocytic
farnesyltransferase




leukemia;
inhibitor; Ras




Hepatitis D virus
GTPase inhibitor




infection;





Myelodysplastic





syndrome;





Peripheral T-cell





lymphoma; Solid





tumor;





Transitional cell





carcinoma




SNS-062
Chronic
Btk tyrosine




lymphocytic
kinase inhibitor




leukemia;





Lymphoplasmacy-





toid lymphoma;





Mantle cell





lymphoma; Non-





Hodgkin





lymphoma




CUDC-907
Breast tumor;
Histone




Carcinoma;
deacetylase-1




Diffuse large B-
inhibitor; Histone




cell lymphoma;
deacetylase-10




Lymphoma;
inhibitor; Histone




Multiple
deacetylase-2




myeloma; Solid
inhibitor; Histone




tumor
deacetylase-3





inhibitor; Histone





deacetylase-6





inhibitor;





Phosphoinositide-





3 kinase alpha





inhibitor;





Phosphoinositide-





3 kinase beta





inhibitor;





Phosphoinositide-





3 kinase delta





inhibitor



niraparib
Advanced solid
Poly ADP ribose




tumor; Ewing
polymerase 1




sarcoma;
inhibitor; Poly ADP




Fallopian tube
ribose polymerase




cancer; Hormone
2 inhibitor




refractory





prostate cancer;





Metastatic breast





cancer; Ovary





tumor; Peritoneal





tumor; Small-cell





lung cancer




azacitidine (oral,
Acute
DNA



cancer), Celgene
myelogenous
methyltransferase




leukemia; Breast
inhibitor




tumor;





Hematological





neoplasm;





Lymphoma;





Metastatic non





small cell lung





cancer;





Myelodysplastic





syndrome; Solid





tumor; Stage IV





melanoma




alvocidib
Acute
Cyclin-dependent




myelogenous
kinase-4 inhibitor;




leukemia;
Cyclin-dependent




Myelodysplastic
kinase-6 inhibitor;




syndrome
Cyclin-dependent





kinase-9 inhibitor



iberdomide
Multiple
DNA binding




myeloma;
protein lkaros




Systemic lupus
inhibitor; Protein




erythematosus
cereblon





modulator; Zinc





finger binding





protein Aiolos





inhibitor



midostaurin
Acute
Flt3 tyrosine




myelogenous
kinase inhibitor;




leukemia;
Kit tyrosine kinase




Systemic
inhibitor; Protein




mastocytosis
kinase C inhibitor



lenalidomide
Acute





myelogenous





leukemia; Adult





T-cell lymphoma;





Amyloidosis; B-





cell acute





lymphoblastic





leukemia;





Bladder cancer;





Chronic





lymphocytic





leukemia;





Cutaneous T-cell





lymphoma;





Follicle center





lymphoma;





Histinocytosis;





Hodgkins





disease; Immune





disorder;





Macroglobulinemi-





a; Mantle cell





lymphoma;





Marginal zone B-





cell lymphoma;





Metastatic non





small cell lung





cancer; Multiple





myeloma;





Myelodysplastic





syndrome; Non-





Hodgkin





lymphoma;





POEMS





syndrome;





Peripheral T-cell





lymphoma; Solid





tumor; T-cell





lymphoma




abemaciclib
Advanced solid
Cyclin-dependent




tumor; Cancer;
kinase-4 inhibitor;




Glioblastoma;
Cyclin-dependent




Mantle cell
kinase-6 inhibitor




lymphoma;





Metastasis;





Metastatic breast





cancer;





Metastatic





pancreas cancer;





Non-small-cell





lung cancer;





Stomach tumor




vincristine sulfate
Acute





lymphoblastic





leukemia; Diffuse





large B-cell





lymphoma;





Leukemia; Non-





Hodgkin





lymphoma




Busulfex
Bone marrow





transplantation;





Hodgkins





disease; Non-





Hodgkin





lymphoma




ASN-002, Asana
Atopic dermatitis;
JAK tyrosine



Biosciences
Inflammatory
kinase inhibitor




disease;
Syk tyrosine




Lymphoma; Solid
kinase inhibitor;




tumor
Unspecified





protein kinase





inhibitor



remetinostat
Alopecia areata;
Histone




Cutaneous T-cell
deacetylase-1




lymphoma;
inhibitor; Histone




Psoriasis
deacetylase-2





inhibitor; Histone





deacetylase-3





inhbitor; Histone





deacetylase-6





inhibitor



ixazomib citrate
Amyloidosis;
Proteasome



(oral, multiple
Bladder
inhibitor



myeloma/
cancer;




amyloidosis),
Breast tumor;




Millennium
HIV infection;





Hematological





neoplasm; Lupus





nephritis;





Lymphoma;





Macroglobulinemi-





a; Multiple





myeloma




fludarabine
Acute
DNA polymerase




myelogenous
alpha inhibitor;




leukemia;
DNA primase




Chronic
inhibitor;




lymphocytic
Ribonucleotide




leukemia;
reductase inhibitor




Chronic





myelocytic





leukemia; Mantle





cell lymphoma;





Multiple





myeloma;





Myelodysplastic





syndrome; Non-





Hodgkin





lymphoma




ganetespib

Hsp 90 inhibitor;





Jak2 tyrosine





kinase inhibitor;





Kit tyrosine kinase





inhibitor; STAT-3





inhibitor; STAT-5





inhibitor



sirolimus
Chondrosarcoma;
mTOR inhibitor




Graft versus





host disease;





Kidney transplant





rejection;





Liposarcoma;





Lymphangioleiomyo-





tosis;





Sytstemic lupus





erythematosus;





Tuberous





sclerosis




radium Ra 223
Bone




dichloride
metastases;





Breast tumor;





Cancer; Hormone





refractory





prostate cancer;





Metastatic breast





cancer;





Metastatic renal





cancer; Multiple





myeloma;





Osteosarcoma









text missing or illegible when filed








In some embodiments, the therapeutic agent is one of those in Table 7, below; or a pharmaceutically acceptable salt thereof.









TABLE 7







Exemplary Therapeutic Agents and Associated Diseases and Disorders











Active
Target-based



Drug Name
Indications
Actions
Structure





sofosbuvir +
Hepatitis C virus
Hepatitis C virus



ledipasvir (fixed-
infection
NS5B polymerase



combination, HCV),

inhibitor; Hepatitis



Gilead

C virus protein





NS5A inhibitor






lenalidomide
Acute myelogenous leukemia; Adult T-cell lymphoma; Amyloidosis; B- cell acute lymphoblastic leukemia; Bladder cancer;



embedded image





Chronic





lymphocytic





leukemia;





Cutaneous T-cell





lymphoma;





Follicle center





lymphoma;





Histiocytosis;





Hodgkins





disease; Immune





disorder;





Macroglobulinemia;





Mantle cell





lymphoma;





Marginal zone B-





cell lymphoma;





Metastatic non





small cell lung





cancer; Multiple





myeloma;





Myelodysplastic





syndrome;





Non-Hodgkin





lymphoma;





POEMS





syndrome;





Peripheral T-cell





lymphoma; Solid





tumor; T-cell





lymphoma




fluticasone
Asthma; Chronic
Beta 2



propionate +
obstructive
adrenoceptor



salmeterol (asthma
pulmonary
agonist



and COPD),
disease




GlaxoSmithKline





sofosbuvir
Hepatitis C virus
Hepatitis C virus




infection
NS5B polymerase





inhibitor



dimethyl fumarate
Demyelinating
Kelch like ECH




disease; Multiple
associated protein




sclerosis;
1 modulator;




Scleroderma
Nuclear erythroid





2-related factor 2





stimulator



budesonide +
Asthma; Chronic
Beta 2



formoterol fumarate,
obstructive
adrenoceptor



AstraZeneca
pulmonary
agonist




disease




fingolimod
Multiple sclerosis;
Cannabinoid




Optic neuritis;
receptor




Rett syndrome;
antagonist;




Uveitis
Sphingosine-1-





phosphate





receptor-1





modulator



ibrutinib
Acute
Btk tyrosine




myelogenous
kinase inhibitor




leukemia; Allergic





rhinitis;





Autoimmune





disease; B-cell





acute





lymphoblastic





leukemia; B-cell





lymphoma:





Breast tumor;





Carcinoid tumor;





Chronic





lymphocytic





leukemia;





Colorectal tumor;





Diffuse large B-





cell lymphoma;





Follicle center





lymphoma; Graft





versus host





disease; Hairy





cell leukemia;





Lymphoplasmacytoid





lymphoma;





Macroglobulinemia;





Mantle cell





lymphoma;





Marginal zone B-





cell lymphoma;





Metastatic non





small cell lung





cancer;





Metastatic renal





cancer; Multiple





myeloma;





Neuroendocrine





tumor; Non-





Hodgkin





lymphoma;





Pancreas tumor;





Renal cell





carcinoma; Solid





tumor; Stomach





tumor; Systemic





mastocytosis; T-





cell lymphoma;





Transitional cell





carcinoma




esomeprazole
Bleeding;
H+ K+ ATPase




Duodenal ulcer;
inhibitor




Esophagitis;





Gastroesophageal





reflux;






Helicobacter







pylori infection;






Peptic ulcer;





Zollinger-Ellison





syndrome




bortezomib
Acute
26S proteasome




lymphoblastic
complex inhibitor;




leukemia; Acute
Proteasome




myelogenous
inhibitor




leukemia; Breast





tumor; Chronic





lymphocytic





leukemia; Diffuse





large B-cell





lymphoma; Graft





versus host





disease; Head





and neck tumor;





Hormone





refractory





prostate cancer.





Kidney transplant





rejection;





Macroglobulinemia;





Mantle cell





lymphoma;





Multiple





myeloma;





Myelodysplastic





syndrome; Non-





Hodgkin





lymphoma; Non-





small-cell lung





cancer; Ovary





tumor; Peripheral





T-cell lymphoma;





Solid tumor;





Squamous cell





carcinoma; Stage





IV melanoma




everolimus
Acute
mTOR complex 1




lymphoblastic
inhibitor; mTOR




leukemia;
inhibitor




Advanced solid





tumor;





Angiomyolipoma;





Astrocytoma;





Bladder cancer;





Breast tumor;





Colorectal tumor;





Cutaneous T-cell





lymphoma;





Diffuse large B-





cell lymphoma;





Endometrioid





carcinoma;





Epilepsy;





Esophagus





tumor; Glioma;





Head and neck





tumor; Heart





transplant





rejection; Kidney





transplant





rejection; Liver





transplant





rejection; Lung





transplant





rejection;





Macroglobulinemia;





Medullary





thyroid cancer;





Metastatic breast





cancer;





Metastatic renal





cancer; Multiple





hamartoma





sydrome;





Neuroendocrine





tumor;





Neurofibromatosis





type I; Non-





Hodgkin





lymphoma; Non-





small-cell lung





cancer;





Pancreatic





endocrine tumor;





Renal cell





carcinoma; Solid





tumor; Stomach





tumor; Thyroid





tumor; Transplant





rejection; Uveal





melanoma




tacrolimus
Bone marrow
Calcineurin




transplantation;
inhibitor




Heart





transplantation;





IgA nephropathy;





Kidney





transplantation;





Liver





transplantation;





Lung





transplantation;





Lupus nephritis;





Myasthenia





gravis;





Pneumonia;





Rheumatoid





arthritis;





Transplant





rejection;





Ulcerative colitis




sofosbuvir +
Hepatitis C virus
Hepatitis C virus



velpatasvir (fixed
infection; Liver
NS5B polymerase



dose combination,
cirrhosis
inhibitor; Hepatitis



HCV), Gilead

C virus protein





NS5A inhibitor



paritaprevir +

Hepatitis C virus



ritonavir +

NS3 protease



ombitasvir (oral,

inhibitor; Hepatitis



HCV infection)

C virus NS5B



AbbVie

polymerase





inhibitor; Hepatitis





C virus protein





NS5A inhibitor



teriflunomide
Multiple sclerosis
Dihydroorotate





dehydrogenase





inhibitor



ruxolitinib (oral,
Acute
Jak1 tyrosine



myeloproliferative
lymphoblastic
kinase inhibitor;



disorders),
leukemia; Acute
Jak2 tyrosine



Incyte/Novartis
myelogenous
kinase inhibitor




leukemia; B-cell





lymphoma;





Breast disease;





Cachexia;





Chronic





lymphocytic





leukemia;





Chronic





myelocytic





leukemia; Graft





versus host





disease; Head





and neck tumor;





Hodgkins





disease;





Leukemia;





Metastatic breast





cancer;





Myelofibrosis;





Polycythemia





vera;





Splenomegaly; T-





cell lymphoma;





Thalassemia





major;





Thrombocythemia




montelukast sodium
Allergic rhinitis;
Leukotriene D4




Asthma
antagonist



pomalidomide
AL amyloidosis;





Cancer; Multiple





myeloma;





Myelofibrosis;





Scleroderma




entecavir
Hepatitis B virus
DNA polymerase




infection
inhibitor



tenofovir disoproxil
HIV infection;
NA polymerase



fumarate
HIV-1 infection;
inhibitor; HIV-1




Hepatitis B virus
reverse




infection
transcriptase





inhibitor



budesonide (inhaled
Allergic rhinitis;




formulations),
Asthma; Chronic




AstraZeneca
obstructive





pulmonary





disease; Nasal





polyps




celecoxib
Ankylosing
Cyclooxygenase 2




spondylitis; Back
inhibitor




pain; Breast





tumor;





Dysmenorrhea;





Familial





adenomatous





polyposis;





Osteoarthritis;





Pain; Periarthritis;





Rheumatoid





arthritis;





Tenosynovitis




salbutamol,
Asthma;
Beta 2



GlaxoSmith Kline
Bronchospasm;
adrenoceptor




Chronic
agonist




obstructive





pulmonary





disease




apremilast
Ankylosing
PDE 4 inhibitor




spondylitis;





Behcets disease;





Hidradenitis





suppurativa;





Psoriasis;





Psoriatic arthritis;





Ulcerative colitis




duloxetine
Back pain;





Chronic fatigue





syndrome;





Depression;





Diabetic





peripheral





neuropathy;





Fibromyalgia;





Generalized





anxiety disorder;





Lower back pain;





Major depressive





disorder;





Musculoskeletal





pain; Obsessive





compulsive





disorder;





Osteoarthritis;





Stress urinary





incontinence




tofacitinib citrate
Discoid lupus
JAK tyrosine



(oral, inflammation),
erythematosus;
kinase inhibitor;



Pfizer
Juvenile
Jak1 tyrosine




rheumatoid
kinase inhibitor;




arthritis;
Jak3 tyrosine




Psoriasis;
kinase inhibitor




Psoriatic arthritis;





Rheumatoid





arthritis; Systemic





lupus





erythematosus;





Ulcerative colitis




fluticasone
Allergic rhinitis;




propionate
Asthma




fluticasone furoate +
Asthma; Chronic




vilanterol trifenatate
obstructive




(oral inhalant,
pulmonary




asthma/COPD),
disease




GlaxoSmith Kline





lansoprazole
Duodenal ulcer;
H+ K+ ATPase




Esophagitis;
inhibitor




Gastroesophageal





reflux;





Gastrointestinal





disease;






Helicobacter







pylori infection;






Peptic ulcer;





Stomach ulcer;





Ulcer; Zollinger-





Ellison syndrome




pirfenidone
Cardiac failure;
PDGF receptor




Idiopathic
antagonist; TGF




pulmonary
beta antagonist;




fibrosis
p38 MAP kinase





inhibitor



mesalazine (oral
Irritable bowel




sustained release,
syndrome;




MMX),
Ulcerative colitis




Giuliani/Shire/





Mochida/Pacific





amoxicillin +
Abdominal
Beta lactamase



clavulanate
abscess; Acute
inhibitor



potassium, GSK
bronchitis;





Bacterial





infection;





Bacterial





pneumonia;





Bacterial





respiratory tract





infection;





Bacterial skin





infection;





Bacterial urinary





tract infection;





Bone and joint





infection;





Bronchitis;





Cellulitis; Cystitis;






Enterobacter






infection;






Escherichia coli






infection; Female





genital tract





infection;






Haemophilus







influenzae






infection;






Haemophilus







parainfluenzae






infection;





Infectious





disease;






Klebsiella






infection;






Klebsiella







pneumoniae






infection;





Laryngitis; Lower





respiratory tract





infection;





Lymphangitis;





Mastoiditis;






Moraxella







catarrhalis






infection;






Neisseria







gonorrhoeae






infection;





Osteomyelitis;





Otitis media;





Pelvic





inflammatory





disease;





Pharyngitis;





Prophylaxis;





Pyelonephritis;





Sinusitis;






Staphylococcus







aureus infection;






Tonsillitis




drospirenone +
Acne;
Estradiol agonist;



ethinylestradiol,
Dysmenorrhea;
Progesterone



Schering AG
Endometriosis;
receptor agonist




Female





contraception;





Folic acid





deficiency;





Premenstrual





syndrome




mycophenolate
Heart transplant
Inosine



mofetil
rejection; IgA
monophosphate




nephropathy;
dehydrogenase




Interstitial lung
inhibitor; PurH




disease; Kidney
purine




transplant
biosynthesis




rejection; Liver
protein inhibitor




transplant





rejection; Lung





transplant





rejection; Lupus





nephritis;





Pancreas





transplant





rejection;





Pemphigus;





Scleroderma;





Transplant





rejection




bendamustine
Amyloidosis; B-
PARP modulator




cell lymphoma;





Chronic





lymphocytic





leukemia; Diffuse





large B-cell





lymphoma;





Glioma; Mantle





cell lymphoma;





Metastatic ovary





cancer; Multiple





myeloma; Non-





Hodgkin





lymphoma




dexlansoprazole
Esophagitis;
H+ K+ ATPase



(oral controlled-
Gastroesophageal
inhibitor



release), Takeda
reflux




carfilzomib
AL amyloidosis;
Proteasome




Acute
inhibitor; Ubiquitin




lymphoblastic
inhibitor




leukemia;





Chronic





lymphocytic





leukemia;





Cutaneous T-cell





lymphoma;





Hormone





refractory





prostate cancer;





Macroglobulinemia;





Mantle cell





lymphoma;





Multiple





myeloma;





Neuroendocrine





tumor; Non-





Hodgkin





lymphoma;





Peripheral T-cell





lymphoma; Renal





cell carcinoma;





Small-cell lung





cancer; Solid





tumor




diclofenac, Novartis
Ankylosing
Cyclooxygenase




spondylitis;
inhibitor




Dysmenorrhea;





Inflammatory





disease;





Keratosis; Ocular





inflammation;





Osteoarthritis;





Pain;





Rheumatoid





arthritis




voriconazole

Aspergillus

Lanosterol-14





fumigatus

demethylase




infection;
inhibitor





Aspergillus






infection;






Candida






infection;






Candida krusei






infection;






Cryptococcus







neoformans






meningitis;





Dermatomycosis;





Fungal infection;





Fungal urinary





tract infection;






Fusarium






infection;






Scedosporium






infection




febuxostat
Gout;
Xanthine oxidase




Hyperuricemia;
inhibitor




Tumor lysis





syndrome




fampridine (oral,
Multiple sclerosis
Potassium



sustained release,

channel inhibitor



multiple sclerosis/





spinal cord injury),





Acorda/Biogen





salbutamol MDI,
Asthma;
Beta 2



IVAX Corp
Bronchospasm;
adrenoceptor




Chronic
agonist




obstructive





pulmonary





disease




ertapenem
Bacterial
Penicillin binding




infection;
protein inhibitor




Bacterial





pneumonia;





Bacterial skin





infection;





Bacterial urinary





tract infection;






Bacteroides







fragilis infection;







Bacteroides






infection;






Clostridium






infection; Diabetic





foot ulcer;






Escherichia coli






infection; Female





genital tract





infection; Gram





negative





bacterium





infection; Gram





positive





bacterium





infection;






Haemophilus







influenzae






infection;






Klebsiella







pneumoniae






infection;






Moraxella







catarrhalis






infection;





Prophylaxis;






Proteus mirabilis






infection;





Pyelonephritis;





Sepsis;






Staphylococcus







aureus infection;







Streptococcus







agalactiae






infection;






Streptococcus







pneumoniae






infection;






Streptococcus







pyogenes






infection




caspofungin
Abdominal
1,3 beta glucan




abscess;
synthase inhibitor





Aspergillus






infection;






Candida






infection; Fungal





infection;





Peritonitis




grazoprevir +
Hepatitis C virus
Hepatitis C virus



elbasvir (oral/FDC
infection
NS3 protease



tablet, HCV

inhibitor; Hepatitis



infection), Merck

C virus protein





NS5A inhibitor



mometasone furoate
Allergic rhinitis;




(nasal), Merck & Co
Nasal polyps;





Perennial allergic





rhinitis; Seasonal





allergic rhinitis




amphotericin B

Absidia infection;





(liposomal iv,

Aspergillus





visceral
infection;




leishmaniasis),

Blastomyces





Drugs for Neglected
infection;




Diseases initiative

Candida






infection;






Cladophialophora






infection;






Coccidioides






infection;






Cryptococcus






infection;






Cryptococcus







neoformans






meningitis;






Exophiala






infection; Fungal





infection; Fungal





meningitis;





Fungal





respiratory tract





infection;






Histoplasma






infection;






Leishmania







donovani






infection; Mucor





infection;






Rhizomucor






infection;






Rhizopus






infection




beclomethasone
Asthma
Glucocorticoid



dipropionate, (CFC-

agonist



free), Teva








mesalazine (oral/rectal controlled-release), Ferring
Crohns disease; Ulcerative colitis



embedded image







etoricoxib
Ankylosing
Cyclooxygenase 2




spondylitis; Gout;
inhibitor




Osteoarthritis;





Pain;





Rheumatoid





arthritis




loxoprofen
Inflammatory
Cyclooxygenase




disease; Pain
inhibitor;





Prostanoid





receptor





antagonist



mometasone +
Asthma
Beta 2



formoterol (inhaled,

adrenoceptor



asthma), Merck &

agonist



Co





colchicine (oral,
Carditis; Familial




gout/familial
mediterranean




Mediterranean
fever; Gout




fever), Takeda





rabeprazole
Gastritis;
H+ K+ ATPase




Gastroesophageal
inhibitor




reflux;





Gastrointestinal





ulcer;






Helicobacter







pylori infection;






Peptic ulcer;





Zollinger-Ellison





syndrome




moxifloxacin
Abdominal
DNA gyrase




abscess; Acute
inhibitor;




bronchitis; Acute
Topoisomerase IV




sinusitis;
inhibitor




Bacterial





infection;





Bacterial





pneumonia;





Bacterial





respiratory tract





infection;





Bacterial skin





infection;






Bacteroides







fragilis infection;







Bacteroides






infection;






Chlamydia







pneumoniae






infection;






Clostridiaceae






infection;






Clostridium






infection;






Enterobacter






infection;






Enterococcus







faecalis infection;







Escherichia coli






infection;






Haemophilus






infection;






Haemophilus







influenzae






infection;






Klebsiella







pneumoniae






infection;






Moraxella







catarrhalis






infection;





Multidrug





resistant





infection;






Mycobacterium







tuberculosis






infection;






Mycoplasma






infection; Pelvic





inflammatory





disease; Proteus






mirabilis






infection;





Salpingitis;






Staphylococcus







aureus infection;







Streptococcus






infection;






Streptococcus







pneumoniae






infection;






Streptococcus







pyogenes






infection; Yersinia






pestis infection





estradiol (vaginal
Atrophic vaginitis;
Estradiol agonist



cream, HRT),
Menopause




Bristol-Myers Squibb





enteric-coated
Kidney transplant
Inosine



mycophenolate
rejection; Lupus
monophosphate



sodium, Novartis
nephritis;
dehydrogenase




Nephrotic
inhibitor




syndrome




fluticasone furoate
Allergic rhinitis
Glucocorticoid



(nasal, allergic

agonist



rhinitis), GSK





mesalazine
Ulcerative colitis;
Cyclooxygenase



(oral/rectal
Ulcerative
inhibitor



extended-release),
proctitis




Dr Falk





limaprost
Spinal stenosis;
PGE1 agonist




Thromboangiitis





obliterans




diclofenac (fast
Osteoarthritis
Cyclooxygenase



penetration topical
inhibitor




formulation), Nuvo/





Horizon Pharma





ceftriaxone
Abscess;






Acinetobacter






infection; Acute





bronchitis;





Bacterial





infection;





Bacterial





meningitis;





Bacterial





pneumonia;





Bacterial





respiratory tract





infection;





Bacterial skin





infection;





Bacterial urinary





tract infection;






Bacteroides







fragilis infection;







Bacteroides






infection;





Bartholinitis;





Bone and joint





infection;





Cellulitis;





Cervicitis;





Cholangitis;





Cholecystitis;






Citrobacter






infection;






Clostridium






infection; Corneal





ulcer; Cystitis;





Empyema;






Enterobacter






infection;





Epididymitis;






Escherichia coli






infection;






Haemophilus






infection;






Haemophilus







influenzae






infection;






Klebsiella






infection;






Klebsiella







pneumoniae






infection;





Laryngitis; Lung





abscess;






Moraxella







catarrhalis






infection;






Morganella






infection;






Morganella







morganii






infection;






Neisseria







gonorrhoeae






infection;






Neisseria







meningitidis






meningitis; Otitis





media; Pelvic





inflammatory





disease;





Peritonitis;





Pharyngitis;






Prevotella






infection;





Proctitis;





Prophylaxis;






Proteus infection;







Proteus mirabilis






infection;






Providencia






infection;






Pseudomonas







aeruginosa






infection;





Pyelonephritis;





Sepsis; Serratia





infection;





Sinusitis;






Staphylococcus







aureus infection;







Staphylococcus






infection;






Streptococcus






infection;






Streptococcus







pneumoniae






infection;






Streptococcus







pyogenes






infection;





Tonsillitis;





Urethritis; Uterus





infection




imipenem +
Abscess;
Dehydropeptidase



cilastatin

Acinetobacter

−1 inhibitor




infection; Acute





bronchitis;





Appendicitis;





Bacterial





infection;





Bacterial





pneumonia;





Bacterial





respiratory tract





infection;





Bacterial skin





infection;





Bacterial urinary





tract infection;






Bacteroides







fragilis infection;







Bacteroides






infection;





Bartholinitis;






Bifidobacterium






infection; Bone





and joint





infection;





Cellulitis;





Cholangitis;





Cholecystitis;






Citrobacter






infection;






Clostridium






infection;





Complicated





urinary tract





infection; Corneal





ulcer; Cystitis;





Empyema;





Endocarditis;





Endophthalmitis;






Enterobacter






infection;






Enterococcus







faecalis infection;







Escherichia coli






infection; Female





genital tract





infection; Gram





negative





bacterium





infection; Gram





positive





bacterium





infection;






Haemophilus






infection;






Haemophilus







influenzae






infection;





Infectious





arthritis; Keratitis;






Klebsiella






infection;






Klebsiella







pneumoniae






infection;






Morganella






infection;





Osteomyelitis;





Panophthalmitis;





Pelvic





inflammatory





disease;





Peritonitis;





Prostatitis;






Proteus infection;







Providencia






infection;






Pseudomonas







aeruginosa






infection;





Pyelonephritis;





Sepsis; Serratia





infection; Skin





ulcer;






Staphylococcus







aureus infection;







Staphylococcus






infection;






Streptococcus







agalactiae






infection;






Streptococcus






infection;






Streptococcus







pneumoniae






infection;






Streptococcus







pyogenes






infection




omeprazole
Duodenal ulcer;
H+ K+ ATPase




Endocrine tumor;
inhibitor




Esophagitis;





Gastroesophageal





reflux;






Helicobacter







pylori infection;






Stomach ulcer;





Zollinger-Ellison





syndrome




azithromycin
Abscess; Acute





sinusitis;





Bacterial





infection;





Bacterial





pneumonia;





Bacterial





respiratory tract





infection;





Bacterial skin





infection;





Bronchitis;






Chlamydia







pneumoniae






infection;






Chlamydia







trachomatis






infection; Chronic





obstructive





pulmonary





disease; Female





genital tract





infection; Genital





tract infection;





Genital ulcer;






Haemophilus







ducreyi infection;







Haemophilus







influenzae






infection;






Legionella







pneumophila






infection;






Moraxella







catarrhalis






infection;






Mycobacterium






infection;






Mycoplasma






infection;






Neisseria







gonorrhoeae






infection; Otitis





media; Pelvic





inflammatory





disease;





Pharyngitis;





Prophylaxis;






Staphylococcus







aureus infection;







Streptococcus







agalactiae






infection;






Streptococcus







pneumoniae






infection;






Streptococcus







pyogenes






infection;





Tonsillitis;





Urethritis




dexamethasone
Diabetic macular




(sustained release
edema; Macular




ophthalmic),
edema; Ocular




Allergan/Sanwa
inflammation;





Retinal venous





occlusion; Uveitis




piperacillin +
Abdominal
Beta lactamase



tazobactam
abscess;
inhibitor



(injectable),
Abscess;




Wyeth/Toyama/

Acinetobacter





Taiho
infection;





Appendicitis;





Bacterial





infection;





Bacterial





pneumonia;





Bacterial skin





infection;





Bacterial urinary





tract infection;






Bacteroides







fragilis infection;







Bacteroides






infection;





Cellulitis;





Cholangitis;





Cholecystitis;





Cystitis; Diabetic





foot ulcer;






Escherichia coli






infection; Febrile





neutropenia;






Haemophilus







influenzae






infection;






Klebsiella







pneumoniae






infection; Lower





respiratory tract





infection; Pelvic





inflammatory





disease;





Peritonitis;






Pseudomonas







aeruginosa






infection;





Pyelonephritis;





Sepsis;






Staphylococcus







aureus infection





fexofenadine
Atopic dermatitis;
Histamine H1




Pruritus;
receptor




Seasonal allergic
antagonist




rhinitis; Urticaria




meropenem
Appendicitis;
Penicillin binding




Bacterial
protein inhibitor




infection;





Bacterial





meningitis;





Bacterial





pneumonia;





Bacterial





respiratory tract





infection;





Bacterial skin





infection;





Bacterial urinary





tract infection;






Bacteroides







fragilis infection;







Bacteroides






infection;






Bacteroides







thetaiotaomicron






infection;





Complicated skin





and skin structure





infection;





Complicated





urinary tract





infection; Cystic





fibrosis;






Enterococcus







faecalis infection;







Escherichia coli






infection;






Haemophilus







influenzae






infection;






Klebsiella







pneumoniae






infection;






Neisseria







meningitidis






meningitis;






Peptostreptococcus






infection;





Peritonitis;





Pneumonia;






Proteus mirabilis






infection;






Pseudomonas







aeruginosa






infection;






Staphylococcus







aureus infection;







Streptococcus







agalactiae






infection;






Streptococcus






infection;






Streptococcus







pneumoniae






infection;






Streptococcus







pyogenes






infection; viridans





group






Streptococcus






infection




gabapentin
Epilepsy; Motor





neurone disease;





Neuropathic pain;





Osteoarthritis;





Postherpetic





neuralgia




bepotastine
Allergic rhinitis;
Histamine H1




Allergy; Atopic
receptor




dermatitis;
antagonist




Perennial allergic





rhinitis; Pruritus




ibuprofen +
Arthritis; Pain
Histamine H2



famotidine

receptor



(oral/tablet,

antagonist



pain/arthritis/gastric





ulcer), Horizon





levofloxacin
Abscess; Acute
DNA gyrase




bronchitis; Acute
inhibitor;




sinusitis; Bacillus
Topoisomerase IV





anthracis

inhibitor




infection;





Bacterial





infection;





Bacterial





pneumonia;





Bacterial skin





infection;





Bacterial urinary





tract infection;






Brucella infection;






Cellulitis;






Chlamydia







pneumoniae






infection;





Cholangitis;





Cholecystitis;





Cystitis;






Enterobacter







cloacae infection;







Enterococcus







faecalis infection;






Epididymitis;






Escherichia coli






infection;






Haemophilus







influenzae






infection;






Haemophilus







parainfluenzae






infection;





Impetigo;






Klebsiella







pneumoniae






infection;






Legionella







pneumophila






infection;






Moraxella







catarrhalis






infection;





Multidrug





resistant





infection;






Mycobacterium







tuberculosis






infection;






Mycoplasma







pneumoniae






infection;





Peritonitis;





Prostatitis;






Proteus
mirabilis






infection;






Pseudomonas







aeruginosa






infection;





Pyelonephritis;





Pyoderma





gangrenosum;






Serratia







marcescens






infection;






Staphylococcus







aureus infection;







Staphylococcus







epidermidis






infection;






Staphylococcus







saprophyticus






infection;






Streptococcus







pneumoniae






infection;






Streptococcus







pyogenes






infection; Yersinia






pestis infection





sirolimus
Chondrosarcoma;
mTOR inhibitor




Graft versus





host disease;





Kidney transplant





rejection;





Liposarcoma;





Lymphangioleiomyomatosis;





Systemic lupus





erythematosus;





Tuberous





sclerosis




idelalisib
AL amyloidosis;
Phosphoinositide-




Chronic
3 kinase delta




lymphocytic
inhibitor




leukemia; Follicle





center





lymphoma;





Macroglobulinemia;





Mantle cell





lymphoma;





Myelofibrosis;





Non-Hodgkin





lymphoma;





Pancreatic ductal





adenocarcinoma




cetirizine
Allergic rhinitis;
Histamine H1




Pruritus; Urticaria
receptor





antagonist



budesonide (oral
Ulcerative colitis




controlled-release





gastrointestinal-





specific (MMX),





ulcerative colitis),





Cosmo/Ferring/Salix





thalidomide,
Multiple




Celgene
myeloma;






Mycobacterium







leprae infection





lamivudine
HIV infection;
DNA polymerase




Hepatitis B virus
inhibitor; HIV-1




infection
reverse





transcriptase





inhibitor;





Nucleoside





reverse





transcriptase





inhibitor; RNA





DNA polymerase





inhibitor



pranlukast
Allergic rhinitis;
Leukotriene C4




Asthma
antagonist;





Leukotriene D4





antagonist;





Leukotriene E4





antagonist; P-





Glycoprotein





inhibitor



salmeterol
Asthma; Chronic
Beta 2




obstructive
adrenoceptor




pulmonary
agonist; Beta




disease
adrenoceptor





agonist



naproxen +
Ankylosing
Cyclooxygenase



esomeprazole (oral
spondylitis;
inhibitor; H+ K+



fixed-dose
Juvenile
ATPase inhibitor



combination,
rheumatoid




inflammatory pain),
arthritis;




AstraZeneca/Aralez
Osteoarthritis;





Pain;





Rheumatoid





arthritis




levocetirizine
Allergic rhinitis;
Histamine H1




Allergy; Perennial
receptor




allergic rhinitis;
antagonist




Pruritus;





Seasonal allergic





rhinitis; Urticaria




fluconazole
Balanitis;
Lanosterol-14





Candida

demethylase




infection;
inhibitor





Cryptococcus






infection;






Cryptococcus







neoformans






meningitis;





Dermatomycosis;





Female genital





tract infection;





Fungal infection;





Fungal





respiratory tract





infection; Fungal





urinary tract





infection;





Prophylaxis;





Tinea capitis;





Tinea corporis;





Tinea cruris;





Tinea pedis




clarithromycin
Abscess; Acute





bronchitis; Acute





sinusitis;





Bacterial





infection;





Bacterial





pneumonia;





Bacterial





respiratory tract





infection;





Bacterial skin





infection;






Bordetella







pertussis






infection;






Campylobacter






infection;





Cervicitis;






Chlamydia






infection;






Chlamydia







pneumoniae






infection; Chronic





bronchitis;





Enterocolitis;






Haemophilus







influenzae






infection;






Haemophilus







parainfluenzae






infection;






Helicobacter







pylori infection;






Laryngitis;






Legionella






infection;





Lymphadenitis;





Lymphangitis;






Moraxella







catarrhalis






infection;






Mycobacterium






infection;






Mycoplasma






infection; Otitis





media;






Peptostreptococcus






infection;





Pericoronitis;





Periodontitis;





Pharyngitis;





Prophylaxis;





Sinusitis;






Staphylococcus







aureus infection;







Staphylococcus






infection;






Streptococcus






infection;






Streptococcus







pneumoniae






infection;






Streptococcus







pyogenes






infection;





Tonsillitis;





Urethritis




gemcitabine
Biliary cancer;





Bladder tumor;





Breast tumor;





Cancer;





Carcinoma;





Hepatobiliary





system tumor;





Lymphoma;





Metastatic breast





cancer;





Metastatic non





small cell lung





cancer;





Metastatic





pancreas cancer;





Non-small-cell





lung cancer;





Ovary tumor;





Pancreas tumor;





Renal cell





carcinoma




simeprevir
Hepatitis C virus
Hepatitis C virus




infection
NS3 protease





inhibitor



cefcapene
Abscess; Acute
Penicillin binding




bronchitis;
protein inhibitor




Bacterial eye





infection;





Bacterial





infection;





Bacterial





pneumonia;





Bacterial





respiratory tract





infection;





Bacterial skin





infection;





Bacterial urinary





tract infection;






Bacteroides






infection;





Bartholinitis;





Cervicitis;





Cholangitis;





Cholecystitis;






Citrobacter






infection; Cystitis;





Dacryocystitis;






Enterobacter






infection;






Escherichia coli






infection;






Haemophilus







influenzae






infection; Jaw





disease;






Klebsiella






infection;





Laryngitis;





Lymphangitis;





Mastitis;






Moraxella







catarrhalis






infection;






Morganella







morganii






infection;






Neisseria







gonorrhoeae






infection; Otitis





externa; Otitis





media; Pelvic





inflammatory





disease;






Peptostreptococcus






infection;





Pericoronitis;





Periodontal





disease;





Pharyngitis;






Prevotella






infection;






Propionibacterium







acnes






infection; Proteus





infection;






Providencia






infection;





Pyelonephritis;





Respiratory





disease; Serratia





infection;





Sinusitis;






Staphylococcus






infection;






Streptococcus






infection;






Streptococcus







pneumoniae






infection;





Tonsillitis;





Urethritis; Uterus





infection




garenoxacin
Acute bronchitis;
DNA gyrase




Bacterial
inhibitor;




infection;
Topoisomerase IV




Bacterial
inhibitor




pneumonia;





Bacterial





respiratory tract





infection;






Chlamydia







pneumoniae






infection;






Enterobacter






infection;






Escherichia coli






infection;






Haemophilus







influenzae






infection;






Klebsiella






infection;





Laryngopharyngitis;






Legionella







pneumophila






infection;






Moraxella







catarrhalis






infection;






Mycoplasma






infection; Otitis





media;





Peritonsillitis;





Sinusitis;






Staphylococcus






infection;






Streptococcus






infection;






Streptococcus







pneumoniae






infection;





Tonsillitis




tazarotene (topical,
Acne; Aging;
Retinoic acid



psoriasis/acne),
Psoriasis
receptor agonist



Allergan





pimecrolimus
Atopic dermatitis
Calcineurin





inhibitor; IL-10





antagonist; IL-2





antagonist; IL-4





antagonist;





Interferon gamma





receptor





antagonist



epinastine
Allergic
Histamine H1



hydrochloride
conjunctivitis
receptor



(topical ophthalmic

antagonist



formulation),





Allergan





hyaluronate sodium
Osteoarthritis;





Rheumatoid





arthritis




vancomycin
Bacterial
Peptidoglycan




infection;
recognition protein




Bacterial
inhibitor




pneumonia;






Clostridium







difficile infection;






Enterocolitis;





MRSA infection;





Osteomyelitis;





Prophylaxis;





Pseudomembranous





colitis;





Sepsis;






Staphylococcus







aureus infection;







Staphylococcus






infection;






Streptococcus







pneumoniae






infection




adefovir dipivoxil
Hepatitis B virus
DNA polymerase




infection
inhibitor;





Nucleoside





reverse





transcriptase





inhibitor



vonoprazan
Duodenal ulcer;
H+ K+ ATPase



fumarate (oral,
Esophagitis;
inhibitor



GERD/peptic ulcer),
Gastroesophageal




Takeda
reflux;






Helicobacter







pylori infection;






Peptic ulcer;





Stomach ulcer




mosapride
Gastritis
5-HT 4 receptor





agonist



ursodeoxycholic
Cholelithiasis;




acid
Hepatitis; Liver





disease; Primary





biliary cirrhosis




betamethasone
Dermatitis;





Discoid lupus





erythematosus;





Eczema; Lichen;





Prurigo; Psoriasis




fluticasone propionate +
Asthma; Chronic
Beta 2



formoterol fumarate
obstructive
adrenoceptor



(asthma/COPD,
pulmonary
agonist



HFA-MDI),
disease




SkyePharma





prednisone (oral,
Inflammatory
Glucocorticoid



delayed release),
disease;
agonist



Horizon/
Rheumatoid




Mundipharma
arthritis; Systemic





lupus





erythematosus




camostat mesylate
Gastroesophageal
Serine protease




reflux;
inhibitor; Trypsin




Pancreatitis
inhibitor



pralatrexate
B-cell lymphoma;
DHFR inhibitor;




Bladder tumor;
Folate antagonist




Breast tumor;
Folate transporter




Cutaneous T-cell
1 modulator




lymphoma;





Esophagus





tumor; Fallopian





tube cancer;





Head and neck





tumor; Multiple





myeloma; Non-





small-cell lung





cancer; Ovary





tumor; Peripheral





T-cell lymphoma;





Peritoneal tumor;





Stomach tumor




dimethyl fumarate +
Psoriasis




ethyl hydrogen





fumarate calcium +





ethyl hydrogen





fumarate





magnesium + ethyl





hydrogen fumarate





zinc





ospemifene
Atrophic vaginitis;
Estrogen receptor




Dyspareunia
modulator



loratadine
Allergy; Pruritus;
Histamine H1




Rhinitis; Urticaria
receptor





antagonist



flomoxef, Shionogi
Abdominal





abscess; Acute





bronchitis;





Bacterial





endocarditis;





Bacterial





infection;





Bacterial skin





infection;






Bacteroides






infection;





Cholangitis;





Cholecystitis;





Cystitis;






Escherichia coli






infection; Female





genital tract





infection;






Haemophilus







influenzae






infection;






Klebsiella






infection;





Laryngitis;






Moraxella







catarrhalis






infection;






Morganella







morganii






infection;






Neisseria







gonorrhoeae






infection; Otitis





media;






Peptostreptococcus






infection;





Peritonitis;





Pharyngitis;






Prevotella






infection;





Prostatitis;






Proteus infection;







Providencia






infection;





Pyelonephritis;





Sepsis; Sinusitis;






Staphylococcus






infection;






Streptococcus






infection;






Streptococcus







pneumoniae






infection;





Tonsillitis;





Urethritis; Uterus





infection




ixazomib citrate
Amyloidosis;
Proteasome



(oral, multiple
Bladder cancer;
inhibitor



myeloma/amyloidosis),
Breast tumor;




Millennium
HIV infection;





Hematological





neoplasm; Lupus





nephritis;





Lymphoma;





Macroglobulinemia;





Multiple





myeloma




doripenem
Abdominal
Penicillin binding




abscess;
protein inhibitor




Abscess;






Acinetobacter







baumanii






infection;






Acinetobacter






infection;





Bacterial





infection;





Bacterial





meningitis;





Bacterial





pneumonia;





Bacterial





respiratory tract





infection;





Bacterial skin





infection;





Bacterial urinary





tract infection;






Bacteroides







caccae infection;







Bacteroides







fragilis infection;







Bacteroides






infection;






Bacteroides







thetaiotaomicron






infection;






Bacteroides







uniformis






infection;






Bacteroides







vulgatus






infection;





Cellulitis;





Cholangitis;





Cholecystitis;






Citrobacter






infection; Corneal





ulcer; Cystitis;





Empyema;





Endophthalmitis;






Enterobacter






infection;






Enterococcus






infection;





Epididymitis;






Escherichia coli






infection;






Haemophilus







influenzae






infection;





Infectious





arthritis;





Infectious





endocarditis;





Keratitis;






Klebsiella






infection;






Klebsiella







pneumoniae






infection;





Laryngopharyngitis;





Liver abscess;






Moraxella







catarrhalis






infection;






Morganella






infection;





Osteomyelitis;





Otitis media;





Panophthalmitis;






Peptostreptococcus






infection;





Peritonitis;






Prevotella






infection;





Prostatitis;






Proteus infection;







Proteus mirabilis






infection;






Providencia






infection;






Pseudomonas







aeruginosa






infection;





Pyelonephritis;





Respiratory tract





infection; Sepsis;






Serratia infection;






Stomach





infection;






Streptococcus







constellatus






infection;






Streptococcus






infection;






Streptococcus







intermedius






infection;






Streptococcus







pneumoniae






infection;





Tonsillitis; Uterus





infection




diclofenac
Dysmenorrhea;
Cyclooxygenase 2



potassium
Inflammatory
inhibitor



(immediate-release,
disease;




oral powder),
Migraine; Pain




Novartis/Depomed/





Tribute





dexamethasone
Allergic rhinitis
Glucocorticoid



cipecilate

agonist



fluticasone furoate
Asthma
Glucocorticoid



(inhaled, respiratory

agonist



disorders),





GlaxoSmithKline





obeticholic acid
Alcoholic
Farnesoid X




hepatitis; Biliary
receptor agonist




atresia; Diarrhea;





Liver disease;





Non-alcoholic





steatohepatitis;





Portal





hypertension;





Primary biliary





cirrhosis; Primary





sclerosing





cholangitis




amifampridine
Lambert-Eaton
Potassium



phosphate
syndrome;
channel inhibitor




Muscle





weakness;





Myasthenia





gravis;





Nystagmus;





Orthostatic





hypotension;





Renal failure




melphalan
AL amyloidosis;




(intravenous/Captiso
Multiple myeloma




I, multiple myeloma),





Spectrum/CASI





Pharmaceuticals





irinotecan
Brain tumor;
Topoisomerase I




Breast tumor;
inhibitor




Colorectal tumor;





Lung tumor;





Metastatic





colorectal cancer;





Metastatic





pancreas cancer;





Non-Hodgkin





lymphoma; Ovary





tumor; Solid





tumor; Squamous





cell carcinoma;





Stomach tumor;





Uterus tumor




belinostat (iv,
Colorectal tumor;
Histone



cancer),
Hepatocellular
deacetylase



Onxeo/Spectrum
carcinoma; Non-
inhibitor




small-cell lung





cancer; Ovary





tumor; Peripheral





T-cell lymphoma;





Solid tumor




ozagrel
Asthma
Thromboxane



hydrochloride (oral,

synthetase



asthma), Ono/Kissei

inhibitor



telaprevir
Hepatitis C virus
Hepatitis C virus




infection
NS3 protease





inhibitor; P-





Glycoprotein





inhibitor



lesinurad
Gout;
Urate anion




Hyperuricemia
exchanger 1





inhibitor; Xanthine





oxidase inhibitor



sofosbuvir +
Hepatitis C virus
Hepatitis C virus



velpatasvir +
infection
NS3 protease



voxilaprevir (fixed

inhibitor; Hepatitis



dose combination,

C virus NS5B



HCV), Gilead

polymerase





inhibitor; Hepatitis





C virus protein





NS5A inhibitor



daclatasvir +
Hepatitis C virus
Hepatitis C virus



asunaprevir +
infection
NS3 protease



beclabuvir (fixed-

inhibitor; Hepatitis



combination, HCV),

C virus NS5B



BMS

polymerase





inhibitor; Hepatitis





C virus protein





NS5A inhibitor



lesinurad +
Gout;
Urate anion



allopurinol
Hyperuricemia
exchanger 1



(hyperuricaemia in

inhibitor; Xanthine



gout), AstraZeneca

oxidase inhibitor



copanlisib
Advanced solid
Phosphoinositide




tumor; Breast
3-kinase inhibitor




tumor;





Cholangiocarcinoma;





Diffuse large





B-cell lymphoma;





Endometrioid





carcinoma;





Follicle center





lymphoma;





Marginal zone B-





cell lymphoma;





Non-Hodgkin





lymphoma;





Peripheral T-cell





lymphoma;





Splenic marginal





zone lymphoma




budesonide (rectal
Rectosigmoiditis;
Glucocorticoid



foam, ulcerative
Ulcerative colitis;
agonist



colitis), Dr Falk
Ulcerative




Pharma/Salix/
proctitis




Ajinomoto/





EA Pharma





baricitinib
Atopic dermatitis;
Jak1 tyrosine




Inflammatory
kinase inhibitor;




disease; Psoriatic
Jak2 tyrosine




arthritis;
kinase inhibitor




Rheumatoid





arthritis; Systemic





lupus





erythematosus




sirolimus (injectable
Uveitis
mTOR inhibitor



ophthalmic,





uveitis/AMD/DME),





Santen





crisaborole
Atopic dermatitis;
PDE 4 inhibitor




Psoriasis




zoledronic acid
Bone





metastases;





Bone resorption;





Breast tumor;





Hypercalcemia;





Male





osteoporosis;





Mesothelioma;





Metastasis;





Multiple





myeloma;





Osteoarthritis;





Osteogenesis





imperfecta;





Osteoporosis;





Pagets bone





disease;





Postmenopausal





osteoporosis




desloratadine
Allergic rhinitis;
Histamine H1




Atopic dermatitis;
receptor




Perennial allergic
antagonist




rhinitis; Seasonal





allergic rhinitis;





Urticaria




glecaprevir +
Hepatitis C virus
Hepatitis C virus



pibrentasvir (once-
infection
N53 protease



daily oral tablet,

inhibitor; Hepatitis



HCV infection),

C virus protein



AbbVie

NS5A inhibitor









2. Definitions

While the terms used herein are believed to be well understood by one of ordinary skill in the art, definitions are set forth herein to facilitate explanation of the presently-disclosed subject matter.


As used herein, the term “about,” when referring to a numerical value or range of a parameter such as mass, weight, volume, time, concentration, biological activity, clogP, or percentage, is meant to encompass variations of, e.g., ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified value or range.


As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.


The term “lipid,” as used herein, refers to natural and non-natural hydrophobic and/or lipophilic fats, oils, polymers, hydrocarbons, and other such materials. In some embodiments, suitable lipids, when incorporated into a lipid prodrug, are processed or metabolized similarly to triglyercides in the GI tract or mimic such processing or metabolism. The term “glyceride” refers to an ester of glycerol (1,2,3-propanetriol) with acyl radicals of fatty acids or other lipids and is also known as an acylglycerol. If only one position of the glycerol molecule is esterified with a fatty acid, a “monoglyceride” is produced; if two positions are esterified, a “diglyceride” is produced; and if all three positions of the glycerol are esterified with fatty acid a “triglyceride” or “triacylglycerol” is produced. A glyceride is called “simple” if all esterified positions contain the same fatty acid; or “mixed” if different fatty acids are involved. The carbons of the glycerol backbone are designated sn-1, sn-2 and sn-3, with sn-2 being in the middle and sn-1 and sn-3 being the ends of the glycerol.


Naturally occurring oils and fats consist largely of triglycerides wherein the 3 fatty acyl residues may or may not be identical. The term “long chain triglycerides” (or “LCT”) means both a simple and mixed triglyceride containing fatty acids with more than 12 carbon atoms (long chain fatty acids, “LCFA”), whereas the term “medium chain triglycerides” (or “MCT”) means both a simple and mixed triglyceride containing fatty acids with 4 to 12 carbon atoms.


The term “ECN” or “equivalent carbon number” means the sum of the number of carbon atoms in the acyl chains of a glyceride molecule. For example, tripalmitin (tripalmitic glycerol), which is a simple triglyceride containing 3 acyl radicals of 16 carbon atoms, has an ECN of 3×16=48. Conversely, a triglyceride with an ECN=40 may have “mixed” acyl chain lengths of 8, 16 and 16; 10, 14 and 16; 8, 14 and 18, etc. Naturally occurring oils are frequently “mixed” with respect to specific fatty acids, but tend not to contain LCFAs and MCFAs on the same glycerol backbone. Thus, triacylglycerols with ECNs of 24-30 typically contain predominately medium chain fatty acids, while triacylglycerols with ECNs of greater than 43 typically contain predominantly long chain fatty acids. Triacylglycerols having an ECNs of 32-42 typically contain one or two MCFA in combination with one or two LCFAs to “fill” the triglyceride. Triacylglycerols with ECNs in the range of greater than 30 to less than 48 typically represent mixed triacylglycerol species that are absent from or are present in significantly lower concentrations in physical mixtures. The fatty acids that occur in foods usually contain an even number of carbon atoms in an unbranched chain, e.g., lauric or dodecanoic acid.


The term “self-immolative group,” as used herein, refers to a bivalent chemical moiety that comprises a covalent, scissile bond as one of its bivalent bonds and a stable, covalent bond with a therapeutic agent as its other bivalent bond, wherein the bond with the therapeutic agent becomes labile upon cleavage of the scissile bond. Examples of self-immolative groups include, but are not limited to, disulfide groups, hydrazones, acetal self-immolative groups, carboxyacetal self-immolative groups, carboxy(methylacetal) self-immolative groups, p-hydroxybenzyl self-immolative groups, para-hydroxybenzyl carbonyl self-immolative groups, flipped ester self-immolative groups, and trimethyl lock, or 2-hydroxyphenyl carbamate (2-HPC) self-immolative groups. A number of other suitable self-immolative groups are known in the art as described, for example, in C. A. Blencowe et al., Polym. Chem. 2011, 2, 773-790 and F. Kratz et al., ChemMedChem. 2008, 3(1), 20-53; Huvelle, S. et al., Org. Biomol. Chem. 2017, 15(16), 3435-3443; and Alouane, A. et al., Angewandte Chemie International Edition 2015, 54 (26), 7492-7509; and Levine, M. N. et al., Chem. Sci. VL-IS-3 (8), 2412-2420; each of which is hereby incorporated by reference in its entirety.


As used here in, the term “therapeutic agent,” “active pharmaceutical agent,” “active agent,” or “pharmaceutical agent” includes any therapeutic agent or imaging (contrasting) agent which would benefit from transport via the intestinal lymphatic system, for example, to enable oral administration (e.g. of an intravenously administered therapeutic agent), to avoid first pass metabolism, avoid liver toxicity or other toxicity, or for targeted delivery within the lymphatic system.


Lipid prodrug compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, Handbook of Chemistry and Physics, 98th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 7th Edition, John Wiley & Sons, 2013, the entire contents of which are hereby incorporated by reference.


The term “aliphatic” or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.


As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:




embedded image


Exemplary bridged bicyclics include:




embedded image


The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.


The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.


The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).


The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.


As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain” refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.


The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., —(CH2)n—, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.


The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.


The term “halogen” means F, Cl, Br, or I.


The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.


The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.


As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N-substituted pyrrolidinyl).


A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, di azepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.


As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.


As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.


Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; —(CH2)0-4R; —(CH2)0-4OR; —O(CH2)0-4R, —O—(CH2)0-4C(O)OR; —(CH2)0-4CH(OR)2; —(CH2)0-4SR; —(CH2)0-4Ph, which may be substituted with R; —(CH2)0-4O(CH2)0-1Ph which may be substituted with R; —CH═CHPh, which may be substituted with R; —(CH2)0-4O(CH2)0-1-pyridyl which may be substituted with R; —NO2; —CN; —N3; —(CH2)0-4N(R)2; —(CH2)0-4N(R)C(O)R; —N(R)C(S)R; —(CH2)0-4N(R)C(O)NR2; —N(R)C(S)NR2; —(CH2)0-4N(R)C(O)OR; —N(R)N(R)C(O)R; —N(R)N(R)C(O)NR2; —N(R)N(R)C(O)OR; —(CH2)0-4C(O)R; —C(S)R; —(CH2)0-4C(O)OR; —(CH2)0-4C(O)SR; —(CH2)0-4C(O)OSiR3; —(CH2)0-4OC(O)R; —OC(O)(CH2)0-4SR—, SC(S)SR; —(CH2)0-4SC(O)R; —(CH2)0-4C(O)NR02; —C(S)NR2; —C(S)SR; —SC(S)SR, —(CH2)0-4OC(O)NR2; —C(O)N(OR)R; —C(O)C(O)R; —C(O)CH2C(O)R; —C(NOR)R; —(CH2)0-4SSR; —(CH2)0-4S(O)2R; —(CH2)0-4S(O)2OR; —(CH2)0-4OS(O)2R; —S(O)2NR2; —S(O)(NR)R; —S(O)2N═C(NR2)2; —(CH2)0-4S(O)R; —N(R)S(O)2NR2; —N(R)S(O)2R; —N(OR)R; —C(NH)NR2; —P(O)2R; —P(O)R2; —OP(O)R2; —OP(O)(OR)2; SiR3; —(C1-4 straight or branched alkylene)O—N(R)2; or —(C1-4 straight or branched alkylene)C(O)O—N(R)2.


Each Ris independently hydrogen, C1-6 aliphatic, —CH2Ph, —O(CH2)0-1Ph, —CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of Rselected from ═O and ═S; or each R is optionally substituted with a monovalent substituent independently selected from halogen, —(CH2)0-2R, -(haloR), —(CH2)0-2OH, —(CH2)0-2OR, —(CH2)0-2CH(OR)2; —O(haloR), —CN, —N3, —(CH2)0-2C(O)R, —(CH2)0-2C(O)OH, —(CH2)0-2C(O)OR, —(CH2)0-2SR, —(CH2)0-2SH, —(CH2)0-2NH2, —(CH2)0-2NHR, —(CH2)0-2NR2, —NO2, —SiR3, —OSiR3, —C(O)SR, —(C1-4 straight or branched alkylene)C(O)OR, or—SSR.


Each R is independently selected from C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from ═O, ═S, ═NNR*2, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)2R*, ═NR*, ═NOR*, —O(C(R*2))2-3O—, or —S(C(R*2))2-3S—, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is —O(CR*2)2-3O—, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.


When R* is C1-6 aliphatic, R* is optionally substituted with halogen, —R, -(haloR), —OH, —OR, —O(haloR), —CN, —C(O)OH, —C(O)OR, —NH2, —NHR, —NR2, or —NO2, wherein each R is independently selected from C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R is unsubstituted or where preceded by halo is substituted only with one or more halogens.


An optional substituent on a substitutable nitrogen is independently —R, —NR2, —C(O)R, —C(O)OR, —C(O)C(O)R, —C(O)CH2C(O)R, —S(O)2R, —S(O)2NR2, —C(S)NR2, —C(NH)NR2, or —N(R)S(O)2R; wherein each R is independently hydrogen, C1-6 aliphatic, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R is C1-6 aliphatic, R is optionally substituted with halogen, —R, -(haloR), —OH, —OR, —O(haloR), —CN, —C(O)OH, —C(O)OR, —NH2, —NHR, —NR2, or —NO2, wherein each R is independently selected from C1_4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R is unsubstituted or where preceded by halo is substituted only with one or more halogens.


As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts include salts of an amino group (or other basic group) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.


Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.


Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.


3. Uses, Formulation and Administration
Uses of Lymphatic-Directing Lipid Prodrugs

Disclosed lymphatic-directing lipid prodrugs, as well as pharmaceutically acceptable compositions comprising a disclosed lipid prodrug, and a pharmaceutically acceptable excipient, diluent, or carrier, are useful for treating a variety of diseases, disorders or conditions. Such diseases, disorders, or conditions include those described herein.


One of ordinary skill in the art will recognize and appreciate that each of the therapeutic agents described herein are known to be associated with treatment of one or more diseases, disorders, or conditions. Accordingly, it will be appreciated that, in certain embodiments, the present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof comprising administering to said patient a disclosed lipid prodrug.


The presently disclosed lipid prodrugs are useful for the stable transport of pharmaceutical agents to the intestinal lymph and release of the pharmaceutical agents in the lymph, lymphocytes, lymphoid tissues, tissues with high lipase activity such as adipose tissue, certain cancers, the liver, or in the systemic circulation. Disclosed lipid prodrugs are particularity useful for the transport and release of pharmaceutical agents that benefit from avoidance of first pass metabolism, for example, therapeutic agents that exhibit greater than about 50% first pass metabolism when administered orally. In some embodiments, the therapeutic agent exhibits greater than about 60% first pass metabolism when administered orally. In some embodiments, the therapeutic agent exhibits greater than about 70%, 80%, or 90% first pass metabolism when administered orally.


The presently disclosed lipid prodrugs are also useful for the targeted release of the therapeutic agent within the lymphatic system, for example, in the lymph, lymphocytes and lymphoid tissues, as well as in tissues with high lipase activity such as adipose tissue, certain cancers, or the liver. In some embodiments, the therapeutic agent exhibits poor lymphatic transport when administered orally. In some embodiments, the therapeutic exhibits less than 70%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25%, 0.2%, 0.15%, or 0.1% lymphatic transport when administered orally. In contrast, the present invention provides for improved lymphatic transport of such therapeutic agents. In some embodiments, a disclosed lipid prodrug exhibits at least 1%, 5%, 7.5%, 10%, 12.5%, 15%, 20%, 25%, 30%, 35%, 40%, or 50% lymphatic transport when administered orally. In some embodiments, a disclosed lipid prodrug exhibits about 1-50%, 5-40%, 10-30%, 15-25%, or about 50%, 40%, 30%, 25%, 20%, 15%, 12.5%, 10%, 7.5%, 5%, 2.5%, or 1% lymphatic transport when administered orally, as measured by either w/w % of the lipid prodrug administered or w/w % of the therapeutic agent in its lipid prodrug form vs. the unmodified therapeutic agent.


In some embodiments, a disclosed lipid prodrug is delivered to the central nervous system (CNS) or crosses the blood-brain barrier (BBB) via the lymphatic system.


In some embodiments, the present invention provides a method of modulating an immune response, comprising administering to a patient in need thereof an effective amount of a disclosed lipid prodrug that comprises an immunomodulatory therapeutic agent. In some embodiments, the immune response includes one or more immune responses mediated by the lymphatic system, or mediated by immune cells in the lymphatic system. In some embodiments, the patient is suffering from a hyperproliferative disease, disorder, or condition such as cancer. In some embodiments, the patient is suffering from an autoimmune disease, disorder, or condition. In certain embodiments, the disease, disorder, or condition is any of those listed in any of Tables 1 through 7.


Therapeutic agents that may benefit from the stable transport to the intestinal lymph and release in the lymph, lymphocytes, lymphoid tissues, tissues with high lipase activity such as adipose tissue, certain cancers, the liver or in the systemic circulation include, but are not limited to, testosterone, mycophenolic acid, oestrogens (estrogen), morphine, tetrahydrocannabinol, cannabidiol, metoprolol, raloxifene, alphaxolone, statins such as atorvastatin, pentazocine, propranolol, L-DOPA, buprenorphine, midazolam, lidocaine, chlorpromazine, amitriptyline, nortriptyline, pentazocine, isosorbidedinitrate, glyceryl trinitrate, oxprenolol, labetalol, verapamil, salbutamol, epitiostanol, melphalan, and lovastatin.


Pharmaceutically Acceptable Compositions

According to another embodiment, the present invention provides a composition comprising a lipid prodrug of the present disclosure and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of lipid prodrug in the composition is an amount effective to treat the relevant disease, disorder, or condition in a patient in need thereof (an “effective amount”). In some embodiments, a composition of the present disclosure is formulated for oral administration to a patient.


The term “patient,” as used herein, means an animal, for example a mammal, such as a human.


The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the agent with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the disclosed compositions include, but are not limited to, ion exchangers, alumina, stearates such as aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. In some embodiments, the composition is formulated as a lipophilic mixture, such as a lipid-based composition.


Compositions of the present invention may be administered orally, parenterally, enterally, intracisternally, intraperitoneally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the composition is administered orally, intraperitoneally, or intravenously. In some embodiments, the composition is a transmucosal formulation. In some embodiments, the composition is injected directly into the lymphatic system. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.


To aid in delivery of the composition, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.


Pharmaceutically acceptable compositions may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, may also be added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.


Alternatively, pharmaceutically acceptable compositions may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.


In some embodiments, the pharmaceutically acceptable composition is formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable composition is administered without food. In other embodiments, the pharmaceutically acceptable composition is administered with food.


It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.


Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.


Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.


Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.


In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.


Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.


Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.


Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.


Therapeutic agents can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.


Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.


In some embodiments, the lipid prodrug is formulated as an orally administerable, lipid-based formulation. Lipid-based formulations for oral delivery are known in the art and may include, for example, substantially non-aqueous vehicles which typically contain one or more lipid components. The lipid vehicles and resulting lipid formulations may be usefully classified as described below according to their shared common features according to the lipid formulation classification system (LFCS) (Pouton, C. W., Eur. J. Pharm. Sci. 11 (Supp 2), S93-S98, 2000; Pouton, C. W., Eur. J. Pharm. Sci. 29 278-287, 2006).


Lipid vehicles, and the resulting lipid formulations, may contain oil/lipids and/or surfactants, optionally with co-solvents. In the LFCS terminology, Type I formulations include oils or lipids which require digestion, such as mono, di and tri-glycerides and combinations thereof. Type II formulations are water-insoluble self emulsifying drug delivery systems (SEDDS) which contain lipids and oils used in Type I formulations, with additional water insoluble surfactants. Type III formulations are SEDDS or self-microemulsifying drug delivery systems (SMEDDS) which contain lipids and oils used in Type I formulations, with additional water-soluble surfactants and/or co-solvents (Type Ma) or a greater proportion of water-soluble components (Type IIIb). Type IV formulations contain predominantly hydrophilic surfactants and co-solvents (e.g. PEG, propylene glycol and diethylene glycol monoethyl ether) and are useful for drugs which are poorly water soluble but not lipophilic. Any such lipid formulation (Type I-IV) is contemplated herein for use with a disclosed lipid prodrug or pharmaceutical composition thereof.


In some embodiments, the lipid vehicle contains one or more oils or lipids, without additional surfactants, co-surfactants or co-emulsifiers, or co-solvents, i.e. it consists essentially of one or more oils or lipids. In some further embodiments, the lipid vehicle contains one or more oils or lipids together with one or more water-insoluble surfactants, optionally together with one or more co-solvents. In some embodiments, the lipid vehicle contains one or more oils or lipids together with one or more water-soluble surfactants, optionally together with one or more co-solvents. In some embodiments, the lipid vehicle contains a mixture of oil/lipid, surfactant and co-solvent. In some embodiments, the lipid vehicle consists essentially of one or more surfactants/co-surfactants/co-emulsifiers, and/or solvents/co-solvents.


Examples of oils or lipids which may be used in the present invention include almond oil, babassu oil, blackcurrant seed oil, borage oil, canola oil, castor oil, coconut oil, cod liver oil, corn oil, cottonseed oil, evening primrose oil, fish oil, grape seed oil, mustard seed oil, olive oil, palm kernel oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, soybean oil, sunflower oil, walnut oil, wheat germ oil, avocado oil, bran oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, partially hydrogenated soybean oil, hydrogenated vegetable oil, caprylic/capric glycerides, fractionated triglycerides, glyceryl tricaprate, glyceryl tricaproate, glyceryl tricaprylate, glyceryl tricaprylate/caprate, glyceryl tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate, glyceryl trilaurate, glyceryl monolaurate, glyceryl behenate, glyceryl monolinoleate, glyceryl trilinolenate, glyceryl trioleate, glyceryl triundecanoate, glyceryl tristearate linoleic glycerides, saturated polyglycolized glycerides, synthetic medium chain triglycerides containing primarily C8-12 fatty acid chains, medium chain triglycerides containing primarily C8-12 fatty acid chains, long chain triglycerides containing primarily >C12 fatty acid chains, modified triglycerides, fractionated triglycerides, and mixtures thereof.


Examples of mono and diglycerides which may be used in such formulations include glycerol mono- and diesters having fatty acid chains from 8 to 40 carbon atoms, including hydrolysed coconut oils (e.g. Capmul® MCM), hydrolysed corn oil (e.g. Maisine™35-1). In some embodiments, the monoglycerides and diglycerides are mono- or di-saturated fatty acid esters of glycerol having fatty acid chains of 8 to 18 carbon chain length (e.g. glyceryl monostearate, glyceryl distearate, glyceryl monocaprylate, glyceryl dicaprylate, glyceryl monocaprate and glyceryl dicaprate). Mixtures of fatty acids (“structured glycerides”) adapted for enhancing the absorption and transport of lipid soluble compounds are disclosed in, e.g., U.S. Pat. No. 6,013,665, which is hereby incorporated by reference.


Suitable surfactants for use in the lipid formulations include propylene glycol mono- and di-esters of C8-22 fatty acids, such as, but not limited to, propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol monolaurate, sold under trade names such as Capryol® 90, Labrafac® PG, Lauroglycol® FCC, sugar fatty acid esters, such as, but not limited to, sucrose palmitate, sucrose laurate, and sucrose stearate; sorbitan fatty acid esters such as, but not limited to, sorbitan laurate, sorbitan palmitate, and sorbitan oleate; polyoxyethylene sorbitan fatty acid esters such as, but not limited to, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polysorbate 85; polyoxyethylene mono- and di-fatty acid esters including, but not limited to, polyoxyl 40 stearate and polyoxyl 40 oleate; a mixture of polyoxyethylene mono- and di-esters of C8-22 fatty acids and glyceryl mono-, di-, and tri-esters of C8-22 fatty acids as sold under tradenames such as Labrasol®, Gelucire® 44/14, Gelucire® 50/13, and Labrafil®; polyoxyethylene castor oils compound such as, but not limited to, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, and polyoxyl 60 hydrogenated castor oil, as are sold under tradenames such as Cremophor®/Kolliphor EL, Cremophor®/Kolliphor® RH40, and Cremophor®/Kolliphor® RH60; polyoxyethylene alkyl ethers including, but not limited to, polyoxyl 20 cetostearyl ether and polyoxyl 10 oleyl ether; DL-α-tocopheryl polyethylene glycol succinate; glyceryl mono-, di-, and tri-esters; glyceryl mono-, di-, and tri-esters of C8-22 fatty acids; sucrose mono-, di-, and tri-esters; sodium dioctylsulfosuccinate; polyoxyethylene-polyoxypropylene copolymers such as, but not limited to poloxamer 124, poloxamer 188, and poloxamer 407; polyoxyethylene ethers of C8-22 fatty alcohols including, but not limited to, polyoxyethylenelauryl alcohol, polyoxyethylenecetyl alcohol, polyoxyethylene stearyl alcohol, polyoxyethyleneoleyl alcohol, as sold under tradenames such as Brij® 35, Brij® 58, Brij® 78, Brij® 98, or a mixture of any two or more thereof.


A co-emulsifier, or co-surfactant, may be used in the formulation. A suitable co-emulsifier or co-surfactant may be a phosphoglyceride; a phospholipid, for example lecithin, or a free fatty acid that is liquid at room temperature, for example, iso-stearic acid, oleic acid, linoelic acid, linolenic acid, palmitic acid, stearic acid, lauric acid, capric acid, caprylic acid, and caproic acid.


Suitable solvents/co-solvents include ethanol, propylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, and glycerol.


A polymer may also be used in the formulation to inhibit drug precipitation or to alter the rate of drug release. A range of polymers have been shown to impart these properties and are well known to those skilled in the art. Suitable polymers include hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetyl succinate, other cellulose-derived polymers such as methylcellulose; poly(meth)acrylates, such as the Eudragit series of polymers, including Eudragit E100, polyvinylpyrrolidone, or others as described in, e.g. Warren et al., Mol. Pharmaceutics 2013, 10, 2823-2848.


Formulations may be chosen specifically to provide for sustained release of the active in the gastrointestinal (GI) tract in order to control the rate of absorption. Many different approaches may be used to achieve these ends including the use of high melting point lipids that disperse/erode slowly in the GI tract, or polymers that form a matrix that slowly erodes. These formulations may take the form of large monolithic dose forms or may be present as micro or nano-particulate matrices as described in, for example, in Mishra, Handbook of Encapsulation and Controlled Release, CRC Press, Boca Raton, (2016) ISBN 978-1-4822-3234-9, Wilson and Crowley Controlled Release in Oral Drug Delivery, Springer, NY, ISBN 978-1-4614-1004-1 (2011) or Wise, Handbook of Pharmaceutical Controlled Release Technology, Marcel Dekker, NY, ISBN 0-82467-0369-3 (2000).


Formulations may also contain materials commonly known to those skilled in the art to be included in lipid based formulations, including antioxidants, for example, butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) and solidifying agents such as microporous silica, for example magnesium alumino-metasilicate (Neusilin).


In some embodiments, the lipid prodrug may be co-administered orally with an enzyme inhibitor to increase stability of the prodrug in the gastrointestinal tract or enterocyte. In certain embodiments, the enzyme inhibitor inhibits pancreatic lipases, examples of which include, but are not limited to, Alli® (orlistat). In other embodiments it is envisaged that the enzyme inhibitor will inhibit cellular lipase enzymes such as monoacylglycerol lipase, an example of which includes, but is not limited to, JZL184 (4-nitrophenyl-4-[bis(1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate).


Combination Therapies

A provided lipid prodrug, or pharmaceutically acceptable composition thereof, may be administered to a patient in need thereof in combination with one or more additional therapeutic agents and/or therapeutic processes.


The lipid prodrug or pharmaceutically acceptable composition thereof can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of the lipid prodrug or composition and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A disclosed lipid prodrug or composition can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.


Such additional agents may be administered separately from a provided lipid prodrug or composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a disclosed lipid prodrug in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another.


As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with the present disclosure. For example, a disclosed lipid prodrug may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a disclosed lipid prodrug, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the additional agent is formulated in a separate composition from the lipid prodrug.


The amount of both a disclosed lipid prodrug and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration. In certain embodiments, compositions of this invention should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of a disclosed lipid prodrug can be administered.


In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the disclosed lipid prodrug may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions, a dosage of between 0.01-1,000 μg/kg body weight/day of the additional therapeutic agent can be administered.


The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.


Examples of agents with which the lipid prodrugs of this invention may be combined include, without limitation: treatments for Alzheimer's Disease such as Aricept® and Excelon®; treatments for HIV such as ritonavir; treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex® and RebiC), Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; agents that prolong or improve pharmacokinetics such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir), and agents for treating immunodeficiency disorders such as gamma globulin.


In certain embodiments, combination therapies of the present invention include a monoclonal antibody or a siRNA therapeutic.


In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder or condition by administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or a biologic and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), JAK inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such as abatacept (Orencia®), “anti-IL-6” agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine (Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®), or any combination(s) thereof.


In another embodiment, the present invention provides a method of treating gout comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol and febuxostat (Uloric®).


In another embodiment, the present invention provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such as abatacept (Orencia®) and “anti-IL-6” agents such as tocilizumab (Actemra®).


In some embodiments, the present invention provides a method of treating osteoarthritis comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanezumab.


In some embodiments, the present invention provides a method of treating lupus comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).


In some embodiments, the present invention provides a method of treating inflammatory bowel disease comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagyl or ciprofloxacin.


In some embodiments, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®).


In some embodiments, the present invention provides a method of treating COPD comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, and combinations thereof.


In some embodiments, the present invention provides a method of treating HIV comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), ab acavir/lamivudine (Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), and combinations thereof.


In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a Bcl-2 inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.


In another embodiment, the present invention provides a method of treating a solid tumor comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a Bcl-2 inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.


In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a disclosed lipid prodrug and a Hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL.


In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL) comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.


In another embodiment, the present invention provides a method of treating multiple myeloma comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a Bcl-2 inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).


In another embodiment, the present invention provides a method of treating Waldenström's macroglobulinemia comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from chlorambucil (Leukeran®), cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine (Leustatin®), rituximab (Rituxan®), a hedgehog signaling inhibitor, a Bcl-2 inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.


In some embodiments, the present invention provides a method of treating Alzheimer's disease comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from donepezil (Aricept®), rivastigmine (Excelon®), galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®).


In another embodiment, the present invention provides a method of treating organ transplant rejection or graft vs. host disease comprising administering to a patient in need thereof a disclosed lipid prodrug and one or more additional therapeutic agents selected from a steroid, cyclosporin, FK506, rapamycin, a hedgehog signaling inhibitor, a Bcl-2 inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.


In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a disclosed lipid prodrug and a BTK inhibitor, wherein the disease is selected from inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, a hyperproliferative disease, rejection of transplanted organs or tissues, Acquired Immunodeficiency Syndrome (AIDS, caused by HIV), type 1 diabetes, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorder, e.g., diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacyti c lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or cancer of the mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, diseases of the bone and joints including, without limitation, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis, a thromboembolic disorder, (e.g., myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, deep venous thrombosis), inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thromb ocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Behcet's disease, scleraderma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia/reperfusion injury), and Graves' disease.


In some embodiments the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a disclosed lipid prodrug and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small-cell lung cancer, non-small-cell lung cancer, myelodysplastic syndrome, lymphoma, a hematological neoplasm, or a solid tumor.


In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a disclosed lipid prodrug and a PI3K inhibitor, wherein the disease is selected from a cancer, a neurodegenative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, and a CNS disorder.


In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a disclosed lipid prodrug and a PI3K inhibitor, wherein the disease is selected from benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, (including, for example, non-Hodgkin's Lymphoma (NHL) and Hodgkin's lymphoma (also termed Hodgkin's or Hodgkin's disease)), a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or a leukemia, diseases include Cowden syndrome, Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases in which the PI3K/PKB pathway is aberrantly activated, asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection, acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy, bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis, pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis, Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.


A disclosed lipid prodrug of the current invention may also be used to advantage in combination with an antiproliferative compound. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (Temodal); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer and leucovorin. The term “aromatase inhibitor” as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozole is marketed under the trade name Afema™. Anastrozole is marketed under the trade name Arimidex™. Letrozole is marketed under the trade names Femara™ or Femar™ Aminoglutethimide is marketed under the trade name Orimeten™. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.


The term “antiestrogen” as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. A combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.


The term “anti-androgen” as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (Casodex™). The term “gonadorelin agonist” as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.


The term “topoisomerase I inhibitor” as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.


The term “topoisomerase II inhibitor” as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as Caelyx™) daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide is marketed under the trade name Etopophos™. Teniposide is marketed under the trade name VM 26-Bristol Doxorubicin is marketed under the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketed under the trade name Farmorubicin™. Idarubicin is marketed under the trade name Zavedos™. Mitoxantrone is marketed under the trade name Novantron.


The term “microtubule active agent” relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere™. Vinblastine sulfate is marketed under the trade name Vinblastin R.P™. Vincristine sulfate is marketed under the trade name Farmistin™.


The term “alkylating agent” as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin™. Ifosfamide is marketed under the trade name Holoxan™.


The term “histone deacetylase inhibitors” or “HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).


The term “antineoplastic antimetabolite” includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.


The term “platin compound” as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Eloxatin™.


The term “compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds” as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB-111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF-IR, especially compounds which inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds targeting, decreasing or inhibiting the activity of the AxI receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, such as imatinib; i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase) and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (a PI3K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1 ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, C1-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF, n) compounds targeting, decreasing or inhibiting the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds targeting, decreasing or inhibiting the kinase activity of PI3 kinase (PI3K) including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and q) compounds targeting, decreasing or inhibiting the signaling effects of hedgehog protein (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).


The term “PI3K inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in this invention include but are not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.


The term “Bcl-2 inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO 2004/106328, hereby incorporated by reference), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments the Bcl-2 inhibitor is a peptidomimetic.


The term “BTK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against Bruton's Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.


The term “SYK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.


Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO 2008/039218 and WO 2011/090760, the entirety of which are incorporated herein by reference.


Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO 2003/063794, WO 2005/007623, and WO 2006/078846, the entirety of which are incorporated herein by reference.


Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO 2004/019973, WO 2004/089925, WO 2007/016176, U.S. Pat. No. 8,138,347, WO 2002/088112, WO 2007/084786, WO 2007/129161, WO 2006/122806, WO 2005/113554, and WO 2007/044729 the entirety of which are incorporated herein by reference.


Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO 2009/114512, WO 2008/109943, WO 2007/053452, WO 2000/142246, and WO 2007/070514, the entirety of which are incorporated herein by reference.


Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (Thalomid™) and TNP-470.


Examples of proteasome inhibitors useful for use in combination with a disclosed lipid prodrug include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.


Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.


Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- or δ-tocotrienol.


The term “cyclooxygenase inhibitor” as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex™), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.


The term “bisphosphonates” as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. Etridonic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the trade name Zometa™. The term “mTOR inhibitors” relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.


The term “heparanase inhibitor” as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88. The term “biological response modifier” as used herein refers to a lymphokine or interferons.


The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a “farnesyl transferase inhibitor” such as L-744832, DK8G557 or R115777 (Zarnestra™). The term “telomerase inhibitor” as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase enzyme, such as telomestatin.


The term “methionine aminopeptidase inhibitor” as used herein refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.


The term “proteasome inhibitor” as used herein refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (Velcade™) and MLN 341.


The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.


The term “compounds used in the treatment of hematologic malignancies” as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.


Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.


The term “HSP90 inhibitors” as used herein includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.


The term “antiproliferative antibodies” as used herein includes, but is not limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 Antibody. By antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.


For the treatment of acute myeloid leukemia (AML), a disclosed lipid prodrug can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, a disclosed lipid prodrug can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.


Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds which target, decrease or inhibit activity of histone deacetylase (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat. No. 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt. Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term “ionizing radiation” referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1, pp. 248-275 (1993).


Also included are EDG binders and ribonucleotide reductase inhibitors. The term “EDG binders” as used herein refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720. The term “ribonucleotide reductase inhibitors” refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.


Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (Avastin™).


Photodynamic therapy as used herein refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as Visudyne™ and porfimer sodium.


Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.


Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.


Disclosed lipid prodrugs are also useful as co-therapeutic compounds for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs. A disclosed lipid prodrug may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance. Accordingly the invention includes a combination of a disclosed lipid prodrug as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said disclosed lipid prodrug and said drug substance being in the same or different pharmaceutical composition.


Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 antagonists such LY293111, CGS025019C, CP-195543, SC-53228, BILL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and beta-2 adrenoceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol, and especially, formoterol and pharmaceutically acceptable salts thereof. Suitable bronchodilatory drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.


Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.


Other useful combinations of disclosed lipid prodrugs with anti-inflammatory drugs are those with antagonists of chemokine receptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).


In some embodiments, the additional therapeutic agent is selected from Abacavir, Abiraterone, Acetylcysteine, acyclovir, adefovir dipivoxil, Alatrofloxacin, Albendazole, albuterol, Alendronic acid, Altropane, Amifostine, Aminolevulinic acid, amiodarone (e.g. cosolvent-free), Amisulpride, amitriptyline, amprenavir, anastrozole, Apomorphine, apremilast, Arbutamine, Argatroban, Arsenic trioxide, aspirin, Atazanavir/cobicistat, Atorvastatin, Avibactam/ceftazidime, Azacitidine, azathioprine, Azithromycin, Belinostat, bendamustine, Bexarotene, Biapenem, Bicalutamide, Bortezomib, Bosentan, bosutinib, Bromfenac, Buprenorphine, Bupropion, Busulfan, C1 esterase inhibitor, Caffeine, calcium levofolinate, Cangrelor, capecitabine, capsaicin, Carfilzomib, Carvedilol, Cefepime, Ceftaroline fosamil, Ceftazidime, Ceftibuten, Ceftolozane/tazobactam, celecoxib, Celgosivir, chlorambucil, Cidofovir, Ciprofloxacin, Cladribine, Clazosentan, Clofarabine, Clopidogrel, cyclophosphamide, cytarabine, danazol, Dantrolene, dasatinib, Daunorubicin, Decitabine, Deferiprone, delavirdine, Deoxycholic acid, deoxythymidine, Dexamethasone, Dexmedetomidine, Dexrazoxane, Diclofenac, Didanosine, diethylcarbamazine, Docetaxel, Dolasetron, Doripenem, Doxapram, Doxercalciferol, Doxorubicin, doxycycline, Efavirenz, Eflapegrastim, elvitegravir, emtricitabine, Entacapone, Epacadostat, epinephrine, epitiostanol, Epoprostenol, ergotamine, Eribulin, Esomeprazole, estradiol, estrogen, etonogestrel, Ezetimibe, Ezetimibe/simvastatin, Fasudil, Fenoldopam, Fentanyl, Ferric carboxymaltose, Finasteride, Fingolimod, Florbenazine F18, Florbetaben F 18, florbetapir F 18, Fludarabine, Fluorine 18 AV 1451, fluorouracil, Fluoxymesterone, Flurpiridaz F-18, Flutafuranol F 18, Flutemetamol F 18, Fomepizole, Fosaprepitant, Fosphenytoin, Fospropofol, fulvestrant, Furosemide, Gadobenic acid, Gadobutrol, Gadoversetamide, Gadoxetate disodium, gemcitabine, Glimepiride, Granisetron, Guadecitabine, hydroxychloroquine, Ibandronic acid, ibuprofen, imatinib, Imiquimod, Iobenguane I-123, Ioflupane 123I, Ioxilan, Irinotecan, Isavuconazonium, isosorbidedinitrate, ivermectin, ixabepilone, labelalol, Lacosamide, lamivudine, Lamotrigine, Lansoprazole, Lapatinib, L-dopa, leflunomide, Letermovir, Letrozole, Levetiracetam, Levofloxacin, Levothyroxine, Lidocaine, lidocaine, Linezolid, Lobaplatin, Lomitapide, lopinavir, maraviroc, Meloxicam, melphalan, mercaptopurine, Meropenem, Mesna, methotrexate, Methylnaltrexone, Methylphenidate, metoprolol, midazolam, Minocycline IV, Mitoxantrone, Moxifloxacin, Mycophenolate mofetil, naloxone, naltrexone, naproxen, Nefazodone, nelarabine, nelfinavir, Nevirapine, nilotinib, Nilutamide, nitrosoureas, nortriptyline, Omacetaxine mepesuccinate, Omadacycline, Omeprazole, an opioid such as codeine, meperidine, fentanyl, morphine, oxycodone, hydrocodone, hydromorphone, or methadone, Oxaliplatin, oxprenolol, Oxybutynin, Oxymetholone, paclitaxel (Taxol®), Palonosetron, Pantoprazole, Paracetamol, Pemetrexed, pentazocine, Pentostatin, Phenylephrine, Pirmenol, platinum, Plazomicin, Plerixafor, ponatinib, pralatrexate, predisone, prednisolone, Propofol, propranolol, Quinapril, Radium-223 chloride, Raloxifene, raltegravir, Raltitrexed, Ramatroban, Regadenoson, Remifentanil, Remimazolam besylate, rilpivirine, rinotecan, Risperidone, Ritonavir, Rivastigmine, rofecoxib, Romidepsin, Ropeginterferon alfa-2b, Rotigotine, salbutamol, Salmeterol, Samarium 153 lexidronam, saquinavir, Selegiline, Sertraline, Sildenafil, Simvastatin, Sorivudine, Stavudine, sulfasalazine, Sulfur hexafluoride, Sumatriptan, Sunitinib, Tacrine, tamoxifen, Technetium Tc 99m trofolastat, Tedizolid, Temozolomide, tenofovir, Terbinafine, Testosterone propionate, thiotepa, Tianeptine, Tigecycline, Tizanidine, Topiramate, Topotecan, toremifene, Treprostinil, Tretinoin, Triciribine, verapamil, Verteporfin, Vinorelbine, Vismodegib, Voglibose, zalcitabine, zidovudine, Zileuton, or Zoledronic acid; or a pharmaceutically acceptable salt thereof.


The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium “The Merck Index” or from databases, e.g. Patents International (e.g. IMS World Publications).


A disclosed lipid prodrug may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a disclosed lipid prodrug is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.


The disclosed lipid prodrugs and compositions, and any co-administered additional therapeutic agents, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of a disease, disorder, or condition such as cancer, an autoimmune disorder, a proliferative disorder, an inflammatory disorder, a neurodegenerative or neurological disorder, schizophrenia, a bone-related disorder, liver disease, or a cardiac disorder. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Disclosed lipid prodrugs are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of a disclosed lipid prodrug or composition thereof and any co-administered additional therapeutic agents will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific lipid prodrug employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific lipid prodrug or composition; the duration of the treatment; drugs used in combination or coincidental with the specific lipid prodrug or composition employed, and like factors well known in the medical arts. The term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.


4. Methods of Making Lipid Prodrugs
General Methods for Making Lipid Prodrugs

The lipid prodrug compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.


The therapeutic agents comprised in disclosed lipid prodrugs (e.g., conjugated to a glyceride-based prodrug) may be purchased commercially or prepared by organic synthesis, semi-synthesis, fermentation (e.g. with viral vectors), and like methods known in the art.


In some embodiments, protecting groups (as defined below) can be used to manipulate therapeutic agents in preparation for conjugation to the remainder of the lipid prodrug structure, for example, to prevent undesired side reactions from taking place.


In the synthesis methods described herein, where a particular protecting group (“PG”), leaving group (“LG”), or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 7th Edition, John Wiley & Sons, 2013, Comprehensive Organic Transformations, R. C. Larock, 3rd Edition, John Wiley & Sons, 2018, and Protective Groups in Organic Synthesis, P. G. M. Wuts, 5th edition, John Wiley & Sons, 2014, the entirety of each of which is hereby incorporated herein by reference.


As used herein, the phrase “leaving group” (LG) includes, but is not limited to, halogens (e.g., fluoride, chloride, bromide, iodide), sulfonates (e.g., mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.


As used herein, the phrase “oxygen protecting group” includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, P. G. M. Wuts, 5th edition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which are incorporated herein by reference. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trim ethyl acetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenyl sulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethyl silyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.


Amino protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, P. G. M. Wuts, 5th edition, John Wiley & Sons, 2014, and Philip Kocienski, in Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which are incorporated herein by reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (Boc), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (Cbz), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.


One of skill in the art will appreciate that various functional groups present in compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens and nitriles can be interconverted by techniques well known in the art including, but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. See, for example, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 7th Edition, John Wiley & Sons, 2013, Comprehensive Organic Transformations, R. C. Larock, 3rd Edition, John Wiley & Sons, 2018, the entirety of each of which is incorporated herein by reference. Such interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of the invention are described below.


As a general strategy, compounds of the present invention may be synthesized via one of the following routes:




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Diacid chlorides i, which are readily available from the corresponding malonic acids, can be reacted with a diglyceride such as ii in the presence of pyridine or another appropriate base to give acid-triglyceride (acid-TG) iii (see Scheme 1). Formula iii is shown with C15H31 fatty acid side chains, but other fatty acids (such as those described above) can be substituted in this and other Formulas described below.




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In cases where acid anhydride i-a is available, acid-TG iii can be generated by ring-opening with diglyceride ii in the presence of pyridine or another appropriate base (Scheme 2). This method works best when R4 and R5 of acid anhydride i-a are identical, e.g. both Me, but will result in a regioisomeric mixture of acid-TG products iv when R4 and R5 differ from each other. Consequently, other methods, such as that outlined in Scheme 3, can advantageously be employed in this circumstance.




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To obtain acid-TG iv as a single regioisomer in the specific example where R4=Me or other alkyl or substitution and R5═H, the known carboxylic acid v (Lienard, B. M. R. et al., Org. Biomol. Chem. 2008, 6, (13), 2282-2292) can be used as a starting point (see Scheme 3). Coupling of acid v with 1,3-DG ii under standard conditions produces TBDPS protected triglyceride vi, which can be treated with appropriate conditions such as TBAF and AcOH to afford alcohol vii. A two-step oxidation process (for example, PCC, then KMn04) can then be used to transform alcohol vii into the desired acid-TG iv via the intermediate aldehyde viii.




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For the synthesis of compounds containing an acetal self-immolative (ASI) group between the pharmaceutical agent and the alkyl spacer, the alcohol-bearing parent molecule must be functionalized and activated prior to conjugation with acid-triglyceride iii as outlined above in Scheme 4. Treatment of an alcohol with DMSO in a mixture of acetic anhydride and acetic acid results in the formation of (methylthio)methyl (MTM) ether ix. Activation of MTM ether ix using sulfuryl chloride forms a presumed sulfoxide species that can react with the carboxylate of acid-triglyceride iv to give the target compound x.




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In cases where the pharmaceutical agent contains an alcohol, phenol or amine (primary or secondary) functional group, a modified version of the acetal self-immolative group can be used where an additional carboxy group is included. Reaction of the parent drug with a chloroalkyl chloroformate gives chloroalkyl carbonates (shown) or carbamates xi (see Scheme 5). Displacement of the halide leaving group is then accomplished by treatment with the carboxylate derived from acid-TG iv in an appropriate solvent such as refluxing toluene to afford the target compound xii.




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For the synthesis of prodrugs containing a trimethyl lock (TML) self-immolative group (Levine, M. N.; Raines, R. T. Chem. Sci. 2012, 3, 2412-2420, hereby incorporated by reference) between the pharmaceutical agent and the alkyl spacer to facilitate systemic release of the parent molecule, the acid-triglyceride iv must be functionalized with the TML moiety prior to conjugation with a pharmaceutical agent as outlined in Scheme 6. Coupling of acid-TG iv with TML phenol xiii under standard conditions gives triglyceride xiv, which can be deprotected under acidic conditions (10-camphorsulfonic acid) to give alcohol xv. Sequential oxidation of alcohol xv firstly to aldehyde xvi and then acid xvii, followed by coupling to either an alcohol (shown), amine or sulfonamide-containing pharmaceutical agent under standard conditions can give the target compound xviii.




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Scheme 7. Synthesis of Compounds of Formula xxiv Wherein -M- is a p-Hydroxybenzyl Carbonyl (PHB) Self-Immolative Group.


For the synthesis of compounds containing a p-hydroxybenzyl (PHB) carbonyl self-immolative group, the primary hydroxyl group of p-hydroxybenzyl alcohol (xix) is first protected as a silyl ether and the free phenolic hydroxyl group coupled with acid-TG iv to give PHB triglyceride xxi (see Scheme 7). After removal of the silicon protecting group, primary alcohol xxii can be activated by treatment with p-nitrophenyl (PNP) chloroformate to give PNP carbonate xxiii. Displacement of the PNP group is then achieved by reaction with a pharmaceutical agent (A-OH shown) under basic conditions to give the desired compound xxiv.




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Without wishing to be bound by theory, it is believed that the flipped-ester self-immolative (FSI) group can liberate the free pharmaceutical agent by a cyclization mechanism, resulting in loss of either a four-carbon (FSI-4) or five-carbon (FSI-5) lactone. Alternatively, liberation of the agent may occur by a chemical or enzymatic mechanism in vivo. FSI prodrugs can be synthesized by coupling the pharmaceutical agent (A-OH shown) with either 4-bromobutyric acid (m=1) or 5-bromovaleric acid (m=2) (xxv) to give bromide xxvi (see Scheme 8). Displacement of bromide xxvi using the carboxylate derived from acid-TG iv generates the desired ester bond in target compound xxvii.


EXEMPLIFICATION
Example 1: Synthesis of Intermediates
List of Abbreviations



  • equiv or eq: molar equivalents

  • rt or RT: room temperature

  • UV: ultra violet

  • HPLC: high pressure liquid chromatography

  • Rt: retention time

  • LCMS or LC-MS: liquid chromatography-mass spectrometry

  • NMR: nuclear magnetic resonance

  • TLC: thin layer chromatography

  • sat: saturated

  • aq: aqueous

  • Ac: acetyl

  • BINAP: (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene

  • Bn: Benzyl

  • DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene

  • DCC: N,N′-Dicyclohexylcarbodiimide

  • DCM: Dichloromethane

  • DCE: Dichloroethane

  • DEA: Diethylamine

  • DIPA: Diisopropylamine

  • DMF: N,N-dimethylformamide

  • DMSO: dimethylsulfoxide

  • DMPU: N,N′-Dimethylpropyleneurea

  • ACN or MeCN: acetonitrile

  • DIPEA: diisopropylethylamine

  • EA or EtOAc: ethyl acetate

  • EDCI, EDC, or EDAC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

  • TEA: triethylamine

  • THF: tetrahydrofuran

  • TBS: tert-butyldimethylsilyl

  • KHMDS: potassium hexamethyl disilylazide

  • Tf: trifluoromethanesulfonate

  • Ms: methanesulfonyl

  • NBS: N-bromosuccinimide

  • PCC: Pyridinium chlorochromate

  • PE: petroleum ether

  • TFA: trifluoroacetic acid

  • MMPP: magnesium monoperoxyphthalate

  • HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide Hexafluorophosphate Cy: cyclohexyl

  • Tol: toluene

  • DMP: Dess-Martin periodinane

  • IBX: 2-iodoxybenzoic acid

  • PMB:p-methoxybenzyl

  • SEM: [2-(Trimethylsilyl)ethoxy]methyl



1,3-DG (Int-2):




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DMF (1 mL, 13.7 mmol) was added into a mixture of palmitic acid (433 g, 1.69 mol) in thionyl chloride (500 mL, 6.3 mol) at room temperature. The resultant reaction mixture was heated under reflux for 3 h. It was concentrated to dryness to afford palmitoyl chloride (453 g, 1.64 mol, 97% yield) as a yellowish oil, which was used in the next step without further purification.


To a mixture of 1,3-dihydroxypropan-2-one (77 g, 0.855 mol) and anhydrous pyridine (140 g, 1.76 mol) in anhydrous dichloromethane (2500 mL) under nitrogen at room temperature, was added with palmitic chloride (453 g, 1.64 mol). The mixture was stirred at room temperature for 16 h. It was diluted with MeOH (1000 mL) and water (2000 mL) and stirred for 30 min. The precipitate was collected by filter and dried to afford Int-1 (462 g, 0.815 mmol, 95% yield) as a white solid.


Int-1 (220 g, 388 mmol) was dissolved in a solution of THF (3000 mL) and water (200 mL) at 0° C. Sodium borohydride (22 g, 579 mmol) was added portion wise. After addition, the mixture was filtered to afford a cake, which was dried to afford compound Int-2 (1,3-DG) (177 g, 311 mmol, 80% yield) as a white solid. LC-MS: MS m/z=591 (M+Na+), RT=4.39 min; 1H NMR (400 MHz, chloroform-d) δ 4.20-4.05 (m, 5H), 2.35 (t, J=7.6 Hz, 4H), 1.62 (t, J=7.6 Hz, 4H), 1.25 (s, 48H), 0.88 (t, J=6.6 Hz, 6H).


C5βMe-acid-2-TG (Int-4):




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A mixture of 3-methylglutaric acid (500 mg, 3.42 mmol) and DMF (two drops) in thionyl chloride (2.48 mL, 34.2 mmol) was heated at reflux for two hours. The reaction was cooled to room temperature, diluted with toluene (5 mL) and concentrated under reduced pressure to give diacid chloride Int-3 (584 mg, 83%) as a yellow oil that was used without purification. 1H NMR (400 MHz, CDCl3) δ 3.02 (dd, J=17.3, 6.1 Hz, 2H), 2.89 (dd, J=17.3, 7.2 Hz, 2H), 2.61 (m, 1H), 1.13 (d, J=6.8 Hz, 2H).


A solution of Int-2 (1,3-DG) (50.0 mg, 0.0879 mmol) and pyridine (71.1 μL, 0.879 mmol) in dichloromethane (2 mL) was added to acid chloride Int-3 (80.4 mg, 0.439) in dichloromethane (1.5 mL) and the mixture heated at reflux for two hours. The reaction was cooled to room temperature, diluted with ethyl acetate (15 mL) and 1 M HCl (5 mL) and the organic phase separated. The aqueous layer was further extracted with ethyl acetate (2×20 mL) and the combined organic extracts washed with 1 M HCl (20 mL) and brine (2×30 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (20% to 45% ethyl acetate/hexanes) gave Int-4 (54.0 mg, 88%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 5.27 (m, 1H), 4.311 (dd, J=11.9, 4.2 Hz, 1H), 4.305 (dd, J=11.9, 4.2 Hz, 1H), 4.14 (dd, J=11.9, 5.6 Hz, 2H), 2.52-2.39 (m, 3H), 2.36-2.24 (m, 6H), 1.66-1.55 (m, 4H), 1.37-1.17 (m, 48H), 1.06 (d, J=6.3 Hz, 3H), 0.88 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 178.1 (C), 173.5 (2C; C), 171.4 (C), 69.3 (CH), 62.2 (2C; CH2), 40.7 (CH2), 40.4 (CH2), 34.1 (2C; CH2), 32.1 (2C; CH2), 29.82 (6C; CH2), 29.78 (4C; CH2), 29.74 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.2 (2C; CH2), 27.3 (CH), 25.0 (2C; CH2), 22.8 (2C; CH2), 19.8 (CH3), 14.2 (2C; CH3); ESI-HRMS: calcd. for C41H76NaO8 [M+Na+] 719.5432; found 719.5451.


Alternate Procedure (Larger Scale):




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A mixture of 3-methylglutaric acid (100 g, 685 mmol) and acetyl chloride (250 mL, 3.53 mol) was heated under reflux for 16 h, then concentrated to dryness before adding into a solution of pyridine (270 g, 3.4 mol) and benzyl alcohol (100 g, 926 mmol) in dichloromethane (1500 mL) at room temperature. The mixture was stirred for 72 h. The reaction was concentrated and the residue was purified by silica column chromatography, eluting with from 0 to 50% ethyl acetate in petroleum ether to afford Int-6 (70 g, 297 mmol, 43% yield) as a yellowish oil. 1H NMR (400 MHz, chloroform-d) δ 7.39-7.30 (m, 5H), 5.12 (s, 2H), 2.52-2.25 (m, 5H), 1.04 (d, J=6.6 Hz, 3H).


To a mixture of Int-6 (70 g, 297 mmol) and Int-2 (1,3-DG) (80 g, 140 mmol) in dichloromethane (1500 mL) was added EDCI (115 g, 600 mmol) and DMAP (3.66 g, 30 mmol). Triethylamine (100 mL, 719 mmol) was added drop wise at 0° C. The mixture was stirred at room temperature for 72 h. The reaction was concentrated to dryness and the residue was purified by silica column chromatography, eluting with ethyl acetate in petroleum ether from 0 to 50% to afford Int-7 (68 g, 86.5 mmol, 29% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 7.40-7.32 (m, 5H), 5.30-5.24 (m, 1H), 5.12 (s, 2H), 4.31-4.27 (m, 2H), 4.17-4.10 (m, 2H), 2.50-2.38 (m, 3H), 2.34-2.28 (m, 6H), 1.61-1.55 (m, 4H), 1.35-1.20 (m, 48H), 1.02 (d, J=6.4 Hz, 3H), 0.88 (t, J=6.6 Hz, 6H).


Int-7 (68 g, 86.5 mmol) and palladium on carbon (3 g) were suspended in THF (400 mL). The mixture was hydrogenated under hydrogen atmosphere at 30° C. for 16 h, then filtered and concentrated to dryness. The residue was further purified by trituration with hexane to afford Int-4 (C5βMe-acid-2-TG) (51 g, 73.2 mmol, 84% yield) as a white solid. LC-MS: MS m/z=719 (M+Na+), RT=3.83 min. 1H NMR (400 MHz, chloroform-d) δ 5.31-5.25 (m, 1H), 4.34-4.29 (m, 2H), 4.16-4.12 (m, 2H), 2.49-2.40 (m, 3H), 2.33-2.28 (m, 6H), 1.62-1.57 (m, 4H), 1.35-1.20 (m, 48H), 1.06 (d, J=6.4 Hz, 3H), 0.88 (t, J=6.6 Hz, 6H).


C10-acid-2-TG:




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A mixture of sebacic acid (88.0 mg, 0.435 mmol) and DMF (one drop) in thionyl chloride (316 μL, 4.35 mmol) was heated at reflux for 1.5 hours. The reaction was cooled to RT, diluted with toluene (5 mL) and concentrated under reduced pressure to give diacid chloride Int-8 (104 mg, quant.) as a yellow oil that was used without purification. 1H NMR (400 MHz, chloroform-d) δ 2.88 (t, J=7.3 Hz, 4H), 1.76-1.66 (m, 4H), 1.42-1.26 (m, 8H).


A solution of Int-2 (1,3-DG) (45.0 mg, 0.0791 mmol) and pyridine (64.0 μL, 0.791 mmol) in dichloromethane (1.5 mL) was added to diacid chloride Int-8 (104 mg, 0.435 mmol) in dichloromethane (1.5 mL) and the mixture stirred at rt for 1.5 hours. The reaction was diluted with ethyl acetate (5 mL), water (10 mL) and 1 M HCl (3 mL) and the aqueous layer extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with 1 M HCl (30 mL) and brine (30 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (20% to 50% ethyl acetate/hexanes) gave Int-9 (C10-acid-2-TG) (24.3 mg, 41%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 5.26 (m, 1H), 4.29 (dd, J=11.9, 4.4 Hz, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 2.37-2.27 (m, 8H), 1.70-1.53 (m, 8H), 1.39-1.19 (m, 56H), 0.87 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 178.6 (C), 173.5 (2C; C), 173.0 (C), 69.0 (CH), 62.2 (CH2), 34.3 (CH2), 34.2 (2C; CH2), 33.9 (CH2), 32.01 (2C; CH2), 29.85 (6C; CH2), 29.81 (4C; CH2), 29.77 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 29.2 (2C; CH2), 29.11 (CH2), 29.10 (CH2), 25.00 (2C; CH2), 24.95 (CH2), 24.8 (CH2), 22.8 (2C; CH2), 14.3 (2C; CH3).


Alternate Procedure (Larger Scale):




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A mixture of sebacic acid (100 g, 495 mmol) and acetyl chloride (250 mL, 3.53 mol) was heated under reflux for 16 h, then cooled and concentrated to dryness. It was added into a solution of pyridine (270 g, 3.4 mol) and benzyl alcohol (100 g, 926 mmol) in dichloromethane (1500 mL) at room temperature and the mixture was stirred for 72 h. The reaction was concentrated and the residue was purified by column chromatography, eluting with from 0 to 50% ethyl acetate in petroleum ether to afford Int-11 (82 g, 281 mmol, 57% yield) as a yellowish oil. LC-MS: MS m/z=293 (M+H+), RT=1.45 min.


To a mixture of Int-11 (82 g, 281 mmol) and Int-2 (1,3-DG) (80 g, 140 mmol) in dichloromethane (1500 mL) was added EDCI (115 g, 600 mmol) and DMAP (3.66 g, 30 mmol). Then triethylamine (100 mL, 719 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature for 72 h. The reaction was concentrated to dryness and the residue was purified by column chromatography, eluting with ethyl acetate in petroleum ether from 0 to 50% to afford Int-12 (65 g, 77 mmol, 27% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 7.38-7.29 (m, 5H), 5.27-5.25 (m, 1H), 5.11 (s, 2H), 4.31-4.27 (m, 2H), 4.17-4.12 (m, 2H), 2.37-2.29 (m, 8H), 1.65-1.57 (m, 8H), 1.35-1.20 (m, 56H), 0.88 (t, J=6.6 Hz, 6H).


Int-12 (65 g, 77 mmol) and palladium on carbon (3 g) were suspended in THF (400 mL). The mixture was hydrogenated under hydrogen atmosphere at 30° C. for 16 h, then it was filtered and the filtrate concentrated to dryness and then further purified by trituration with hexane to afford Int-9 (C10-acid-2-TG) (50 g, 66.4 mmol, 86% yield) as a white solid. LC-MS: MS m/z=775 (M+Na+), RT=5.95 min; 1H NMR (400 MHz, chloroform-d) δ 5.29-5.24 (m, 1H), 4.31-4.27 (m, 2H), 4.19-4.12 (m, 2H), 2.37-2.39 (m, 8H), 1.65-1.58 (m, 8H), 1.35-1.20 (m, 56H), 0.88 (t, J=6.6 Hz, 6H).


Int-120 was Prepared Using Similar Methods:




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1H NMR (401 MHz, CDCl3) δ 5.25 (m, 1H), 4.28 (dd, J=11.9, 4.3 Hz, 2H), 4.13 (dd, J=11.9, 5.9 Hz, 2H), 2.35-2.26 (m, 8H), 1.65-1.54 (m, 8H), 1.35-1.18 (m, 58H), 0.86 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 179.9 (C), 173.4 (2C; C), 173.0 (C), 69.0 (CH), 62.2 (2C; CH2), 34.3 (CH2), 34.2 (2C; CH2), 34.1 (CH2), 32.0 (2C; CH2), 29.81 (6C; CH2), 29.77 (4C; CH2), 29.74 (2C; CH2), 29.59 (2C; CH2), 29.48 (2C; CH2), 29.38 (2C; CH2), 29.36 (CH2), 29.31 (2C; CH2), 29.22 (2C; CH2), 29.15 (CH2), 29.13 (CH2), 25.0 (3C; CH2), 24.8 (CH2), 22.8 (2C; CH2), 14.2 (2C; CH3). ESI-HRMS: calcd. for C46H86NaO8 [M+Na+] 789.6215; found 789.6218.


C12α′βMe-acid-2-TG (Int-23 and Int-27):




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Int-13: prepared according to: Young, I. S.; Kerr, M. A. J. Am. Chem. Soc. 2007, 129, 1465-1469.


Int-14: prepared according to: Chowdhury, R.; Ghosh, S. K. Org. Lett. 2009, 11, 3270-3273.


n-Butyllithium (n-BuLi, 1.6 M in hexanes, 765 μL, 1.23 mmol) was added slowly to a solution of TMS-acetylene (198 μL, 1.40 mmol) in THF (1.5 mL) at −78° C. and the mixture stirred at −78° C. for five minutes then warmed to rt and stirred for a further 15 minutes. The reaction was re-cooled to −50° C., a solution of bromide Int-14 (90.0 mg, 0.350 mmol) in THF (1 mL) was added dropwise and the mixture stirred at −50° C. for 15 minutes and then at room temperature for 17 hours. The reaction was diluted with brine (15 mL) and the aqueous phase extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (4% to 5% ethyl acetate/hexanes) gave TMS alkyne Int-15 (45.9 mg, 48%) as a colorless oil also containing desilylated alkyne Int-16 (9.7 mg, 14% by 1H NMR integration) and small amounts of PPh3. 1H NMR (400 MHz, CDCl3) δ 7.37-7.26 (m, 5H), 4.50 (s, 2H), 3.48 (t, J=6.5 Hz, 2H), 2.23 (t, J=7.0 Hz, 2H), 1.68-1.60 (m, 2H), 1.58-1.42 (m, 4H), 0.14 (s, J=3.4 Hz, 7H).


Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 201 μL, 0.201 mmol) was added dropwise to a 7:2 mixture of silylalkyne Int-15 and alkyne Int-16 (55.6 mg combined, 0.215 mmol) in THF (1 mL) at 0° C. and the mixture stirred at room temperature for one hour. The reaction was diluted with water (5 mL) and sat. aq. NH4Cl (3 mL) and the aqueous phase extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (4% ethyl acetate/hexanes) gave alkyne Int-16 (37.5 mg, 53% over two steps) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.39-7.27 (m, 5H), 4.51 (s, 2H), 3.49 (t, J=6.5 Hz, 2H), 2.21 (td, J=6.9, 2.6 Hz, 2H), 1.95 (t, J=2.7 Hz, 1H), 1.70-1.61 (m, 2H), 1.60-1.48 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 138.7 (C), 128.5 (2C; CH), 127.7 (2C; CH), 127.6 (CH), 84.6 (C), 73.0 (CH2), 70.3 (CH2), 68.4 (CH), 29.4 (CH2), 28.4 (CH2), 25.5 (CH2), 18.5 (CH2).


Int-17: prepared according to: Kim, H.-O. et al. Synlett 1998, 1059-1060.


A suspension of PdCl2(PPh3)2 (16.8 mg, 0.0240 mmol) in DMF (1.5 mL) was degassed using N2 gas for five minutes, and then CuI (9.1 mg, 0.0480 mmol), Et3N (66.8 μL, 0.480 mmol) and a degassed solution of alkyne Int-16 (48.5 mg, 0.240 mmol) and enol triflate Int-17 (94.3 mg, 0.360 mmol) in DMF (2 mL) were added. The mixture was degassed using a stream of N2 for a further five minutes and then heated at 0° C. for one hour. The reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with 1 M HCl, sat. aq. NaHCO3, water and brine (20 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (4% to 5% ethyl acetate/hexanes) gave enyne Int-18 (46.6 mg, 62%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.37-7.24 (m, 5H), 5.92 (m, 1H), 4.50 (s, 2H), 4.17 (q, J=7.1 Hz, 2H), 3.48 (t, J=6.5 Hz, 2H), 2.45 (t, J=7.0 Hz, 2H), 2.01 (d, J=1.4 Hz, 3H), 1.69-1.59 (m, 4H), 1.56-1.49 (m, 2H), 1.27 (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.4 (C), 138.8 (C), 135.9 (C), 128.5 (2C; CH), 127.7 (2C; CH), 127.6 (CH), 123.4 (CH), 102.9 (C), 80.0 (C), 73.0 (CH2), 70.4 (CH2), 60.0 (CH2), 29.4 (CH2), 28.4 (CH2), 26.0 (CH3), 25.7 (CH2), 20.1 (CH2), 14.4 (CH3).


A solution of benzyl ether Int-18 (31.4 mg, 0.100 mmol) in ethyl acetate (8 mL) in a three-neck round-bottom flask was twice evacuated and flushed with N2 gas, then palladium on carbon (10% w/w, 26.6 mg, 0.0250 mmol) was added and the resulting suspension re-evacuated and flushed with N2 three times. The flask was fitted with a H2 balloon, evacuated and flushed with H2 three times and the reaction mixture stirred at RT under 1 atm of H2 for one hour. The flask was then evacuated and flushed with N2 and the reaction mixture filtered through a pad of Celite, washing with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure to give saturated alcohol Int-19 (23.0 mg, quant.) as a colorless oil that was used without purification. 1H NMR (400 MHz, CDCl3) δ 4.12 (q, J=7.1 Hz, 2H), 3.63 (t, J=6.6 Hz, 2H), 2.28 (dd, J=14.6, 6.1 Hz, 1H), 2.09 (dd, J=14.6, 8.1 Hz, 1H), 1.94 (m, 1H), 1.60-1.50 (m, 2H), 1.25 (t, J=6.6 Hz, 3H), 1.40-1.13 (m, 10H), 0.92 (d, J=6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.6 (C), 63.2 (CH2), 60.2 (CH2), 42.1 (CH2), 36.8 (CH2), 32.9 (CH2), 30.5 (CH), 29.8 (CH2), 29.5 (CH2), 26.9 (CH2), 25.8 (CH2), 19.9 (CH3), 14.4 (CH3).


Imidazole (9.6 mg, 0.141 mmol) and tert-butyl(chloro)diphenylsilane (TBDPSCl, 50.8 μL, 0.195 mmol) were added to a solution of alcohol Int-19 (18.0 mg, 0.0781 mmol) in DMF (3 mL) and the mixture stirred at RT for 16 hours. The reaction was diluted with ethyl acetate (20 mL), washed with brine (2×20 mL), dried (MgSO4), and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (4% ethyl acetate/hexanes with 0.5% Et3N) gave TBDPS ether Int-20 (33.7 mg, 92%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.70-7.64 (m, 4H), 7.45-7.33 (m, 6H), 4.13 (q, J=7.1 Hz, 2H), 3.65 (t, J=6.5 Hz, 2H), 2.28 (dd, J=14.6, 6.0 Hz, 1H), 2.09 (dd, J=14.6, 8.2 Hz, 1H), 1.94 (m, 1H), 1.60-1.50 (m, 2H), 1.38-1.21 (m, 3H), 1.05 (s, J=2.9 Hz, 2H), 1.05 (s, 9H), 0.93 (d, J=6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.6 (C), 135.7 (4C; CH), 134.3 (2C; C), 129.6 (2C; CH), 127.7 (4C; CH), 64.1 (CH2), 60.2 (CH2), 42.1 (CH2), 36.9 (CH2), 32.7 (CH2), 30.5 (CH), 29.9 (CH2), 29.5 (CH2), 27.01 (3C; CH3), 26.99 (CH2), 25.9 (CH2), 19.9 (CH3), 19.4 (C), 14.4 (CH3).


A solution of potassium hydroxide (2.0 M, 427 μL, 0.853 mmol) was added to ester Int-20 (40.0 mg, 0.0853 mmol) in ethanol (2 mL) and the mixture heated at 80° C. for two hours. The reaction was cooled to RT, acidified to pH 1 by addition of 1 M HCl and the organic solvent removed under reduced pressure. The residue was diluted with water (5 mL) and the aqueous phase extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4) and concentrated under reduced pressure to give crude acid Int-21 (37.6 mg, quant.) as a colorless oil that was used without purification. 1H NMR (400 MHz, CDCl3) δ 7.74-7.63 (m, 4H), 7.45-7.34 (m, 6H), 3.65 (t, J=6.5 Hz, 2H), 2.35 (dd, J=15.0, 5.9 Hz, 1H), 2.14 (dd, J=15.0, 8.2 Hz, 1H), 1.95 (m, 1H), 1.61-1.50 (m, 2H), 1.38-1.18 (m, 10H), 1.04 (s, 9H), 0.96 (d, J=6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 179.5 (C), 135.7 (4C; CH), 134.3 (2C; C), 129.6 (2C; CH), 127.7 (4C; CH), 64.1 (CH2), 41.7 (CH2), 36.8 (CH2), 32.7 (CH2), 30.3 (CH), 29.8 (CH2), 29.5 (CH2), 27.01 (3C; CH3), 26.97 (CH2), 25.9 (CH2), 19.8 (CH3), 19.4 (C). Note: While two sets of signals were observed in both the 1H and 13C NMR spectra, only the major set of signals are reported above. It was unclear if the doubling was due to the presence of two closely-related compounds or the presence of both monomeric and dimeric species due to the high concentration of the NMR sample.


DMAP (10.1 mg, 0.0831 mmol), EDC.HCl (39.8 mg, 0.208 mmol) and Int-2 (1,3-DG) (70.9 mg, 0.125 mmol) were added to a solution of acid Int-21 (36.6 mg, 0.0831 mmol) in dichloromethane (2.5 mL) and the mixture stirred at room temperature for 21 hours. The reaction was diluted with dichloromethane (5 mL), silica gel was added and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (4% to 5% ethyl acetate/hexanes) gave triglyceride Int-22 (39.9 mg, 48% over two steps) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.69-7.64 (m, 4H), 7.44-7.34 (m, 6H), 5.28 (m, 1H), 4.289/4.287 (each dd, J=11.8, 4.2 Hz, 2H), 4.14 (dd, J=12.0, 5.9 Hz, 2H), 3.65 (t, J=6.5 Hz, 2H), 2.37-2.27 (m, 5H), 2.11 (dd, J=14.7, 8.4 Hz, 1H), 1.92 (m, 1H), 1.67-1.50 (m, 8H), 1.39-1.14 (m, 56H), 1.04 (s, 9H), 0.93 (d, J=6.6 Hz, 3H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.5 (2C; C), 172.5 (C), 135.7 (4C; CH), 134.3 (2C; C), 129.6 (2C; CH), 127.7 (4C; CH), 68.9 (CH), 64.1 (CH2), 62.3 (2C; CH2), 41.8 (CH2), 36.8 (CH2), 34.2 (2C; CH2), 32.7 (CH2), 32.1 (2C; CH2), 30.5 (CH), 29.9 (CH2), 29.84 (6C; CH2), 29.80 (4C; CH2), 29.76 (2C; CH2), 29.6 (2C; CH2), 29.54 (CH2), 29.51 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 27.02 (CH2), 27.00 (3C; CH3), 25.9 (CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 19.7 (CH3), 19.4 (C), 14.3 (2C; CH3).


Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 98.3 μL, 98.3 μmol) was added to a solution of TBDPS ether Int-22 (39.0 mg, 39.3 μmol) in THF (2.5 mL) at 0° C. and the mixture stirred at room temperature for three hours. The reaction was diluted with water (10 mL), extracted with ethyl acetate (3×15 mL), and the organic extracts washed with brine (30 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% to 20% ethyl acetate/hexanes) gave alcohol Int-23 (21.8 mg, 74%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 5.28 (m, 1H), 4.29 (dd, J=11.9, 4.3 Hz, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 3.64 (t, J=6.6 Hz, 2H), 2.36-2.27 (m, 5H), 2.12 (dd, J=14.7, 8.2 Hz, 1H), 1.93 (m, 1H), 1.65-1.52 (m, 6H), 1.39-1.16 (m, 58H), 0.93 (d, J=6.6 Hz, 3H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.5 (2C; C), 172.5 (C), 68.9 (CH), 63.2 (CH2), 62.3 (2C; CH2), 41.8 (CH2), 36.7 (CH2), 34.2 (2C; CH2), 32.9 (CH2), 32.1 (2C; CH2), 30.5 (CH), 29.84 (4C; CH2), 29.83 (2C; CH2), 29.80 (4C; CH2), 29.77 (2C; CH2), 29.6 (2C; CH2), 29.5 (3C; CH2), 29.4 (2C; CH2), 29.3 (3C; CH2), 26.9 (CH2), 25.8 (CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 19.7 (CH3), 14.3 (2C; CH3).


Pyridinium chlorochromate (PCC, 12.0 mg, 55.8 μmol) was added to a suspension of alcohol Int-23 (21.0 mg, 27.9 μmol) and celite (15 mg) in dichloromethane (1.5 mL) at 0° C. and the mixture stirred at room temperature for 1.75 hours. The reaction was filtered through a short pad of silica gel, eluting with ethyl acetate, and the filtrate concentrated under reduced pressure to give crude aldehyde Int-24 (20.9 mg, quant.) as a yellow oil that was used without purification.



1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 5.28 (m, 1H), 4.29 (dd, J=11.6, 3.5 Hz, 2H), 4.14 (dd, J=11.6, 5.7 Hz, 2H), 2.42 (t, J=7.1 Hz, 2H), 2.36-2.25 (m, 5H), 2.12 (dd, J=14.5, 8.3 Hz, 1H), 1.93 (m, 1H), 1.72-1.53 (m, 6H), 1.42-1.05 (m, 56H), 0.93 (d, J=6.5 Hz, 3H), 0.88 (t, J=6.6 Hz, 6H).


Int-25: prepared according to: Gossauer, A.; Kuhne, G. Liebigs. Ann. Chem. 1977, 664-686.


A solution of ylide Int-25 (8.1 mg, 19.0 μmol) in toluene (0.4 mL) was added to aldehyde Int-24 (11.0 mg, 14.6 μmol) in toluene (0.6 mL) and the mixture heated at reflux for four hours. The reaction was cooled to rt and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (5% to 10% ethyl acetate/hexanes) gave α,β-unsaturated benzyl ester Int-26 (7.1 mg, 54%) as a yellow oil. 1H NMR (401 MHz, CDCl3) δ 7.41-7.27 (m, 5H), 6.81 (td, J=7.5, 1.4 Hz, 1H), 5.27 (m, 1H), 5.18 (s, 2H), 4.29 (dd, J=11.9, 4.3 Hz, 2H), 4.14 (dd, J=11.9, 6.0 Hz, 2H), 2.36-2.27 (m, 5H), 2.20-2.08 (m, 3H), 1.93 (m, 1H), 1.85 (d, J=1.2 Hz, 3H), 1.67-1.54 (m, 6H), 1.47-1.38 (m, 2H), 1.37-1.19 (m, 54H), 0.93 (d, J=6.6 Hz, 3H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.4 (2C; C), 172.4 (C), 168.2 (C), 143.2 (CH), 136.6 (C), 128.7 (2C; CH), 128.2 (CH), 128.1 (2C; CH), 127.6 (C), 69.0 (CH), 66.3 (CH2), 62.3 (2C; CH2), 41.8 (CH2), 36.8 (CH2), 34.2 (2C; CH2), 32.1 (2C; CH2), 30.5 (CH), 29.85 (6C; CH2), 29.81 (4C; CH2), 29.77 (2C; CH2), 29.74 (CH2), 29.63 (2C; CH2), 29.56 (CH2), 29.51 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 28.9 (CH2), 28.7 (CH2), 27.0 (CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 19.7 (CH2), 14.3 (2C; CH2), 12.6 (CH2).


A solution of benzyl ether Int-26 (48.5 mg, 54.0 μmol) in ethyl acetate (2.5 mL) in a two-neck flask was evacuated and flushed with N2 gas (three times each), then palladium on carbon (10% w/w, 11.5 mg, 10.8 μmol) was added and the resulting suspension re-evacuated and flushed with N2 (three times each). The flask was fitted with a H2 balloon, evacuated and flushed with H2 (three times each) and the reaction mixture stirred at room temperature under 1 atm of H2 for three hours. The reaction was filtered through a pad of celite, washing with ethyl acetate, and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% to 20% ethyl acetate/hexanes) gave saturated acid Int-27 (C12a′(3Me-acid-2-TG) (28.1 mg, 64%) as a colorless oil. 1H NMR (401 MHz, CDCl3) δ 5.27 (m, 1H), 4.29 (dd, J=11.9, 4.3 Hz, 2H), 4.14 (dd, J=11.9, 6.1 Hz, 2H), 2.46 (m, 1H), 2.37-2.26 (m, 5H), 2.12 (dd, J=14.7, 8.2 Hz, 1H), 1.94 (m, 1H), 1.73-1.55 (m, 5H), 1.41 (m, 1H), 1.37-1.20 (m, 60H), 1.18 (d, J=7.0 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 182.3 (C), 173.5 (2C; C), 172.5 (C), 69.0 (CH), 62.3 (2C; CH2), 41.8 (CH2), 39.4 (CH), 36.8 (CH2), 34.2 (2C; CH2), 33.7 (CH2), 32.1 (2C; CH2), 30.5 (CH), 29.84 (6C; CH2), 29.80 (4C; CH2), 29.77 (2C; CH2), 29.62 (2C; CH2), 29.60 (CH2), 29.57 (CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 27.3 (CH2), 27.0 (CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 19.7 (CH3), 17.0 (CH3), 14.3 (2C; CH3).


C4-acid-2-TG (Int-28):




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4-(Dimethylamino)pyridine (DMAP, 15.5 mg, 0.127 mmol) was added to a solution of 1,3-diglyceride Int-2 (72.2 mg, 0.127 mmol) and succinic anhydride (25.4 mg, 0.254 mmol) in pyridine/THF/CH2Cl2 (0.5 mL each) and the mixture stirred at room temperature for 17 hours. An extra portion of succinic anhydride (25.4 mg, 0.254 mmol) and DMAP (15.5 mg, 0.127 mmol) was added and the solution heated at 40° C. for a further 22 hours. The reaction was diluted with ethyl acetate (25 mL), washed with 1 M HCl (20 mL) and brine (2×30 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (15% to 25% ethyl acetate/hexanes) gave acid-TG Int-28 (77.0 mg, 91%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 5.27 (m, 1H), 4.30 (dd, J=12.0, 4.3 Hz, 2H), 4.15 (dd, J=12.0, 5.8 Hz, 2H), 2.72-2.61 (m, 4H), 2.31 (t, J=7.6 Hz, 4H), 1.67-1.54 (m, 4H), 1.36-1.19 (m, 48H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 176.9 (C), 173.5 (2C; C), 171.4 (C), 69.8 (CH), 62.0 (2C; CH2), 34.2 (2C; CH2), 32.1 (2C; CH2), 29.84 (6C; CH2), 29.81 (4C; CH2), 29.77 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 29.0 (CH2), 28.8 (CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 14.3 (2C; CH3).


C6-acid-2-TG (Int-29):




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A solution of 1,3-diglyceride Int-2 (75.0 mg, 0.132 mmol) and pyridine (107 μL, 1.32 mmol) in CH2Cl2 (2.5 mL) was added to diacid chloride 1 (96.1 mL, 0.659 mmol) in CH2Cl2 (2.5 mL) and the mixture heated at reflux for 3.5 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (30 mL) and the organic extract washed with 1 M HCl (20 mL) and brine (2×20 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (15% to 25% ethyl acetate/hexanes) gave acid-TG Int-29 (52.7 mg, 57%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 5.26 (m, 1H), 4.30 (dd, J=11.9, 4.3 Hz, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 2.41-2.34 (m, 4H), 2.31 (t, J=7.6 Hz, 4H), 1.72-1.65 (m, 4H), 1.65-1.56 (m, 4H), 1.35-1.20 (m, 48H), 0.88 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 178.3 (C), 173.5 (2C; C), 172.4 (C), 69.3 (CH), 62.2 (2C; CH2), 34.2 (2C; CH2), 33.8 (CH2), 33.5 (CH2), 32.1 (2C; CH2), 29.84 (6C; CH2), 29.81 (4C; CH2), 29.77 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 25.0 (2C; CH2), 24.3 (CH2), 24.1 (CH2), 22.8 (2C; CH2), 14.3 (2C; CH2).


C10βMe-acid-2-TG (Int-30):




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A solution of sodium chlorite (22.7 mg, 0.251 mmol) and sodium phosphate monobasic (NaH2PO4, 23.4 mg, 0.195 mmol) in water (1 mL) was added dropwise to aldehyde Int-24 (20.9 mg, 0.0279 mmol) in t-BuOH (1.5 mL) and 2,3-dimethyl-2-butene (0.3 mL) and the reaction stirred at room temperature for 2.25 hours. The reaction was diluted with water (10 mL) and the aqueous layer extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% to 20% ethyl acetate/hexanes with 0.5% acetic acid) gave acid Int-30 (16.1 mg, 75%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 5.27 (m, 1H), 4.29 (dd, J=11.9, 4.3 Hz, 2H), 4.14 (dd, J=12.0, 6.0 Hz, 2H), 2.37-2.27 (m, 7H), 2.12 (dd, J=14.7, 8.2 Hz, 1H), 1.93 (m, 1H), 1.67-1.55 (m, 6H), 1.40-1.14 (m, 56H), 0.93 (d, J=6.6 Hz, 3H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 179.7 (C), 173.5 (2C; C), 172.4 (C), 69.0 (CH), 62.3 (2C; CH2), 41.8 (CH2), 36.7 (CH2), 34.2 (2C; CH2), 34.1 (CH2), 32.1 (2C; CH2), 30.4 (CH), 29.82 (6C; CH2), 29.79 (4C; CH2), 29.75 (2C; CH2), 29.6 (2C; CH2), 29.5 (3C; CH2), 29.4 (2C; CH2), 29.24 (2C; CH2), 29.16 (CH2), 26.8 (CH2), 25.0 (2C; CH2), 24.8 (CH2), 22.8 (2C; CH2), 19.7 (CH3), 14.2 (2C; CH3).


Using similar methods to those described above, Int-121 was prepared:




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1H NMR (401 MHz, CDCl3) δ 5.28 (m, 1H), 4.29 (dd, J=11.9, 4.3 Hz, 2H), 4.14 (dd, J=11.8, 6.0 Hz, 2H), 3.64 (t, J=6.6 Hz, 2H), 2.32 (dd, J=14.6, 5.8 Hz, 1H), 2.30 (t, J=7.5 Hz, 4H), 2.12 (dd, J=14.6, 8.2 Hz, 1H), 1.94 (m, 1H), 1.64-1.49 (m, 6H), 1.40-1.13 (m, 62H), 0.93 (d, J=6.6 Hz, 3H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.3 (2C; C), 172.4 (C), 68.9 (CH), 62.9 (CH2), 62.2 (2C; CH2), 41.7 (CH2), 36.7 (CH2), 34.1 (2C; CH2), 32.9 (CH2), 32.0 (2C; CH2), 30.4 (CH), 29.80 (CH2), 29.76 (6C; CH2), 29.72 (4C; CH2), 29.68 (2C; CH2), 29.65 (CH2), 29.62 (CH2), 29.53 (2C; CH2), 29.50 (CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 29.2 (2C; CH2), 27.0 (CH2), 25.8 (CH2), 24.9 (2C; CH2), 22.7 (2C; CH2), 19.6 (CH3), 14.2 (2C; CH3).


C12-acid-2-TG (Int-37):




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A mixture of dodecanedioic acid (700 mg, 3.04 mmol) and DMF (two drops) in thionyl chloride (2.20 mL, 30.4 mmol) was heated at reflux for two hours. The reaction was cooled to room temperature, diluted with toluene (5 mL) and concentrated under reduced pressure to give diacid chloride Int-36 (812 mg, quant.) as a yellow oil that was used without purification. 1H NMR (400 MHz, CDCl3): δ 2.88 (t, J=7.3 Hz, 4H), 1.76-1.65 (m, 4H), 1.42-1.23 (m, 12H).


A solution of 1,3-diglyceride Int-2 (40.0 mg, 0.0703 mmol) and pyridine (56.9 μL, 0.703 mmol) in CH2Cl2 (1.5 mL) was added to diacid chloride Int-36 (93.9 mg, 0.352 mmol) in CH2Cl2 (1.5 mL) and the mixture stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate (3 mL), water (10 mL) and 1 M HCl (2 mL) and the aqueous layer extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with 1 M HCl (30 mL) and brine (2×30 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (20% to 45% ethyl acetate/hexanes) gave acid-TG Int-37 (30.7 mg, 56%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 5.26 (m, 1H), 4.29 (dd, J=11.9, 4.3 Hz, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 2.38-2.26 (m, 8H), 1.69-1.54 (m, 8H), 1.38-1.19 (m, 60H), 0.87 (t, J=6.9 Hz, 6H).


C1513Me-acid-2-TG (Int-49):




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A solution of 1,10-decanediol (1.05 g, 6.00 mmol) in DMF (7 mL) was added dropwise to a suspension of sodium hydride (60% w/w in mineral oil, washed twice with dry petrol, 240 mg, 6.00 mmol) in DMF (8 mL) at 0° C. and the mixture stirred at room temperature for one hour. Benzyl bromide (784 μL, 3.50 mmol) was added dropwise and the mixture stirred at room temperature for 1.5 hours. The reaction was diluted with ethyl acetate (30 mL), quenched with water (20 mL) and the aqueous phase extracted with ethyl acetate (3×30 mL). The combined organic extracts washed with water and brine (60 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (20% to 30% ethyl acetate/hexanes) gave benzyl ether Int-38 (657 mg, 41%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.39-7.24 (m, 5H), 4.50 (s, 2H), 3.64 (t, J=6.6 Hz, 2H), 3.46 (t, J=6.7 Hz, 2H), 1.65-1.52 (m, 4H), 1.40-1.25 (m, 12H).


Carbon tetrabromide (1.05 g, 3.17 mmol) and triphenylphosphine (1.07 g, 4.08 mmol) were added to a solution of alcohol Int-38 (600 mg, 1.11 mmol) in CH2Cl2 (20 mL) at 0° C. and the mixture stirred at room temperature for 2.5 hours. The reaction was diluted with CH2Cl2 (20 mL), silica gel was added and the solvent evaporated under reduced pressure. Purification by silica gel chromatography (3% to 4% ethyl acetate/hexanes) gave bromide Int-39 (658 mg, 89%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.41-7.26 (m, 5H), 4.50 (s, 2H), 3.46 (t, J=6.6 Hz, 2H), 3.40 (t, J=6.9 Hz, 2H), 1.91-1.79 (m, 2H), 1.68-1.56 (m, 2H), 1.47-1.23 (m, 12H).


n-Butyllithium (n-BuLi, 1.6 M in hexanes, 4.01 mL, 6.42 mmol) was added slowly to a solution of TMS-acetylene (1.02 mL, 7.22 mmol) in THF (9 mL) at −78° C. and the mixture stirred at −78° C. for five minutes then warmed to room temperature and stirred for a further 15 minutes. The reaction was re-cooled to −50° C., a solution of bromide Int-39 (525 mg, 1.60 mmol) and DMPU (1.06 mL, 8.82 mmol) in THF (6 mL) was added dropwise and the mixture stirred at −50° C. for 30 minutes and then at room temperature for 22 hours. The reaction was diluted with brine (15 mL) and the organic solvent evaporated under reduced pressure. The aqueous residue was extracted with ethyl acetate (3×25 mL) and the combined organic extracts washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (3.5% to 4.5% ethyl acetate/hexanes) gave TMS alkyne Int-40 (489 mg, 88%) as a colorless oil containing small amounts of desilylated alkyne Int-41 (<10%). 1H NMR (400 MHz, CDCl3) δ 7.37-7.25 (m, 5H), 4.50 (s, 2H), 3.46 (t, J=6.7 Hz, 2H), 2.21 (t, J=7.2 Hz, 2H), 1.65-1.58 (m, 2H), 1.54-1.46 (m, 2H), 1.41-1.24 (m, 12H), 0.14 (s, 9H).


Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 1.61 mL, 1.61 mmol) was added dropwise to silylalkyne Int-40 (463 mg, 1.34 mmol) in THF (12 mL) at 0° C. and the mixture stirred at room temperature for 40 minutes. The reaction was diluted with water (10 mL) and the aqueous phase extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (4% to 5% ethyl acetate/hexanes) gave alkyne Int-41 (361 mg, 98%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.38-7.25 (m, 5H), 4.50 (s, 2H), 3.46 (t, J=6.7 Hz, 2H), 2.18 (td, J=7.1, 2.6 Hz, 2H), 1.94 (t, J=2.7 Hz, 1H), 1.65-1.57 (m, 2H), 1.55-1.48 (m, 2H), 1.43-1.24 (m, 12H). 13C NMR (101 MHz, CDCl3) δ 138.86 (C), 128.49 (2C; CH), 127.77 (2C; CH), 127.61 (CH), 84.97 (C), 73.00 (CH2), 70.67 (CH2), 68.18 (CH), 29.91 (CH2), 29.67 (CH2), 29.59 (CH2), 29.57 (CH2), 29.23 (CH2), 28.89 (CH2), 28.63 (CH2), 26.33 (CH2), 18.54 (CH2).


A suspension of PdCl2(PPh3)2 (32.2 mg, 0.0459 mmol) in DMF (4 mL) was degassed using a stream of N2 gas for five minutes, and then CuI (35.0 mg, 0.184 mmol), Et3N (256 μL, 1.84 mmol) and a degassed solution of alkyne Int-41 (250 mg, 0.918 mmol) and enol triflate Int-17 (313 mg, 1.19 mmol) in DMF (6 mL) were added. The mixture was degassed using a stream of N2 for a further five minutes and then heated at 70° C. for one hour. The reaction was cooled to room temperature, diluted with ethyl acetate (40 mL), washed with 1 M HCl, sat. aq. NaHCO3, water and brine (30 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (4% to 5% ethyl acetate/hexanes) gave enyne Int-42 (269 mg, 76%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.38-7.24 (m, 5H), 5.92 (m, 1H), 4.50 (s, 2H), 4.18 (t, J=7.1 Hz, 2H), 3.46 (t, J=6.7 Hz, 2H), 2.43 (t, J=7.2 Hz, 2H), 2.01 (d, J=1.4 Hz, 3H), 1.65-1.55 (m, 4H), 1.46-1.24 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 165.4 (C), 138.8 (C), 135.9 (C), 128.5 (2C; CH), 127.7 (2C; CH), 127.6 (CH), 123.3 (CH), 103.3 (C), 79.9 (C), 73.0 (CH2), 70.6 (CH2), 60.0 (CH2), 29.9 (CH2), 29.65 (CH2), 29.59 (CH2), 29.56 (CH2), 29.2 (CH2), 29.1 (CH2), 28.6 (CH2), 26.3 (CH2), 26.0 (CH3), 20.1 (CH2), 14.4 (CH3).


A solution of benzyl ether Int-42 (246 mg, 0.640 mmol) in ethyl acetate (25 mL) in a three-neck round-bottom flask was twice evacuated and flushed with N2 gas, then palladium on carbon (10% w/w, 102 mg, 0.0960 mmol) was added and the resulting suspension re-evacuated and flushed with N2 three times. The flask was fitted with a H2 balloon, evacuated and flushed with H2 three times and the reaction mixture stirred at room temperature under 1 atm of H2 for one hour. The reaction mixture was then filtered through a pad of celite and the pad washed with ethyl acetate (40 mL). The filtrate was concentrated under reduced pressure to give saturated alcohol Int-43 (192 mg, quant.) as a colorless oil that was used without purification. 1H NMR (400 MHz, CDCl3) δ 4.12 (q, J=7.1 Hz, 2H), 3.63 (t, J=6.6 Hz, 2H), 2.28 (dd, J=14.6, 6.0 Hz, 1H), 2.08 (dd, J=14.6, 8.1 Hz, 1H), 1.93 (m, 1H), 1.60-1.51 (m, 2H), 1.43-1.12 (m, 23H), 0.92 (d, J=6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 173.6 (C), 63.2 (CH2), 60.2 (CH2), 42.1 (CH2), 36.9 (CH2), 32.9 (CH2), 30.5 (CH), 29.9 (CH2), 29.74 (4C; CH2), 29.70 (CH2), 29.6 (CH2), 27.0 (CH2), 25.9 (CH2), 19.9 (CH3), 14.4 (CH3).


Imidazole (32.0 mg, 0.0.469 mmol) and tert-butyl(chloro)diphenylsilane (TBDPSCl, 183 μL, 0.704 mmol) were added to a solution of alcohol Int-43 (70.5 mg, 0.235 mmol) in DMF (7 mL) and the mixture stirred at room temperature for 17 hours. The reaction was diluted with ethyl acetate (20 mL), washed with water (20 mL) and brine (2×20 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (3% to 4% ethyl acetate/hexanes with 0.5% Et3N) gave TBDPS ether Int-44 (117 mg, 93%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.70-7.63 (m, 4H), 7.44-7.34 (m, 6H), 4.12 (q, J=7.1 Hz, 2H), 3.65 (t, J=6.5 Hz, 2H), 2.29 (dd, J=14.6, 6.0 Hz, 1H), 2.09 (dd, J=14.6, 8.2 Hz, 1H), 1.95 (m, 1H), 1.60-1.50 (m, 2H), 1.38-1.14 (m, 23H), 1.04 (s, J=2.8 Hz, 9H), 0.92 (d, J=6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.5 (C), 135.7 (4C; CH), 134.3 (2C; C), 129.6 (2C; CH), 127.7 (4C; CH), 64.1 (CH2), 60.2 (CH2), 42.1 (CH2), 36.9 (CH2), 32.7 (CH2), 30.5 (CH), 29.9 (CH2), 29.79 (3C; CH2), 29.77 (2C; CH2), 29.5 (CH2), 27.1 (CH2), 27.0 (3C; CH3), 25.9 (CH2), 19.9 (CH3), 19.4 (C), 14.4 (CH3).


A solution of potassium hydroxide (2.0 M, 390 μL, 0.781 mmol) was added to ester Int-44 (42.1 mg. 0.0781 mmol) in ethanol (2 mL) and the mixture heated at 60° C. for 1.5 hours. The reaction was acidified to pH 1 by addition of 1 M HCl, diluted with water (10 mL) and the aqueous phase extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4) and concentrated under reduced pressure to give crude acid Int-45 (39.9 mg, quant.) as a colorless oil that was used without purification. 1H NMR (400 MHz, CDCl3) δ 7.75-7.66 (m, 4H), 7.46-7.35 (m, 6H), 3.67 (t, J=6.5 Hz, 2H), 2.36 (dd, J=15.0, 5.9 Hz, 1H), 2.15 (dd, J=14.9, 8.2 Hz, 1H), 1.97 (m, 1H), 1.61-1.52 (m, 2H), 1.41-1.17 (m, 20H), 1.06 (s, 9H), 0.98 (d, J=6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 179.7 (C), 135.7 (4C; CH), 134.3 (2C; C), 129.6 (2C; CH), 127.7 (4C; CH), 64.2 (CH2), 41.7 (CH2), 36.8 (CH2), 32.7 (CH2), 30.3 (CH), 29.9 (CH2), 29.80 (2C; CH2), 29.78 (2C; CH2), 29.75 (CH2), 29.5 (CH2), 27.1 (CH2), 27.0 (3C; CH3), 25.9 (CH2), 19.8 (CH3), 19.4 (C).


4-(Dimethylamino)pyridine (DMAP, 9.5 mg, 0.0781 mmol), EDC.HCl (29.9 mg, 0.156 mmol) and 1,3-diglyceride Int-2 (53.3 mg, 0.0937 mmol) were added to a solution of acid Int-45 (39.9 mg, 0.0781 mmol) in CH2Cl2 (2.5 mL) and the mixture stirred at room temperature for 19 hours. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (4% to 5% ethyl acetate/hexanes) gave triglyceride Int-46 (72.8 mg, 88% over two steps) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.73-7.63 (m, 4H), 7.49-7.31 (m, 6H), 5.29 (m, 1H), 4.30 (dd, J=11.9, 4.2 Hz, 2H), 4.15 (dd, J=11.9, 6.1 Hz, 2H), 3.66 (t, J=6.5 Hz, 2H), 2.34 (dd, J=14.6, 6.0 Hz, 1H), 2.31 (t, J=7.5 Hz, 4H), 2.13 (dd, J=14.6, 8.3 Hz, 1H), 1.94 (m, 1H), 1.68-1.52 (m, 6H), 1.44-1.16 (m, 68H), 1.05 (s, 9H), 0.94 (d, J=6.6 Hz, 3H), 0.88 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.4 (2C; C), 172.5 (C), 135.7 (4C; CH), 134.3 (2C; C), 129.6 (2C; CH), 127.7 (4C; CH), 68.9 (CH), 64.1 (CH2), 62.3 (2C; CH2), 41.8 (CH2), 36.8 (CH2), 34.2 (2C; CH2), 32.7 (CH2), 32.1 (2C; CH2), 30.5 (CH), 30.0 (CH2), 29.84 (8C; CH2), 29.80 (6C; CH2), 29.76 (2C; CH2), 29.61 (2C; CH2), 29.54 (CH2), 29.50 (3C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 27.2 (CH2), 27.0 (3C; CH3), 25.9 (CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 19.7 (CH3), 19.3 (C), 14.3 (2C; CH3).


Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 186 μL, 0.186 mmol) and acetic acid (10.6 μL, 0.186 mmol) were added dropwise to TBDPS ether Int-46 (65.7 mg, 0.0619 mmol) in THF (3 mL) at 0° C. and the mixture stirred at room temperature for 19 hours. The reaction was diluted with water (10 mL) and the aqueous phase extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with sat. aq. NaHCO3 and brine (30 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% to 15% ethyl acetate/hexanes) gave alcohol Int-47 (34.2 mg, 67%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.27 (m, 1H), 4.28 (dd, J=11.9, 4.3 Hz, 2H), 4.14 (dd, J=11.8, 6.0 Hz, 2H), 3.63 (t, J=6.6 Hz, 2H), 2.32 (dd, J=14.6, 5.9 Hz, 1H), 2.30 (t, J=7.6 Hz, 4H), 2.11 (dd, J=14.6, 8.3 Hz, 1H), 1.92 (m, 1H), 1.66-1.52 (m, 6H), 1.40-1.13 (m, 68H), 0.92 (d, J=6.6 Hz, 3H), 0.87 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.5 (2C; C), 172.5 (C), 68.9 (CH), 63.2 (CH2), 62.3 (2C; CH2), 41.8 (CH2), 36.8 (CH2), 34.2 (2C; CH2), 32.9 (CH2), 32.1 (2C; CH2), 30.5 (CH), 29.9 (CH2), 29.84 (8C; CH2), 29.80 (6C; CH2), 29.76 (2C; CH2), 29.73 (CH2), 29.62 (2C; CH2), 29.57 (CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 27.1 (CH2), 25.9 (CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 19.7 (CH3), 14.3 (2C; CH3).


Pyridinium chlorochromate (PCC, 14.7 mg, 68.0 μmol) was added to a suspension of alcohol Int-47 (28.0 mg, 34.0 μmol) and celite (15 mg) in CH2Cl2 (1.5 mL) at 0° C. and the mixture stirred at room temperature for one hour. The reaction was filtered through a short pad of silica gel, eluting with ethyl acetate, and the filtrate concentrated under reduced pressure to give crude aldehyde Int-48 (27.9 mg, quant.) as a yellow oil that was used without purification. 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 5.28 (m, 1H), 4.29 (dd, J=11.6, 3.5 Hz, 2H), 4.14 (dd, J=11.9, 5.8 Hz, 2H), 2.42 (t, J=6.8 Hz, 2H), 2.36-2.25 (m, 5H), 2.12 (dd, J=14.4, 8.5 Hz, 1H), 1.94 (m, 1H), 1.69-1.51 (m, 6H), 1.42-1.09 (m, 66H), 0.93 (d, J=6.4 Hz, 3H), 0.88 (t, J=6.3 Hz, 6H).


A solution of sodium chlorite (27.6 mg, 0.306 mmol) and sodium phosphate monobasic (NaH2PO4, 28.8 mg, 0.238 mmol) in water (1.2 mL) was added dropwise to aldehyde Int-48 (27.9 mg, 0.0340 mmol) in t-BuOH (1.8 mL) and 2,3-dimethyl-2-butene (0.4 mL) and the reaction stirred at room temperature for 16 hours. The reaction was acidified to pH 2 using 1 M HCl, diluted with water (10 mL) and the aqueous layer extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (30 mL), dried ((MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% to 15% ethyl acetate/hexanes with 0.5% acetic acid) gave acid Int-49 (24.3 mg, 85%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 5.29 (m, 1H), 4.29 (dd, J=11.9, 3.8 Hz, 2H), 4.14 (dd, J=11.9, 6.1 Hz, 2H), 2.37-2.27 (m, 7H), 2.11 (dd, J=14.7, 8.3 Hz, 1H), 1.92 (m, 1H), 1.68-1.54 (m, 6H), 1.40-1.13 (m, 66H), 0.93 (d, J=6.6 Hz, 3H), 0.87 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 179.5 (C), 173.5 (2C; C), 172.5 (C), 68.9 (CH), 62.3 (2C; CH2), 41.9 (CH2), 36.8 (CH2), 34.2 (2C; CH2), 34.1 (CH2), 32.1 (2C; CH2), 30.5 (CH), 29.93 (CH2), 29.85 (8C; CH2), 29.81 (4C; CH2), 29.77 (2C; CH2), 29.73 (CH2), 29.62 (2C; CH2), 29.58 (CH2), 29.51 (2C; CH2), 29.42 (2C; CH2), 29.39 (CH2), 29.26 (2C; CH2), 29.2 (CH2), 27.1 (CH2), 25.0 (2C; CH2), 24.8 (CH2), 22.8 (2C; CH2), 19.7 (CH2), 14.3 (2C; CH2).


Using similar methods, Int-118 was prepared from 1,8-octanediol:




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1H NMR (400 MHz, CDCl3) δ 5.31 (s, 1H), 4.33 (dd, J=8.4, 4.4 Hz, 2H), 4.19 (dd, J=11.8, 5.9 Hz, 2H), 2.47 (m, 1H), 2.37 (dt, J=15.6, 7.4 Hz, 6H), 1.65 (s, 7H), 1.31 (d, J=13.3 Hz, 58H), 1.18 (d, J=6.9 Hz, 3H), 0.92 (t, J=6.6 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 179.73 (1C), 175.87 (1C), 173.31 (2C), 68.70 (1C), 62.13 (1C), 39.50 (1C), 34.04 (3C), 33.57 (1C), 31.93 (4C), 29.71-29.01 (18C), 27.07 (1C), 24.85 (3C), 24.62 (1C), 22.70 (4C), 17.03 (1C), 14.14 (3C). MASS (ESI, −ve) m/z: 766.0 (M−1). (ESI, +ve) m/z: 785.0 (M+18).


C15α′βMe-acid-2-TG (Int-62):




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Int-50: prepared according to: Subba Reddy, B. V. et al. Helv. Chim. Acta. 2013, 96, 1983-1990.


Int-51: known compound that may be prepared as disclosed in Takagi, Y. et al. Tetrahedron: Asymm. 2004, 15, 2591-2594). 1H NMR (401 MHz, CDCl3) δ 7.39-7.23 (m, 5H), 4.50 (s, 2H), 3.47 (t, J=6.6 Hz, 2H), 3.40 (t, J=6.9 Hz, 2H), 1.90-1.80 (m, 2H), 1.66-1.57 (m, 2H), 1.48-1.26 (m, 8H).


n-Butyllithium (n-BuLi, 2.0 M in cyclohexane, 18.1 mL, 36.3 mmol) was added slowly to a solution of TMS-acetylene (5.7 mL, 41.5 mmol) in THF (45 mL) at −78° C. and the mixture stirred at −78° C. for five minutes then warmed to room temperature and stirred for a further 15 minutes. The reaction was re-cooled to −78° C., a solution of bromide Int-51 (3.10 g, 10.4 mmol) and DMPU (6.3 mL, 51.8 mmol) in THF (30 mL) was added slowly and the mixture stirred at −78° C. for 30 minutes and then at room temperature for 18 hours. The reaction was diluted with water (60 mL) and the majority of the organic solvent removed under reduced pressure. The residue was diluted with brine (120 mL) and the aqueous phase extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (3×100 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (Reveleris 80 g column, 60 mL/min, 4% to 40% ethyl acetate/hexanes) gave TMS alkyne Int-52 (3.05 g, 93%) as a colorless oil. 1H NMR (401 MHz, CDCl3) δ 7.36-7.25 (m, 5H), 4.50 (s, 2H), 3.46 (t, J=6.6 Hz, 2H), 2.21 (t, J=7.2 Hz, 2H), 1.65-1.57 (m, 2H), 1.55-1.46 (m, 2H), 1.41-1.27 (m, 8H), 0.15 (s, 9H).


Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 9.7 mL, 9.70 mmol) was added dropwise to silylalkyne Int-52 (3.05 g, 9.62 mmol) in THF (40 mL) at 0° C. and the mixture stirred at room temperature for one hour. The reaction was diluted with water (25 mL) and the organic solvent removed under reduced pressure. The resulting solution was diluted with brine (100 mL) and the aqueous phase extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (3×50 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (Reveleris 80 g column, 60 mL/min, 3% to 10% ethyl acetate/hexanes) gave alkyne Int-53 (2.17 g, 92%). 1H NMR (401 MHz, CDCl3) δ 7.38-7.25 (m, 5H), 4.50 (s, 2H), 3.46 (t, J=6.6 Hz, 2H), 2.18 (td, J=7.1, 2.6 Hz, 2H), 1.94 (t, J=2.7 Hz, 1H), 1.66-1.56 (m, 2H), 1.57-1.48 (m, 2H), 1.43-1.27 (m, 8H); 13C NMR (101 MHz, CDCl3) δ 138.8 (C), 128.4 (2C; CH), 127.7 (2C; CH), 127.6 (CH), 84.8 (C), 73.0 (CH), 70.6 (CH2), 68.2 (CH), 29.8 (CH2), 29.4 (CH2), 29.1 (CH2), 28.8 (CH2), 28.6 (CH2), 26.2 (CH2), 18.5 (CH2).


Int-17 was prepared as described above.


A suspension of PdCl2(PPh3)2 (605 mg, 0.862 mmol) in DMF (40 mL) was degassed using N2 gas for five minutes, and then CuI (335 mg, 1.76 mmol), Et3N (2.40 mL, 17.2 mmol) and a degassed solution of alkyne 4 (2.11 g, 8.62 mmol) and enol triflate Int-17 (3.40 g, 13.00 mmol) in DMF (50 mL) were added. The mixture was degassed using a stream of N2 for a further five minutes and then heated at 70° C. for one hour. The reaction was cooled to room temperature and concentrated under reduced pressure to about one-quarter of its original volume. The resulting solution was diluted with ethyl acetate (80 mL), washed with 1 M HCl, sat. aq. NaHCO3, water and brine (30 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (Reveleris 80 g column, 60 mL/min, 5% to 20% ethyl acetate/hexanes) gave enyne Int-54 (2.35 g, 76%) as a pale yellow oil. 1H NMR (401 MHz, CDCl3) δ 7.37-7.24 (m, 5H), 5.92 (d, J=1.4 Hz, 1H), 4.50 (s, 2H), 4.18 (q, J=7.1 Hz, 2H), 3.46 (t, J=6.6 Hz, 2H), 2.43 (t, J=7.2 Hz, 2H), 2.01 (d, J=1.4 Hz, 3H), 1.65-1.55 (m, 4H), 1.46-1.30 (m, 8H), 1.28 (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.4 (C), 138.8 (C), 135.9 (C), 128.5 (2C; CH), 127.7 (2C; CH), 127.6 (CH), 123.4 (CH), 103.2 (C), 79.9 (C), 73.0 (CH2), 70.6 (CH2), 60.0 (CH2), 29.9 (CH2), 29.4 (CH2), 29.2 (CH2), 29.0 (CH2), 28.6 (CH2), 26.3 (CH2), 26.0 (CH3), 20.1 (CH2), 14.4 (CH3).


A solution of benzyl ether Int-54 (707 mg, 1.98 mmol) in ethyl acetate (80 mL) in a three-neck round-bottom flask was twice evacuated and flushed with N2 gas, then palladium on carbon (10% w/w, 525 mg, 0.494 mmol) was added and the resulting suspension re-evacuated and flushed with N2 three times. The flask was fitted with a H2 balloon, evacuated and flushed with H2 three times and the reaction mixture stirred at room temperature under 1 atm of H2 for two hours. The flask was then evacuated and flushed with N2 and the reaction mixture filtered through a pad of celite, washing with ethyl acetate (80 mL). The filtrate was concentrated under reduced pressure to give saturated alcohol Int-55 (540 mg, quant.) as a colorless oil that was used without purification. 1H NMR (401 MHz, CDCl3) δ 4.13 (q, J=7.1 Hz, 2H), 3.64 (t, J=6.6 Hz, 2H), 2.28 (dd, J=14.6, 6.0 Hz, 1H), 2.09 (dd, J=14.6, 8.1 Hz, 1H), 1.94 (m, 1H), 1.62-1.51 (m, 2H), 1.39-1.21 (m, 16H), 1.25 (t, J=7.1 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H).


Imidazole (670 mg, 9.85 mmol) and tert-butyl(chloro)diphenylsilane (TBDPSCl, 3.5 mL, 13.6 mmol) were added to a solution of alcohol Int-55 (1.48 g, 5.42 mmol) in CH2Cl2 (80 mL) at 0° C. and the mixture stirred at room temperature for 2.5 hours. The reaction was concentrated to half its volume under reduced pressure, washed with water (2×20 mL) and brine (30 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (Reveleris 80 g column, 60 mL/min, 1% to 16% ethyl acetate/hexanes) gave TBDPS ether Int-56 (2.46 g, 89%) as a colorless oil. 1H NMR (401 MHz, CDCl3) δ 7.75-7.64 (m, 4H), 7.46-7.35 (m, 6H), 4.13 (q, J=7.1 Hz, 2H), 3.65 (t, J=6.5 Hz, 2H), 2.29 (dd, J=14.6, 6.0 Hz, 1H), 2.09 (dd, J=14.6, 8.2 Hz, 1H), 1.95 (m, 1H), 1.61-1.50 (m, 2H), 1.38-1.20 (m, 19H), 1.05 (s, 9H), 0.93 (d, J=6.6 Hz, 3H).


A solution of potassium hydroxide (2.0 M, 11.3 mL, 22.6 mmol) was added to ester Int-56 (1.15 g, 2.26 mmol) in ethanol (40 mL) and the mixture stirred at room temperature for 19 hours. The reaction was adjusted to pH 2 by addition of 1 M HCl and the organic solvent removed under reduced pressure. The residue was diluted with water (15 mL) and the aqueous phase extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (5% to 25% ethyl acetate/hexanes) gave a pure sample of acid Int-57 (321 mg, 29%) as a pale yellow oil that was used for analytical purposes. An additional >750 mg of 9 was obtained containing slight contamination by an unknown TBDPS species—this material was carried forward and purified at a later stage in the reaction sequence. 1H NMR (401 MHz, CDCl3) δ 7.70-7.64 (m, 4H), 7.44-7.34 (m, 6H), 3.65 (t, J=6.5 Hz, 2H), 2.35 (dd, J=15.0, 5.9 Hz, 1H), 2.14 (dd, J=15.0, 8.2 Hz, 1H), 1.95 (m, 1H), 1.60-1.51 (m, 2H), 1.39-1.16 (m, 16H), 1.04 (s, 9H), 0.96 (d, J=6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 179.3 (C), 135.7 (4C; CH), 134.4 (2C; C), 129.6 (2C; CH), 127.7 (4C; CH), 64.2 (CH2), 41.7 (CH2), 36.8 (CH2), 32.7 (CH2), 30.3 (CH), 29.9 (CH2), 29.76 (2C; CH2), 29.72 (CH2), 29.5 (CH2), 27.1 (CH2), 27.0 (3C; CH3), 25.9 (CH2), 19.8 (CH3), 19.4 (C).


DMAP (80.8 mg, 0.661 mmol), EDC.HCl (230 mg, 1.20 mmol) and 1,3-diglyceride Int-2 (374 mg, 0.658 mmol) were added to a solution of acid Int-57 (288 mg, 0.597 mmol) in CH2Cl2 (20 mL) and the mixture stirred at room temperature for 20 hours. The reaction was diluted with CH2Cl2 (20 mL), silica gel was added and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (5% to 8% ethyl acetate/hexanes) gave triglyceride Int-58 (416 mg, 67%) as a colorless solid. 1H NMR (401 MHz, CDCl3) δ 7.69-7.64 (m, 4H), 7.44-7.34 (m, 6H), 5.28 (m, 1H), 4.289/4.288 (each dd, J=11.9, 4.3 Hz, 2H), 4.14 (dd, J=12.0, 6.0 Hz, 2H), 3.65 (t, J=6.5 Hz, 2H), 2.34 (dd, J=15.0, 5.9 Hz, 1H), 2.30 (t, J=7.5 Hz, 4H), 2.12 (dd, J=14.6, 8.3 Hz, 1H), 1.93 (m, 1H), 1.66-1.50 (m, 6H), 1.45-1.14 (m, 64H), 1.04 (s, 9H), 0.93 (d, J=6.6 Hz, 3H), 0.88 (t, J=6.6 Hz, 6H).


Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 574 μL, 0.574 mmol) and acetic acid (32.8 μL, 0.574 mmol) were added to a solution of TBDPS ether Int-58 (395 mg, 0.383 mmol) in THF (15 mL) at 0° C. and the mixture stirred at room temperature for 17 hours. The reaction was concentrated under reduced pressure and the residue diluted with ethyl acetate (30 mL), washed with water (2×20 mL) and brine (30 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (5% to 25% ethyl acetate/hexanes) gave alcohol Int-59 (282 mg, 93%) as a colorless solid. 1H NMR (401 MHz, CDCl3) δ 5.28 (m, 1H), 4.286/4.285 (each dd, J=11.8, 4.2 Hz, 2H), 4.14 (dd, J=11.9, 5.7 Hz, 2H), 3.63 (t, J=6.6 Hz, 2H), 2.33 (dd, J=15.0, 5.9 Hz, 1H), 2.30 (t, J=7.5 Hz, 4H), 2.12 (dd, J=14.7, 8.3 Hz, 1H), 1.93 (m, 1H), 1.68-1.52 (m, 6H), 1.49-1.15 (m, 64H), 0.93 (d, J=6.6 Hz, 3H), 0.88 (t, J=6.6 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.5 (2C; C), 172.5 (C), 69.0 (CH), 63.2 (CH2), 62.3 (2C; CH2), 41.9 (CH2), 36.8 (CH2), 34.2 (2C; CH2), 33.0 (CH2), 32.1 (2C; CH2), 30.5 (CH), 29.9 (CH2), 29.84 (6C; CH2), 29.81 (4C; CH2), 29.77 (2C; CH2), 29.74 (CH2), 29.71 (CH2), 29.62 (2C; CH2), 29.57 (CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (3C; CH2), 27.1 (CH2), 25.9 (CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 19.7 (CH3), 14.3 (2C; CH3).


Pyridinium chlorochromate (PCC, 143 mg, 0.664 mmol) was added to a suspension of alcohol Int-59 (263 mg, 0.331 mmol) and Celite (150 mg) in CH2Cl2 (18 mL) at 0° C. and the mixture stirred at room temperature for four hours. The reaction was filtered through a short pad of silica gel, eluting with ethyl acetate, and the filtrate concentrated under reduced pressure to give crude aldehyde Int-60 (262 mg, quant.) as a yellow oil that was used without purification. 1H NMR (401 MHz, CDCl3) δ 9.76 (t, J=1.8 Hz, 1H), 5.27 (m, 1H), 4.29 (dd, J=11.8, 4.1 Hz, 2H), 4.14 (dd, J=11.8, 6.0 Hz, 2H), 2.42 (td, J=7.4, 1.8 Hz, 2H), 2.33 (dd, J=15.0, 5.9 Hz, 1H), 2.30 (t, J=7.5 Hz, 4H), 2.12 (dd, J=14.7, 8.3 Hz, 1H), 1.93 (m, 1H), 1.69-1.53 (m, 6H), 1.45-1.16 (m, 62H), 0.93 (d, J=6.6 Hz, 3H), 0.88 (t, J=6.8 Hz, 6H).


Int-25 was prepared as described above.


A solution of ylide Int-25 (270 mg, 0.637 mmol) in toluene (10 mL) was added to aldehyde Int-60 (262 mg, 0.331 mmol) in toluene (8 mL) and the mixture heated at reflux for 20 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (5% to 15% ethyl acetate/hexanes) gave α,β-unsaturated benzyl ester Int-61 (273 mg, 88%) as a yellow oil. 1H NMR (401 MHz, CDCl3) δ 7.40-7.27 (m, 5H), 6.82 (td, J=7.5, 1.4 Hz, 1H), 5.28 (m, 1H), 5.18 (s, 2H), 4.29 (dd, J=11.9, 4.3 Hz, 2H), 4.14 (dd, J=11.9, 6.0 Hz, 2H), 2.33 (dd, J=15.0, 5.9 Hz, 1H), 2.30 (t, J=7.5 Hz, 4H), 2.20-2.07 (m, 3H), 1.92 (m, 1H), 1.85 (d, J=1.2 Hz, 3H), 1.65-1.53 (m, 4H), 1.47-1.37 (m, 2H), 1.36-1.14 (m, 62H), 0.93 (d, J=6.6 Hz, 3H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.4 (2C; C), 172.5 (C), 168.2 (C), 143.3 (CH), 136.6 (C), 128.6 (2C; CH), 128.13 (CH), 128.11 (2C; CH), 127.5 (C), 68.9 (CH), 66.3 (CH2), 62.3 (2C; CH2), 41.8 (CH2), 36.8 (CH2), 34.2 (2C; CH2), 32.1 (2C; CH2), 30.5 (CH), 29.9 (CH2), 29.84 (6C; CH2), 29.80 (4C; CH2), 29.76 (2C; CH2), 29.70 (CH2), 29.61 (3C; CH2), 29.57 (CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (3C; CH2), 28.9 (CH2), 28.7 (CH2), 27.1 (CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 19.7 (CH3), 14.3 (2C; CH3), 12.5 (CH3).


A solution of benzyl ester Int-61 (246 mg, 0.262 mmol) in ethyl acetate (10 mL) in a two-neck flask was evacuated and flushed with N2 gas (three times each), then palladium on carbon (10% w/w, 55.7 mg, 0.0524 mmol) was added and the resulting suspension re-evacuated and flushed with N2 (three times each). The flask was fitted with a H2 balloon, evacuated and flushed with H2 (three times each) and the reaction mixture stirred at room temperature under 1 atm of H2 for 1.5 hours. The reaction was filtered through a pad of celite, washing with ethyl acetate, and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (5% to 20% ethyl acetate/hexanes) gave saturated acid Int-62 (193 mg, 87%) as a colorless solid. 1H NMR (401 MHz, CDCl3) δ 5.28 (m, 1H), 4.291/4.289 (each dd, J=11.8, 4.2 Hz, 2H), 4.147/4.144 (each dd, J=11.9, 6.0 Hz, 2H), 2.46 (m, 1H), 2.33 (dd, J=15.0, 5.9 Hz, 1H), 2.31 (t, J=7.5 Hz, 4H), 2.12 (dd, J=14.7, 8.2 Hz, 1H), 1.94 (m, 1H), 1.73-1.55 (m, 5H), 1.50-1.21 (m, 67H), 1.18 (d, J=7.0 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 0.88 (t, J=6.9 Hz, 6H).


Ph-C3-phenol-2-TG (Int-67):




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DBU (108 μL, 1.08 mmol) and t-butyldiphenylsilyl chloride (TBDPSCl, 338 μL, 1.30 mmol) were added to a solution of (4-hydroxyphenyl)propionic acid (Int-63; commercially available) (120 mg, 0.722 mmol) in DMF (4 mL) and the mixture stirred at room temperature for one hour. The reaction was diluted with ethyl acetate (15 mL) and organic phase washed with water and brine (15 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (4.5% ethyl acetate/hexanes) gave silyl ester Int-64 (165 mg, 36%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.75-7.70 (m, 4H), 7.63-7.58 (m, 4H), 7.46-7.31 (m, 12H), 6.97-6.91 (m, 2H), 6.71-6.67 (m, 2H), 2.87 (t, J=7.6 Hz, 2H), 2.72 (t, J=7.6 Hz, 2H), 1.11 (s, 9H), 1.07 (s, 9H); 13C NMR (101 MHz, CDCl3): δ 172.3 (C), 154.1 (C), 135.7 (4C; CH), 135.4 (4C; CH), 133.2 (2C; C), 133.0 (C), 132.0 (2C; C), 130.1 (2C; CH), 130.0 (2C; CH), 129.2 (2C; CH), 127.9 (4C; CH), 127.8 (4C; CH), 119.7 (2C; CH), 37.9 (CH2), 30.4 (CH2), 27.0 (3C; CH3), 26.7 (3C; CH3), 19.6 (C), 19.2 (C).


Potassium carbonate (157 mg, 1.14 mmol) was added to a solution of TBDPS ester Int-64 (147 mg, 0.228 mmol) in THF (3 mL), methanol (1.5 mL) and water (1.5 mmol) and the mixture stirred at room temperature for 2.5 hours. The reaction was acidified to pH 2 by the addition of 1 M HCl and the aqueous layer extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with water (30 mL), sat. aq. NaHCO3 (30 mL) and brine (30 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (20% to 35% to 50% ethyl acetate/hexanes) gave acid Int-65 (82.4 mg, 89%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.74-7.67 (m, 4H), 7.45-7.32 (m, 6H), 6.95-6.88 (m, 2H), 6.71-6.65 (m, 2H), 2.82 (t, J=7.8 Hz, 2H), 2.58 (t, J=7.8 Hz, 2H), 1.09 (s, 9H); 13C NMR (101 MHz, CDCl3): δ 179.2 (C), 154.3 (C), 135.7 (4C; CH), 133.1 (2C; C), 132.7 (C), 130.0 (2C; CH), 129.1 (2C; CH), 127.9 (4C; CH), 119.8 (2C; CH), 35.9 (CH2), 29.9 (CH2), 26.7 (3C; CH3), 19.6 (C).


DMAP (8.2 mg, 0.0667 mmol), EDC.HCl (25.6 mg, 0.133 mmol) and 1,3-diglyceride Int-2 (41.7 mg, 0.0734 mmol) were added to a solution of acid Int-65 (27.0 mg, 0.0666 mmol) in CH2Cl2 (2 mL) and the mixture stirred at room temperature for 19 hours. The reaction was diluted with CH2Cl2 (3 mL), silica gel was added and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (5% to 7.5% ethyl acetate/hexanes) gave triglyceride Int-66 (54.4 mg, 85%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.74-7.66 (m, 4H), 7.45-7.33 (m, 6H), 6.94-6.87 (m, 2H), 6.71-6.64 (m, 2H), 5.24 (m, 1H), 4.25 (dd, J=11.9, 4.3 Hz, 2H), 4.11 (dd, J=11.9, 5.9 Hz, 2H), 2.81 (t, J=7.8 Hz, 2H), 2.60-2.51 (m, 2H), 2.28 (t, J=7.5 Hz, 4H), 1.64-1.56 (m, 4H), 1.35-1.20 (m, 48H), 1.09 (s, 9H), 0.88 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.4 (2C; C), 172.2 (C), 154.2 (C), 135.7 (4C; CH), 133.1 (2C; C), 132.7 (C), 130.0 (2C; CH), 129.1 (2C; CH), 127.9 (4C; CH), 119.8 (2C; CH), 69.2 (CH), 62.1 (2C; CH2), 36.0 (CH2), 34.2 (2C; CH2), 32.1 (2C; CH2), 30.1 (CH2), 29.85 (2C; CH2), 29.81 (2C; CH2), 29.76 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 26.7 (3C; CH3), 25.0 (2C; CH2), 22.8 (2C; CH2), 19.6 (C), 14.3 (2C; CH3).


Acetic acid (6.5 μL, 0.114 mmol) and tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 114 μL, 0.114 mmol) were added to a solution of TBDPS ether Int-66 (54.5 mg, 0.0570 mmol) in THF (1.2 mL) at 0° C. and the mixture stirred at room temperature for 30 minutes. The reaction was diluted with water (10 mL) and the aqueous layer extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with sat. aq. NaHCO3 (20 mL) and brine (20 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% to 15% ethyl acetate/hexanes) gave phenol Int-67 (37.0 mg, 90%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.09-7.03 (m, 2H), 6.78-6.72 (m, 2H), 5.25 (m, 1H), 4.62 (s, 1H), 4.25 (dd, J=11.9, 4.4 Hz, 2H), 4.11 (dd, J=11.9, 5.8 Hz, 2H), 2.88 (t, J=7.7 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H), 2.29 (t, J=7.6 Hz, 4H), 1.64-1.56 (m, 4H), 1.34-1.18 (m, 48H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.6 (2C; C), 172.3 (C), 154.4 (C), 132.3 (C), 129.5 (2C; CH), 115.5 (2C; CH), 69.2 (CH), 62.2 (2C; CH2), 36.2 (CH2), 34.2 (2C; CH2), 32.1 (2C; CH2), 30.2 (CH2), 29.83 (6C; CH2), 29.79 (4C; CH2), 29.76 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.2 (2C; CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 14.3 (2C; CH3).


C6-ET-alcohol-2-TG (Int-73):




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Int-69 is a known compound that may be prepared as described in, e.g., Sang-sup, J. et al. Tetrahedron: Asymmetry 1997, 8, 1187-1192).


Alcohol Int-68 (commercially available; 90.0 mg, 0.499 mmol) was added in a single portion to a suspension of t-BuOK (84.1 mg, 0.749 mmol) in THF (2 mL) and the mixture stirred at room temperature for one hour. A solution of bromide Int-69 (190 mg, 0.699 mmol) in THF (1 mL) and TBAI (36.9 mg, 0.100 mmol) were then added and the resulting mixture heated at reflux for 20 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (10 mL), quenched with water (15 mL) and the aqueous phase extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with water and brine (50 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (5 to 15% to 25% ethyl acetate/hexanes) gave a sample of semi-pure product, which was re-subjected to column chromatography (5% to 12.5% ethyl acetate/toluene) to give ether-linked glycerol Int-70 (48.0 mg, 26%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.54-7.49 (m, 2H), 7.39-7.26 (m, 8H), 5.55 (s, 1H), 4.50 (s, 2H), 4.33 (dd, J=12.5, 1.4 Hz, 2H), 4.07-4.01 (m, 2H), 3.55 (t, J=6.7 Hz, 2H), 3.47 (t, J=6.6 Hz, 2H), 3.25 (m, 1H), 1.71-1.59 (m, 4H), 1.45-1.39 (m, 4H).


A mixture of benzylidene acetal Int-70 (46.0 mg, 0.124 mmol), conc. HCl (2 drops) and MeOH (1.5 mL) was heated at reflux for two hours and then cooled to room temperature. The reaction was diluted with ethyl acetate (30 mL) and water (10 mL), and the organic phase washed sat. aq. NaHCO3, water and brine (30 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (40% to 80% ethyl acetate/hexanes) gave diol Int-71 (23.5 mg, 67%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.36-7.27 (m, 5H), 4.50 (s, 2H), 3.76 (dd, J=11.6, 4.4 Hz, 2H), 3.67 (dd, J=11.6, 5.1 Hz, 2H), 3.57 (t, J=6.6 Hz, 2H), 3.50-3.42 (m, 3H), 1.67-1.56 (m, 4H), 1.43-1.36 (m, 4H).


A solution of freshly-prepared palmitoyl chloride (91.6 mg, 0.333 mmol) in CH2Cl2 (1.5 mL) and pyridine (30.3 μL, 0.375 mmol) were added to the diol Int-71 (23.5 mg, 0.0833 mmol) and the reaction stirred at room temperature for 16 hours. The reaction mixture was diluted with CH2Cl2 (30 mL) and quenched with water (10 mL). The organic phase was washed with water, sat. aq. NaHCO3 and brine (30 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (5% to 10% ethyl acetate/hexanes) gave glyceride Int-72 (44.8 mg, 71%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 7.36-7.26 (m, 5H), 4.50 (s, 2H), 4.18 (dd, J=11.6, 4.9 Hz, 2H), 4.11 (dd, J=11.6, 5.5 Hz, 2H), 3.68 (dd, J=10.4, 5.3 Hz, 1H), 3.55 (t, J=6.6 Hz, 2H), 3.46 (t, J=6.6 Hz, 2H), 2.32 (t, J=7.6 Hz, 4H), 1.67-1.54 (m, 8H), 1.34-1.21 (m, 52H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 173.7 (2C; C), 138.8 (C), 128.5 (2C; CH), 127.7 (2C; CH), 127.6 (CH), 75.3 (CH), 73.0 (CH2), 70.7 (CH2), 70.5 (CH2), 63.2 (2C; CH2), 34.3 (2C; CH2), 32.1 (2C; CH2), 30.0 (CH2), 29.87 (CH2), 29.84 (2C; CH2), 29.80 (2C; CH2), 29.76 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 26.2 (CH2), 26.0 (CH2), 25.1 (2C; CH2), 22.8 (2C; CH2), 14.3 (2C; CH3).


A solution of benzyl ether Int-72 (43.5 mg, 57.3 μmol) in ethyl acetate/hexanes (10 mL each) was subjected to hydrogenolysis using an HCube hydrogenation apparatus under recycling conditions (10% Pd/C cartridge, full H2 mode at 6 bar, flow rate=1 mL/min), with the column temperature set at 25° C. for 1.5 hours then at 35° C. for a further hour. Concentration of the reaction mixture under reduced pressure gave alcohol Int-73 (38.2 mg, quant.) as a colorless solid that was used without purification. 1H NMR (400 MHz, CDCl3): δ 4.19 (dd, J=11.6, 4.9 Hz, 2H), 4.11 (dd, J=11.6, 5.5 Hz, 2H), 3.67 (m, 1H), 3.64 (t, J=6.5 Hz, 2H), 3.55 (t, J=6.5 Hz, 2H), 2.32 (t, J=7.6 Hz, 4H), 1.66-1.56 (m, 8H), 1.41-1.34 (m, 4H), 1.33-1.18 (m, 48H), 0.88 (t, J=6.8 Hz, 6H).


C4-ET-alcohol-2-TG (Int-78):




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Int-74 is a known compound that may be prepared as described in Charette, A. B. et al. J Am. Chem. Soc. 2001, 123, 11829-11830.


Alcohol Int-68 (commercially available; 135 mg, 0.749 mmol) was added in a single portion to a suspension of t-BuOK (118 mg, 1.05 mmol) in THF (2.5 mL) and the mixture stirred at RT for one hour. A solution of bromide Int-74 (273 mg, 1.12 mmol) in THF (2 mL) was then added and the resulting mixture heated at reflux for 26 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (10 mL), quenched with water (20 mL) and the aqueous phase extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with water and brine (60 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (10% to 20% ethyl acetate/hexanes) gave ether-linked glycerol Int-75 (103 mg, 40%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.53-7.48 (m, 2H), 7.38-7.27 (m, 8H), 5.55 (s, 1H), 4.50 (s, 2H), 4.37-4.27 (m, 2H), 4.08-3.98 (m, 2H), 3.61-3.55 (m, 2H), 3.54-3.50 (m, 2H), 3.25 (m, 1H), 1.82-1.65 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 138.8 (C), 138.3 (C), 128.9 (CH), 128.4 (2C; CH), 128.3 (2C; CH), 127.7 (2C; CH), 127.6 (CH), 126.3 (2C; CH), 101.4 (C), 73.0 (CH2), 70.7 (CH), 70.3 (CH2), 69.1 (2C; CH2), 68.7 (CH2), 26.7 (CH2), 26.6 (CH2).


A mixture of benzylidene acetal Int-75 (102 mg, 0.298 mmol), conc. HCl (2 drops) and MeOH (4 mL) was heated at reflux for two hours and then cooled to RT. The reaction was diluted with ethyl acetate (40 mL) and water (15 mL), and the organic phase washed sat. aq. NaHCO3, water and brine (40 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (25% to 65% to 90% ethyl acetate/hexanes) gave diol Int-76 (58.8 mg, 78%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.38-7.24 (m, 5H), 4.50 (s, 2H), 3.71 (dd, J=11.6, 4.6 Hz, 2H), 3.64 (dd, J=11.6, 4.9 Hz, 2H), 3.60-3.55 (m, 2H), 3.52-3.46 (m, 2H), 3.41 (m, 1H), 2.59 (br s, 2H), 1.75-1.61 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 138.5 (C), 128.5 (2C; CH), 127.8 (2C; CH), 127.7 (CH), 78.8 (CH), 73.0 (CH2), 70.2 (CH2), 69.8 (CH2), 62.2 (2C; CH2), 27.1 (CH2), 26.4 (CH2).


A solution of palmitoyl chloride (131 mg, 0.475 mmol) in CH2Cl2 (2 mL) and pyridine (48.0 μL, 0.594 mmol) were added to the diol Int-76 (30.2 mg, 0.119 mmol) and the reaction stirred at room temperature for 19 hours. The reaction mixture was diluted with CH2Cl2 (40 mL) and quenched with water (20 mL). The organic phase was washed with water, sat. aq. NaHCO3 and brine (40 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (6% ethyl acetate/hexanes) gave triglyceride Int-77 (72.4 mg, 83%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 7.38-7.26 (m, 5H), 4.50 (s, 2H), 4.18 (dd, J=11.6, 4.9 Hz, 2H), 4.11 (dd, J=11.6, 5.5 Hz, 2H), 3.67 (m, 1H), 3.58 (t, J=6.1 Hz, 2H), 3.48 (t, J=6.1 Hz, 2H), 2.31 (t, J=7.6 Hz, 4H), 1.73-1.55 (m, 8H), 1.37-1.19 (m, 48H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 173.7 (2C; C), 138.7 (C), 128.5 (2C; CH), 127.7 (2C; CH), 127.6 (CH), 75.4 (CH), 73.0 (CH2), 70.4 (CH2), 70.2 (CH2), 63.1 (2C; CH2), 34.3 (2C; CH2), 32.1 (2C; CH2), 29.82 (6C; CH2), 29.79 (4C; CH2), 29.74 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; H2), 29.3 (2C; CH2), 26.8 (CH2), 26.5 (CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 14.2 (2C; CH3).


A solution of benzyl ether Int-77 (70.0 mg, 95.8 μmol) in ethyl acetate/hexanes (25 mL each) was subjected to hydrogenolysis using an HCube hydrogenation apparatus under recycling conditions (10% Pd/C cartridge, full H2 mode at 6 bar, flow rate=1 mL/min), with the column temperature set at 50° C. for 2.5 hours. Concentration of the reaction mixture under reduced pressure gave the crude product, which was purified by silica gel chromatography (10% to 30% ethyl acetate/hexanes) to give alcohol Int-78 (55.0 mg, 90%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 4.20 (dd, J=11.7, 4.8 Hz, 2H), 4.11 (dd, J=11.7, 5.5 Hz, 2H), 3.69 (m, 1H), 3.64 (t, J=5.9 Hz, 2H), 3.60 (t, J=5.8 Hz, 2H), 2.32 (t, J=7.5 Hz, 4H), 1.70-1.55 (m, 8H), 1.33-1.19 (m, 48H), 0.87 (t, J=6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 173.7 (2C; C), 75.5 (CH), 70.5 (CH2), 63.0 (2C; CH2), 62.6 (CH2), 34.3 (2C; CH2), 32.0 (2C; CH2), 29.9 (CH2), 29.82 (2C; CH2), 29.78 (2C; CH2), 29.7 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 26.7 (CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 14.2 (2C; CH3).


C5ββDiMe-acid-2-TG (Int-79):




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To a solution of compound Int-2 (5.0 g, 8.78 mmol) in chloroform (150 ml) was added DCC (3.62 g, 17.57 mmol) and DMAP (0.53 g, 4.39 mmol), followed by addition of 3,3-dimethylglutaric acid (2.81 g, 17.57 mmol) at room temperature and then stirring for 48 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with dichloromethane (100 ml) and the filtrate was evaporated to give the crude desired compound, which was purified by combi-flash purification. The compound was eluted using 6% ethyl acetate in hexane and concentrated to give Int-79 (C5ββDiMe-acid-2-TG) (2.0 g, 32%) as off-white solid. 1H NMR (400 MHz, CDCl3) δ 5.33 (m, 1H), 4.33 (m, 2H), 4.18 (m, 2H), 2.51 (s, 4H), 2.35 (t, 4H), 1.64 (t, 4H), 1.29 (m, 49H), 1.19 (s, 6H), 0.92 (t, 6H); 13C NMR (101 MHz, CDCl3) δ 176.4 (1C), 173.3 (2C), 171.0 (1C), 69.1 (1C), 62.1 (2C), 45.0 (1C) 44.7 (1C), 34.0 (3C), 32.6 (1C), 31.9 (3H), 29.7-29.1 (14C), 27.7 (3C), 24.8 (3C), 22.7 (3C), 14.1 (3C); HPLC (ELSD): 10.07 min, 97.74% purity; MASS (ESI, −ve) m/z: 710 (M−1).


C12a′aMe-acid-2-TG (Int-81):




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To a solution of diisopropylamine (DIPA) (3.18 g, 81.08 mmol) in dry THF (45 mL) was added n-BuLi (2.5 M in hexane) (32 mL, 81.08 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 30 min, then then propionic acid (1.5 g, 20.27 mmol) was added and the reaction mixture was stirred at −78° C. for further 30 min. 1,8-dibromooctane (2.75 g, 10.13 mmol) was added and the reaction mixture was stirred and allowed to warm from −78° C. to room temperature over 3 h. The reaction was monitored by TLC for completeness. An additional identical batch starting with 1.5 g propionic acid was prepared and the two batches combined before workup. The combined reaction mixture was diluted with water (100 mL) and acidified with 1N HCl (25 ml) and extracted with ethyl acetate (3×100 ml), and the combined organic layer was dried over Na2SO4 and evaporated to give crude compound. The title compound was purified by combi flash purification, eluting with 10% ethyl acetate/hexane as the mobile phase. After evaporation, Int-80 (0.99 g, 9.5%) was obtained as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 2.57-2.39 (m, 2H), 1.71 (m, 2H), 1.50-1.43 (m, 2H), 1.40-1.25 (m, 14H), 1.22 (d, J=7.2 Hz 6H).


To a solution of compound Int-2 (2.7 g, 4.74 mmol) in chloroform (50 ml) was added DCC (1.95 g, 9.49 mmol) and DMAP (0.28 g, 2.30 mmol), then the reaction was stirred at room temperature for 30 min. Int-80 (2.44 g, 9.49 mmol) was added at room temperature and stirred for 2 h. The reaction was monitored by TLC until completion, after which the reaction mixture was filtered through celite and washed with DCM (45 ml), then evaporated to give the crude product, which was purified by combi flash purification, eluting with 7% ethyl acetate/hexane. After evaporation, Int-81 (C12a′aMe-acid-2-TG) (1.7 g, 44.3%) was obtained as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 5.32 (m, 1H), 4.33 (m, 2H), 4.19 (m, 2H), 2.49 (m, 2H), 2.34 (m, 4H), 1.72-1.62 (m, 4H), 1.49-1.40 (m, 4H). 1.38-1.29 (m, 59H), 1.24-1.17 (m, 8H), 0.92 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 181.7 (1C), 176.0 (1C), 173.4 (2C), 68.7 (2C), 62.2 (3C), 39.6 (2C), 39.2 (1C), 34.1 (3C), 33.7 (1C), 32.0 (3C), 29.7-29.2 (17C), 27.2 (1C), 24.9 (3C), 22.7 (3C), 17.1 (2C), 16.9 (1C), 14.2 (3C).




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Bromotriglyceride Int-91:


DMAP (10.7 mg, 0.0979 mmol) and EDC.HCl (41.8 mg, 0.220 mmol) were added to a solution of bromoacetic acid (24.4 mg, 0.176 mmol) and Int-2 (50.0 mg, 0.0879 mmol) in CH2Cl2 (2 mL) and the mixture stirred at RT for 22 hours. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added, and the solvent removed under reduced pressure. Silica gel chromatography (4% ethyl acetate/hexanes) gave bromotriglyceride Int-91 (50.3 mg, 83%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 5.31 (m, 1H), 4.34 (dd, J=12.1, 4.0 Hz, 2H), 4.17 (dd, J=12.1, 6.1 Hz, 2H), 3.84 (s, 2H), 2.32 (t, J=7.6 Hz, 4H), 1.66-1.56 (m, 4H), 1.35-1.20 (m, 48H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.4 (2C; C), 166.7 (C), 71.3 (CH), 61.9 (2C; CH2), 34.1 (2C; CH2), 32.1 (2C; CH2), 29.84 (2C; CH2), 29.80 (2C; CH2), 29.75 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 25.5 (CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 14.3 (2C; CH2).


Iodotriglyceride Int-95:




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Int-93 is a known compound prepared from cycloheptanone as shown above (see Kai, K. et al. Tetrahedron 2008, 64, 6760-6769). To prepare Int-94, chlorotrimethylsilane (TMSCl, 208 μL, 1.64 mmol) was added to a suspension of lactone Int-93 (70.0 mg, 0.546 mmol) and sodium iodide (246 mg, 1.64 mmol) in acetonitrile (1.5 mL) and the mixture heated at reflux for 16 hours. The reaction was cooled to RT, diluted with ethyl acetate and water (10 mL each), and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with 1 M Na2S2O3 and brine (40 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (100% CH2Cl2 to 50% ethyl acetate/hexanes) gave semi-pure acid Int-94 (59.8 mg, 43%) as a yellow oil. However, an accurate yield and clean NMR spectra could not be obtained due to the presence of the m-CPBA impurities, which were carried forward to the next step. 1H NMR (400 MHz, CDCl3) δ 3.19 (t, J=7.0 Hz, 2H), 2.37 (t, J=7.4 Hz, 2H), 1.88-1.80 (m, 2H), 1.71-1.61 (m, 2H), 1.46-1.33 (m, 4H).


DMAP (15.2 mg, 0.124 mmol) and DCC (51.3 mg, 0.248 mmol) were added sequentially to a solution of acid Int-94 (35.0 mg, 0.137 mmol) and 1,3-diglyceride Int-2 (70.7 mg, 0.124 mmol) in CH2Cl2 (4 mL) and the mixture stirred at RT for 17 hours. The resulting suspension was diluted with CH2Cl2, cooled to 0° C. and filtered through Celite, washing with further CH2Cl2. The organic phase was washed with 1 M HCl, sat. aq. NaHCO3 and brine, dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (3.5% to 4.5% ethyl acetate/hexanes) gave semi-pure iodotriglyceride Int-95 (83.6 mg, 84%) as a colorless solid. However, an accurate yield and clean NMR spectra could not be obtained due to the presence of the m-CPBA impurities, which were carried forward to the next step. 1H NMR (400 MHz, CDCl3) δ 5.26 (m, 1H), 4.30 (dd, J=11.9, 4.4 Hz, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 3.18 (t, J=7.0 Hz, 2H), 2.36-2.27 (m, 6H), 1.86-1.77 (m, 2H), 1.68-1.52 (m, 6H), 1.45-1.18 (m, 52H), 0.88 (t, J=6.9 Hz, 6H).




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DMAP (17.2 mg, 0.141 mmol) and EDC.HCl (67.4 mg, 0.352 mmol) were added to a solution of 1,3-diglyceride Int-2 (80.0 mg, 0.141 mmol) and 12-bromododecanoic acid (51.0 mg, 0.183 mmol) in CH2Cl2 (2.5 mL) and the mixture stirred at RT for 18 hours. The reaction was diluted with CH2Cl2 (10 mL), silica gel was added, and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (5% to 10% ethyl acetate/hexanes) gave bromotriglyceride Int-97 (105 mg, 90%) as a colorless solid. 1H NMR (401 MHz, CDCl3) δ 5.25 (m, 1H), 4.28 (dd, J=11.9, 4.3 Hz, 2H), 4.13 (dd, J=11.9, 5.9 Hz, 2H), 3.38 (t, J=6.9 Hz, 2H), 2.30 (t, J=7.5 Hz, 2H), 2.29 (t, J=7.5 Hz, 4H), 1.88-1.79 (m, 2H), 1.65-1.55 (m, 6H), 1.45-1.36 (m, 2H), 1.34-1.18 (m, 60H), 0.86 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.4 (2C; C), 172.9 (C), 69.0 (CH), 62.2 (2C; CH2), 34.3 (CH2), 34.2 (2C; CH2), 34.0 (CH2), 33.0 (CH2), 32.1 (2C; CH2), 29.82 (6C; CH2), 29.78 (4C; CH2), 29.74 (2C; CH2), 29.60 (3C; CH2), 29.54 (2C; CH2), 29.48 (2C; CH2), 29.39 (2C; CH2), 29.38 (CH2), 29.23 (2C; CH2), 29.17 (CH2), 28.9 (CH2), 28.3 (CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 14.2 (2C; CH3).


Int-105:




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Int-99:


A suspension of 1,16-hexanediol (200 mg, 0.774 mmol) in DMF (2 mL) was added a suspensiom of NaH (34.1 mg, 60% w/w dispersion in mineral oil, washed twice with dry petrol, 8.51 mmol) in DMF (1 mL) at 0° C. and the mixture stirred at 0° C. for 10 minutes and then at rt for 30 minutes. TBDPSCl (221 μL, 0.851 mmol) was added and the mixture stirred at rt for 17 hours. The reaction was diluted with ethyl acetate (50 mL), washed with water and brine (2×40 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (15% ethyl acetate/hexanes) gave TBDPS ether Int-99 (124 mg, 32%) as a colorless solid. 1H NMR (401 MHz, CDCl3) δ 7.70-7.63 (m, 4H), 7.45-7.34 (m, 6H), 3.64 (td, J=6.5, 3.6 Hz, 4H), 1.61-1.46 (m, 4H), 1.39-1.19 (m, 24H), 1.04 (s, 9H).


Int-100:


Pyridinium chlorochromate (PCC, 106 mg, 0.491 mmol) and Celite (100 mg) were added to alcohol Int-99 (122 mg, 0.246 mmol) in CH2Cl2 (6 mL) at 0° C. and the mixture stirred at 0° C. for 10 minutes and then at rt for 1. 5 hours. The reaction was filtered through a short pad of silica gel, eluting with 50% ethyl acetate/hexanes (80 mL), and the filtrate concentrated under reduced pressure to give crude aldehyde Int-100 (121 mg, quant.) as a yellow oil that was immediately used without purification.


Int-101:


Ylide methyl 2-(triphenyl-λ5-phosphaneylidene)acetate (205 mg, 0.614 mmol) was added to crude aldehyde Int-100 (121 mg, 0.246 mmol) in toluene (6 mL) and the mixture heated at reflux for one hour. The reaction was cooled to rt and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (4% ethyl acetate/hexanes) gave alpha,beta-unsaturated methyl ester Int-101 (100 mg, 74%, 6:1 mixture of E/Z isomers) as a yellow oil. NMR data is provided for the major isomer. 1H NMR (401 MHz, CDCl3) δ 7.74-7.66 (m, 4H), 7.48-7.36 (m, 6H), 7.01 (dt, J=15.6, 7.0 Hz, 1H), 5.85 (dt, J=15.6, 1.5 Hz, 1H), 3.74 (s, 3H), 3.69 (t, J=6.5 Hz, 2H), 2.22 (qd, J=7.3, 1.5 Hz, 2H), 1.64-1.55 (m, 2H), 1.47 (dd, J=13.9, 6.9 Hz, 2H), 1.42-1.25 (m, 22H), 1.09 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 167.3 (C), 149.9 (CH), 135.7 (4C; CH), 134.3 (2C; C), 129.6 (2C; CH), 127.7 (4C; CH), 120.9 (CH), 64.1 (CH2), 51.4 (CH3), 32.7 (CH2), 32.3 (CH2), 29.79 (2C; CH2), 29.75 (2C; CH2), 29.74 (CH2), 29.66 (CH2), 29.52 (CH2), 29.50 (CH2), 29.3 (CH2), 28.1 (CH2), 27.0 (3C; CH2), 25.9 (CH2), 19.3 (C).


Int-102:


A solution of alkene Int-101 (99.0 mg, 0.180 mmol) in ethyl acetate (5 mL) in a two-neck flask was evacuated and flushed with N2 gas three times each, then palladium on carbon (10% w/w, 28.7 mg, 0.0270 mmol) was added and the resulting suspension re-evacuated and flushed with N2 three times. The flask was fitted with a H2 balloon, evacuated and flushed with H2 three times and the reaction mixture stirred at rt under 1 atm of H2 for one hour. The reaction was filtered through a pad of Celite, washing with ethyl acetate (80 mL), and concentrated under reduced pressure to give saturated methyl ester Int-102 (99.4 mg, quant.) as a colorless oil that was used without purification. 1H NMR (401 MHz, CDCl3) δ 7.75-7.67 (m, 4H), 7.47-7.36 (m, 6H), 3.69 (t, J=6.5 Hz, 2H), 3.68 (s, 3H), 2.33 (t, J=7.5 Hz, 2H), 1.70-1.54 (m, 4H), 1.43-1.23 (m, 26H), 1.09 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 174.4 (C), 135.7 (4C; CH), 134.3 (2C; C), 129.6 (2C; CH), 127.7 (4C; CH), 64.1 (CH2), 51.5 (CH3), 34.2 (CH2), 32.7 (CH2), 29.82 (2C; CH2), 29.81 (2C; CH2), 29.78 (CH2), 29.76 (CH2), 29.75 (CH2), 29.73 (CH2), 29.6 (CH2), 29.5 (CH2), 29.4 (CH2), 29.3 (CH2), 27.0 (3C; CH3), 25.9 (CH2), 25.1 (CH2), 19.3 (C).


Int-103:


A solution of potassium hydroxide (2.0 M, 530 μL, 1.06 mmol) was added to ester Int-102 (26.0 mg. 0.0854 mmol) in ethanol (3 mL) and the mixture heated at 70° C. for 50 minutes. The reaction was acidified to pH 3 by addition of 1 M HCl and diluted with ethyl acetate (40 mL). The organic phase was washed with water (2×30 mL) and brine (30 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (15% ethyl acetate/hexanes) gave acid Int-103 (76.8 mg, 80%) as a colorless oil.



1H NMR (401 MHz, CDCl3) δ 7.73-7.67 (m, 4H), 7.44-7.37 (m, 6H), 3.68 (t, J=6.5 Hz, 2H), 2.37 (t, J=7.5 Hz, 2H), 1.70-1.53 (m, 4H), 1.41-1.23 (m, 26H), 1.07 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 180.4 (C), 135.7 (4C; CH), 134.3 (2C; C), 129.6 (2C; CH), 127.7 (4C; CH), 64.2 (CH2), 34.2 (CH2), 32.7 (CH2), 29.83 (4C; CH2), 29.81 (CH2), 29.78 (2C; CH2), 29.76 (CH2), 29.6 (CH2), 29.5 (CH2), 29.4 (CH2), 29.2 (CH2), 27.0 (3C; CH3), 25.9 (CH2), 24.8 (CH2), 19.4 (C).


Int-104:


DMAP (10.2 mg, 0.0839 mmol), EDC.HCl (40.2 mg, 0.210 mmol) and 1,3-diglyceride Int-2 (52.5 mg, 0.0923 mmol) were added to a solution of acid Int-103 (45.2 mg, 0.0839 mmol) in CH2Cl2 (4 mL) and the mixture stirred at RT for 22 hours. The reaction was diluted with CH2Cl2 (10 mL), silica gel was added and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (4% to 6% ethyl acetate/hexanes) gave triglyceride Int-104 (84.9 mg, 93%) as a colorless solid. 1H NMR (401 MHz, CDCl3) δ 7.71-7.65 (m, 4H), 7.45-7.34 (m, 6H), 5.28 (m, 1H), 4.31 (dd, J=11.9, 4.3 Hz, 2H), 4.16 (dd, J=11.9, 6.0 Hz, 2H), 3.66 (t, J=6.5 Hz, 2H), 2.325 (t, J=7.5 Hz, 2H), 2.319 (t, J=7.5 Hz, 4H), 1.69-1.52 (m, 8H), 1.42-1.20 (m, 74H), 1.06 (s, 9H), 0.89 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.4 (2C; C), 173.0 (C), 135.7 (4C; CH), 134.3 (2C; C), 129.6 (2C; CH), 127.7 (4C; CH), 69.0 (CH), 64.1 (CH2), 62.2 (2C; CH2), 34.3 (CH2), 34.2 (2C; CH2), 32.7 (CH2), 32.1 (2C; CH2), 29.86 (2C; CH2), 29.84 (9C; CH2), 29.80 (5C; CH2), 29.77 (2C; CH2), 29.76 (2C; CH2), 29.65 (CH2), 29.61 (2C; CH2), 29.53 (CH2), 29.50 (2C; CH2), 29.44 (CH2), 29.41 (2C; CH2), 29.25 (2C; CH2), 29.22 (CH2), 27.0 (3C; CH3), 25.9 (CH2), 25.04 (CH2), 24.99 (2C; CH2), 22.8 (2C; CH2), 19.3 (C), 14.2 (2C; CH3).


Int-105:


Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 154 μL, 0.154 mmol) and acetic acid (8.8 μL, 0.154 mmol) were added to a solution of TBDPS ether Int-104 (84.0 mg, 0.0771 mmol) in THF (3 mL) at 0° C. and the mixture stirred at 0° C. for 15 minutes and then at rt for seven hours. The reaction was diluted with ethyl acetate (40 mL), washed with water (30 mL) and brine (2×30 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (7.5% to 20% ethyl acetate/hexanes) gave alcohol Int-105 (40.5 mg, 62%) as a colorless solid. 1H NMR (401 MHz, CDCl3) δ 5.26 (m, 1H), 4.29 (dd, J=11.9, 4.3 Hz, 2H), 4.14 (dd, J=11.9, 6.0 Hz, 2H), 3.64 (t, J=6.6 Hz, 2H), 2.31 (t, J=7.5 Hz, 2H), 2.30 (t, J=7.5 Hz, 4H), 1.67-1.51 (m, 8H), 1.44-1.17 (m, 74H), 0.88 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.5 (2C; C), 173.1 (C), 69.0 (CH), 63.3 (CH2), 62.3 (2C; CH2), 34.4 (CH2), 34.2 (2C; CH2), 33.0 (CH2), 32.1 (2C; CH2), 29.82 (10C; CH2), 29.80 (6C; CH2), 29.76 (3C; CH2), 29.75 (CH2), 29.65 (CH2), 29.63 (2C; CH2), 29.59 (CH2), 29.51 (2C; CH2), 29.45 (CH2), 29.42 (2C; CH2), 29.27 (2C; CH2), 29.23 (CH2), 25.9 (CH2), 25.1 (CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 14.3 (2C; CH3).


Int-110 (TML(CO2H)-C4-2-TG):




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Int-106: prepared according to: Amsberry, K. L. et al. Pharm Res. 1991, 8, 455-461.


DMAP (18.3 mg, 0.149 mmol) and EDC.HCl (71.6 mg, 0.374 mmol) were added to a solution of Int-28 (100 mg, 0.149 mmol) and phenol Int-106 (53.0 mg, 0.164 mmol) in CH2Cl2 (4 mL) and the mixture stirred at room temperature for 19 hours. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added, and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (3% to 7.5% ethyl acetate/hexanes) gave TML-TG Int-107 (84.6 mg, 58%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δ 6.80 (d, J=2.0 Hz, 1H), 6.55 (d, J=1.9 Hz, 1H), 5.29 (m, 1H), 4.31 (dd, J=11.9, 4.4 Hz, 2H), 4.16 (dd, J=12.0, 5.8 Hz, 2H), 3.51-3.44 (m, 2H), 2.85 (t, J=6.9 Hz, 2H), 2.75 (t, J=6.9 Hz, 2H), 2.51 (s, 3H), 2.30 (t, J=7.6 Hz, 4H), 2.22 (s, 3H), 2.06-1.99 (m, 2H), 1.65-1.56 (m, 4H), 1.46 (s, 6H), 1.37-1.20 (m, 48H), 0.88 (t, J=6.9 Hz, 6H), 0.84 (s, 9H), −0.03 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 173.4 (2C; C), 171.5 (C), 171.3 (C), 149.7 (C), 138.5 (C), 136.1 (C), 134.1 (C), 132.5 (CH), 123.1 (CH), 69.8 (CH), 62.0 (2C; CH2), 60.9 (CH2), 46.1 (CH2), 39.2 (C), 34.1 (2C; CH2), 32.1 (2C; CH2), 31.9 (2C; CH3), 29.9 (CH2), 29.83 (6C; CH2), 29.79 (4C; CH2), 29.75 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.2 (2C; CH2), 29.0 (CH2), 26.1 (3C; CH3), 25.4 (CH3), 25.0 (2C; CH2), 22.8 (2C; CH2), 20.3 (CH3), 18.3 (C), 14.3 (2C; CH3), −5.21 (2C; CH3). ESI-HRMS: calcd. for C58H110O9Si [M+H+] 973.7522; found 973.7515.


10-Camphorsulfonic acid (3.0 mg, 12.9 μmol) was added to TBS ether Int-107 (83.7 mg, 86.0 μmol) in CH2Cl2 (1 mL) and MeOH (1 mL) and the mixture stirred at room temperature for one hour. The reaction was diluted with CH2Cl2 (20 mL) and the organic phase washed with sat. aq. NaHCO3 and brine (20 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (15% to 25% ethyl acetate/hexanes) gave alcohol Int-108 (59.9 mg, 81%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δ 6.81 (d, J=2.0 Hz, 1H), 6.56 (d, J=1.4 Hz, 1H), 5.28 (m, 1H), 4.30 (dd, J=12.0, 4.4 Hz, 2H), 4.17 (dd, J=12.0, 5.8 Hz, 2H), 3.51 (t, J=6.8 Hz, 2H), 2.88 (t, J=6.6 Hz, 2H), 2.75 (t, J=6.6 Hz, 2H), 2.52 (s, 3H), 2.29 (t, J=7.6 Hz, 4H), 2.22 (s, 3H), 2.05 (t, J=7.4 Hz, 2H), 1.65

    • 1.57 (m, 4H), 1.50 (s, 6H), 1.37-1.20 (m, 48H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.5 (2C; C), 171.71 (C), 171.70 (C), 149.8 (C), 138.5 (C), 136.3 (C), 133.9 (C), 132.6 (CH), 123.2 (CH), 69.8 (CH), 62.0 (2C; CH2), 60.5 (CH2), 45.9 (CH2), 39.2 (C), 34.1 (2C; CH2), 32.1 (2C; CH3), 32.0 (2C; CH2), 29.84 (CH2), 29.80 (6C; CH2), 29.77 (4C; CH2), 29.72 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.2 (2C; CH2), 28.9 (CH2), 25.5 (CH3), 24.9 (2C; CH2), 22.8 (2C; CH2), 20.3 (CH3), 14.2 (2C; CH3). ESI-HRMS: calcd. for C52H90NaO9 [M+Na+] 881.6477; found 881.6489.


Pyridinium chlorochromate (PCC, 30.1 mg, 0.139 mmol) was added to a suspension of alcohol Int-108 (59.9 mg, 0.0697 mmol) and Celite (30 mg) in CH2Cl2 (3 mL) at 0° C. and the mixture stirred at room temperature for two hours. The reaction was filtered through a short pad of silica gel, eluting with 50% ethyl acetate/hexanes (50 mL), and the filtrate concentrated under reduced pressure to give crude aldehyde Int-109 (59.8 mg, quant.) as a yellow oil that was used without purification. 1H NMR (400 MHz, CDCl3) δ 9.54 (t, J=2.6 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.60 (d, J=1.4 Hz, 1H), 5.28 (m, 1H), 4.30 (dd, J=12.0, 4.3 Hz, 2H), 4.16 (dd, J=12.0, 5.8 Hz, 2H), 2.86 (t, J=6.7 Hz, 2H), 2.83 (d, J=2.6 Hz, 2H), 2.75 (t, J=6.3 Hz, 2H), 2.53 (s, 3H), 2.30 (t, J=7.6 Hz, 4H), 2.23 (s, 3H), 1.64-1.58 (m, 4H), 1.56 (s, 3H), 1.55 (s, 3H), 1.32-1.22 (m, 48H), 0.88 (t, J=6.9 Hz, 6H).


Potassium permanganate (12.2 mg, 76.7 mol) in 1:1 acetone/water (1.6 mL total) was added to aldehyde Int-109 (59.8 mg, 69.7 μmol) in acetone (1.6 mL) and the mixture stirred at room temperature for 17 hours. The reaction was diluted with water (10 mL), acidified to pH 2 using 1 M HCl, and the aqueous layer extracted with CH2Cl2 (3×15 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% to 25% ethyl acetate/hexanes) gave acid Int-110 (30.4 mg, 50%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 6.81 (d, J=1.6 Hz, 1H), 6.58 (d, J=1.4 Hz, 1H), 5.28 (m, 1H), 4.30 (dd, J=11.9, 4.4 Hz, 2H), 4.16 (dd, J=12.0, 5.8 Hz, 2H), 2.88 (t, J=6.6 Hz, 2H), 2.84 (s, 2H), 2.75 (t, J=6.6 Hz, 2H), 2.53 (s, 3H), 2.29 (t, J=7.6 Hz, 4H), 2.22 (s, 3H), 1.64-1.58 (m, J=9.3 Hz, 4H), 1.57 (s, 6H), 1.34-1.20 (m, 48H), 0.88 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 176.1 (C), 173.6 (2C; C), 171.6 (C), 171.4 (C), 149.5 (C), 138.2 (C), 136.5 (C), 133.4 (C), 132.7 (CH), 123.0 (CH), 69.8 (CH), 62.0 (2C; CH2), 47.6 (CH2), 38.8 (C), 34.1 (2C; CH2), 32.1 (2C; CH2), 31.5 (2C; CH3), 29.9 (CH2), 29.84 (6C; CH2), 29.80 (4C; CH2), 29.76 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.2 (2C; CH2), 29.0 (CH2), 25.4 (CH3), 25.0 (2C; CH2), 22.8 (2C; CH2), 20.4 (CH3), 14.3 (2C; CH3). ESI-HRMS: calcd. for C52H88NaO10 [M+Na+] 895.6270; found 895.6266.


Using similar methods, Int-119 was prepared by EDC coupling with Int-37 in 84% yield:




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1H NMR (401 MHz, CDCl3) δ 6.80 (d, J=1.9 Hz, 1H), 6.55 (d, J=1.7 Hz, 1H), 5.26 (m, 1H), 4.29 (dd, J=11.9, 4.4 Hz, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 2.83 (s, 2H), 2.55 (t, J=7.5 Hz, 2H), 2.53 (s, 3H), 2.32 (t, J=7.5 Hz, 2H), 2.31 (t, J=7.5 Hz, 4H), 2.22 (s, 3H), 1.78-1.69 (m, 2H), 1.67-1.54 (m, 6H), 1.57 (s, 6H), 1.45-1.20 (m, 60H), 0.88 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 176.3 (C), 173.5 (2C; C), 173.1 (C), 173.0 (C), 149.7 (C), 138.2 (C), 136.4 (C), 133.5 (C), 132.5 (CH), 123.2 (CH), 69.0 (CH), 62.2 (2C; CH2), 47.4 (CH2), 38.9 (C), 35.2 (CH2), 34.3 (CH2), 34.2 (2C; CH2), 32.1 (2C; CH2), 31.4 (2C; CH3), 29.84 (6C; CH2), 29.80 (4C; CH2), 29.76 (2C; CH2), 29.62 (2C; CH2), 29.53 (2C; CH2), 29.50 (2C; CH2), 29.41 (2C; CH2), 29.38 (2C; CH2), 29.30 (CH2), 29.26 (2C; CH2), 29.19 (CH2), 25.4 (CH3), 25.0 (3C; CH2), 24.8 (CH2), 22.8 (2C; CH2), 20.4 (CH3), 14.3 (2C; CH3).


Int-122 was also prepared using similar methods:




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1H NMR (401 MHz, CDCl3) δ 6.79 (d, J=1.9 Hz, 1H), 6.51 (d, J=1.8 Hz, 1H), 5.26 (m, 1H), 4.292/4.284 (each dd, J=11.8, 4.2 Hz, 2H), 4.14 (dd, J=11.9, 6.1 Hz, 2H), 2.84 (s, 2H), 2.67 (m, 1H), 2.53 (s, 3H), 2.44 (m, 1H), 2.30 (t, J=7.6 Hz, 4H), 2.22 (s, 3H), 1.84 (m, 1H), 1.69-1.45 (m, 7H), 1.573 (s, 3H), 1.567 (s, 3H), 1.45-1.19 (m, 63H), 1.14 (d, J=7.0 Hz, 3H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 176.1 (2C; C), 175.9 (C), 173.5 (2C; C), 150.1 (C), 138.2 (C), 136.4 (C), 133.6 (C), 132.5 (CH), 123.0 (CH), 68.9 (CH), 62.30/62.27 (2C; CH2), 47.3 (CH2), 40.2 (CH), 39.7 (CH), 39.0 (C), 34.2 (2C; CH2), 33.8 (CH2), 33.6 (CH2), 32.1 (2C; CH2), 31.5 (CH3), 29.84 (2C; CH2), 29.80 (2C; CH2), 29.76 (2C; CH2), 29.65 (2C; CH2), 29.61 (2C; CH2), 29.59 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.28/29.27 (2C; CH2), 27.34 (CH2), 27.28 (CH2), 25.5 (CH3), 25.0 (2C; CH2), 22.8 (2C; CH2), 20.4 (CH3), 17.2 (CH3), 16.9 (CH3), 14.3 (2C; CH3).


Int-112 1,3-di-oleoyl glycerol (1,3-DG-oleate):




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To a solution of 2,5-bis(hydroxymethyl)-1,4-dioxane-2,5-diol (5 g, 27.7 mol) in chloroform (20 vol) was added pyridine (5.5 mL, 69.4 mol) followed by oleoyl chloride (11 mL, 54.9 mol) and the mixture was stirred at room temperature for 1 h. The solvent was evaporated and the reaction mixture dissolved in ethyl acetate (30 vol) and washed with 1N HCl (10 vol). The organic layer was dried and solvent evaporated under vaccum. The crude material was recrystallized with cold methanol (20 vol). The solid obtained was further washed with cold methanol, and dried to give ketone Int-111 (11 g, 62%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.36 (t, J=11.6 Hz, 4H), 4.78 (s, 4H), 2.47 (m, 4H), 2.38 (m, 8H), 1.71 (m, 2H), 1.34-1.30 (m, 42H), 0.93 (m, 6H).


Sodium borohydride (NaBH4, 307 mg, 8.09 mmol), was added to a solution of Int-111 (5 g, 8.09 mmol) in THF (20 vol) at 0° C. and then the reaction mixture was stirred at room temperature for 15 mins. The reaction was monitored by TLC and after completion, the reaction mixture was filtered through a celite bed to remove excess of sodium borohydride and the celite bed was washed with ethyl acetate (30 vol), the organic layer was washed with 1N solution of acetic acid (10 vol). The solvent was dried over Na2SO4 and solvent removed under vacuum. The crude material was column purified. The product was eluted at 5%-10% ethyl acetate/hexane to afford 1,3-DG-oleate (Int-112) (2 g, 39%) as viscous liquid. 1H NMR (400 MHz, CDCl3) δ 5.39 (m, 4H), 4.20 (m, 5H), 2.44 (d, 1H), 2.36 (m, 4H), 2.01 (m, 8H), 2.47-2.25 (m, 12H), 2.17 (m, 1H), 2.02 (ddd, J=13.4, 4.9, 3.3 Hz, 1H), 1.85 (m, 1H), 1.77 (m, 1H), 1.64 (m, 2H), 1.57-1.26 (m, 42H), 0.9 (t, 6H); 13C NMR (101 MHz, CDCl3) δ 173.9 (2C, C═O), 130.1 (2C), 129.7 (2C), 68.4 (C, CH), 65.1 (2C), 34.1 (2C), 31.9 (2C), 29.8-29.1 (18C), 27.3 (2C), 24.9 (2C), 22.7 (2C), 14.1 (2C). HPLC (ELSD): 9.62 min, 99.27% purity. MS (ESI, +ve) m/z: 639.2 (MH++H2O).


Int-113 (C10-acid-TG-oleate):




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Pyridine (0.19 mL, 2.41 mmol) was added to a suspension of DG-oleate Int-112 (150 mg, 0.241 mmol) in DCM (20 Vol). After 5 min, sebacoyl chloride (289 mg, 1.2 mmol) was added dropwise with stirring at room temperature. Reaction mixture allowed to stir at 40° C. for 2 h. The reaction was monitored by TLC and after completion, diluted with DCM (20 vol), washed with water (20 vol), aqueous sodium bicarbonate (10 vol) and brine (10 vol). The obtained organic layer was dried over Na2SO4, filtered and solvent was removed under reduced pressure. The crude material was column purified. The product was eluted at 5-10% ethyl acetate/hexane to afford C10-acid-TG-oleate Int-113 (60 mg, 30%) as viscous liquid. 1H NMR (400 MHz, CDCl3) δ 5.43 (m, 4H), 5.29 (m, 1H), 4.35 (d, 2H), 4.20 (m, 2H), 2.40 (m, 8H), 2.05 (m, 8H), 1.65 (m, 10H), 1.33-1.18 (m 46H), 0.93 (t, 6H); 13C NMR (101 MHz, CDCl3) δ 1.78 (1C, C═O, 173.3 (2C, C═O), 172.8 (1C, C═O), 130.1 (2C), 129.8 (2C), 68.9 (C, CH), 62.1 (2C), 60.5 (2C), 34.2 (4C), 31.9 (2C), 29.8-29.0 (18C), 27.3 (4C), 24.9 (4C), 22.7 (2C), 14.2 (2C). HPLC (ELSD): 10.90 min, 99% purity. MS (ESI, +ve) m/z: 823.8 (MH++H2O).


Int-115 (1,3-DG-butyrate):




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To a solution of 2,5-bis-(hydroxymethyl)-1,4-dioxane-2,5-diol (2.0 g, 1.11 mmol) in chloroform (40 ml) was added pyridine (2.2 mL, 2.77 mmol) followed by butyryl chloride (2.3 mL, 2.22 mol) before stirring at room temperature for 16 h. After completion, the solvent was evaporated and re-dissolved in ethyl acetate (60 ml) and washed with 1N HCl (20 ml). The combined organic layer was dried and evaporated under vacuum. The crude material was purified by column. The product was eluted at 5-10% ethyl acetate/hexane to afford Int-114 (1.4 g, 54%) as viscous liquid. 1H NMR (400 MHz, CDCl3) δ 4.8 (s, 4H), 2.45 (t, 4H), 1.79-1.69 (m, 4H), 1.04-0.98 (t, 6H); 13C NMR (101 MHz, CDCl3) δ 198.2 (1C═O), 172.2 (2C═O), 66.1 (2C), 35.9 (2C), 18.3 (2C), 14.1 (2C). HPLC (ELSD): 1.73 min, 99.8% purity.


Sodium borohydride (NaBH4, 230 mg, 6.10 mmol), was added to a solution of Int-114 (1.3 g, 6.1 mmol) in THF (26 ml) at 0° C. and then the reaction mixture was stirred at room temperature for 15 mins. The reaction was monitored by TLC and after completion, the reaction mixture was filtered through a celite bed to remove excess sodium borohydride, the celite bed was washed with ethyl acetate (40 ml), and the combined organic layer was washed with a 1N solution of acetic acid (13 ml). The organic layer was dried over Na2SO4 and solvent removed under vacuum. The crude material was purified by column. The product was eluted at 5-10% ethyl acetate/hexane to afford Int-115 (1.0 g, 70.6%) as a viscous liquid. 1H NMR (400 MHz, CDCl3) δ 4.25-4.13 (m, 5H), 2.4 (s, 1H), 2.38 (t, 4H), 1.75-1.66 (m, 4H), 1.01-0.98 (t, 6H); 13C NMR (101 MHz, CDCl3) δ 173.8 (2C═O), 68.3 (1C), 65.0 (2C), 35.9 (2C), 18.4 (2C), 13.6 (2C). HPLC (ELSD): 1.8 min, 100% purity. MS (ESI, +ve) m/z: 255.37 (M++23).


Int-125:




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Int-45 was prepared as described above and coupled with Int-115 using EDC and DMAP similarly to methods described above to provide Int-124. Int-124: 1H NMR (401 MHz, CDCl3) δ 7.70-7.64 (m, 4H), 7.42-7.35 (m, 6H), 5.29 (m, 1H), 4.307/4.305 (each dd, J=11.9, 4.2 Hz, 2H), 4.159/4.157 (each dd, J=11.9, 6.0 Hz, 2H), 3.66 (t, J=6.5 Hz, 2H), 2.34 (dd, J=14.7, 5.9 Hz, 1H), 2.30 (t, J=7.4 Hz, 4H), 2.13 (dd, J=14.7, 8.3 Hz, 1H), 1.95 (m, 1H), 1.70-1.50 (m, 6H), 1.37-1.17 (m, 20H), 1.05 (s, 9H), 0.95 (t, J=7.5 Hz, 6H). 0.94 (d, J=6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.2 (2C; C), 172.5 (C), 135.7 (4C; CH), 134.3 (2C; C), 129.6 (2C; CH), 127.7 (4C; CH), 68.9 (CH), 64.1 (CH2), 62.3 (2C; CH2), 41.8 (CH2), 36.8 (CH2), 36.0 (2C; CH2), 32.7 (CH2), 30.5 (CH), 29.9 (CH2), 29.80 (3C; CH2), 29.76 (CH2), 29.75 (CH2), 29.5 (CH2), 27.1 (CH2), 27.0 (3C; CH3), 25.9 (CH2), 19.7 (CH3), 19.3 (C) 18.5 (2C; CH2), 13.7 (2C; CH3).


Int-125:


Tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 243 μL, 0.243 mmol) and AcOH (13.9 L, 0.243 mmol) were added dropwise to TBDPS ether 3 (58.7 mg, 0.0809 mmol) in THF (4 mL) at 0° C. and the mixture stirred at rt for 19 hours. The reaction was diluted with water (10 mL) and the aqueous phase extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with sat. aq. NaHCO3 and brine (30 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (6% to 20% ethyl acetate/hexanes) gave alcohol Int-125 (26.7 mg, 68%) as a colorless oil. 1H NMR (401 MHz, CDCl3) δ 5.28 (m, 1H), 4.298/4.295 (each dd, J=11.9, 4.3 Hz, 2H), 4.153/4.151 (each dd, J=11.9, 6.0 Hz, 2H), 3.64 (t, J=6.6 Hz, 2H), 2.33 (dd, J=14.7, 5.9 Hz, 1H), 2.30 (t, J=8.4, 6.5 Hz, 4H), 2.12 (dd, J=14.7, 8.3 Hz, 1H), 1.93 (m, 1H), 1.70-1.46 (m, 8H), 1.38-1.16 (m, 18H), 0.95 (t, J=7.4 Hz, 6H), 0.93 (d, J=6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.3 (2C; C), 172.5 (C), 69.0 (CH), 63.2 (CH2), 62.3 (2C; CH2), 41.9 (CH2), 36.8 (CH2), 36.1 (2C; CH2), 33.0 (CH2), 30.5 (CH), 29.9 (CH2), 29.78 (CH2), 29.76 (2C; CH2), 29.74 (CH2), 29.71 (CH2), 29.6 (CH2), 27.1 (CH2), 25.9 (CH2), 19.7 (CH3), 18.5 (2C; CH2), 13.8 (2C; CH3).




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Int-126:


Prepared using similar methods as those shown above. 1H NMR (401 MHz, CDCl3) δ 5.23 (m, 1H), 4.26 (dd, J=11.9, 4.3 Hz, 2H), 4.11 (dd, J=11.9, 6.0 Hz, 2H), 3.36 (t, J=6.9 Hz, 2H), 2.28 (t, J=7.4 Hz, 2H), 2.26 (t, J=7.4 Hz, 4H), 1.84-1.75 (m, 2H), 1.66-1.52 (m, 6H), 1.42-1.33 (m, 2H), 1.31-1.19 (m, 12H), 0.90 (t, J=7.4 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.1 (2C; C), 172.9 (C), 68.9 (CH), 62.1 (2C; CH2), 35.9 (2C; CH2), 34.2 (CH2), 34.0 (CH2), 32.9 (CH2), 29.5 (CH2), 29.43 (CH2), 29.42 (CH2), 29.3 (CH2), 29.1 (CH2), 28.8 (CH2), 28.2 (CH2), 24.9 (CH2), 18.4 (2C; CH2), 13.7 (2C; CH3); ESI-HRMS: calcd. for C23H4179BrNaO6 [M+Na+] 515.1979; found 515.1995.


Int-117 1,3-bis-decanoyl glycerol (1,3-DG-decanoate):




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To a solution of 2, 5-bis-(hydroxymethyl)-1,4-dioxane-2,5-diol (0.2 g, 1.11 mmol) in chloroform (4.0 ml) was added pyridine (0.22 mL, 2.77 mmol) followed by decanoyl chloride (0.45 mL, 2.22 mmol) and stirred at room temperature for 16 h. The solvent was evaporated and re-dissolved in ethyl acetate (6 ml) and washed with 1N HCl (2 ml). The organic layer was dried and solvent evaporated under vacuum. The crude material was purified by column. The product was eluted at 5-10% ethyl acetate/hexane to afford Int-116 (0.09 g, 20.36%) as viscous liquid. 1H NMR (400 MHz, CDCl3) δ 4.8 (m, 4H), 2.46 (m, 4H), 1.73-1.66 (m, 4H), 1.30 (m, 24H), 0.91 (t, 6H); 13C NMR (101 MHz, CDCl3) δ 198.2 (1C═O), 172.0 (2C═O), 66.1 (2C), 33.7 (2C), 31.8 (2C), 29.3 (2C), 29.2 (2C), 29.0 (2C), 24.8 (2C), 22.6 (2C), 14.12 (2C). HPLC (ELSD): 2.88 min, 100% purity.


Sodium borohydride (NaBH4) (7 mg, 0.2 mmol), was added to a solution of Int-116 (80 mg, 0.2 mmol) in THF (2 ml) at 0° C. and then the reaction mixture was stirred at room temperature for 15 mins. The reaction was monitored by TLC and after completion, the reaction mixture was filtered through a celite bed to remove excess sodium borohydride and the celite bed was washed with ethyl acetate (3 ml). The organic layer was washed with 1 M acetic acid (1 ml). The solvent was dried over Na2SO4 and solvent removed under vacuum. The crude material was purified by column. The product was eluted at 5-10% ethyl acetate/hexane to afford Int-117 (70 mg, 100%) as viscous liquid. 1H NMR (400 MHz, CDCl3) δ 4.2-4.1 (m, 5H), 2.51 (s, 1H), 2.38 (t, 4H), 1.68-1.64 (m, 4H), 1.32-1.29 (m, 22H), 0.91 (t, 6H); 13C NMR (101 MHz, CDCl3) δ 173.0 (2C═O), 68.3 (1C), 65.0 (2C), 34.1 (2C), 31.8 (2C), 29.7 (2C), 29.4 (2C), 29.3 (2C), 29.1 (2C), 24.9 (2C), 22.7 (2C), 14.1 (2C). HPLC (ELSD): 10.70 min, 97.6% purity.


Int-123:




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Tetra-n-butyl ammonium hydrogen sulfate (0.034 g, 0.098 mmol) and potassium bicarbonate (0.198 g, 1.977 mmol) in distilled water (10 ml) was added to a stirred solution of Int-81 (0.4 g, 0.494 mmol) and tetra-n-butyl ammonium hydrogen sulfate (0.034 g, 0.098 mmol) in dichloromethane (10 ml) at rt and stirred for 0.5 h. Then chloromethyl chlorosulfate (0.062 ml, 0.618 mmol) was added dropwise at rt and stirred vigorously at rt for 18 h. The reaction was monitored by TLC, and after completion of reaction, the reaction mixture was diluted with DCM (25 ml). The organic phase was separated and the aqueous phase extracted with DCM (2×50 ml). Combined organic layers were washed with water (50 ml), brine (50 mL), dried over sodium sulphate, filtered and concentrated at reduced pressure to get crude material. Crude material was purified by column chromatography over silica 100-200 mesh; compound eluted at 20% ethyl acetate/hexane as a mobile phase; visualization was with KMnO4 solution. Int-123 (0.250 g, 59%) was obtained as a viscous liquid. 1H NMR (400 MHz, CDCl3) δ 5.75 (m, 2H), 5.32-5.30 (m, 1H), 4.33 (dd, J=11.9, 4.3 Hz, 2H), 4.18 (dd, J=11.9, 6.0 Hz, 2H), 2.56-2.45 (m, 2H), 2.36-2.32 (t, J=7.2 Hz, 4H), 1.66-1.62 (m, 4H), 1.48-1.40 (m, 8H), 1.29 (m, 56H), 1.19 (dd, J=11.2, 7.0 Hz, 6H), 0.92 (t, J=6.7 Hz, 6H).


Example 2: Synthesis of (4-acetamidophenoxy)methyl (1,3-bis(palmitoyloxy)propan-2-yl) succinate, I-1



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Synthesis of I-1. I-1 is prepared according to the following procedure. N-(4-((methylthio)methoxy)phenyl)acetamide, 1.1, is prepared by treating acetaminophen with chloromethyl methyl thioether as described in WO 2009/143295, which is hereby incorporated by reference in its entirety. A solution of sulfuryl chloride (2.2 equiv.) in CH2Cl2 (0.16 M) is added to a solution of 1.1 (1.8 equiv.) in CH2Cl2 (0.07 M) at 0° C. and the mixture stirred at 0° C. for 30 minutes and then at rt for a further hour. The reaction is concentrated under a stream of N2, co-evaporated from toluene (twice) and dried under reduced pressure. The crude residue is re-dissolved in toluene (0.1 M based on 1.1), added to a solution of acid 1.2 (1 equiv.), as prepared in WO 2017/041139, and DBU (1.5 equiv.) in toluene (0.05 M) that had been pre-stirred for one hour, and the mixture is stirred at rt for two hours. The reaction is diluted with CH2Cl2 (20 mL) and the organic phase washed with sat. aq. NaHCO3 (20 mL) and brine (20 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography with a suitable solvent mixture affords I-1.


Example 3: Synthesis of (((4-acetamidophenoxy)carbonyl)oxy)methyl (1,3-bis(palmitoyloxy)propan-2-yl) succinate, 1-2



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Synthesis of 2.2. 2.2 is prepared according to the following procedure. Chloromethyl chloroformate (1.6 equiv.) and pyridine (3.0 equiv.) are added to acetaminophen 2.1 (1.0 equiv.) in CH2Cl2 (0.03 M) at 0° C. and the mixture is stirred at 0° C. for 15 minutes and then at rt for one hour. The reaction is diluted with CH2Cl2 and the organic phase washed with sat. aq. NaHCO3 and brine, dried (MgSO4) and concentrated under reduced pressure to give 2.2 which is used without purification.


Synthesis of I-2. I-2 is prepared according to the following procedure. Silver carbonate (0.7 equiv.) is added to acid 2.3 (1.2 equiv.) as prepared in WO 2017/041139, in DMF (0.03 M) and the mixture stirred at rt for one hour. The reaction is concentrated under reduced pressure to give a grey residue, to which is added chloromethyl carbonate 2.2 (1.0 equiv.) in toluene (0.03 M) and TBAI (0.3 equiv.) and the mixture heated at reflux for 1.5 hours. The reaction is cooled to rt, then diluted with ethyl acetate. The organic phase is washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography with a suitable solvent mixture affords 1-2.


Example 4: Synthesis of 2-(4-(4-acetamidophenoxy)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl (1,3-bis(palmitoyloxy)propan-2-yl) succinate, 1-3



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Synthesis of I-3. I-3 is prepared according to the following procedure. 4-(Dimethylamino)pyridine (DMAP, 1.3 equiv.) and EDC.HCl (2.1 equiv.) is added to a solution of acid 3.1 (1.0 equiv.) as prepared in WO 2017/041139, and acetaminophen 3.2 (1.3 equiv.) in CH2Cl2 (0.02 M) and the mixture stirred at rt for 19 hours. The reaction is diluted with CH2Cl2 (10 mL), silica gel is added and the mixture concentrated under reduced pressure. Purification by silica gel chromatography with a suitable solvent mixture affords 1-3.


Example 5: Synthesis of 4-((((4-acetamidophenoxy)carbonyl)oxy)methyl)phenyl (1,3-bis(palmitoyloxy)propan-2-yl) succinate, 1-4



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Synthesis of I-4. I-4 is prepared according to the following procedure. 4-(Dimethylamino)pyridine (DMAP, 1.3 equiv.) and DIPEA (0.3 equiv.) were added to a solution of acetaminophen, 4.1 (1.2 equiv.) and PNP carbonate 4.2 (1.0 equiv.) as prepared in WO 2017/041139, in CH2Cl2 (0.01 M) and the mixture stirred at rt for five days. The reaction was diluted with CH2Cl2, washed with 1 M HCl, water and brine, dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography with a suitable solvent mixture affords 1-4.


Example 6: Synthesis of 4-(4-acetamidophenoxy)-4-oxobutyl (1,3-bis(palmitoyloxy)propan-2-yl) succinate (I-5) and Additional Paracetamol (Acetaminophen) Lipid Prodrugs



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Synthesis of 5.3. 5.3 is prepared according to the following procedure. 4-(Dimethylamino)pyridine (1.3 equiv.) and DCC (2.1 equiv.) are added to a solution of acetaminophen (1.0 equiv.) and 4-bromobutyric acid 5.2 (1.3 equiv.) in CH2Cl2 (0.03 M) and the mixture is stirred at rt for 24 hours. Another 0.6 eq. of acid, 1 eq. of DCC, 0.6 eq. of DMAP are added and the mixture is stirred at rt for a further two days. The reaction is diluted with CH2Cl2, silica gel is added and the mixture is concentrated under reduced pressure. Purification by silica gel chromatography gives bromide 5.3.


Synthesis of I-5. I-5 is prepared according to the following procedure. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (1.6 equiv.) is added to a suspension of acid 5.4 (1.1 equiv.) as prepared in WO 2017/041139, and bromide 5.3 (1.0 equiv.) in toluene (0.03 M) and the mixture is heated at reflux for 21 hours. The reaction is cooled to rt, then diluted with ethyl acetate. The organic phase is washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography with a suitable solvent mixture affords 1-5.


Additional compounds were prepared according to methods similar to those described in this and the foregoing Examples. These compounds and their characterization data are shown below in Table 8.









TABLE 8







Additional Lipid Prodrugs of Paracetamol (Acetaminophen)









Cmpd.




#
Structure

1H NMR; 13C NMR; MS






I-6 


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1H NMR (401 MHz, CDCl3) δ 7.50 (d, J = 8.9 Hz, 2H), 7.15 (s, 1H), 7.03 (d, J = 8.9 Hz, 2H), 5.29 (m, 1H), 4.318/4.313 (each dd, J = 11.9, 4.2 Hz, 2H), 4.146/4.144 (each dd, J = 11.9, 6.0 Hz, 2H), 2.68-2.45 (m, 4H), 2.39-2.27 (m, 5H), 2.17 (s, 3H), 1.66-1.53 (m, 4H), 1.25 (s, 48H), 1.12 (d, J = 6.5 Hz, 3H), 0.88 (t, J = 6.8 Hz, 6H).






I-7 


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1H NMR (401 MHz, CDCl3) δ 7.49 (d, J = 8.8 Hz, 2H), 7.30 (br s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 5.26 (m, 1H), 4.29 (dd, J = 11.9, 4.4 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 2.53 (t, J = 7.5 Hz, 2H), 2.32 (t, J = 7.5 Hz, 2H), 2.31 (t, J = 7.5 Hz, 4H), 2.16 (s, 3H), 1.78-1.69 (m, 2H), 1.68-1.54 (m, 6H), 1.44-1.19 (m, 56H), 0.88 (t, J = 6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.5 (2C; C), 173.0 (C), 172.5 (C), 168.3 (C), 147.1 (C), 135.6 (C), 122.1 (2C; CH), 120.9 (2C; CH), 69.0 (CH), 62.2 (2C, CH2), 34.5 (CH2), 34.3 (CH2), 34.2 (2C; CH2), 32.1 (2C; CH2), 29.84 (6C; CH2), 29.80 (4C; CH2), 29.77 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.26 (2C; CH2), 29.22 (CH2), 29.20 (CH2), 29.17 (CH2), 29.12 (CH2),





25.01 (2C; CH2), 24.96 (CH2), 24.7




(CH3), 22.8 (2C; CH2), 14.3 (2C;




CH3).





I-8 


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1H NMR (401 MHz, CDCl3) δ 7.49 (d, J = 8.9 Hz, 2H), 7.31 (br s, 1H), 7.01 (d, J = 8.9 Hz, 2H), 5.28 (m, 1H), 4.288/4.284 (each dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 2.66 (m, 1H), 2.32 (dd, J = 14.7, 5.8 Hz, 1H), 2.30 (t, J = 7.5 Hz, 4H), 2.16 (s, 3H), 2.12 (dd, J = 14.7, 8.3 Hz, 1H), 1.93 (m, 1H), 1.79 (m, 1H), 1.68-1.47 (m, 6H), 1.45-1.15 (m, 62H), 0.93 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 175.6 (C), 173.5 (2C; C), 172.5 (C), 168.3 (C), 147.1 (C), 135.6 (C), 122.1 (2C; CH), 120.9 (2C; CH), 68.9 (CH), 62.3 (2C; CH2), 41.8 (CH2), 39.8 (CH), 36.8 (CH2), 34.2 (2C; CH2), 33.9 (CH2), 32.1 (2C; CH2), 30.5 (CH), 29.84 (7C; CH2), 29.80 (4C; CH2), 29.76 (2C; CH2), 29.6 (4C; CH2), 29.5 (2C; CH2), 29.4





(2C; CH2), 29.3 (2C; CH2), 27.4




(CH2), 27.0 (CH2), 25.0 (2C; CH2),




24.6 (CH3), 22.8 (2C; CH2), 19.7




(CH3), 17.2 (CH3), 14.3 (2C; CH3);




ESI-HRMS: calcd. for C57H99NNaO9




[M + Na+] 964.7212; found 964.7214.





I-9 


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1H NMR (401 MHz, CDCl3) δ 7.53 (d, J = 8.9 Hz, 2H), 7.20 (br s, 1H), 7.15 (d, J = 9.0 Hz, 2H), 5.85 (s, 2H), 5.27 (m, 1H), 4.33-4.27 (m, 2H), 4.13 (dd, J = 11.9, 6.0 Hz, 2H), 2.56- 2.24 (m, 9H), 2.18 (s, 3H), 1.67- 1.53 (m, 4H), 1.37-1.19 (m, 48H), 1.06 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.5





(2C; C), 171.4 (C), 170.7 (C), 152.7




(C), 121.5 (2C; CH), 120.9 (2C; CH),




82.4 (CH2), 69.4 (CH), 62.2 (2C;




CH2), 40.6 (CH2), 40.3 (CH2), 34.2




(2C; CH2), 32.1 (2C; CH2), 29.85 (6C;




CH2), 29.81 (4C; CH2), 29.77 (2C;




CH2), 29.6 (2C; CH2), 29.5 (2C; CH2),




29.4 (2C; CH2), 29.3 (2C; CH2), 27.3




(CH), 25.0 (2C; CH2), 24.7 (CH3),




22.8 (2C; CH2), 19.8 (CH3), 14.3 (2C;




CH3).





I-10


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1H NMR (401 MHz, CDCl3) δ 7.49 (d, J = 8.9 Hz, 2H), 7.41 (br s, 1H), 7.01 (d, J = 8.9 Hz, 2H), 5.26 (m, 1H), 4.288/4.281 (each dd, J = 11.9, 4.3 Hz, 2H), 4.16-4.09 (m, 4H), 2.58 (t, J = 7.1 Hz, 2H), 2.50-2.35 (m, 3H), 2.30 (t, J = 7.5 Hz, 4H), 2.33-2.20 (m, 2H), 2.15 (s, 3H), 1.86-1.71 (m, 4H), 1.65-1.54 (m, 4H), 1.34-1.18 (m, 48H), 1.02 (d, J = 6.5 Hz, 3H),





0.87 (t, J = 6.8 Hz, 6H); 13C NMR




(101 MHz, CDCl3) δ 173.5 (2C; C),




172.3 (C), 172.0 (C), 171.5 (C),




168.4 (C), 146.9 (C), 135.8 (C),




122.0 (2C; CH), 120.9 (2C; CH), 69.2




(CH), 64.0 (CH2), 62.2 (2C; CH2),




40.8 (2C; CH2), 34.12 (2C; CH2),




33.9 (CH2), 32.1 (2C; CH2), 29.83




(6C; CH2), 29.79 (4C; CH2), 29.75




(2C; CH2), 29.6 (2C; CH2), 29.5 (2C;




CH2), 29.4 (2C; CH2), 29.3 (2C; CH2),




28.2 (CH2), 27.5 (CH), 25.0 (2C;




CH2), 24.6 (CH3), 22.8 (2C; CH2),




21.6 (CH2), 19.8 (CH3), 14.2 (2C;




CH3).









Example 7: Synthesis of Buprenorphine Lipid Prodrugs



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Synthesis of I-12. DMAP (2.0 mg, 16.0 μmol) and EDC.HCl (7.7 mg, 40.0 μmol) were added to a solution of Int-28 (13.9 mg, 20.8 μmol) and buprenorphine (7.5 mg, 16.0 μmol) in CH2Cl2 (0.8 mL) and the mixture stirred at rt for two hours. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added, and the solvent removed under reduced pressure. Purification by silica gel chromatography (10% to 15% ethyl acetate/hexanes with 0.5% Et3N) gave BUP prodrug I-12 (15.6 mg, 87%) as a colorless oil. 1H NMR (401 MHz, CDCl3) δ 6.78 (d, J=8.1 Hz, 1H), 6.58 (d, J=8.1 Hz, 1H), 5.89 (s, 1H), 5.26 (m, 1H), 4.42 (d, J=1.6 Hz, 1H), 4.29 (dt, J=11.9, 4.4 Hz, 2H), 4.19-4.12 (m, 2H), 3.45 (s, 3H), 3.05-2.97 (m, 2H), 2.93-2.83 (m, 3H), 2.70 (t, J=6.9 Hz, 2H), 2.62 (dd, J=11.8, 4.9 Hz, 1H), 2.37-2.20 (m, 8H), 2.11 (t, J=9.8 Hz, 1H), 1.96 (m, 1H), 1.91-1.75 (m, 2H), 1.70 (dd, J=13.0, 2.4 Hz, 1H), 1.65-1.53 (m, 4H), 1.35 (s, 3H), 1.37-1.16 (m, 49H), 1.06 (m, 1H), 1.03 (s, 9H), 0.88 (t, J=6.9 Hz, 6H), 0.80 (m, 1H), 0.67 (m, 1H), 0.54-0.42 (m, 2H), 0.15-0.08 (m, 2H).


Additional compounds were prepared according to methods similar to those described in this and the foregoing Examples. These compounds and their characterization data are shown below in Table 9.









TABLE 9







Additional Lipid Prodrugs of Buprenorphine









Cmpd.




#
Structure

1H NMR; 13C NMR; MS






I-13


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1H NMR (401 MHz, CDCl3) δ 1H NMR (401 MHz, CDCl3) δ 6.76 (d, J = 7.6 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 5.88 (s, 1H), 5.28 (m, 1H), 4.42 (s, 1H), 4.34-4.26 (m, 2H), 4.13 (dd, J = 11.9, 6.0 Hz, 2H), 3.45 (s, 3H), 3.06- 2.98 (m, 2H), 2.88 (m, 1H), 2.67- 2.59 (m, 2H), 2.57-2.41 (m, 3H), 2.39-2.21 (m, 9H), 2.11 (m, 1H), 2.02-1.78 (m, 3H), 1.71 (m, 1H), 1.65-1.54 (m, 4H), 1.35 (s, 3H), 1.38- 1.19 (m, 49H), 1.102/1.091 (each d, J = 6.4 Hz, 3H), 1.04 (m, 1H), 1.03 (s, 9H), 0.87 (t, J = 6.9 Hz, 8H), 0.79 (m, 1H), 0.70 (m, 1H), 0.55-0.42 (m, 2H), 0.15-0.08 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 173.4 (2C; C), 171.4 (C), 170.1 (C), 149.9 (C), 134.6 (C), 133.9 (C), 131.3 (C), 122.1 (CH), 119.4 (CH), 98.2 (CH), 80.9 (C), 79.4 (C), 69.3 (CH), 62.2 (2C; CH2), 59.7





(CH2), 58.3 (CH), 52.7 (CH3), 46.4 (C),




44.4 (CH), 43.7 (CH2), 40.69/40.60




(CH2), 40.5 (C), 40.36/40.32 (CH2),




36.1 (C), 35.6 (CH2), 34.1 (2C; CH2),




33.5 (CH2), 32.1 (2C; CH2), 29.9




(CH2), 29.85 (6C; CH2), 29.81 (4C;




CH2), 29.77 (2C; CH2), 29.6 (2C;




CH2), 29.5 (2C; CH2), 29.4 (2C; CH2),




29.3 (2C; CH2), 27.68/27.64 (CH),




26.6 (3C; CH3), 25.0 (2C; CH2), 23.5




(CH2), 22.8 (2C; CH2), 2.01 (CH3),




19.62/19.60 (CH3), 17.7 (CH2), 14.3




(2C; CH3), 9.6 (CH), 4.3 (CH2), 3.4




(CH2).





I-14


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1H NMR (400 MHz, CDCl3) δ 6.76 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 5.90 (s, 1H), 5.26 (m, 1H), 4.42 (d, J = 1.7 Hz, 1H), 4.29 (dd, J = 11.9, 4.4 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 3.45 (s, 3H), 3.05-2.98 (m, 2H), 2.88 (m, 1H), 2.62 (dd, J = 11.8, 4.9 Hz, 1H), 2.51 (t, J = 7.5 Hz, 2H), 2.38-2.21 (m, 10H), 2.12 (m, 1H), 2.03-1.77 (m, 3H), 1.73-1.66 (m, 3H), 1.65-1.52 (m, 6H), 1.35 (s, 3H), 1.43-1.18 (m, 57H), 1.06 (m, 1H), 1.03 (s, 9H), 0.88 (t, J = 6.9 Hz, 6H), 0.80 (m, 1H), 0.68 (m, 1H), 0.54- 0.42 (m, 2H), 0.15-0.08 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 173.4 (2C; C), 172.9 (C), 171.7 (C), 150.0 (C), 134.5 (C), 133.8 (C), 131.6 (C), 122.2 (CH), 119.4 (CH), 98.3 (CH), 80.9 (C), 79.4 (C), 69.0 (CH), 62.2 (2C; CH2), 59.7 (CH2), 58.3 (CH), 52.7 (CH3),





46.4 (C), 44.5 (CH), 43.7 (CH2), 40.5




(C), 36.1 (C), 35.6 (CH2), 34.3 (CH2),




34.2 (2C; CH2), 34.0 (CH2), 33.5




(CH2), 32.1 (2C; CH2), 29.9 (CH2),




29.84 (6C; CH2), 29.80 (4C; CH2),




29.76 (2C; CH2), 29.6 (2C; CH2), 29.5




(2C; CH2), 29.4 (2C; CH2), 29.25 (2C;




CH2), 29.23 (2C; CH2), 29.15 (2C;




CH2), 26.6 (3C; CH3), 25.2 (CH2),




25.00 (2C; CH2), 24.96 (CH2), 23.5




(CH2), 22.8 (2C; CH2), 20.1 (CH3),




17.6 (CH2), 14.3 (2C; CH3), 9.6 (CH),




4.3 (CH2), 3.4 (CH2).





I-15


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1H NMR (401 MHz, CDCl3) δ 6.79 (d, J = 1.8 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 1.4 Hz, 1H), 6.53 (d, J = 8.1 Hz, 1H), 5.90 (s, 1H), 5.28 (m, 1H), 4.39 (d, J = 1.4 Hz, 1H), 4.30 (dt, J = 11.9, 3.7 Hz, 2H), 4.14 (dd, J = 11.9, 6.0 Hz, 2H), 3.37 (s, 3H), 3.10- 2.95 (m, 4H), 2.87 (m, 1H), 2.70 (dd, J = 14.8, 5.0 Hz, 1H), 2.64-2.49 (m, 4H), 2.55 (s, 3H), 2.40-2.18 (m, 9H), 2.22 (s, 3H), 2.10 (t, J = 9.8 Hz, 1H), 1.97 (m, 1H), 1.88-1.73 (m, 2H), 1.71-1.53 (m, 11H), 1.35 (s, 3H), 1.44-1.19 (m, 49H), 1.13 (d, J = 6.3 Hz, 3H), 1.05 (m, 1H), 1.02 (s, 9H), 0.87 (t, J = 6.8 Hz, 6H), 0.79 (m, 1H),





0.66 (m, 1H), 0.53-0.42 (m, 2H),




0.15-0.07 (m, 2H); 13C NMR (101




MHz, CDCl3) δ 173.4 (2C; C), 171.4




(C), 171.3 (C), 169.4 (C), 150.0 (C),




149.5 (C), 138.2 (C), 136.4 (C), 134.4




(C), 133.7 (C), 133.5 (C), 132.6 (CH),




131.3 (C), 123.1 (CH), 122.3 (CH),




119.3 (CH), 98.1 (CH), 80.8 (C), 79.4




(C), 69.3 (CH), 62.2 (2C; CH2), 59.6




(CH2), 58.3 (CH), 52.7 (CH3), 47.3




(CH2), 46.3 (C), 44.3 (CH), 43.7 (CH2),




41.3 (CH2), 40.7 (CH2), 40.5 (C), 39.0




(C), 36.1 (C), 35.5 (CH2), 34.1 (2C;




CH2), 33.5 (CH2), 32.1 (2C; CH2), 31.4




(CH3), 31.33/31.31 (CH3), 29.9 (CH2),




29.83 (6C; CH2), 29.79 (4C; CH2),




29.75 (2C; CH2), 29.6 (2C; CH2), 29.5




(2C; CH2), 29.4 (2C; CH2), 29.2 (2C;




CH2), 27.3 (CH), 26.5 (3C; CH3), 25.5




(CH3), 25.0 (2C; CH2), 23.4 (CH2),




22.8 (2C; CH2), 20.4 (CH3), 20.1




(CH3), 19.9 (CH3), 17.7 (CH2), 14.3




(2C; CH3), 9.6 (CH), 4.3 (CH2), 3.4




(CH2).





I-16


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1H NMR (401 MHz, CDCl3) δ 6.78 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 5.89 (s, 1H), 5.27 (m, 1H), 4.42 (d, J = 1.7 Hz, 1H), 4.299/4.296 (each dd, J = 11.9, 4.3 Hz, 2H), 4.20-4.09 (m, 4H), 3.45 (s, 3H), 3.06-2.98 (m, 2H), 2.88 (m, 1H), 2.67-2.58 (m, 3H), 2.52-2.20 (m, 13H), 2.19-1.78 (m, 6H), 1.70 (dd, J = 13.2, 5.5 Hz, 1H), 1.66-1.49 (m, 4H), 1.35 (s, 3H), 1.38-1.17 (m, 49H), 1.04 (m, 1H), 1.03 (s, 9H), 1.02 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H), 0.80 (m, 1H), 0.68 (m, 1H), 0.54-0.43 (m, 2H), 0.16-0.08 (m, 2H).






I-17


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1H NMR (401 MHz, CDCl3) δ 6.88 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 5.86 (s, 1H), 5.82 (s, 2H), 5.27 (m, 1H), 4.46 (s, 1H), 4.30 (dd, J = 12.0, 4.3 Hz, 2H), 4.15 (dd, J = 12.0, 5.9 Hz, 2H), 3.49 (s, 3H), 3.06-2.98 (m, 2H), 2.89 (m, 1H), 2.73-2.60 (m, 5H), 2.39-2.22 (m, 8H), 2.12 (t, J = 9.2 Hz, 1H), 2.01 (m, 1H), 1.93-1.80 (m, 2H), 1.75-1.49 (m, 5H), 1.35 (s, 3H), 1.34-1.20 (m, 49H), 1.05 (m, 1H), 1.03 (s, 9H), 0.88 (t, J = 6.9 Hz, 6H), 0.80 (m, 1H), 0.66 (m, 1H), 0.56- 0.44 (m, 2H), 0.16-0.09 (m, 2H); ESI-HRMS: Calcd. for C70H114NO14 [M + H+] 1192.8234; found 1192.8244.






I-18


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1H NMR (401 MHz, CDCl3) δ 6.87 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 5.89 (s, 1H), 5.81 (ddd, J = 8.5, 5.6, 2.5 Hz, 2H), 5.27 (m, 1H), 4.46 (s, 1H), 4.285/4.283 (each dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.8, 5.9 Hz, 2H), 3.48 (s, 3H), 3.07-2.97 (m, 2H), 2.89 (m, 1H), 2.63 (dd, J = 11.9, 4.8 Hz, 1H), 2.47 (m, 1H), 2.41-2.22 (m, 9H), 2.16-2.06 (m, 2H), 2.03- 1.77 (m, 4H), 1.75-1.50 (m, 7H), 1.48-1.20 (m, 61H), 1.35 (s, 3H), 1.172/1.167 (each d, J = 7.0 Hz, 3H), 1.05 (m, 1H), 1.03 (s, 9H), 0.92 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.9 Hz, 6H), 0.80 (m, 1H), 0.67 (m, 1H), 0.54- 0.43 (m, 2H), 0.15-0.08 (m, 2H).






I-19


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1H NMR (401 MHz, CDCl3) δ 6.88/6.87 (each d, J = 8.2 Hz, 1H), 6.77 (m, 1H), 6.59 (d, J = 8.2 Hz, 1H), 5.89/5.88 (each s, 1H), 5.25 (m, 1H), 4.46 (br s, 1H), 4.33-4.26 (m, 2H), 4.19-4.11 (m, 2H), 3.49/3.48 (each s, 3H), 3.06-2.98 (m, 2H), 2.89 (m, 1H), 2.74-2.57 (m, 5H), 2.38-2.20 (m, 8H), 2.12 (t, J = 10.0 Hz, 1H), 1.98 (td, J = 12.5, 5.5 Hz, 1H), 1.91-1.77 (m, 2H), 1.70 (dd, J = 13.4, 2.9 Hz, 1H), 1.64-1.52 (m, 7H), 1.35 (s, 3H), 1.33-1.18 (m, 49H), 1.06 (m, 1H), 1.03 (s, 5H), 0.88 (t, J = 6.9 Hz, 6H), 0.81 (m, 1H), 0.66 (m, 1H), 0.55- 0.43 (m, 2H), 0.15-0.07 (m, 2H); ESI-HRMS: Calcd. for C71H116NO14 [M + H+] 1206.8390; found 1206.8401.










Example 8: Synthesis of BODIPY and Cy5 Lipid Prodrugs



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DMAP (2.9 mg, 24.1 μmol) and EDC.HCl (11.5 mg, 60.2 μmol) were added to a solution of 1,3-diglyceride Int-2 (13.7 mg, 24.1 μmol) and BODIPY-558 acid (10.0 mg, 28.9 μmol) in CH2Cl2 (1 mL) and the mixture stirred at rt for 18 hours. The reaction was concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (7.5% to 9% ethyl acetate/hexanes) gave BODIPY-TG I-11 (8.0 mg, 37%) as a purple solid. 1H NMR (401 MHz, CDCl3) δ 8.16 (dd, J=3.9, 1.0 Hz, 1H), 7.50 (dd, J=5.1, 1.0 Hz, 1H), 7.18 (dd, J=5.0, 3.9 Hz, 1H), 7.12 (s, 1H), 7.04 (d, J=4.4 Hz, 1H), 6.97 (d, J=4.1 Hz, 1H), 6.80 (d, J=4.2 Hz, 1H), 6.38 (d, J=4.1 Hz, 1H), 5.28 (m, 1H), 4.29 (dd, J=11.9, 4.3 Hz, 2H), 4.14 (dd, J=12.1, 5.8 Hz, 2H), 3.37 (t, J=7.4 Hz, 2H), 2.82 (t, J=7.4 Hz, 2H), 2.29 (t, J=7.6 Hz, 4H), 1.65-1.52 (m, 4H), 1.37-1.19 (m, 48H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.5 (C), 171.7 (C), 131.5 (CH), 130.8 (CH), 129.7 (CH), 129.2 (CH), 126.8 (CH), 120.6 (CH), 118.8 (CH), 114.2 (CH), 69.6 (CH), 62.2 (2C; CH2), 34.2 (2C; CH2), 33.2 (CH2), 32.1 (2C; CH2), 29.85 (2C; CH2), 29.81 (2C; CH2), 29.77 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 25.0 (2C; CH2), 24.1 (CH2), 22.8 (2C; CH2), 14.3 (2C; CH3). Note: All five aromatic quaternary carbon signals were too weak to be observed, while several of the aromatic CH signals were also relatively weak.




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DMAP, 2.2 mg, 18.0 μmol) and EDC.HCl (8.6 mg, 44.9 μmol) were added to a solution of 1,3-diglyceride Int-2 (10.2 mg, 18.0 μmol) and cyanine-5 acid 1 (9.8 mg, 18.9 μmol) in CH2Cl2 (1 mL) and the mixture stirred at rt for two days and 21 hours. The reaction was concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (1% to 4% MeOH/CH2Cl2) gave Cy5-TG I-22 (6.5 mg, 35%) as a blue solid. 1H NMR (401 MHz, CDCl3) δ 8.19 (t, J=11.9 Hz, 2H), 7.41-7.31 (m, 4H), 7.29-7.18 (m, 2H), 7.13-7.02 (m, 2H), 6.92 (t, J=12.5 Hz, 1H), 6.40 (dd, J=13.5, 3.5 Hz, 2H), 5.23 (m, 1H), 4.30 (dd, J=11.9, 4.4 Hz, 2H), 4.17-4.02 (m, 4H), 3.71 (s, 3H), 2.38 (t, J=7.4 Hz, 2H), 2.31 (t, J=7.5 Hz, 4H), 1.78 (s, 6H), 1.74 (s, 6H), 1.88-1.49 (m, 10H), 1.39-0.98 (m, 48H), 0.91-0.84 (m, 6H).


Example 9: Synthesis of Cannabidiol Lipid Prodrugs

Lipid prodrugs of cannabidiol (CBD) were synthesized as follows.




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DMAP (2.7 mg, 22.3 μmol) and EDC.HCl (10.7 mg, 55.6 μmol) were added to a solution of triglyceride intermediate Int-4 (18.6 mg, 26.7 μmol) and cannabidiol (7.0 mg, 22.3 μmol) in CH2Cl2 (1 mL) and the mixture stirred at rt for 19 hours. The reaction was then concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (5% to 7.5% to 10% ethyl acetate/hexanes gave CBD prodrug CBD-C5bMe-2-TG (I-20) (9.9 mg, 45%); 1H NMR (401 MHz, CDCl3) δ 6.55 (s, 1H), 6.38 (dd, J=3.4, 1.7 Hz, 1H), 5.97 (br s, 1H), 5.52 (br s, 1H), 5.28 (m, 1H), 4.60 (m, 1H), 4.44 (br s, 1H), 4.36-4.27 (m, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 3.47 (m, 1H), 2.67-2.27 (m, 8H), 2.30 (t, J=7.6 Hz, 4H), 2.21 (m, 1H), 2.06 (m, 1H), 1.86-1.67 (m, 5H), 1.65-1.51 (m, 9H), 1.47-1.19 (m, 52H), 1.11 (d, J=6.5 Hz, 3H), 0.88 (t, J=6.8 Hz, 9H); 13C NMR (101 MHz, CDCl3) δ 173.43 (2C; C), 171.44/171.41 (C), 170.68/170.66 (C), 69.34 (CH), 62.20 (2C; CH2), 45.73 (CH), 40.78 (CH2), 40.64 (CH2), 40.58 (CH2), 38.14 (CH), 35.54 (CH2), 34.16 (2C; CH2), 32.07 (2C; CH2), 31.63 (CH2), 30.67 (CH2), 29.85 (6C; CH2), 29.81 (4C; CH2), 29.77 (2C; CH2), 29.63 (2C; CH2), 29.51 (2C; CH2), 29.42 (2C; CH2), 29.27 (2C; CH2), 27.42 (CH), 24.99 (2C; CH2), 23.76 (CH3), 22.84 (2C; CH2), 22.64 (CH2), 19.88/19.85 (CH3), 14.27 (2C; CH3), 14.17 (CH3). Note: i) 37% of bis-prodrug (i.e. coupling of C10-acid-TG to both phenolic hydroxyl groups of cannabidiol) was also isolated; ii) A number of the aromatic signals were not observed in the 13C NMR spectrum.


Compound CBD-FSI5-C5bMe-2-TG (I-21) was prepared as follows.




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Intermediate 2 in the scheme above was prepared as follows. DMAP (5.2 mg, 42.9 μmol) and tert-butyl(chloro)diphenylsilane (TBDPSCl, 7.4 μL, 28.6 μmol) were added to a solution of cannabidiol (1) (9.0 mg, 28.6 μmol) in CH2Cl2 (0.8 mL) and the mixture stirred at rt for 23 hours. An additional amount of TBDPS (4.9 μL, 19.1 mol) was added and the mixture stirred at rt for a further seven hours. The reaction was concentrated under a stream of N2 to give the crude product. Purification by silica gel chromatography (2% to 3% ethyl acetate/hexanes) gave mono-TBDPS ether 2 (2.6 mg, 16%) as a colorless oil; 1H NMR (401 MHz, CDCl3) δ 7.76-7.71 (m, 2H), 7.62 (d, J=6.9 Hz, 2H), 7.47-7.27 (m, 6H), 6.18 (br s, 1H), 5.90 (br s, 1H), 5.77 (d, J=1.5 Hz, 1H), 5.58 (br s, 1H), 4.67 (m, 1H), 4.57 (s, 1H), 4.23 (m, 1H), 2.57 (m, 1H), 2.31-2.10 (m, 2H), 2.07 (t, J=7.4 Hz, 2H), 1.92-1.74 (m, 2H), 1.80 (s, 3H), 1.62 (s, 3H), 1.15-0.99 (m, 4H), 1.07 (s, 9H), 0.97-0.86 (m, 2H), 0.74 (t, J=7.3 Hz, 3H).


Intermediate 3 in the scheme above was prepared as follows. DMAP (0.7 mg, 5.8 μmol) and EDC.HCl (3.3 mg, 17.4 μmol) were added to a solution of phenol 2 (3.2 mg, 5.8 μmol) and 5-bromovaleric acid (2.1 mg, 11.6 μmol) in CH2Cl2 (0.6 mL) and the mixture stirred at rt for 19 hours. The reaction was concentrated under a stream of N2 gas to give the crude product. Purification by silica gel chromatography (4% to 5% ethyl acetate/hexanes) gave bromovalerate ester 3 (3.1 mg, 76%) as a colorless oil. 1H NMR (401 MHz, CDCl3) δ 7.76-7.56 (m, 4H), 7.46-7.30 (m, 6H), 6.28 (d, J=1.5 Hz, 1H), 6.05 (s, 1H), 5.24 (m, 1H), 4.61 (s, 2H), 4.22 (m, 1H), 3.46 (t, J=6.5 Hz, 2H), 2.76 (m, 1H), 2.60-2.14 (m, 4H), 2.13-1.94 (m, 6H), 1.93-1.71 (m, 4H), 1.67 (s, 3H), 1.62 (s, 3H), 1.32-1.24 (m, 2H), 1.07 (s, 9H), 1.12-1.01 (m, 2H), 0.97-0.83 (m, 2H), 0.73 (t, J=7.3 Hz, 3H).


Intermediate 5 in the scheme above was prepared as follows. Silver carbonate (2.7 mg, 9.7 μmol) was added to a solution of acid-TG Int-4 (10.2 mg, 14.6 μmol) and bromide 3 (8.7 mg, 12.2 μmol) in toluene (1 mL) and the mixture heated at 80° C. for one hour and at reflux for a further 1.5 hours. The reaction was cooled to rt, tetra-n-butylammonium iodide (TBAI, 4.5 mg, 12.2 μmol) was added and the mixture heated at reflux for an additional hour. The reaction was re-cooled to rt, diluted with ethyl acetate (40 mL) and the organic phase washed with water and brine (40 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (5% to 12.5% ethyl acetate/hexanes) gave protected CBD prodrug 1-21 (9.8 mg, 60%) as a colourless oil. 1H NMR (401 MHz, CDCl3) δ 7.76-7.56 (m, 4H), 7.47-7.29 (m, 6H), 6.28 (d, J=1.5 Hz, 1H), 6.05 (s, 1H), 5.27 (m, 1H), 4.61 (br s, 1H), 4.300/4.296 (each dd, J=11.9, 4.3 Hz, 2H), 4.26-4.07 (m, 4H), 2.76 (m, 1H), 2.60-2.36 (m, 5H), 2.31 (t, J=7.5 Hz, 4H), 2.28-2.18 (m, 2H), 2.17-2.02 (m, 2H), 1.89-1.70 (m, 6H), 1.66 (s, 3H), 1.64-1.53 (m, 9H), 1.38-1.18 (m, 52H), 1.07 (s, 9H), 1.03 (d, J=6.5 Hz, 3H), 0.88 (t, J=6.9 Hz, 6H), 0.73 (t, J=7.3 Hz, 3H); ESI-HRMS: Calcd. for C83H131O11Si [M+H+] 1331.9455; found 1331.9417.


Example 10: Synthesis of Raloxifene, Rasagiline, Testosterone, Tetrahydrocannabinol (THC), and Other Lipid Prodrugs

Additional lipid prodrugs were prepared using methods similar to those described herein.









TABLE 10







Additional Lipid Prodrugs









Cmpd.




#
Structure

1H NMR; 13C NMR; MS






I-23


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1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.9 Hz, 2H), 7.59 (d, J = 2.1 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 7.08 (dd, J = 8.8, 2.2 Hz, 1H), 6.67 (d, J = 7.3 Hz, 2H), 6.61 (d, J = 8.6 Hz, 2H), 5.26 (m, 1H), 4.30 (dd, J = 11.9, 4.3 Hz, 2H), 4.15 (dd, J = 11.9, 5.9 Hz, 2H), 4.09 (t, J = 5.7 Hz, 2H), 2.77 (t, J = 5.8 Hz, 2H), 2.62-2.50 (m, 6H), 2.37-2.27 (m, 6H), 1.82- 1.73 (m, 2H), 1.69-1.55 (m, 10H),





1.50-1.19 (m, 58H), 0.87 (t, J =




6.8 Hz, 6H); ESI-HRMS: calcd. for




C73H110NO11S [M + H+] 1208.7794;




found 1208.7815.





I-24


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1H NMR (400 MHz, CDCl3) δ 7.76- 7.71 (m, 2H), 7.49 (d, J = 8.8 Hz, 1H), 7.42-7.38 (m, 2H), 7.28 (d, J = 2.1 Hz, 1H), 6.97-6.93 (m, 2H), 6.87 (dd, J = 8.8, 2.3 Hz, 1H), 6.77- 6.71 (m, 2H), 5.25 (m, 1H), 4.29 (dd, J = 11.9, 4.4 Hz, 2H), 4.27- 4.19 (m, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 2.97 (br s, 2H), 2.72 (br s, 4H), 2.51 (t, J = 7.5 Hz, 2H), 2.32 (t,





J = 7.5 Hz, 2H), 2.31 (t, J = 7.6 Hz,




4H), 1.84-1.49 (m, 10H), 1.42-




1.19 (m, 58H), 0.88 (t, J = 6.9 Hz,




6H).





I-25


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1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.9 Hz, 2H), 7.60 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 8.6 Hz, 2H), 7.09 (dd, J = 8.8, 2.2 Hz, 1H), 6.65 (d, J = 8.9 Hz, 2H), 6.61 (d, J = 8.6 Hz, 2H), 5.31 (m, 1H), 4.331/4.328 (each dd, J = 11.9, 4.2 Hz, 2H), 4.16 (dd, J = 12.1, 5.7 Hz, 3H), 4.13 (t, J = 5.5 Hz, 2H), 2.83 (t, J = 5.2 Hz, 2H), 2.71 (dd, J = 14.8, 5.5 Hz, 1H), 2.67- 2.48 (m, 7H), 2.39 (dd, J = 15.3,





7.2 Hz, 1H), 2.310/2.308 (each t,




J = 7.8 Hz, 4H), 1.71-1.64 (m, 4H),




1.63-1.55 (m, 4H), 1.53-1.43 (m,




2H), 1.37-1.19 (m, 48H), 1.16 (d,




J = 6.5 Hz, 3H), 0.87 (t, J = 6.8 Hz,




6H); 13C NMR (101 MHz, CDCl3) δ




192.8 (C), 173.5 (2C; C), 171.4 (C),




171.0 (C), 162.0 (C), 157.5 (C),




148.0 (C), 139.1 (C), 137.8 (C),




132.5 (2C; CH), 131.0 (2C; CH),




130.2 (C), 125.1 (C), 124.4 (CH),




119.7 (CH), 116.1 (2C; CH), 114.7




(CH), 114.4 (2C; CH), 69.4 (CH),




65.2 (CH2), 62.2 (2C; CH2), 57.2




(CH2), 55.0 (2C; CH2), 40.8 (2C;




CH2), 34.2 (2C; CH2), 32.1 (2C;




CH2), 29.84 (6C; CH2), 29.80 (4C;




CH2), 29.76 (2C; CH2), 29.6 (2C;




CH2), 29.5 (2C; CH2), 29.4 (2C;




CH2), 29.3 (2C; CH2), 27.6 (CH),




25.0 (2C; CH2), 24.7 (CH2), 23.3




(CH2), 22.8 (2C; CH2), 19.9 (CH3),




14.3 (2C; CH3); ESI-HRMS: calcd.




for C69H102NO11S [M + H+]




1152.7168; found 1152.7186.





I-26


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1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.9 Hz, 2H), 7.65 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 1.9 Hz, 1H), 7.46-7.40 (m, 2H), 7.08 (dd, J = 8.8, 2.2 Hz, 1H), 7.01-6.96 (m, 2H), 6.77 (d, J = 8.9 Hz, 2H), 5.30 (m, 1H), 4.331/4.327 (each dd, J = 11.9, 4.2 Hz, 2H), 4.18-4.13 (m, 4H), 2.88-2.77 (m, 2H), 2.71 (dd, J = 14.8, 5.5 Hz, 1H), 2.66-2.48 (m, 7H), 2.39 (dd, J = 15.3, 7.1 Hz, 1H), 2.309/2,307 (each t, J = 7.8





Hz, 4H), 2.26 (s, 3H), 1.70-1.54




(m, 8H), 1.51-1.41 (m, 2H), 1.34-




1.19 (m, 48H), 1.16 (d, J = 6.5 Hz,




3H), 0.87 (t, J = 6.8 Hz, 6H); 13C




NMR (101 MHz, CDCl3) δ 192.6




(C), 173.4 (2C; C), 171.4 (C), 170.9




(C), 169.1 (C), 163.2 (C), 151.1 (C),




148.3 (C), 144.4 (C), 139.5 (C),




137.7 (C), 132.5 (2C; CH), 131.8




(C), 130.9 (C), 130.4 (C), 130.3




(2C; CH), 124.4 (CH), 122.0 (2C;




CH), 119.8 (CH), 114.8 (CH), 114.5




(2C; CH), 69.5 (CH), 66.0 (CH2),




62.2 (2C; CH2), 57.6 (CH2), 55.1




(2C; CH2), 40.7 (2C; CH2), 34.2




(2C; CH2), 32.1 (2C; CH2), 29.84




(6C; CH2), 29.80 (4C; CH2), 29.76




(2C; CH2), 29.6 (2C; CH2), 29.5




(2C; CH2), 29.4 (2C; CH2), 29.3




(2C; CH2), 27.6 (CH), 25.6 (2C;




CH2), 25.0 (2C; CH2), 24.0 (CH2),




22.8 (2C; CH2), 21.3 (CH3), 19.9




(CH3), 14.3 (2C; CH3); ESI-HRMS:




calcd. for C71H104NO12S [M + H+]




1194.7274; found 1194.7285.





I-27


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1H NMR (401 MHz, CDCl3) δ 7.77- 7.71 (m, 2H), 7.68-7.61 (m, 2H), 7.46-7.41 (m, 2H), 7.08 (dd, J = 8.8, 2.2 Hz, 1H), 7.00-6.94 (m, 2H), 6.81-6.74 (m, 2H), 5.30 (m, 1H), 4.332/4.329 (each dd, J = 11.9, 4.2 Hz, 2H), 4.24-4.11 (m, 4H), 2.89-2.68 (m, 5H), 2.66- 2.48 (m, 6H), 2.39 (dd, J = 15.3, 7.1 Hz, 1H), 2.311/2.307 (each t, J = 7.7 Hz, 4H), 1.73-1.41 (m, 10H), 1.36-1.20 (m, 48H), 1.28 (d, J =





7.0 Hz, 6H), 1.16 (d, J = 6.5 Hz,




3H), 0.87 (t, J = 6.9 Hz, 6H); 13C




NMR (101 MHz, CDCl3) δ 192.7




(C), 175.3 (C), 173.4 (2C; C), 171.4




(C), 170.9 (C), 151.4 (C), 148.3 (C),




139.5 (C), 137.7 (C), 132.5 (2C;




CH), 131.7 (C), 130.7 (C), 130.3




(2C; CH), 124.4 (CH), 122.0 (2C;




CH), 119.8 (CH), 114.8 (CH), 114.5




(2C; CH), 69.5 (CH), 62.2 (2C;




CH2), 40.8 (2C; CH2), 34.3 (CH),




34.2 (2C; CH2), 32.1 (2C; CH2),




29.85 (6C; CH2), 29.81 (4C; CH2),




29.77 (2C; CH2), 29.6 (2C; CH2),




29.5 (2C; CH2), 29.4 (2C; CH2),




29.3 (2C; CH2), 27.6 (CH), 25.0




(2C; CH2), 22.8 (2C; CH2), 19.9




(CH3), 19.0 (2C; CH3), 14.3 (2C;




CH3). Note: Some signals were not




observed in the 13C NMR spectrum.





I-28


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1H NMR (401 MHz, CDCl3) δ 7.77- 7.71 (m, 2H), 7.63 (d, J = 8.9 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.38- 7.33 (m, 2H), 7.06 (dd, J = 8.8, 2.2 Hz, 1H), 6.79-6.74 (m, 4H), 5.30 (m, 1H), 4.330/4.227 (each dd, J = 11.9, 4.2 Hz, 2H), 4.19-4.10 (m, 4H), 3.76 (s, 3H), 2.84-2.76 (m, 2H), 2.71 (dd, J = 14.8, 5.5 Hz, 1H), 2.66-2.48 (m, 6H), 2.38 (dd, J = 15.3, 7.1 Hz, 1H), 2.310/2.306 (each t, J = 7.6 Hz, 4H), 1.76-1.54





(m, 9H), 1.51-1.42 (m, 2H), 1.35-




1.18 (m, 48H), 1.16 (d, J = 6.5 Hz,




3H), 0.87 (t, J = 6.9 Hz, 6H); 13C




NMR (101 MHz, CDCl3) δ 193.0




(C), 173.5 (2C; C), 171.4 (C), 171.0




(C), 160.2 (C), 148.0 (C), 145.6 (C),




139.2 (C), 137.9 (C), 132.5 (2C; C),




130.54 (2C; C), 130.48 (C), 125.8




(C), 124.1 (CH), 119.6 (CH), 114.8




(CH), 114.4 (2C; CH), 114.3 (2C;




CH), 69.4 (CH), 66.0* (CH2), 62.2




(2C; CH2), 57.7 (CH2), 55.4 (CH3),




55.1 (CH2), 40.7 (2C; CH2), 34.2




(2C; CH2), 32.1 (2C; CH2), 29.85




(6C; CH2), 29.81 (4C; CH2), 29.77




(2C; CH2), 29.6 (2C; CH2), 29.5




(2C; CH2), 29.4 (2C; CH2), 29.3




(2C; CH2), 27.6 (CH), 25.7* (2C;




CH2), 25.0 (2C; CH2), 24.0* (CH2),




22.8 (2C; CH2), 19.9 (CH3), 14.3




(2C; CH3). Note: Two signals were




missing from the 13C NMR




spectrum, possibly the quaternary




signals of the thiophene ring, while




the signals marked with an asterisk




(*) were very weak/broad and their




presence was supported by cross-




peaks in the HSQC spectrum.





I-29


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1H NMR (401 MHz, CDCl3) δ 7.75 (d, J = 8.9 Hz, 2H), 7.51 (d, J = 8.9 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 2.3 Hz, 1H), 7.00-6.93 (m, 3H), 6.77 (d, J = 9.0 Hz, 2H), 5.27 (m, 1H), 4.29 (dd, J = 11.9, 4.2 Hz, 2H), 4.18-4.09 (m, 4H), 3.89 (s, 3H), 2.84-2.75 (m, 2H), 2.62- 2.47 (m, 6H), 2.33 (dd, J = 14.7, 5.8 Hz, 1H), 2.30 (t, J = 7.5 Hz, 4H),





2.12 (dd, J = 14.7, 8.3 Hz, 1H), 1.94




(m, 1H), 1.75-1.56 (m, 9H), 1.50-




1.16 (m, 59H), 0.93 (d, J = 6.6 Hz,




3H), 0.87 (t, J = 6.9 Hz, 6H); 13C




NMR (101 MHz, CDCl3) δ 193.1




(C), 173.4 (2C; C), 172.4 (C), 172.0




(C), 158.0 (C), 150.9 (C),




140.5 (C), 134.0 (C), 132.5 (2C;




CH), 131.8 (C), 131.2 (C), 130.5




(C), 130.2 (2C; CH), 124.4 (CH),




121.9 (2C; CH), 115.2 (CH), 114.4




(2C; CH), 104.6 (CH), 69.0 (CH),




65.9* (CH2), 62.3 (2C; CH2), 57.6




(CH2), 55.8 (CH2), 55.1 (2C; CH2),




41.8 (CH2), 36.8 (CH2), 34.5 (CH2),




34.2 (2C; CH2), 32.1 (2C; CH2),




30.5 (CH), 29.85 (6C; CH2), 29.81




(4C; CH2), 29.77 (2C; CH2), 29.62




(2C; CH2), 29.55 (CH2), 29.51 (2C;




CH2), 29.42 (2C; CH2), 29.27 (2C;




CH2), 29.23 (CH2), 26.9 (CH2),




25.6* (2C; CH2), 25.00 (2C; CH2),




24.97 (CH2), 23.9* (CH2), 22.8 (2C;




CH2), 19.7 (CH3), 14.3 (2C; CH3).




Note: One signals was missing from




the 13C NMR spectrum, possibly




one of the quaternary signals from




the thiophene ring, while the signals




marked with an asterisk (*) were




very weak/broad and their presence




was supported by cross-peaks in




the HSQC spectrum.





I-30


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1H NMR (400 MHz, CDCl3) δ 7.14 (m, 4H), 6.31 (m, 1H), 5.6 (m, 2H), 5.4 (m, 2H) 4.30 (m. 4H), 4.2 (m, 4H), 3.91 (m, 1H), 3.70 (m, 1H), 3.4 (m, 1H), 3.08 (m, 2H), 2.56 (m, 4H), 2.36 (m, 10H), 1.74 (m, 3H), 1.64 (m, 6H), 1.37 (m, 44H), 0.93 (t, 6H); 13C NMR (101 MHz, CDCl3) δ 173.9 (1C, C═O), 173.3 (2C, C═O), 172.9





(1C, C═O), 144.2-143.3 (2C),




141.03-140.229 (2C), 128.45-128.0




(2C), 126.99-126.72 (2C), 125.33-




125.05 (2C), 124.34-123.92 (2C),




81.13-80.60 (2C), 71.78 (1C), 69.85




(1C), 68.88 (2C), 63.29 (1C), 62.10




(2C), 59.36 (1C), 34.04-33.86 (4C),




33.20 (2C), 31.96-31.63 (2C),




30.64-30.08 (2C), 29.73-29.04 (13),




25.40-25.18 (2C), 24.8 (2C), 22.74




(2C), 14.18 (2C). HPLC (ELSD):




14.67 min, 100% purity; HPLC




(Chiral): 6.71 min, 100% purity; MS




(ESI, +ve) m/z: 907.5 (MH+ + 1).





I-31


embedded image



1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.3 Hz, 1H), 7.31-7.16 (m, 3H), 7.11-7.07 (m, 1H), 6.99- 6.88 (m, 2H), 6.85-6.77 (m, 1H), 5.54-5.46 (m, 0.6H), 5.33-5.22 (m, 1.4H), 4.43-4.24 (m, 2H), 4.18 (br s, 1H), 4.15-4.09 (m, 2H), 2.72- 2.66 (m, 3H), 2.55-2.36 (m, 3H), 2.34-2.20 (m, 7H), 2.06-1.97 (m, 1H), 1.84-1.70 (m, 2H), 1.64- 1.49 (m, 7H), 1.37-1.16 (m, 48H),





1.07/1.02 (each d, J = 6.4 Hz, 3H),




0.87 (t, J = 6.9 Hz, 6H); Note:




Fractional integrations, doubled




signals and the lack of well-defined




signals were observed due to the




presence of diastereomers and/or




rotational isomers. 13C NMR (101




MHz, CDCl3) δ 173.4 (C), 69.2




(CH), 62.2 (2C; CH2), 34.1 (2C;




CH2), 32.1 (2C; CH2), 29.84 (6C;




CH2), 29.80 (4C; CH2), 29.76 (2C;




CH2), 29.6 (2C; CH2), 29.5 (2C;




CH2), 29.4 (2C; CH2), 29.3 (2C;




CH2), 25.0 (2C; CH2), 22.8 (2C;




CH2), 14.3 (2C; CH2). Note: Only




the signals for the glyceride portion




are listed—multiple signals are




observed in almost all other cases.





I-32


embedded image



1H NMR (400 MHz, CDCl3): δ 5.72 (s, 1H), 5.26 (m, 1H), 4.61 (dd, J = 9.0, 7.9 Hz, 1H), 4.291/4.288 (each dd, J = 11.9, 4.3, 1.3 Hz, 2H), 4.15 (dd, J = 12.1, 6.0 Hz, 2H), 2.68- 2.58 (m, 4H), 2.47-2.24 (m, 4H), 2.31 (t, J = 7.6 Hz, 4H), 2.17 (m, 1H), 2.02 (m, 1H), 1.84 (m, 1H), 1.78 (m, 1H), 1.73-1.44 (m, 9H), 1.42-1.13 (m, 51H), 1.18 (s, 3H), 1.12-0.91 (m, 3H), 0.87 (t, J = 6.9





Hz, 6H), 0.83 (s, 3H); 13C NMR




(100 MHz, CDCl3): δ 199.6 (C),




173.5 (2C; C), 172.1 (C), 171.6 (C),




171.1 (C), 124.1 (CH), 83.0 (CH),




69.6 (CH), 62.0 (2C; CH2), 53.8




(CH), 50.3 (CH), 42.7 (C), 38.7 (C),




36.7 (CH2), 35.8 (CH2), 35.5 (CH),




34.14 (2C; CH2), 34.05 (CH2), 32.9




(CH2), 32.1 (2C; CH2), 31.6 (CH2),




29.84 (6C; CH2), 29.80 (4C; CH2),




29.77 (2C; CH2), 29.6 (2C; CH2),




29.5 (2C; CH2), 29.42 (2C; CH2),




29.26 (2C; CH2), 29.25 (CH2), 29.22




(CH2), 27.6 (CH2), 25.0 (2C; CH2),




23.6 (CH2), 22.8 (2C; CH2), 20.6




(CH2), 17.5 (CH3), 14.3 (2C; CH3),




12.2 (CH3); ESI-HRMS: calcd. for




C59H101O9 [M + H+] 953.7440; found




953.7452.





I-33


embedded image



1H NMR (401 MHz, CDCl3) δ 5.73 (s, 1H), 5.25 (m, 1H), 4.61 (dd, J = 8.1, 8.1 Hz, 1H), 4.29 (dd, J = 11.9, 4.4 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 2.47-2.14 (m, 12H), 2.09 (dd, J = 14.5, 8.2 Hz, 1H), 2.02 (ddd, J = 13.1, 4.7, 3.2 Hz, 1H), 1.92 (m, 1H), 1.85 (m, 1H), 1.78 (m, 1H), 1.74-1.46 (m, 11H), 1.44- 1.21 (m, 58H), 1.19 (s, 3H), 1.18-





0.96 (m, 4H), 0.93 (d, J = 6.6 Hz,




3H), 0.88 (t, J = 6.9 Hz, 6H), 0.83




(s, 3H); 13C NMR (101 MHz,




CDCl3) δ 199.5 (C), 173.42 (2C; C),




173.39/173.37 (C), 172.9 (C), 171.0




(C), 124.1 (CH), 82.3 (CH), 69.1




(CH), 62.2 (2C; CH2), 53.9 (CH),




50.4 (CH), 42.6 (C), 42.23/42.22




(CH2), 38.8 (C), 36.84 (CH2), 36.81




(CH2), 35.9 (CH2), 35.6 (CH), 34.3




(CH2), 34.2 (2C; CH2), 34.1 (CH2),




32.9 (CH2), 32.1 (2C; CH2), 31.6




(CH2), 30.59/30.55 (CH), 29.84 (6C;




CH2), 29.80 (4C; CH2), 29.77 (2C;




CH2), 29.62 (2C; CH2), 29.59 (CH2),




29.5 (2C; CH2), 29.4 (2C; CH2),




29.3 (2C; CH2), 29.2 (CH2),




27.68/27.65 (CH2), 26.9 (CH2),




25.01 (2C; CH2), 24.99 (CH2), 23.7




(CH2), 22.8 (2C; CH2), 20.7 (CH2),




19.85/19.83 (CH3), 17.6 (CH3), 14.3




(2C; CH3), 12.2 (CH3).





I-34


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1H NMR (401 MHz, CDCl3) δ 5.73 (s, 1H), 5.27 (m, 1H), 4.61 (m, 1H), 4.289/4.287 (each dd, J = 11.7, 4.2 Hz, 2H), 4.14 (d, J = 11.9, 6/0 Hz, 2H), 2.47-2.24 (m, 10H), 2.23- 2.08 (m, 2H), 2.02 (m, 1H), 1.93 (m, 1H), 1.86 (m, 1H), 1.80-1.76 (m, 1H), 1.72-1.46 (m, 10H), 1.44- 1.22 (m, 64H), 1.19 (s, 3H), 1.139/1.132 (each d, J = 7.0 Hz,





3H), 1.11-0.95 (m, 3H), 0.93 (d, J =




6.6 Hz, 3H), 0.88 (d, J = 6.9 Hz,




6H), 0.84 (s, 3H); 13C NMR (101




MHz, CDCl3) δ 199.6 (C), 176.9 (C),




173.4 (2C; C), 172.5 (C), 171.0 (C),




124.1 (CH), 82.1 (CH), 69.0 (CH),




62.3 (2C; CH2), 53.9 (CH), 50.5




(CH), 42.7 (C), 41.9 (CH2),




39.93/39.88 (CH), 38.8 (C), 36.9




(CH2), 36.8 (CH2), 35.9 (CH2), 35.6




(CH), 34.2 (2C; CH2), 34.1 (CH2),




34.00/33.96 (CH2), 32.9 (CH2), 32.1




(2C; CH2), 31.7 (CH2), 30.5 (CH),




29.92 (CH2), 29.85 (2C; CH2), 29.81




(2C; CH2), 29.78 (2C; CH2), 29.70




(CH2), 29.69 (CH2), 29.6 (2C; CH2),




29.5 (2C; CH2), 29.4 (2C; CH2),




29.3 (2C; CH2), 27.68/27.66 (CH2),




27.4 (CH2), 27.1 (CH2), 25.1 (2C;




CH2), 23.7 (CH2), 22.8 (2C; CH2),




20.7 (CH2), 19.7 (CH3), 17.6 (CH3),




17.42/17.26 (CH3), 14.3 (2C; CH3),




12.23/12.21 (CH3).





I-35


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1H NMR (401 MHz, CDCl3) δ 5.73 (s, 1H), 5.27 (m, 1H), 4.61/4.60 (each dd, J = 9.1, 7.8 Hz, 1H), 4.28 (dd, J = 11.9, 3.8 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 2.47-2.24 (m, 10H), 2.18 (m, 1H), 2.11 (dd, J = 14.7, 8.3 Hz, 1H), 2.02 (m, 1H), 1.93 (m, 1H), 1.85 (m, 1H), 1.77 (m, 1H), 1.73-1.54 (m, 9H), 1.52- 1.21 (m, 71H), 1.19 (s, 3H),





1.133/1.126 (each d, J = 7.0 Hz,




3H), 1.11-0.94 (m, 3H), 0.92 (d,




J = 6.6 Hz, 3H), 0.87 (t, J = 6.9 Hz,




6H), 0.84 (s, 3H); 13C NMR (101




MHz, CDCl3) δ 199.6 (C), 177.0 (C),




173.4 (2C; C), 172.5 (C), 171.1 (C),




124.1 (CH), 82.10/82.08 (CH), 69.0




(CH), 62.3 (2C; CH2), 53.9 (CH),




50.4 (CH), 42.7 (C), 41.8 (CH2),




39.90/39.87 (CH), 38.7 (C), 36.84




(CH2), 36.79 (CH2), 35.8 (CH2),




35.6 (CH), 34.2 (2C; CH2), 34.1




(CH2), 34.01/33.97 (CH2), 32.9




(CH2), 32.1 (2C; CH2), 31.6 (CH2),




30.5 (CH), 30.0 (CH2), 29.83 (6C;




CH2), 29.80 (4C; CH2), 29.76 (3C;




CH2), 29.68 (2C; CH2), 29.6 (2C;




CH2), 29.5 (3C; CH2), 29.4 (2C;




CH2), 29.3 (3C; CH2), 27.7 (CH2),




27.6 (CH2), 27.4 (CH2), 27.1 (CH2),




25.0 (2C; CH2), 23.6 (CH2), 22.8




(2C; CH2), 20.7 (CH2), 19.7 (CH3),




17.5 (CH3), 17.4/17.3 (CH3), 14.3




(2C; CH3), 12.20/12.18 (CH3).





I-36


embedded image



1H NMR (401 MHz, CDCl3) δ 5.74 (d, J = 8.6 Hz, 1H), 5.73 (s, 1H), 4.60 (dd, J = 8.9, 8.1 Hz, 1H), 4.46 (m, 1H), 4.22 (dd, J = 11.4, 5.4 Hz, 2H), 4.07 (dd, J = 11.4, 5.3 Hz, 2H), 2.47-2.23 (m, 10H), 2.22-2.12 (m, 3H), 2.02 (m, 1H), 1.85 (m, 1H), 1.77 (m, 1H), 1.73-1.45 (m, 13H), 1.43-1.21 (m, 58H), 1.19 (s, 3H), 1.16-0.90 (m, 4H), 0.88 (t, J = 6.8





Hz, 6H), 0.83 (s, 3H); 13C NMR




(101 MHz, CDCl3) δ 199.6 (C),




174.0 (C), 173.9 (2C; C), 173.0 (C),




171.1 (C), 124.1 (CH), 82.3 (CH),




62.8 (2C; CH2), 53.9 (CH), 50.4




(CH), 47.6 (CH), 42.7 (C), 38.8 (C),




36.84 (CH2), 36.80 (CH2), 35.9




(CH2), 35.6 (CH), 34.7 (CH2), 34.2




(2C; CH2), 34.1 (CH2), 32.9 (CH2),




32.1 (2C; CH2), 31.6 (CH2), 29.85




(2C; CH2), 29.81 (2C; CH2), 29.77




(2C; CH2), 29.6 (2C; CH2), 29.5




(2C; CH2), 29.4 (2C; CH2), 29.32




(2C; CH2), 29.30 (2C; CH2), 29.24




(2C; CH2), 27.7 (CH2), 25.7 (CH2),




25.2 (CH2), 25.0 (2C; CH2), 23.6




(CH2), 22.8 (2C; CH2), 20.7 (CH2),




17.5 (CH2), 14.3 (2C; CH2), 12.2




(CH2).





I-37


embedded image



1H NMR (401 MHz, CDCl3) δ 5.73 (s, 1H), 4.61 (dd, J = 9.0, 7.9 Hz, 1H), 4.18 (dd, J = 11.6, 4.9 Hz, 2H), 4.12 (dd, J = 11.4, 5.4 Hz, 2H), 3.67 (m, 1H), 3.54 (t, J = 6.6 Hz, 2H), 2.48-2.25 (m, 9H), 2.18 (m, 1H), 2.01 (m, 1H), 1.83 (m, 1H), 1.77 (m, 1H), 1.73-1.49 (m, 16H), 1.48- 1.22 (m, 58H), 1.19 (s, 3H), 1.17- 0.92 (m, 4H), 0.88 (t, J = 6.9 Hz,





6H), 0.84 (s, 3H); 13C NMR (101




Hz, CDCl3) δ 199.6 (C), 174.0 (C),




173.7 (2C; C), 171.1 (C), 124.1




(CH), 82.3 (CH), 75.3 (CH), 70.8




(CH2), 63.2 (2C; CH2), 53.9 (CH),




50.4 (CH), 42.7 (C), 38.8 (C), 36.8




(CH2), 35.9 (CH2), 35.6 (CH), 34.7




(CH2), 34.3 (2C; CH2), 34.1 (CH2),




32.9 (CH2), 32.1 (2C; CH2), 31.6




(CH2), 30.1 (CH2), 29.84 (6C; CH2),




29.80 (4C; CH2), 29.77 (2C; CH2),




29.62 (2C; CH2), 29.59 (CH2), 29.56




(CH2), 29.50 (2C; CH2), 29.43 (2C;




CH2), 29.40 (CH2), 29.29 (3C; CH2),




27.7 (CH2), 26.1 (CH2), 25.2 (CH2),




25.1 (2C; CH2), 23.6 (CH2), 22.8




(2C; CH2), 20.7 (CH2), 17.5 (CH3),




14.3 (2C; CH3), 12.2 (CH3).





I-38


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1H NMR (400 MHz, CDCl3) δ 5.73 (s, 1H), 5.33-5.22 (m, 3H), 4.30 (dd, J = 11.9, 4.4 Hz, 2H), 4.13 (dd, J = 11.9, 5.9 Hz, 2H), 3.54 (dd, J = 8.3, 8.3 Hz, 1H), 2.48-2.23 (m, 12H), 2.08-1.79 (m, 6H), 1.75- 1.50 (m, 9H), 1.49-1.21 (m, 49H), 1.19 (s, 3H), 1.17-0.83 (m, 5H), 0.88 (t, J = 6.9 Hz, 6H), 0.80 (s, 3H); 13C NMR (101 MHz, CDCl3) δ





199.6 (C), 173.4 (2C; C), 172.4 (C),




172.1 (C), 171.2 (C), 124.1 (CH),




89.6 (CH), 89.3 (CH2), 69.4 (CH),




62.1 (2C; CH2), 54.0 (CH), 50.4




(CH), 42.8 (C), 38.8 (C), 36.9 (CH2),




35.9 (CH2), 35.5 (CH), 34.2 (2C;




CH2), 34.1 (CH2), 33.4 (CH2), 33.2




(CH2), 32.9 (CH2), 32.1 (2C; CH2),




31.6 (CH2), 29.85 (6C; CH2), 29.81




(4C; CH2), 29.77 (2C; CH2), 29.6




(2C; CH2), 29.5 (2C; CH2), 29.4




(2C; CH2), 29.3 (2C; CH2), 28.3




(CH2), 25.0 (2C; CH2), 23.5 (CH2),




22.8 (2C; CH2), 20.7 (CH2), 19.9




(CH2), 17.5 (CH3), 14.3 (2C; CH3),




11.8 (CH3).





I-39


embedded image



1H NMR (400 MHz, CDCl3) δ 5.73 (s, 1H), 5.32-5.21 (m, 3H), 4.29 (dd, J = 11.9, 4.4 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 3.55 (dd, J = 8.3, 8.3 Hz, 1H), 2.48-2.23 (m, 11H), 2.11 (dd, J = 14.9, 8.2 Hz, 1H), 2.07-1.99 (m, 2H), 1.98- 1.80 (m, 3H), 1.74-1.51 (m, 11H), 1.49-1.21 (m, 57H), 1.19 (s, 3H), 1.17-0.95 (m, 5H), 0.94 (d, J = 6.6





Hz, 3H), 0.88 (t, J = 6.8 Hz, 6H),




0.80 (s, 3H); 13C NMR (101 MHz,




CDCl3) δ 199.6 (C), 173.4 (2C; C),




172.94 (C), 172.90 (C), 171.2 (C),




124.1 (CH), 89.3 (CH), 89.0 (CH2),




69.1 (CH), 62.2 (2C; CH2), 54.0




(CH), 50.5 (CH), 42.8 (C),




42.17/42.16 (CH2), 38.8 (C), 37.0




(CH2), 36.8 (CH2), 35.9 (CH2), 35.6




(CH), 34.3 (CH2), 34.2 (2C; CH2),




34.1 (CH2), 32.9 (CH2), 32.1 (2C;




CH2), 31.7 (CH2), 30.29/30.28 (CH),




29.85 (6C; CH2), 29.81 (4C; CH2),




29.77 (2C; CH2), 29.63 (2C; CH2),




29.57 (CH2), 29.5 (2C; CH2), 29.4




(2C; CH2), 29.3 (2C; CH2), 29.2




(CH2), 28.2 (CH2), 26.9 (CH2),




25.01 (2C; CH2), 24.98 (CH2), 23.5




(CH2), 22.8 (2C; CH2), 20.7 (CH2),




19.8 (CH3), 17.5 (CH3), 14.3 (2C;




CH3), 11.8 (CH3).





I-40


embedded image



1H NMR (401 MHz, CDCl3) δ 5.72 (s, 1H), 5.32-5.23 (m, 3H), 4.28 (dd, J = 11.9, 4.0 Hz, 2H), 4.14 (dd, J = 11.9, 6.0 Hz, 2H), 3.55 (dd, J = 8.3, 8.3 Hz, 1H), 2.47-2.23 (m, 10H), 2.11 (dd, J = 14.7, 8.3 Hz, 1H), 2.07-1.98 (m, 2H), 1.95- 1.87 (m, 2H), 1.83 (m, 1H), 1.71 (m, 1H), 1.66-1.51 (m, 9H), 1.49- 1.35 (m, 2H), 1.49-1.35 (m, 60H),





1.19-0.85 (m, 5H), 1.18 (s, 3H),




1.15 (d, J = 7.0 Hz, 3H), 0.92 (d, J =




6.6 Hz, 3H), 0.87 (t, J = 6.9 Hz, 6H),




0.80 (s, 3H); 13C NMR (101 MHz,




CDCl3) δ 199.6 (C), 176.5 (C),




173.4 (2C; C), 172.4 (C), 171.2 (C),




124.1 (CH), 89.27/89.23 (CH),




89.00/88.97 (CH2), 69.0 (CH), 62.3




(2C; CH2), 54.1 (CH), 50.5 (CH),




42.8 (C), 41.8 (CH2), 39.9 (CH),




38.8 (C), 37.0 (CH2), 36.8 (CH2),




35.9 (CH2), 35.6 (CH), 34.2 (2C;




CH2), 34.1 (CH2), 33.7 (CH2), 32.9




(CH2), 32.1 (2C; CH2), 31.7 (CH2),




30.5 (CH), 29.9 (CH2), 29.84 (6C;




CH2), 29.80 (4C; CH2), 29.76 (2C;




CH2), 29.69 (CH2), 29.68 (CH2),




29.6 (2C; CH2), 29.5 (2C; CH2),




29.4 (2C; CH2), 29.3 (2C; CH2),




28.27 (CH2), 28.26 (CH2), 27.4




(CH2), 27.1 (CH2), 25.0 (2C; CH2),




23.5 (CH2), 22.8 (2C; CH2), 20.7




(CH2), 19.7 (CH3), 17.5 (CH3),




17.10/17.08 (CH3), 14.3 (2C; CH3),




11.8 (CH3).





I-41


embedded image



1H NMR (401 MHz, CDCl3) δ 5.72 (s, 1H), 5.31-5.22 (m, 3H), 4.28 (dd, J = 11.9, 4.2 Hz, 2H), 4.14 (dd, J = 11.9, 6.0 Hz, 2H), 3.55 (dd, J = 8.3, 8.3 Hz, 1H), 2.47-2.23 (m, 10H), 2.11 (dd, J = 14.7, 8.3 Hz, 1H), 2.07-1.98 (m, 2H), 1.96- 1.78 (m, 3H), 1.73-1.52 (m, 11H), 1.18 (s, 3H), 1.49-1.06 (m, 68H), 1.15 (d, J = 7.0 Hz, 3H), 1.13-0.94





(m, 4H), 0.92 (d, J = 6.6 Hz, 3H),




0.87 (t, J = 6.8 Hz, 6H), 0.80 (s,




3H); 13C NMR (101 MHz, CDCl3) δ




199.6 (C), 176.5 (C), 173.4 (2C; C),




172.4 (C), 171.2 (C), 124.0 (CH),




89.18/89.16 (CH2), 88.94/88.92




(CH), 68.9 (CH), 62.3 (2C; CH2),




54.0 (CH), 50.4 (CH), 42.7 (C), 41.8




(CH2), 39.86/39.84 (CH), 38.8 (C),




36.9 (CH2), 36.8 (CH2), 35.9 (CH2),




35.5 (CH), 34.2 (2C; CH2), 34.1




(CH2), 33.7 (CH2), 32.9 (CH2), 32.0




(2C; CH2), 31.6 (CH2), 30.5 (CH),




30.0 (CH2), 29.82 (6C; CH2), 29.78




(4C; CH2), 29.74 (3C; CH2), 29.70




(CH2), 29.69 (CH2), 29.60 (2C;




CH2), 29.48 (3C; CH2), 29.39 (2C;




CH2), 29.24 (3C; CH2), 28.22/28.21




(CH2), 27.4 (CH2), 27.1 (CH2), 25.0




(2C; CH2), 23.4 (CH2), 22.8 (2C;




CH2), 20.7 (CH2), 19.7 (CH3), 17.5




(CH3), 17.09/17.06 (CH3), 14.2 (2C;




CH3), 11.7 (CH3).





I-42


embedded image



1H NMR (401 MHz, CDCl3) δ 5.75 (s, 2H), 5.73 (s, 1H), 5.26 (m, 1H), 4.54 (dd, J = 9.0, 7.8 Hz, 1H), 4.301/4.296 (each dd, J = 11.9, 4.3 Hz, 2H), 4.13 (dd, J = 11.9, 6.0 Hz, 2H), 2.52-2.16 (m, 14H), 2.02 (ddd, J = 13.3, 4.8, 3.2 Hz, 1H), 1.90-1.80 (m, 2H), 1.75-1.55 (m, 9H), 1.47-1.17 (m, 51H), 1.19 (s, 3H), 1.04 (d, J = 6.4 Hz, 3H), 1.11-





0.90 (m, 3H), 0.88 (t, J = 6.7 Hz,




6H), 0.86 (s, 3H); 13C NMR (101




MHz, CDCl3) δ 199.6 (C), 173.4




(2C; C), 171.4 (C), 170.87 (C),




170.85 (C), 154.0 (C), 124.2 (CH),




87.1 (CH), 81.9 (CH2), 69.3 (CH),




62.2 (2C; CH2), 53.8 (CH), 50.2




(CH), 42.7 (C), 40.6 (CH2), 40.3




(CH2), 38.7 (C), 36.6 (CH2), 35.9




(CH2), 35.5 (CH), 34.2 (2C; CH2),




34.1 (CH2), 32.8 (CH2), 32.1 (2C;




CH2), 31.6 (CH2), 29.85 (6C; CH2),




29.81 (4C; CH2), 29.77 (2C; CH2),




29.6 (2C; CH2), 29.5 (2C; CH2),




29.4 (2C; CH2), 29.3 (2C; CH2),




27.4 (CH2), 27.2 (CH), 25.0 (2C;




CH2), 23.5 (CH2), 22.8 (2C; CH2),




20.6 (CH2), 19.7 (CH3), 17.5 (CH3),




14.3 (2C; CH3), 12.1 (CH3).





I-43


embedded image



1H NMR (401 MHz, CDCl3) δ 5.77- 5.71 (m, 3H), 5.26 (m, 1H), 4.55 (dd, J = 8.8, 8.0 Hz, 1H), 4.28 (dd, J = 11.9, 4.3 Hz, 2H), 4.13 (dd, J = 11.9, 5.9 Hz, 2H), 2.47 (m, 1H), 2.43-2.17 (m, 10H), 2.11 (dd, J = 13.8, 7.5 Hz, 1H), 2.01 (ddd, J = 14.9, 10.7, 6.8 Hz, 1H), 1.92 (m, 1H), 1.88-1.81 (m, 2H), 1.75- 1.55 (m, 4H), 1.47-1.12 (m, 26H),





1.18 (s, 3H), 1.16 (d, J = 7.0 Hz,




3H), 1.11-0.94 (m, 1H), 0.92 (d, J =




6.6 Hz, 1H), 0.88 (d, J = 6.7 Hz,




2H), 0.85 (s, 1H); 13C NMR (101




MHz, CDCl3) δ 199.6 (C), 175.4 (C),




173.4 (2C; C), 172.5 (C), 170.9 (C),




154.1 (C), 124.2 (CH), 87.0 (CH),




82.0 (CH2), 69.0 (CH), 62.3 (2C;




CH2), 53.8 (CH), 50.2 (CH), 42.8




(C), 41.8 (CH2), 39.4 (CH), 38.7




(CH), 36.8 (CH2), 36.7 (CH2), 35.9




(CH2), 35.5 (CH), 34.2 (2C; CH2),




34.1 (CH2), 33.5 (CH2), 32.8 (CH2),




32.1 (2C; CH2), 31.6 (CH2), 30.5




(CH), 29.85 (6C; CH2), 29.81 (4C;




CH2), 29.77 (2C; CH2), 29.6 (3C;




CH2), 29.5 (3C; CH2), 29.4 (2C;




CH2), 29.3 (3C; CH2), 27.4 (CH2),




27.2 (CH2), 27.1 (CH2), 25.0 (2C;




CH2), 23.5 (CH2), 22.8 (2C; CH2),




20.6 (CH2), 19.7 (CH3), 17.5 (CH3),




16.83/16.81 (CH3), 14.3 (2C; CH3),




12.1 (CH3).





I-44


embedded image



1H NMR (401 MHz, CDCl3) δ 6.75 (qd, J = 5.4, 2.4 Hz, 1H), 5.73 (s, 1H), 5.26 (m, 1H), 4.53 (dd, J = 14.4, 8.0 Hz, 1H), 4.33-4.26 (m, 2H), 4.132/4.130 (each dd, J = 11.9, 5.9 Hz, 2H), 2.51-2.15 (m, 14H), 2.02 (m, 1H), 1.91-1.81 (m, 2H), 1.75-1.55 (m, 9H), 1.512/1.509 (each d, J = 5.4 Hz, 3H), 1.47-1.20 (m, 50H), 1.19 (s,





3H), 1.03 (d, J = 6.2 Hz, 3H), 1.11-




0.84 (m, 4H), 0.87 (t, J = 7.1 Hz,




6H), 0.85 (s, 3H); 13C NMR (101




MHz, CDCl3) δ 199.5 (C), 173.4




(2C; C), 171.4 (C), 170.88/170.86




(C), 170.33/170.29/170.27 (C),




153.22/153.19 (C), 124.2 (CH),




91.4 (CH), 86.76/86.68 (CH), 69.3




(CH), 62.2 (2C; CH2), 53.8 (CH),




50.2 (CH), 42.80/42.72 (C),




40.69/40.63/40.61 (CH2),




40.58/40.55/40.47/40.44 (CH2),




38.74 (C), 36.69/36.65 (CH2), 35.8




(CH2), 35.5 (CH), 34.2 (2C; CH2),




34.1 (CH2), 32.8 (CH2), 32.1 (2C;




CH2), 31.6 (CH2), 29.84 (6C; CH2),




29.80 (4C; CH2), 29.77 (2C; CH2),




29.6 (2C; CH2), 29.5 (2C; CH2),




29.4 (2C; CH2), 29.3 (2C; CH2),




27.38/27.35 (CH2), 27.3 (CH), 25.0




(2C; CH2), 23.5 (CH2), 22.8 (2C;




CH2), 20.66/20.63 (CH2), 19.7




(CH3), 19.60/19.57 (CH3), 17.5




(CH3), 14.3 (2C; CH3), 12.08/12.04




(CH3). Note: Doubled/multiple




signals were observed in some




cases due to the presence of




diastereomers.





I-45


embedded image



1H NMR (401 MHz, CDCl3) δ 6.747/6.741 (each q, J = 5.5 Hz, 1H), 5.73 (s, 1H), 5.25 (m, 1H), 4.535/4.527 (each dd, J = 9.0, 7.7 Hz, 1H), 4.29 (dd, J = 11.9, 4.4 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 2.48-2.19 (m, 13H), 2.03 (m, 1H), 1.93-1.80 (m, 2H), 1.75-1.54 (m, 12H), 1.511/1.507 (each d, J = 5.4 Hz, 3H), 1.47-1.20 (m, 59H), 1.19 (s, 3H), 1.12-0.90 (m, 4H), 0.88 (t,





J = 7.0 Hz, 6H), 0.86 (s, 3H). Note:




Doubled signals were observed in




some cases due to the presence of




diastereomers.





I-46


embedded image



1H NMR (401 MHz, CDCl3) δ 6.73 (qd, J = 5.4, 2.6 Hz, 1H), 5.72 (s, 1H), 5.26 (m, 1H), 4.52 (m, 1H), 4.28 (dd, J = 11.9, 4.3 Hz, 2H), 4.13 (dd, J = 11.6, 6.2 Hz, 2H), 2.47- 2.15 (m, 12H), 2.10 (dd, J = 14.7, 8.3 Hz, 1H), 2.01 (m, 1H), 1.96- 1.79 (m, 3H), 1.75-1.53 (m, 11H), 1.501/1.498 (each d, J = 5.4 Hz, 3H), 1.46-1.20 (m, 58H), 1.18 (s,





3H), 1.10-0.92 (m, 4H), 0.92 (d, J =




6.0 Hz, 3H), 0.87 (t, J = 6.9 Hz,




6H), 0.85 (s, 3H); 13C NMR (101




MHz, CDCl3) δ 199.6 (C), 173.4




(2C; C), 172.4 (C), 171.8 (C), 170.9




(C), 153.2 (C), 124.1 (CH), 91.3




(CH), 86.68/86.62 (CH), 69.0 (CH),




62.3 (2C; CH2), 53.8 (CH), 50.2




(CH), 42.78/42.71 (C), 41.8 (CH2),




38.7 (C), 36.7 (CH2), 36.67/36.65




(CH2), 35.8 (CH2), 35.5 (CH), 34.2




(3C; CH2), 34.0 (CH2), 32.8 (CH2),




32.1 (2C; CH2), 31.5 (CH2), 30.4




(CH), 29.82 (6C; CH2), 29.78 (4C;




CH2), 29.75 (2C; CH2), 29.60 (2C;




CH2), 29.52 (CH2), 29.49 (2C; CH2),




29.4 (2C; CH2), 29.2 (2C; CH2),




29.13/29.11 (CH2), 27.38/27.33




(CH2), 26.86/26.85 (CH2), 25.0 (2C;




CH2), 24.69/24.66 (CH2), 23.4




(CH2), 22.8 (2C; CH2), 20.64/20.61




(CH2), 19.7 (CH3), 19.6 (CH3), 17.5




(CH3), 14.2 (2C; CH3), 12.06/12.03




(CH3). Note: Doubled signals was




observed in some cases due to the




presence of diastereomers.





I-47


embedded image



1H NMR (401 MHz, CDCl3) δ 6.74 (m, 1H), 5.73 (s, 1H), 5.27 (m, 1H), 4.53 (m, 1H), 4.29 (dd, J = 11.9, 4.3 Hz, 2H), 4.14 (dd, J = 11.9, 6.0 Hz, 2H), 2.48-2.25 (m, 10H), 2.20 (m, 1H), 2.11 (m, 1H), 2.02 (m, 1H), 1.97-1.80 (m, 3H), 1.77-1.54 (m, 10H), 1.51 (d, J = 5.4 Hz, 3H), 1.48- 1.20 (m, 63H), 1.19 (s, 3H), 1.16- 1.12 (m, 3H), 1.11-0.94 (m, 4H),





0.92 (d, J = 6.6 Hz, 3H), 0.88 (t, J =




6.6 Hz, 6H), 0.85 (s, 3H); 13C NMR




(101 MHz, CDCl3) δ 199.6 (C),




174.9 (C), 173.4 (2C; C), 172.5 (C),




170.9 (c), 153.2 (C), 124.2 (CH),




91.4 (CH), 86.6 (CH), 69.0 (CH),




62.3 (2C; CH2), 53.8 (CH), 50.2




(CH), 41.8 (CH2), 39.5 (CH), 36.9




(CH2), 36.7 (CH2), 35.9 (CH2), 35.5




(CH), 34.2 (2C; CH2), 34.1 (CH2),




33.6 (CH2), 32.8 (CH2), 32.1 (2C;




CH2), 31.6 (CH2), 30.5 (CH), 29.85




(7C; CH2), 29.81 (4C; CH2), 29.77




(2C; CH2), 29.67 (2C; CH2), 29.63




(2C; CH2), 29.51 (2C; CH2), 29.42




(2C; CH2), 29.27 (2C; CH2), 27.5-




27.1 (3C; CH2), 25.0 (2C; CH2),




23.5 (CH2), 22.8 (2C; CH2), 20.6




(CH2), 19.69 (CH3), 19.67 (CH3),




17.53 (CH3), 16.9/16.8 (CH3), 14.3




(2C; CH3), 12.1 (CH3). Note:




Doubled signals were observed in




some cases due to the presence of




diastereomers.





I-48


embedded image


[α]D27 + 42.0 (c 0.340, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 6.80 (d, J = 1.9 Hz, 1H), 6.56 (d, J = 1.8 Hz, 1H), 5.72 (s, 1H), 5.28 (m, 1H), 4.45 (dd, J = 9.1, 7.3 Hz, 1H), 4.32 (dd, J = 11.9, 4.4 Hz, 2H), 4.15 (dd, J = 11.9, 5.8 Hz, 2H), 2.79 (ABq, J = 14.5 Hz, 2H), 2.64 (t, J = 7.4 Hz, 2H), 2.54 (s, 3H), 2.49 (t, J = 7.1 Hz, 2H), 2.44-2.24 (m, 8H), 2.22 (s, 3H), 2.11-1.96 (m, 4H), 1.81 (m, 1H), 1.70 (dd, J = 13.7, 5.1 Hz,




1H), 1.65-1.48 (m, 8H), 1.55 (s,




6H), 1.44-1.18 (m, 51H), 1.17 (s,




3H), 1.11-0.92 (m, 4H), 0.88 (t,




J = 6.9 Hz, 6H), 0.65 (s, 3H); 13C




NMR (101 MHz, CDCl3) δ 199.6




(C), 173.4 (2C; C), 172.1 (C),




171.88 (C), 171.85 (C), 171.1 (C),




149.6 (C), 138.2 (C), 136.3 (C),




133.6 (C), 132.5 (CH), 124.1 (CH),




123.1 (CH), 82.5 (CH), 69.5 (CH),




62.1 (2C; CH2), 53.8 (CH), 50.2




(CH), 48.2 (CH2), 42.4 (C), 39.2 (C),




38.7 (C), 36.5 (CH2), 35.8 (CH2),




35.5 (CH), 34.2 (2C; CH2), 34.1




(CH2), 34.0 (CH2), 33.2 (CH2), 32.9




(CH2), 32.1 (2C; CH2), 31.66 (CH3),




31.60 (CH2), 31.58 (CH3), 29.84




(6C; CH2), 29.81 (4C; CH2), 29.77




(2C; CH2), 29.6 (2C; CH2), 29.5




(2C; CH2), 29.4 (2C; CH2), 29.3




(2C; CH2), 27.4 (CH2), 25.4 (CH3),




25.0 (2C; CH2), 23.6 (CH2), 22.8




(2C; CH2), 20.6 (CH2), 20.4 (CH3),




19.9 (CH2), 17.5 (CH3), 14.3 (2C;




CH3), 12.0 (CH3); ESI-HRMS:




calcd. for C72H116NaO11 [M + Na+]




1179.8410; found 1179.8461;




purity (LC-MS): >99% TST prodrug.





I-49


embedded image



1H NMR (400 MHz, CDCl3) δ 5.72 (s, 1H), 5.25 (m, 1H), 4.60 (dd, J = 9.0, 7.9 Hz, 1H), 4.29/4.28 (each dd, J = 11.9, 4.3 Hz, 2H), 4.12 (dd, J = 12.0, 5.9 Hz, 2H), 4.07 (t, J = 5.8 Hz, 2H), 2.49-2.09 (m, 12H), 2.29 (t, J = 7.4 Hz, 4H), 2.01 (m, 1H), 1.83 (m, 1H), 1.76 (m, 1H), 1.72-1.43 (m, 13H), 1.43-1.19 (m, 50H), 1.18 (s, 3H), 1.15-0.88





(m, 4H), 1.01 (d, J = 6.5 Hz, 3H),




0.86 (t, J = 6.8 Hz, 6H), 0.82 (s,




3H); 13C NMR (101 MHz, CDCl3) δ




199.6 (C), 173.4 (2C; C), 173.3 (C),




172.3 (C), 171.5 (C), 171.1 (C),




124.1 (CH), 82.5 (CH), 69.2 (CH),




64.0 (CH2), 62.2 (2C; CH2), 53.8




(CH), 50.3 (CH), 42.6 (C), 40.78




(CH2), 40.77 (CH2), 38.7 (C), 36.8




(CH2), 35.8 (CH2), 35.5 (CH), 34.1




(2C; CH2), 34.0 (2C; CH2), 32.8




(CH2), 32.0 (2C; CH2), 31.6 (CH2),




29.81 (6C; CH2), 29.77 (4C; CH2),




29.73 (2C; CH2), 29.6 (2C; CH2),




29.5 (2C; CH2), 29.4 (2C; CH2),




29.2 (2C; CH2), 28.2 (CH2), 27.6




(CH2), 27.5 (CH), 24.9 (2C; CH2),




23.6 (CH2), 22.8 (2C; CH2), 21.6




(CH2), 20.6 (CH2), 19.7 (CH3), 17.5




(CH3), 14.2 (2C; CH3), 12.2 (CH3).





I-50


embedded image



1H NMR (401 MHz, CDCl3) δ 5.72 (s, 1H), 5.27 (m, 1H), 4.61 (dd, J = 9.0, 7.9 Hz, 1H), 4.28 (dd, J = 11.9, 3.7 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 4.10-4.03 (m, 2H), 2.47- 2.25 (m, 13H), 2.17 (m, 1H), 2.11 (dd, J = 14.7, 8.4 Hz, 1H), 2.02 (ddd, J = 13.3, 4.8, 3.2 Hz, 1H), 1.93 (m, 1H), 1.84 (m, 1H), 1.80- 1.55 (m, 17H), 1.53-1.21 (m,





72H), 1.19 (s, 4H), 1.13 (d, J = 7.0




Hz, 3H), 1.10-0.95 (m, 3H), 0.92




(d, J = 6.6 Hz, 4H), 0.87 (t, J = 6.7




Hz, 6H), 0.83 (s, 3H); 13C NMR




(101 MHz, CDCl3) δ 199.6 (C),




177.0 (C), 173.43 (2C; C), 173.37




(C), 172.5 (C), 171.0 (C), 124.1




(CH), 82.5 (CH), 69.0 (CH), 63.8




(CH2), 62.3 (2C; CH2), 53.8 (CH),




50.4 (CH), 42.7 (C), 41.8 (CH2),




39.7 (CH), 38.7 (C), 36.84 (CH2),




36.79 (CH2), 35.8 (CH2), 35.5 (CH),




34.18 (2C; CH2), 34.11 (CH2), 34.06




(CH2), 33.9 (CH2), 32.9 (CH2), 32.1




(2C; CH2), 31.6 (CH2), 30.5 (CH),




29.9 (CH2), 29.84 (6C; CH2), 29.80




(4C; CH2), 29.76 (2C; CH2), 29.70




(CH2), 29.67 (CH2), 29.61 (2C;




CH2), 29.5 (2C; CH2), 29.4 (2C;




CH2), 29.3 (2C; CH2), 28.3 (CH2),




27.7 (CH2), 27.4 (CH2), 27.1 (CH2),




25.0 (2C; CH2), 23.6 (CH2), 22.8




(2C; CH2), 21.7 (CH2), 20.7 (CH2),




19.7 (CH3), 17.5 (CH3), 17.2 (CH3),




14.3 (2C; CH3), 12.2 (CH3).





I-51


embedded image



1H NMR (400 MHz, CDCl3) δ 5.77 (s, 1H), 5.39 (m, 6H), 4.66 (d, 1H), 4.35 (m, 2H), 4.20 (m, 2H), 2.46 (m, 6H), 2.39 (m, 8H), 2.2 (m, 2H), 2.05 (m, 8H), 1.8 (m, 4H), 1.66 (m, 8H), 1.4 (m, 54H), 13C NMR (101 MHz, CDCl3) δ 199 (1C), 173.3 (2C), 172.8 (1C), 170.98 (1C), 130.02 (2C) 123.9 (1C), 82.1 (1C), 68.87 (1C), 62.12 (1C), 53.69 (1C), 50.23 (1C), 42.4 (1C), 38.6





(1C), 36.6 (1C) 35.6 (2C), 34.5




(6C), 32.7 (2C), 31.9 (2C),




29.7 (30C), 27.5 (3C), 25.05 (2C),




23.49 (2C), 22.6 (2C), 20.5 (1C),




17.3 (1C), 14.1 (2C), 12.0 (1C);




HPLC (ELSD): 9.17 min, 99.33%




purity; MS (ESI, +ve) m/z: 1.77




(MH+ + 1).





I-52


embedded image



1H NMR (400 MHz, CDCl3) δ 5.77 (s, 1H), 5.39 (m, 1H), 4.66 (d, 1H), 4.35 (m, 2H), 4.20 (m, 2H), 2.46 (m, 12H), 2.39 (m, 2H), 2.08 (m, 2H), 1.9 (m, 2H), 1.8 (m, 2H), 1.7 (m, 6H), 1.52 (m, 5H) 1.4 (m, 10H), 1.3 (m, 3H), 1.2 (m, 2H), 1.02 (m, 6H), 0.87 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 199 (1C), 173.3 (2C), 172.9 (1C), 171.03 (1C),





123.9 (1C), 82.2 (1C), 68.9 (1C),




62.08 (2C), 53.72 (1C), 50.26 (1C),




42.53 (1C), 38.6 (1C), 36.6 (1C)




35.7 (3C), 34.5 (1C), 33.9 (1C),




32.7 (1C), 31.5 (1C), 29.1 (4C),




27.4 (2C), 25.08 (1C), 24.8 (2C),




23.52 (1C), 20.5 (1C), 18.38 (2C),




17.43 (1C), 13.67 (2C), 12.1 (1C);




HPLC (ELSD): 2.62 min, 100%




purity; LCMS (ESI, +ve) m/z: 687.7




(MH+ + 1).





I-53


embedded image



1H NMR (401 MHz, CDCl3) δ 6.54 (d, J = 1.7 Hz, 1H), 6.38 (d, J = 1.7 Hz, 1H), 5.95 (m, 1H), 5.26 (m, 1H), 4.29 (dd, J = 11.9, 4.4 Hz, 2H), 4.14 (dd, J = 11.9, 5.9 Hz, 2H), 3.05 (m, 1H), 2.54 (t, J = 7.5 Hz, 2H), 2.51- 2.46 (m, 2H), 2.32 (t, J = 7.5 Hz, 2H), 2.31 (td, J = 7.5 Hz, 4H), 2.16- 2.10 (m, 2H), 1.90 (m, 1H), 1.79- 1.71 (m, 2H), 1.65 (s, 3H), 1.70- 1.53 (m, 9H), 1.40 (s, 3H), 1.44- 1.20 (m, 61H), 1.08 (s, 3H), 0.91-





0.85 (m, 9H); 13C NMR (101 MHz,




CDCl3) δ 173.5 (2C; C), 173.0 (C),




171.6 (C), 154.6 (C), 149.5 (C),




142.8 (C), 134.7 (C), 123.6 (CH),




115.31 (CH), 115.25 (C), 114.1




(CH), 77.6 (C), 69.1 (CH), 62.2 (2C;




CH2), 45.7 (CH), 35.6 (CH2), 34.6




(CH2), 34.31 (CH2), 34.28 (CH),




34.2 (2C; CH2), 32.1 (2C; CH2),




31.6 (CH2), 31.2 (CH2), 30.7 (CH2),




29.85 (6C; CH2), 29.81 (4C; CH2),




29.78 (2C; CH2), 29.6 (2C; CH2),




29.5 (2C; CH2), 29.4 (2C; CH2),




29.32 (CH2), 29.31 (CH2), 29.29




(CH2), 29.27 (2C; CH2), 29.2 (CH2),




27.6 (CH3), 25.1 (CH2), 25.01 (2C;




CH2), 25.00 (CH2), 24.96 (CH2),




23.5 (CH3), 22.8 (2C; CH2), 22.7




(CH2), 19.5 (CH3), 14.3 (2C; CH3),




14.2 (CH3).





I-54


embedded image



1H NMR (401 MHz, CDCl3) δ 6.82 (d, J = 1.6 Hz, 1H), 6.60 (s, 1H), 6.48 (d, J = 1.6 Hz, 1H), 5.98 (d, J = 1.6 Hz, 1H), 5.91 (s, 1H), 5.28 (m, 1H), 4.309/4.301 (each dd, J = 11.9, 4.1, 3.2 Hz, 2H), 4.14 (dd, J = 11.9, 6.0 Hz, 2H), 3.13 (d, J = 15.1 Hz, 1H), 2.99 (d, J = 15.2 Hz, 1H), 2.90 (d, J = 10.9 Hz, 1H), 2.70 (dd, J = 15.4, 5.0 Hz, 1H), 2.64-2.49 (m, 3H), 2.58 (s, 3H), 2.45-2.26





(m, 3H), 2.30 (t, J = 7.1 Hz, 4H),




2.24 (s, 3H), 2.15-2.08 (m, 2H),




1.87 (m, 1H), 1.70-1.46 (m, 7H),




1.67 (s, 3H), 1.65 (s, 6H), 1.38 (s,




3H), 1.35-1.21 (m, 53H), 1.13 (d,




J = 6.3 Hz, 3H), 1.02 (s, 3H), 0.88




(t, J = 6.9 Hz, 9H); 13C NMR (101




MHz, CDCl3) δ 173.4 (2C; C), 171.4




(C), 171.3 (C), 169.7 (C), 154.4 (C),




149.7 (C), 149.4 (C), 142.7 (C),




138.4 (C), 136.4 (C), 134.4 (C),




133.3 (C), 132.6 (CH), 123.8 (CH),




123.2 (CH), 115.24 (C), 115.20




(CH), 113.9 (CH), 77.5 (C), 69.3




(CH), 62.2 (2C; CH2), 47.8 (CH2),




45.7 (CH), 41.4 (CH2), 40.7 (CH2),




39.4 (C), 35.5 (CH2), 34.19 (CH),




34.15 (2C; CH2), 32.1 (2C; CH2),




31.9 (2C; CH3), 31.6 (CH2), 31.2




(CH2), 30.6 (CH2), 29.85 (6C; CH2),




29.81 (4C; CH2), 29.77 (2C; CH2),




29.6 (2C; CH2), 29.5 (2C; CH2),




29.4 (2C; CH2), 29.3 (2C; CH2),




27.5 (CH3), 27.3 (CH), 25.5 (CH3),




25.0 (3C; CH2), 23.6 (CH3), 22.8




(2C; CH2), 22.7 (CH2), 20.4 (CH3),




19.9 (CH3), 19.4 (CH3), 14.3 (2C;




CH3), 14.2 (CH3).





I-55


embedded image



1H NMR (401 MHz, CDCl3) δ 6.57 (d, J = 1.7 Hz, 1H), 6.51 (d, J = 1.7 Hz, 1H), 5.94 (m, 1H), 5.87 (dd, J = 5.7, 3.3 Hz, 1H), 5.83 (dd, J = 5.6, 4.3 Hz, 1H), 5.27 (m, 1H), 4.306/4.303 (each dd, J = 11.9, 4.2 Hz, 2H), 4.14 (dd, J = 11.9, 6.0 Hz, 2H), 3.15 (m, 1H), 2.55-2.41 (m, 5H), 2.38-2.25 (m, 6H), 2.17-





2.09 (m, 2H), 1.90 (m, 1H), 1.66 (s,




3H), 1.71-1.53 (m, 7H), 1.41 (s,




3H), 1.40-1.19 (m, 53H), 1.09 (s,




3H), 1.05 (d, J = 5.8 Hz, 3H), 0.88




(t, J = 6.9 Hz, 9H).





I-56


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1H NMR (401 MHz, CDCl3) δ 6.55 (d, J = 1.6 Hz, 1H), 6.38 (d, J = 1.7 Hz, 1H), 5.93 (m, 1H), 5.27 (m, 1H), 4.298/4.294 (each dd, J = 11.9, 4.3 Hz, 2H), 4.18-4.08 (m, 4H), 3.04 (m, 1H), 2.65-2.54 (m, 2H), 2.52- 2.36 (m, 5H), 2.33-2.19 (m, 6H), 2.17-2.10 (m, 2H), 1.93-1.71 (m, 5H), 1.65 (s, 3H), 1.70-1.49 (m,





7H), 1.40 (s, 3H), 1.40-1.19 (m,




53H), 1.08 (s, 3H), 1.03 (d, J = 6.5




Hz, 3H), 0.88 (t, J = 6.7 Hz, 9H);





13C NMR (101 MHz, CDCl3) δ 173.4





(2C; C), 172.3 (C), 171.5 (C), 171.1




(C), 154.6 (C), 149.4 (C), 142.9 (C),




134.9 (C), 123.5 (CH), 115.4 (CH),




115.2 (C), 114.0 (CH), 77.6 (C),




69.3 (CH), 64.0 (CH2), 62.2 (2C;




CH2), 45.7 (CH), 40.83 (CH2), 40.81




(CH2), 35.6 (CH2), 34.3 (CH), 34.2




(2C; CH2), 34.0 (CH2), 32.1 (2C;




CH2), 31.6 (CH2), 31.1 (CH2), 30.7




(CH2), 29.85 (6C; CH2), 29.81 (4C;




CH2), 29.78 (2C; CH2), 29.6 (2C;




CH2), 29.5 (2C; CH2), 29.4 (2C;




CH2), 29.3 (2C; CH2), 28.3 (CH2),




27.6 (CH3), 27.5 (CH), 25.1 (CH2),




25.0 (2C; CH2), 23.6 (CH3), 22.8




(2C; CH2), 22.7 (CH2), 21.5 (CH2),




19.8 (CH3), 19.5 (CH3), 14.3 (2C;




CH3), 14.2 (CH3).









Example 11: Synthesis of (E)-6-(4-(((4-(1,3-bis(palmitoyloxy)propan-2-yl)oxy)-4-oxobutanoyl)oxy)methoxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid (MPA-I-6)



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Synthesis of MPA-I-6

Synthesis of MPA-I-6. MPA-I-6 is prepared according to the following procedure. 1.1 is prepared by treating a suitably protected mycophenolic acid (i.e., wherein P is a suitable carboxyl protecting group) with chloromethyl methyl thioether as described in WO 2009/143295, which is hereby incorporated by reference in its entirety. A solution of sulfuryl chloride (2.2 equiv.) in CH2Cl2 (0.16 M) is added to a solution of 1.1 (1.8 equiv.) in CH2Cl2 (0.07 M) at 0° C. and the mixture stirred at 0° C. for 30 minutes and then at rt for a further hour. The reaction is concentrated under a stream of N2, co-evaporated from toluene (twice) and dried under reduced pressure. The crude residue is re-dissolved in toluene (0.1 M based on 1.1), added to a solution of acid 1.2 (1 equiv.), as prepared in WO 2017/041139, and DBU (1.5 equiv.) in toluene (0.05 M) that had been pre-stirred for one hour, and the mixture is stirred at rt for two hours. The reaction is diluted with CH2Cl2 (20 mL) and the organic phase washed with sat. aq. NaHCO3 (20 mL) and brine (20 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Deprotection and purification by silica gel chromatography with a suitable solvent mixture affords MPA-I-6.


Example 12: Synthesis of (E)-6-(6-methoxy-7-methyl-3-oxo-4-((5,8,13-trioxo-10-((palmitoyloxy)methyl)-2,4,9,12-tetraoxaoctacosanoyl)oxy)-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid, MPA-I-7



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Synthesis of MPA-I-7

Synthesis of 2.2. 2.2 is prepared according to the following procedure. Chloromethyl chloroformate (1.6 equiv.) and pyridine (3.0 equiv.) are added to a suitably protected mycophenolic acid (ie where P is a suitable carboxyl protecting group) 2.1 (1.0 equiv.) in CH2Cl2 (0.03 M) at 0° C. and the mixture is stirred at 0° C. for 15 minutes and then at rt for one hour. The reaction is diluted with CH2Cl2 and the organic phase washed with sat. aq. NaHCO3 and brine, dried (MgSO4) and concentrated under reduced pressure to give 2.2 which is used without purification.


Synthesis of MPA-I-7. 2.4 is prepared according to the following procedure. Silver carbonate (0.7 equiv.) is added to acid 2.3 (1.2 equiv.) as prepared in WO 2017/041139, in DMF (0.03 M) and the mixture stirred at rt for one hour. The reaction is concentrated under reduced pressure to give a grey residue, to which is added chloromethyl carbonate 2.2 (1.0 equiv.) in toluene (0.03 M) and TBAI (0.3 equiv.) and the mixture heated at reflux for 1.5 hours. The reaction is cooled to rt, then diluted with ethyl acetate. The organic phase is washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give the crude product 2.4. Deprotection and purification by silica gel chromatography with a suitable solvent mixture affords MPA-I-7.


Example 13: Synthesis of (E)-6-(4-((3-(2-((4-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-4-oxobutanoyl)oxy)-4,6-dimethylphenyl)-3-methylbutanoyl)oxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid, MPA-I-8



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Synthesis of MPA-I-8

Synthesis of MPA-I-8. MPA-I-8 is prepared according to the following procedure. DMAP (1.3 equiv.) and EDC.HCl (2.1 equiv.) is added to a solution of acid 3.1 (1.0 equiv.) as prepared in WO 2017/041139, and a suitably protected mycophenolic acid (i.e. where P is a suitable carboxyl protecting group such as an alkyl or phenyl ester) 3.2 (1.3 equiv.) in CH2Cl2 (0.02 M) and the mixture stirred at RT for 19 hours. The reaction is diluted with CH2Cl2 (10 mL), silica gel is added, and the mixture concentrated under reduced pressure and purified by silica gel chromatography. Deprotection of the ester and purification, e.g. by silica gel chromatography with a suitable solvent mixture, affords MPA-I-8.




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Compound MPA-I-8′ was prepared as follows. DMAP (2.4 mg, 19.8 μmol) and EDC.HCl (9.5 mg, 49.4 μmol) were added to a solution of TML acid-TG 3.1 (19.0 mg, 21.8 μmol) and methyl ester 3.2 (6.6 mg, 19.8 μmol, P=Me) in CH2Cl2 (1 mL) and the mixture stirred at RT for 3.5 hours. The reaction was diluted with CH2Cl2 (10 mL), silica gel was added and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (20% to 25% ethyl acetate/hexanes) gave prodrug MPA-(O-TML-C4-2-TG)-OMe (MPA-I-8′) (22.0 mg, 94%) as a colorless solid. 1H NMR (401 MHz, CDCl3) δ 6.78 (d, J=1.9 Hz, 1H), 6.58 (d, J=1.8 Hz, 1H), 5.28 (m, 1H), 5.10 (s, 2H), 4.99 (m, 1H), 4.29 (dd, J=11.9, 4.4 Hz, 2H), 4.16 (dd, J=11.9, 5.8 Hz, 2H), 3.72 (s, 3H), 3.61 (s, 3H), 3.32 (s, 2H), 3.11 (d, J=5.1 Hz, 2H), 2.92 (t, J=6.7 Hz, 2H), 2.76 (t, J=6.7 Hz, 2H), 2.57 (s, 3H), 2.36-2.22 (m, 8H), 2.19 (s, 3H), 2.17 (s, 3H), 1.73 (s, 3H), 1.65 (s, 6H), 1.64-1.54 (m, 4H), 1.35-1.19 (m, 48H), 0.87 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.8 (C), 173.5 (2C; C), 171.5 (C), 171.4 (C), 170.0 (C), 168.4 (C), 162.8 (C), 149.6 (C), 146.3 (C), 146.0 (C), 138.2 (C), 136.3 (C), 134.2 (C), 133.5 (C), 132.6 (CH), 129.6 (C), 123.1 (CH), 122.79 (C), 122.77 (CH), 113.6 (C), 69.7 (CH), 68.4 (CH2), 62.0 (2C; CH2), 61.2 (CH3), 51.6 (CH3), 47.0 (CH2), 38.9 (C), 34.5 (CH2), 34.1 (2C; CH2), 32.8 (CH2), 32.1 (2C; CH2), 31.4 (2C; CH3), 29.9 (CH2), 29.84 (6C; CH2), 29.80 (4C; CH2), 29.76 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.2 (2C; CH2), 29.0 (CH2), 25.5 (CH3), 25.0 (2C; CH2), 23.5 (CH2), 22.8 (2C; CH2), 20.4 (CH3), 16.4 (CH3), 14.3 (2C; CH3), 11.9 (CH3); ESI-HRMS: calcd. for C70H108NaO15 [M+Na+ ]1211.7580; found 1211.7563.


Example 14: Synthesis of (E)-6-(4-(2-((4-((4-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-4-oxobutanoyl)oxy)benzyl)oxy)-2-oxoethoxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid, MPA-I-9



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Synthesis of MPA-I-9

Synthesis of MPA-I-9. MPA-I-9 is prepared according to the following procedure. DMAP (1.3 equiv.) and DIPEA (0.3 equiv.) are added to a solution of a suitably protected mycophenolic acid (i.e. where P is a suitable carboxyl protecting group), 4.1 (1.2 equiv.) and PNP carbonate 4.2 (1.0 equiv.) as prepared in WO 2017/041139, in CH2Cl2 (0.01 M) and the mixture stirred at rt for about five days. The reaction is diluted with CH2Cl2, washed with 1 M HCl, water and brine, dried (MgSO4) and concentrated under reduced pressure to give the crude product. Deprotection and purification by silica gel chromatography with a suitable solvent mixture affords MPA-I-9.


Example 15: Synthesis of (E)-6-((4-((4-((4-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-4-oxobutanoyl)oxy)butanoyl)oxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid, MPA-I-10



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Synthesis of MPA-I-10

Synthesis of 5.3. DMAP (1.3 equiv.) and DCC (2.1 equiv.) are added to a solution of a suitably protected mycophenolic acid (i.e., where P is a suitable carboxyl protecting group) (1.0 equiv.) and 4-bromobutyric acid 5.2 (1.3 equiv.) in CH2Cl2 (0.03 M) and the mixture is stirred at rt for 24 hours. Another 0.6 eq. of acid, 1 eq. of DCC, 0.6 eq. of DMAP are added and the mixture is stirred at rt for a further two days. The reaction is diluted with CH2Cl2, silica gel is added, and the mixture is concentrated under reduced pressure. Purification by silica gel chromatography gives bromide 5.3.


Synthesis of MPA-I-10. DBU (1.6 equiv.) is added to a suspension of acid 5.4 (1.1 equiv.) as prepared in WO 2017/041139, and bromide 5.3 (1.0 equiv.) in toluene (0.03 M) and the mixture is heated at reflux for 21 hours. The reaction is cooled to rt, then diluted with ethyl acetate. The organic phase is washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give the crude product. Deprotection and purification by silica gel chromatography with a suitable solvent mixture affords MPA-I-10.


Compounds MPA-I-1, MPA-I-2, MPA-I-3, MPA-I-4, MPA-I-5, MPA-I-11, MPA-I-12, MPA-I-13, MPA-I-14, and MPA-I-15 may be prepared by methods substantially similar to those described in Examples 1 through 5, the General Synthetic Schemes provided herein, and methods known to one of ordinary skill in the art.


Example 16: Synthesis of MPA-Phenol Prodrugs



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Synthesis of MPA-Phenol Prodrugs (Directly-Linked)
MPA Methyl Ester (Methyl (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate) (2)



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DMAP (95.3 mg, 0.280 mmol) and EDC.HCl (300 mg, 1.56 mmol) were added to a solution of mycophenolic acid (1) (250 mg, 0.780 mmol) in CH2Cl2 (5 mL) and MeOH (3 mL) and the mixture stirred at rt for 17 hours. The reaction was diluted with CH2Cl2 (20 mL), silica gel was added and the solvent removed under reduced pressure. Purification by silica gel chromatography (25% to 30% ethyl acetate/hexanes) gave methyl ester 2 (125 mg, 48%) as a colorless solid. 1H NMR (401 MHz, CDCl3) δ 7.66 (s, 1H), 5.23 (m, 1H), 5.19 (s, 2H), 3.75 (s, 3H), 3.61 (s, 3H), 3.37 (d, J=6.8 Hz, 2H), 2.42-2.36 (m, 2H), 2.33-2.26 (m, 2H), 2.14 (s, 3H), 1.79 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 173.9 (C), 173.1 (C), 163.8 (C), 153.8 (C), 144.1 (C), 134.3 (C), 122.9 (CH), 122.3 (C), 116.8 (C), 106.5 (C), 70.2 (CH2), 61.1 (CH3), 51.6 (CH3), 34.7 (CH2), 33.0 (CH2), 22.7 (CH2), 16.2 (CH3), 11.7 (CH3).


(E)-1-(1,3-Bis(palmitoyloxy)propan-2-yl) 10-(6-methoxy-5-(6-methoxy-3-methyl-6-oxohex-2-en-1-yl)-7-methyl-3-oxo-1,3-dihydroisobenzofuran-4-yl) 3-methyldecane-dioate (4d; n=4, Rβ=Me) (MPA-I-16)



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DMAP (2.4 mg, 19.6 μmol) and EDC.HCl (9.4 mg, 48.9 μmol) were added to a solution of methyl ester 2 (6.5 mg, 19.6 μmol) and acid-TG Int-30 (15.0 mg, 19.6 μmol) in CH2Cl2 (1.2 mL) and the mixture stirred at RT for 18 hours. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (25% ethyl acetate/hexanes) gave MPA prodrug MPA-(O-C10bMe-2-TG)-OMe (4d) (MPA-I-16) (19.3 mg, 91%) as a colorless oil. 1H NMR (401 MHz, CDCl3) δ 5.27 (m, 1H), 5.13 (s, 2H), 5.10 (m, 1H), 4.28 (dd, J=12.0, 3.9 Hz, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 3.78 (s, 3H), 3.62 (s, 3H), 3.33 (d, J=6.5 Hz, 2H), 2.67 (t, J=7.5 Hz, 2H), 2.41-2.25 (m, 9H), 2.21 (s, 3H), 2.11 (dd, J=14.7, 8.6 Hz, 1H), 1.94 (m, 1H), 1.83-1.73 (m, 2H), 1.76 (s, 3H), 1.65-1.55 (m, 4H), 1.49-1.16 (m, 56H), 0.93 (d, J=6.6 Hz, 3H), 0.87 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.8 (C), 173.4 (2C; C), 172.5 (C), 171.8 (C), 168.4 (C), 162.8 (C), 146.3 (C), 146.2 (C), 134.6 (C), 129.4 (C), 122.9 (C), 122.5 (CH), 113.7 (C), 68.9 (CH), 68.4 (CH2), 62.3 (2C; CH2), 61.3 (CH3), 51.6 (CH3), 41.8 (CH2), 36.8 (CH2), 34.6 (CH2), 34.2 (2C; CH2), 34.0 (CH2), 32.9 (CH2), 32.1 (2C; CH2), 30.5 (CH), 29.84 (6C; CH2), 29.80 (4C; CH2), 29.76 (2C; CH2), 29.62 (3C; CH2), 29.50 (2C; CH2), 29.41 (2C; CH2), 29.30 (CH2), 29.26 (2C; CH2), 26.9 (CH2), 25.0 (2C; CH2), 24.7 (CH2), 23.7 (CH2), 22.8 (2C; CH2), 19.6 (CH3), 16.4 (CH3), 14.3 (2C; CH3), 11.9 (CH3).


Further compounds were prepared in a similar manner as described below.




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DMAP (11.4 mg, 0.0933 mmol) and EDC.HCl (32.1 mg, 0.167 mmol) were added to a solution of methyl ester 2 (31.0 mg, 0.0930 mmol) and acid-TG Int-28 (62.2 mg, 0.0930 μmol) in CH2Cl2 (4 mL) and the mixture stirred at RT for 18 hours. The reaction was diluted with CH2Cl2 (20 mL), washed with water (20 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (15% ethyl acetate/hexanes) gave MPA prodrug MPA-(O-C4-2-TG)-OMe (MPA-I-17) (38.5 mg, 42%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.28 (m, 1H), 5.14 (s, 2H), 5.12 (m, 1H), 4.29 (dd, J=11.9, 4.4 Hz, 2H), 4.16 (dd, J=11.9, 5.7 Hz, 2H), 3.78 (s, 3H), 3.61 (s, 3H), 3.35 (d, J=6.8 Hz, 2H), 3.03 (t, J=7.1 Hz, 2H), 2.83 (t, J=7.0 Hz, 2H), 2.41-2.35 (m, 2H), 2.33-2.27 (m, 6H), 2.22 (s, 3H), 1.79 (s, 3H), 1.64-1.55 (m, 4H), 1.37-1.17 (m, 48H), 0.87 (t, J=6.9 Hz, 6H).




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DMAP, 6.0 mg, 49.1 μmol) and DCC (19.0 mg, 92.1 μmol) were added to a solution of methyl ester 2 (17.0 mg, 50.8 μmol) and acid-TG Int-29 (35.0 mg, 50.2 μmol) in CH2Cl2 (2 mL) and the mixture stirred at RT for 18 hours. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (20% ethyl acetate/hexanes) gave MPA prodrug MPA-(O-C6-2-TG)-OMe (4b) (MPA-I-18) (25.0 mg, 49%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.26 (m, 1H), 5.14 (s, 2H), 5.10 (td, J=6.7, 1.1 Hz, 1H), 4.30 (dd, J=11.9, 4.4 Hz, 2H), 4.15 (dd, J=11.9, 5.8 Hz, 2H), 3.78 (s, 3H), 3.62 (s, 3H), 3.33 (d, J=6.5 Hz, 2H), 2.70 (t, J=6.8 Hz, 2H), 2.44-2.25 (m, 10H), 2.22 (s, 3H), 1.89-1.73 (m, 4H), 1.77 (s, 3H), 1.65-1.55 (m, 4H), 1.33-1.20 (m, 48H), 0.88 (t, J=6.9 Hz, 6H).




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DMAP (5.2 mg, 42.5 μmol) and EDC.HCl (14.1 mg, 73.5 μmol) were added to a solution of methyl ester 2 (12.0 mg, 35.8 μmol) and acid-TG Int-9 (28.0 mg, 19.6 μmol) in CH2Cl2 (0.8 mL) and the mixture stirred at RT for 20 hours. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (10% to 25% ethyl acetate/hexanes) gave MPA prodrug MPA-(O-C10-2-TG)-OMe (4c) (MPA-I-19) (30.5 mg, 80%) as a colorless oil. 1H NMR (401 MHz, CDCl3) δ 5.26 (m, 1H), 5.13 (s, 2H), 5.10 (td, J=6.7, 1.1 Hz, 1H), 4.29 (dd, J=11.9, 4.4 Hz, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 3.77 (s, 3H), 3.62 (s, 3H), 3.33 (d, J=6.6 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 2.41-2.25 (m, 10H), 2.21 (s, 3H), 1.82-1.73 (m, 2H), 1.76 (s, 3H), 1.68-1.55 (m, 6H), 1.47-1.19 (m, 66H), 0.87 (t, J=6.8 Hz, 6H).




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DMAP (2.2 mg, 17.9 μmol) and EDC.HCl (7.1 mg, 37.1 μmol) were added to a solution of methyl ester 2 (6.0 mg, 17.9 μmol) and acid-TG Int-27 (14.5 mg, 17.9 μmol) in CH2Cl2 (1 mL) and the mixture stirred at RT for 18 hours. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (20% ethyl acetate/hexanes) gave MPA prodrug MPA-(O-C12a′bMe-2-TG)-OMe (4e) (MPA-I-20) (18.8 mg, 93%) as a colorless oil. 1H NMR (401 MHz, CDCl3) δ 5.27 (m, 1H), 5.13 (s, 2H), 5.10 (td, J=6.5, 1.1 Hz, 1H), 4.284/4.282 (each dd, J=11.8, 4.3 Hz, 2H), 4.14 (dd, J=11.8, 6.0 Hz, 2H), 3.77 (s, 3H), 3.61 (s, 3H), 3.32 (br s, 2H), 2.79 (m, 1H), 2.40-2.34 (m, 2H), 2.33-2.26 (m, 7H), 2.21 (s, 3H), 2.11 (dd, J=14.7, 8.5 Hz, 1H), 1.98-1.85 (m, 2H), 1.76 (s, 3H), 1.65-1.54 (m, 4H), 1.36 (d, J=7.0 Hz, 3H), 1.47-1.16 (m, 61H), 0.93 (d, J=6.6 Hz, 3H), 0.87 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 174.6 (C), 173.7 (C), 173.4 (2C; C), 172.5 (C), 168.3 (C), 162.8 (C), 146.3 (C), 146.2 (C), 134.6 (C), 129.4 (C), 122.9 (C), 122.6 (CH), 113.8 (C), 68.9 (CH), 68.3 (CH2), 62.3 (2C; CH2), 61.2 (CH3), 51.6 (CH3), 41.8 (CH2), 39.5 (CH), 36.9 (CH2), 34.5 (CH2), 34.2 (2C; CH2), 33.4 (CH2), 32.9 (CH2), 32.1 (2C; CH2), 30.5 (CH), 29.9 (CH2), 29.82 (6C; CH2), 29.78 (4C; CH2), 29.74 (3C; CH2), 29.68 (CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.2 (2C; CH2), 27.3 (CH2), 27.1 (CH2), 25.0 (2C; CH2), 23.6 (CH2), 22.8 (2C; CH2), 19.6 (CH3), 16.8 (CH3), 16.5 (CH3), 14.2 (2C; CH3), 11.9 (CH3).


(E)-15-(1,3-bis(palmitoyloxy)propan-2-yl) 1-(6-methoxy-5-(6-methoxy-3-methyl-6-oxohex-2-en-1-yl)-7-methyl-3-oxo-1,3-dihydroisobenzofuran-4-yl) 2,13-dimethylpentadecanedioate (MPA-I-29)



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DMAP (4.3 mg, 35.1 μmol) and EDC.HCl (11.8 mg, 61.5 μmol) were added to a solution of methyl ester 2 (10.0 mg, 29.9 μmol) and acid-TG Int-62 (27.5 mg, 32.3 μmol) in CH2Cl2 (0.8 mL) and the mixture stirred at RT for 18 hours. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added, and the mixture was concentrated under reduced pressure. Purification by silica gel chromatography (25% ethyl acetate/hexanes) gave prodrug MPA-(O-C15a′bMe-2-TG)-OMe 4f (MPA-I-29) (34.3 mg, 98%) as a colorless oil. 1H NMR (401 MHz, CDCl3) δ 5.27 (m, 1H), 5.14 (s, 2H), 5.10 (td, J=6.6, 1.2 Hz, 1H), 4.29 (dd, J=11.9, 4.3 Hz, 2H), 4.14 (td, J=11.9, 6.0 Hz, 2H), 3.77 (s, 3H), 3.62 (s, 3H), 3.32 (br s, 2H), 2.80 (dd, J=13.9, 7.0 Hz, 1H), 2.41-2.26 (m, 9H), 2.22 (s, 3H), 2.11 (dd, J=14.7, 8.4 Hz, 1H), 1.97-1.86 (s, 2H), 1.76 (s, 3H), 1.65-1.53 (m, 6H), 1.36 (d, J=7.0 Hz, 3H), 1.47-1.15 (m, 69H), 0.92 (d, J=6.6 Hz, 3H), 0.87 (t, J=6.9 Hz, 6H).


(E)-1-(1,3-bis(palmitoyloxy)propan-2-yl) 12-(6-methoxy-5-(6-methoxy-3-methyl-6-oxohex-2-en-1-yl)-7-methyl-3-oxo-1,3-dihydroisobenzofuran-4-yl) dodecanedioate (MPA-I-30)



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DMAP (2.9 mg, 23.9 μmol) and EDC.HCl (11.5 mg, 59.8 μmol) were added to a solution of methyl ester 2 (8.0 mg, 23.9 μmol) and acid-TG Int-37 (22.4 mg, 28.7 μmol) in CH2Cl2 (0.8 mL) and the mixture stirred at RT for 17 hours. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (4% to 8% ethyl acetate/toluene) gave prodrug MPA(O-C12-2-TG)-OMe 4g (MPA-I-30) (9.1 mg, 35%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.26 (m, 1H), 5.14 (s, 2H), 5.10 (td, J=6.7, 1.2 Hz, 1H), 4.29 (dd, J=11.9, 4.4 Hz, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 3.78 (s, 3H), 3.62 (s, 3H), 3.33 (d, J=6.6 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 2.41-2.35 (m, 2H), 2.34-2.27 (m, 8H), 2.22 (s, 3H), 1.83-1.73 (m, 2H), 1.76 (s, 3H), 1.66-1.55 (m, 6H), 1.48-1.20 (m, 60H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.8 (C), 173.5 (2C; C), 173.0 (C), 171.8 (C), 168.4 (C), 162.8 (C), 146.3 (C), 146.2 (C), 134.6 (C), 129.4 (C), 122.9 (C), 122.5 (CH), 113.8 (C), 69.0 (CH), 68.4 (CH2), 62.2 (2C; CH2), 61.3 (CH3), 51.6 (CH3), 34.6 (CH2), 34.4 (CH2), 34.2 (2C; CH2), 34.0 (CH2), 32.9 (CH2), 32.1 (2C; CH2), 29.85 (6C; CH2), 29.81 (4C; CH2), 29.77 (2C; CH2), 29.62 (4C; CH2), 29.51 (2C; CH2), 29.47 (CH2), 29.44 (CH2), 29.42 (2C; CH2), 29.34 (CH2), 29.27 (3C; CH2), 25.1 (CH2), 25.0 (2C; CH2), 24.8 (CH2), 23.7 (CH2), 22.8 (2C; CH2), 16.4 (CH3), 14.3 (2C; CH3), 11.9 (CH3).


(E)-1-(1,3-bis(palmitoyloxy)propan-2-yl) 15-(6-methoxy-5-(6-methoxy-3-methyl-6-oxohex-2-en-1-yl)-7-methyl-3-oxo-1,3-dihydroisobenzofuran-4-yl) 3-methylpentadecanedioate (MPA-I-31)



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DMAP (1.5 mg, 11.9 μmol) and EDC.HCl (5.7 mg, 29.9 μmol) were added to a solution of methyl ester 2 (4.0 mg, 11.9 μmol) and acid-TG Int-49 (12.0 mg, 14.3 μmol) in CH2Cl2 (0.8 mL) and the mixture stirred at RT for five hours. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added, and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (5% to 8% ethyl acetate/toluene) gave prodrug MPA(O-C15bMe-2-TG)-OMe 4h (MPA-I-31) (10.8 mg, 78%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.27 (m, 1H), 5.14 (s, 2H), 5.10 (td, J=6.7, 1.2 Hz, 1H), 4.286/4.285 (each dd, J=11.9, 4.2 Hz, 2H), 4.141-4.139 (dd, J=11.9, 6.0 Hz, 2H), 3.78 (s, 3H), 3.62 (s, 3H), 3.33 (d, J=6.5 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 2.41-2.25 (m, 5H), 2.30 (t, J=7.6 Hz, 4H), 2.22 (s, 3H), 2.11 (dd, J=14.7, 8.4 Hz, 1H), 1.93 (m, 1H), 1.83-1.73 (m, 2H), 1.76 (s, 3H), 1.65-1.55 (m, 4H), 1.47-1.14 (m, 66H), 0.93 (d, J=6.6 Hz, 3H), 0.87 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.8 (C), 173.5 (2C; C), 172.5 (C), 171.8 (C), 168.4 (C), 162.8 (C), 146.3 (C), 146.2 (C), 134.6 (C), 129.4 (C), 122.9 (C), 122.5 (CH), 113.8 (C), 68.9 (CH), 68.4 (CH2), 62.3 (2C; CH2), 61.3 (CH3), 51.7 (CH3), 41.9 (CH2), 36.9 (CH2), 34.6 (CH2), 34.2 (2C; CH2), 34.0 (CH2), 32.9 (CH2), 32.1 (2C; CH2), 30.5 (CH), 30.0 (CH2), 29.85 (7C; CH2), 29.81 (4C; CH2), 29.77 (2C; CH2), 29.67 (CH2), 29.62 (2C; CH2), 29.51 (4C; CH2), 29.42 (2C; CH2), 29.36 (CH2), 29.27 (3C; CH2), 27.1 (CH2), 25.0 (2C; CH2), 24.8 (CH2), 23.7 (CH2), 22.8 (2C; CH2), 19.7 (CH3), 16.4 (CH3), 14.3 (2C; CH3), 11.9 (CH3).


(E)-12-(1,3-bis(palmitoyloxy)propan-2-yl) 1-(6-methoxy-7-methyl-5-(3-methyl-6-(2-morpholinoethoxy)-6-oxohex-2-en-1-yl)-3-oxo-1,3-dihydroisobenzofuran-4-yl) 2,10-dimethyldodecanedioate (MPA-I-32)



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DMAP (1.7 mg, 13.6 μmol) and EDC.HCl (6.5 mg, 34.0 μmol) were added to a solution of mofetil (prepared by esterification of MPA with 2-(morpholino)ethanol; see, e.g., US 2010/0298560, hereby incorporated by reference in its entirety) (5.9 mg, 13.6 μmol) and acid-TG Int-27 (11.0 mg, 13.6 μmol) in CH2Cl2 (0.8 mL) and the mixture stirred at RT for 18 hours. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added, and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (50% to 75% ethyl acetate/hexanes) gave prodrug MPA-(O-C12a′bMe-2-TG)-OMF 4i (MPA-I-32) (11.7 mg, 70%) as a colorless oil. 1H NMR (400 MHz, CD3OD) δ 5.31-5.24 (m, 3H), 5.07 (td, J=6.3, 1.0 Hz, 1H), 4.357/4.355 (each dd, J=11.9, 3.8 Hz, 2H), 4.21 (t, J=5.4 Hz, 2H), 4.159/4.155 (each dd, J=12.0, 6.3 Hz, 2H), 3.81 (s, 3H), 3.77-3.68 (m, 4H), 3.37 (d, J=5.0 Hz, 2H), 2.94-2.64 (m, 7H), 2.49-2.41 (m, 2H), 2.36-2.24 (m, 7H), 2.27 (s, 3H), 2.15 (dd, J=14.7, 7.7 Hz, 1H), 1.98-1.84 (m, 2H), 1.80 (s, 3H), 1.66-1.54 (m, 4H), 1.34 (d, J=7.0 Hz, 3H), 1.52-1.19 (m, 62H), 0.96 (d, J=6.7 Hz, 3H), 0.90 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CD3OD) δ 174.8 (2C; C), 170.3 (C), 164.2 (C), 148.5 (C), 147.1 (C), 135.8 (C), 130.4 (C), 124.7 (C), 123.8 (CH), 114.5 (C), 70.6 (CH), 69.9 (CH2), 66.9 (2C; CH2), 63.4 (2C; CH2), 61.9 (CH3), 61.3 (CH2), 57.8 (CH2), 54.5 (2C; CH2), 42.6 (CH2), 40.6 (CH), 37.7 (CH2), 35.3 (CH2), 34.9 (CH2), 34.7 (CH2), 33.5 (CH2), 33.1 (CH2), 31.6 (CH), 30.9 (CH2), 30.82 (6C; CH2), 30.81 (5C; CH2), 30.75 (3C; CH2), 30.6 (2C; CH2), 30.5 (2C; CH2), 30.4 (2C; CH2), 30.2 (2C; CH2), 28.3 (CH2), 28.1 (CH2), 26.0 (2C; CH2), 24.4 (CH2), 23.7 (2C; CH2), 20.2 (CH3), 17.4 (CH3), 16.7 (CH3), 14.5 (2C; CH3), 11.8 (CH3). Note: A number of C═O signals were not observed, while a number of other signals were significantly broadened in both the 1H and 13C NMR spectra. A larger amount of sample will be required to re-acquire the 13C NMR spectrum to observe all signals; ESI-HRMS: calcd. for C72H122NO14 [M+H+] 1224.8860; found 1224.8866.


(E)-1-(1,3-bis(palmitoyloxy)propan-2-yl) 12-(6-methoxy-5-(6-methoxy-3-methyl-6-oxohex-2-en-1-yl)-7-methyl-3-oxo-1,3-dihydroisobenzofuran-4-yl) 2,11-dimethyldodecanedioate (MPA-I-42)



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To a solution of methyl ester 2 (0.2 g, 0.247 mmol) in chloroform (10 ml) were added DCC (0.101 g, 0.494 mmol) and DMAP (0.060 g, 0.494 mmol), then the reaction mixture was stirred at rt for 30 min, then Int-81 (0.165 g, 0.494 mmol) was added and stirred at rt for 18 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with DCM (50 mL), then the filtrate was evaporated to obtain crude product, which was purified by combi flash purification to obtain MPA-(O-C12a′aMe-2-TG)-OMe (MPA-I-42) (0.080 g, 28.7%) as a viscous liquid. 1H NMR (400 MHz, CDCl3) δ 5.30 (t, J=5.3 Hz, 1H), 5.16 (s, 2H,), 5.13 (d, J=16.8 Hz, 1H), 4.31 (dd, J=11.7, 3.7 Hz, 2H), 4.17 (dd, J=11.9, 6.1 Hz, 2H), 3.79 (s, 3H), 3.64 (s, 3H), 3.34 (bs, 2H), 2.82 (q, J=6.9 Hz, 1H), 2.48-2.30 (m, 10H), 2.24 (s, 3H), 1.92 (s, 2H), 1.78 (s, 3H), 1.64-1.52 (m, 10H), 1.39-1.37 (m, 10H), 1.28 (m, 48H), 1.16 (d, J=6.8 Hz, 3H), 0.89 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 175.96 (1C), 174.55 (1C), 173.65 (1C), 173.32 (2C), 168.19 (1C), 162.63 (1C), 146.22 (1C), 146.01 (1C), 134.53 (1C), 129.32 (1C), 122.80 (1C), 122.47 (2C), 113.72 (1C), 68.69 (1C), 68.26 (1C), 62.16 (1C), 61.15 (1C), 51.55 (1C), 39.55 (1C), 39.39 (1C), 34.38 (1C), 34.07 (2C), 33.65 (1C), 33.33 (1C), 32.74 (1C), 31.96 (3C), 29.73-29.16 (23C), 27.22 (1C), 24.88 (2C), 23.53 (1C), 22.73 (2C), 17.04 (1C), 16.74 (1C), 16.39 (1C), 14.17 (3C), 11.79 (1C). HPLC (ELSD): 9.90 min, 100% purity; HPLC (uv-215 nm): 9.86 min, 99.03% purity; LCMS: 9.22 min 100% purity. MASS (ESI, +ve) m/z: 1143.05 (MH+1). ELSD Method: -PDS_HPLC_GEMINI_C4 JUPITER_GRA-1. Mobile Phase: 100% MeOH; System: Agilent Technologies 1260 Infinity with PDA Detector & ELSD Detector; Column: Phenomenex JUPITER C4, 100*4.6 mm, 5μ; Column Flow: 1.0 ml/min; Column Temp: Ambient; ELSD: SPRAY CHAMBER −50° C.


Compound MPA-(O-C10aMe-2-TG)-OMe (MPA-I-45) was prepared using similar methods as those described above.




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1H NMR (400 MHz, CDCl3) δ 5.31 (t, J=4.8 Hz, 1H), 5.18 (s, 2H), 5.14 (m, 1H), 4.31 (dd, J=11.9, 3.9 Hz, 2H), 4.17 (dd, J=11.9, 6.1 Hz, 2H), 3.82 (s, 3H), 3.67 (s, 3H), 3.38 (d, J=6.0 Hz, 2H), 2.71 (t, J=6.8 Hz, 2H), 2.51-2.49 (m, 1H), 2.47 (m, 2H), 2.38 (dt, J=28.8, 7.3 Hz, 6H), 2.26 (s, 3H), 1.81 (s, 4H), 1.69-1.58 (m, 4H), 1.45 (s, 4H), 1.29 (s, 54H), 1.19 (d, J=7.0 Hz, 4H), 0.92 (t, J=6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 175.93 (1C), 173.66 (1C), 173.33 (2C), 171.65 (1C), 168.29 (1C), 162.65 (1C), 146.18 (1C), 146.02 (1C), 134.48 (1C), 129.23 (1C), 122.84 (1C), 122.37 (2C), 113.60 (1C), 68.71 (1C), 68.34 (1C), 62.16 (2C), 61.19 (2C), 51.55 (2C), 39.53 (1C), 34.43 (1C), 34.08 (2C), 33.84 (1C), 33.58 (1C), 32.74 (1C), 31.96 (2C), 29.74-28.95 (20C), 27.16 (1C), 24.89 (2C), 24.60 (1C), 23.57 (1C), 22.73 (2C), 17.04 (1C), 16.30 (1C), 14.17 (2C), 11.82 (1C). HPLC (ELSD): 9.42 min, 100% purity; HPLC (uv-215 nm): 8.95 min, 96.05% purity; LCMS: 9.08 min 100% purity; MS (ESI, +ve) m/z: 1101.10 (MH+18). ELSD Method: —PDS_HPLC_GEMINI_C4_JUPITER_GRA-1; Mobile Phase: 100% MeOH; System: Agilent Technologies 1260 Infinity with PDA Detector & ELSD Detector; Column: Phenomenex JUPITER C4, 100*4.6 mm, 5μ; Column Flow: 1.0 ml/min; Column Temp: Ambient; ELSD: SPRAY CHAMBER −50° C.


MPA-phenol lipid prodrugs such as MPA(O-TML-C12-2-TG)-OMe (MPA-I-47), which includes a trimethyl lock SI group, were synthesized in a similar manner, i.e., by coupling of the appropriate carboxylic acid-containing prodrug group with DMAP and EDC.




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MPA-I-47 was prepared by coupling methyl ester 2 to the appropriate prodrug intermediate in 80% yield using DMAP and EDC. 1H NMR (401 MHz, CDCl3) δ 6.77 (d, J=2.0 Hz, 1H), 6.55 (d, J=1.9 Hz, 1H), 5.26 (m, 1H), 5.10 (s, 2H), 4.98 (m, 1H), 4.29 (dd, J=11.9, 4.4 Hz, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 3.72 (s, 3H), 3.61 (s, 3H), 3.32 (br s, 2H), 3.10 (br d, J=4.9 Hz, 2H), 2.58 (t, J=7.6 Hz, 2H), 2.57 (s, 3H), 2.36-2.20 (m, 10H), 2.19 (s, 3H), 2.17 (s, 3H), 1.79-1.71 (m, 2H), 1.73 (s, 3H), 1.65 (br s, 6H), 1.67-1.56 (m, 6H), 1.43-1.20 (m, 60H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.8 (C), 173.4 (2C; C), 173.0 (C), 172.9 (C), 170.1 (C), 168.4 (C), 162.8 (C), 149.8 (C), 146.2 (C), 146.0 (C), 138.2 (C), 136.2 (C), 134.1 (C), 133.5 (C), 132.5 (CH), 129.6 (C), 123.2 (CH), 122.82 (CH), 122.77 (C), 113.6 (C), 69.0 (CH), 68.4 (CH2), 62.2 (2C; CH2), 61.2 (CH3), 51.6 (CH3), 47.1 (CH2), 39.0 (C), 35.2 (CH2), 34.5 (CH2), 34.3 (CH2), 34.2 (2C; CH2), 32.8 (CH2), 32.1 (2C; CH2), 31.5 (2C; CH3), 29.84 (6C; CH2), 29.80 (4C; CH2), 29.77 (2C; CH2), 29.62 (4C; CH2), 29.50 (2C; CH2), 29.48 (CH2), 29.44 (CH2), 29.41 (2C; CH2), 29.38 (CH2), 29.26 (3C; CH2), 25.5 (CH3), 25.03 (CH2), 25.00 (2C; CH2), 24.9 (CH2), 23.5 (CH2), 22.8 (2C; CH2), 20.4 (CH3), 16.4 (CH3), 14.3 (2C; CH3), 11.9 (CH3); ESI-HRMS: calcd. for C78H124NaO15 [M+Na+] 1323.8832; found 1323.8844.


Compound MPA(O-TML-C12a′aMe-2-TG)-OMe (MPA-I-52) was prepared using similar methods as those described above and employing Int-122.




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Note: The 1H NMR spectrum of this compound suggested the presence of ca. 10% of a related MPA species that could not be removed even after a second attempt at chromatography. 1H NMR (401 MHz, CDCl3) δ 6.76 (d, J=1.8 Hz, 1H), 6.50 (d, J=1.6 Hz, 1H), 5.26 (m, 1H), 5.10 (s, 2H), 4.97 (m, 1H), 4.291/4.283 (each dd, J=11.8, 4.2 Hz, 2H), 4.14 (dd, J=11.9, 6.1 Hz, 2H), 3.72 (s, 3H), 3.61 (s, 3H), 3.33 (br s, 2H), 3.12 (br s, 2H), 2.69 (m, 1H), 2.57 (s, 3H), 2.43 (m, 1H), 2.36-2.27 (m, 6H), 2.25-2.14 (m, 2H), 2.19 (s, 3H), 2.17 (s, 3H), 1.84 (m, 1H), 1.72 (s, 3H), 1.70-1.51 (m, 13H), 1.46-1.19 (m, 63H), 1.13 (d, J=7.0 Hz, 3H), 0.88 (t, J=6.8 Hz, 6H).


Compound MPA(O-C11-2-TG)-OMe (MPA-I-48) was prepared using similar methods as those described above.




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1H NMR (401 MHz, CDCl3) δ 5.25 (m, 1H), 5.13 (s, 2H), 5.10 (m, 1H), 4.28 (dd, J=11.9, 4.4 Hz, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 3.77 (s, 3H), 3.61 (s, 3H), 3.32 (d, J=6.5 Hz, 2H), 2.66 (t, J=7.6 Hz, 2H), 2.40-2.24 (m, 10H), 2.21 (s, 3H), 1.81-1.72 (m, 2H), 1.76 (d, J=0.8 Hz, 3H), 1.66-1.55 (m, 6H), 1.46-1.18 (m, 58H), 0.87 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.8 (C), 173.4 (2C; C), 173.0 (C), 171.8 (C), 168.4 (C), 162.8 (C), 146.3 (C), 146.2 (C), 134.6 (C), 129.3 (C), 122.9 (C), 122.5 (CH), 113.7 (C), 69.0 (CH), 68.4 (CH2), 62.2 (2C; CH2), 61.3 (CH3), 51.6 (CH3), 34.5 (CH2), 34.3 (CH2), 34.2 (2C; CH2), 34.0 (CH2), 32.8 (CH2), 32.1 (2C; CH2), 29.83 (6C; CH2), 29.79 (4C; CH2), 29.75 (2C; CH2), 29.60 (2C; CH2), 29.49 (2C; CH2), 29.45 (CH2), 29.42 (CH2), 29.40 (2C; CH2), 29.28 (CH2), 29.24 (2C; CH2), 29.21 (CH2), 25.01 (CH2), 24.99 (2C; CH2), 24.7 (CH2), 23.7 (CH2), 22.8 (2C; CH2), 16.4 (CH3), 14.3 (2C; CH3), 11.9 (CH3); ESI-HRMS: calcd. for C64H107013 [M+Et] 1083.7706; found 1083.7710.


Compound MPA(O-C12bMe-2-TG)-OMe (MPA-I-53) was prepared using similar methods as those described above.




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1H NMR (401 MHz, CDCl3) δ 5.27 (m, 1H), 5.13 (s, 2H), 5.10 (m, 1H), 4.284/4.282 (each dd, J=11.8, 4.3 Hz, 2H), 4.139/4.138 (each dd, J=11.9, 6.0 Hz, 2H), 3.77 (s, 3H), 3.62 (s, 3H), 3.33 (d, J=6.5 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 2.41-2.25 (m, 9H), 2.21 (s, 3H), 2.11 (dd, J=15.4, 9.2 Hz, 1H), 1.93 (m, 1H), 1.82-1.73 (m, 2H), 1.76 (d, J=0.8 Hz, 3H), 1.65-1.55 (m, 4H), 1.47-1.15 (m, 60H), 0.93 (d, J=6.6 Hz, 3H), 0.87 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.8 (C), 173.4 (2C; C), 172.5 (C), 171.8 (C), 168.4 (C), 162.8 (C), 146.3 (C), 146.2 (C), 134.6 (C), 129.4 (C), 122.9 (C), 122.5 (C), 113.7 (C), 68.9 (CH), 68.4 (CH2), 62.3 (2C; CH2), 61.3 (CH3), 51.6 (CH3), 41.8 (CH2), 36.9 (CH2), 34.5 (CH2), 34.2 (2C; CH2), 34.0 (CH2), 32.9 (CH2), 32.1 (2C; CH2), 30.5 (CH), 29.9 (CH2), 29.83 (6C; CH2), 29.79 (4C; CH2), 29.76 (2C; CH2), 29.63 (CH2), 29.61 (2C; CH2), 29.50 (2C; CH2), 29.47 (CH2), 29.40 (2C; CH2), 29.33 (CH2), 29.25 (2C; CH2), 27.1 (CH2), 25.0 (2C; CH2), 24.8 (CH2), 23.7 (CH2), 22.8 (2C; CH2), 19.7 (CH3), 16.4 (CH3), 14.3 (2C; CH3), 11.9 (CH3).


Example 17: Synthesis of MPA-Phenol Prodrugs with CASI/CMSI Group



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Synthesis of MPA-Phenol Prodrugs with CASI/CMSI Group
Methyl (E)-6-(4-(((chloromethoxy)carbonyl)oxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate (5a; R═H)



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Chloromethyl chloroformate (7.3 μL, 82.2 μmol) and pyridine (12.5 μL, 154 μmol) were added to methyl ester 2 (17.2 mg, 51.4 μmol) in CH2Cl2 (1.5 mL) at 0° C. and the mixture stirred at 0° C. for 20 minutes and then at RT for one hour. The reaction was diluted with CH2Cl2 (20 mL) and the organic phase washed with sat. aq. NaHCO3 (3×20 mL) and brine (2×20 mL each), dried (MgSO4) and concentrated under reduced pressure to give chloromethyl carbonate 5a (21.9 mg, quant.) as a colorless oil that was used without purification; 1H NMR (401 MHz, CDCl3) δ 5.85 (s, 2H), 5.18 (s, 2H), 5.10 (m, 1H), 3.81 (s, 3H), 3.62 (s, 3H), 3.41 (d, J=6.8 Hz, 2H), 2.41-2.36 (m, 2H), 2.32-2.26 (m, 2H), 2.25 (s, 3H), 1.78 (d, J=0.8 Hz, 3H).


Methyl (E)-6-(4-(((1-chloroethoxy)carbonyl)oxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methylhex-4-enoate (5b; R=Me)



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1-Chloroethyl chloroformate (5.8 μL, 53.8 μmol) and pyridine (6.5 μL, 80.7 μmol) were added to methyl ester 2 (15.0 mg, 44.9 μmol) in CH2Cl2 (1 mL) at 0° C. and the mixture stirred at 0° C. for five minutes and then at rt for 40 minutes. The reaction was diluted with CH2Cl2 (30 mL) and the organic phase washed with water and brine (30 mL each), dried (MgSO4) and concentrated under reduced pressure to give chloroethyl carbonate 5b (19.8 mg, quant.) as a colorless oil that was used without purification. 1H NMR (401 MHz, CDCl3) δ 6.52 (q, J=5.8 Hz, 1H), 5.18 (s, 2H), 5.11 (td, J=6.9, 1.2 Hz, 1H), 3.80 (s, 3H), 3.62 (s, 3H), 3.46-3.34 (m, 2H), 2.41-2.35 (m, 2H), 2.32-2.25 (m, 2H), 2.24 (s, 3H), 1.94 (d, J=5.8 Hz, 3H), 1.78 (d, J=0.6 Hz, 3H).


(E)-12-(1,3-Bis(palmitoyloxy)propan-2-yl) 1-(((((6-methoxy-5-(6-methoxy-3-methyl-6-oxohex-2-en-1-yl)-7-methyl-3-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)carbonyl)oxy)methyl) 2,10-dimethyldodecanedioate (6a) (MPA-I-21)



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Potassium carbonate (13.8 mg, 99.8 μmol) and tetra-n-butylammonium iodide (TBAI, 10.2 mg, 27.6 μmol) were added to a solution of acid-TG Int-27 (50.0 mg, 61.7 μmol) and chloride 5a (24.0 mg, 56.2 μmol) in DMF (2 mL) and the mixture heated at 80° C. for two hours. The reaction was cooled to RT, diluted with water (20 mL) and the aqueous phase extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with water (2×20 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (5% to 20% ethyl acetate/hexanes) gave MPA-CASI prodrug MPA(O-CASI-C12a′bMe-2-TG)-OMe (6a) (MPA-I-21) (8.6 mg, 13%) as a colorless oil. 1H NMR (401 MHz, CDCl3) δ 5.91 (d, J=5.6 Hz, 1H), 5.86 (d, J=5.6 Hz, 1H), 5.37 (m, 1H), 5.16 (s, 2H), 5.11 (m, 1H), 4.28 (dd, J=11.8, 4.2 Hz, 2H), 4.14 (dd, J=12.3, 5.1 Hz, 2H), 3.79 (s, 3H), 3.62 (s, 3H), 3.38 (d, J=7.1 Hz, 2H), 2.55 (m, 1H), 2.41-2.26 (m, 9H), 2.23 (s, 3H), 2.10 (dd, J=14.7, 8.5 Hz, 1H), 1.92 (m, 1H), 1.76 (s, 3H), 1.66-1.50 (m, 6H), 1.38-1.23 (m, 60H), 1.21 (d, J=7.0 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 0.88 (t, J=6.9 Hz, 6H).


Example 18: Synthesis of MPA-Phenol Prodrugs with FSI5 Group



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Synthesis of MPA-Phenol Prodrugs with FSI5 Group
Methyl (E)-6-(4-((5-bromopentanoyl)oxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate (7)



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DMAP (10.9 mg, 0.0897 mmol) and EDC.HCl (43.0 mg, 0.224 mmol) were added to a solution of 5-bromovaleric acid (24.4 mg, 0.135 mmol) and methyl ester 2 (30.0 mg, 0.0897 mmol) in CH2Cl2 (2 mL) and the mixture stirred at RT for 30 minutes. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added, and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (35% ethyl acetate/hexanes) gave 5-bromovalerate ester 7 (38.1 mg, 85%) as a colorless solid; 1H NMR (401 MHz, CDCl3) δ 5.13 (s, 2H), 5.08 (m, 1H), 3.77 (s, 3H), 3.61 (s, 3H), 3.47 (t, J=6.4 Hz, 2H), 3.33 (d, J=6.6 Hz, 2H), 2.71 (t, J=7.0 Hz, 2H), 2.40-2.33 (m, 2H), 2.32-2.25 (m, 2H), 2.21 (s, 3H), 2.07-1.88 (m, 4H), 1.76 (d, J=0.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 173.7 (C), 171.2 (C), 168.4 (C), 162.8 (C), 146.3 (C), 146.0 (C), 134.7 (C), 129.3 (C), 123.1 (C), 122.4 (CH), 113.6 (C), 68.5 (CH2), 61.3 (CH3), 51.6 (CH3), 34.5 (CH2), 33.4 (CH2), 32.82 (CH2), 32.81 (CH2), 31.9 (CH2), 23.7 (CH2), 23.2 (CH2), 16.4 (CH3), 11.9 (CH3).


(E)-12-(1,3-Bis(palmitoyloxy)propan-2-yl) 1-(5-((6-methoxy-5-(6-methoxy-3-methyl-6-oxohex-2-en-1-yl)-7-methyl-3-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)-5-oxopentyl) 2,10-dimethyldodecanedioate (8a) (MPA-I-22)




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Silver carbonate (4.3 mg, 15.4 μmol) and tetra-n-butylammonium iodide (TBAI, 3.5 mg, 9.7 μmol) were added to a solution of acid-TG Int-27 (17.2 mg, 21.2 μmol) and bromide 7 (9.6 mg, 19.3 μmol) in toluene (1 mL) and the mixture heated at 90° C. for two hours. The reaction was cooled to RT, diluted with ethyl acetate (40 mL) and the organic phase washed with water and brine (30 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (20% to 25% ethyl acetate/hexanes) gave MPA-(O-FSI5-C12a′bMe-2-TG)-OMe prodrug 8a (MPA-I-22) (17.6 mg, 74%) as a colorless oil; 1H NMR (401 MHz, CDCl3) δ 5.27 (m, 1H), 5.14 (s, 2H), 5.10 (td, J=6.6, 1.1 Hz, 1H), 4.28 (dd, J=11.9, 3.6 Hz, 2H), 4.17-4.08 (m, 4H), 3.78 (s, 3H), 3.62 (s, 3H), 3.33 (d, J=6.7 Hz, 2H), 2.73 (t, J=6.5 Hz, 1H), 2.46-2.25 (m, 6H), 2.30 (t, J=7.6 Hz, 4H), 2.22 (s, 2H), 2.10 (dd, J=14.7, 8.4 Hz, 1H), 1.97-1.74 (m, 5H), 1.77 (d, J=0.8 Hz, 3H), 1.70-1.52 (m, 6H), 1.45-1.20 (m, 60H), 1.14 (d, J=7.0 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 177.1 (C), 173.7 (C), 173.4 (2C; C), 172.5 (C), 171.3 (C), 168.4 (C), 162.8 (C), 146.3 (C), 146.1 (C), 134.7 (C), 129.3 (C), 123.0 (C), 122.5 (CH), 113.7 (C), 68.9 (CH), 68.5 (CH2), 63.9 (CH2), 62.3 (2C; CH2), 61.3 (CH3), 51.7 (CH3), 41.8 (CH2), 39.7 (CH), 36.9 (CH2), 34.5 (CH2), 34.2 (2C; CH2), 33.9 (CH2), 33.4 (CH2), 32.9 (CH2), 32.1 (2C; CH2), 30.5 (CH), 29.9 (CH2), 29.84 (6C; CH2), 29.80 (4C; CH2), 29.76 (2C; CH2), 29.72 (CH2), 29.68 (CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 28.2 (CH2), 27.4 (CH2), 27.1 (CH2), 25.0 (2C; CH2), 23.7 (CH2), 22.8 (2C; CH2), 21.3 (CH2), 19.7 (CH3), 17.2 (CH3), 16.4 (CH3), 14.3 (2C; CH3), 11.9 (CH3).


(E)-1-(1,3-bis(palmitoyloxy)propan-2-yl) 10-(5-((6-methoxy-5-(6-methoxy-3-methyl-6-oxohex-2-en-1-yl)-7-methyl-3-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)-4-methyl-5-oxopentyl) 3-methyldecanedioate (MPA-I-33)



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Synthesis of Additional MPA-Phenol Prodrugs with FSI5 Group
Methyl (E)-6-(4-((5-iodo-2-methylpentanoyl)oxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate (Int-89)



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DMAP (3.4 mg, 27.5 μmol) and EDC.HCl (13.2 mg, 68.8 mmol) were added to a solution of 5-iodo-2-valeric acid (9.9 mg, 41.3 mmol) and MPA methyl ester 2 (9.2 mg, 27.5 mmol) in CH2Cl2 (0.8 mL) and the mixture stirred at RT for 17 hours. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added, and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (40% ethyl acetate/hexanes) gave semi-pure ester Int-89 (13.0 mg, 85%) as a colorless solid. Note: The quoted yield is not accurate due to significant amounts of inseparable impurities in the sample, presumably carried forward from 5-iodo-2-valeric acid. As a result, the NMR spectra contained a number of additional signals—the major peaks are reported. 1H NMR (401 MHz, CDCl3) δ 5.14 (s, 2H), 5.09 (m, 1H), 3.77 (s, 3H), 3.62 (s, 3H), 3.35-3.22 (m, 4H), 2.83 (m, 1H), 2.40-2.33 (m, 2H), 2.32-2.25 (m, 2H), 2.22 (s, 3H), 2.03-1.93 (m, 2H), 1.77 (s, 3H), 1.67-1.58 (m, 2H), 1.39 (d, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 174.0 (C), 173.7 (C), 168.4 (C), 162.8 (C), 146.4 (C), 146.0 (C), 134.9 (C), 129.5 (C), 123.1 (C), 122.5 (CH), 113.8 (C), 68.4 (CH2), 61.3 (CH3), 51.7 (CH3), 38.6 (CH), 34.5 (CH2), 34.3 (CH2), 32.9 (CH2), 31.0 (CH2), 23.6 (CH2), 17.2 (CH3), 16.6 (CH3), 11.9 (CH3), 6.8 (CH2).




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Silver carbonate (2.6 mg, 9.3 μmol) and tetra-n-butylammonium iodide (TBAI, 1.7 mg, 4.7 μmol) were added to a solution of acid-TG Int-30 (9.8 mg, 12.8 μmol) and iodide Int-89 (6.5 mg, 11.6 μmol) in toluene (0.8 mL) and the mixture heated at reflux for two hours. The reaction was cooled to RT, diluted with ethyl acetate (40 mL) and the organic phase washed with water and brine (30 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (20% to 25% ethyl acetate/hexanes) gave prodrug MPA-(O-FSI5α-C10βMe-2-TG)-OMe (MPA-I-33) (6.9 mg, 50%) as a colorless oil. 1H NMR (401 MHz, CDCl3) δ 5.26 (m, 1H), 5.14 (s, 2H), 5.09 (td, J=6.4, 1.0 Hz, 1H), 4.28 (dd, J=12.0, 4.1 Hz, 2H), 4.18-4.06 (m, 4H), 3.77 (s, 3H), 3.62 (s, 3H), 3.32 (br s, 2H), 2.84 (m, 1H), 2.40-2.25 (m, 11H), 2.22 (s, 3H), 2.10 (dd, J=14.7, 8.5 Hz, 1H), 2.01-1.87 (m, 2H), 1.85-1.77 (m, 2H), 1.76 (s, 3H), 1.69-1.52 (m, 7H), 1.39 (d, J=7.0 Hz, 3H), 1.35-1.14 (m, 56H), 0.92 (d, J=6.6 Hz, 3H), 0.88 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 174.2 (C), 174.0 (C), 173.5 (2C; C), 172.5 (C), 168.3 (C), 162.8 (C), 146.4 (C), 146.0 (C), 134.8 (C), 129.4 (C), 123.0 (C), 122.5 (CH), 113.8 (C), 69.0 (CH), 68.4 (CH2), 64.3 (CH2), 62.3 (2C; CH2), 61.3 (CH3), 51.7 (CH3), 41.8 (CH2), 39.2 (CH), 36.8 (CH2), 34.5 (CH2), 34.4 (CH2), 34.2 (2C; CH2), 32.9 (CH2), 32.1 (2C; CH2), 30.5 (CH), 29.85 (6C; CH2), 29.81 (4C; CH2), 29.77 (2C; CH2), 29.6 (3C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.34 (CH2), 29.27 (2C; CH2), 26.9 (CH2), 26.4 (CH2), 25.1 (CH2), 25.0 (2C; CH2), 23.6 (CH2), 22.8 (2C; CH2), 19.6 (CH3), 17.1 (CH3), 16.5 (CH3), 14.3 (2C; CH3), 11.9 (CH3). Note: Two signals were not observed in the 13C NMR spectrum, possibly due to broadening of signals in proximity to the phenol ester functionality.


Example 19: Synthesis of MPA-phenol Prodrugs with ASI Group



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Synthesis of MPA-I-41 and other MPA-phenol Prodrugs

To a solution of compound Int-123 (0.190 g, 0.250 mmol) in acetone (10 ml) was added NaI (0.093 g, 0.626 mmol) at room temperature and the mixture stirred at rt for 18 h. Then mycophenolic acid methyl ester 2 (0.084 g, 0.250 mmol) and sodium carbonate (0.066 g, 0.626 mmol) were added at rt and stirred for 18 h. Progress of the reaction was monitored by TLC/Mass analysis; TLC analysis showed one non-polar spot along with some amount of unreacted 2. Then the reaction mixture was diluted with DCM (25 mL) and filtered through celite and washed with DCM (10 ml). Then the organic layer was directly distilled out at reduced pressure; the resulting crude material was purified by combi flash purification, pure product eluted with 10% ethyl acetate/hexane to obtain pure compound MPA-(O-ASI-C12aaDiMe-2-TG)-OMe (MPA-I-41) (50 mg, 17%) as a viscous liquid. 1H NMR (400 MHz, CDCl3) δ 6.01 (d, J=6.4 Hz, 1H), 5.96 (d, J=6.4 Hz, 1H), 5.31 (d, J=6.3 Hz, 1H), 5.20 (s, 3H), 4.33 (dd, J=11.9, 4.3 Hz, 2H), 4.18 (dd, J=11.9, 6.0 Hz, 2H), 3.80 (s, 3H), 3.66 (s, 3H), 3.39 (d, J=6.9 Hz, 2H), 2.51-2.34 (m, 12H), 2.23 (s, 3H), 1.81 (s, 2H), 1.61 (s, 15H), 1.35-1.29 (m, 52H), 1.17 (dd, J=11.2, 7.0 Hz, 6H), 0.92 (t, J=6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 175.91 (2C), 175.86 (1C), 173.78 (1C), 173.31 (2C), 169.09 (1C), 162.79 (1C), 153.07 (1C), 146.68 (1C), 13.95 (1C), 129.03 (1C), 123.05 (2C), 120.93 (1C), 111.91 (1C), 90.06 (2C), 68.67 (1C), 68.43 (1C), 62.13 (1C), 60.95 (1C), 51.50 (1C), 39.52 (1C), 39.40 (1C), 34.58 (1C), 34.05 (3C), 33.61 (1C), 33.43 (1C), 32.83 (1C), 31.94 (3C), 29.72-29-14 (17C), 27.17 (1C), 24.86 (3C), 23.77 (1C), 22.71 (3C), 17.04 (1C), 16.83 (1C), 16.16 (1C), 14.15 (4C), 11.68 (1C). HPLC (ELSD): 9.73 min, 100% purity; HPLC (uv-215 nm): 9.69 min, 97.28% purity; LCMS: 7.91 min 100% purity. MASS (ESI, +ve) m/z: 1173.10 (MH+18). ELSD Method:—PDS_HPLC_GEMINI_C4_JUPITER_GRA-1; Mobile Phase: 100% Methanol; Column: Phenomenex JUPITER C4 (100*4.6) mm, 5μ; Column Flow: 1.0 mL/min; Column Temperature: Ambient; ELSD: SPRAY CHAMBER −50° C.


Compound MPA(O-ASI-C12a′bMe-2-TG)-OMe (MPA-I-44) was prepared using similar methods.




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1H NMR (400 MHz, CDCl3) δ 6.01-5.99 (dd, J=6.4 Hz, 2H), 5.34-5.30 (m, 1H), 5.19 (s, 3H), 4.34-4.30 (dd, J=11.9, 4.3 Hz, 2H), 4.20-4.16 (dd, J=11.9, 6.0 Hz, 2H), 3.80 (s, 3H), 3.65 (s, 3H), 3.40-3.38 (d, J=6.9 Hz, 2H), 2.48-2.40 (m, 4H), 2.38-2.29 (m, 7H), 2.22 (s, 3H), 1.96 (m, 1H), 1.81 (s, 3H), 1.65-1.62 (m, 4H), 1.38-1.24 (m, 4H), 1.29 (m, 57H), 1.15 (d, J=7.0 Hz, 4H), 0.97-0.93 (d, J=7.0 Hz, 3H), 0.91-0.90 (t, J=6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) 175.87 (1C), 173.78 (1C), 173.32 (1C), 172.35 (1C), 169.09 (1C), 162.82 (1C), 153.10 (1C), 146.70 (1C), 133.97 (1C), 129.07 (1C), 123.10 (1C), 120.94 (1C), 111.94 (1C), 90.09 (1C), 68.82 (1C), 68.43 (1C), 62.16 (1C), 60.96 (1C), 51.50 (1C), 41.71 (1C), 39.43 (1C), 36.73 (1C), 34.61 (1C), 34.07 (1C), 33.45 (1C), 32.86 (1C), 31.96 (1C), 30.38 (1C), 29.80-29.15 (30C), 27.17 (1C), 26.96 (1C), 24.88 (1C), 23.80 (1C), 22.73 (1C), 19.55 (1C), 16.84 (1C), 16.18 (1C), 14.16 (1C), 11.68 (1C). HPLC (ELSD): 9.77 min, 98.71% purity; HPLC (uv-215 nm): 9.74 min, 95.42% purity; LCMS: 8.80 min 100% purity; MS (ESI, +ve) m/z: 1173.10 (MH+18). ELSD Method: -PDS_HPLC_GEMINI_C4_JUPITER_GRA-1; Mobile Phase: 100% MEOH; System: Agilent Technologies 1260 Infinity with PDA Detector & ELSD Detector. Column: Phenomenex JUPITER C4, 100*4.6 mm, 5μ; Column Flow: 1.0 ml/min; Column Temp: Ambient; ELSD: SPRAY CHAMBER −50° C.


Using similar methods to those described above, compound MPA-(O-ET-C2-2-TG)-OMe (MPA-I-23) was prepared.




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Synthesis of MPA-I-23

Potassium carbonate (6.6 mg, 47.9 μmol) and tetra-n-butylammonium iodide (4.4 mg, 12.0 μmol) were added to a solution of methyl ester 2 (8.0 mg, 23.9 μmol) and bromide Int-91 (20.1 mg, 31.1 μmol) in DMF (1.5 mL) and the mixture heated at 100° C. for 30 minutes. The reaction was cooled to rt, diluted with ethyl acetate (20 mL) and the organic phase washed with water and brine (20 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (15% to 20% ethyl acetate/hexanes) gave MPA prodrug MPA-I-23 (10.1 mg, 45%) as a colourless solid. 1H NMR (401 MHz, CDCl3) δ 5.32 (m, 1H), 5.20 (m, 1H), 5.13 (s, 2H), 5.08 (s, 2H), 4.30 (dd, J=12.0, 4.4 Hz, 2H), 4.15 (dd, J=12.0, 5.9 Hz, 2H), 3.77 (s, 3H), 3.60 (s, 3H), 3.56 (d, J=6.8 Hz, 2H), 2.41-2.34 (m, 2H), 2.32-2.26 (m, 6H), 2.17 (s, 3H), 1.78 (s, 3H), 1.68-1.54 (m, 4H), 1.35-1.19 (m, 48H), 0.88 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.9 (C), 173.4 (2C; C), 169.2 (C), 168.7 (C), 163.1 (C), 154.6 (C), 146.7 (C), 134.0 (C), 129.1 (C), 123.6 (CH), 120.4 (C), 111.4 (C), 71.0 (CH2), 70.0 (CH), 68.7 (CH2), 62.0 (2C; CH2), 61.1 (CH3), 51.6 (CH3), 34.7 (CH2), 34.1 (2C; CH2), 33.0 (CH2), 32.1 (2C; CH2), 29.85 (6C; CH2), 29.81 (4C; CH2), 29.77 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 24.9 (2C; CH2), 23.9 (CH2), 22.8 (2C; CH2), 16.3 (CH3), 14.3 (2C; CH3), 11.7 (CH3); ESI-HRMS: Calcd. for C55H91O12 [M+H+] 943.6505; found 943.6508.


Using similar methods to those described above, compound MPA-(O-ET-C5-2-TG)-OMe (MPA-I-24) was prepared.




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Synthesis of MPA-I-24

DBU (4.4 μL, 29.6 μmol) was added to a suspension of methyl ester 2 (5.5 mg, 16.4 μmol) and the bromide intermediate above (13.2 mg, 18.1 μmol) in toluene (0.8 mL) and the mixture heated at reflux for two hours. The reaction was cooled to rt, then diluted with ethyl acetate (40 mL). The organic phase was washed with water and brine (30 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (15% to 20% ethyl acetate/hexanes) gave MPA prodrug MPA-I-24 (7.0 mg, 43%) as a colorless solid.



1H NMR (401 MHz, CDCl3) δ 5.26 (m, 1H), 5.15 (m, 1H), 5.11 (s, 2H), 4.29 (dd, J=11.9, 4.4 Hz, 2H), 4.21 (t, J=6.0 Hz, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 3.76 (s, 3H), 3.61 (s, 3H), 3.40 (d, J=6.6 Hz, 2H), 2.44 (t, J=7.1 Hz, 2H), 2.41-2.26 (m, 4H), 2.31 (t, J=7.5 Hz, 4H), 2.17 (s, 3H), 1.92-1.81 (m, 4H), 1.79 (s, 3H), 1.67-1.55 (m, 4H), 1.36-1.19 (m, 48H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.48 (3C; C), 172.70 (C), 169.07 (C), 163.00 (C), 155.82 (C), 146.85 (C), 133.91 (C), 129.13 (C), 123.89 (CH), 120.00 (C), 112.75 (C), 74.99 (CH2), 69.11 (CH), 68.37 (CH2), 65.19 (CH2), 62.20 (2C; CH2), 61.07 (CH3), 51.62 (CH3), 34.68 (CH2), 34.26 (CH2), 34.17 (2C; CH2), 33.92 (CH2), 32.97 (CH2), 32.08 (2C; CH2), 29.85 (2C; CH2), 29.81 (2C; CH2), 29.77 (2C; CH2), 29.64 (2C; CH2), 29.51 (3C; CH2), 29.43 (2C; CH2), 29.27 (2C; CH2), 25.00 (2C; CH2), 23.65 (CH2), 22.84 (2C; CH2), 21.41 (CH2), 16.39 (CH3), 14.27 (2C; CH3), 11.68 (CH3); ESI-HRMS: Calcd. for C58H97O12 [M+H+] 985.6975; found 985.6971.


Example 20: Synthesis of (E)-2-(4-((6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)butoxy)propane-1,3-diyl dipalmitate (MPA-I-25) and (E)-2-((6-((6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)hexyl)oxy)propane-1,3-diyl dipalmitate (MPA-I-25 and MPA-I-26)



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Synthesis of MPA-I-25

Synthesis of Int-82:




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Imidazole (128 mg, 1.87 mmol) and tert-butyl(chloro)dimethylsilane (TBSCl, 141 mg, 0.937 mmol) were added to a solution of mycophenolic acid (MPA, 200 mg, 0.624 mmol) in DMF (7 mL) and the mixture stirred at rt for 22 hours. Extra portions of imidazole (65.0 mg, 0.954 mmol) and TB (80.0 mg, 0.531 mmol) were added and the mixture stirred at rt for an additional two days and 18 hours. The reaction was diluted with ethyl acetate (20 mL) and water (30 mL) and the aqueous phase extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water and brine (80 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography (10% to 35% ethyl acetate/hexanes) gave MPA(OTBS) Int-82 (164 mg, 60%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 5.19 (m, 1H), 5.06 (s, 2H), 3.73 (s, 3H), 3.38 (d, J=6.3 Hz, 2H), 2.46-2.36 (m, 2H), 2.33-2.24 (m, 2H), 2.14 (s, 3H), 1.75 (s, 3H), 1.02 (s, 9H), 0.23 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 179.4 (C), 169.4 (C), 163.3 (C), 151.9 (C), 146.2 (C), 133.5 (C), 127.7 (C), 124.0 (CH), 118.1 (C), 111.8 (C), 67.8 (CH2), 60.8 (CH3), 34.2 (CH2), 32.9 (CH2), 26.2 (3C; CH3), 23.8 (CH2), 18.9 (C), 16.4 (CH3), 11.5 (CH3), −3.4 (2C; CH3).


Synthesis of Int-83:




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DMAP (5.0 mg, 40.6 μmol) and DCC (11.7 mg, 56.9 μmol) were added to a solution of acid Int-82 (17.8 mg, 40.6 μmol) and alcohol Int-78 (26.0 mg, 40.6 μmol) in CH2Cl2 (1.5 mL) and the mixture stirred at rt for 16 hours. To ensure complete reaction, extra portions of DMAP (4 mg) and DCC (8 mg) were added and stirring continued at rt for a further five hours. The resulting suspension was diluted with CH2Cl2 (15 mL), cooled to 0° C. and filtered through Celite, washing with further CH2Cl2 (50 mL). The organic phase was washed with 1 M HCl, water, sat. aq. NaHCO3 and brine (60 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (12.5% to 17.5% ethyl acetate/hexanes) gave protected MPA triglyceride Int-83 (37.8 mg, 88%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 5.17 (dt, J=6.5, 3.2 Hz, 1H), 5.06 (s, 2H), 4.18 (dd, J=11.6, 4.9 Hz, 2H), 4.10 (dd, J=11.6, 5.5 Hz, 2H), 4.03 (t, J=6.4 Hz, 2H), 3.73 (s, 3H), 3.67 (m, 1H), 3.56 (t, J=6.1 Hz, 2H), 3.37 (d, J=6.3 Hz, 2H), 2.41-2.22 (m, 8H), 2.15 (s, 3H), 1.75 (s, 3H), 1.70-1.53 (m, 8H), 1.36-1.16 (m, 48H), 1.03 (s, 9H), 0.88 (t, J=6.9 Hz, 6H), 0.24 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 173.7 (2C; C), 173.5 (C), 169.3 (C), 163.4 (C), 151.9 (C), 146.2 (C), 133.9 (C), 127.8 (C), 123.7 (CH), 118.0 (C), 111.8 (C), 75.5 (CH), 70.0 (CH2), 67.8 (CH2), 64.2 (CH2), 63.1 (2C; CH2), 60.9 (CH3), 34.6 (CH2), 34.3 (2C; CH2), 33.2 (CH2), 32.1 (2C; CH2), 29.84 (6C; CH2), 29.80 (4C; CH2), 29.76 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 26.5 (CH2), 26.2 (CH2), 25.5 (CH2), 25.1 (2C; CH2), 23.8 (CH2), 22.8 (2C; CH2), 18.9 (C), 16.5 (CH3), 14.3 (2C; CH3), 11.6 (CH3), −3.4 (CH3).


Synthesis of MPA-I-25:




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Tetrabutylammonium fluoride (TBAF, 1 M in THF, 38.1 μL, 38.1 μmol) was added to a solution of TBS ether Int-83 (26.9 mg, 38.1 μmol) in THF (1.5 mL) at 0° C. and the mixture was stirred at 0° C. for 50 minutes. The reaction was diluted with ethyl acetate, quenched with water and the aqueous phase extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (20% ethyl acetate/hexanes) gave prodrug MPA-C4-ET-2-TG (MPA-I-25) (20.0 mg, 83%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 7.68 (s, 1H), 5.23 (dd, J=7.5, 6.4 Hz, 1H), 5.19 (s, 2H), 4.18 (dd, J=11.6, 4.9 Hz, 2H), 4.10 (dd, J=11.6, 5.5 Hz, 2H), 4.03 (t, J=6.3 Hz, 2H), 3.76 (s, 3H), 3.67 (m, 1H), 3.56 (t, J=6.0 Hz, 2H), 3.38 (d, J=6.9 Hz, 2H), 2.41-2.35 (m, 2H), 2.34-2.26 (m, 6H), 2.14 (s, 3H), 1.79 (s, 3H), 1.69-1.56 (m, 8H), 1.35-1.20 (m, 48H), 0.88 (t, J=6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 173.7 (2C; C), 173.5 (C), 173.1 (C), 163.8 (C), 153.8 (C), 144.2 (C), 134.3 (C), 122.8 (CH), 122.3 (C), 116.8 (C), 106.5 (C), 75.5 (CH), 70.2 (CH2), 70.0 (CH2), 64.2 (CH2), 63.1 (2C; CH2), 61.1 (CH3), 34.8 (CH2), 34.3 (2C; CH2), 33.3 (CH2), 32.1 (2C; CH2), 29.84 (6C; CH2), 29.80 (4C; CH2), 29.76 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 26.5 (CH2), 25.5 (CH2), 25.1 (2C; CH2), 22.8 (2C; CH2), 22.7 (CH2), 16.3 (CH3), 14.3 (2C; CH3), 11.7 (CH3); ESI-HRMS: calcd. for C56H94NaO11 [M+Na+] 965.6688; found 965.6697.


Using similar procedures employing Int-73 instead of Int-78, compound (E)-2-((6-((6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl hex-4-enoyl)oxy)hexyl)oxy)propane-1,3-diyl dipalmitate (MPA-I-26) was prepared.




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Synthesis of MPA-I-26

Synthesis of Int-84:




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DMAP (6.4 mg, 52.1 μmol) and DCC (15.1 mg, 72.9 μmol) were added to a solution of acid Int-82 (22.7 mg, 52.1 μmol) and alcohol Int-73 (38.2 mg, 57.3 μmol) in CH2Cl2 (1.5 mL) and the mixture stirred at rt for 16 hours. The resulting suspension was diluted with CH2Cl2 (10 mL), cooled to 0° C. and filtered through Celite, washing with further CH2Cl2 (40 mL). The organic phase was washed with 1 M HCl, water, sat. aq. NaHCO3 and brine (40 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (10% to 15% ethyl acetate/hexanes) gave MPA triglyceride Int-84 (43.6 mg, 77% over two steps) as a colorless oil; 1H NMR (400 MHz, CDCl3): δ 5.18 (dd, J=6.5, 5.3 Hz, 1H), 5.06 (s, 2H), 4.18 (dd, J=11.6, 5.0 Hz, 2H), 4.11 (dd, J=11.6, 5.5 Hz, 2H), 4.00 (t, J=6.7 Hz, 2H), 3.74 (s, 3H), 3.66 (m, 1H), 3.54 (t, J=6.5 Hz, 2H), 3.38 (d, J=6.3 Hz, 2H), 2.40-2.24 (m, 8H), 2.15 (s, 3H), 1.75 (s, 3H), 1.66-1.51 (m, 8H), 1.39-1.18 (m, 52H), 1.03 (s, 9H), 0.88 (t, J=6.9 Hz, 6H), 0.23 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 173.7 (2C; C), 173.6 (C), 169.3 (C), 163.3 (C), 151.9 (C), 146.2 (C), 133.9 (C), 127.8 (C), 123.7 (CH), 118.1 (C), 111.8 (C), 75.4 (CH), 70.6 (CH2), 67.8 (CH2), 64.5 (CH2), 63.1 (2C; CH2), 60.9 (CH3), 34.6 (CH2), 34.3 (2C; CH2), 33.2 (CH2), 32.1 (2C; CH2), 30.0 (CH2), 29.85 (6C; CH2), 29.81 (4C; CH2), 29.77 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 28.7 (CH2), 26.2 (3C; CH3), 25.9 (CH2), 25.8 (CH2), 25.1 (2C; CH2), 23.8 (CH2), 22.8 (2C; CH2), 18.9 (C), 16.5 (CH3), 14.3 (2C; CH3), 11.6 (CH3), −3.4 (2C; CH3).


Synthesis of MPA-I-26:




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Tetrabutylammonium fluoride (TBAF, 1 M in THF, 60.2 μL, 60.2 μmol) was added to a solution of TBS ether Int-84 (43.6 mg, 40.2 μmol) in THF (2.5 mL) at 0° C. and the mixture was stirred at 0° C. for one hour. The reaction was diluted with ethyl acetate (10 mL) and water (20 mL) and the aqueous phase extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with water and brine (50 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (20% ethyl acetate/hexanes) gave MPA prodrug MPA-C6-ET-2-TG (MPA-I-26) (30.8 mg, 79%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 7.67 (s, 1H), 5.24 (td, J=6.9, 1.1 Hz, 1H), 5.19 (s, 2H), 4.18 (dd, J=11.6, 5.0 Hz, 2H), 4.11 (dd, J=11.6, 5.5 Hz, 2H), 4.00 (t, J=6.7 Hz, 2H), 3.76 (s, 3H), 3.67 (m, 1H), 3.54 (t, J=6.5 Hz, 2H), 3.38 (d, J=6.9 Hz, 2H), 2.42-2.35 (m, 2H), 2.35-2.26 (m, 6H), 2.14 (s, 3H), 1.80 (s, 3H), 1.66-1.51 (m, 8H), 1.39-1.19 (m, 52H), 0.88 (t, J=6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 173.7 (C), 173.6 (2C; C), 173.1 (C), 163.8 (C), 153.8 (C), 144.1 (C), 134.2 (C), 122.8 (CH), 122.3 (C), 116.8 (C), 106.5 (C), 75.4 (CH), 70.6 (CH2), 70.2 (CH2), 64.5 (CH2), 63.1 (2C; CH2), 61.1 (CH3), 34.8 (CH2), 34.3 (CH2), 33.3 (CH2), 32.1 (CH2), 30.0 (CH2), 29.84 (6C; CH2), 29.80 (4C; CH2), 29.76 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 28.7 (CH2), 25.9 (CH2), 25.8 (CH2), 25.1 (2C; CH2), 22.8 (2C; CH2), 22.7 (CH2), 16.3 (CH3), 14.3 (2C; CH3), 11.7 (CH3); ESI-HRMS: calcd. for C58H98NaO11 [M+Na+] 993.7001; found 993.7012.


Example 21: Synthesis of (E)-2-(((3-((6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)propoxy)carbonyl)oxy)propane-1,3-diyl dipalmitate (MPA-I-27)



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Synthesis of MPA-I-27

3-Chloropropyl chloroformate (20.3 μL, 0.169 mmol) and N,N-diethylisopropylamine (DIPEA, 54.2 μL, 0.316 mmol) were added to 1,3-diglyceride Int-2 (60.0 mg, 0.105 mmol) and DMAP (2.6 mg, 0.0211 mmol) in CH2Cl2 (3 mL) at 0° C. and the mixture stirred at RT for 18 hours. The reaction was diluted with CH2Cl2 (30 mL) and the organic phase washed with water, sat. aq. NaHCO3 and brine (25 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (4% to 5.5% ethyl acetate/hexanes) gave an inseparable mixture of chloropropyl carbonates Int-85 and a regioisomer (ca. 1:1 ratio, 49.8 mg, 69%) as a colorless solid. This mixture was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 5.28 (m, 1H), 4.38-4.13 (m, 6H), 3.63 (t, J=6.3 Hz, 2H), 2.35-2.29 (m, 4H), 2.18-2.10 (m, 2H), 1.66-1.56 (m, 4H), 1.36-1.19 (m, 48H), 0.88 (t, J=6.9 Hz, 6H). Note: The 1H NMR spectrum was acquired using a sample enriched in target carbonate Int-85.


Compound Int-86 is a known compound that may be prepared as described in WO 2016/023082, hereby incorporated by reference in its entirety.


DBU (15.1 μL, 0.101 mmol) was added to a suspension of acid Int-86 (31.2 mg, 0.0867 mmol) and chloride Int-85 and its regioisomer (49.8 mg combined, 0.0722 mmol) and the mixture heated at reflux for 30 minutes. TLC analysis at this time showed very little reaction progress, so tetra-n-butylammonium iodide (TBAI, 5.0 mg, 0.0135 mmol) was added and the mixture heated at reflux for a further 3.5 hours. The reaction was cooled to rt, then diluted with ethyl acetate and water (10 mL each). The aqueous layer was separated and acidified to pH 2 with 1 M HCl, and then extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with water, sat. aq. NaHCO3 and brine (40 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (10% to 20% ethyl acetate/hexanes) gave unreacted chlorides Int-85 and its regioisomer (ca. 3:1 ratio, 30 mg) along with protected MPA prodrug Int-87 (14.5 mg) as a colorless oil. Re-subjection of the unreacted starting materials under the same reaction conditions (acid Int-86, DBU, TBAI, reflux for four hours) gave an additional batch of product Int-87 (31.9 mg total, 30% over two steps from 1,3-diglyceride Int-2). 1H NMR (400 MHz, CDCl3): δ 6.09 (ddt, J=16.3, 10.4, 5.9 Hz, 1H), 5.37 (ddd, J=17.2, 3.0, 1.5 Hz, 1H), 5.23 (dd, J=10.4, 1.5 Hz, 1H), 5.13 (s, 2H), 5.06 (m, 1H), 4.78 (dt, J=5.9, 1.2 Hz, 2H), 4.33 (dd, J=12.1, 4.2 Hz, 2H), 4.20 (t, J=6.7 Hz, 2H), 4.18 (dd, J=12.3, 5.9 Hz, 2H), 4.12 (t, J=6.3 Hz, 2H), 3.76 (s, 3H), 3.41 (d, J=6.7 Hz, 2H), 2.42-2.36 (m, 2H), 2.34-2.26 (m, 6H), 2.18 (s, 3H), 2.02-1.93 (m, 2H), 1.78 (s, 3H), 1.64-1.56 (m, 4H), 1.39-1.16 (m, 48H), 0.87 (t, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 173.4 (2C; C), 173.3 (C), 169.2 (C), 162.9 (C), 155.4 (C), 154.4 (C), 146.8 (C), 134.0 (CH), 133.8 (C), 129.3 (C), 123.8 (CH), 120.1 (C), 118.3 (CH2), 112.8 (C), 76.2 (CH2), 73.3 (CH), 68.4 (CH2), 65.2 (CH2), 62.0 (2C; CH2), 61.1 (CH3), 60.8 (CH2), 34.6 (CH2), 34.1 (2C; CH2), 33.0 (CH2), 32.1 (2C; CH2), 29.84 (6C; CH2), 29.81 (4C; CH2), 29.77 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 28.1 (CH2), 24.9 (2C; CH2), 23.8 (CH2), 22.8 (2C; CH2), 16.4 (CH3), 14.3 (2C; CH3), 11.7 (CH3).


Synthesis of MPA-I-27:




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1,3-Dimethylbarbituric acid (DMBA; 9.1 mg, 58.2 μmol) and Pd(PPh3)4 (1.7 mg, 1.5 μmol) were added to allyl ether Int-87 (29.5 mg, 29.1 μmol) in CH2Cl2 (1.5 mL) and the mixture stirred at rt for one hour. The reaction mixture was directly applied to a short pad of silica gel and eluted with ethyl acetate (50 mL). The eluent was concentrated under reduced pressure to give the crude product. Silica gel chromatography (20% ethyl acetate/hexanes) gave prodrug MPA-C5-CN-2-TG (MPA-I-27) (22.3 mg, 79%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 7.68 (s, 1H), 5.23 (td, J=6.9, 1.2 Hz, 1H), 5.19 (s, 2H), 5.07 (tt, J=5.8, 4.3 Hz, 1H), 5.29-5.21 (m, 2H), 4.33 (dd, J=12.1, 4.2 Hz, 2H), 4.20 (t, J=6.5 Hz, 2H), 4.18 (dd, J=12.1, 5.8 Hz, 2H), 4.12 (t, J=6.3 Hz, 2H), 3.76 (s, 3H), 3.38 (d, J=6.9 Hz, 2H), 2.43-2.35 (m, 2H), 2.35-2.26 (m, 6H), 2.14 (s, 3H), 2.01-1.94 (m, 2H), 1.79 (s, 3H), 1.63-1.56 (m, 4H), 1.34-1.19 (m, 48H), 0.87 (t, J=6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 173.4 (2C; C), 173.3 (C), 173.0 (C), 163.8 (C), 154.5 (C), 153.8 (C), 144.2 (C), 134.2 (C), 122.9 (CH), 122.2 (C), 116.9 (C), 106.5 (C), 73.3 (CH), 70.2 (CH2), 65.2 (CH2), 62.0 (2C; CH2), 61.1 (CH3), 60.7 (CH2), 34.7 (CH2), 34.1 (2C; CH2), 33.1 (CH2), 32.1 (2C; CH2), 29.83 (6C; CH2), 29.80 (4C; CH2), 29.75 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.2 (2C; CH2), 28.1 (CH2), 24.9 (2C; CH2), 22.8 (2C; CH2), 22.7 (CH2), 16.3 (CH3), 14.3 (2C; CH3), 11.7 (CH3).


Using similar methods, (E)-2-((3-(4-((6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)phenyl)propanoyl)oxy)propane-1,3-diyl dipalmitate (MPA-I-28) was prepared.




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Synthesis of MPA-I-28

The allyl ether Int-88 was prepared as follows. DMAP (5.5 mg, 44.6 μmol), EDC.HCl (17.1 mg, 89.3 μmol) and MPA allyl ether Int-86 (16.1 mg, 44.6 μmol) were added to a solution of phenol intermediate Int-67 (32.0 mg, 44.6 μmol) in CH2Cl2 (3 mL) and the mixture stirred at RT for 18 hours. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (15% to 20% ethyl acetate/hexanes) gave the allyl ether Int-88 (37.8 mg, 80%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.18-7.12 (m, 2H), 6.93-6.88 (m, 2H), 6.10 (ddt, J=16.3, 10.4, 5.9 Hz, 1H), 5.37 (ddd, J=17.2, 3.1, 1.5 Hz, 1H), 5.30-5.20 (m, 3H), 5.14 (s, 2H), 4.79 (dt, J=5.9, 1.3 Hz, 2H), 4.28 (dd, J=11.9, 4.4 Hz, 2H), 4.13 (dd, J=11.9, 5.9 Hz, 2H), 3.76 (s, 3H), 3.45 (d, J=6.6 Hz, 2H), 2.92 (t, J=7.8 Hz, 2H), 2.66-2.58 (m, 4H), 2.41 (t, J=7.7 Hz, 2H), 2.29 (t, J=7.6 Hz, 4H), 2.18 (s, 3H), 1.84 (s, 3H), 1.66-1.54 (m, 4H), 1.34-1.17 (m, 48H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.4 (2C; C), 171.9 (2C; C), 169.1 (C), 162.9 (C), 155.4 (C), 149.3 (C), 146.8 (C), 137.8 (C), 133.9 (CH), 133.6 (C), 129.3 (2C; CH), 129.2 (C), 124.1 (CH), 121.7 (2C; CH), 120.1 (C), 118.3 (CH2), 112.8 (C), 76.2 (CH2), 69.4 (CH), 68.4 (CH2), 62.1 (2C; CH2), 61.1 (CH3), 35.7 (CH2), 34.7 (CH2), 34.1 (2C; CH2), 33.1 (CH2), 32.0 (2C; CH2), 30.3 (CH2), 29.81 (6C; CH2), 29.77 (4C; CH2), 29.73 (2C; CH2), 29.6 (2C; CH2), 29.5. (2C; CH2), 29.4 (2C; CH2), 29.2 (2C; CH2), 25.0 (2C; CH2), 23.8 (CH2), 22.8 (2C; CH2), 16.5 (CH3), 14.2 (2C; CH3), 11.7 (CH3).


DMBA (11.1 mg, 71.4 μmol) and Pd(PPh3)4 (8.2 mg, 7.1 μmol) were added to allyl ether Int-88 (37.8 mg, 35.7 μmol) in CH2Cl2 (2 mL) and the mixture stirred at RT for 18 hours. The reaction mixture was directly applied to a short pad of silica gel and eluted with ethyl acetate. The eluent was concentrated under reduced pressure to give the crude product. Silica gel chromatography (15% to 20% ethyl acetate/hexanes) gave prodrug MPA-Ph-C3-2-TG MPA-I-28 (28.0 mg, 77%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.17-7.12 (m, 2H), 6.94-6.87 (m, 2H), 5.33 (td, J=6.9, 1.2 Hz, 1H), 5.25 (m, 1H), 5.20 (s, 2H), 4.28 (dd, J=11.9, 4.3 Hz, 2H), 4.13 (dd, J=11.9, 5.8 Hz, 2H), 3.76 (s, 3H), 3.42 (d, J=6.9 Hz, 2H), 2.92 (t, J=7.8 Hz, 2H), 2.68-2.59 (m, 4H), 2.42 (t, J=7.6 Hz, 2H), 2.29 (t, J=7.6 Hz, 4H), 2.15 (s, 3H), 1.85 (s, 3H), 1.66-1.54 (m, 4H), 1.36-1.18 (m, 48H), 0.87 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.5 (2C; C), 173.0 (C), 171.99 (C), 171.96 (C), 163.8 (C), 153.8 (C), 149.3 (C), 144.2 (C), 137.8 (C), 134.0 (C), 129.3 (2C; CH), 123.2 (CH), 122.2 (C), 121.7 (2C; CH), 116.9 (C), 106.5 (C), 70.2 (CH2), 69.4 (CH), 62.1 (2C; CH2), 61.1 (CH3), 35.8 (CH2), 34.8 (CH2), 34.2 (2C; CH2), 33.2 (CH2), 32.1 (2C; CH2), 30.3 (CH2), 29.83 (6C; CH2), 29.80 (4C; CH2), 29.76 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 25.0 (2C; CH2), 22.83 (2C; CH2), 22.76 (CH2), 16.3 (CH3), 14.3 (2C; CH3), 11.7 (CH3).


Using similar methods, (E)-2-((6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)propane-1,3-diyl dipalmitate (MPA-I-34) was prepared from allyl-protected MPA Int-86 and Int-2 as follows.




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Synthesis of (E)-2-((6-(4-(allyloxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)propane-1,3-diyl dipalmitate (Int-90)



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DMAP (55.0 mg, 0.450 mmol) and EDC.HCl (173 mg, 0.900 mmol) were added to a solution of Int-86 (162 mg, 0.450 mmol) and Int-2 (282 mg, 0.495 mmol) in CH2Cl2 (10 mL) and the mixture stirred at RT for 18 hours. The reaction was diluted with CH2Cl2 (20 mL), silica gel was added, and the solvent removed under reduced pressure. Silica gel chromatography (10% to 20% ethyl acetate/hexanes) gave the desired allyl-protected product (E)-2-((6-(4-(allyloxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)propane-1,3-diyl dipalmitate Int-90 (356 mg, 87%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 6.10 (ddt, J=16.3, 10.4, 5.9 Hz, 1H), 5.37 (dq, J=17.2, 1.5 Hz, 1H), 5.25-5.15 (m, 3H), 5.13 (s, 2H), 4.79 (dt, J=5.9, 1.3 Hz, 2H), 4.24 (dd, J=11.9, 4.5 Hz, 2H), 4.11 (dd, J=11.9, 5.8 Hz, 2H), 3.77 (s, 3H), 3.42 (d, J=6.7 Hz, 2H), 2.43-2.37 (m, 2H), 2.33-2.25 (m, 6H), 2.18 (s, 3H), 1.79 (s, 3H), 1.63-1.51 (m, 8H), 1.35-1.21 (s, 48H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.1 (2C; C), 172.2 (C), 168.9 (C), 162.8 (C), 155.2 (C), 146.7 (C), 133.9 (CH), 133.5 (C), 129.0 (C), 123.8 (CH), 119.9 (C), 118.0 (CH2), 112.6 (C), 76.0 (CH2), 69.0 (CH), 68.2 (CH2), 61.9 (2C; CH2), 60.9 (CH3), 34.4 (CH2), 34.0 (2C; CH2), 32.9 (CH2), 31.9 (2C; CH2), 29.68 (6C; CH2), 29.64 (4C; CH2), 29.60 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.2 (2C; CH2), 29.1 (2C; CH2), 24.8 (2C; CH2), 23.6 (CH2), 22.7 (2C; CH2), 16.2 (CH3), 14.1 (2C; CH3), 11.5 (CH3).


DMBA (122 mg, 0.781 mmol) and Pd(PPh3)4 (67.7 mg, 0.0586 mmol) were added to allyl-protected prodrug Int-90 from the previous step (356 mg, 0.391 mmol) in CH2Cl2 (15 mL) and the mixture stirred at RT for 2.5 hours. The reaction mixture was directly applied to a short pad of silica gel, eluted with ethyl acetate (100 mL) and the filtrate concentrated under reduced pressure to give the crude product. Silica gel chromatography (15% ethyl acetate/hexanes) gave a slightly impure white solid, which was recrystallized from hexanes to give prodrug MPA-2-TG (MPA-I-34) (226 mg, 66%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 5.26-5.20 (m, 2H), 5.20 (s, 2H), 4.24 (dd, J=11.9, 4.5 Hz, 2H), 4.12 (dd, J=11.9, 5.8 Hz, 2H), 3.76 (s, 3H), 3.38 (d, J=6.9 Hz, 2H), 2.45-2.38 (m, 2H), 2.35-2.26 (m, 6H), 2.15 (s, 3H), 1.80 (s, 3H), 1.64-1.52 (m, 8H), 1.35-1.18 (m, 48H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.4 (2C; C), 173.0 (C), 172.5 (C), 163.8 (C), 153.8 (C), 144.1 (C), 134.1 (C), 123.0 (CH), 122.2 (C), 116.9 (C), 106.6 (C), 70.2 (CH2), 69.1 (CH), 62.1 (2C; CH2), 61.1 (CH3), 34.6 (CH2), 34.2 (2C; CH2), 33.1 (CH2), 32.1 (2C; CH2), 29.85 (6C; CH2), 29.81 (4C; CH2), 29.77 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 22.7 (CH2), 16.3 (CH3), 14.3 (2C; CH3), 11.7 (CH3); ESI-HRMS: calcd. for C52H87O10 [M+H] 871.6294; found 871.6328.


Using similar methods, (E)-2-(2-((6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)acetoxy)propane-1,3-diyl dipalmitate (MPA-I-35) was prepared from allyl-protected MPA Int-86 and Int-91 as follows.




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Synthesis of (E)-2-(2-((6-(4-(allyloxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)acetoxy)propane-1,3-diyl dipalmitate (Int-92)



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DBU (15.6 μL, 104 μmol) was added to a suspension of acid Int-86 (25.9 mg, 71.7 μmol) and bromide Int-91 (prepared as described above) (45.0 mg, 65.2 μmol) in toluene (3 mL) and the mixture heated at reflux for three hours. The reaction was cooled to RT and diluted with water (10 mL). The aqueous phase was extracted with ethyl acetate (3×15 mL) and the combined organic extracts washed with sat. aq. NaHCO3 and brine (30 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (12% to 15% ethyl acetate/hexanes) gave the allyl-protected MPA triglyceride Int-92 (45.6 mg, 72%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.09 (ddt, J=16.3, 10.4, 5.9 Hz, 1H), 5.37 (ddd, J=17.2, 3.1, 1.5 Hz, 1H), 5.30 (m, 1H), 5.25-5.17 (m, 2H), 5.13 (s, 2H), 4.78 (dt, J=5.9, 1.3 Hz, 2H), 4.57 (s, 2H), 4.28 (dd, J=12.1, 4.2 Hz, 2H), 4.15 (dd, J=12.0, 5.9 Hz, 2H), 3.76 (s, 3H), 3.42 (d, J=6.7 Hz, 2H), 2.52-2.45 (m, 2H), 2.37-2.27 (m, 6H), 2.17 (s, 3H), 1.79 (s, 3H), 1.63-1.55 (m, 4H), 1.37-1.17 (m, 48H), 0.87 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.4 (2C; C), 172.6 (C), 169.2 (C), 167.2 (C), 163.0 (C), 155.4 (C), 146.8 (C), 134.0 (CH), 133.7 (C), 129.2 (C), 123.9 (CH), 120.1 (C), 118.2 (CH2), 112.8 (C), 76.2 (CH2), 70.4 (CH), 68.4 (CH2), 61.9 (CH2), 61.1 (CH3), 60.4 (CH2), 34.4 (CH2), 34.1 (2C; CH2), 32.6 (CH2), 32.1 (2C; CH2), 29.82 (6C; CH2), 29.78 (4C; CH2), 29.74 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.2 (2C; CH2), 24.9 (2C; CH2), 23.8 (CH2), 22.8 (2C; CH2), 16.4 (CH3), 14.2 (2C; CH3), 11.7 (CH3).


DMBA (13.4 mg, 85.6 μmol) and Pd(PPh3)4 (2.5 mg, 2.14 μmol) were added to allyl ether Int-92 (41.5 mg, 42.8 μmol) in CH2Cl2 (2.5 mL) and the mixture stirred at rt for 2.5 hours. The reaction mixture was directly applied to a short pad of silica gel, eluted with ethyl acetate (40 mL) and the filtrate concentrated under reduced pressure to give the crude product. Silica gel chromatography (15% ethyl acetate/hexanes) gave prodrug MPA-C2-2-TG (MPA-I-35) (30.9 mg, 78%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 5.31 (m, 1H), 5.25 (m, 1H), 5.20 (s, 2H), 4.57 (s, 2H), 4.29 (dd, J=12.1, 4.2 Hz, 2H), 4.16 (dd, J=12.1, 6.0 Hz, 2H), 3.76 (s, 3H), 3.38 (d, J=6.9 Hz, 2H), 2.54-2.47 (m, 2H), 2.35-2.29 (m, 6H), 2.14 (s, 3H), 1.80 (s, 3H), 1.64-1.55 (m, 4H), 1.34-1.19 (m, 48H), 0.87 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.42 (2C; C), 173.04 (C), 172.61 (C), 167.26 (C), 163.79 (C), 153.77 (C), 144.16 (C), 134.01 (C), 123.02 (CH), 122.20 (C), 116.84 (C), 106.51 (C), 70.41 (CH), 70.17 (CH2), 61.86 (2C; CH2), 61.12 (CH3), 60.44 (CH2), 34.46 (CH2), 34.08 (2C; CH2), 32.64 (CH2), 32.06 (2C; CH2), 29.83 (6C; CH2), 29.79 (4C; CH2), 29.75 (2C; CH2), 29.60 (2C; CH2), 29.50 (2C; CH2), 29.39 (2C; CH2), 29.24 (2C; CH2), 24.93 (2C; CH2), 22.82 (2C; CH2), 22.72 (CH2), 16.27 (CH3), 14.26 (2C; CH3), 11.69 (CH3).


Using similar methods, (E)-2-((7-((6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)heptanoyl)oxy)propane-1,3-diyl dipalmitate (MPA-I-36) was prepared from allyl-protected MPA Int-86 and Int-95 as follows.




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Synthesis of (E)-2-((7-((6-(4-(allyloxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)heptanoyl)oxy)propane-1,3-diyl dipalmitate (Int-96)



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DBU (13.6 μL, 90.7 μmol) was added to a suspension of acid Int-86 (26.2 mg, 72.6 μmol) and iodide Int-95 (48.8 mg, 60.5 μmol) and the mixture heated at reflux for 3.5 hours. The reaction was cooled to RT, then diluted with ethyl acetate and water and the aqueous layer extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (7.5% to 15% to 20% ethyl acetate/hexanes) gave protected MPA prodrug Int-96 (47.5 mg, 76%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.09 (ddt, J=17.1, 10.4, 5.9 Hz, 1H), 5.37 (dq, J=17.2, 1.5 Hz, 1H), 5.28-5.21 (m, 2H), 5.17 (m, 1H), 5.12 (s, 2H), 4.78 (dt, J=5.9, 1.3 Hz, 2H), 4.29 (dd, J=11.9, 4.4 Hz, 2H), 4.13 (dd, J=11.9, 5.9 Hz, 2H), 4.00 (t, J=6.7 Hz, 2H), 3.76 (s, 3H), 3.41 (d, J=6.7 Hz, 2H), 2.40-2.34 (m, 2H), 2.33-2.25 (m, 8H), 2.17 (s, 3H), 1.78 (s, 3H), 1.66-1.54 (m, 8H), 1.36-1.18 (m, 52H), 0.87 (t, J=6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 173.5 (C), 173.4 (2C; C), 172.8 (C), 169.2 (C), 163.0 (C), 155.4 (C), 146.8 (C), 133.99 (CH), 133.97 (C), 129.3 (C), 123.7 (CH), 120.1 (C), 118.2 (CH), 112.8 (C), 76.2 (CH2), 69.1 (CH), 68.4 (CH2), 64.4 (CH2), 62.2 (2C; CH2), 61.1 (CH3), 34.7 (CH2), 34.17 (2C; CH2), 34.16 (CH2), 33.2 (CH2), 32.1 (2C; CH2), 29.83 (6C; CH2), 29.79 (4C; CH2), 29.75 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.3 (2C; CH2), 28.8 (CH2), 28.6 (CH2), 25.8 (CH2), 25.0 (2C; CH2), 24.8 (CH2), 23.8 (CH2), 22.8 (2C; CH2), 16.4 (CH3), 14.3 (2C; CH3), 11.7 (CH3).


DMBA (10.8 mg, 69.3 mol) and Pd(PPh3)4 (2.0 mg, 1.7 μmol) were added to allyl ether Int-96 (36.0 mg, 34.6 mol) in CH2Cl2 (2 mL) and the mixture stirred at RT for one hour. The reaction mixture was directly applied to a short pad of silica gel and eluted with ethyl acetate (50 mL). The eluent was concentrated under reduced pressure to give the crude product. Silica gel chromatography (5% ethyl acetate/toluene) gave MPA prodrug MPA-C7-2-TG MPA-I-36 (30.6 mg, 88%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 5.28-5.22 (m, 2H), 5.19 (s, 2H), 4.29 (dd, J=11.9, 4.3 Hz, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 4.00 (t, J=6.7 Hz, 2H), 3.75 (s, 3H), 3.38 (d, J=6.9 Hz, 2H), 2.40-2.35 (m, 2H), 2.34-2.25 (m, 8H), 2.14 (s, 3H), 1.80 (s, 3H), 1.66-1.52 (m, 8H), 1.37-1.19 (m, 52H), 0.87 (t, J=6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 173.6 (C), 173.4 (2C; C), 173.1 (C), 172.8 (C), 163.8 (C), 153.8 (C), 144.1 (C), 134.3 (C), 122.8 (CH), 122.3 (C), 116.8 (C), 106.5 (C), 70.2 (CH2), 69.1 (CH), 64.4 (CH2), 62.2 (2C; CH2), 61.1 (CH3), 34.8 (CH2), 34.2 (3C; CH2), 33.2 (CH2), 32.1 (2C; CH2), 29.83 (6C; CH2), 29.79 (4C; CH2), 29.75 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (2C; CH2), 29.2 (2C; CH2), 28.8 (CH2), 28.6 (CH2), 25.8 (CH2), 25.0 (2C; CH2), 24.8 (CH2), 22.8 (2C; CH2), 22.7 (CH2), 16.3 (CH3), 14.3 (2C; CH3), 11.7 (CH3); ESI-HRMS: calcd. for C59H98Na012 [M+Na+] 1021.6951; found 1021.6946.


Using similar methods, (E)-2-((12-((6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)dodecanoyl)oxy)propane-1,3-diyl dipalmitate (MPA-I-37) was prepared from allyl-protected MPA Int-86 and Int-97 as follows.




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Synthesis of (E)-2-(((12-(((6-(4-(allyloxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)dodecanoyl)oxy)propane-1,3-diyl dipalmitate (Int-98)



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DBU (27.4 μL, 0.183 mmol) was added to a suspension of Int-86 (43.3 mg, 0.120 mmol) and bromide Int-97 (95.0 mg, 0.114 mmol) in toluene (4 mL) and the mixture heated at reflux for two hours. The reaction was cooled to rt, then diluted with ethyl acetate (40 mL). The organic phase was washed with water and brine (30 mL each), dried (MgSO4) and concentrated under reduced pressure to give the crude product. Silica gel chromatography (10% to 20% ethyl acetate/hexanes) gave Int-98 (88.2 mg, 69%) as a colorless solid. 1H NMR (401 MHz, CDCl3) δ 6.07 (ddt, J=16.3, 10.4, 5.9 Hz, 1H), 5.35 (dq, J=17.2, 1.5 Hz, 1H), 5.28-5.13 (m, 3H), 5.10 (s, 2H), 4.76 (dt, J=5.9, 1.2 Hz, 2H), 4.27 (dd, J=11.9, 4.3 Hz, 2H), 4.12 (dd, J=11.9, 5.9 Hz, 2H), 3.98 (t, J=6.8 Hz, 2H), 3.74 (s, 3H), 3.39 (d, J=6.7 Hz, 2H), 2.39-2.23 (m, 10H), 2.16 (s, 3H), 1.76 (s, 3H), 1.63-1.51 (m, 8H), 1.35-1.13 (m, 62H), 0.85 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.5 (C), 173.4 (2C; C), 172.9 (C), 169.1 (C), 162.9 (C), 155.4 (C), 146.7 (C), 133.94 (CH), 133.92 (C), 129.3 (C), 123.6 (CH), 120.0 (C), 118.1 (CH2), 112.7 (C), 76.1 (CH2), 69.0 (CH), 68.4 (CH2), 64.6 (CH2), 62.2 (2C; CH2), 61.0 (CH3), 34.7 (CH2), 34.3 (CH2), 34.1 (2C; CH2), 33.1 (CH2), 32.0 (2C; CH2), 29.78 (6C; CH2), 29.74 (4C; CH2), 29.70 (2C; CH2), 29.63 (CH2), 29.60 (CH2), 29.55 (3C; CH2), 29.44 (2C; CH2), 29.35 (4C; CH2), 29.19 (2C; CH2), 29.15 (CH2), 28.7 (CH2), 26.0 (CH2), 24.9 (2C; CH2), 23.7 (CH2), 22.8 (2C; CH2), 16.4 (CH3), 14.2 (2C; CH3), 11.6 (CH3).


DMBA (24.2 mg, 0.155 mmol) and Pd(PPh3)4 (13.4 mg, 0.0116 mmol) were added to allyl ether Int-98 (86.0 mg, 0.0775 mmol) in CH2Cl2 (3 mL) and the mixture stirred at rt for 4.5 hours. The reaction mixture was directly applied to a short pad of silica gel and eluted with ethyl acetate. The eluent was concentrated under reduced pressure to give the crude product. Silica gel chromatography (15% to 20% ethyl acetate/hexanes) gave prodrug MPA-I-37 (80.0 mg, 96%) as a colorless solid. 1H NMR (401 MHz, CDCl3) δ 7.66 (s, 1H), 5.27-5.19 (m, 2H), 5.17 (s, 2H), 4.28 (dd, J=11.9, 4.3 Hz, 2H), 4.13 (dd, J=11.8, 5.9 Hz, 2H), 3.98 (t, J=6.8 Hz, 2H), 3.74 (s, 3H), 3.36 (d, J=6.9 Hz, 2H), 2.40-2.33 (m, 2H), 2.32-2.24 (m, 8H), 2.13 (s, 3H), 1.78 (s, 3H), 1.64-1.50 (m, 8H), 1.37-1.18 (m, 62H), 0.86 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.5 (C), 173.4 (2C; C), 173.0 (C), 172.9 (C), 163.8 (C), 153.7 (C), 144.1 (C), 134.3 (C), 122.7 (CH), 122.2 (C), 116.8 (C), 106.4 (C), 70.1 (CH2), 69.0 (CH), 64.5 (CH2), 62.2 (2C; CH2), 61.1 (CH3), 34.7 (CH2), 34.3 (CH2), 34.1 (2C; CH2), 33.2 (CH2), 32.0 (2C; CH2), 29.79 (6C; CH2), 29.75 (4C; CH2), 29.71 (2C; CH2), 29.63 (CH2), 29.61 (CH2), 29.56 (2C; CH2), 29.45 (2C; CH2), 29.36 (4C; CH2), 29.20 (2C; CH2), 29.16 (CH2), 28.7 (CH2), 26.0 (CH2), 24.97 (CH2), 24.95 (2C; CH2), 22.8 (2C; CH2), 22.7 (CH2), 16.2 (CH3), 14.2 (2C; CH3), 11.6 (CH3).


Using similar methods, (E)-2-((18-((6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)octadecanoyl)oxy)propane-1,3-diyl dipalmitate (MPA-I-38) was prepared from allyl-protected MPA Int-86 and Int-105 as follows.


Synthesis of (E)-2-((18-((6-(4-(allyloxy)-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)octadecanoyl)oxy)propane-1,3-diyl dipalmitate (Int-128)



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DMAP (4.6 mg, 37.4 μmol), EDC.HCl (17.9 mg, 93.4 μmol) and Int-86 (18.8 mg, 52.3 μmol) were added to a solution of alcohol Int-105 (31.8 mg, 37.4 μmol) in CH2Cl2 (1 mL) and the mixture stirred at RT for 19 hours. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added and the mixture concentrated under reduced pressure. Purification by silica gel chromatography (12.5% to 17.5% ethyl acetate/hexanes) gave allyl-protected prodrug Int-128 (40.6 mg, 91%) as a colorless solid. 1H NMR (401 MHz, CDCl3) δ 6.10 (ddt, J=17.1, 10.4, 5.9 Hz, 1H), 5.37 (ddd, J=17.2, 3.1, 1.5 Hz, 1H), 5.30-5.21 (m, 2H), 5.17 (td, J=6.7, 1.1 Hz, 1H), 5.13 (s, 2H), 4.78 (dt, J=5.9, 1.3 Hz, 2H), 4.29 (dd, J=11.9, 4.3 Hz, 2H), 4.14 (dd, J=11.9, 6.0 Hz, 2H), 4.00 (t, J=6.8 Hz, 2H), 3.76 (s, 3H), 3.41 (d, J=6.7 Hz, 2H), 2.39-2.25 (m, 10H), 2.18 (s, 3H), 1.78 (s, 3H), 1.66-1.52 (m, 8H), 1.37-1.18 (m, 74H), 0.88 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.6 (C), 173.4 (2C; C), 173.0 (C), 169.1 (C), 163.0 (C), 155.4 (C), 146.8 (C), 134.00 (C), 133.97 (CH), 129.3 (C), 123.7 (CH), 120.1 (C), 118.2 (CH2), 112.8 (C), 76.2 (CH2), 69.0 (CH), 68.4 (CH2), 64.6 (CH2), 62.2 (2C; CH2), 61.1 (CH3), 34.7 (CH2), 34.3 (CH2), 34.2 (2C; CH2), 33.2 (CH2), 32.1 (2C; CH2), 29.83 (10C; CH2), 29.79 (6C; CH2), 29.75 (3C; CH2), 29.68 (CH2), 29.65 (CH2), 29.60 (2C; CH2), 29.49 (2C; CH2), 29.44 (CH2), 29.40 (3C; CH2), 29.24 (2C; CH2), 29.22 (CH2), 28.7 (CH2), 26.0 (CH2), 25.03 (CH2), 24.99 (2C; CH2), 23.8 (CH2), 22.8 (2C; CH2), 16.4 (CH3), 14.2 (2C; CH3), 11.7 (CH3).


DMBA (10.6 mg, 68.0 mol) and Pd(PPh3)4 (7.8 mg, 6.8 mol) were added to allyl ether Int-128 (40.6 mg, 34.0 mol) in CH2Cl2 (1.5 mL) and the mixture stirred at RT for 4 h. The reaction was diluted with (10 mL), silica gel was added, and the mixture concentrated under reduced pressure. Silica gel chromatography (15% to 20% ethyl acetate/hexanes) gave MPA prodrug MPA-I-38 (38.3 mg, 98%) as a colorless solid. 1H NMR (401 MHz, CDCl3) δ 7.67 (s, 1H), 5.29-5.21 (m, 2H), 5.20 (s, 2H), 4.29 (dd, J=11.9, 4.3 Hz, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 4.00 (t, J=6.7 Hz, 2H), 3.76 (s, 3H), 3.38 (d, J=6.7 Hz, 2H), 2.42-2.35 (m, 2H), 2.35-2.26 (m, 8H), 2.14 (s, 3H), 1.80 (s, 3H), 1.67-1.51 (m, 8H), 1.45-1.15 (m, 74H), 0.88 (t, J=6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.6 (C), 173.4 (2C; C), 173.0 (2C; C), 163.8 (C), 153.8 (C), 144.1 (C), 134.4 (C), 122.8 (CH), 122.3 (C), 116.8 (C), 106.5 (C), 70.2 (CH2), 69.0 (CH), 64.6 (CH2), 62.2 (2C; CH2), 61.1 (CH3), 34.8 (CH2), 34.4 (CH2), 34.2 (2C; CH2), 33.3 (CH2), 32.1 (2C; CH2), 29.83 (10C; CH2), 29.79 (6C; CH2), 29.75 (3C; CH2), 29.68 (CH2), 29.65 (CH2), 29.61 (2C; CH2), 29.49 (2C; CH2), 29.44 (CH2), 29.40 (3C; CH2), 29.25 (2C; CH2), 29.22 (CH2), 28.7 (CH2), 26.1 (CH2), 25.04 (CH2), 24.99 (2C; CH2), 22.8 (2C; CH2), 22.7 (CH2), 16.3 (CH3), 14.2 (2C; CH3), 11.7 (CH3).


Using similar methods, (E)-2-((4-((6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoyl)oxy)-3-methylbutanoyl)oxy)propane-1,3-diyl dibutyrate (MPA-I-43) was prepared from Int-86 and Int-125 via the allyl-protected intermediate Int-127:




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Int-127: 1H NMR (401 MHz, CDCl3) δ 6.09 (ddt, J=17.1, 10.4, 5.9 Hz, 1H), 5.37 (dq, J=17.2, 1.5 Hz, 1H), 5.28 (m, 1H), 5.23 (m, 1H), 5.18 (m, 1H), 5.13 (s, 2H), 4.78 (dt, J=5.9, 1.3 Hz, 2H), 4.296/4.293 (each dd, J=11.9, 4.3 Hz, 2H), 4.150/4.148 (each dd, J=11.9, 6.0 Hz, 2H), 4.00 (t, J=6.8 Hz, 2H), 3.76 (s, 3H), 3.41 (d, J=6.7 Hz, 2H), 2.39-2.25 (m, 9H), 2.17 (s, 3H), 2.12 (dd, J=14.7, 8.3 Hz, 1H), 1.93 (m, 1H), 1.78 (d, J=0.7 Hz, 3H), 1.68-1.52 (m, 8H), 1.35-1.17 (m, 18H), 0.94 (t, J=7.4 Hz, 6H), 0.93 (d, J=6.7 Hz, 3H).


MPA-I-43:




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MPA-I-43 was prepared from the corresponding allyl-protected compound in 58% yield after Pd-mediated deprotection. 1H NMR (401 MHz, CDCl3) δ 7.67 (s, 1H), 5.31-5.21 (m, 2H), 5.19 (s, 2H), 4.295/4.292 (each dd, J=11.9, 4.2 Hz, 2H), 4.149/4.197 (each dd, J=11.9, 6.0 Hz, 2H), 4.00 (t, J=6.8 Hz, 2H), 3.76 (s, 3H), 3.38 (d, J=6.9 Hz, 2H), 2.41-2.26 (m, 9H), 2.14 (s, 3H), 2.12 (dd, J=14.7, 8.3 Hz, 1H), 1.93 (m, 1H), 1.79 (s, 3H), 1.69-1.52 (m, 8H), 1.36-1.15 (m, 18H), 0.94 (t, J=7.4, 2.8 Hz, 6H), 0.92 (d, J=6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.6 (C), 173.3 (2C; C), 173.1 (C), 172.5 (C), 163.8 (C), 153.8 (C), 144.1 (C), 134.4 (C), 122.8 (CH), 122.3 (C), 116.8 (C), 106.5 (C), 70.2 (CH2), 68.9 (CH), 64.6 (CH2), 62.3 (2C; CH2), 61.1 (CH3), 41.9 (CH2), 36.8 (CH2), 36.1 (2C; CH2), 34.8 (CH2), 33.3 (CH2), 30.5 (CH), 29.9 (CH2), 29.81 (CH2), 29.79 (2C; CH2), 29.74 (CH2), 29.68 (CH2), 29.4 (CH2), 28.8 (CH2), 27.1 (CH2), 26.1 (CH2), 22.7 (CH2), 19.7 (CH3), 18.5 (2C; CH2), 16.3 (CH3), 13.8 (2C; CH3), 11.7 (CH3).


Using similar methods, MPA-C10-2-TG (MPA-I-46) was prepared.




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1H NMR (401 MHz, CDCl3) δ 7.67 (s, 1H), 5.29-5.21 (m, 2H), 5.19 (s, 2H), 4.29 (dd, J=11.9, 4.4 Hz, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 4.00 (t, J=6.8 Hz, 2H), 3.76 (s, 3H), 3.38 (d, J=6.9 Hz, 2H), 2.41-2.35 (m, 2H), 2.33-2.24 (m, 8H), 2.14 (s, 3H), 1.80 (s, 3H), 1.66-1.52 (m, 8H), 1.37-1.17 (m, 58H), 0.87 (t, J=6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.6 (C), 173.4 (2C; C), 173.1 (C), 173.0 (C), 163.8 (C), 153.8 (C), 144.1 (C), 134.4 (C), 122.8 (CH), 122.3 (C), 116.8 (C), 106.5 (C), 70.2 (CH2), 69.0 (CH), 64.6 (CH2), 62.2 (2C; CH2), 61.1 (CH3), 34.8 (CH2), 34.3 (CH2), 34.2 (2C; CH2), 33.3 (CH2), 32.1 (2C; CH2), 29.84 (6C; CH2), 29.80 (4C; CH2), 29.76 (2C; CH2), 29.62 (2C; CH2), 29.50 (3C; CH2), 29.41 (2C; CH2), 29.36 (2C; CH2), 29.26 (2C; CH2), 29.19 (CH2), 28.8 (CH2), 26.1 (CH2), 25.0 (3C; CH2), 22.8 (2C; CH2), 22.7 (CH2), 16.3 (CH3), 14.3 (2C; CH3), 11.7 (CH3).


Using similar methods to those described above, MPA-C12-2-TG-butyrate (MPA-I-49) was prepared using Int-126.




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1H NMR (401 MHz, CDCl3) δ 7.66 (s, 1H), 5.29-5.19 (m, 2H), 5.18 (s, 2H), 4.29 (dd, J=11.9, 4.3 Hz, 2H), 4.14 (dd, J=11.9, 6.0 Hz, 2H), 3.99 (t, J=6.8 Hz, 2H), 3.75 (s, 3H), 3.37 (d, J=7.0 Hz, 2H), 2.41-2.34 (m, 2H), 2.33-2.24 (m, 8H), 2.13 (s, 3H), 1.78 (s, 3H), 1.69-1.51 (m, 8H), 1.35-1.19 (m, 14H), 0.93 (t, J=7.4 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.6 (C), 173.2 (2C; C), 173.0 (2C; C), 163.8 (C), 153.8 (C), 144.1 (C), 134.3 (C), 122.8 (CH), 122.3 (C), 116.8 (C), 106.5 (C), 70.2 (CH2), 69.0 (CH), 64.6 (CH2), 62.2 (2C; CH2), 61.1 (CH3), 36.0 (2C; CH2), 34.8 (CH2), 34.3 (CH2), 33.2 (CH2), 29.63 (CH2), 29.61 (CH2), 29.5 (CH2), 29.4 (2C; CH2), 29.2 (CH2), 28.7 (CH2), 26.0 (CH2), 25.0 (CH2), 22.7 (CH2), 18.5 (2C; CH2), 16.3 (CH3), 13.7 (2C; CH3), 11.7 (CH3).


Using similar methods to those described above, MPA-C10bMe-2-TG (MPA-I-50) was prepared using Int-23.




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1H NMR (401 MHz, CDCl3) δ 7.67 (s, 1H), 5.30-5.20 (m, 2H), 5.19 (s, 2H), 4.28 (dd, J=11.9, 4.3 Hz, 2H), 4.13 (dd, J=13.1, 4.8 Hz, 2H), 4.00 (t, J=6.8 Hz, 2H), 3.75 (s, 3H), 3.38 (d, J=6.9 Hz, 2H), 2.41-2.35 (m, 2H), 2.34-2.26 (m, 7H), 2.14 (s, J=6.2 Hz, 3H), 2.11 (dd, J=14.7, 8.4 Hz, 1H), 1.90 (m, 1H), 1.79 (s, 3H), 1.67-1.52 (m, 6H), 1.36-1.14 (m, 58H), 0.92 (d, J=6.6 Hz, 3H), 0.87 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.6 (C), 173.4 (2C; C), 173.1 (C), 172.4 (C), 163.8 (C), 153.8 (C), 144.1 (C), 134.4 (C), 122.8 (CH), 122.3 (C), 116.8 (C), 106.5 (C), 70.2 (CH2), 69.0 (CH), 64.6 (CH2), 62.3 (2C; CH2), 61.1 (CH3), 41.8 (CH2), 36.8 (CH2), 34.8 (CH2), 34.2 (2C; CH2), 33.3 (CH2), 32.1 (2C; CH2), 30.5 (CH), 29.83 (7C; CH2), 29.79 (4C; CH2), 29.76 (2C; CH2), 29.6 (2C; CH2), 29.5 (2C; CH2), 29.4 (3C; CH2), 29.3 (2C; CH2), 28.7 (CH2), 27.0 (CH2), 26.1 (CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 22.7 (CH2), 19.7 (CH3), 16.3 (CH3), 14.3 (2C; CH3), 11.7 (CH3); ESI-HRMS: calcd. for C63H106NaO12 [M+Na+] 1077.7576; found 1077.7576.


Using similar methods to those described above, MPA-C12bMe-2-TG (MPA-I-51) was prepared using Int-121.




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1H NMR (401 MHz, CDCl3) δ 7.67 (s, 1H), 5.30-5.21 (m, 2H), 5.19 (s, 2H), 4.285/4.283 (each dd, J=11.8, 4.3 Hz, 2H), 4.14 (dd, J=11.9, 5.9 Hz, 2H), 4.00 (t, J=6.8 Hz, 2H), 3.75 (s, 3H), 3.38 (d, J=6.9 Hz, 2H), 2.41-2.26 (m, 9H), 2.14 (s, 3H), 2.09 (dd, J=14.8, 8.3 Hz, 1H), 1.93 (m, 1H), 1.79 (d, J=0.7 Hz, 3H), 1.64-1.52 (m, 6H), 1.41-1.15 (m, 62H), 0.92 (d, J=6.6 Hz, 3H), 0.87 (t, J=6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 173.6 (C), 173.4 (2C; C), 173.1 (C), 172.5 (C), 163.8 (C), 153.8 (C), 144.1 (C), 134.4 (C), 122.8 (CH), 122.3 (C), 116.8 (C), 106.5 (C), 70.2 (CH2), 68.9 (CH), 64.6 (CH2), 62.3 (2C; CH2), 61.1 (CH3), 41.8 (CH2), 36.8 (CH2), 34.8 (CH2), 34.2 (2C; CH2), 33.3 (CH2), 32.1 (2C; CH2), 30.5 (CH), 29.9 (CH2), 29.84 (6C; CH2), 29.80 (4C; CH2), 29.76 (2C; CH2), 29.74 (CH2), 29.68 (CH2), 29.62 (2C; CH2), 29.5 (2C; CH2), 29.4 (3C; CH2), 29.3 (2C; CH2), 28.8 (CH2), 27.1 (CH2), 26.1 (CH2), 25.0 (2C; CH2), 22.8 (2C; CH2), 22.7 (CH2), 19.7 (CH3), 16.3 (CH3), 14.3 (2C; CH3), 11.7 (CH3).


Example 22: Synthesis of TAC-I-1



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Synthesis of TAC-I-1:



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Synthesis of 1.1: 1.1, is prepared by treating a macrolide with chloromethyl methyl thioether as described in WO 2009/143295, which is hereby incorporated by reference in its entirety. A solution of sulfuryl chloride (2.2 equiv.) in CH2Cl2 (0.16 M) is added to a solution of 1.1 (1.8 equiv.) in CH2Cl2 (0.07 M) at 0° C. and the mixture stirred at 0° C. for 30 minutes and then at rt for an additional hour. The reaction is concentrated under a stream of N2, co-evaporated from toluene (twice) and dried under reduced pressure.


Synthesis of TAC-I-1 (TAC-32-(ASI-C4-2-TG)): TAC-I-1 is prepared according to the following procedure. The crude residue is re-dissolved in toluene (0.1 M based on 1.1), added to a solution of acid Int-28 (1 eq) as prepared in WO 2017/041139, and DBU (1.5 eq) in toluene (0.05 M) that had been pre-stirred for one hour, and the mixture is stirred at rt for two hours. The reaction is diluted with CH2Cl2 (20 mL) and the organic phase washed with sat. aq. NaHCO3 (20 mL) and brine (20 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude protected product. Deprotection and purification by silica gel chromatography with a suitable solvent mixture affords TAC-I-1. In the instance protecting groups are not utilized, regioisomers are separated by known purification techniques to afford TAC-I-1 and TAC-I-3.


Example 23: Synthesis of TAC-I-4



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Synthesis of TAC-I-4:



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Synthesis of 3.2: 3.2 is prepared according to the following procedure. PG indicates an optional hydroxyl protecting group. Chloromethyl chloroformate (1.6 equiv.) and pyridine (3.0 equiv.) are added to macrolide 3.1 (1.0 equiv.) in CH2Cl2 (0.03 M) at 0° C. and the mixture is stirred at 0° C. for 15 minutes and then at rt for one hour. The reaction is diluted with CH2Cl2 and the organic phase washed with sat. aq. NaHCO3 and brine, dried (MgSO4) and concentrated under reduced pressure to give 3.2 which is used without purification.


Synthesis of TAC-I-4 (TAC-32-(CASI-C4-2-TG)): TAC-I-4 is prepared according to the following procedure. Silver carbonate (0.7 equiv.) is added to acid Int-28 (1.2 equiv.) as prepared in WO 2017/041139, in DMF (0.03 M) and the mixture stirred at rt for one hour. The reaction is concentrated under reduced pressure to give a grey residue, to which is added chloromethyl carbonate (1.0 equiv.) in toluene (0.03 M) and TBAI (0.3 equiv.) and the mixture heated at reflux for 1.5 hours. The reaction is cooled to rt, then diluted with ethyl acetate. The organic phase is washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give the crude 3.3. Deprotection and purification by silica gel chromatography with a suitable solvent mixture affords TAC-I-4. In the instance protecting groups are not utilized, regioisomers are separated via known purification techniques.


Example 24: Synthesis of TAC-I-7 and TAC-I-9



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Synthesis of TAC-I-7 and TAC-I-9:



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Synthesis of TAC-I-7 (TAC-32-(TML-C4-2-TG): TAC-I-7 is prepared according to the following procedure. 4-(Dimethylamino)pyridine (DMAP, 1.3 equiv.) and EDC.HCl (2.1 equiv.) is added to a solution of macrolide 4.1 (1.3 equiv.) and acid 4.2 (1.0 equiv.), as prepared in WO 2017/041139, in CH2Cl2 (0.02 M) and the mixture stirred at rt for 19 hours. The reaction is diluted with CH2Cl2 (10 mL), silica gel is added and the mixture concentrated under reduced pressure to yield crude. Deprotection and purification by silica gel chromatography with a suitable solvent mixture affords TAC-I-7. In the instance protecting groups are not utilized, regioisomers are separated via known purification techniques.


Example 25: Synthesis of TAC-I-10



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Synthesis of TAC-I-10:



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Synthesis of TAC-I-10. TAC-I-10 is prepared according to the following procedure. PG indicates an optional hydroxyl protecting group. 4-(Dimethylamino)pyridine (DMAP, 1.3 equiv.) and DIPEA (0.3 equiv.) were added to a solution of protected macrolide 5.1 (1.2 equiv.) and PNP carbonate 5.2 (1.0 equiv.) as prepared in WO 2017/041139, in CH2Cl2 (0.01 M) and the mixture stirred at rt for five days. The reaction was diluted with CH2Cl2, washed with 1 M HCl, water and brine, dried (MgSO4) and concentrated under reduced pressure to give the crude product 5.3. Deprotection and purification by silica gel chromatography with a suitable solvent mixture affords TAC-I-10. In the instance protecting groups are not utilized, regioisomers are separated by known purification techniques.


Example 26: Synthesis of TAC-I-13



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Synthesis of TAC-I-13:



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Synthesis of 6.3: 6.3 is prepared according to the following procedure. PG indicates an optional hydroxyl protecting group. 4-(Dimethylamino)pyridine (1.3 equiv.) and DCC (2.1 equiv.) are added to a solution of macrolide 6.1 (1.0 equiv.) and 4-bromobutyric acid 6.2 (1.3 equiv.) in CH2Cl2 (0.03 M) and the mixture is stirred at rt for 24 hours. Another 0.6 eq. of acid, 1 eq. of DCC, 0.6 eq. of DMAP are added and the mixture is stirred at rt for an additional two days. The reaction is diluted with CH2Cl2, silica gel is added and the mixture is concentrated under reduced pressure. Purification by silica gel chromatography gives bromide mixture 6.3.


Synthesis of TAC-I-13 (TAC-32-(FSI-4-C4-2-TG)): TAC-I-13 is prepared according to the following procedure. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (1.6 equiv.) is added to a suspension of acid Int-28 (1.1 equiv.) as prepared in WO 2017/041139, and bromide 6.3 (1.0 equiv.) in toluene (0.03 M) and the mixture is heated at reflux for 21 hours. The reaction is cooled to rt, then diluted with ethyl acetate. The organic phase is washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give the crude 6.4. Deprotection and purification by silica gel chromatography with a suitable solvent mixture affords TAC-I-13. In the instance protecting groups are not utilized, regioisomers are separated via known purification techniques.


Example 27: Synthesis of TAC-I-16



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Synthesis of TAC-I-16:



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Synthesis of 7.2: 7.2 is prepared according to the following procedure. PG indicates an optional hydroxyl protecting group. Chloromethyl chloroformate (1.6 equiv.) and pyridine (3.0 equiv.) are added to macrolide 7.1 (1.0 equiv.) in CH2Cl2 (0.03 M) at 0° C. and the mixture is stirred at 0° C. for 15 minutes and then at rt for one hour. The reaction is diluted with CH2Cl2 and the organic phase washed with sat. aq. NaHCO3 and brine, dried (MgSO4) and concentrated under reduced pressure to give 7.2 which is used without purification.


Synthesis of TAC-I-16: TAC-I-16 is prepared according to the following procedure. Silver carbonate (0.7 equiv.) is added to acid 7.3 (1.2 equiv.) as prepared in WO 2017/041139, in DMF (0.03 M) and the mixture stirred at rt for one hour. The reaction is concentrated under reduced pressure to give a grey residue, to which is added chloromethyl carbonate 7.2 (1.0 equiv.) in toluene (0.03 M) and TBAI (0.3 equiv.) and the mixture heated at reflux for 1.5 hours. The reaction is cooled to rt, then diluted with ethyl acetate. The organic phase is washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give the crude TAC-I-16. Purification by silica gel chromatography with a suitable solvent mixture affords TAC-I-16. Regioisomers are separated via known purification techniques.


Example 28: Synthesis of TAC-I-17



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Synthesis of TAC-I-17:



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Synthesis of 8.2: 8.2 is prepared according to the following procedure. 4-(Dimethylamino)pyridine (1.3 equiv.) and DCC (2.1 equiv.) are added to a solution of macrolide 8.1 (1.0 equiv.) and 5-bromopentanoic acid (1.3 equiv.) in CH2Cl2 (0.03 M) and the mixture is stirred at rt for 24 hours. Another 0.6 eq. of acid, 1 eq. of DCC, 0.6 eq. of DMAP are added and the mixture is stirred at rt for an additional two days. The reaction is diluted with CH2Cl2, silica gel is added and the mixture is concentrated under reduced pressure. Purification by silica gel chromatography gives bromide 8.2.


Synthesis of TAC-I-17: TAC-I-17 is prepared according to the following procedure. Silver carbonate (0.7 equiv.) is added to acid 8.3 (1.2 equiv.) as prepared in WO 2017/041139, in DMF (0.03 M) and the mixture stirred at rt for one hour. The reaction is concentrated under reduced pressure to give a grey residue, to which is added bromide 8.2 (1.0 equiv.) in toluene (0.03 M) and the mixture is heated at reflux for 21 hours. The reaction is cooled to rt, then diluted with ethyl acetate. The organic phase is washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give the crude TAC-I-17. Purification by silica gel chromatography with a suitable solvent mixture affords TAC-I-17. Regioisomers may be separated via known purification techniques. TAC-I-18, TAC-I-19, TAC-I-20, TAC-I-21, TAC-I-22, and TAC-I-23:




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Example 29: Synthesis of TAC-I-18 and TAC-I-19



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Synthesis of TAC-I-18 (TAC-32 (C10-2-TG)) and TAC-I-19 (TAC-24-(C10-2-TG)): 4-(Dimethylamino)pyridine (DMAP, 2.7 mg, 21.9 μmol) and EDC.HCl (12.6 mg, 65.7 μmol) were added to a solution of tacrolimus hydrate (18.0 mg, 21.9 μmol) and acid-TG (Int-9; 18.1 mg, 24.1 μmol) in CH2Cl2 mL) and the mixture stirred at rt for seven days. The reaction was diluted with CH2Cl2 (5 mL), silica gel was added, and the solvent was removed under reduced pressure. Purification by silica gel chromatography (30% to 100% ethyl acetate/hexanes) gave TAC prodrugs TAC-I-18 (9.2 mg, 27%) and TAC-I-19 (8.0 mg, 24%) as colourless oils.


TAC-I-18:

ESI-HRMS: Calcd. for C89H151NNaO19 [M+Na+] 1561.0773; found 1561.0745


Rf (50% EtOAc/Hexanes): 0.68.
TAC-I-19:

ESI-HRMS: Calcd. for C89H151NNaO19 [M+Na+] 1561.0773; found 1561.0774


Rf (50% EtOAc/Hexanes): 0.41.
Example 30: Synthesis of TAC-I-20 and TAC-I-21



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Synthesis of TAC-I-20 (TAC-32-(C12α′MeβMe-2TG)) and TAC-I-21 (TAC-24-(C12α′MeβMe-2TG)): 4-(Dimethylamino)pyridine (DMAP, 1.9 mg, 15.5 μmol) and EDC.HCl (6.0 mg, 31.1 μmol) were added to a solution of tacrolimus (12.5 mg, 15.5 μmol) and acid-TG (Int-27; 15.1 mg, 18.7 μmol) in CH2Cl2 (1 mL) and the mixture stirred at rt for seven days. The reaction was diluted with CH2Cl2 (5 mL), silica gel was then added and the solvent was removed under reduced pressure. Purification by silica gel chromatography (30% to 100% ethyl acetate/hexanes) gave TAC prodrugs TAC-I-20 (7.3 mg, 29%) and TAC-I-21 (2.3 mg, 9%) as colourless oils.


TAC-I-20:

ESI-HRMS: Calcd. for C89H151NNaO19 [M+Na+] 1617.1399; found 1617.1357


Rf (50% EtOAc/Hexanes): 0.73.
TAC-I-21:

ESI-HRMS: Calcd. for C89H151NNaO19 [M+Na+] 1617.1399; found 1617.1361


Rf (50% EtOAc/Hexanes): 0.38.
Example 31: Synthesis of TAC-I-22 and TAC-I-23



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Synthesis of TAC-I-22 (TAC-24-C5βMe-2-TG) and TAC-I-23 (TAC-24-C5βMe-2-TG): 4-(Dimethylamino)pyridine (DMAP, 2.1 mg, 17.0 μmol) and EDC.HCl (6.5 mg, 34.1 μmol) were added to a solution of tacrolimus hydrate (14.0 mg, 17.0 μmol) and acid-TG 2 (Int-4; 14.2 mg, 20.4 μmol) in CH2Cl2 (1 mL) and the mixture was stirred at rt for five days. The reaction was diluted with CH2Cl2 (5 mL), then silica gel was added and the solvent was removed under reduced pressure. Purification by silica gel chromatography (25% to 60%) EtOAc/hexanes) gave TAC-I-22 (4.3 mg, 17%) and TAC-I-23 (8.6 mg, 34%) as colorless oils.


TAC-I-22:
Rf (50% EtOAc/Hexane): 0.31.
TAC-I-23:
Rf (50% EtOAc/Hexane): 0.65.
Example 32: Synthesis of TAC-I-24 and TAC-I-25



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Synthesis of TAC-I-24 and TAC-I-25.



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Synthesis of TAC-I-24 (TAC-32-(TML-CβMe-2-TG)) and TAC-I-25 (TAC-24-(TML-CβMe-2-TG)). TAC-I-24 and TAC-I-25 are prepared according to the following procedure. DMAP (1.3 equiv.) and EDC.HCl (2.1 equiv.) is added to a solution of acid 12.1 (1.0 equiv.) as prepared in WO 2017/041139 with Int-4, and tacrolimus 12.2 (1.3 equiv.) in CH2Cl2 (0.02 M) and the mixture stirred at RT for 19 hours. The reaction is diluted with CH2Cl2 (10 mL), silica gel is added, and the mixture concentrated under reduced pressure and purified by silica gel chromatography to affords TAC-I-24 and TAC-I-25. Optionally, hydroxyl protecting groups are utilized to enhance regioselectivity, yielding the target compounds after deprotection and purification.


Example 33: Synthesis of TAC-I-26 and TAC-I-27



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Synthesis of TAC-I-26 and TAC-I-27.



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Synthesis of 13.2: 13.2 is prepared by treating a macrolide 13.1 with chloromethyl methyl thioether as described in WO 2009/143295, which is hereby incorporated by reference in its entirety. A solution of sulfuryl chloride (2.2 equiv.) in CH2Cl2 (0.16 M) is added to a solution of 13.1 (1.8 equiv.) in CH2Cl2 (0.07 M) at 0° C. and the mixture stirred at 0° C. for 30 minutes and then at rt for an additional hour. The reaction is concentrated under a stream of N2, co-evaporated from toluene (twice) and dried under reduced pressure.


Synthesis of TAC-I-26 (TAC-32-(ASI-C5βMe-2-TG)) and TAC-I-27 (TAC-24-(ASI-C5βMe-2-TG)): TAC-I-26 and TAC-I-27 are prepared according to the following procedure. The crude residue of 13.2 is re-dissolved in toluene (0.1 M based on 13.1), added to a solution of acid Int-4 (1 eq) as prepared in WO 2017/041139, and DBU (1.5 eq) in toluene (0.05 M) that had been pre-stirred for one hour, and the mixture is stirred at rt for two hours. The reaction is diluted with CH2Cl2 (20 mL) and the organic phase washed with sat. aq. NaHCO3 (20 mL) and brine (20 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude products. Purification by silica gel chromatography with a suitable solvent mixture affords TAC-I-26 and TAC-I-27.


Example 34: Synthesis of TAC-I-28 and TAC-I-29



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Synthesis of TAC-I-28 (TAC-32-(MASI-C5βMe-2-TG)) and TAC-I-29 (TAC-32-(MASI-C5βMe-2-TG)): 4-(Dimethylamino)pyridine (DMAP, 2.7 mg, 21.9 μmol) and EDC.HCl (12.6 mg, 65.7 μmol) are added to a solution of tacrolimus hydrate (18.0 mg, 21.9 μmol) and acid-TG (Int-4; 18.1 mg, 24.1 μmol) in CH2Cl2 (2 mL) and the mixture is stirred at rt for seven days. The reaction is diluted with CH2Cl2 (5 mL), silica gel is added, and the solvent is removed under reduced pressure. Purification by silica gel chromatography with suitable solvents gives TAC prodrugs TAC-I-28 and TAC-I-29.


Example 35: Lymphatic Transport Assay in Rats

In order to assess the lymphatic transport of disclosed lipid prodrugs in rats, the mesenteric lymph ducts of the rats used in this study were cannulated to allow continual collection of mesenteric lymph. Lipid formulations containing the compound of interest were then administered to the animals, lymph was collected, and drug concentrations in the lymph samples were quantified.


Lipid-based formulations of the compounds of the invention or control compounds were prepared as previously described (Trevaskis, N. L. et al., Pharmaceutical Research, 2005, 22(11), 1863-1870, WO 2016/023082, and WO 2017/041139, hereby incorporated by reference.


In brief, either 1 or 2 mg of test prodrug, 40 mg oleic acid and 25 mg Tween 80 were mixed in a glass vial and incubated at 37° C. for 12-18 h to equilibrate. An aqueous phase consisting of 5.6 ml phosphate buffered saline (PBS, pH 7.4) was subsequently added to the lipid phase (MPA was dissolved in PBS for the preparation of MPA containing formulations) and the formulation emulsified by ultrasonication with a Misonix XL 2020 ultrasonic processor (Misonix, Farmingdale, N.Y., USA) equipped with a 3.2-mm microprobe tip running at 30% of the maximal amplitude of 240 μm and a frequency of 20 kHz for 2 min at room temperature. Doses for administering to more than one animal can be prepared in one batch by suitably increasing the quantities given above. Drug/prodrug concentrations in all formulations were verified using HPLC-MS.


Male Sprague-Dawley (SD) rats were selected for the lymphatic transport studies involving mycophenolic acid lipid prodrugs. Depending on the therapeutic agent, male, female, or both may be selected for study. Rats (typically 240-320 g) were maintained on a standard diet and fasted overnight with free access to water prior to experiments.


Anesthetized rats were placed on a heated pad at 37° C. and cannulas inserted into the duodenum (for formulation administration and rehydration), mesenteric lymph duct (for lymph collection), and carotid artery (in cases where blood collection was conducted). Post-surgery, rats were re-hydrated for 0.5 h via intraduodenal infusion of normal saline at 2.8 mL/h. The lipid formulations were infused into the duodenum at 2.8 mL/h for 2 h after which, normal saline was infused at 2.8 mL/h for the remainder of the experiment. Lymph was continuously collected for up to 8 h into pre-weighed Eppendorf tubes containing 10 μL of 1,000 IU/mL heparin. The collection tubes were changed hourly and lymph flow was measured gravimetrically. Aliquots of hourly lymph samples were stored at −20° C. prior to assay.


Drug concentration in lymph is expressed as total drug and includes free drug and drug associated with different glycerides. Lymph samples are first treated with a lipase or other appropriate conditions to liberate free active agent prior to measurement of active agent levels in the lymph. Treatment with a lipase or other hydrolysis conditions liberates free active agent from any corresponding re-esterified glycerides. Porcine pancreatic lipase is appropriate for this purpose. Alternatively, hydrolysis with 0.5 M NaOH may be used. For MPA “phenol” prodrugs (i.e. prodrugs linked to the triglyceride at the aromatic —OH group of MPA), hydrolysis was performed with 0.5 M NaOH except for the lymph samples collected from 3 rats in the group of compound MPA-I-20 (MPA-O-C12α′βMe-TG), which were hydrolyzed by porcine pancreatic lipase.


Transport of compounds into lymph during each hourly collection period was calculated from the product of the volume of lymph collected and the measured concentrations in lymph. For fluorescently-labelled compounds such as a BDP-conjugate, the concentrations of total compound may be measured by fluorescence spectroscopy without hydrolysis.


The results of the lymphatic transport assays are summarized in Table B, below, and e.g. in the attached Figures. Table B summarizes lymphatic transport of total MPA related compound (% of administered dose) following intraduodenal infusion to anaesthetised, mesenteric lymph-duct cannulated rats. Data are presented as mean±SD when n≥3 or mean±range when n=2. Compounds with a lymphatic transport assay result of greater than 10% (>10%) are designated as “A.” Compounds with a lymphatic transport assay result between 1% and 10% (1%-10%) are designated as “B.” Compounds with a lymphatic transport assay result of less than 1% and greater than 0.24% (<1% and >0.24%) are designated as “C.”


Importantly, the cumulative lymphatic transport percentages of MPA and MMF measured in this assay are very low (0.17±0.12% for MPA and even less for MMF; see FIG. 8). Accordingly, a lymphatic transport assay result of “A” means that the lipid prodrug increases cumulative lymphatic transport relative to MPA or MMF by a factor of >59. A result of “B” indicates an increase by a factor of between 5.9 and 59. A result of “C” indicates an increase by a factor of between about 1.4 and <5.9.









TABLE B







Lymphatic transport of total compounds related to parent therapeutic agent (% of administered dose) following intraduodenal infusion to


anesthetised, mesenteric lymph-duct cannulated rats (data are presented as mean ± SD when n ≥3 or as mean ± range when n = 2).













Cumu-





lative





lym-





phatic





transport





% dose





(Mean ±





SD, or


Compound


Range if


Name
#
Structure
n = 2)





MPA (n = 5)



embedded image


0.17 ± 0.12





MMF


0.14 ±


(n = 3)


0.08





MPA- TG (n = 5)
MPA- I-34


embedded image


A





MPA- Ph-C3- TG
MPA- I-28


embedded image


B





MPA- C4(ether)- TG (n = 3)
MPA- I-25


embedded image


C





MPA-C5- Carbonate- TG (n = 4)
MPA- I-27


embedded image


B





MPA- C6(ether)- TG (n = 4)
MPA- I-26


embedded image


C





MPA-C7- TG (n = 2)
MPA- I-36


embedded image


B





MPA- C12-TG (n = 2) (dose 1 mg/rat)
MPA- I-37


embedded image


A





MPA- C18-TG (n = 3) (dose 1 mg/rat)
MPA- I-38


embedded image


B





MPA- O-C4- TG(OMe) (n = 2)
MPA- I-17


embedded image


C





MPA- O-C6- TG(OMe) (n = 2)
MPA- I-18


embedded image


B





MPA- O-C10- TG(OMe) (n = 3)
MPA- I-19


embedded image


A





MPA- O-C12- TG(OMe) (n = 3)
MPA- I-30


embedded image


A





MPA-O- C12α′MeβMe- TG(OMe) (n = 5)
MPA- I-20


embedded image


A





MPA-O- CASI- C12α′MeβMe- TG(OMe) (n = 3)
MPA- I-21


embedded image


B





MPA-O- C12α′βMe- TG (OMF) (n = 3)
MPA- I-32


embedded image


A





MPA-O- FSI(5)- C12α′MeβMe- TG(OMe) (n = 5)
MPA- I-22


embedded image


A





MPA-2-PL (n = 4)
MPA- I-39


embedded image


C





MPA-O-TML-
MPA-

B


C12-TG (n = 3)
I-47




MPA-O-ASI-
MPA-

A


C12α′βMe-TG
I-44




(n = 3)








MPA-O-C15β- TG (n = 2)
MPA- I-31


embedded image


A





MPA-C10-TG (n = 3)
MPA- I-46


embedded image


A





MPA(O-C11-2- TG)-OMe
MPA- I-48


embedded image


A





MPA-C10β-TG (n = 3)
MPA- I-50


embedded image


A







text missing or illegible when filed








The half-life of monoglyceride (MG) intermediates in rat bile and pancreatic fluid was determined for selected compounds. The data are presented in Table 3 below. The designation “A” indicates that the half-life of the MG intermediate was between 15 and 90 minutes. “B” indicates a half-life between >90 minutes and 300 minutes. “C” indicates a half-life between >300 minutes and 600 minutes. “D” indicates a half-life between >600 and 1200 minutes.


The percentage of MPA released at 60 minutes in LPL-supplemented rat plasma was also determined for selected compounds. As shown in Table C below, the designation “*” indicates a release % of 1 to 25%. The designation “**” indicates a release % of >25% to 50%. The designation “***” indicates a release % of >50% to 75%. The designation “****” indicates a release % of >75%.









TABLE C







Stability of the Monoglyceride (MG)


Intermediates of Lipid Prodrugs in


Rat Plasma, Bile, and Pancreatic Fluid.















Percentage





Half-life of
MPA





MG
release at





intermediates
60 min in





in rat bile
LPL





and
supple-





pancreatic
mented rat





fluid (min)
plasma





(n = 3
(n = 3





unless
unless



Compound

specified
specified



Name
#
otherwise)
otherwise)







MPA-TG
MPA-
C
***



(n = 5)
I-34





MPA-
MPA-
C




C4(ether)-
I-25





TG (n = 3)






MPA-C5-
MPA-
A




Carbonate-
I-27





TG (n = 4)






MPA-
MPA-
B




C6(ether)-
I-26





TG (n = 4)






MPA-C7-
MPA-
A




TG (n = 2)
I-36





MPA-O-C10-
MPA-

****



TG(OMe)
I-19





(n = 3)






MPA-O-
MPA-

***



C12α′Meβ
I-20





TG(OMe)






(n = 3)






MPA-O-
MPA-

***



FSI(5)-
I-22





C12α′Meβ






Me-






TG(OMe)






(n = 2)






MPA-2-PL
MPA-
D




(n = 4)
I-39










DESCRIPTION OF THE DRAWINGS


FIG. 1: Lymphatic transport of mycophenolic acid prodrug MPA-I-17 in rats following the procedure described above. Rat 1 (●); rat 2 (▪).



FIG. 2: Lymphatic transport of mycophenolic acid prodrug MPA-I-18 in rats following the procedure described above. Rat 1 (●); rat 2 (▪).



FIG. 3: Lymphatic transport of mycophenolic acid prodrug MPA-I-19 in rats following the procedure described above. Rat 1 (●); rat 2 (▪); rat 3 (▴).



FIG. 4: Lymphatic transport of mycophenolic acid prodrug MPA-I-20 in rats following the procedure described above. Rat 1 (●); rat 2 (▾); rat 3 (▪); rat 4 (∘); rat 5 (⋄).



FIG. 5: Lymphatic transport of mycophenolic acid prodrug MPA-I-21 in rats following the procedure described above. Rat 1 (●); rat 2 (▾); rat 3 (▪).



FIG. 6: lymphatic transport of phenol-conjugated MPA prodrugs (mean±SD when n≥3 or as mean±range when n=2).



FIG. 7: lymphatic transport of mycophenolic acid (MPA) and mycophenolate mofetil (MMF) (mean±SD).









TABLE D







Pharmacokinetic and Lymph Data for Testosterone Lipid Prodrugs























Rat-










cumu-










lative










lympha-







Plasma


tic




Plasma


PK

Rat-
trans-




PK


measure-

cumu-
port:




measure-

Plasma
ments:
Plasma
lative
Mean,



Plasma
ments:
Plasma
PK
Fold
PK
lym-
lympha-



PK
Mean
PK
measure-
increase
measure-
pha-
tic



measure-
Plasma
measure-
ments:
relative
ments:
tic
trans-


Cmd
ments:
AUC (0-
ments:
Cmax
to
Compa-
transport:
port over


Name
Repeat
24 hr)
Tmax
nmol/
Compa-
rator
Repeat
6 or 8


and #
number
(nmol.h/L
(h)
L)
rator
drug
Number
hours (%)


















TST-FSI5-
5
504.6
1.2
293.3
74
TU
2
11.3


C12abMe-





(testoster-




2-TG (I-





one




50)





undeca-










noate)




TST-FSI5-05bMe-
4
583.3
0.9
822.1
85.5
TU




2-TG (I-49)










TST-
3
591
0.92
638
86.6
TU
3
11.4


CMSI-










C10bMe-










2-TG (I-










46)










TST-
4
631.6
0.9
595.8
92.6
TU




CMSI-C5bMe-










2-TG










(1-44)










TST-
3
268.1
0.8
358.1
39.3
TU
3
2.8


CASI-C5bMe-










2-TG (1-42)










TST-ASI-
3
255.4
1.1
190.8
37.4
TU
4
8.3


C15a'bMe










-2-TG (I-










41)










TST-ASI-C12a'bMe
3
901
1.08
968
132.1
TU
3
27.2


-2-TG ((I-










40)










TST-ASI-C10b'Me-
4
588.7
1.8
311
86.3
TU




2-TG (I-39)










TST-ASI-05-2-TG
4
236
1.2
95.6
34.6
TU
3
2.3


(I-38)










TST-C10-ET-2-TG






3
6.9


(I-37)










TST-C10-AM-2-TG






3
1.8


(I-36)










TST-C15a'bMe-
3
47.7
1.5
86.8
7
TU
2
14.2


2-TG (I-










35)










TST-C12a'bMe
2
187.9
1.9
24.9
27.5
TU




-2-TG (I-










34)










TST-C10b'Me-
3
39.6
1.5
28
5.8
TU




2-TG (I-33)










TST-C4-2-
4
18.9
1.1
13.2
2.8
TU
4
13.5


TG (1-32)
















TABLE E







Pharmacokinetic and Lymph


Data for Additional Lipid Prodrugs














Rat-cumulative
Rat-





lymphatic
cumulative




Rat-
transport:
lymphatic




cumulative
Mean,
transport:




lymphatic
lymphatic
SD, lymphatic




transport:
transport
transport



Cmpd
Repeat
over 6 or 8
over 6 or 8



Name and #
Number
hours (%)
hours (%)
















THC-CASI-
3
66.9
18



C5bMe-2-






TG (I-55)






THC-TML-
3
3.4
0.9



C5bMe-2-






TG (I-54)






THC-C10-2-
2
82.2
1.1



TG (I-53)






CBD-FSI5-
2
29.1
14



C5bMe-2-






TG (I-56)






CBD-C5bMe-2-
3
26.1
6.6



TG (I-20)






BUP-TML-
3
44.7
19



C5bMe-2-






TG (I-15)






BUP-C10-2-
5
59.8
17



TG (I-14)






BUP-C5bMe-2-
2
45.6
14



TG (I-13)






BUP-C4-2-
3
12.9
4.1



TG (I-12)










Example 36: Prodrug Lymph Node Studies in Mice

This experiment included a single and multiple dose study. In the multiple dose study, dosing of either free MPA or MPA-2-TG (MPA-I-34, structure below) 2 times daily was performed for 2 days followed by collecting samples from mesenteric or peripheral lymph nodes on the 3rd day after dosing.




embedded image


The concentrations of free MPA were measured for both groups of mice.


Much higher concentrations in mesenteric lymph nodes after MPA-TG administration were observed compared with MPA. In contrast, the peripheral lymph nodes showed similar concentrations following administration of MPA-TG and MPA. The results of the multi-dose study are shown in FIGS. 8A and 8B.


As shown in FIG. 9, conversion of MPA-I-20 into its monoglyceride form (in which both palmitic acid groups are cleaved) and release of MPA from the monoglyceride could be followed over time in rat plasma supplemented with LPL. FIG. 10 shows conversion over time after administration of MPA-I-22. For both MPA-I-20 and MPA-I-22, about 80% of the MPA was released after 180 min and the monoglyceride (MG) peak had almost completely disappeared.


In FIG. 10, the “Acid” intermediate is believed to have the following structure:




embedded image


“FSI(5)-OH” refers to the following intermediate structure:




embedded image


Example 37: Pharmacokinetic (PK) Studies in Rats and Dogs

In order to assess the oral bioavailability of test compounds, pharmacokinetic studies were conducted using the following procedure. The day before drug administration, male Sprague-Dawley rats (240-320 g) were anesthetised and the carotid artery cannulated. The rats were then allowed to regain consciousness and fasted overnight prior to the commencement of experiments with free access to water. The next morning, formulations containing parent compounds or prodrugs were administered via oral gavage and blood samples collected from the carotid artery cannula from −5 min up to 24 h post dosing and centrifuged at 5000 rpm for 5 min to separate plasma. During the blood sample collection period, the rats had free access to water but remained fasted for a further 8 h following drug administration. Plasma samples were stored at −80° C. prior to assay by HPLC-MS-MS. Samples were assayed for free drug (i.e. non-glyceride associated drug) to determine hydrolysis (if any) prior to assay.


For the dog studies, beagle dogs will be held in a large-animal research facility prior to the commencement of studies. The dogs will be fasted for 12 h up to 30 min prior to drug administration. For the fed state studies, dogs will receive ˜20 g of high fat dog food (containing ˜34% fat), administered by hand, followed by 10 mL water to aid in swallowing, followed by 100 g standard canned dog food (˜2.5% fat) 30 min prior to drug administration. Water will be available ad libitum throughout the study for all dogs. Test compounds may be prepared in a suitable formulation such as a long-chain lipid based self-emulsifying drug delivery system (SEDDS) consisting of 30.5% w/w soybean oil, 30.5% w/w Maisine-CC, 31.6% w/w Cremophor EL and 7.4% w/w ethanol. Formulations may be filled into hard gelatin capsules. Compound dissolved in the formulation may be administrated to the fed dog by placing the capsules as far posterior to the pharynx as possible, closing the mouth and rubbing the throat to stimulate swallowing. Subsequently 50 mL of water will be administered orally via a syringe. After oral administration, blood samples (approx. 1.5 mL each) will be taken via venepuncture of the cephalic vein 5 min prior to administration up to 120 hours post-dosing. Plasma will be separated by centrifugation and aliquots of each plasma sample transferred into eppendorf tubes and stored at −80° C. prior to analysis.


For comparison purposes and to allow calculation of bioavailability, the parent drug may be administered intravenously by either infusion (over 5 min) or bolus injection of a suitable dose of drug dissolved in appropriate aqueous formulation (dependent on the nature of the parent drug (for example, for MPA, 95:5 PBS/ethanol may be used, while for other drugs, a 20% hydroxypropyl-β-cyclodextrin solution may be used). The dose also depends on nature of the parent drug. For MPA, about ˜2-3 mg per beagle is used, while for others, a higher or lower dose per beagle is used. After IV administration, blood samples (approx. 1.5 mL each) will be taken via venepuncture of the cephalic vein 5 min prior to administration up to 120 hours post-dosing. Plasma will be separated by centrifugation and aliquots of each plasma sample transferred into eppendorf tubes and stored at −80° C. prior to analysis.


Example 38: In Vitro Hydrolysis of Compounds by Rat Digestive Fluid or Porcine Pancreatic Lipase

In vitro hydrolysis of test compounds may be performed via incubation with rat digestive fluid. Rat digestive fluid will be collected from anesthetized rats via cannulation of the common bile-pancreatic duct immediately prior to the entry of the duct into the duodenum (i.e. below the point of entry of pancreatic secretions). This allows simultaneous collection of bile and pancreatic fluid. The digestive fluid will be collected continuously for 2 h, during which time a blank lipid formulation (prepared as described in the rat lymphatic transport studies but without the addition of drug) will be infused into the duodenum at a rate of 2.8 mL/h to mimic conditions following drug administration. Bile and pancreatic fluid will be maintained at 37° C. and used within 0.5 h of collection for in vitro prodrug hydrolysis experiments. The hydrolysis experiments will be conducted via incubation (at 37° C.) of ˜0.375 mL of rat digestive fluid with 0.625 ml of the drug-loaded lipid formulations (as described in the rat lymphatic transport studies). The volume ratio of digestive fluid to formulation will mimic the flow rate of bile and pancreatic fluid (−1.5 mL/h) and the infusion rate of the intraduodenal formulations (2.8 mL/h) during the in vivo lymphatic transport studies. Aliquots of 10 μL (samples taken at 0, 2, 5, 10, 15, 30, 60, 90, 120, 180 min) will be added to 990 μL of acetonitrile/water (4:1, v/v) to stop lipolysis, vortexed for 1 min and centrifuged at 4500 g for 5 min to precipitate proteins prior to analysis. The supernatant will be analyzed by HPLC-MS for residual compound concentrations, and the potential products of compound hydrolysis analyzed.


To provide for higher throughput of experiments, unless otherwise stated, in vitro hydrolysis of test compounds will generally be performed via incubation with porcine pancreatic lipase. This provides a more reproducible source of pancreatic enzymes, facilitates enhanced experimental throughput, and is also a greater challenge than collected rat enzymes (since enzyme activity in rat intestinal fluid is low). Briefly, pancreatic lipase solution will be prepared prior to the hydrolysis experiment by dispersion of 1 g porcine pancreatin in 5 ml of lipolysis buffer and 16.9 μL of 0.5 M NaOH. The suspension will be mixed well and centrifuged at 3500 rpm for 15 minutes at 5° C. to provide a supernatant. An amount of 1000 mL of lipolysis buffer will be prepared with 0.474 g of tris-maleate (2 mM), 0.206 g of CaCl2.H2O (1.4 mM) and 8.775 g of NaCl (150 mM) adjusted with NaOH to pH 6.5. To assess the potential for prodrug hydrolysis in the intestine, 20 μL of prodrug solution (1 mg/mL dissolved in acetonitrile), 900 μL of simulated intestinal micellar solution [prepared with 0.783 g of NaTDC (3 mM) and 0.291 g of phosphatidyl choline (0.75 mM) in 500 mL lipolysis buffer] and 100 μL of enzyme solution will be incubated at 37° C. 20 μL samples of the incubation solution will be taken at 0, 5, 10, 15, 30, 60, 90, 120 and 180 minutes post incubation and added to 180 μL of MeCN to stop lipolysis. The mixture will be vortexed and centrifuged at 5000 rpm for 5 minutes to precipitate proteins prior to analysis. The supernatant will be analyzed by HPLC-MS for residual compound concentrations, and the potential products of compound hydrolysis analyzed.


On incubation with digestive enzymes, the monoglyceride forms of the prodrugs are formed very rapidly. The stability in simulated intestinal conditions is therefore better assessed by the stability of the monoglyceride form that is generated by the initial digestion process. The monoglyceride form must remain intact to be absorbed and re-esterified in the enterocyte prior to entry into the lymphatics. A comparison of the stability profiles of the monoglyceride forms of test compounds during in vitro incubation with freshly collected rat bile and pancreatic fluid (BPF) or porcine pancreatic lipase will be used to evaluate the influence of linker structure on the stability of the monoglyceride intermediates.


Example 39: In Vitro Release of Therapeutic Agent From Prodrugs in Lymph Supplemented with Lipoprotein Lipase

In order to probe the release of free therapeutic agent from lipid prodrugs in the lymphatics, prodrugs will be incubated with rat lymph supplemented with lipoprotein lipase (LPL, 200 unit/mL). LPL is a key enzyme required for the hydrolysis of lipoprotein associated TG in normal physiological conditions and is therefore expected to be a key contributor to lipolysis of the re-esterified drug-TG construct in plasma, largely via liberation of fatty acids in the sn-1 and the sn-3 position of the TG-mimetic, prior to drug release from the 2′ positon via esterase hydrolysis. LPL is tethered to lymphocytes or lymphatic/vascular endothelial cells under physiological conditions. In these in vitro studies, rat lymph will therefore be supplemented with LPL to better reflect the in vivo situation. To start hydrolysis, 10 μL of LPL solution (10,000 unit/ml) will be added to a mixture of 10 μL of prodrug solution (1 mg/mL dissolved in acetonitrile) and 500 μL of blank Sprague Dawley rat lymph. The solution will be incubated at 37° C. Samples (20 μL) of the incubation solution will be taken at 0, 5, 10, 15, 30, 60, 90, 120 and 180 minutes post incubation and added to 980 μL of 9:1 (v/v) MeCN/water to stop lipolysis. The mixture will be vortexed and centrifuged at 4500 g for 5 minutes to precipitate proteins prior to analysis. The supernatant will be analyzed by HPLC-MS/MS for concentrations of the released therapeutic agent.


Example 40: Lymphocyte Proliferation Assay

Immune cells from rats (MLN and spleen cells) and PBMCs from human participants will be cultured in flat clear-bottom 96-well microplates (Thermo Scientific Nunc®) at a concentration of 8.4×104 and 5.2×104 cells/well, respectively. Working stock solutions of test and control compounds in RMPI-1640 culture medium-DMSO (99:1, v/v) will be prepared at concentrations of 10, 25, 50, 75, 100, 150, and 200m/mL. Working stock solutions of test and control compounds will be incubated with cells at final concentrations of 1, 2.5, 5, 7.5, 10, 15, and 20 μg/mL in a humidified atmosphere of 5% CO2 at 37° C. for 30 min. Cells will then be stimulated by the T cell-selective mitogen Phytohaemagglutinin (PHA, 10 μg/mL, Sigma Aldrich; see Janossy, G. et al., Clin. Exp. Immunol. 9, 483-& (1971)) or other stimulant such as Concanavalin A (ConA), and incubated in a humidified atmosphere of 5% CO2 at 37° C. for 2 days. Cell proliferation will be assessed by enzyme-linked immunosorbent assay (ELISA) based on bromo-2′-deoxyuridine (BrdU) incorporation into newly synthesized DNA according to the manufacturer protocol (Roche Applied Science, Roche Diagnostics Ltd, UK). Finally, the absorbance of these wells will be observed at 370 nm, with reference wavelength at 492 nm using plate reader (EnVision® Multilabel Plate Reader, PerkinElmer Inc., USA). Absorbance values will be normalized to the absorbance of culture medium-treated cells.


Reference: Zgair, A. et al., Scientific Reports 2017, 7: 14542, 1-12.


Example 41: Flow Cytometry Analysis

Freshly isolated immune cells of MLN and splenocytes from rats and thawed PBMCs from human participants will be incubated with control or test compound (1-20 μg/mL) for 30 min in FACS tubes. Cells will then be stimulated with phorbol myristate acetate and ionomycin (PMA & I) in the presence of brefeldin A and incubated in a humidified atmosphere of 5% CO2 at 37° C. for 5 hours. After stimulation, cells will be washed with PBS and centrifuged to pellet (290 g, 5 min, 20° C.). Cell pellet will be resuspended and labelled with Zombie UV™ Fixable Viability kit according to the manufacturer's protocol (Biolegend) for the purpose of excluding dead cells during the analysis of data (effect of relevant control compounds on the variability of immune cells isolated from healthy volunteers can be evaluated by methods known in the art). Fixation and permeabilization will be performed using BD Cytofix/Cytoperm™ kit according to the manufacturer's protocol (BD Bioscience). Rat immune cells will be labelled with APC anti-rat CD3, PE anti-mouse/rat TNF-α, and FITC anti-rat IFN-γ antibodies (Biolegend). Human PBMCs will be labelled with BV421 anti-human TNF-α and PerCP/Cy5.5 anti-human IL-2 antibodies (Biolegend), ECD anti-human CD3, FITC anti-human IFN-γ antibodies (Beckman Coulter), and PE anti-human IL-17A, and APC anti-human GM-CSF antibodies (eBioscience). Isotype and fluorescence minus one (FMO) controls will be prepared for all antibodies in each flow cytometry run. Data will be collected on MoFlo® Astrios™ EQ flow cytometer and analyzed using Kaluza analysis software v 1.5 (Beckman Coulter). An appropriate gating strategy may be selected using methods known in the art and the reference below.


Reference: Zgair, A. et al., Scientific Reports 2017, 7: 14542, 1-12.


Example 42: Preparation of Single-Cell Suspension From Mesenteric Lymph Node (MLN) and Spleen of Rats

Following 5 days of acclimatization, animals will be euthanized and the ventral abdominal wall incised to expose the intestine. MLN and spleen will be aseptically collected. MLN will be gently dissected from surrounding tissue and spleen will be scored with a clean scalpel before being mashed on cell strainer (70 μm Nylon, Corning Falcon™). Red blood cells in the cell suspension of the splenocytes will be lysed by lysing buffer (BD Bioscience). Immune cells from MLN and splenocytes will then be washed twice with PBS. Cell suspension will be centrifuged (400 g, 5 min at room temperature) and resuspended in complete RMPI-1640 culture medium (RMPI-1640 culture medium with L-glutamine supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin, all purchased, e.g., from Sigma-Aldrich) at concentration of 1.2×106 cells/mL to be used for proliferation and flow cytometry experiments.


Reference: Zgair, A. et al., Scientific Reports 2017, 7: 14542, 1-12 and Han, S. et al., Journal of Controlled Release 2014, 177, 1-10.


Example 43: In Vitro Release of Therapeutic Agent From Prodrugs in Plasma Supplemented with Lipoprotein Lipase

In order to probe the release of free drug from TG prodrugs in the systemic circulation, prodrugs were incubated with plasma (rat, mouse, dog, pig or human) supplemented with lipoprotein lipase (LPL, 200 IU/ml). LPL is a key enzyme required for the hydrolysis of lipoprotein associated TG in the systemic circulation and is therefore expected to be a key contributor to lipolysis of the re-esterified drug-TG construct in plasma, largely via liberation of fatty acids in the sn-1 and the sn-3 position of the TG-mimetic, prior to drug release from the 2′ position via esterase hydrolysis. LPL is active in plasma but is tethered to the luminal surface of vascular endothelial cells under physiological conditions. In the current in vitro studies, plasma was therefore supplemented with LPL to better reflect the in vivo situation. To start hydrolysis, 10 μl of LPL solution (10,000 IU/ml) was added to a mixture of 10 μl of prodrug solution (1 mg/ml dissolved in acetonitrile) and 500 μl of blank plasma. The mixture was incubated at 37° C. Samples (20 μl) of the incubation solution were taken at 0, 5, 15, 30, 60, 90, 120 and 180 minutes post-incubation and added to 180 μl of MeCN to stop lipolysis. The mixture was vortexed and centrifuged at 4500×g for 5 minutes to precipitate proteins prior to analysis. The supernatant was analyzed by HPLC-MS/MS for the potential products (MG form, acid form, and free drug) of prodrug hydrolysis.


To assess the stability and release profile of compounds of the present invention, compounds TAC-I-18 and TAC-I-20 were incubated with rat plasma and the concentrations of compounds, parent drug tacrolimus, and acid were monitored by LCMS for about three hours. The plasma release profiles for TAC-I-18 are summarized in FIG. 20. The plasma release profiles for TAC-I-20 are summarized in FIG. 21.


Example 44: Oral Ovalbumin Challenge Model
Purification and Labelling of Ovalbumin Specific T Cells

OVA specific CD4+ and CD8+ T cells were purified from the lymph nodes of OT2 and OT1 mice, respectively, and employed in independent experiments to simplify the studies. Lymph nodes collected from OT mice (including MLN, inguinal, brachial, axillary, cervical, iliac) were pressed through a 40 μm sieve using the back of 1 ml syringe plunger, to form a single cell suspension in RPMI 1640 with 2% Fetal Bovine Serum. T cells were then purified using negative selection separation and employing a magnet assisted cell sorting (MACS®) protocol from Miltenyi Biotec. The protocol provided in the kit supplied by Miltenyi Biotec was followed. Briefly, cell suspensions obtained from the lymph node of the OT mice were resuspended in MACS buffer (PBS with 2 mM EDTA and 0.2% Bovine Serum Albumin (BSA)) and labelled with antibodies against all other surface markers, except for the marker for the cells of interest (i.e. CD4+ T cells are isolated by depletion of non CD4+ T cells using a cocktail of biotin-conjugated antibodies against CD8a, CD11b, CD11c, CD19, CD45R (B220), CD49b (DX5), CD105, Anti-MHC-class II, Ter-119 and TCR γ/δ as primary labelling reagent). The cells were then incubated with Anti-biotin labelled magnetic microbeads and passed through the MACS LS column along with MACS buffer within the magnetic field of the Vario MACS separator. The labelled cells are retained within the column while the unlabelled cells flow through the column. The quantity of reagents used was as described in the kit. The purity of the isolated cells was confirmed by flow cytometry of a small sample. These cells were stained with antibodies to CD4 (OT2) or CD8 (OT1) and for Ly 5.1 (surface protein present in lymphocytes of OT mice). The purified CD4 or CD8 T cells were subsequently labelled with CellTrace violet (CTV) dye to allow downstream quantification of cell proliferation. CTV labelling was performed in two steps. First the CTV dye was diluted 100 fold (from 5 mM to 50 μM) with 0.1% BSA in PBS in an eppendorf tube. This solution was then further diluted 10 fold (to 5 μm) at the same time as adding to the cell suspension (≤50×106 cells/ml) in a 10 mL Falcon tube. The tube was sealed and vortexed immediately to allow even distribution of the dye to the cells. The number of OT cells purified and thus labelled were counted using a haemocytometer under the microscope. The cells were then pelleted and resuspended in PBS, pH 7.4 (107 cells/nil), for administration to the recipient mice.


Oral Ovalbumin Challenge Model (Late Dosing Protocol)

Recipient female C57B1/6 mice (20-22 g) were administered 50 mg ovalbumin in 0.2 mL of PBS as a single dose, by oral gavage on Day 1. A negative control group received only PBS (the saline “treatment” group). Each mouse was then administered ˜0.2 ml of the appropriate cell suspension containing 2×106 donor cells, by the tail vein (from above; purified and labelled CD4 or CD8 T cells, obtained from donor OT mice), within 0.5-3 hours of ovalbumin administration. The ovalbumin dosed mice were then divided into four treatment groups and administered different treatments via oral gavage. One group received no additional treatment (OVA treated group), a second received 50 mg/kg parent drug (MPA) as a suspension in 0.2 ml of 0.5% CMC (MPA treatment group), a third received the MPA-2-TG prodrug at a dose equivalent to 50 mg/kg of MPA formulated in a lipid emulsion (MPA-2-TG treatment group) and the fourth received the blank lipid emulsion (blank lipid treatment group) in which the prodrug was administered. The treatments were administered on days 2, 3 and 4, twice a day in the morning and evening. The mice were killed on day 5 and mesenteric lymph nodes (MLN) and peripheral lymph nodes (PLN, including inguinal, brachial, axillary, cervical, iliac) were collected and analyzed by flow cytometry (as below) to assess the proliferation of ovalbumin specific T cells.


Flow Cytometry Analysis

For flow cytometry analysis, cells were isolated from the MLN and PLN and formed into a single cell suspension as described above in PBS buffer containing 2% Foetal Bovine Serum. The cells were then incubated for 20 mins at 4° C. with FITC anti-mouse CD45.1 antibody or FITC anti-mouse TCR Va2 antibody to label lymphocytes derived from the OT mice (for transgenic mice obtained from WEHI, TCR Va2 antibody was used, for mice from Bio21 CD45.1 antibody was employed). APC anti-mouse CD8a antibody was used to label CD8 cells and PE anti-mouse CD4 antibody to label CD4 cells. Cells were then washed with buffer. All antibodies were used as per the dilution suggested by the commercial (Biolegend) labelling procedure. Propidium iodide, 10 ng/ml, was added to the cells just prior to flow cytometry analysis to stain for dead cells. Cells that were double positive for CD4/CD8 and CD45.1 (i.e. CD4 or CD8 lymphocytes derived from OT mice) were selected to detect the CTV fluorescence, using the Pacific blue filter (450/50). One million total events were acquired by the flow cytometer (BD Biosciences FACSCanto II analyser, Becton, Dickinson and Company, NJ, USA) and data were analysed using FlowJo software, by Tree Star Inc., Ashland, Oreg., USA.


Example 45: Lymph Transport Study in Beagle Dogs

A modified version of protocols described in Han, S. et al., “Lymphatic Transport and Lymphocyte Targeting of a Triglyceride Mimetic Prodrug Is Enhanced in a Large Animal Model: Studies in Greyhound Dogs,” Mol. Pharm. 2016, 13 (10), 3351-3361, may be used to perform lymph transport assays of test compounds in beagle dogs. The assay will be performed as follows.


The thoracic lymph duct will be cannulated under surgical anesthesia as previously described (Edwards, et al. Adv. Drug Delivery Rev. 2001, 50 (1-2), 45-60.). Following surgery, dogs will be allowed to recover unrestrained in a closed run overnight (12-16 h) and returned to normal ambulatory movement before commencement of the study. In the initial recovery period fluids will be administered IV to ensure adequate hydration and to prevent hypoproteinemia. Water will be also available ad libitum throughout the experiment period. Prior to drug administration, a 20 G intravenous catheter will be inserted into the cephalic vein to enable serial blood sampling and the catheter kept patent by periodic flushing with heparinized saline (1 IU/mL). To limit possible dehydration due to the continuous collection of thoracic lymph, 25 mL of normal saline will be also administered hourly by IV bolus during the sampling period. The dogs will be fasted for 12 h up to 30 min prior to drug administration. For fed state studies, dogs will receive ˜20 g of high fat dog food (containing ˜34% fat), administered by hand, followed by 10 mL water to aid in swallowing, followed by 100 g standard canned dog food (˜2.5% fat) 30 min prior to drug administration. Water will be available ad libitum throughout the study for all dogs. Test compounds may be prepared in a suitable formulation such as a long-chain lipid based self-emulsifying drug delivery system (SEDDS) consisting of 30.5% w/w soybean oil, 30.5% w/w Maisine-CC, 31.6% w/w Cremophor EL and 7.4% w/w ethanol. Formulations may be filled into hard gelatin capsules. Compound dissolved in the formulation may be administrated to the fed dog by placing the capsules as far posterior to the pharynx as possible, closing the mouth and rubbing the throat to stimulate swallowing. Subsequently 50 mL of water will be administered orally via a syringe. Lymph will be collected continuously into preweighed 50 mL collection tubes containing 75 mg of disodium EDTA for the duration of the 10 h postdosing period. Individual lymph samples for each half hourly or hourly collection period will be combined, and the mass of lymph collected will be determined gravimetrically. Several 20 and 200 μL aliquots of each lymph sample will be transferred into individual 1.5 mL Eppendorf tubes and stored at −80° C. until analysis of drug concentrations. The remaining lymph from each collection period (half hourly or hourly) will be transferred into 10 mL tubes, which will be centrifuged at 2000 g for 10 min to obtain lymphocyte pellets, which will be stored at −80° C. until analysis of drug concentrations. Systemic blood samples (3 mL) will be taken via the indwelling cephalic vein catheter and placed in individual heparinized tubes (13×75 mm BD Vacutainer, 68 IU). Blood samples will be collected at predose (−5 min) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, and 10 h following drug administration. Plasma will be separated by centrifugation and stored at −80° C. prior to analysis.

Claims
  • 1. A compound of Formula X-a or X-h:
  • 2. The compound according to claim 1, wherein R1 and R2 are —C(O)R3.
  • 3. The compound according to claim 1, wherein each R3 is independently a saturated or unsaturated, unbranched C2-37 hydrocarbon chain.
  • 4. The compound according to claim 1, wherein the compound is of Formula X-c:
  • 5. The compound according to claim 1, wherein the compound is of Formula X-e:
  • 6. The compound according to claim 1, wherein the compound is of Formula X-f:
  • 7. The compound according to claim 1, wherein the compound is of Formula XI-a:
  • 8. The compound according to claim 1, wherein the compound is of Formula XI-b:
  • 9. The compound according to claim 1, wherein -M- is selected from one of the following:
  • 10. The compound according to claim 9, wherein -M- is selected from
  • 11. The compound according to claim 9, wherein -M- is selected from
  • 12. The compound according to claim 1, wherein each R4 is independently hydrogen, deuterium, halogen, —CN, or C1-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R4 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered saturated monocyclic carbocyclic ring or 3-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that at least one instance of R4 is not hydrogen.
  • 13. The compound according to claim 1, wherein each R5 is independently hydrogen, deuterium, halogen, —CN, or C1-4 aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; or two instances of R5 attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a 3-6 membered saturated monocyclic carbocyclic ring or 3-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that at least one instance of R5 is not hydrogen.
  • 14. The compound according to claim 1, wherein each R4 and R5 is independently hydrogen or C1-4 alkyl optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms; provided that at least one instance of R4 is not hydrogen and at least one instance of R5 is not hydrogen.
  • 15. The compound according to claim 14, wherein one instance of R4 is C1-4 alkyl and one instance of R5 is C1-4 alkyl.
  • 16. The compound according to claim 1, wherein A is selected from an immunomodulatory therapeutic agent.
  • 17. The compound according to claim 16, wherein the immunomodulatory therapeutic agent is selected from thalidomide, lenalidomide, pomalidomide, apremilast, azathioprine, mycophenolic acid, leflunomide, teriflunomide, methotrexate, a macrolide IL-2 inhibitor, tacrolimus, sirolimus (Rapamune®), everolimus (Certican™), CCI-779, ABT578, temsirolimus, TAFA-93, vistusertib, ciclosporin, pimecrolimus, abetimus, or gusperimus.
  • 18. (canceled)
  • 19. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • 20. The pharmaceutical composition according to claim 19, further comprising an additional therapeutic agent.
  • 21. A method of treating a disease, disorder, or condition in a patient in need thereof comprising administering to said patient an effective amount of a compound according to claim 1.
  • 22. The method according to claim 21, wherein the disease, disorder, or condition is one of those recited in Tables 1 through 7.
  • 23. The compound of claim 1, wherein one instance of R4 is methyl and one instance of R5 is methyl.
  • 24. The compound according to claim 1, wherein the therapeutic agent is selected from testosterone, mycophenolic acid (MPA), buprenorphine, oestrogens (estrogen), opiates, tetrahydrocannabinol (THC), cannabidiol, metoprolol, raloxifene, alphaxolone, statins, pentazocine, propranolol, L-DOPA, lidocaine, chlorpromazine, sertraline, amitriptyline, nortriptyline, pentazocine, glyceryl trinitrate, oxprenolol, labetalol, salbutamol, epitiostanol, melphalan, lovastatin, non-steroidal antiinflammatory medications (NSAIDS), COX-2 inhibitors, corticosteroid anti-inflammatory medications, anti-malarial medications, nitrosoureas, methotrexate, dactinomycin, anthracyclines, mitomycin C, bleomycin, mithramycin, drugs acting on immunophilins, sulfasalazine, leflunomide, fingolimod, myriocin, chlorambucil, doxorubicin, nelarabine, cortisone, pralatrexate, vinblastine, bortezomib, nelarabine, clofarabine, cytarabine, dasatinib, imatinib mesylate, ponatinib hydrochloride, vincristine sulfate, bendamustine hydrochloride, fludarabine phosphate, bosutinib, nilotinib, omacetaxine mepesuccinate, capecitabine, paclitaxel, gemcitabine, fulvestrant, tamoxifen, lapatinib, toremifene, ixabepilone, eribulin, albendazole, ivermectin, diethylcarbamazine, albendazole, doxycycline, closantel, maraviroc, enfuvirtide, deoxythymidine, zidovudine, stavudine, didanosine, zalcitabine, abacavir, lamivudine, emtricitabine, tenofovir, delavirdine, rilpivirine, raltegravir, elvitegravir, lopinavir, indinavir, nelfinavir, amprenavir, ritonavir, and acyclovir; or a pharmaceutically acceptable salt thereof.
  • 25. The compound according to claim 1, wherein the therapeutic agent is selected from morphine, atorvastatin, aspirin, ibuprofen, naproxen, celecoxib, prednisolone, prednisone, dexamethasone, hydroxychloroquine, daunorubicin, cyclosporin, tacrolimus, and sirolimus.
  • 26. The compound according to claim 1, wherein the therapeutic agent is selected from testosterone, mycophenolic acid (MPA), buprenorphine, tetrahydrocannabinol (THC), cannabidiol, celecoxib, and dexamethasone.
PCT Information
Filing Document Filing Date Country Kind
PCT/US2018/048642 8/29/2018 WO 00
Provisional Applications (6)
Number Date Country
62551627 Aug 2017 US
62607700 Dec 2017 US
62607749 Dec 2017 US
62714029 Aug 2018 US
62724274 Aug 2018 US
62724440 Aug 2018 US