Patent Application
20230167150
CD33 ligands which are useful for the synthesis of CD33 ligand-bearing carriers, wherein said CD33 ligand-bearing carriers are directly or indirectly linked to or associated with at least one anti-cancer agent, and uses of said CD33 ligand-bearing carriers for treating and/or preventing a disease, disorder, or condition such as acute myeloid leukemia (AML) are described herein.
Acute myeloma leukemia (AML) is one of the most common types of leukemia among adults, and the most common acute leukemia affecting adults. AML is a cancer of myeloid stem cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cells. Symptoms may include fatigue, shortness of breath, easy bruising and bleeding, and increased risk of infection. It can progress rapidly and is typically fatal within weeks or months if left untreated. The 5-year survival rate for AML is 27.4%. It accounts for roughly 1.8% of cancer deaths in the United States.
First-line treatment of AML consists primarily of chemotherapy with an anthracycline/cytarabine combination, and is divided into two phases: induction and post-remission (or consolidation) therapy. The goal of induction therapy is to achieve a complete remission by reducing the number of leukemic cells to an undetectable level; the goal of consolidation therapy is to eliminate any residual undetectable disease and achieve a cure. The specific genetic mutations present within the cancer cells may guide therapy, as well as determine how long that person is likely to survive.
Despite advances in our understanding of the pathogenesis of AML, the short- and long-term outcomes for AML patients have remained unchanged over three decades. (Roboz et al., (2012) Curr. Opin. Oncol., 24: 711-719.) The median age at diagnosis is 66 years with cure rates of less than 10% and median survival of less than 1 year. (Burnett et al., (2010), J. Clin. Oncol., 28: 586-595.) Although 70-80% of patients younger than 60 years achieve complete remission, most eventually relapse, and overall survival is only 40-50% at 5 years. (Fernandez et al., (2009) N. Engl. J. Med., 361: 1249-1259; Mandelli et al., (2009) J. Clin. Oncol., 27: 5397-5403; Ravandi et al., (2006) Clin. Can. Res., 12(2): 340-344.) Relapse is thought to occur due to leukemic stem cells that escape initial induction therapy and drive reoccurrence of AML. (Dean et al., (2005) Nat. Rev. Cancer, 5(4): 275-294; Guan et al., (2003) Blood, 101(8): 3142; and Konopleva et al., (2002) Br. J. Haematol. 118(2): 521-534.) Chemoresistance, the ability of cancer cells to evade or to cope with the presence of therapeutics, is also a key challenge for therapeutic success.
Siglecs comprise a family of receptors that are differentially expressed on leukocytes and other immune cells. Each siglec contains an N-terminal ‘V-set’ Ig domain that binds sialic acid containing ligands, followed by a variable number (1-16) of ‘C2-set’ Ig domains that extend the ligand binding site away from the membrane surface. Each siglec also exhibits distinct and varied specificity for sialoside sequences on glycoprotein and glycolipid glycans that are expressed on the same cell (cis) or on adjacent cells (trans). There are currently 14 known siglecs in humans, four of which are highly conserved in all mammalian species and the rest are classified as Siglec-3 (CD33) related siglecs, which comprise a rapidly evolving sub-family. (Padler-Karavani et al., The FASEB Journal, 23(3), 2017, pp. 1280-1293.)
The restricted expression of several siglecs to one or a few cells types make them attractive targets for cell-directed therapies. (O'Reilly and Paulson, Trends Pharmacol Sci., 30(5), 2009, pp. 240-248.) As siglecs are endocytic receptors, attaching suitable siglec ligands to carriers of therapeutic agents can facilitate efficient targeting of cells expressing the siglec receptors, enabling the therapeutic agents to be efficiently carried into the cells.
CD33 was identified as a marker of myeloid leukemias and is overexpressed in AML cells. Thus, therapeutics incorporating CD33 ligands may be useful for cell-directed drug delivery to treat AML. Accordingly, there is a need in the art for CD33 ligands, and for the development of methods employing such compounds as a way to target diseases, disorders, and/or conditions associated with expression of CD33, such as AML. The present disclosure may fulfill one or more of these needs and/or may provide other advantages.
Disclosed are compounds of Formula (I):
and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5, R6, R7, L1, X, Y, Z, and q are as defined herein.
In some embodiments, a process for making CD33 ligand-bearing carriers of Formula (II) is provided, wherein the process comprises reacting or associating a compound of Formula (I) with a compound of Formula (III):
wherein R1, R2, R3, R4, R5, R6, R7, L1, L2, X, Y, Z, Z′, W, q, and carrier are as defined herein.
In some embodiments, a method for treatment and/or prevention of AML is disclosed, the method comprising administering to a subject in need thereof at least one compound of Formula (II) or a composition comprising same, wherein said at least one compound of Formula (II) delivers an effective amount of at least one anti-cancer agent.
In some embodiments, a method for treatment and/or prevention of AML is disclosed, the method comprising administering to a subject in need thereof an effective amount of at least one compound of Formula (II) or a composition comprising same, wherein at least one anti-cancer agent is directly or indirectly linked to or associated with said at least one compound of Formula (II).
In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the disclosed embodiments may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. These and other embodiments will become apparent upon reference to the following detailed description and attached drawings.
Disclosed herein are CD33 ligands, which are useful for the synthesis of CD33 ligand-bearing carriers. The CD33 ligand-bearing carriers may be useful for treating and/or preventing at least one disease, disorder, or condition, including AML.
In some embodiments, disclosed are compounds of Formula (I):
and pharmaceutically acceptable salts thereof, wherein:
R1 is chosen from C6-18 aryl and C1-13 heteroaryl groups, wherein the C6-18 aryl and C1-13 heteroaryl groups are optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, C2-8 haloalkynyl, C1-8 hydroxyalkyl, C2-8 hydroxyalkenyl, C2-8 hydroxyalkynyl, C6-18 aryl, C1-13 heteroaryl, -OT1, -ST1, —C(═O)OT1, —C(═O)NT1T2, -NT1T2, -NT1C(═O)T2, -NT1SO2T2, —S(═O)T1, and —SO2T1 groups, wherein T1 and T2, which may be identical or different, are independently chosen from H, C1-8 alkyl, and C1-8 haloalkyl groups, or T1 and T2 join together along with the heteroatom to which they are attached to form an optionally substituted, saturated or unsaturated, 3-10 membered ring;
R2 is chosen from C6-18 aryl and C1-13 heteroaryl groups, wherein the C6-18 aryl and C1-13 heteroaryl groups are optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, C2-8 haloalkynyl, C1-8 hydroxyalkyl, C2-8 hydroxyalkenyl, C2-8 hydroxyalkynyl, C6-18 aryl, C1-13 heteroaryl, -OT3, -ST3, —C(═O)OT3, —C(═O)NT3T4, -NT3T4, -NT3C(═O)T4, -NT3SO2T4, —S(═O)T3, and —SO2T3 groups, wherein T3 and T4, which may be identical or different, are independently chosen from H, C1-8 alkyl, and C1-8 haloalkyl groups, or T3 and T4 join together along with the heteroatom to which they are attached to form an optionally substituted, saturated or unsaturated, 3-10 membered ring;
R3 is chosen from H, C7-19 arylalkyl, and C2-14 heteroarylalkyl groups, wherein the C7-19 arylalkyl and C2-14 heteroarylalkyl groups are optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 haloalkyl, and C6-18 aryl groups;
R4 and R5, which may be identical or different, are independently chosen from H and hydroxy protecting groups, or R4 and R5 join together along with the oxygen atoms to which they are attached to form an optionally substituted, saturated or unsaturated, 3-10 membered ring;
R6 is chosen from H and hydroxy protecting groups;
R7 is chosen from H and carboxy protecting groups;
L1 is a linker group;
X is chosen from —O—, —S—, —CH2—, and —N(T5)-, wherein T5 is chosen from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C2-8 haloalkenyl, C2-8 haloalkynyl, and —C(═O)T6 groups, wherein T6 is chosen from H, halo, C1-8 alkyl, C6-18 aryl, and C1-13 heteroaryl groups;
Y is chosen from H, halo, and -OT7 groups, wherein T7 is chosen from H and C1-8 alkyl groups;
Z is chosen from lipids, nucleophiles, electrophiles, and groups capable of undergoing a cycloaddition reaction; and
q is chosen from integers ranging from 1 to 8.
In some embodiments, R1 is chosen from C6-12 aryl and C1-12 heteroaryl groups, wherein the C6-12 aryl and C1-12 heteroaryl groups are optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 haloalkyl, C1-8 hydroxyalkyl, C6-12 aryl, C1-12 heteroaryl, -OT1, —C(═O)OT1, and —C(═O)NT1T2 groups, wherein T1 and T2, which may be identical or different, are independently chosen from H, C1-8 alkyl, and C1-8 haloalkyl groups, or T1 and T2 join together along with the heteroatom to which they are attached to form an optionally substituted, saturated or unsaturated, 3-10 membered ring.
In some embodiments, R1 is chosen from C6-12 aryl and C1-12 heteroaryl groups, wherein the C6-12 aryl and C1-12 heteroaryl groups are optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 haloalkyl, C1-8 hydroxyalkyl, -OT1, and —C(═O)OT1 groups, wherein T1 is chosen from H, C1-8 alkyl, and C1-8 haloalkyl groups.
In some embodiments, R1 is chosen from C6-10 aryl and C1-5 heteroaryl groups, wherein the C6-10 aryl and C1-5 heteroaryl groups are optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 haloalkyl, C1-8 hydroxyalkyl, -OT1, and —C(═O)OT1 groups, wherein T1 is chosen from H, C1-8 alkyl, and C1-8 haloalkyl groups.
In some embodiments, R1 is chosen from C6-10 aryl and C1-5 heteroaryl groups, wherein the C6-10 aryl and C1-5 heteroaryl groups are optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 hydroxyalkyl, and -OT1, wherein T1 is chosen from H and C1-8 alkyl groups.
In some embodiments, R1 is chosen from C6-10 aryl and C1-5 heteroaryl groups, wherein the C6-10 aryl and C1-5 heteroaryl groups are optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 hydroxyalkyl, and —OH groups.
In some embodiments, R1 is chosen from C6-10 aryl groups optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 hydroxyalkyl, and —OH groups.
In some embodiments, R1 is phenyl substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 hydroxyalkyl, and —OH groups.
In some embodiments, R1 is phenyl substituted with one or more groups independently chosen from halo, C1-4 alkyl, and —OH groups.
In some embodiments, R1 is phenyl substituted with one or more groups independently chosen from fluoro, methyl, and —OH.
In some embodiments, R1 is
In some embodiments, R2 is chosen from C1-13 heteroaryl groups optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 haloalkyl, C1-8 hydroxyalkyl, C6-18 aryl, C1-13 heteroaryl, -OT3, and —C(═O)OT3 groups.
In some embodiments, R2 is chosen from C1-13 heteroaryl groups optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 haloalkyl, C1-8 hydroxyalkyl, and -OT3 groups.
In some embodiments, R2 is chosen from C2-6 heteroaryl groups optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 haloalkyl, and -OT3 groups.
In some embodiments, R2 is chosen from triazole groups optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 haloalkyl, and -OT3 groups.
In some embodiments, R2 is chosen from triazole groups substituted with one or more groups independently chosen from C1-8 alkyl groups.
In some embodiments, R2 is
In some embodiments, R3 is chosen from C7-19 arylalkyl and C2-14 heteroarylalkyl groups, wherein the C7-19 arylalkyl and C2-14 heteroarylalkyl groups are optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 haloalkyl, and C6-18 aryl groups.
In some embodiments, R3 is chosen from C7-19 arylalkyl groups, wherein the C7-19 arylalkyl groups are optionally substituted with one or more halo groups. In some embodiments, R3 is chosen from C7-19 arylalkyl groups, wherein the C7-19 arylalkyl groups are optionally substituted with one or more C1-8 alkyl groups. In some embodiments, R3 is chosen from C7-19 arylalkyl groups, wherein the C7-19 arylalkyl groups are optionally substituted with one or more C1-8 haloalkyl groups. In some embodiments, R3 is chosen from C7-19 arylalkyl groups, wherein the C7-19 arylalkyl groups are optionally substituted with one or more C6-18 aryl groups.
In some embodiments, R3 is chosen from C7-10 arylalkyl groups, wherein the C7-10 arylalkyl groups are optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 haloalkyl, and C6-18 aryl groups. In some embodiments, R3 is chosen from C10 arylalkyl groups, wherein the C10 arylalkyl groups are optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 haloalkyl, and C6-18 aryl groups. In some embodiments, R3 is chosen from C9 arylalkyl groups, wherein the C9 arylalkyl groups are optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 haloalkyl, and C6-18 aryl groups. In some embodiments, R3 is chosen from C8 arylalkyl groups, wherein the C8 arylalkyl groups are optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 haloalkyl, and C6-18 aryl groups. In some embodiments, R3 is chosen from C7 arylalkyl groups, wherein the C7 arylalkyl groups are optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 haloalkyl, and C6-18 aryl groups.
In some embodiments, R3 is chosen from
In some embodiments, R3 is
In some embodiments, R3 is
In some embodiments, R3 is chosen from C2-14 heteroarylalkyl groups, wherein the C2-14 heteroarylalkyl groups are optionally substituted with one or more groups independently chosen from halo, C1-8 alkyl, C1-8 haloalkyl, and C6-18 aryl groups. In some embodiments, R3 is chosen from C2-14 heteroarylalkyl groups, wherein the C2-14 heteroarylalkyl groups are optionally substituted with one or more groups halo groups. In some embodiments, R3 is chosen from C2-14 heteroarylalkyl groups, wherein the C2-14 heteroarylalkyl groups are optionally substituted with one or more C1-8 alkyl groups. In some embodiments, R3 is chosen from C2-14 heteroarylalkyl groups, wherein the C2-14 heteroarylalkyl groups are optionally substituted with one or more C1-8 haloalkyl groups. In some embodiments, R3 is chosen from C2-14 heteroarylalkyl groups, wherein the C2-14 heteroarylalkyl groups are optionally substituted with one or more C6-18 aryl groups.
In some embodiments, at least one of R4 and R5 is H. In some embodiments, R4 and R5 are H. In some embodiments, at least one of R4 and R5 is chosen from hydroxy protecting groups. In some embodiments, R4 and R5, which may be identical or different, are independently chosen from hydroxy protecting groups. In some embodiments, the hydroxy protecting groups are independently chosen from formyl, acetyl, chloroacetyl, o-nitrophenylacetyl, o-nitrophenoxy-acetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, methoxytrityl [(4-methoxyphenyl)diphenylmethyl], p-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, trityl, and silyl groups.
In some embodiments, R4 and R5 join together along with the oxygen atoms to which they are attached to form an optionally substituted, saturated or unsaturated, 5-12 membered ring. In some embodiments, R4 and R5 join together along with the oxygen atoms to which they are attached to form a ketal. In some embodiments, R4 and R5 join together along with the oxygen atoms to which they are attached to form an acetal. In some embodiments, R4 and R5 join together along with the oxygen atoms to which they are attached to form an acetonide. In some embodiments, R4 and R5 join together along with the oxygen atoms to which they are attached to form a carbonate. In some embodiments, R4 and R5 join together along with the oxygen atoms to which they are attached to form a benzaldehyde acetal.
In some embodiments, R6 is H. In some embodiments, R6 is chosen from hydroxy protecting groups. In some embodiments, the hydroxy protecting groups are chosen from formyl, acetyl, chloroacetyl, o-nitrophenylacetyl, o-nitrophenoxy-acetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, methoxytrityl [(4-methoxyphenyl)diphenylmethyl], p-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, tetrahydrofuranyl, trityl, and silyl groups. In some embodiments, the hydroxy protecting group is an acetyl.
In some embodiments, R7 is H. In some embodiments, R7 is chosen from carboxy protecting groups. In some embodiments, the carboxy protecting groups are chosen from methyl, benzyl, tert-butyl, and silyl groups. In some embodiments, R7 is methyl.
In some embodiments, R4 and R5 join together along with the oxygen atoms to which they are attached to form an acetonide, R6 is acetyl, and R7 is methyl.
In some embodiments, R4 and R5 join together along with the oxygen atoms to which they are attached to form an acetonide, R6 is H, and R7 is methyl. In some embodiments, R4, R5, and R6 are H, and R7 is methyl. In some embodiments, R4, R5, R6, and R7 are H.
In some embodiments, q is chosen form integers ranging from 1 to 7. In some embodiments, q is chosen from integers ranging from 1 to 6. In some embodiments, q is chosen from integers ranging from 1 to 5. In some embodiments, q is chosen from integers ranging from 1 to 4. In some embodiments, q is chosen from integers ranging from 1 to 3. In some embodiments, q is 1 or 2. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. In some embodiments, q is 6. In some embodiments, q is 7. In some embodiments, q is 8.
In some embodiments, L1 is chosen from —(CH2)mCH2V—, —CH2(OCH2CH2)mOCH2V—, —CH2(OCH2CH2)mOCH2CH2V—, —CH2CH2(OCH2CH2)mOCH2—V, and —CH2CH2(OCH2CH2)mOCH2CH2V— groups, wherein V is chosen from a bond,
and m is chosen from integers ranging from 0 to 46.
In some embodiments, L1 is chosen from —(CH2)mCH2V— groups, wherein m is chosen from integers ranging from 0 to 46. In some embodiments, L1 is chosen from —(CH2)mCH2V— groups, wherein m is chosen from integers ranging from 0 to 36. In some embodiments, L1 is chosen from —(CH2)mCH2V— groups, wherein m is chosen from integers ranging from 0 to 24. In some embodiments, L1 is chosen from —(CH2)mCH2V— groups, wherein m is chosen from integers ranging from 0 to 18. In some embodiments, L1 is chosen from —(CH2)mCH2V— groups, wherein m is chosen from integers ranging from 0 to 12.
In some embodiments, L1 is chosen from —(CH2)mCH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 46. In some embodiments, L1 is chosen from —(CH2)mCH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 36. In some embodiments, L1 is chosen from —(CH2)mCH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 24. In some embodiments, L1 is chosen from —(CH2)mCH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 18. In some embodiments, L1 is chosen from —(CH2)mCH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 12.
In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2V— groups, wherein m is chosen from integers ranging from 0 to 46. In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2V— groups, wherein m is chosen from integers ranging from 0 to 36. In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2V— groups, wherein m is chosen from integers ranging from 0 to 24. In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2V— groups, wherein m is chosen from integers ranging from 0 to 18. In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2V— groups, wherein m is chosen from integers ranging from 0 to 12.
In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 46. In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 36. In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 24. In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 18. In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 12.
In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2CH2V— groups, wherein m is chosen from integers ranging from 0 to 46. In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2CH2V— groups, wherein m is chosen from integers ranging from 0 to 36. In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2CH2V— groups, wherein m is chosen from integers ranging from 0 to 24. In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2CH2V— groups, wherein m is chosen from integers ranging from 0 to 18. In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2CH2V— groups, wherein m is chosen from integers ranging from 0 to 12.
In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2CH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 46. In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2CH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 36. In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2CH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 24. In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2CH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 18. In some embodiments, L1 is chosen from —CH2(OCH2CH2)mOCH2CH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 12.
In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2V— groups, wherein m is chosen from integers ranging from 0 to 46. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2V— groups, wherein m is chosen from integers ranging from 0 to 36. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2V— groups, m is chosen from integers ranging from 0 to 24. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2V— groups, wherein m is chosen from integers ranging from 0 to 18. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2V— groups, wherein m is chosen from integers ranging from 0 to 12.
In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 46. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 36. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 24. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 18. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 12.
In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2CH2V— groups, wherein m is chosen from integers ranging from 0 to 46. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2CH2V— groups, wherein m is chosen from integers ranging from 0 to 36. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2CH2V— groups, wherein m is chosen from integers ranging from 0 to 24. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2CH2V— groups, wherein m is chosen from integers ranging from 0 to 18. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2CH2V— groups, wherein m is chosen from integers ranging from 0 to 12.
In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2CH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 46. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2CH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 36. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2CH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 24. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2CH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 18. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)mOCH2CH2V— groups, wherein V is a bond and m is chosen from integers ranging from 0 to 12.
In some embodiments, L1 is chosen from —(CH2)24CH2V— groups. In some embodiments, L1 is chosen from —(CH2)2OCH2V— groups. In some embodiments, L1 is chosen from —(CH2)16CH2V— groups. In some embodiments, L1 is chosen from —(CH2)12CH2V— groups. In some embodiments, L1 is chosen from —(CH2)8CH2V— groups. In some embodiments, L1 is chosen from —(CH2)7CH2V— groups. In some embodiments, L1 is chosen from —(CH2)6CH2V— groups. In some embodiments, L1 is chosen from —(CH2)5CH2V— groups. In some embodiments, L1 is chosen from —(CH2)4CH2V— groups. In some embodiments, L1 is chosen from —(CH2)3CH2V— groups. In some embodiments, L1 is chosen from —(CH2)2CH2V— groups. In some embodiments, L1 is chosen from —CH2CH2V— groups. In some embodiments, L1 is chosen from —CH2V— groups.
In some embodiments, L1 is chosen from —(CH2)24CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —(CH2)2OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —(CH2)16CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —(CH2)12CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —(CH2)8CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —(CH2)7CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —(CH2)6CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —(CH2)5CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —(CH2)4CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —(CH2)3CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —(CH2)2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2V— groups, wherein V is a bond.
In some embodiments, L1 is chosen from —CH2(OCH2CH2)24OCH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)20OCH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)16OCH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)12OCH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)8OCH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)7OCH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)6OCH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)5OCH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)4OCH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)3OCH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)2OCH2V— groups. In some embodiments, L1 is chosen from —CH2OCH2CH2OCH2V— groups. In some embodiments, L1 is chosen from —CH2OCH2V— groups.
In some embodiments, L1 is chosen from —CH2(OCH2CH2)24OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)20OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)16OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)12OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)8OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)7OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)6OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)5OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)4OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)3OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)2OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2OCH2CH2OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2OCH2V— groups, wherein V is a bond.
In some embodiments, L1 is chosen from —CH2(OCH2CH2)24OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)20OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)16OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)12OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)8OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)7OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)6OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)5OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)4OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)3OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2(OCH2CH2)2OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2OCH2CH2OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2OCH2CH2V— groups.
In some embodiments, L1 is chosen from —CH2(OCH2CH2)24OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)20OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)16OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)12OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)8OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)7OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)6OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)5OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)4OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)3OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2(OCH2CH2)2OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2OCH2CH2OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2OCH2CH2V— groups, wherein V is a bond.
In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)24OCH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)20OCH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)16OCH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)12OCH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)8OCH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)7OCH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)6OCH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)5OCH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)4OCH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)3OCH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)2OCH2V— groups. In some embodiments, L1 is chosen from —CH2CH2OCH2CH2OCH2V— groups. In some embodiments, L1 is chosen from —CH2CH2OCH2V— groups.
In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)24OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)20OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)16OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)12OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)8OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)7OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)6OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)5OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)4OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)3OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)2OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2OCH2CH2OCH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2OCH2V— groups, wherein V is a bond.
In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)24OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)20OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)16OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)12OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)8OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)7OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)6OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)5OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)4OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)3OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)2OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2CH2OCH2CH2OCH2CH2V— groups. In some embodiments, L1 is chosen from —CH2CH2OCH2CH2V— groups.
In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)24OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)20OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)16OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)12OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)8OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)7OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)6OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)5OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)4OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)3OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2(OCH2CH2)2OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2OCH2CH2OCH2CH2V— groups, wherein V is a bond. In some embodiments, L1 is chosen from —CH2CH2OCH2CH2V— groups, wherein V is a bond.
In some embodiments, V is a bond. In some embodiments, V is chosen from
In some embodiments, V is chosen from
In some embodiments, V is chosen from
In some embodiments, V is
In some embodiments, X is —O—.
In some embodiments, X is —S—.
In some embodiments, X is —CH2—.
In some embodiments, Y is H.
In some embodiments, Y is chosen from halo groups.
In some embodiments, Y is fluoro.
In some embodiments, Y is —OH.
In some embodiments, Y is —OMe.
In some embodiments, Z is chosen from lipids. In some embodiments, Z is chosen from glycerol-based lipids. In some embodiments, Z is chosen from phospholipids. In some embodiments, Z is chosen from symmetric phospholipids. In some embodiments, Z is chosen from asymmetric phospholipids. In some embodiments, Z is chosen from sphingolipids. In some embodiments, Z is chosen from ceramides.
In some embodiments, Z is chosen from phospholipids that have 16 to 30 carbon atoms. In some embodiments, Z is chosen from phospholipids that have 16, 20, 22, 24, 26, 28, or 30 carbon atoms. In some embodiments, Z is chosen from phospholipids that have 16 carbon atoms. In some embodiments, Z is chosen from phospholipids that have 18 carbon atoms. In some embodiments, Z is chosen from phospholipids that have 20 carbon atoms. In some embodiments, Z is chosen from phospholipids that have 22 carbon atoms. In some embodiments, Z is chosen from phospholipids that have 24 carbon atoms. In some embodiments, Z is chosen from phospholipids that have 26 carbon atoms. In some embodiments, Z is chosen from phospholipids that have 28 carbon atoms. In some embodiments, Z is chosen from phospholipids that have 30 carbon atoms.
In some embodiments, Z is chosen from saturated phospholipids. In some embodiments, Z is chosen from unsaturated phospholipids. In some embodiments, Z is chosen from phosphatidylcholine, phosphatidyethanolamine, phosphatidic acid, and phosphatidyl inositol. In some embodiments, Z is chosen from phospholipid derivatives of 6-cis-octadecenoic, 9-cis-octadecenoic, 9-trans-octadecenoic, 9-cis-12-octadecadienoic, 9-cis-12-cis-15-cis-octadecatrienoic, 11-cis-eicosenoic, 5, 8, 11, 14 (all-cis) eicosatetraenoic, 13-cis-docosenoic, 4, 7, 10, 13, 16, 19 (all-cis) docosahexaenoic, and/or 15-cis-tetracosenoic acids. In some embodiments, Z is chosen from phospholipid derivatives of stearoyl, oleoyl, linoleoyl, arachidonoyl, and/or docosahexaenoyl acids.
In some embodiments, Z is chosen from nucleophiles. In some embodiments, the nucleophiles are chosen from amines, mercaptans, and alcohols. In some embodiments, Z is chosen from amine groups.
In some embodiments, Z is chosen from electrophiles. In some embodiments, the electrophiles are chosen from epoxides, aziridines, episulfides, sulfates, sulfonates, carbonates, lactones, lactams, halides, acid halides, and esters. In some embodiments, the electrophiles are chosen from epoxides. In some embodiments, the electrophiles are chosen from aziridines. In some embodiments, the electrophiles are chosen from episulfides. In some embodiments, the electrophiles are chosen from sulfates. In some embodiments, the electrophiles are chosen from sulfonates. In some embodiments, the electrophiles are chosen from carbonates. In some embodiments, the electrophiles are chosen from lactones. In some embodiments, the electrophiles are chosen from lactams. In some embodiments, the electrophiles are chosen from halides. In some embodiments, the electrophiles are chosen from acid halides. In some embodiments, the electrophiles are chosen from esters. In some embodiments, the esters are chosen from activated esters.
In some embodiments, Z is chosen from esters. In some embodiments, the esters are chosen from anhydrides, carboxylic acid-succinimides, carboxylic acid phosphoesters, and carboxylic acid imidazolides. In some embodiments, Z is chosen from esters formed with t-butanol, p-nitrophenol, 2,4-dinitrophenol, trichlorophenol, 1-hydroxy-1H-benzotriazole, 1-hydroxy-6-chloro-1H-benzotriazole, and N-hydroxysuccinimide.
In some embodiments, Z is chosen from —C(═O)T8 groups, wherein T8 is chosen from H, —OH, —OtBu, C2-8 alkenyl, C1-8 haloalkyl, C1-8 alkoxy, halo, C6-18 aryloxy, C1-13 heteroaryloxy, and C2-12 heterocyclyloxy groups and wherein the C1-8 alkoxy, C6-18 aryloxy, C1-13 heteroaryloxy, and C2-12 heterocyclyloxy groups are optionally substituted with at least one halo group.
In some embodiments, Z is chosen from groups capable of undergoing a cycloaddition reaction. In some embodiments, the groups capable of undergoing a cycloaddition reaction are chosen from alkenes, alkynes, dienes, dienophiles, 1,3-dipoles, and 1,3-dipolarophiles.
In some embodiments, the dienophiles are chosen from —C(═O)T9 groups, wherein T9 is chosen from alkene and alkyne groups, wherein said alkene and alkyne groups are optionally substituted with C1-8 alkoxy, —C(═O)H, —C(═O)OT10, and —C(═O)NT10T11 groups, wherein T10 and T11, which may be identical or different, are independently chosen from H and C1-8 alkyl groups, or T10 and T11 join together along with the nitrogen to which they are attached to form an optionally substituted, saturated or unsaturated, 3-10 membered ring.
In some embodiments, the 1,3-dipoles are chosen from nitrile ylides, nitrile imines, nitrile oxides, diazolalkanes, azides, azomethine ylides, azomethine imines, nitrones, carbonyl ylides, carbonyl imines, and carbonyl oxides.
In some embodiments, Z is chosen from alkene and alkyne groups. In some embodiments, Z is chosen from alkene groups. In some embodiments, Z is chosen from alkyne groups. In some embodiments, Z is —CH═CH2. In some embodiments, Z is —C≡CH.
In some embodiments, Z is chosen from dienes and dienophiles. In some embodiments, Z is chosen from dienes. In some embodiments, Z is chosen from dienophiles.
In some embodiments, Z is chosen from 1,3-dipoles and 1,3-dipolarophiles. In some embodiments, Z is chosen from 1,3-dipoles. In some embodiments, Z is chosen from 1,3-dipolarophiles.
In some embodiments, Z is chosen from —N3, —NH2, —SH, —OH, —Cl, —Br, —I, —CH═CH2, —C≡CH,
In some embodiments, Z is —N3.
In some embodiments, Z is chosen from —NH2, —SH, and —OH. In some embodiments, Z is —NH2. In some embodiments, Z is —SH. In some embodiments, Z is —OH.
In some embodiments, Z is —C(═O)H. In some embodiments, Z is —C(═O)OH. In some embodiments, Z is —C(═O)Cl. In some embodiments, Z is —C(═O)OtBu.
In some embodiments, the compound of Formula (I) is chosen from:
In some embodiments, the compound of Formula (I) is chosen from:
In some embodiments, the compound of Formula (I) is chosen from:
In some embodiments, a process for making CD33 ligand-bearing carriers of Formula (II) is provided, wherein the process comprises reacting or associating a compound of Formula (I) with a compound of Formula (III):
wherein:
R1, R2, R3, R4, R5, R6, R7, L1, q, X, Y, and Z are as defined above;
L2 is chosen from a bond and linker groups;
W is chosen from lipids, nucleophiles, electrophiles, and groups capable of undergoing a cycloaddition reaction; and
Z′ is a moiety generated by the reaction or association of the Z group of the compound of Formula (I) with the W group of the compound of Formula (III).
In some embodiments, L2 is a bond. In some embodiments, L2 is chosen from linker groups.
In some embodiments, W is chosen from lipids. In some embodiments, W is chosen from glycerol-based lipids. In some embodiments, W is chosen from phospholipids. In some embodiments, W is chosen from symmetric phospholipids. In some embodiments, W is chosen from asymmetric phospholipids. In some embodiments, W is chosen from sphingolipids. In some embodiments, W is chosen from ceramides.
In some embodiments, W is chosen from phospholipids that have 16 to 30 carbon atoms. In some embodiments, W is chosen from phospholipids that have 16, 20, 22, 24, 26, 28, or 30 carbon atoms. In some embodiments, W is chosen from phospholipids that have 16 carbon atoms. In some embodiments, W is chosen from phospholipids that have 18 carbon atoms. In some embodiments, W is chosen from phospholipids that have 20 carbon atoms. In some embodiments, W is chosen from phospholipids that have 22 carbon atoms. In some embodiments, W is chosen from phospholipids that have 24 carbon atoms. In some embodiments, W is chosen from phospholipids that have 26 carbon atoms. In some embodiments, W is chosen from phospholipids that have 28 carbon atoms. In some embodiments, W is chosen from phospholipids that have 30 carbon atoms.
In some embodiments, W is chosen from saturated phospholipids. In some embodiments, W is chosen from unsaturated phospholipids. In some embodiments, W is chosen from phosphatidylcholine, phosphatidyethanolamine, phosphatidic acid, and phosphatidyl inositol. In some embodiments, W is chosen from phospholipid derivatives of 6-cis-octadecenoic, 9-cis-octadecenoic, 9-trans-octadecenoic, 9-cis-12-octadecadienoic, 9-cis-12-cis-15-cis-octadecatrienoic, 11-cis-eicosenoic, 5, 8, 11, 14 (all-cis) eicosatetraenoic, 13-cis-docosenoic, 4, 7, 10, 13, 16, 19 (all-cis) docosahexaenoic, and/or 15-cis-tetracosenoic acids. In some embodiments, W is chosen from phospholipid derivatives of stearoyl, oleoyl, linoleoyl, arachidonoyl, and/or docosahexaenoyl acids.
In some embodiments, W is chosen from nucleophiles. In some embodiments, the nucleophiles are chosen from amines, mercaptans, and alcohols. In some embodiments, W is chosen from amine groups.
In some embodiments, W is chosen from electrophiles. In some embodiments, the electrophiles are chosen from epoxides, aziridines, episulfides, sulfates, sulfonates, carbonates, lactones, lactams, halides, acid halides, and esters. In some embodiments, the electrophiles are chosen from epoxides. In some embodiments, the electrophiles are chosen from aziridines. In some embodiments, the electrophiles are chosen from episulfides. In some embodiments, the electrophiles are chosen from sulfates. In some embodiments, the electrophiles are chosen from sulfonates. In some embodiments, the electrophiles are chosen from carbonates. In some embodiments, the electrophiles are chosen from lactones. In some embodiments, the electrophiles are chosen from lactams. In some embodiments, the electrophiles are chosen from halides. In some embodiments, the electrophiles are chosen from acid halides. In some embodiments, the electrophiles are chosen from esters. In some embodiments, the esters are chosen from activated esters.
In some embodiments, W is chosen from esters. In some embodiments, the esters are chosen from anhydrides, carboxylic acid-succinimides, carboxylic acid phosphoesters, and carboxylic acid imidazolides. In some embodiments, W is chosen from esters formed with t-butanol, p-nitrophenol, 2,4-dinitrophenol, trichlorophenol, 1-hydroxy-1H-benzotriazole, 1-hydroxy-6-chloro-1H-benzotriazole, and N-hydroxysuccinimide.
In some embodiments, W is chosen from —C(═O)T12 groups, wherein T12 is chosen from H, —OH, —OtBu, C2-8 alkenyl, C1-8 haloalkyl, C1-8 alkoxy, halo, C6-18 aryloxy, C1-13 heteroaryloxy, and C2-12 heterocyclyloxy groups and wherein the C1-8 alkoxy, C6-18 aryloxy, C1-13 heteroaryloxy, and C2-12 heterocyclyloxy groups are optionally substituted with at least one halo group.
In some embodiments, W is chosen from groups capable of undergoing a cycloaddition reaction. In some embodiments, the groups capable of undergoing a cycloaddition reaction are chosen from alkenes, alkynes, dienes, dienophiles, 1,3-dipoles, and 1,3-dipolarophiles.
In some embodiments, the dienophiles are chosen from —C(═O)T13 groups, wherein T13 is chosen from alkene and alkyne groups, wherein said alkene and alkyne groups are optionally substituted with C1-8 alkoxy, —C(═O)H, —C(═O)OT14, and —C(═O)NT14T15 groups, wherein T14 and T15, which may be identical or different, are independently chosen from H and C1-8 alkyl groups, or T14 and T15 join together along with the nitrogen to which they are attached to form an optionally substituted, saturated or unsaturated, 3-10 membered ring.
In some embodiments, the 1,3-dipoles are chosen from nitrile ylides, nitrile imines, nitrile oxides, diazolalkanes, azides, azomethine ylides, azomethine imines, nitrones, carbonyl ylides, carbonyl imines, and carbonyl oxides.
In some embodiments, W is chosen from alkene and alkyne groups. In some embodiments, W is chosen from alkene groups. In some embodiments, W is chosen from alkyne groups. In some embodiments, W is —CH═CH2. In some embodiments, W is —C≡CH.
In some embodiments, W is chosen from dienes and dienophiles. In some embodiments, W is chosen from dienes. In some embodiments, W is chosen from dienophiles.
In some embodiments, W is chosen from 1,3-dipoles and 1,3-dipolarophiles. In some embodiments, W is chosen from 1,3-dipoles. In some embodiments, W is chosen from 1,3-dipolarophiles.
In some embodiments, W is chosen from —N3, —NH2, —SH, —OH, —Cl, —Br, —I, —CH═CH2, —C≡CH,
In some embodiments, W is —N3.
In some embodiments, W is chosen from —NH2, —SH, and —OH. In some embodiments, W is —NH2. In some embodiments, W is —SH. In some embodiments, W is —OH.
In some embodiments, W is —C(═O)H. In some embodiments, W is —C(═O)OH. In some embodiments, W is —C(═O)Cl. In some embodiments, W is —C(═O)OtBu.
In some embodiments, a process for making CD33 ligand-bearing carriers of Formula (II) is provided, wherein the process comprises reacting or associating a compound of Formula (I) with a compound of Formula (III):
wherein:
R1, R2, R3, R4, R5, R6, R7, q, L1, L2, X, and Y are as defined above; and
Z, W, and Z′ are as shown below:
In some embodiments, the carriers are chosen from particles, nanoparticles, liposomes, beads, proteins, polysaccharides, lipids, and combinations thereof. In some embodiments, the carriers are chosen from lipid-based, protein-based, nucleic acid based, and carbohydrate-based carriers. In some embodiments, the carriers are chosen from carriers composed of polymer and/or non-polymer molecules. In some embodiments, the carriers are chosen from macromolecular carriers. In some embodiments, the carriers comprise crosslinking chains of molecules. In some embodiments, the crosslinking chains of molecules are chosen from nucleic acids. In some embodiments, the carriers are chosen from polyamino-based carriers.
Liposomes bearing Siglec ligands can be prepared as described herein and other sources such as PCT Publication No. WO2012/018377 and WO2007/056525 and U.S. Patent Appl. Publication No. US20190151444, which are incorporated by reference herein in their entireties.
In some embodiments, the carriers are chosen from lipid-based nanoparticles, polymeric nanoparticles, metallic nanoparticles, surfactant-based emulsion, dendrimers, and nanoparticles.
In some embodiments, the carriers are formed by self-assembly. In some embodiments, self-assembly occurs in vitro. In some embodiments, self-assembly occurs in vivo. In some embodiments, the carriers are formed using amphiphilic biomaterials which orient themselves with respect to one another to form carriers of predictable dimension, constituents, and placement of constituents.
In some embodiments, the carriers are chosen from carriers having a mean geometric diameter that is less than 500 nm. In some embodiments, the carriers are chosen from carriers having a mean geometric diameter that is greater than 50 nm but less than 500 nm.
In some embodiments, the carriers are nanoparticles.
In embodiments, the Z group of Formula (I) is a lipid and the carrier is chosen from liposomes.
In some embodiments, the compound of Formula (II) is chosen from:
In some embodiments, the compound of Formula (II) is chosen from:
In some embodiments, the compound of Formula (II) is chosen from:
In some embodiments, the compound of Formula (II) is chosen from:
In some embodiments, at least one compound of Formula (II) or compositions comprising the same can be administered to treat a subject in need thereof or a subject who may develop a need for such treatment. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same delivers at least one anti-cancer agent.
In some embodiments, a method for treating at least one disease, disorder, or condition is provided, said method comprising administering to a subject in need thereof an effective amount of at least therapeutic agent by administering the at least one compound of Formula (II) or a composition comprising the same, wherein the at least one compound of Formula (II) delivers said at least one therapeutic agent.
In some embodiments, a method for treating AML is provided, said method comprising administering to a subject in need thereof an effective amount of at least one anti-cancer agent by administering the at least one compound of Formula (II) or a composition comprising the same, wherein the at least one compound of Formula (II) delivers said at least one anti-cancer agent.
In some embodiments, a method for treatment and/or prevention of at least one disease, disorder, or condition is disclosed, the method comprising administering to a subject in need thereof an effective amount of at least one compound of Formula (II) or a composition comprising same, wherein at least one therapeutic agent is directly or indirectly linked to or associated with said at least one compound of Formula (II).
In some embodiments, a method for treatment and/or prevention of AML is disclosed, the method comprising administering to a subject in need thereof an effective amount at least one compound of Formula (II) or a composition comprising same, wherein at least one anti-cancer agent is directly or indirectly linked to or associated with said at least one compound of Formula (II).
In some embodiments, the at least one anti-cancer agent is chosen from inhibitors of phosphoinositide-3 kinase (PI3K) and inhibitors of VEGF. In some embodiments, the at least one anti-cancer agent is chosen from inhibitors of PI3K. In some embodiments, the at least one anti-cancer agent is chosen from inhibitors of VEGF. In some embodiments, the at least one anti-cancer agent is the compound named by Exelixis as “XL499.” In some embodiments, the at least one anti-cancer agent is the compound “cabo” (previously known as XL184). In some embodiments, the at least one anti-cancer agent is chosen from alkylating agents, antimetabolites, anthracyclines, plant alkaloids, and topoisomerase inhibitors.
In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with mitoxantrone. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with etoposide. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with cytarabine. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with at least one of mitoxantrone, etoposide, or cytarabine. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with daunomycin. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with idarubicin. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with MEC (mitoxantrone, etoposide, cytarabine) chemotherapy. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with 7+3 (cytarabine for 7 days then daunorubicin, idarubicin, or mitoxantrone for 3 days) chemotherapy.
In some embodiments, the at least one anti-cancer agent is chosen from anti-leukemic agents. In some embodiments, the anti-leukemic agents are chosen from cyclophosphamide, methotrexate, and etoposide. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with 6-mercaptopurine. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with 6-thioguanine. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with aminopterin. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with arsenic trioxide. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with asparaginase. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with cladribine. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with clofarabine. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with cyclophosphamide. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with cytosine arabinoside. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with dasatinib. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with decitabine. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with dexamethasone. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with fludarabine. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with gemtuzumab ozogamicin. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with imatinib mesylate. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with interferon-α. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with interleukin-2. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with melphalan. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with methotrexate. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with nelarabine. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with nilotinib. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with oblimersen. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with pegaspargase. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with pentostatin. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with ponatinib. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with prednisone. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with rituximab. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with tretinoin. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered in combination with vincristine.
In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered over one or more doses, with one or more intervals between doses. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 doses. In some embodiments, the at least one compound of Formula (II) or a composition comprising the same is administered at 6-hour, 12-hour, 18-hour, 24-hour, 48-hour, 72-hour, or 96-hour intervals.
In some embodiments, the subject has been diagnosed with AML as per the World Health Organization (WHO) criteria. Arber DA et al., “The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.” Blood (2016) 127(20):2391-2405. In some embodiments, the subject is ≥18 years of age with relapsed or refractory AML after ≤2 prior induction regiments, at least one containing anthracyclines. In some embodiments, the subject is ≥60 years of age with newly diagnosed AML. In some embodiments, the subject has an absolute blast count 9ABC of ≤40,000/mm. In some embodiments, the subject is medically eligible to receive MEC chemotherapy. In some embodiments, the subject is medically eligible to receive 7+3 cytarabine/idarubicin chemotherapy. In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. In some embodiments, the subject has hemodynamically stable and adequate organ function. In some embodiments, the subject does not have acute promyelocytic leukemia. In some embodiments, the subject does not have acute leukemia of ambiguous lineage. In some embodiments, the subject does not have active signs or symptoms of CNS involvement by malignancy. In some embodiments, the subject has no prior G-CSF, GM-CSF or plerixafor within 14 days of treatment with the pharmaceutical composition disclosed herein. In some embodiments, the subject has no known history or evidence of active hepatitis A, B, or C or HIV. In some embodiments, the subject does not have uncontrolled acute life-threatening bacterial, viral, or fungal infection. In some embodiments, the subject does not have active graft versus host disease (GVHD)≥Grade 2 or extensive chronic GVHD requiring immunosuppressive therapy. In some embodiments, the subject does not have hematopoietic stem cell transplantation ≤4 months prior to the treatments disclosed herein. In some embodiments, the subject does not have clinically significant cardiovascular disease.
Whenever a term in the specification is identified as a range (e.g., C1-4 alkyl) or “ranging from”, the range independently discloses and includes each element of the range. As a non-limiting example, C1-4 alkyl groups include, independently, C1 alkyl groups, C2 alkyl groups, C3 alkyl groups, and C4 alkyl groups. As another non-limiting example, “n is chosen from integers ranging from 0 to 2” includes, independently, 0, 1, and 2.
The term “at least one” refers to one or more, such as one, two, etc. For example, the term “at least one C1-4 alkyl group” refers to one or more C1-4 alkyl groups, such as one C1-4 alkyl group, two C1-4 alkyl groups, etc.
The term “1,3-dipole”includes compounds that contains a consecutive series of three atoms, a-b-c, where atom a contains a sextet of electrons in its outer shell and atom c contains an octet with at least one unshared pair of electrons in its outer shell. Because molecules that have six electrons in the outer shell of an atom are typically unstable, the a-b-c atom example is one canonical structure of a resonance hybrid, where at least one structure can be drawn. The term 1,3-dipoles include those in which one of the canonical forms has a double bond on the sextet atom (atom a) and the other canonical form has a triple bond on that atom:
The term 1,3-dipoles also includes those in which the dipolar canonical form has a single bond on the sextet atom (atom a) and the other canonical form has a double bond on that atom:
The term “1,3-dipolarophile” includes dienophiles and dienes.
The term “activated ester” means an ester derivative that has sufficient reactivity such that it can react with a nucleophile (e.g., an amino group).
The term “alkyl” includes saturated straight, branched, and cyclic (also identified as cycloalkyl), primary, secondary, and tertiary hydrocarbon groups. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, secbutyl, isobutyl, tertbutyl, cyclobutyl, 1-methylbutyl, 1,1-dimethylpropyl, pentyl, cyclopentyl, isopentyl, neopentyl, cyclopentyl, hexyl, isohexyl, and cyclohexyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted.
The term “alkenyl” includes straight, branched, and cyclic hydrocarbon groups comprising at least one double bond. The double bond of an alkenyl group can be unconjugated or conjugated with another unsaturated group. Non-limiting examples of alkenyl groups include vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, and cyclopent-1-en-1-yl. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted.
The term “alkynyl” includes straight and branched hydrocarbon groups comprising at least one triple bond. The triple bond of an alkynyl group can be unconjugated or conjugated with another unsaturated group. Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and hexynyl. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted.
The term “aryl” includes hydrocarbon ring system groups comprising at least 6 carbon atoms and at least one aromatic ring. The aryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Non-limiting examples of aryl groups include aryl groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl group may be optionally substituted.
The term “carboxy protecting group” includes groups known in the art to protect an acidic hydrogen of a carboxyl group against undesirable reaction during synthetic procedures, e.g., to block or protect the acid functionality while the reactions involving other functional sites of the compound are carried out, and to be removable.
The terms “CD33” and “Siglec-3” are used interchangeably herein.
The term “diene” includes a molecule bearing two conjugated double bonds. The diene may also be non-conjugated, if the geometry of the molecule is constrained so as to facilitate a cycloaddition reaction (see Cookson J. Chem. Soc. 5416 (1964), which is incorporated by reference in its entirety). The atoms forming these double bonds can be carbon or a heteroatom or any combination thereof.
The term “dienophile” includes a molecule bearing an alkene group, or a double bond between a carbon and a heteroatom, or a double bond between two heteroatoms.
The term “electrophile” includes chemical moieties which can accept a pair of electrons from a nucleophile. Electrophiles include, but are not limited to, cyclic compounds such as epoxides, aziridines, episulfides, cyclic sulfates, carbonates, lactones, lactams and the like. Non-cyclic electrophiles include, but are not limited to, sulfates, sulfonates (e.g., tosylates), chlorides, bromides, iodides, and the like.
The term “halo” or “halogen” includes fluoro, chloro, bromo, and iodo.
The term “haloalkyl” includes alkyl groups, as defined herein, substituted by at least one halogen, as defined herein. Non-limiting examples of haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl. A “fluoroalkyl” is a haloalkyl wherein at least one halogen is fluoro. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.
The term “haloalkenyl” includes alkenyl groups, as defined herein, substituted by at least one halogen, as defined herein. Non-limiting examples of haloalkenyl groups include fluoroethenyl, 1,2-difluoroethenyl, 3-bromo-2-fluoropropenyl, and 1,2-dibromoethenyl. A “fluoroalkenyl” is a haloalkenyl substituted with at least one fluoro group. Unless stated otherwise specifically in the specification, a haloalkenyl group may be optionally substituted.
The term “haloalkynyl” includes alkynyl groups, as defined herein, substituted by at least one halogen, as defined herein. Non-limiting examples include fluoroethynyl, 1,2-difluoroethynyl, 3-bromo-2-fluoropropynyl, and 1,2-dibromoethynyl. A “fluoroalkynyl” is a haloalkynyl wherein at least one halogen is fluoro. Unless stated otherwise specifically in the specification, a haloalkynyl group may be optionally substituted.
The term “heterocyclyl” or “heterocyclic ring” includes 3- to 24-membered saturated or partially unsaturated non-aromatic ring groups comprising 2 to 23 ring carbon atoms and 1 to 8 ring heteroatom(s) each independently chosen from N, O, and S. Unless stated otherwise specifically in the specification, the heterocyclyl groups may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which may include fused or bridged ring systems, and may be partially or fully saturated; any nitrogen, carbon or sulfur atom(s) in the heterocyclyl group may be optionally oxidized; any nitrogen atom in the heterocyclyl group may be optionally quaternized. Non-limiting examples of heterocyclic ring include dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group may be optionally substituted.
The term “heteroaryl” includes 5- to 14-membered ring groups comprising 1 to 13 ring carbon atoms and 1 to 6 ring heteroatom(s) each independently chosen from N, O, and S, and at least one aromatic ring. Unless stated otherwise specifically in the specification, the heteroaryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Non-limiting examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group may be optionally substituted.
The term “hydroxy protecting group” includes groups known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be removable. The use of hydroxy protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known
The term “nucleophile” includes a chemical moiety having a reactive pair of electrons. Non-limiting examples of nucleophiles include uncharged compounds such as amines, mercaptans and alcohols, and charged moieties such as alkoxides, thiolates, carbanions, and a variety of organic and inorganic anions Illustrative anionic nucleophiles include, but are not limited to, simple anions such as azide, cyanide, thiocyanate, acetate, formate or chloroformate, and bisulfite Organometallic reagents such as organocuprates, organozines, organolithiums, Grignard reagents, enolates, acetylides, and the like may, under appropriate reaction conditions, be suitable nucleophiles.
The term “pharmaceutically acceptable salts” includes both acid and base addition salts. Non-limiting examples of pharmaceutically acceptable acid addition salts include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methane sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, and ascorbates. Non-limiting examples of pharmaceutically acceptable base addition salts include sodium, potassium, lithium, ammonium (substituted and unsubstituted), calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Pharmaceutically acceptable salts may, for example, be obtained using standard procedures well known in the field of pharmaceuticals.
The term “prodrug” includes compounds that may be converted, for example, under physiological conditions or by solvolysis, to a biologically active compound described herein. Thus, the term “prodrug” includes metabolic precursors of compounds described herein that are pharmaceutically acceptable. A discussion of prodrugs can be found, for example, in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. The term “prodrug” also includes covalently bonded carriers that release the active compound(s) as described herein in vivo when such prodrug is administered to a subject. Non-limiting examples of prodrugs include ester and amide derivatives of hydroxy, carboxy, mercapto and amino functional groups in the compounds described herein.
“Self-assembly” refers to the process of the formation of, for example, a carrier using components that will orient themselves in a predictable manner forming carriers predictably and reproducibly.
The term “substituted” includes the situation where, in any of the above groups, at least one hydrogen atom is replaced by a non-hydrogen atom such as, for example, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. “Substituted” also includes the situation where, in any of the above groups, at least one hydrogen atom is replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
This application contemplates all the isomers of the compounds disclosed herein. “Isomer” as used herein includes optical isomers (such as stereoisomers, e.g., enantiomers and diastereoisomers), geometric isomers (such as Z (zusammen) or E (entgegen) isomers), and tautomers. The present disclosure includes within its scope all the possible geometric isomers, e.g., Z and E isomers (cis and trans isomers), of the compounds as well as all the possible optical isomers, e.g., diastereomers and enantiomers, of the compounds. Furthermore, the present disclosure includes in its scope both the individual isomers and any mixtures thereof, e.g., racemic mixtures. The individual isomers may be obtained using the corresponding isomeric forms of the starting material or they may be separated after the preparation of the end compound according to conventional separation methods. For the separation of optical isomers, e.g., enantiomers, from the mixture thereof conventional resolution methods, e.g., fractional crystallization, may be used.
The present disclosure includes within its scope all possible tautomers. Furthermore, the present disclosure includes in its scope both the individual tautomers and any mixtures thereof. Each compound disclosed herein includes within its scope all possible tautomeric forms. Furthermore, each compound disclosed herein includes within its scope both the individual tautomeric forms and any mixtures thereof. With respect to the methods, uses and compositions of the present application, reference to a compound or compounds is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof. Where a compound of the present application is depicted in one tautomeric form, that depicted structure is intended to encompass all other tautomeric forms.
Biological activity of the CD33 ligands and/or CD33 ligand-bearing carriers described herein may be determined, for example, by performing at least one in vitro and/or in vivo study routinely practiced in the art.
Conditions for a particular assay include temperature, buffers (including salts, cations, media), and other components that maintain the integrity of any cell used in the assay and the compound, which a person of ordinary skill in the art will be familiar and/or which can be readily determined. A person of ordinary skill in the art also readily appreciates that appropriate controls can be designed and included when performing the in vitro methods and in vivo methods described herein.
The source of a compound that is characterized by at least one assay and techniques described herein and in the art may be a biological sample that is obtained from a subject who has been treated with the compound. The cells that may be used in the assay may also be provided in a biological sample. A “biological sample” may include a sample from a subject, and may be a blood sample (from which serum or plasma may be prepared), a biopsy specimen, one or more body fluids (e.g., lung lavage, ascites, mucosal washings, synovial fluid, urine), bone marrow, lymph nodes, tissue explant, organ culture, or any other tissue or cell preparation from the subject or a biological source. A biological sample may further include a tissue or cell preparation in which the morphological integrity or physical state has been disrupted, for example, by dissection, dissociation, solubilization, fractionation, homogenization, biochemical or chemical extraction, pulverization, lyophilization, sonication, or any other means for processing a sample derived from a subject or biological source. In some embodiments, the subject or biological source may be a human or non-human animal, a primary cell culture (e.g., immune cells), or culture adapted cell line, including but not limited to, genetically engineered cell lines that may contain chromosomally integrated or episomal recombinant nucleic acid sequences, immortalized or immortalizable cell lines, somatic cell hybrid cell lines, differentiated or differentiable cell lines, transformed cell lines, and the like.
As described herein, methods for characterizing CD33 ligands and/or CD33 ligand-bearing carriers include animal model studies.
In certain aspects, the compounds and compositions as described herein can be used to treat patients suffering from a condition associated with overexpression of CD33. In some embodiments, the condition associated with overexpression of CD33 is AML.
In certain aspects, the compounds and compositions as described herein can be used to treat patients suffering from cancers of the blood and complications associated therewith. Non-limiting examples of cancers of the blood include AML.
Acute myelogenous leukemia (also known as acute myeloid leukemia or AML) is a cancer of white blood cells, and in particular the myeloid line. It appears that AML arises from a single progenitor cell which has undergone genetic transformation to an abnormal cell with the ability to proliferate rapidly. These abnormal immature myeloid cells accumulate in the bone marrow. This accumulation in the bone marrow interferes with the production of normal blood cells, including a reduction in red blood cells, platelets and neutrophils. Eventually the bone marrow stops working correctly.
AML is one of the most common types of leukemia among adults, and the most common acute leukemia affecting adults. In the U.S. alone, there are approximately 12,000 new cases each year. The incidence of AML is expected to increase as the population ages. In addition, in the U.S., about 11% of the cases of leukemia in childhood are AML. Chemotherapy is generally used to treat AML. Only a minority of patients are cured with current therapy.
Chemotherapy has a number of deleterious side effects. One of the side effects is myeloablative bone marrow toxicities. Bone marrow is the tissue that fills the inside of some bones. Examples of such bones are sternum, hip, femur and humerus. Bone marrow contains stem cells that develop into several types of blood cells: erythrocytes (red blood cells), leukocytes (white blood cells) and thrombocytes (platelets). Cells in the bone marrow are susceptible to the effects of chemotherapy due to their rapid rate of division. Bone marrow is prevented by chemotherapeutic agents from forming new blood cells. With time after exposure to a chemotherapeutic agent, counts of the blood cells will fall at various rates, depending upon the particular type of cell as their average life spans differ. Low white blood cell count, for example, makes an individual more susceptible to infection. Low red blood cell count, for example, causes an individual to be fatigued. Low platelet count, for example, impairs an individual's ability to make a blood clot.
As understood by a person of ordinary skill in the medical art, the terms, “treat” and “treatment,” include medical management of a disease, disorder, or condition of a subject (i.e., patient, individual) (see, e.g., Stedman's Medical Dictionary). In general, an appropriate dose and treatment regimen provide at least one of the compounds of the present disclosure in an amount sufficient to provide therapeutic and/or prophylactic benefit. For both therapeutic treatment and prophylactic or preventative measures, therapeutic and/or prophylactic benefit includes, for example, an improved clinical outcome, wherein the object is to prevent or slow or retard (lessen) an undesired physiological change or disorder, or to prevent or slow or retard (lessen) the expansion or severity of such disorder. As discussed herein, beneficial or desired clinical results from treating a subject include, but are not limited to, abatement, lessening, or alleviation of symptoms that result from or are associated with the disease, condition, or disorder to be treated; decreased occurrence of symptoms; improved quality of life; longer disease-free status (i.e., decreasing the likelihood or the propensity that a subject will present symptoms on the basis of which a diagnosis of a disease is made); diminishment of extent of disease; stabilized (i.e., not worsening) state of disease; delay or slowing of disease progression; amelioration or palliation of the disease state; and remission (whether partial or total), whether detectable or undetectable; and/or overall survival. “Treatment” can include prolonging survival when compared to expected survival if a subject were not receiving treatment. Subjects in need of treatment include those who already have the disease, condition, or disorder as well as subjects prone to have or at risk of developing the disease, condition, or disorder, and those in which the disease, condition, or disorder is to be prevented (i.e., decreasing the likelihood of occurrence of the disease, disorder, or condition).
In some embodiments of the methods described herein, the subject is a human. In some embodiments of the methods described herein, the subject is a non-human animal. A subject in need of treatment as described herein may exhibit at least one symptom or sequelae of the disease, disorder, or condition described herein or may be at risk of developing the disease, disorder, or condition. Non-human animals that may be treated include mammals, for example, non-human primates (e.g., monkey, chimpanzee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, rabbits), lagomorphs, swine (e.g., pig, miniature pig), equine, canine, feline, bovine, and other domestic, farm, and zoo animals.
The effectiveness of the compounds of the present disclosure in treating and/or preventing a disease, disorder, or condition described herein can readily be determined by a person of ordinary skill in the medical and clinical arts. Determining and adjusting an appropriate dosing regimen (e.g., adjusting the amount of compound per dose and/or number of doses and frequency of dosing) can also readily be performed by a person of ordinary skill in the medical and clinical arts. One or any combination of diagnostic methods, including physical examination, assessment and monitoring of clinical symptoms, and performance of analytical tests and methods described herein, may be used for monitoring the health status of the subject.
Also provided herein are pharmaceutical compositions comprising at least one compound of Formula (I). In some embodiments, the pharmaceutical composition further comprises at least one additional pharmaceutically acceptable ingredient.
In pharmaceutical dosage forms, any one or more of the compounds of the present disclosure may be administered in the form of a pharmaceutically acceptable derivative, such as a salt, and/or it/they may also be used alone and/or in appropriate association, as well as in combination, with other pharmaceutically active compounds.
An effective amount or therapeutically effective amount refers to an amount of a compound of the present disclosure or a composition comprising at least one such compound that, when administered to a subject, either as a single dose or as part of a series of doses, is effective to produce at least one therapeutic effect. Optimal doses may generally be determined using experimental models and/or clinical trials. Design and execution of pre-clinical and clinical studies for each of the therapeutics (including when administered for prophylactic benefit) described herein are well within the skill of a person of ordinary skill in the relevant art. The optimal dose of a therapeutic may depend upon the body mass, weight, and/or blood volume of the subject.
An effective amount or therapeutically effective amount refers to an amount of a compound of the present disclosure or a composition comprising at least one such compound that, when administered to a subject, either as a single dose or as part of a series of doses, is effective to produce at least one therapeutic effect. Optimal doses may generally be determined using experimental models and/or clinical trials. Design and execution of pre-clinical and clinical studies for each of the therapeutics (including when administered for prophylactic benefit) described herein are well within the skill of a person of ordinary skill in the relevant art. The optimal dose of a therapeutic may depend upon the body mass, weight, and/or blood volume of the subject.
The minimum dose that is sufficient to provide effective therapy may be used in some embodiments. Subjects may generally be monitored for therapeutic effectiveness using assays suitable for the disease or condition being treated or prevented, which assays will be familiar to those having ordinary skill in the art and are described herein. The level of a compound that is administered to a subject may be monitored by determining the level of the compound (or a metabolite of the compound) in a biological fluid, for example, in the blood, blood fraction (e.g., serum), and/or in the urine, and/or other biological sample from the subject. Any method practiced in the art to detect the compound, or metabolite thereof, may be used to measure the level of the compound during the course of a therapeutic regimen.
The dose of a compound described herein may depend upon the subject's condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person of ordinary skill in the medical art. Similarly, the dose of the therapeutic for treating a disease or disorder may be determined according to parameters understood by a person of ordinary skill in the medical art.
Pharmaceutical compositions may be administered in any manner appropriate to the disease or disorder to be treated as determined by persons of ordinary skill in the medical arts. An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as discussed herein, including the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose (or effective dose) and treatment regimen provides the pharmaceutical composition(s) as described herein in an amount sufficient to provide therapeutic and/or prophylactic benefit (for example, an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity or other benefit as described in detail above).
The pharmaceutical compositions described herein may be administered to a subject in need thereof by any one of several routes that effectively delivers an effective amount of the compound. Non-limiting suitable administrative routes include topical, oral, nasal, intrathecal, enteral, buccal, sublingual, transdermal, rectal, vaginal, intraocular, subconjunctival, sublingual, and parenteral administration, including subcutaneous, intravenous, intramuscular, intrasternal, intracavernous, intrameatal, and intraurethral injection and/or infusion.
The pharmaceutical composition described herein may be sterile aqueous or sterile non-aqueous solutions, suspensions or emulsions, and may additionally comprise at least one pharmaceutically acceptable excipient (i.e., a non-toxic material that does not interfere with the activity of the active ingredient). Such compositions may be in the form of a solid, liquid, or gas (aerosol). Alternatively, the compositions described herein may be formulated as a lyophilizate, or compounds described herein may be encapsulated within liposomes using technology known in the art. The pharmaceutical compositions may further comprise at least one additional pharmaceutical acceptable ingredient, which may be biologically active or inactive. Non-limiting examples of such ingredients include buffers (e.g., neutral buffered saline or phosphate buffered saline), carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitol, proteins, polypeptides, amino acids (e.g., glycine), antioxidants, chelating agents (e.g., EDTA and glutathione), stabilizers, dyes, flavoring agents, suspending agents, and preservatives.
Any suitable excipient or carrier known to those of ordinary skill in the art for use in pharmaceutical compositions may be employed in the compositions described herein. Excipients for therapeutic use are well known, and are described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, Pa. (2005)). In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s). Pharmaceutical compositions may be formulated for the particular mode of administration. For parenteral administration, pharmaceutical compositions may further comprise water, saline, alcohols, fats, waxes, and buffers. For oral administration, pharmaceutical compositions may further comprise at least one ingredient chosen, for example, from any of the aforementioned excipients, solid excipients and carriers, such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, kaolin, glycerin, starch dextrins, sodium alginate, carboxymethylcellulose, ethyl cellulose, glucose, sucrose, and magnesium carbonate.
The pharmaceutical compositions (e.g., for oral administration or delivery by injection) may be in the form of a liquid. A liquid pharmaceutical composition may include, for example, at least one the following: a sterile diluent such as water for injection, saline solution, such as physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic. In some embodiments, the pharmaceutical composition comprises physiological saline. In some embodiments, the pharmaceutical composition is an injectable pharmaceutical composition, and in some embodiments, the injectable pharmaceutical composition is sterile.
For oral formulations, at least one of the compounds of the present disclosure can be used alone or in combination with at least one additive appropriate to make tablets, powders, granules and/or capsules, for example, those chosen from conventional additives, disintegrators, lubricants, diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical compositions may be formulated to include at least one buffering agent, which may provide for protection of the active ingredient from low pH of the gastric environment and/or an enteric coating. A pharmaceutical composition may be formulated for oral delivery with at least one flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating.
Oral formulations may be provided as gelatin capsules, which may contain the active compound or biological along with powdered carriers. Similar carriers and diluents may be used to make compressed tablets. Tablets and capsules can be manufactured as sustained release products to provide for continuous release of active ingredients over a period of time. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
A pharmaceutical composition may be formulated for sustained or slow release. Such compositions may generally be prepared using well-known technology and administered by, for example, oral, rectal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain the active therapeutic dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible and may also be biodegradable. The formulation may provide a relatively constant level of active component release. The amount of active therapeutic contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition to be treated or prevented.
The pharmaceutical compositions described herein can be formulated as suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. The pharmaceutical compositions may be prepared as aerosol formulations to be administered via inhalation. The compositions may be formulated into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen and the like.
The compounds of the present disclosure and pharmaceutical compositions comprising these compounds may be administered topically (e.g., by transdermal administration). Topical formulations may be in the form of a transdermal patch, ointment, paste, lotion, cream, gel, and the like. Topical formulations may include one or more of a penetrating agent or enhancer (also call permeation enhancer), thickener, diluent, emulsifier, dispersing aid, or binder. Physical penetration enhancers include, for example, electrophoretic techniques such as iontophoresis, use of ultrasound (or “phonophoresis”), and the like. Chemical penetration enhancers are agents administered either prior to, with, or immediately following administration of the therapeutic, which increase the permeability of the skin, particularly the stratum corneum, to provide for enhanced penetration of the drug through the skin. Additional chemical and physical penetration enhancers are described in, for example, Transdermal Delivery of Drugs, A. F. Kydonieus (ED) 1987 CRL Press; Percutaneous Penetration Enhancers, eds. Smith et al. (CRC Press, 1995); Lenneräs et al., J. Pharm. Pharmacol. 54:499-508 (2002); Karande et al., Pharm. Res. 19:655-60 (2002); Vaddi et al., Int. J. Pharm. 91:1639-51 (2002); Ventura et al., J. Drug Target 9:379-93 (2001); Shokri et al., Int. J. Pharm. 228(1-2):99-107 (2001); Suzuki et al., Biol. Pharm. Bull. 24:698-700 (2001); Alberti et al., J. Control Release 71:319-27 (2001); Goldstein et al., Urology 57:301-5 (2001); Kiijavainen et al., Eur. J. Pharm. Sci. 10:97-102 (2000); and Tenjarla et al., Int. J. Pharm. 192:147-58 (1999).
Kits comprising unit doses of at least one compound of the present disclosure, for example in oral or injectable doses, are provided. Such kits may include a container comprising the unit dose, an informational package insert describing the use and attendant benefits of the therapeutic in treating the pathological condition of interest, and/or optionally an appliance or device for delivery of the at least one compound or composition comprising the same.
Compounds of Formula (I) may be prepared as shown in, for example,
It will also be appreciated by those skilled in the art that in the processes described herein the functional groups of intermediate compounds may need to be protected by suitable protecting groups, even if not specifically described. Such functional groups include, but are not limited to, hydroxy, amino, mercapto, and carboxylic acid. Suitable protecting groups for hydroxy include, but are not limited to, trialkylsilyl or diarylalkylsilyl (for example, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino, and guanidino include, but are not limited to, t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include, but are not limited to, —C(O)R″ (where R″ is alkyl, aryl, or arylalkyl), p-methoxybenzyl, trityl, and the like. Suitable protecting groups for carboxylic acid include, but are not limited to, alkyl, aryl, or arylalkyl esters. Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T. W. and P. G. M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the art would appreciate, the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.
Analogous reactants to those described herein may be identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., may be contacted for more details). Chemicals that are known but not commercially available in catalogs may be prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the present disclosure is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts,” Verlag Helvetica Chimica Acta, Zurich, 2002.
Methods known to one of ordinary skill in the art may be identified through various reference books, articles, and databases. Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds of the present disclosure, or provide references to articles that describe the preparation, include, for example, “Synthetic Organic Chemistry,” John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure,” 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds of the present disclosure, or provide references to articles that describe the preparation, include, for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modem Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Quin, L. D. et al. “A Guide to Organophosphorus Chemistry” (2000) Wiley-Interscience, ISBN: 0-471-31824-8; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.
Compound 2: To a solution of compound 1 (6.7 g, 15 mmol, depicted in
Compound 3: Compound 2 (3.4 g, 8.5 mmol) was dissolved in DMF (50 mL) under an argon atmosphere and cooled on an ice bath. Triethylamine (3.6 mL, 26 mmol) was added followed by 2-(4-cyclohexyl-1-H-1,2,3-triazol-1-yl)acetic acid NHS ester (2.9 g, 9.4 mmol, prepared according to Rillahan et al, Chem. Sci., 2014, 5, 2398). The reaction mixture was stirred for 2 hours, allowing to warm to room temperature. The reaction mixture was diluted with ethyl acetate, transferred to a separatory funnel, and washed with water. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to afford 1.7 g of compound 3. (33% yield) MS (ESI): m/z calculated for C26H35N7O7S: 589.2, found 590.0 (M+1).
Compound 4: Compound 3 (3.74 g, 6.3 mmol) was dissolved in DMF at room temperature. Dithiothreitol (2.9 g 19 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (90 μL, 0.6 mmol) were added. The reaction mixture was stirred overnight at room temperature. To this reaction mixture was added 3,5 dimethyl, 4-hydroxy benzoic acid NHS ester (2.2 g, 8.2 mmol) and triethylamine (0.7 mL, 6.9 mmol). The reaction mixture was stirred 3 hours at room temperature. The reaction mixture was diluted with ethyl acetate, transferred to a separatory funnel, and washed with 0.1 M HCl, then with water. The organic phase was concentrated and purified by flash chromatography to afford 3.7 g compound 4 as a light brown foam. (82% yield) MS (ESI): m/z calculated for C35H45N5O9S: 711.3, found 734.0 (M+Na+).
Compound 5: Compound 4 (3.6 g, 5 mmol) and 4-dimethylaminopyridine (60 mg) were dissolved in pyridine (50 mL) and cooled on an ice bath. Acetic anhydride (9.5 mL, 100 mmol) was added, and the reaction mixture was stirred overnight, allowing to warm to room temperature. The reaction mixture was cooled on an ice bath and quenched by the addition of MeOH (20 mL). The reaction mixture was stirred 30 minutes, then concentrated. The residue was dissolved in ethyl acetate, transferred to a separatory funnel, and washed three times with water. The organic phase was concentrated and separated by flash chromatography to afford 3.45 g compound 5 as a yellow foam. (78% yield) MS (ESI): m/z calculated for C43H53N5O13S: 879.3, found 880.0 (M+H).
Compound 6: A mixture of compound 5 (240 mg, 0.27 mmol) and 3-[N-benzyl-N-(tert-butoxycarbonyl)amino]propan-1-ol (360 mg, 1.36 mmol) was azeotroped two times from toluene. The mixture was dissolved in DCM (1 mL) and acetonitrile (0.4 mL) under an argon atmosphere. Heat activated, powdered 4 Å molecular sieves (500 mg) were added. The mixture was stirred for 1 hour at room temperature, then cooled on an ice bath. N-Iodosuccinimide (130 mg, 0.54 mmol) was added, followed by dropwise addition of triflic acid (24 μL, 0.27 mmol). The reaction mixture was stirred 30 minutes. The reaction mixture was quenched by the addition of triethylamine (0.1 mL). The reaction mixture was filtered through Celite and concentrated. The residue was dissolved in ethyl acetate, transferred to a separatory funnel, and washed with saturated sodium bisulfite solution followed by water. The organic phase was dried over magnesium sulfate, filtered, then concentrated. The residue was purified by flash chromatography to afford 164 mg compound 6 as an α/β mixture. (59% yield) MS (ESI): m/z calculated for C52H70N6O16: 1034.5, found 1035.1 (M+H).
Compound 7: To a solution of compound 6 (56 mg, 0.054 mmol) dissolved in DCM (2 mL) at room temperature was added trifluoroacetic acid (0.5 mL). The reaction mixture was stirred for 1 hour. The reaction mixture was transferred to a separatory funnel and washed 2 times with a saturated sodium bicarbonate solution. The organic phase was concentrated and separated by flash chromatography to afford 43 mg compound 7 as an α/β mixture. (84%) MS (ESI): m/z calculated for C47H62N6O14: 934.3, found 935.0 (M+H).
The following compounds can be prepared as shown in
Compound 8: Compound 8 can be prepared as shown in
Compound 9: Compound 9 was prepared as shown in
Compound 10: Compound 10 can be prepared as shown in
Compound 11: Azido-PEG1-NHS ester (Broadpharm catalog item BP-21857) (16 mg, 0.1 mmol) and triethylamine (16 μL, 0.11 mmol) were dissolved in DMF (0.1 mL) under argon and cooled on an ice bath. HATU (39 mg, 0.1 mmol) was added, and the reaction mixture stirred for 10 minutes. Compound 7 (63 mg, 0.067 mmol) dissolved in DMF (1 mL) was added. The reaction mixture was stirred overnight, allowing to warm to room temperature. The reaction mixture was diluted with ethyl acetate, transferred to a separatory funnel, and washed two times with water. The organic phase was concentrated. The residue was separated by flash chromatography to afford 57 mg of compound 11 as a clear oil. (79% yield) MS (ESI): m/z calculated for C52H69N9O16: 1075.5, found 1076.0 (M+H).
Compound 12: Compound 11 (57 mg, 0.053 mmol) was dissolved in MeOH (1 mL) and cooled on an ice bath. Water (0.1 mL) was added followed by sodium methoxide (3 drops of a 25 weight % solution of NaOMe in MeOH). The reaction mixture was stirred for 1 hour on the ice bath, then for 1 hour at room temperature. The reaction was quenched by addition of acetic acid (0.1 mL) and concentrated. The residue was separated by HPLC to afford 18 mg compound 12 as a white solid.
1H NMR (400 MHz, MeOD) δ 8.02 (s, 1H), 7.58 (d, J=4.6 Hz, 1H), 7.35 (d, J=4.9 Hz, 2H), 7.25-7.07 (m, 5H), 5.10-5.00 (m, 1H), 4.57 (d, J=15.3 Hz, 1H), 4.46 (d, J=15.2 Hz, 1H), 4.00-3.83 (m, 1H), 3.74-3.63 (m, 1H), 3.59-3.48 (m, 1H), 3.39 (dt, J=13.2, 3.4 Hz, 5H), 3.31-3.14 (m, 3H), 2.69 (s, 3H), 2.61 (s, 2H), 2.46 (t, J=6.0 Hz, 1H), 2.10 (d, J=6.8 Hz, 6H), 1.91 (td, J=11.9, 10.4, 5.0 Hz, 3H), 1.77-1.73 (m, 1H), 1.63 (d, J=12.9 Hz, 1H), 1.33 (t, J=10.2 Hz, 4H), 1.19 (s, 1H). MS (ESI): m/z calculated for C43H59N9O12: 893.4, found 892.1 (M−H).
Compound 13: Compound 13 was prepared as shown in
1H NMR (400 MHz, MeOD) δ 7.72 (d, J=5.8 Hz, 1H), 7.48 (d, J=3.8 Hz, 2H), 7.38-7.17 (m, 5H), 5.23-5.07 (m, 2H), 4.57 (d, J=15.1 Hz, 1H), 3.99 (d, J=23.3 Hz, 1H), 3.78 (d, J=28.2 Hz, 5H), 3.69-3.60 (m, 21H), 3.60-3.46 (m, 3H), 3.38 (t, J=5.0 Hz, 2H), 3.33 (p, J=1.7 Hz, 2H), 2.84 (d, J=6.4 Hz, 2H), 2.73 (s, 1H), 2.59 (d, J=4.9 Hz, 1H), 2.22 (d, J=6.6 Hz, 6H), 2.04 (s, 2H), 1.87-1.81 (m, 4H), 1.76 (d, J=13.5 Hz, 1H), 1.62 (s, 1H), 1.53-1.40 (m, 4H), 1.31 (s, 4H), 0.99-0.83 (m, 1H). MS (ESI): m/z calculated for C53H79N9O17: 1113.6, found 1112.4 (M−H).
Compound 14: Compound 14 was prepared as shown in
1H NMR (400 MHz, MeOD) δ 7.70 (d, J=4.9 Hz, 1H), 7.49 (d, J=3.9 Hz, 2H), 7.42-7.30 (m, 4H), 7.27-7.18 (m, 3H), 5.21-5.06 (m, 2H), 4.70 (s, 1H), 4.63 (q, J=15.2, 13.4 Hz, 1H), 3.98 (d, J=10.1 Hz, OH), 3.81 (dd, J=12.2, 6.0 Hz, 2H), 3.59-3.43 (m, 9H), 3.42-3.31 (m, 3H), 2.86-2.67 (m, 4H), 2.59 (s, 1H), 2.23 (d, J=7.2 Hz, 6H), 2.04 (s, 2H), 1.88-1.80 (m, 5H), 1.73 (d, J=10.3 Hz, 1H), 1.45 (t, J=10.1 Hz, 5H), 1.36-1.29 (m, 3H). MS (ESI): m/z calculated for C65H103N9O23: 1377.7, found 1376.1 (M−H).
Compound 15: Compound 15 was be prepared as shown in
1H NMR (400 MHz, MeOD) δ 7.71 (d, J=4.0 Hz, 1H), 7.56-7.42 (m, 2H), 7.35-7.08 (m, 5H), 5.19-5.02 (m, 2H), 3.88-3.71 (m, 6H), 3.72-3.42 (m, 32H), 3.41-3.34 (m, 3H, overlapped with solvent peak), 2.96-2.79 (m, 2H), 2.78-2.66 (m, 2H), 2.25 (s, 6H), 2.09-1.96 (m, 2H), 1.91-1.71 (m, 6H), 1.70-1.61 (m, 1H), 1.55-1.40 (m, 4H), MS (ESI): m/z calculated for C54H81N9O17: 1127.5, found 1126.9 (M−H).
Compound 16: Compound 16 was be prepared as shown in
1H NMR (400 MHz, MeOD) δ 7.61-7.45 (d, J=8.0 Hz, 1H), 7.43-7.30 (m, 2H), 7.29-7.01 (m, 5H), 5.14-4.88 (m, 2H), 4.61-4.51 (m, 1H), 4.50-4.40 (m, 1H), 3.95-3.56 (m, 5H), 3.49-3.26 (m, 4H), 3.27-3.13 (m, 3H, overlapped with solvent peak), 3.80 (t, J=6.0 Hz, 1H), 2.69-2.52 (m, 2H), 2.40 (t, J=8.0 Hz, 2H), 2.31-2.17 (m, 1H), 2.16-2.03 (2s, 6H), 2.00-1.83 (m, 2H), 1.82-0.97 (m, 17H), MS (ESI): m/z calculated for C44H61N9O11: 891.4, found 890.0 (M−H).
The following compounds can be prepared as shown in
A number of additional ligands may be prepared by substituting compound 8, compound 9, or compound 10 for compound 7 in the scheme of
Compound 108: Compound 14 (34 mg, 0.025 mmol) and the commercially available compound 107 (0.27 mL of a 0.1 M solution in chloroform) were dissolved in methanol at room temperature. An aqueous solution of CuSO4 and THPTA (0.1 mL of a 40 mM solution of both reagents in water) was added. The mixture was degassed by bubbling argon through for 5 minutes. Sodium ascorbate (10 mg, 0.05 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was separated by reverse phase chromatography using a C-8 cartridge and eluting with water, then methanol, then ethyl acetate to afford 28 mg of compound 108. (51% yield) MS (ESI): m/z calculated for C108H182N10NaO32P: 2185.2, found 1083.1 (M/2).
The following compounds can be prepared as shown in
Compound 109: Compound 109 can be prepared as shown in
Compound 110: Compound 110 can be prepared as shown in
Compound 111: Compound 111 can be prepared as shown in
Compound 113: Compound 33 and the commercially available compound 112 are dissolved in water at room temperature. Triethylamine is added, and the reaction mixture is stirred at room temperature overnight. The reaction mixture is separated by reverse phase chromatography to afford compound 113.
CD33 Activity—Binding Assay
The assay to screen for and characterize glycomimetic ligands of CD33 is a competitive binding assay, which allows the determination of IC50 values. CD33-Fc (BioLegend catalog item 750106) was immobilized in 96 well microtiter plates by incubation at 4° C. overnight. To reduce non-specific binding, bovine serum albumin was added to each well and incubated at room temperature for 3 hours. The plate was washed and serial dilutions of the test compounds were added to the wells in the presence of biotinylated polyacrylamide conjugated with Neu5Acα2-3Galβ1-3GalNAc-PAA-biotin (GlycoTech catalog item 01-088). After incubation at room temperature for 2 hours and washing, streptavidin/horseradish peroxidase was added to each well and incubated at room temperature for 30 minutes followed by an additional wash.
To determine the amount of glycopolymer bound to the immobilized CD33, the peroxidase substrate 3.3′0.5.5′ tetramethylbenzidine (TMB) was added. After 5 minutes, the enzyme reaction was stopped by the addition of H3PO4, and the absorbance of light at a wavelength of 450 nm was determined. The concentration of test compound required to inhibit binding by 50% was determined and reported as the IC50 value.
This application claims the benefit of priority of U.S. Provisional Application No. 63/018,258, filed Apr. 30, 2020, the contents of which are herein incorporated by reference in their entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2021/030218 | 4/30/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63018258 | Apr 2020 | US |
