Patent Application
20250059156
The present disclosure relates to the field of medicine, including the discovery of novel alkaloid compounds useful for inhibiting phosphodiesterase-4 (PDE4) and the serotonin transporter protein (5-HTT).
Certain bioactive indole alkaloid compounds obtained from plants of the genus Sceletium, such as mesembrine and mesembrenone, can inhibit serotonin (5-HT) uptake and phosphodiesterase-4 (PDE-4) and have been explored as potential treatments for certain central nervous system (CNS) conditions, such as mild to moderate depression.
Phosphodiesterase-4 (PDE-4) enzymes hydrolyze the cyclic nucleotide intracellular second messengers (cAMP and cGMP), leading to inactivation or inhibition of these enzymes and resulting in elevated levels of cAMP and cGMP in the cell and prolonging the action of these enzymes on downstream signaling pathways. Four isoforms of PDE-4 enzymes (designated PDE4a, PDE4b, PDE4c and PDE4d) have been identified, with the PDE4a, PDE4b and PDE4d isoforms predominantly expressed in the brain. Signaling pathways including PDE-4 are believed to be involved in diseases and disorders such as depression. Therapeutic compounds for selective inhibition of the certain PDE4 isoforms can be utilized for the treatment or prevention of depression and/or anxiety while minimizing or alleviating detrimental effects of inhibiting other PDE4 isoenzymes. One concern with the use of known PDE4 inhibitors is the side effect of emesis, which has been observed for several candidate compounds. PDE4 inhibitors, such as the brain-penetrant inhibitor rolipram, influence central function in a dose-dependent manner, consistent with their potential use in the treatment of depression and cognitive disorders in humans. However higher doses of these compounds can give rise to mechanism-related side effects such as emesis.
Natural products obtained from plants of the genus Sceletium contain varying amounts of (−) mesembrine and (+)/(−) mesembrenone. Naturally occurring (−) mesembrine from Sceletium tortuosum has been reported as having serotonin (5-HT) uptake inhibitory activity useful in treating mental health conditions, such as mild to moderate depression, and mesembrine hydrochloride has been reported to be a phosphodiesterase 4 (PDE4) inhibitor. Naturally occurring (−) mesembrenone from Sceletium tortuosum is reported as a potent selective serotonin reuptake inhibitor (Ki=27 nM) and inhibitor of a phosphodiesterase 4 (PDE4) inhibitor. Mesembrenone is a most potent inhibitor of PDE4, while mesembrine is more selective towards the serotonin receptor.
The therapeutic use of mesembrine and mesembrenone has been limited by the variability and instability of the content of the compounds in natural extract products, and the instability and pharmacokinetic profile of these compounds as obtained from natural products.
There remains a need in the art for an effective therapy for the treatment or prevention of depression and/or anxiety which utilizes a PDE4 inhibitor yet minimizes the side effect of nausea and/or emesis associated with the PDE4 inhibitor. There remains an unmet need for therapeutic compounds for inhibiting SERT and selectively inhibiting desired isoenzyme forms of PDE4.
Described herein are compounds of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, a compound is of formula (I-1):
or a pharmaceutically acceptable salt thereof, wherein
In certain embodiments, the compound of formula (I) is a compound of formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, wherein the compound is of formula (Ia-1):
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, the compound of formula (I) is N
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of formula (I) is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of formula (I) is selected from the group consisting of
or a pharmaceutically acceptable salt thereof; wherein the compound has the absolute stereochemistry shown.
In certain embodiments, the present disclosure provides a method of treating a central nervous condition, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure.
In certain embodiments, the present disclosure provides a method of treating a condition by administering a PDE4 inhibitor, comprising administering to a subject in need thereof an effective amount a compound of the present disclosure.
Numerous embodiments are further provided that can be applied to any aspect of the present invention described herein.
The present invention is based, at least in part, on analogs of mesembrine and mesembrenone. Although (−) mesembrine is bioactive with certain desirable pharmacologic effects, certain other properties are less than ideal for use as a therapeutic. For example, the pharmacokinetics described for (−) mesembrine show rapid metabolism and excretion, with an undesirably low half-life in plasma of less than 2 hours. To take advantage of the desirable properties of mesembrine and mesembrenone, compounds have been developed and described here.
In certain aspects, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, a compound is of formula (I-1):
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, R1 is H or C1-C7 alkyl, and is preferably C1-C3 alkyl. In some embodiments, R1 is methyl. In some embodiments, R1 is methyl, ethyl, or isopropyl.
In some embodiments, ring A is
wherein * denotes the attachment points of ring A to the compound of formula (I). In some embodiments, ring A is
wherein * denotes the attachment points of ring A to the compound of formula (I), and n is 0, 1, 2, 3, or 4. In some embodiments, ring A is
wherein * denotes the attachment points of ring A to the compound of formula (I), and m is 1, 2, 3, 4, 5, or 6. In some embodiments, ring A is
wherein * denotes the attachment points of ring A to the compound of formula (I), and n is 0, 1, 2, 3, 4, 5 or 6. In some embodiments, ring A is
wherein * denotes the attachment points of ring A to the compound of formula (I), and m is 1, 2, 3, 4, 5, 6, 7, or 8.
In some embodiments, m is 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, m is 1, 2, 3, 4, 5, or 6. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.
In some embodiments, R2 is independently C1-C6 alkyl, C1-C6 haloalkyl, 5- to 7-membered heteroaryl wherein each hydrogen atom in the 5- to 7-membered heteroaryl is optionally substituted by C1-C6 haloalkyl. In some embodiments, R2 is 5- to 7-membered heteroaryl wherein each hydrogen atom in the 5- to 7-membered heteroaryl is optionally substituted by C1-C6 haloalkyl. In some embodiments, wherein R2 is
wherein the * denotes the attachment point of R2 to the compound. In some embodiments, R2 is 3- to 7-membered heterocyclyl, for example,
wherein the * denotes the attachment point of R2 to the compound of formula (I).
In some embodiments, m is greater than 1. Illustratively, two R2s on a single carbon atom together with the carbon atom to which they are attached combine to form a 3- to 7-membered heterocyclyl. In some embodiments, R2 is 3- to 7-membered heterocyclyl, wherein each hydrogen atom in the 3- to 7-membered heterocyclyl is optionally substituted by C1-C6 haloalkyl. In some embodiments, R2 is
wherein the * denotes the attachment point of R2 to the compound of formula (I).
In some embodiments, m is 2, 3, 4, or 5. Illustratively the two R2s on different carbon atoms together with the carbon atoms to which they are attached combine to form a 5- to 7-membered heteroaryl. In some embodiments, ring A is
wherein * denotes the attachment points of ring A to the compound of formula (I).
In some embodiments, ring A is
wherein * denotes the attachment points of ring A to the compound of formula (I).
In some embodiments, n is 0, 1, 2, 3, 4, 5 or 6. In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.
In some embodiments, each R3 is independently C1-C6 alkyl, C1-C6 haloalkyl, —Si(C1-C6 alkyl)3, —C(O)C1-C6 alkyl, or phenyl. In some embodiments, each R3 is independently C1-C6 alkyl. In some embodiments, each R3 is independently C1-C6 haloalkyl. In some embodiments, each R3 is independently —Si(C1-C6 alkyl)3. In some embodiments, each R3 is independently —C(O)C1-C6 alkyl. In some embodiments, each R3 is independently phenyl.
In some embodiments, n is greater than 1 and two R3s on different carbon atoms together with the carbon atoms to which they are attached combine to form a 3- to 7-membered heterocyclyl or a 5- to 6-membered cycloalkyl. In some embodiments, ring A is
In some embodiments, n is greater than 1 and two R3s on a single carbon atom together with the carbon atom to which they are attached combine to form a 3- to 7-membered heterocyclyl or a 3- to 6-membered cycloalkyl. In some embodiments, ring A is
In some embodiments, r is 0, 1, or 2 if the double bond is present. In some embodiments, r is 0, 1, 2, 3, or 4 if the double bond is absent. In some embodiments, r is 0.
In some embodiments, each R4, if present, is C1-C6 alkyl, —OH, or —NH2.
In some embodiments, the compound is of formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, the compound is of formula (Ia-1):
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, q is 1 or 2. In some embodiments, q is 2 or 3. In some embodiments, q is 4. 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, Z is O. In some embodiments, Z is NR6. In some embodiments, R6 is H or C1-C6 alkyl. In some embodiments, R6 is H. In some embodiments, R6 is C1-C6 alkyl.
In some embodiments, R6 is H such that Z is NH.
In some embodiments, each R5 is independently H, C1-C6 alkyl. or C1-C6 haloalkyl. In some embodiments, R5 is H. In some embodiments, R5 is C1-C6 haloalkyl, for example trifluormethyl.
In some embodiments, the compound is of formula (Ib):
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, the compound is of formula (Ic):
or a pharmaceutically acceptable salt thereof, wherein
the dashed bond is an optional bond to form a double bond;
In some embodiments, a compound is of formula (Ic-1):
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, the compound is of formula (Id-1) or (Id-2):
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, the compound is of formula (Id-1-1) or (Id-2-1):
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, the compound is of formula (Ie)
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, the compound is of formula (Ie-1):
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, the compound is of formula (If):
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, compound of formula (If-1):
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, the compound is of formula (Ig):
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, the compound is of formula (Ig-1):
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, the dashed bond is present to form a double bond. In some embodiments, the dashed bond is absent and the bond is a single bond. In some embodiments, if n is 0 for a compound of formula (I), then the optional dashed bond is present to form the double bond.
In certain embodiments, the compound is of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
In certain embodiments, the compound is of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
In certain embodiments, the compound is of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
the dashed bond is an optional bond to form a double bond;
In certain embodiments, the compound is of formula (II):
or a pharmaceutically acceptable salt thereof, wherein
In certain embodiments, the compound is of formula (II):
or a pharmaceutically acceptable salt thereof, wherein
In certain embodiments, the compound is of formula (II):
or a pharmaceutically acceptable salt thereof, wherein
In certain embodiments, the compound is of formula (II):
or a pharmaceutically acceptable salt thereof, wherein
In certain embodiments, the compound is of formula (II):
or a pharmaceutically acceptable salt thereof, wherein
In certain embodiments, the compound is of formula (II):
or a pharmaceutically acceptable salt thereof, wherein
In certain embodiments, the compound is of formula (Tl):
or a pharmaceutically acceptable salt thereof, wherein
In certain embodiments, the compound is of formula (II):
or a pharmaceutically acceptable salt thereof, wherein
In certain embodiments, the compound is of formula (II):
or a pharmaceutically acceptable salt thereof, wherein
In certain embodiments, the compound of formula (I) is a compound of formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein
In certain embodiments, the compound of formula (I) is a compound of formula (IIa):
or a pharmaceutically acceptable salt thereof, wherein
In certain embodiments, the compound of formula (I) is a compound of formula (IIa):
or a pharmaceutically acceptable salt thereof, wherein
In certain embodiments, the compound of formula (I) is a compound of formula (IIa):
or a pharmaceutically acceptable salt thereof, wherein
In some embodiments, the compound is selected from:
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound is selected from:
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound is selected from:
or a pharmaceutically acceptable salt thereof; wherein the compound has the absolute stereochemistry shown.
A total synthesis of (±)-mesembrine has also been reported (Jeffs P. Sceletium alkaloids. In: Jeffs P. The Alkaloids: Chemistry and Physiology. Vol 19. New York, NY: Academic Press; 1981:1-80). Mesembrine alkaloids have been synthesized in a manner similar to that of Amaryllidaceae alkaloids (e.g., Roe C, Sandoe E J, Stephenson G R, Anson C E. Stereoselectivity in the organoiron-mediated synthesis of (±)-mesembrine. Tetrahedron Lett. 2008; 49(4):650-653; and Shamma M, Rodriguez H R. The synthesis of (+)-mesembrine. Tetrahedron. 1968; 24(22):6583-6589.5714008).
In certain embodiments, the present application is directed to a pharmaceutical composition comprising an active pharmaceutical ingredient. In certain embodiments, the pharmaceutical composition comprises a compound as disclosed herein as the active pharmaceutical ingredient (API) and a pharmaceutically acceptable carrier comprising one or more excipients. In some embodiments, the pharmaceutical composition optionally further comprises an additional therapeutic compound (i.e., agent) with the pharmaceutically acceptable carrier. The pharmaceutical composition can be a medicament.
Pharmaceutically acceptable carriers include those known in the art. The choice of a pharmaceutically acceptable carrier can depend, for example, on the desired route of administration of the composition. A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, parenteral administration (e.g. intravenously, subcutaneously, or intramuscularly), oral administration (for example, tablets, and capsules); absorption through the oral mucosa (e.g., sublingually) or transdermally (for example as a patch applied to the skin) or topically (for example, as a cream, ointment or spray applied to the skin).
In some embodiments, pharmaceutical compositions comprising compounds of Formula (I) or pharmaceutically acceptable salts thereof can be formulated for oral administration. For example, a compound provided herein can be combined with suitable compendial excipients to form an oral unit dosage form, such as a capsule or tablet, containing a target dose of a compound of Formula (I). The drug product can be prepared by first manufacturing the compound of Formula (I) as an active pharmaceutical ingredient (API), followed by roller compaction/milling with intragranular excipients and blending with extra granular excipients. A Drug Product can contain the selected compound of Formula (I) as the API and excipient components in a tablet in a desired dosage strength of Compound 1. The blended material can be compressed to form tablets and then film coated. The excipients can be selected from materials appropriate for inclusion in a pharmaceutical composition for an intended purpose and route of delivery including providing a desired manufacturing and stability properties and/or desired in vivo characteristics or other properties to the pharmaceutical composition. In some embodiments, the pharmaceutical composition can include a compound of Formula (I) as the API in combination with a filler (e.g., a form of microcrystalline cellulose), a dry binder or disintegrant (e.g., a cross-linked polymer), a glidant (e.g., colloidal silicon dioxide) and/or a lubricant (e.g., magnesium stearate). In some embodiments, the pharmaceutical composition can comprise a material such as an extended release or disintegrant involved in carrying or transporting the API pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject, including materials to desirable control the absorption of the API in the intestine.
The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
To prepare solid dosage forms for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, (2) binders, (3) humectants, (4) disintegrating agents, (5) solution retarding agents, (6) absorption accelerators, (7) wetting agents, (8) absorbents, (9) lubricants, (10) complexing agents, and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using suitable excipients. The pharmaceutical compositions according to the present invention may contain conventional pharmaceutical carriers and/or auxiliary agents. In some embodiments, the pharmaceutical compositions according to the present invention may contain conventional carrier agents including a binder, a lubricant and/or a glidant selected from those products and materials generally used in pharmaceutical industry for preparation of pharmaceutical compositions for an intended route of administration.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
Liquid dosage forms useful for oral administration include pharmaceutically acceptable carriers and the active ingredient provided as a solid form for reconstitution prior to administration or as a liquid (e.g., solutions, suspensions, or emulsions). In addition to the active ingredient, a liquid dosage forms may contain inert diluents commonly used in the art. For example, formulations of pharmaceutically acceptable compositions for injection can include aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles suitable for the intended route of administration. In some embodiments, the pharmaceutical composition is formulated for parenteral administration.
The therapeutically effective amount of a pharmaceutical composition can be determined by human clinical trials to determine the safe and effective dose for a patient with a relevant diagnosis. It is generally understood that the effective amount of the compound may vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the pharmaceutical composition at a dose and dose interval determined to be safe and effective for the patient.
The present disclosure includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts. The acid that is added to a compound to form an acid-addition salt can be an organic acid or an inorganic acid. A base that is added to a compound to form a base-addition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt, in some embodiments, a pharmaceutically-acceptable salt is an ammonium salt. For example, a pharmaceutically acceptable acid addition salt can exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
In some embodiments, ring A of the compound of formula (I) can be selected to provide beneficial properties. For example, the compounds described herein may provide beneficial therapeutic properties while minimizing emesis. For example, ring A can be selected to improve the selectivity of the compound of formula (I) for inhibiting PDE4 and the specific variants thereof. In some embodiments, the compounds described herein inhibit specific variants of PDE4 Preferred compounds, depending on indication, exhibit one of three major profiles: (A) <50 nM IC50 at SERT with greater than 10-fold selectivity over PDE4; (B) <50 nM IC50 at PBE4 with greater than 10-fold selectivity over SERT; (C) <50 nM IC50 at SERT and PDE4. In certain instances, preferred compounds will have PDE4 isoform selectivity with a 10-fold bias for one or more isoforms over the others in-class. For example, PDE4b selective and PDE4d selective compounds are desirable. Furthermore, compounds that have a high brain exposure with brain:plasma ratios (expressed as Kp) >0.3 and ideally >0.7 are most desirable. In some embodiments, a compound of formula (I) can inhibit SERT with an IC50 of less than about 1 micromolar in the assay of Example 1A.
In some embodiments, ring A of the compound of formula (I) can be selected to provide beneficial properties. For example, ring A can be selected to improve the selectivity of the compound of formula (I) for inhibiting PDE4 compared to SERT. In some embodiments, compounds disclosed herein are at least 2×, at least 3×, at least 5×, or at least 10× selective for PDE4 over SERT.
Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art.
The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g. “Principles of Neural Science”, McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000).
All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.
The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known, and those whose structure is not known.
A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).
“Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread 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. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
“Administering” or “administration of” a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and/or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.
As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.
A “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject's size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.
As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.
It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
As used herein, the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, —OCO—CH2—O-alkyl, —OP(O)(O-alkyl)2 or —CH2—OP(O)(O-alkyl)2. Preferably, “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.
As used herein, the term “alkyl” refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups, C1-C10 branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. Preferably, the “alkyl” group refers to C1-C7 straight-chain alkyl groups or C1-C7 branched-chain alkyl groups. Most preferably, the “alkyl” group refers to C1-C3 straight-chain alkyl groups or C1-C3 branched-chain alkyl groups. Examples of “alkyl” include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl and the like. The “alkyl” group may be optionally substituted.
The term “haloalkyl” refers to an alkyl group substituted with at least one hydrogen atom on a carbon replaced by a halogen. Illustrative halogens include fluoro, chloro, bromo, and iodo. Illustrative haloalkyl groups include trifluoromethyl and 2,2,2-trifluoroethyl, etc.
The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
The term “Cx-y” or “Cx-Cy”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. C0alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. A C1-6alkyl group, for example, contains from one to six carbon atoms in the chain.
The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group.
The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS—.
The term “amide”, as used herein, refers to a group
wherein Re and Rf each independently represent a hydrogen or hydrocarbyl group, or Re and Rf taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)—, preferably alkylC(O)—.
The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH—.
The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O—, preferably alkylC(O)O—.
The term “alkoxy” refers to an alkyl group having an oxygen attached thereto. Preferably, the “alkoxy” group refers to C1-C7 straight-chain alkoxy groups or C1-C7 branched-chain alkoxy groups. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by
wherein Re, Rf, and Rg, each independently represent a hydrogen or a hydrocarbyl group, or Re and Rf taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group.
The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.
The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring, for example a phenyl. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
The term “carbamate” is art-recognized and refers to a group
wherein Re and Rf independently represent hydrogen or a hydrocarbyl group.
The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.
The term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.
The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.
The term “carbonate” is art-recognized and refers to a group —OCO2—.
The term “carboxy”, as used herein, refers to a group represented by the formula —CO2H.
The term “ester”, as used herein, refers to a group —C(O)OR9 wherein R9 represents a hydrocarbyl group.
The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.
The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a ═O or ═S substituent, and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a ═O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.
The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.
The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains six or fewer carbon atoms, preferably four or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
The term “sulfate” is art-recognized and refers to the group —OSO3H, or a pharmaceutically acceptable salt thereof.
The term “sulfonamide” is art-recognized and refers to the group represented by the general formulae
wherein Re and Rf independently represents hydrogen or hydrocarbyl.
The term “sulfoxide” is art-recognized and refers to the group-S(O)—.
The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.
The term “sulfone” is art-recognized and refers to the group —S(O)2—.
The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group.
The term “thioester”, as used herein, refers to a group —C(O)SRe or —SC(O)Re
The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
The term “urea” is art-recognized and may be represented by the general formula
wherein Re and Rf independently represent hydrogen or a hydrocarbyl.
The term “modulate” as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.
“Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.
The term “pharmaceutically acceptable acid addition salt” as used herein means any non-toxic organic or inorganic salt of any base compounds represented by Formula I. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts, e.g., oxalates, may be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
The term “pharmaceutically acceptable basic addition salt” as used herein means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or any of their intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intraocular (such as intravitreal), intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01/062726.
Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixture and separate individual isomers.
Some of the compounds may also exist in tautomeric forms. Such forms, although not explicitly indicated in the formulae described herein, are intended to be included within the scope of the present disclosure.
“Prodrug” or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of formula I). Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs include using ester or phosphoramidate as biologically labile or cleavable (protecting) groups. The prodrugs of this disclosure are metabolized to produce a compound of Formula I. The present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.
The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.
The term “Log of solubility”, “Log S” or “log S” as used herein is used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption. Log S value is a unit stripped logarithm (base 10) of the solubility measured in mol/liter.
Methods of using compounds disclosed herein are also provided. The disclosure also includes pharmaceutical compositions comprising one or more SERT inhibiting compounds as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, pharmaceutical compositions reported herein can be provided in a unit dosage form (e.g., capsule, tablet or the like). Pharmaceutical compositions comprising a compound of formula (I) can be provided in an oral dosage form such as a capsule or tablet. The oral dosage form optionally comprises one or more fillers, disintigrants, lubricants, glidants, anti-adherents and/or anti-statics. In some embodiments, an oral dosage form is prepared via dry blending. In some embodiments, an oral dosage form is a tablet and is prepared via dry granulation. For example, a SERT Inhibitor compound of the present disclosure can be formulated as a test article for evaluation in animal models and (if appropriate) subsequent human clinical trials to determine the dosed at a therapeutically effective dose and dose frequency for humans. The pharmaceutical compositions may be orally administered in any orally acceptable dosage form. Accordingly, a patient and/or subject can be selected for treatment using a compound described herein by first evaluating the patient and/or subject to determine whether the subject is in need of inhibition of SERT, and if the subject is determined to be in need of inhibition of SERT, then administering to the subject a pharmaceutical composition comprising one or more compounds described herein, or pharmaceutically acceptable salts thereof.
The compounds described herein may be administered to treat CNS disorders and/or inflammatory conditions. Exemplary CNS disorders include generalized anxiety, acute anxiety and panic attacks, social anxiety, panic disorders, major depressive disorder, cognitive disorders, including Alzheimer's disease and other neurodegenerative disorders, neurodevelopmental disorders, schizophrenia, bipolar disorder, obsessive-compulsive disorder, multiple sclerosis, attention deficit-hyperactivity disorder, Bulimia nervosa, Huntington's disease, stroke, autism, premenstrual dysphoric disorder. Exemplary inflammatory conditions include chronic obstructive pulmonary disease (COPD), asthma and rheumatoid arthritis.
In some embodiments, methods of treating a patient suffering from a disease comprise administering to a patient a composition comprising a compound disclosed herein for the treatment or prevention of a mental health disorder. In some embodiments, methods of treating a patient suffering from a disease comprise administering to a patient a composition comprising a compound disclosed herein for the treatment or prevention of a diagnosed condition selected from anxiety and depression. In some embodiments, the compound disclosed herein is administered to the patient in a unit dose. In some embodiments, a method comprises the administration to a patient in need thereof of a therapeutically effective amount of a compound of Formula (I) for the treatment of a disease selected from the group consisting of mild to moderate depression and major depressive episodes. In some embodiments, a method comprises the administration to a patient in need thereof of a therapeutically effective amount of a compound of Formula (I) for the treatment of anxiety. In some embodiments, a method comprises the administration to a patient in need thereof of a therapeutically effective amount of a compound of Formula (I) for the treatment of depression. In some embodiments, a method comprises the administration to a patient in need thereof of a therapeutically effective amount of a compound of Formula (I) for the treatment of a condition selected from the group consisting of: anxiety associated with depression, anxiety with depression, mixed anxiety and depressive disorder. In some embodiments, a method comprises the administration to a patient in need thereof of a therapeutically effective amount of a compound of Formula (I) for the treatment of anxiety and hysteria or anxiety and depression.
Unless otherwise indicated in the tables of compounds herein, the abbreviation RAC or rac indicates a racemic mixture, and DIAST indicates a specific diastereomer. In illustrative embodiments, although a compound may be depicted with or
bonds, such a depiction may be denoting relative stereochemistry based on elution peaks from a chiral separation.
In some aspects, embodiments of the inventions disclosed herein include without limitation the following additional embodiments.
LC/MS spectra were obtained using Agilent 1200G1956A or SHIMADZU LC-MS-2020. Standard LC/MS conditions were as follows (running time 1.55 minutes):
Acidic condition: Mobile Phase A: 0.0375% TFA in water (v/v). Mobile Phase B: 0.01875% TFA in acetonitrile (v/v); Column: Kinetex EVO C18 30*2.1 mm, 5 μm.
Basic condition: Mobile Phase A: 0.025% NH3·H2O in water (v/v). Mobile Phase B: Acetonitrile; Column: Kinetex EVO C18 2.1×30 mm, 5 μm.
To a solution of 2-(3,4-dimethoxyphenyl)acetonitrile (20 g, 112 mmol) in DMF (93 mL) was added NaH (18.0 g, 451 mmol, 60% purity) in portions. The mixture was allowed to stir at 25° C. for 20 min. 1-Bromo-2-chloro-ethane (16.1 g, 112 mmol) was added, and the mixture was allowed to stir at 25° C. for 16 hr. The reaction was quenched by the addition of a MeOH/water mixture (1:1, 1000 mL) and the resulting solution was extracted with EtOAc (3×500 mL). The organic solutions were combined, washed with water (4×500 mL) and brine (1×200 mL) and dried over (Na2SO4). The solution was filtered and the solvent was evaporated under reduced pressure. The resulting solid was purified by column chromatography (SiO2, Petroleum ether/EtOAc=10/1 to 3/1) to give 1-(3,4-dimethoxyphenyl)cyclopropane-1-carbonitrile (15 g, 65%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.88 (s, 1H), 6.82 (d, J=1.2 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 1.68-1.65 (m, 2H), 1.35 (d, J=2.4 Hz, 2H).
To a solution of 1-(3,4-dimethoxyphenyl)cyclopropane-1-carbonitrile (11 g, 54.1 mmol) in THF (160 mL) was added DIBAL-H (1M in toluene, 81.2 mL). The mixture was allowed to stir at 25° C. for 3 hr and then the reaction was cautiously quenched by addition of aqueous 2M HCl. The solution was extracted with DCM (3×200 mL). The organic solutions were combined, washed with water (2×200 mL) and brine (2×200 mL), and then dried over Na2SO4 to give 1-(3,4-dimethoxyphenyl)cyclopropane-1-carbaldehyde (9.6 g, 85%) as yellow oil. LC-MS (ESI+) m/z 207.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 6.94-6.61 (m, 3H), 3.89 (d, J=2.8 Hz, 6H), 1.61-1.52 (m, 2H), 1.42-1.37 (m, 2H)
To a solution of 1-(3, 4-dimethoxyphenyl)-cyclopropanecarbaldehyde (5.0 g, 24.2 mmol) in DCM (50 mL) was added MeNH2 (2 M, 121 mL) and Na2SO4 (15.5 g, 109 mmol, 11.0 mL). The mixture was allowed to stir at 25° C. for 16 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give (Z)-1-(1-(3,4-dimethoxyphenyl)cyclopropyl)-N-methylmethanimine (5.1 g, 99%) as white solid. LC-MS (ESI+) m/z 219.9 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 7.55 (q, J=1.2 Hz, 1H), 6.93-6.77 (m, 3H), 3.88 (d, J=7.2 Hz, 6H), 3.24 (d, J=1.6 Hz, 3H), 1.29-1.23 (m, 2H), 1.18-1.12 (m, 2H).
To a solution of (Z)-1-(1-(3,4-dimethoxyphenyl)cyclopropyl)-N-methylmethanimine (5.4 g, 24.6 mmol) in DMF (19 mL) was added NaI (366 mg, 2.44 mmol) and TMSCl (267 mg, 2.46 mmol). The mixture was allowed to stir at 90° C. for 3 hr. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL×3). The organic solutions were combined, washed with water and brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 4-(3,4-dimethoxyphenyl)-1-methyl-2,3-dihydro-1H-pyrrole (6.25 g, 80%) as yellow oil. LC-MS (ESI+) m/z 220.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 6.90-6.66 (m, 3H), 6.31 (t, J=1.6 Hz, 1H), 3.95-3.80 (m, 6H), 3.18-3.11 (m, 2H), 2.79 (dt, J=1.2, 9.0 Hz, 2H), 2.65 (s, 3H).
4-(3,4-Dimethoxyphenyl)-1-methyl-2,3-dihydro-1H-pyrrole (6.25 g, 28.5 mmol) was dissolved in DCM (100 mL). To this solution was added HCl (1M in dioxane, 25 mL, 100 mmol). The mixture was evaporated to dryness and then dissolved in ACN (90 mL). To this solution was added (E)-4-methoxybut-3-en-2-one (4.28 g, 42.7 mmol). The reaction mixture was allowed to stir at 90° C. for 16 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (column: Phenomenex luna C18 (250*70 mm, 10 um); mobile phase: [water (NH4HCO3)-ACN]; B %: 22%-52%, 20 min). The eluant was acidified with aq. HCl to give rac-3a-(3,4-dimethoxyphenyl)-1-methyl-1,2,3,3a,7,7a-hexahydro-6H-indol-6-one (3.0 g, 30%) as a white solid. LC-MS (ESI+) m/z 288.3 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 6.90-6.88 (m, 1H), 6.87-6.83 (m, 2H), 6.74 (dd, J=2.0, 10.1 Hz, 1H), 6.11 (d, J=10.0 Hz, 1H), 3.89 (d, J=4.0 Hz, 6H), 3.33 (dt, J=2.4, 8.8 Hz, 1H), 2.69-2.66 (m, 1H), 2.58-2.51 (m, 2H), 2.50-2.41 (m, 2H), 2.33 (s, 3H), 2.27-2.18 (m, 1H).
A mixture of rac-3a-(3,4-dimethoxyphenyl)-1-methyl-1,2,3,3a,7,7a-hexahydro-6H-indol-6-one (12.0 g, 43.9 mmol) and 10% Pd/C (300 mg) in EtOAc (120 mL) was degassed and then purged with H2 for 3 times. The mixture was allowed to stir at 25° C. for 2 hr under 15 psi H2. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give rac-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-6H-indol-6-one (10 g, 80%) as brown oil. LC-MS (ESI+) m/z 290.4 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 6.99-6.89 (m, 2H), 6.89-6.84 (m, 1H), 3.91 (d, J=7.6 Hz, 6H), 3.20-3.11 (m, 1H), 2.97 (t, J=3.6 Hz, 1H), 2.69-2.56 (m, 2H), 2.51-2.31 (m, 5H), 2.27-2.18 (m, 3H), 2.18-2.07 (m, 2H).
Compound 022 (15 g, 90% purity) was subjected to separation by SFC (column: DAICEL CHIRALCEL OD (250 mm*50 mm, 10 um); mobile phase: [Neu-MeOH]; B %: 25%-25%, 2; 1230 min) to give 001 (peak 1, 5.4 g, free base, 36%) as yellow oil and 002 (peak 2, 5.6 g, free base, 37%) as yellow oil.
001: LC-MS (ESI+) m/z 290.4 (M+H)+ 1H NMR (400 MHz, CDCl3) δ 6.99-6.89 (m, 2H), 6.89-6.84 (m, 1H), 3.91 (d, J=7.6 Hz, 6H), 3.20-3.11 (m, 1H), 2.97 (t, J=3.6 Hz, 1H), 2.69-2.56 (m, 2H), 2.51-2.31 (m, 5H), 2.27-2.18 (m, 3H), 2.18-2.07 (m, 2H).
002: LC-MS (ESI+) m/z 290.4 (M+H)+ 1H NMR (400 MHz, CDCl3) δ 6.99-6.89 (m, 2H), 6.89-6.84 (m, 1H), 3.91 (d, J=7.6 Hz, 6H), 3.20-3.11 (m, 1H), 2.97 (t, J=3.6 Hz, 1H), 2.69-2.56 (m, 2H), 2.51-2.31 (m, 5H), 2.27-2.18 (m, 3H), 2.18-2.07 (m, 2H).
A mixture of 001 (200 mg, 691 umol) and PtO2 (20.0 mg, 88.0 umol) in IPA (4 mL) was degassed and purged with N2 3 times. The mixture was allowed to stir at 25° C. for 16 hr under an atmosphere of N2. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by re-crystallization from EtOH (1 mL) at 25° C. to give (3aS,6R,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol (018) (100 mg, 49%) as a white solid. LC-MS (ESI+) m/z 292.4 (M+H). 1H NMR (400 MHz, CDCl3) δ 6.86-6.78 (m, 2H), 6.77-6.71 (m, 1H), 3.86 (s, 1H), 3.81 (d, J=6.8 Hz, 6H), 3.30 (dt, J=6.8, 9.6 Hz, 1H), 2.83 (s, 1H), 2.40 (s, 3H), 2.33-2.20 (m, 1H), 2.09 (dd, J=2.8, 14.8 Hz, 1H), 1.90-1.82 (m, 2H), 1.78 (dd, J=6.8, 11.6 Hz, 1H), 1.67-1.62 (m, 2H), 1.57 (td, J=2.8, 14.8 Hz, 1H), 1.39-1.30 (m, 2H).
To a solution of 001 (2.00 g, 6.91 mmol) and CeCl3·7H2O (3.09 g, 8.29 mmol, 788 uL) in MeOH (80 mL) was added NaBH4 (1.57 g, 41.4 mmol). The mixture was allowed to stir at 0° C. for 2 hr. The reaction mixture was added into 50 mL NH4Cl aqueous solution, the organic and aqueous layers were separated, and the aqueous solution was extracted with DCM (50 mL×3). The organic solutions were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (NH3H2O)-ACN]; B %: 28%-58%, 8 min) to give (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol (019, (−)-6-epimesembranol) (730 mg, 37%) as white oil. 1H NMR (400 MHz, CDCl3) δ 6.95-6.88 (m, 2H), 6.86-6.80 (m, 1H), 3.95 (s, 1H), 3.90 (d, J=6.8 Hz, 6H), 3.46-3.35 (m, 1H), 2.93 (s, 1H), 2.50 (s, 3H), 2.45-2.29 (m, 2H), 2.19 (dd, J=2.4, 14.9 Hz, 1H), 2.01-1.82 (m, 2H), 1.79-1.72 (m, 1H), 1.70-1.59 (m, 3H), 1.44 (tt, J=2.8, 13.6 Hz, 1H).
To a solution of 018 (200 mg, 686 umol), 3-(trifluoromethyl)-1H-pyrazole (140 mg, 1.03 mmol), and PPh3 (270 mg, 1.03 mmol) in THF (3 mL) was added DIAD (208 mg, 1.03 mmol, 200 uL). The reaction mixture was allowed to stir at 25° C. for 10 hr and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (NH3H2O)-ACN]; B %: 42%-72%, 8 min) to give 101 (30 mg) as colorless oil. LC-MS (ESI+) m/z 410.7 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 6.98-6.92 (m, 1H), 6.91 (s, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.46 (d, J=1.6 Hz, 1H), 4.70-4.57 (m, 1H), 3.90 (d, J=4.0 Hz, 6H), 3.36-3.24 (m, 1H), 2.88 (s, 1H), 2.39 (s, 4H), 2.33 (d, J=18.0 Hz, 1H), 2.28-2.16 (m, 2H), 2.15-2.05 (m, 1H), 1.99-1.92 (m, 2H), 1.91-1.81 (m, 1H), 1.79-1.68 (m, 1H).
To a solution of 001 and tert-butyl hydrazinecarboxylate (200 mg, 1.52 mmol) in DCM (3.5 mL) was added NaBH3CN (130 mg, 2.07 mmol) and AcOH (320 mg, 5.33 mmol, 304 uL). The reaction mixture was allowed to stir at 0° C. for 3 hr and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (NH3H2O)-ACN]; B %: 30%-60%, 8 min) to give the title compound (300 mg, 54%) as yellow solid. LC-MS (ESI+) m/z 406.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 6.86-6.80 (m, 2H), 6.76-6.71 (m, 1H), 3.80 (d, J=7.2 Hz, 6H), 3.18-3.08 (m, 1H), 2.89 (s, 1H), 2.64 (s, 1H), 2.31 (s, 3H), 2.27-2.14 (m, 2H), 1.94-1.86 (m, 2H), 1.85-1.77 (m, 4H), 1.61-1.52 (m, 2H), 1.39 (s, 9H), 1.32-1.23 (m, 1H).
To a solution of tert-butyl 2-((3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl)hydrazine-1-carboxylate_(140 mg, 345 umol) in DCM (1 mL) was added HCl (4M in dioxane, 86.3 uL). The reaction mixture was allowed to stir at 25° C. for 30 min and was then concentrated in vacuo to give the title compound (140 mg, 90%) as yellow solid which was used in the next step without purification. LC-MS (ESI+) m/z 306.1 (M+H)+.
To a solution of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-6-hydrazineyl-1-methyloctahydro-1H-indole hydrochloride (100 mg, 292 umol) in EtOH (3 mL) was added 1,1,3,3-tetramethoxypropane (52.8 mg, 321 umol, 53.2 uL). The reaction mixture was allowed to stir at 85° C. for 1 hr and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (HCl)-ACN]; B %: 10%-40%, 10 min) to give 102 (47.4 mg, 47%) as yellow gum. LC-MS (ESI+) m/z 341.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.76-7.62 (m, 1H), 7.53 (s, 1H), 7.05-6.92 (m, 2H), 6.85 (d, J=8.4 Hz, 1H), 6.27 (s, 1H), 4.44-4.28 (m, 1H), 3.97-3.83 (m, 6H), 3.28-3.02 (m, 1H), 2.98-2.82 (m, 1H), 2.74-2.54 (m, 1H), 2.44-2.26 (m, 3H), 2.25-2.19 (m, 1H), 2.15-2.06 (m, 2H), 2.04-1.92 (m, 3H), 1.38-1.21 (m, 2H).
To a solution of 001 (200 mg, 691 umol), tert-butyl N-aminocarbamate (100 mg, 760 umol), and AcOH (160 mg, 2.66 mmol, 152 uL) in DCM (3 mL) was added NaBH4 (52.3 mg, 1.38 mmol). The reaction mixture was allowed to stir at 0° C. for 3 hr. The reaction was quenched by pouring the mixture into a cold saturated aqueous NH4Cl solution (3 mL). The aqueous solution was extracted with ethyl acetate (5 mL×2). The organic solutions was combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (HCl)-ACN]; B %: 11%-41%, 10 min) to give the title compound (160 mg, 14%) as yellow solid. LC-MS (ESI+) m/z 406.4 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.00-6.86 (m, 3H), 4.14 (s, 1H), 3.83-3.70 (m, 6H), 3.65-3.42 (m, 4H), 3.17 (tt, J=5.2, 11.2 Hz, 2H), 2.88 (dd, J=4.4, 8.4 Hz, 3H), 2.44-2.30 (m, 1H), 2.23 (d, J=14.0 Hz, 1H), 2.17-1.97 (m, 4H), 1.89-1.71 (m, 2H), 1.62-1.37 (m, 9H), 1.10 (s, 1H).
To a solution of tert-butyl 2-((3aS,6R,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl)hydrazine-1-carboxylate (80.0 mg, 197 umol) in DCM (2 mL) was added HCl (4M in Dioxane, 0.7 mL) in one portion at 25° C. under an atmosphere of N2. The reaction mixture was allowed to stir at 25° C. for 30 min and then concentrated to give the title compound (60 mg crude, 90%) as yellow solid. LC-MS (ESI+) m/z 306.1 (M+H)+.
A solution of [(3aS,6R)-3a-(3,4-dimethoxyphenyl)-1-methyl-3,4,5,6,7,7a-hexahydro-2H-indol-6-yl]hydrazine (80 mg, 261 umol) and 1,1,3,3-tetramethoxypropane (43.0 mg, 261 umol, 43.36 uL) in EtOH (3 mL) was allowed to stir at 85° C. for 1 hr and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (HCl)-ACN]; B %: 7%-37%, 10 min) to give 103 (43.1 mg, 44%) as yellow solid. LC-MS (ESI+) m/z 342.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.06-10.92 (m, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.40 (d, J=1.2 Hz, 1H), 7.03 (d, J=1.6 Hz, 1H), 7.01-6.94 (m, 2H), 6.20 (t, J=2.0 Hz, 1H), 5.23-5.03 (m, 1H), 4.15 (d, J=8.8 Hz, 2H), 3.78 (d, J=13.2 Hz, 6H), 3.31-3.17 (m, 1H), 2.97 (d, J=4.8 Hz, 3H), 2.40-2.39 (m, 1H), 2.32 (dd, J=1.6, 3.6 Hz, 1H), 2.30-2.24 (m, 1H), 2.24-2.20 (m, 1H), 2.17-2.14 (m, 2H), 2.13-2.06 (m, 1H), 1.63-1.50 (m, 1H).
To a mixture of 001 (218 mg, 753 umol) and azetidine (215 mg, 3.77 mmol) in MeOH (5 mL) was added NaBH(OAc)3 (479 mg, 2.26 mmol). The reaction mixture was allowed to stir at 25° C. for 16 hr and then concentrated in vacuo. The residue was purified by prep-HPLC (neutral condition: column: column: Waters xbridge 150*25 mm 10 um; mobile phase: [water (NH4HCO3)-ACN]; B %: 5%-35%, 11 min) to give 104 (57.6 mg, 28%) as a yellow gum. LC-MS (ESI+) m/z 331.2 (M+H)+ 1H NMR (400 MHz, CDCl3) δ=6.98-6.92 (m, 2H), 6.81 (d, J=8.8 Hz, 1H), 3.88 (d, J=12.4 Hz, 6H), 3.23-3.13 (m, 4H), 2.97 (dd, J=5.8, 8.8 Hz, 1H), 2.81 (d, J=2.5 Hz, 1H), 2.58 (d, J=8.8 Hz, 1H), 2.33 (s, 3H), 2.17-1.91 (m, 6H), 1.81 (s, 1H), 1.75-1.68 (m, 1H), 1.65-1.50 (m, 1H), 1.31-1.19 (m, 2H).
A mixture of 001 (200 mg, 691 umol), pyrrolidine (58.9 mg, 829 umol, 69.2 uL), and Pd/C (50.0 mg, 691 umol, 10% purity) in MeOH (2.5 mL) was degassed with nitrogen and purged with H2 3 times. The mixture was allowed to stir at 25° C. for 16 hr under an atmosphere of H2. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters xbridge 150*25 mm 10 um; mobile phase: [water (NH4HCO3)-ACN]; B %: 13%-43%, 11 min) to give (3aS,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyl-6-(pyrrolidin-1-yl)octahydro-1H-indole (100 mg) as a white oil. LC-MS (ESI+) m/z 345.1 (M+H)+
(3aS,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyl-6-(pyrrolidin-1-yl)octahydro-1H-indole (100 mg) was purified by SFC (column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H2O MeOH]; B %: 50%-50%, 2.5; 25 min) to give 105 (65.9 mg) as a yellow oil. LC-MS (ESI+) m/z 345.1 (M+H)+ 1H NMR (400 MHz, CDCl3) δ 6.97-6.86 (m, 2H), 6.80 (d, J=8.4 Hz, 1H), 3.89 (d, J=11.2 Hz, 6H), 3.26 (dt, J=4.4, 9.2 Hz, 1H), 2.71 (s, 1H), 2.60 (s, 4H), 2.51-2.40 (m, 1H), 2.37 (s, 3H), 2.34-2.28 (m, 1H), 2.23-2.15 (m, 1H), 2.10-2.01 (m, 2H), 1.98-1.89 (m, 1H), 1.89-1.81 (m, 2H), 1.81-1.74 (m, 4H), 1.65-1.62 (m, 1H), 1.30-1.21 (m, 1H).
To a solution of 001 (200 mg, 691 umol) in DCM (10 mL) was added pyrrolidine (49.1 mg, 691 umol) and NaBH(OAc)3 (219 mg, 1.04 mmol). The reaction mixture was allowed to stir at 25° C. for 16 hr. The reaction was quenched by pouring the mixture into a cold saturated aqueous sodium bicarbonate solution until pH=8 was achieved. The aqueous solution was extracted with DCM (30 mL). The organic solution was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The aqueous solution was lyophilized. The crude product was purified by reversed-phase PLC (neutral condition) to give 106 (50.7 mg) as a white solid. LC-MS (ESI+) m/z 345.3 (M+H)+ 1H NMR (400 MHz, CDCl3) δ 7.03-6.95 (m, 2H), 6.83 (d, J=8.4 Hz, 1H), 3.90 (d, J=13.6 Hz, 6H), 3.14 (dd, J=5.6, 10.4 Hz, 1H), 2.80-2.67 (m, 2H), 2.61 (s, 4H), 2.37 (s, 3H), 2.22-2.02 (m, 4H), 1.94 (s, 1H), 1.81 (t, J=3.2 Hz, 6H), 1.58-1.48 (m, 1H), 1.46-1.33 (m, 1H).
To a solution of 001 (200 mg, 691 umol) and piperidine (588 mg, 6.91 mmol, 682 uL) in toluene (3.0 mL) was added NaBH(OAc)3 (439 mg, 2.07 mmol). The reaction mixture was allowed to stir at 110° C. for 12 hr and then poured into water (50 mL) and extracted with ethyl acetate (30 mL). The organic solutions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (HCl)-ACN]; B %: 0%-25%, 10 min) to give 107 (160 mg, 65%) as a yellow solid. LC-MS (ESI+) m/z 359.2 (M+H). 1H NMR (400 MHz, CDCl3) δ 12.67-12.29 (m, 1H), 12.02-11.44 (m, 1H), 7.02-6.85 (m, 3H), 4.36-4.11 (m, 1H), 4.05-3.90 (m, 6H), 3.91-3.90 (m, 1H), 3.90-3.86 (m, 1H), 3.53-3.44 (m, 2H), 3.39-3.24 (m, 1H), 3.10-2.99 (m, 2H), 2.95-2.83 (m, 2H), 2.79 (s, 3H), 2.56-2.38 (m, 3H), 2.35-2.23 (m, 2H), 2.21-2.08 (m, 1H), 2.04-1.88 (m, 4H), 1.49-1.35 (m, 1H), 1.28 (s, 1H).
To a solution of 001 (200 mg, 691 umol) and morpholine (602.14 mg, 6.91 mmol) in MeOH (5 mL) was added Pd/C (20 mg, 34.56 umol, 3.46 uL, 10% purity). The reaction mixture was allowed to stir at 25° C. for 5 hr under 15 psi of H2. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (neutral condition column: Phenomenex C18 150*25 mm*10 um; mobile phase: [water (NH4HCO3)-ACN]; B %: 9%-39%, 5 min) to give 108 (40 mg) as a yellow oil. LC-MS (ESI+) m/z 361.4 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 6.95-6.77 (m, 3H), 3.89 (d, J=7.2 Hz, 6H), 3.69 (t, J=4.4 Hz, 4H), 3.30-3.20 (m, 1H), 2.79-2.64 (m, 2H), 2.52 (d, J=4.0 Hz, 4H), 2.36 (s, 4H), 2.13-2.00 (m, 3H), 1.96-1.72 (m, 3H), 1.32-1.02 (in, 2H).
A solution of 001 (100 mg, 345 umol) and morpholine (301 mg, 3.46 mmol, 304.11 uL) in toluene (5.0 mL) was allowed to stir at 120° C. for 2 hr and then cooled to 25° C. To this solution was added NaBH(OAc)3 (219 mg, 1.04 mmol). The reaction mixture was allowed to stir at 25° C. for 12 hr under an atmosphere of N2. The reaction was quenched by the addition of 2M sodium hydroxide aqueous solution (20 mL) and the mixture was extracted with ethyl acetate (15 mL×3). The organic solutions were separated, combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (basic condition column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (NH3H2O)-ACN]; B %: 24%-54%, 8 min) to give the title compound (220 mg) as a yellow oil. LC-MS (ESI+) m/z 361.4 (M+H)+.
4-((3aS,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl)morpholine (125 mg, 346 umol) was subjected to SFC purification (Column: Chiralcel OD-3 50×4.6 mm I.D., 3 um Mobile phase: Phase A for C02, and Phase B for MeOH (0.05% DEA); Gradient elution: MeOH (0.05% DEA) in C02 from 5% to 40% Flow rate: 3 mL/min; Detector: PDA; Column Temp: 35 C; Back Pressure: 100 Bar) to give 109 (75 mg) as a yellow oil. LC-MS (ESI+) m/z 361.4 (M+H)+ 1H NMR (400 MHz, CDCl3) δ 6.92 (s, 3H), 3.89 (d, J=12.8 Hz, 6H), 3.77-3.70 (m, 4H), 3.46-3.26 (m, 1H), 3.25-2.95 (m, 1H), 2.91-2.73 (m, 1H), 2.62-2.54 (m, 4H), 2.48 (s, 3H), 2.39-2.33 (m, 1H), 2.23-2.18 (m, 2H), 2.00-1.83 (m, 3H), 1.73-1.65 (m, 1H), 1.59-1.45 (m, 2H).
To a solution of 001 (100 mg, 345 umol) in MeOH (15 mL) was added ammonia:formic acid (217 mg, 3.46 mmol) and sodium cyanoborohydride (65.1 mg, 1.04 mmol). The reaction mixture was allowed to stir at 25° C. for 16 hr and then concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (10 mL*3). The organic solutions were combined washed with brine (10 mL*2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (75.0 mg, 75%) as a yellow oil. LC-MS (ESI+) m/z 291.2 (M+H)+
To a solution of (3aS,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-amine (140 mg, 482 umol) in DCM (6 mL) was added Na2SO4 (273 mg, 1.93 mmol, 195 uL), NaOH (57.8 mg, 1.45 mmol) and 4-chlorobutanoyl chloride (101 mg, 723 umol, 80.9 uL). The reaction mixture was allowed to stir at 25° C. for 3 hr and then filtered. The filtrate was concentrated in vacuo to give the title compound (180 mg, 95%) as a yellow oil. LC-MS (ESI+) m/z 395.5 (M+H)+
A solution of 4-chloro-N-((3aS,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl)butanamide_(180 mg, 455 umol) in DMF (5.0 mL) was allowed to stir at 25° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (HCl)-ACN]; B %: 1%-31%, 10 min) to give 112 (60 mg, 37%) as a yellow oil.
1-((3aS,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl)pyrrolidin-2-one was subjected to SFC purification (“Column: Chiralpak IG-3 50×4.6 mm I.D., 3 um Mobile phase: Phase A for CO2, and Phase B for MeOH (0.05% DEA); Gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40% Flow rate: 3 mL/min; Detector: PDA; Column Temp: 35 C; Back Pressure: 100 Bar”) to give 110 (14.2 mg, 8.7%) and 111 (43.1 mg, 26%) each as a yellow oil.
111: LC-MS (ESI+) m/z 359.23 (M+H)+; 1H NMR (400 MHz, CDCl3) δ=7.01-6.84 (m, 3H), 4.24-4.07 (m, 2H), 3.93 (d, J=15.4 Hz, 6H), 3.52 (d, J=5.6 Hz, 1H), 3.37 (br d, J=5.6 Hz, 1H), 2.93-2.75 (m, 1H), 2.67-2.36 (m, 9H), 2.20-1.88 (m, 5H), 1.75-1.61 (m, 4H).
To a solution of 4-(3,4-dimethoxyphenyl)-1-methyl-2,3-dihydro-1H-pyrrole (500 mg, 2.28 mmol) in DCM (10 mL) was added HCl in dioxane (2.85 mL of a 4.0M solution, 11.4 mmol). The mixture was evaporated to dryness and redissolved in ACN (10 mL). To this solution was added 4-phenylbut-3-yn-2-one (490 mg, 3.40 mmol). The reaction mixture was allowed to stir at reflux for 16 hr and then the solvent was removed under reduced pressure. The resulting dark oil was partitioned between 3M HCl solution (20 mL) and EtOAc (30 mL). The aqueous solution was separated and washed with EtOAc (2×300 mL). The remaining aqueous solution was brought to basic pH using 3M NaOH solution and further extracted into ethyl acetate (4×30 mL). The organic solutions were combined and washed with brine (1×30 mL). The organic solution was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by pre-HPLC (column: Phenomenex C18 250*50 mm*10 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 30%-60%, 8 min) to give 201 (90.0 mg) as a yellow solid. LC-MS (ESI+) m/z 364.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ=7.82 (s, 1H), 7.13-6.98 (m, 5H), 6.74-6.60 (m, 2H), 6.36 (s, 1H), 3.89 (d, J=7.6 Hz, 2H), 3.83 (d, J=0.4 Hz, 3H), 3.52-3.45 (m, 5H), 3.17 (s, 3H), 2.90-2.84 (m, 2H).
To a solution of 4-(3,4-dimethoxyphenyl)-1-methyl-2,3-dihydropyrrole (1.00 g, 4.56 mmol) in DCM (9 mL) was HCl (4M in dioxane, 4.0 mL) at 25° C. over 10 min. After addition was complete, the mixture was filtered and concentrated in vacuo. To the residue was added cyclohex-2-en-1-one (2.19 g, 22.8 mmol, 2.21 mL) in ACN (7 mL). The reaction mixture was allowed to stir at 90° C. for 16 hr and then quenched by pouring into a cold saturated aqueous sodium hydroxide solution (30 mL) until pH=8 was achieved. The solution was extracted with ethyl acetate (60 mL). The organic solution was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (neutral condition) to give 202 (230 mg, 15%) as a yellow oil. LC-MS (ESI+) m/z 316.1 (M+H)+
SFC separation of 202 (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 um); mobile phase: [Neu-IPA]; B %: 30%-30%, 7.4; 59 min) gave 203 (89.9 mg, 29%) as a yellow gum and 204 (100 mg, 310 umol, 83% purity). 204 was further purified by prep-HPLC (column: Waters xbridge 150*25 mm 10 um; mobile phase: [water (NH4HCO3)-ACN]; B %: 24%-54%, 11 min) to give 204 (71.4 mg, 34%) as a yellow gum.
203: LC-MS (ESI+) m/z 316.2 (M+H)+; 1H NMR (400 MHz, CDCL3) δ 7.05-6.93 (m, 2H), 6.84 (d, J=8.4 Hz, 1H), 3.92 (d, J=5.2 Hz, 6H), 3.14 (d, J=4.4 Hz, 1H), 2.90-2.80 (m, 2H), 2.74-2.68 (m, 1H), 2.51 (s, 1H), 2.40 (s, 3H), 2.39-2.32 (m, 1H), 2.25-2.18 (m, 1H), 2.18-2.10 (m, 1H), 1.92 (dd, J=5.6, 12.4 Hz, 1H), 1.75-1.68 (m, 1H), 1.61-1.53 (m, 1H), 1.38-1.27 (m, 2H).
204: LC-MS (ESI+) m/z 316.2 (M+H)+; 1H NMR (400 MHz, CDCL3) δ 7.04-6.92 (m, 2H), 6.84 (d, J=8.4 Hz, 1H), 3.92 (d, J=5.6 Hz, 6H), 3.14 (d, J=4.0 Hz, 1H), 2.90-2.81 (m, 2H), 2.74-2.68 (m, 1H), 2.51 (s, 1H), 2.41 (s, 3H), 2.39-2.32 (m, 1H), 2.25-2.18 (m, 1H), 2.18-2.09 (m, 1H), 1.93 (dd, J=5.6, 12.0 Hz, 1H), 1.76-1.66 (m, 1H), 1.59-1.52 (m, 1H), 1.37-1.27 (m, 2H).
To a solution of 4-(3,4-dimethoxyphenyl)-1-methyl-2,3-dihydro-1H-pyrrole (2.00 g, 9.12 mmol) in ACN (30 mL) was added HCl/dioxane (4M, 10.0 mL). After addition, the reaction mixture was filtered and concentrated in vacuo. To the residue was 4-phenylbut-3-en-2-one (4.00 g, 27.3 mmol) in DCM (40 mL). The reaction mixture was allowed to stir at 90° C. for 16 hr and then concentrated. The residue was purified by prep-HPLC (column: Phenomenex C18 150*25 mm*10 um; mobile phase: [water (NH4HCO3)-ACN]; B %: 34%-64%, 5 min), SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 um); mobile phase: [Neu-IPA]; B %: 30%-30%, 9.7; 136 min) to give racemic 205 (1.70 g, 50%) as a yellow solid. LC-MS (ESI+) m/z 366.4 (M+H)+.
205 (500 mg) was subjected to purification by SFC (column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H2O MeOH]; B %: 50%-50%, 2.5; 25 min) to give 206 (189 mg, 37%) and 207 (196 mg, 39%) each as a single enantiomer with unknown absolute configuration and as a white solid.
206: LC-MS (ESI+) m/z 366.4 (M+H)+ 1H NMR (CDCl3): δ 7.00-7.14 (3H, m), 6.41-6.76 (5H, m), 3.83 (3H, s), 3.65 (3H, s), 3.32-3.46 (1H, m), 2.83-3.13 (4H, m), 2.72-2.81 (1H, m), 2.34-2.48 (1H, m), 2.21 (3H, s), 2.02-2.18 (2H, m), 1.94 (1H, s), 1.79-1.87 (1H, m).
207: LC-MS (ESI+) m/z 366.4 (M+H)+ 1H NMR (CDCl3): δ 7.10-7.23 (3H, m), 6.43-6.88 (5H, m), 3.92 (3H, s), 3.75 (3H, s), 3.40-3.53 (1H, m), 3.01-3.36 (4H, m), 2.94 (1H, s), 2.48-2.58 (1H, m), 2.36 (3H, s), 2.17-2.34 (2H, m), 1.99 (1H, d, J=3.2 Hz).
To a solution of 019 (146 mg, 501 umol) and 4-methylbenzenesulfonyl chloride (143 mg, 751 umol) in DCM (4 mL) was added DMAP (122 mg, 1.00 mmol) and TEA (101 mg, 1.00 mmol, 139 uL). The reaction mixture was allowed to stir at 20° C. for 2 hr and then concentrated in vacuo. The residue was purified by reverse phase flash chromatography [ACN/(0.1% TFA in water), 0% to 90%] to give the title compound as the TFA salt (240 mg, 46%) as yellow solid. LC-MS (ESI+) m/z 446.5 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ=9.10-8.69 (m, 1H), 7.88-7.81 (m, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.15-7.01 (m, 1H), 6.99-6.85 (m, 2H), 5.05-4.72 (m, 1H), 4.25-4.01 (m, 1H), 3.82-3.71 (m, 6H), 3.35-3.24 (m, 1H), 3.23-3.01 (m, 1H), 2.74 (d, J=4.8 Hz, 2H), 2.58 (d, J=4.8 Hz, 1H), 2.43 (s, 3H), 2.31-2.09 (m, 3H), 2.07-1.79 (m, 2H), 1.77-1.27 (m, 2H).
To a solution of (3aS,6S,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl 4-methylbenzenesulfonate (240 mg, 428 umol, TFA salt) in DMF (4 mL) was added NaH (34.3 mg, 857 umol, 60% purity) and 3-(trifluoromethyl)-1H-pyrazole (87.5 mg, 643 umol). The reaction mixture was allowed to stir at 0-80° C. for 2 hr. The reaction mixture was quenched by pouring into cold H2O (3 mL). The mixture was extracted with ethyl acetate (5 mL×2). The organic solutions were separated, combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (HCl)-ACN]; B %: 21%-51%, 10 min) to give 115 (11.5 mg, 6%) as off-white solid. LC-MS (ESI+) m/z 410.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 12.97-12.53 (m, 1H), 7.48 (s, 1H), 6.98-6.85 (m, 3H), 6.58 (s, 1H), 5.49 (td, J=5.2, 10.0 Hz, 1H), 4.32-4.21 (m, 1H), 3.92 (d, J=12.4 Hz, 6H), 3.01-2.81 (m, 5H), 2.62-2.54 (m, 1H), 2.51 (dd, J=4.0, 7.2 Hz, 1H), 2.48-2.37 (m, 1H), 2.37-2.29 (m, 1H), 2.23 (d, J=14.4 Hz, 1H), 2.09-1.98 (m, 1H), 1.97-1.83 (m, 1H).
To a solution of 016 (500 mg, 1.74 mmol) in MeOH (2 mL) was added NaOH (0.5 M, 696 uL) and H2O2 (986 mg, 8.70 mmol, 835 μL, 30% purity). The reaction mixture was allowed to stir at 0° C. for 2 hr. The reaction mixture was poured into sodium sulfite solution (50 mL) and wet starch potassium iodide paper was used to test negative (pH<8). The mixture was then poured to the water (30 mL) and extracted with DCM (50 mL). The organic solution was separate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (NH3H2O)-ACN]; B %: 12%-42%, 8 min) to give 208 (170 mg, 31.8%) as a yellow solid. LC-MS (ESI+) m/z 304.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 6.90-6.77 (m, 2H), 6.71 (s, 1H), 3.87 (s, 6H), 3.56 (d, J=4.0 Hz, 1H), 3.45 (d, J=4.4 Hz, 1H), 3.31-3.22 (m, 1H), 2.99-2.92 (m, 2H), 2.75-2.61 (m, 1H), 2.59-2.44 (m, 3H), 2.30 (s, 3H).
To a solution of 001 (500 mg, 1.73 mmol) in THF (8 mL) was added allyl(bromo)magnesium (1M, 17.28 mL) at −20° C. The reaction mixture was allowed to stir at 25° C. for 16 hr and then quenched with saturated ammonium chloride aqueous solution (50 mL). The mixture was extracted with ethyl acetate (30 mL×3). The organic solutions were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=3:1 to 0:1) to give the title compound (396 mg, 69%) as yellow oil. LC-MS (ESI+) m/z 332 (M+H)+ 1H NMR (400 MHz, CDCl3) δ 6.84 (br s, 3H), 5.92-5.80 (m, 1H), 5.25-4.82 (m, 3H), 3.89 (d, J=5.0 Hz, 6H), 3.73-3.56 (m, 1H), 3.48-3.32 (m, 1H), 3.11-2.98 (m, 1H), 2.05 (s, 10H), 1.62 (s, 6H), 1.36-1.15 (m, 2H).
To a solution of (3aS,7aS)-6-allyl-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol (322 mg, 971 umol) in THF (6 mL) was added BH3·THF (2M, 971 uL) at 0° C. The reaction mixture was allowed to warm and stir at 25° C. for 2 hr. The reaction mixture was cooled to 0° C. and NaOH (10M, 679.15 uL) and H2O2 (2.30 g, 22.3 mmol, 1.95 mL, 33% purity) were added at 0° C. The reaction mixture was allowed to stir at 25° C. for 1.5 hr and then quenched by the addition of sodium sulfite solution (15 mL). The mixture was extracted with ethyl acetate (10 mL×3). The organic solutions were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1:1 to 0:1) to give the title compound (225 mg, 495 umol, 51%) as yellow oil. LC-MS (ESI+) m/z 350 (M+H)+ 1H NMR (400 MHz, CDCl3) δ=6.84 (br d, J=11.2 Hz, 3H), 3.89 (d, J=7.2 Hz, 6H), 3.73-3.59 (m, 2H), 3.43-3.42 (m, 1H), 3.13-2.91 (m, 1H), 2.52-2.21 (m, 4H), 2.05 (s, 2H), 1.99-1.83 (m, 2H), 1.71-1.56 (m, 8H), 1.27 (t, J=7.6 Hz, 2H).
To a solution of (3aS,7aS)-3a-(3,4-dimethoxyphenyl)-6-(3-hydroxypropyl)-1-methyloctahydro-1H-indol-6-ol (225 mg, 643 umol) in DCM (3 mL) was added 4-methylbenzenesulfonyl chloride (368 mg, 1.93 mmol), TEA (195. mg, 1.93 mmol, 268 uL) and DMAP (78.6 mg, 643 umol). The reaction mixture was allowed to stir at 45° C. for 16 hr and then concentrated. The residue was purified by prep-HPLC (column: Welch Ultimate C18 150*25 mm*5 um; mobile phase: [water (TFA)-ACN]; B %: 15%-45%, 2 min) and then further purified by reversed-phase HPLC (column: Phenomenex C18 250*50 mm*10 um; mobile phase: [water (NH4HCO3)-ACN]; B %: 12%-42%, 8 min) to give 117 (14.8 mg, 95%) as yellow oil. LC-MS (ESI+) m/z 332.3 (M+H)+ 1H NMR (400 MHz, CDCl3) δ=7.02-6.77 (m, 3H), 3.96-3.84 (m, 8H), 2.92-2.55 (m, 3H), 2.33-2.21 (m, 1H), 2.13-1.96 (m, 4H), 1.93-1.85 (m, 2H), 1.82-1.71 (m, 2H), 1.65 (br t, J=7.6 Hz, 4H), 1.26 (br s, 2H).
Compound 116 was subjected to SFC separation (column: DAICEL CHIRALPAK IE (250 mm*30 mm, 10 um); mobile phase: [Neu-ETOH]; B %: 20%-20%, C20; 80 min) to give 2 compounds, peak 1 and peak 2. Peak1 was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (NH3H2O)-ACN]; B %: 15%-45%, 8 min) to give 209 (12 mg, 23%) as a yellow solid. Peak2 was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (NH3H2O)-ACN]; B %: 15%-45%, 8 min) to give 210 (20 mg, 39%) as a yellow solid.
209: LC-MS (ESI+) m/z 304.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 6.88-6.80 (m, 2H), 6.73 (s, 1H), 3.89 (s, 6H), 3.58 (d, J=4.0 Hz, 1H), 3.48 (d, J=4.0 Hz, 1H), 3.37-3.25 (m, 1H), 2.96 (br t, J=12.4 Hz, 2H), 2.78-2.65 (m, 1H), 2.63-2.49 (m, 3H), 2.35 (br s, 3H).
210: LC-MS (ESI+) m/z 304.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 6.89-6.80 (m, 2H), 6.73 (br s, 1H), 3.97-3.83 (m, 6H), 3.59 (br d, J=3.0 Hz, 1H), 3.48 (d, J=4.0 Hz, 1H), 3.41-3.27 (m, 1H), 3.07-2.82 (m, 2H), 2.79-2.65 (m, 1H), 2.63-2.51 (m, 3H), 2.36 (br s, 2H).
To a solution of 001 (500 mg, 1.73 mmol) in MeOH (3 mL) was added NaBH3CN (325 mg, 5.18 mmol) and ammonia:formic acid (544 mg, 8.64 mmol). The reaction mixture was allowed to stir at 25° C. for 4 hr and then poured into water (30 mL). The solution was extracted with ethyl acetate (30 mL). The organic solutions were combined, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (500 mg, 65%) as a yellow oil. LC-MS (ESI+) m/z 291.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 6.89-6.62 (m, 3H), 3.84-3.77 (m, 6H), 3.23-3.11 (m, 1H), 2.72 (br s, 1H), 2.39-2.31 (m, 2H), 2.29-2.21 (m, 3H), 2.13-2.04 (m, 2H), 2.01-1.96 (m, 2H), 1.92 (br s, 2H), 1.83-1.75 (m, 2H), 1.72-1.65 (m, 1H), 1.62-1.36 (m, 1H)
To a solution of (3aS,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-amine (400 mg, 1.38 mmol) in DCM (4 mL) was added Na2SO4 (782 mg, 5.51 mmol, 559 uL), NaOH (165 mg, 4.13 mmol) and 5-chloropentanoyl chloride (320 mg, 2.07 mmol, 266 uL). The reaction mixture was allowed to stir at 25° C. for 2 hr and then concentrated in vacuo to give the title compound (520 mg, 57%) as a yellow solid. LC-MS (ESI+) m/z 410.0 (M+H)+.
A solution of 5-chloro-N-((3aS,7aS)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl)pentanamide (100 mg, 244 umol) and NaOH (19.5 mg, 489 umol) in DMF (1 mL) was allowed to stir at 25° C. for 12 hr. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL). The organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Welch Ultimate AQ-C18 150*30 mm*5 um; mobile phase: [water (HCl)-ACN]; B %: 4%-34%, 10 min) to give 120 (41.8 mg, 45%) as a white solid. LC-MS (ESI+) m/z 373.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.01-6.96 (m, 1H), 6.94-6.89 (m, 2H), 4.85-4.70 (m, 1H), 4.25-4.02 (m, 2H), 4.01-3.90 (m, 6H), 3.56-3.44 (m, 1H), 3.39-3.33 (m, 1H), 3.25 (br s, 3H), 2.97-2.81 (m, 1H), 2.74 (br s, 2H), 2.60 (br s, 4H), 2.52-2.36 (m, 2H), 2.25-2.13 (m, 1H), 2.07-1.97 (m, 1H), 1.94-1.89 (m, 2H), 1.79-1.71 (m, 1H).
To a solution of 001 (200 mg, 691 umol) and azetidine (197 mg, 3.46 mmol) in DCM (6 mL) was added NaBH(OAc)3 (293 mg, 1.38 mmol). The reaction mixture was allowed to stir at 25° C. for 16 hr and then concentrated in vacuo. The residue was purified by SFC (SFC: DAICEL CHIRALCELOD (250 mm*30 mm, 10 um); mobile phase [0.1% NH3H2O MeOH]; B %:25%-25%, 7.5; 67 min). Peak 1 was re-purified by prep-HPLC (Phenomenex C18 150*25 mm*10 um; mobile phase: [water (NH4HCO3)-ACN]; B %: 15%-45%, 5 min) to give 116 (10.2 mg, 10.2%) as a yellow oil. LC-MS (ESI+) m/z 331.2 (M+H)+ 1H NMR (400 MHz, CDCl3) δ=6.98-6.81 (d, J=8.8 Hz, 1H), 3.88 (d, J=12.4 Hz, 6H), 3.23-3.13 (m, 5H), 2.87 (dd, J=5.8, 8.8 Hz, 1H), 2.58-2.33 (m, 5H), 2.17-1.91 (m, 5H), 1.81 (m, 2H), 1.75-1.68 (m, 1H), 1.65-1.50 (m, 1H), 1.02-0.90 (m, 1H).
To a solution of 002 (300 mg, 1.04 mmol), CeCl3·7H2O (463 mg, 1.24 mmol) in MeOH (5 mL) was added NaBH4 (235 mg, 6.22 mmol). The reaction mixture was allowed to stir at 0° C. for 2 hr and then poured into NH4Cl (5 mL) aqueous solution. The aqueous solution was extracted with DCM (5 mL×3). The organic solutions were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (NH3H2O)-ACN]; B %: 28%-58%, 8 min) to give the title compound (200 mg, 63%) as yellow solid. LC-MS (ESI+) m/z 292.4 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 6.94-6.86 (m, 2H), 6.85-6.79 (m, 1H), 6.30-5.82 (m, 1H), 3.94 (s, 1H), 3.89 (d, J=6.8 Hz, 6H), 3.44-3.34 (m, 1H), 2.91 (s, 1H), 2.49 (s, 3H), 2.44-2.26 (m, 2H), 2.17 (dd, J=2.4, 14.8 Hz, 1H), 2.00-1.90 (m, 1H), 1.89-1.80 (m, 1H), 1.78-1.69 (m, 1H), 1.68-1.58 (m, 2H), 1.42 (tt, J=3.2, 13.8 Hz, 1H).
To a solution of (3aR,6R,7aR)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol (150 mg, 514 umol) and 4-methylbenzenesulfonyl chloride (147 mg, 772 umol) in DCM (4 mL) was added DMAP (125 mg, 1.03 mmol) and TEA (104 mg, 1.03 mmol, 143 uL). The reaction mixture was allowed to stir at 20° C. for 2 hr and then concentrated in vacuo. The residue was purified by reverse phase flash chromatography [ACN/(0.1% TFA in water), 0% to 90%] to give the title compound (190 mg, 82%) as yellow solid. LC-MS (ESI+) m/z 446.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.89-7.80 (m, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.14-7.01 (m, 1H), 6.99-6.87 (m, 2H), 5.04-4.75 (m, 1H), 3.82-3.72 (m, 6H), 2.74 (d, J=4.8 Hz, 2H), 2.69-2.65 (m, 1H), 2.58 (d, J=4.8 Hz, 2H), 2.43 (s, 3H), 2.35-2.31 (m, 1H), 2.26-2.10 (m, 3H), 2.08-1.97 (m, 1H), 1.92-1.80 (m, 1H), 1.78-1.67 (m, 1H), 1.64-1.50 (m, 1H), 1.41-1.10 (m, 1H).
To a solution of (3aR,6R,7aR)-3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-yl 4-methylbenzenesulfonate (110 mg, 246 umol) in DMF (2 mL) was added NaH (11.8 mg, 493 umol) and 3-(trifluoromethyl)-1H-pyrazole (50.3 mg, 370 umol). The reaction mixture was allowed to stir and warm from 0-80° C. over 2 hr. The reaction was quenched by pouring the mixture cold H2O (3 mL). The aqueous solution was extracted with ethyl acetate (5 mL×2). The organic solutions were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (HCl)-ACN]; B %: 21%-51%, 10 min) to give 121 (9.0 mg, 8%) as yellow oil and 122 (14.1 mg, 13%) as yellow solid.
121: LC-MS (ESI+) m/z 410.4 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 12.43 (s, 1H), 7.63 (d, J=1.2 Hz, 1H), 6.95-6.79 (m, 3H), 6.45 (d, J=2.0 Hz, 1H), 5.71-5.56 (m, 1H), 4.30-4.18 (m, 1H), 3.96-3.89 (m, 6H), 3.84 (d, J=5.2 Hz, 1H), 3.08-3.03 (m, 4H), 2.86-2.71 (m, 1H), 2.60-2.49 (m, 1H), 2.49-2.35 (m, 2H), 2.34-2.19 (m, 2H), 2.05-1.95 (m, 1H), 1.94-1.81 (m, 1H).
122: LC-MS (ESI+) m/z 410.3 (M+H)+. 1H NMR (400 MHz, CDCl3) δ=12.82-12.60 (m, 1H), 7.48 (s, 1H), 6.96-6.89 (m, 3H), 6.59 (s, 1H), 5.56-5.43 (m, 1H), 4.32-4.20 (m, 1H), 4.00 (d, J=4.8 Hz, 1H), 3.93 (d, J=12.4 Hz, 6H), 3.02-3.01 (m, 1H), 2.91 (s, 3H), 2.87-2.80 (m, 1H), 2.63-2.37 (m, 3H), 2.36-2.19 (m, 2H), 2.08-1.86 (m, 2H).
To a solution of 4-(3,4-dimethoxyphenyl)-1-methyl-2,3-dihydropyrrole (1.00 g, 4.56 mmol) in DCM (10 mL) was added HCl (4M in dioxane, 4.56 mL) and cyclopent-2-en-1-one (449 mg, 5.47 mmol, 458 uL) in ACN (8.0 mL). The reaction mixture was allowed to stir at 90° C. for 16 hr and then aqueous sodium bicarbonate (15 mL) was added to the reaction mixture. The mixture was extracted with EtOAc (20 mL×3). The organic solutions were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-TLC (SiO2, EtOAc:MeOH=10:1) to give 211 (400 mg, 27%) as a yellow oil and impure 212. Impure 212 was subjected to additional purification by reversed-phase HPLC (column: Phenomenex C18 150*25 mm*10 um; mobile phase: [water (NH4HCO3)-ACN]; B %: 18%-48%, 8 min) to give 212 (120 mg, 8.67%) as a yellow oil.
211: LC-MS (ESI+) m/z 302.2 (M+H)+. 1H NMR (400 MHz, CDCL3) δ 6.98-6.89 (m, 2H), 6.83 (d, J=8.4 Hz, 1H), 3.90 (d, J=10.6 Hz, 6H), 3.53 (d, J=5.2 Hz, 1H), 3.06-2.96 (m, 1H), 2.90 (br d, J=4.6 Hz, 1H), 2.80 (br d, J=5.4 Hz, 1H), 2.75-2.64 (m, 1H), 2.63-2.53 (m, 1H), 2.39 (s, 3H), 2.36-2.28 (m, 1H), 2.24-2.12 (m, 1H), 2.04-1.92 (m, 1H), 1.76 (br d, J=10.2 Hz, 2H).
212: LC-MS (ESI+) m/z 302.1 (M+H)+. 1H NMR (400 MHz, CDCL3) δ 6.84-6.75 (m, 1H), 6.71 (s, 2H), 3.86 (d, J=5.6 Hz, 6H), 2.97 (s, 1H), 2.95-2.87 (m, 1H), 2.84 (s, 1H), 2.60 (s, 1H), 2.52 (s, 3H), 2.48-2.37 (m, 2H), 2.16 (d, J=6.4 Hz, 1H), 1.97-1.84 (m, 2H), 1.84-1.79 (m, 1H), 1.59 (br dd, J=5.2, 18.0 Hz, 1H).
211 was purified by SFC (column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 um); mobile phase: [Neu-IPA]; B %: 35%-35%, A3.1; 15 min) to give 213 and 214, which were each subjected separately to additional purification by prep-HPLC (column: Phenomenex C18 150*25 mm*10 um; mobile phase: [water (NH4HCO3)—CN]; %: 22%-52%, min) to give 213 (135 mg, 33% yield, 100% purity) as a colorless gum and 214 (146 mg, 36% yield, 99% purity) as a yellow gum.
213: LC-MS (ESI+) m/z 302.2 (M+H)+. 1H NMR (400 MHz, CDCL3) δ 6.93 (s, 2H), 6.83 (d, J=8.4 Hz, 1H), 3.91 (d, J=10.6 Hz, 6H), 3.55-3.50 (m, 1H), 3.04-2.98 (m, 1H), 2.93-2.88 (m, 1H), 2.83-2.77 (m, 1H), 2.74-2.64 (m, 1H), 2.62-2.54 (m, 1H), 2.39 (s, 3H), 2.36-2.29 (m, 1H), 2.20-2.11 (m, 1H), 2.00-1.94 (m, 1H), 1.79-1.70 (m, 2H).
214: LC-MS (ESI+) m/z 302.1 (M+H)+. 1H NMR (400 MHz, CDCL3) δ 6.98-6.89 (m, 2H), 6.83 (d, J=8.4 Hz, 1H), 3.91 (d, J=10.6 Hz, 6H), 3.59-3.48 (m, 1H), 3.01 (br t, J=8.2 Hz, 1H), 2.90 (br s, 1H), 2.81 (br d, J=4.2 Hz, 1H), 2.75-2.65 (m, 1H), 2.62-2.52 (m, 1H), 2.40 (s, 3H), 2.36-2.29 (m, 1H), 2.20-2.11 (m, 1H), 2.00-1.94 (m, 1H), 1.79-1.70 (m, 2H).
Racemic compound 212 was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [Neu-ETOH]; B %: 35%-35%, C7; 40 min) to give 215 mg, 47%, 97.64% purity) as a colorless gum and 216 (35 mg, 44%, 99% purity) as a colorless gum.
215: LC-MS (ESI+) m/z 302.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 6.78 (s, 1H), 6.74-6.69 (m, 2H), 3.87 (d, J=5.4 Hz, 6H), 2.98 (s, 1H), 2.96-2.91 (m, 1H), 2.85 (br d, J=3.2 Hz, 1H), 2.62 (s, 1H), 2.53 (s, 3H), 2.49-2.40 (m, 2H), 2.17 (br d, J=6.2 Hz, 1H), 1.90 (br d, J=17.2 Hz, 2H), 1.86-1.80 (m, 1H), 1.62 (d, J=5.2 Hz, 1H).
216: LC-MS (ESI+) m/z 302.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 6.81-6.77 (m, 1H), 6.71 (s, 2H), 3.87 (d, J=5.4 Hz, 6H), 2.98 (s, 1H), 2.96-2.90 (m, 1H), 2.88-2.83 (m, 1H), 2.62 (s, 1H), 2.53 (s, 3H), 2.49-2.38 (m, 2H), 2.22-2.11 (m, 1H), 1.98-1.87 (m, 2H), 1.86-1.79 (m, 1H), 1.63-1.60 (m, 1H).
To a solution of 4-(3,4-dimethoxyphenyl)-1-methyl-2,3-dihydropyrrole (1 g, 4.56 mmol) in DCM (600 mL) was added HCl (4M in dioxane, 3.42 mL). The reaction mixture was allowed to stir at 25° C. for 0.1 hr and then filtered to remove the insoluble materials. To the filtered solution was added a solution of 4 cyclohept-2-en-1-one (604 mg, 5.49 mmol) in ACN (20 mL). The reaction mixture was degassed and purged with N2 3 times, and then allowed to stir at 90° C. for 16 hr under at atmosphere of N2. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between water (300 mL) and EtOAc (300 mL) and then brought to pH>10 using aqueous NaOH solution (3M). The aqueous solution was separated and washed with EtOAc (300 ml*3). The organic solutions were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: Phenomenex C18 250*50 mm*10 um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B %: 29%-59%, 8 min) to give 217 (0.9 g, 59%) as a yellow solid. LC-MS (ESI+) m/z 330.2 (M+H)+.
Compound 217 was purified by SFC (condition: column: YMC Triart 30*150 mm*7 um; mobile phase: [water (ammonia hydroxide v/v)-MeOH]; B %: 0%-0%, A6.7; 1072 min) to give 218 (132 mg, 35%) as a white solid and 219 (140 mg, 37%) as a white solid.
218: LC-MS (ESI+) m/z 330.20 (M+H)+; 1H NMR (400 MHz, CDCl3) δ=7.03 (dd, J=2.4, 8.4 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 3.91 (d, J=2.4 Hz, 6H), 3.28 (d, J=2.4 Hz, 1H), 3.00 (dd, J=5.2, 19.6 Hz, 1H), 2.88-2.77 (m, 2H), 2.69-2.60 (m, 1H), 2.39 (s, 4H), 2.37-2.33 (m, 1H), 1.89-1.76 (m, 2H), 1.74-1.57 (m, 3H), 1.48-1.35 (m, 3H).
219: LC-MS (ESI+) m/z 320.30 (M+H)+; 1H NMR (400 MHz, CDCl3) δ=7.02 (dd, J=1.6, 8.8 Hz, 1H), 6.96 (s, 1H), 6.87 (d, J=8.5 Hz, 1H), 3.91 (d, J=2.8 Hz, 6H), 3.33 (br s, 1H), 3.02 (br dd, J=3.6, 18.8 Hz, 1H), 2.95-2.80 (m, 2H), 2.66 (br d, J=1.5 Hz, 1H), 2.50-2.35 (m, 5H), 1.91-1.79 (m, 2H), 1.75-1.59 (m, 3H), 1.48-1.35 (m, 3H).
Compound 217 was purified by SFC (column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 um); mobile phase: [Neu-IPA]; B %: 35%-35%, C8.6; 78 min) to give 220* (20 mg, 35%) as a white solid and 221* (20 mg, 35%) as a white solid.
220*: LC-MS (ESI+) m/z 330.30 (M+H)+; 1H NMR (400 MHz, CDCl3) δ=6.82-6.71 (m, 3H), 3.87 (d, J=3.0 Hz, 6H), 3.14-3.02 (m, 2H), 2.86 (t, J=6.4 Hz, 1H), 2.57 (dt, J=7.6, 12.0 Hz, 1H), 2.39-2.23 (m, 6H), 2.14-2.03 (m, 2H), 1.92-1.74 (m, 3H), 1.61 (br dd, J=6.4, 12.4 Hz, 1H), 1.51-1.42 (m, 1H).
221*: LC-MS (ESI+) m/z 320.20 (M+H)+; 1H NMR (400 MHz, CDCl3) δ=6.82-6.72 (m, 3H), 3.87 (d, J=2.8 Hz, 6H), 3.14-3.03 (m, 2H), 2.86 (t, J=6.6 Hz, 1H), 2.62-2.52 (m, 1H), 2.38-2.21 (m, 6H), 2.13-2.03 (m, 2H), 1.92-1.74 (m, 3H), 1.65-1.59 (m, 1H), 1.48 (br dd, J=6.4, 13.6 Hz, 1H).
Compound 221 was further characterized by xray diffraction. 2 mg 221 was dissolved in 200 μL dichloromethane/cyclohexane (1:1). The solution was allowed to slowly evaporate at room temperature. Crystals were observed on the second day and were analyzed using a Rigaku Oxford Diffraction XtaLAB Synergy-S equipped with a HyPix-6000HE area detector.
A total of 61953 reflections were collected in the 20 range from 10.864 to 133.058. The limiting indices were: −9≤h≤9, −10≤k≤10, −30≤l≤30; which yielded 3077 unique reflections (Rint=0.0991). The structure was solved using SHELXT (Sheldrick, G. M. 2015. Acta Cryst. A71, 3-8) and refined using SHELXL (against F) (Sheldrick, G. M. 2015. Acta Cryst. C71, 3-8). The total number of refined parameters was 222, compared with 3077 data. All reflections were included in the refinement. The goodness of fit on F was 1.042 with a final R value for [I>=2σ (I)]R1=0.0489 and wR2=0.1193. The largest differential peak and hole were 0.31 and −0.32 Å-3.
The crystal was a colourless block with the following dimensions: 0.20×0.10×0.10 mm3. The symmetry of the crystal structure was assigned the orthorhombic space group P212121 with the following parameters: a=7.88200(10) Å, b=8.5822(2) Å, c=25.8074(7) Å, α=90°, β=90°, γ 25=90°, V=1745.74(7) Å3, Z=4, Dc=1.253 g/cm3, F(000)=712.0, μ(CuKα)=0.665 mm-1, and T=149.99(10) K.
It has been determined that the absolute configuration and ORTEP structure of 221 are not as shown in Example 27 but rather as shown in
To a solution of 1-(3,4-dimethoxyphenyl)cyclopropanecarbaldehyde (10.0 g, 48.5 mmol) in DCM (200 mL) was added ethanamine hydrochloride (20.0 g, 242 mmol), Na2SO4 (103 g, 727 mmol, 73.8 mL) and Na2CO3 (15.4 g, 145 mmol). The reaction mixture was allowed to stir at 25° C. for 16 hr and then filtered and in vacuo to give the title compound (10.0 g, 80%) as a red solid. 1H NMR (400 MHz, CDCl3): δ=7.66 (s, 1H), 6.97-6.71 (m, 3H), 3.88 (d, J=6.0 Hz, 6H), 3.49-3.27 (m, 2H), 1.36-1.25 (m, 2H), 1.20-1.08 (m, 5H).
To a solution of (E)-1-(1-(3,4-dimethoxyphenyl)cyclopropyl)-N-ethylmethanimine (10.0 g, 42.9 mmol) in ACN (100 mL) was added NH4Cl (687 mg, 12.9 mmol). The reaction mixture was allowed to stir at 120° C. for 2 hr. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL). The organic solution was separated, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (8.50 g, 68%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=6.88-6.68 (m, 3H), 6.40 (s, 1H), 3.86 (d, J=12.4 Hz, 6H), 3.17 (t, J=9.0 Hz, 2H), 2.95-2.83 (m, 2H), 2.78 (t, J=8.8 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H).
To a solution of 4-(3,4-dimethoxyphenyl)-1-ethyl-2,3-dihydro-1H-pyrrole (8.50 g, 36.4 mmol) in DCM (150 mL) was added HCl (4M in dioxane, 29.6 mL). After the addition was complete, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. To the residue was added (E)-4-methoxybut-3-en-2-one (4.01 g, 40.1 mmol, 4.02 mL) in ACN (100 mL). The reaction mixture was allowed to stir at 90° C. for 16 hr. After cooling, the solvent was removed under reduced pressure and the resulting dark oil was partitioned between 3M HCl solution (10 mL) and ether (50 mL). The aqueous solution was separated and was further washed with ether (2×20 mL), and then brought to basic pH using 3 M NaOH (30 mL) solution. The aqueous solutions were then extracted into ethyl acetate (4×50 mL). The organic solutions were combined, washed with brine (1×20 mL), dried over Na2SO4, filtered and concentrated to give 301 (3.50 g, 30%) as a yellow oil. LC-MS (ESI+) m/z 302.1 (M+H)+ 1H NMR (400 MHz, CDCl3): δ 6.91-6.74 (m, 3H), 6.71-6.58 (m, 1H), 6.03 (d, J=10.0 Hz, 1H), 3.81 (d, J=3.6 Hz, 6H), 3.39-3.19 (m, 1H), 2.96-2.75 (m, 2H), 2.60-2.46 (m, 1H), 2.46-2.32 (m, 3H), 2.19-2.02 (m, 2H), 1.00 (t, J=7.2 Hz, 3H).
To a solution of 301 (1.50 g, 4.98 mmol) in EtOAc (100 mL) was added Pd/C (0.35 g, 498 umol). The mixture was allowed to stir at 25° C. for 1 hr under an atmosphere of H2. The reaction mixture was then filtered and concentrated in vacuo to give 222 (1.40 g, 88%) as a yellow oil. LC-MS (ESI+) m/z 304.3 (M+H)+; 1H NMR (400 MHz, CDCl3): δ 7.09-6.77 (m, 3H), 3.90 (d, J=7.2 Hz, 6H), 3.27-3.18 (m, 1H), 3.12 (t, J=3.6 Hz, 1H), 2.95-2.82 (m, 1H), 2.59 (d, J=3.6 Hz, 2H), 2.52-2.37 (m, 1H), 2.34-1.96 (m, 7H), 1.08 (t, J=7.2 Hz, 3H).
Compound 222 was separated by SFC (Column: Chiralpak AS-3 50×4.6 mm I.D., 3 um, Mobile phase: Phase A for CO2, and Phase B for IPA (0.05% DEA); Gradient elution: B in A from 5% to 40%, Flow rate: 3 mL/min; Detector: PDA; Column Temp: 35 C; Back Pressure: 100 Bar) to give 223 (117 mg, 37%) as a yellow gum and 224 (106 mg, 34%) as a yellow gum.
223: LC-MS (ESI+) m/z 302.2 (M+H)+; 1H NMR (400 MHz, MeOD) δ 7.02-6.97 (m, 2H), 6.94 (s, 1H), 3.83 (d, J=9.2 Hz, 6H), 3.17 (s, 2H), 2.96-2.85 (m, 1H), 2.76-2.64 (m, 1H), 2.63-2.51 (m, 1H), 2.43-2.31 (m, 1H), 2.30-2.21 (m, 3H), 2.20-2.04 (m, 4H), 1.10 (t, J=7.2 Hz, 3H).
224: LC-MS (ESI+) m/z 302.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 7.05-6.78 (m, 3H), 3.89 (d, J=7.6 Hz, 6H), 3.25 (t, J=6.8 Hz, 1H), 3.15 (s, 1H), 3.00-2.84 (m, 1H), 2.71-2.55 (m, 2H), 2.52-2.38 (m, 1H), 2.35-2.23 (m, 2H), 2.23-2.00 (m, 5H), 1.10 (t, J=7.2 Hz, 3H)
To a solution of 2-(3,4-dimethoxyphenyl)acetonitrile (100 g, 564 mmol) in THF (2000 mL) was added LDA (2M in THF, 705 mL) at −50° C. over 1 hr. Following the addition, the reaction mixture was allowed to at −50° C. for 30 min and then 1,2-dibromoethane (127 g, 677 mmol, 51 mL) was added at −50° C. over 30 min. The reaction mixture was allowed to warm and to stir at 25° C. for 4 hr and then poured into saturated ammonium chloride solution (1000 mL). The mixture was extracted with ethyl acetate (5000 mL). The organic solutions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/0 to 100/7) to give the title compound (47.7 g, 40%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.80 (s, 1H), 6.75 (d, J=1.2 Hz, 2H), 3.82 (d, J=13.2 Hz, 6H), 1.59 (d, J=2.4 Hz, 2H), 1.28 (d, J=2.4 Hz, 2H).
To a solution of 1-(3,4-dimethoxyphenyl)cyclopropanecarbonitrile (44 g, 216 mmol) in THF (800 mL) was added DIBAL-H (1M in Tol, 324 mL) over 30 minutes at 0° C. under at atmosphere of N2. The reaction mixture was allowed to warm and to stir at 25° C. for 16 hr under at atmosphere of N2. The reaction mixture was then poured into hydrochloric acid solution (2M, 600 mL) and extracted with ethyl acetate (1000 mL). The organic solutions were combined, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (44.5 g, 98%) as orange solid. 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 6.89-6.63 (m, 3H), 3.82 (d, J=2.8 Hz, 6H), 1.50-1.47 (m, 2H), 1.35-1.25 (m, 2H).
To a solution of 1-(3,4-dimethoxyphenyl)cyclopropanecarbaldehyde (13 g, 63.0 mmol) in DCM (200 mL) was added propan-2-amine (18.6 g, 315 mmol, 27.0 mL) and Na2SO4 (134 g, 945 mmol). The mixture was allowed to stir at 25° C. for 24 hr then filtered and concentrated in vacuo to give the title compound (15.4 g, 69%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 6.83-6.77 (m, 2H), 6.76-6.71 (m, 1H), 3.85-3.75 (m, 6H), 3.37-3.09 (m, 1H), 1.27-1.21 (m, 2H), 1.15-0.99 (m, 8H).
A mixture of (E)-1-(1-(3,4-dimethoxyphenyl)cyclopropyl)-N-isopropylmethanimine (6 g, 24.2 mmol) and NH4Cl (1.04 g, 19.4 mmol) in ACN (60 mL) was degassed and purged with N2 3 times, and then the reaction mixture was allowed to stir at 120° C. for 2 hr under an atmosphere of N2. The reaction mixture was then concentrated in vacuo to give the title compound (6 g, 70%) as a yellow oil. LC-MS (ESI+) m/z 247.8 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 6.74-6.68 (m, 2H), 6.68-6.61 (m, 1H), 6.41 (s, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.16 (t, J=9.2 Hz, 2H), 3.07-2.95 (m, 1H), 2.76-2.63 (m, 2H), 1.10 (d, J=6.5 Hz, 6H).
To a solution of 4-(3,4-dimethoxyphenyl)-1-isopropyl-2,3-dihydro-1H-pyrrole (6 g, 16.9 mmol, 70% purity) in DCM (60 mL) was added HCl (4M in dioxane, 6.0 mL) at 25° C. over 10 min.
After the addition was complete, the reaction mixture was filtered and concentrated in vacuo to give a residue. To this residue was added (E)-4-methoxybut-3-en-2-one (2.04 g, 20.3 mmol, 2.0 mL) in ACN (60 mL). The reaction mixture was allowed to stir at 60° C. for 2 hr and then filtered and concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% NH3H2O) to give 302 (300 mg, 3.7%) as a yellow gum. LC-MS (ESI+) m/z 316.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 6.91-6.86 (m, 3H), 6.70 (dd, J=2.0, 8.0 Hz, 1H), 6.13 (d, J=10.0 Hz, 1H), 3.90 (s, 6H), 3.29-3.26 (m, 1H), 3.11-2.96 (m, 1H), 2.92 (dt, J=5.2, 9.2 Hz, 1H), 2.57-2.48 (m, 2H), 2.45-2.31 (m, 1H), 2.16-2.05 (m, 2H), 1.09 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.4 Hz, 3H).
A mixture of 302 (400 mg, 1.27 mmol) and Pd/C (30 mg, 126 umol, 10% purity) in EtOAc (1.0 mL) was degassed and purged with H2 3 times, and then the reaction mixture was allowed to stir at 25° C. for 2 hr under an atmosphere of H2. The reaction mixture was then filtered and concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% NH3H2O) to give 225 (130 mg, 30%) as a yellow oil. LC-MS (ESI+) m/z 318.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 6.94 (s, 2H), 6.86 (d, J=8.0 Hz, 1H), 3.91 (d, J=6.8 Hz, 6H), 3.53 (s, 1H), 3.13 (s, 1H), 3.05-2.87 (m, 1H), 2.69 (d, J=8.4 Hz, 1H), 2.60 (s, 2H), 2.48-2.37 (m, 1H), 2.36-2.26 (m, 1H), 2.26-2.14 (m, 2H), 2.05 (d, J=18.8 Hz, 2H), 1.15 (s, 3H), 0.96 (s, 3H).
Compound 225 was separated by SFC (column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 um); mobile phase: [IPA-ACN]; B %: 20%-20%, A10; 470 min) to give 226 (41.53 mg, 30%) and 227 (43.3 mg, 32%) each as a yellow gum.
226: LC-MS (ESI+) m/z 318.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 6.99-6.77 (m, 3H), 3.90 (d, J=6.4 Hz, 6H), 3.65-3.41 (m, 1H), 3.24-3.07 (m, 1H), 3.06-2.84 (m, 1H), 2.81-2.49 (m, 3H), 2.41 (dd, J=6.0, 11.6 Hz, 2H), 2.27-1.91 (m, 4H), 1.25-1.06 (m, 3H), 1.05-0.77 (m, 3H).
227: LC-MS (ESI+) m/z 318.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 6.84 (s, 2H), 6.79-6.75 (m, 1H), 3.82 (d, J=6.4 Hz, 6H), 3.54-3.37 (m, 1H), 3.06 (s, 1H), 2.98-2.80 (m, 1H), 2.70-2.43 (m, 3H), 2.41-2.23 (m, 2H), 2.19-1.90 (m, 4H), 1.17-1.00 (m, 3H), 0.89 (s, 3H).
To a solution of EtOAc (761 mg, 8.64 mmol) in THF (20 mL) was added LiHDMS (1M, 8.64 mL). The reaction mixture was allowed to stir at 0° C. for 30 min and then 001 (500 mg, 1.73 mmol) was added. The reaction mixture was allowed to stir at 0° C. for 12 hr under at atmosphere of N2. To the reaction mixture was added saturated ammonium chloride solution (30 mL). The mixture was extracted with EtOAc (30 mL×2). The organic solutions were combined, washed with brine (30 mL) dried of sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (0.1% TFA condition) to give the title compound (800 mg, 98% yield, 80% purity) as a colorless oil. LC-MS (ESI+) m/z 378.3 (M+H)+.
To a mixture of ethyl 2-((3aS,7aS)-3a-(3,4-dimethoxyphenyl)-6-hydroxy-1-methyloctahydro-1H-indol-6-yl)acetate (400 mg, 1.06 mmol) in THF (20 mL) was added LiAlH4 (120 mg, 3.18 mmol). The reaction mixture was allowed to at 25° C. for 2 hr under an atmosphere of N2. The reaction mixture was added to HCl (1M, 20 mL) and extracted with EtOAc (30 mL×2). The organic solutions were combined, washed with brine (30 mL×1), dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM:MeOH=10:1) to give the title compound (300 mg, 84%) as a white solid. LC-MS (ESI+) m/z 336.0 (M+H)+.
A mixture of (3aS,7aS)-3a-(3,4-dimethoxyphenyl)-6-(2-hydroxyethyl)-1-methyloctahydro-1H-indol-6-ol (230 mg, 685 umol), DMAP (83.8 mg, 685. umol), TsCl (261 mg, 1.37 mmol) and TEA (346 mg, 3.43 mmol) in DCM (15 mL) was degassed and purged with N2 3 times. The reaction mixture was allowed to stir at 25° C. for 12 hr under an atmosphere of N2 and then concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (50 mg, 15%) as a yellow liquid. LC-MS (ESI+) m/z 490.0 (M+H)+
A mixture of 2-((3aS,7aS)-3a-(3,4-dimethoxyphenyl)-6-hydroxy-1-methyloctahydro-1H-indol-6-yl)ethyl 4-methylbenzenesulfonate_(50 mg, 102 umol) and t-BuOK (17.1 mg, 153 umol) in DMF (2 mL) was degassed and purged with N2 3 times. The reaction mixture was then allowed to stir at 25° C. for 12 hr under an atmosphere of N2. The mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC (Waters xbridge 150*25 mm 10 um; mobile phase: [water (NH4HCO3)-ACN]; B %: 10%-40%, 8 min) to give 118 (9.87 mg, 30%) as a brown gum. LC-MS (ESI+) m/z 331.2 (M+H)+ 1H NMR (400 MHz, CDCl3) δ 7.21-7.1 (m, 1H), 6.91-6.88 (m, 1H), 6.82-6.78 (m, 1H), 6.82-6.78 (m, 1H), 4.52-4.49 (m, 1H), 3.88 (d, J=12.4 Hz, 6H), 3.50-3.38 (m, 1H), 3.25-3.01 (m, 1H), 2.75 (s, 1H), 2.58-2.50 (m, 1H), 2.27-2.11 (m, 4H), 2.13-2.01 (m, 4H), 1.87-1.70 (m, 1H), 1.45-1.30 (m, 1H).
SERT inhibition was measured using a Neruotransmitter Transportation Fluorescence assay. Briefly, stable 5HHH cells were prepared in a 384 microwell plate. Compounds were prepared by in assay buffer (20 mM HEPES, 0.1% BSA). The compounds were added to the plated cells and incubated for 30 minutes at 37° C. 25 μL of dye solution (Molecular Devices Neurotransmitter Transporter Uptake Assay Kit) was added per well and incubated for 30 minutes at 37° C. The plates were then read on a plate reader.
The results are shown in Table 1 as follows: A: IC50</=50 nM or lower; B: 50 nM<IC50</=100 nM; C: 100 nM<IC50</=500 nM; D: 500 nM<IC50</=1 micromolar; E: IC50>1 micromolar.
PDE4 assay kit (BPS Bioscience, San Diego, CA), as described below.
100 M dilutions of the test compounds were prepared in assay buffer (10% DMSO concentration) and 5 μl of the dilution was added to a 50 μl reaction so that the final concentration of DMSO is 1% in all of reactions.
The enzymatic reactions were conducted at room temperature for 60 minutes in a 50 μl mixture containing PDE assay buffer, 100 nM FAM-cAMP, a PDE enzyme and the test compound.
After the enzymatic reaction, 100 Is of a binding solution (1:100 dilution of the binding agent with the binding agent diluent) was added to each reaction and the reaction was performed at room temperature for 60 minutes.
Fluorescence intensity was measured at an excitation of 485 nm and an emission of 528 nm using a Tecan Infinite M1000 microplate reader. The results are shown in Table 2. In the table, the percent inhibitions are labeled as A if the % inhibition is greater than or equal to 70%, B if the percent inhibition is 50-70%, C is the percent inhibition is 30-50%, and D if the percent inhibition is less than 30%.
Assay Conditions for PDE4 IC50 determination:
The serial dilution of the compounds was first performed in 100% DMSO with the highest concentration at 3 mM. Each intermediate compound dilution (in 100% DMSO) will then get directly diluted 10× fold into assay buffer for 10% DMSO and 5 μl of the dilution was added to a 50 μl reaction so that the final concentration of DMSO is 1% in all of reactions.
The enzymatic reactions were conducted at room temperature for 60 minutes in a 50 μl mixture containing PDE assay buffer, 100 nM FAM-cAMP, a PDE enzyme and the test compound.
After the enzymatic reaction, 100 μl of a binding solution (1:100 dilution of the binding agent with the binding agent diluent) was added to each reaction and the reaction was performed at room temperature for 60 minutes.
Fluorescence intensity was measured at an excitation of 485 nm and an emission of 528 nm using a Tecan Infinite M1000 microplate reader. The results are shown in Tables 3-6.
The CNS-like activity of test compounds after acute intraperitoneal administration was evaluated in naïve C57/Bl6 mice using the SmartCube® test.
Male C57/Bl6 mice from Taconic Laboratories (Germantown, NY) were used. Upon receipt, mice were group-housed in Optimice® ventilated cages with 4 mice per cage. Mice were acclimated to the colony room for at least one week prior to test, and subsequently tested at approximately 8-9 weeks of age. All animals were examined, handled, and weighed prior to initiation of the study to assure adequate health and suitability and to minimize nonspecific stress associated with manipulation. During the course of the study, 12/12 light/dark cycles were maintained. The room temperature was 20-23° C. with a relative humidity maintained between 30-70%. Chow and water were provided ad libitum for the duration of the study.
Test compounds were formulated in 5% Pharmasolve, 30% P3 (1:1:1 PEG200, PEG400, propylene glycol) and 65% saline. Compounds were injected intraperitoneally at a dose volume of 10 mL/kg, 15 minutes prior to test. The SmartCube® test session lasted for 45 minutes.
For class and subclass analysis, a reference dataset has been built from hundreds of drug doses in multiple drug classes plus a control group. Each reference drug was tested at multiple doses appropriate for that drug in mice. The best performing classifiers were chosen from evaluation tests and two separate types of classifiers were built that make independent predictions at drug class and sub-class levels. The Class consists of drugs that are currently in the market or have been clinically validated for that specific indication. The sub-class consists of both marketed drugs and other compounds that have been mechanistically validated and is a larger set than the Class. Data was processed using proprietary computer vision and data mining algorithms and the results were compared to signatures of the reference compounds in a database. Multiple analyses of the data was performed to quantitatively produce independent predictions of drug class, and drug subclass. The behavioral signatures of the test drug were evaluated using these classifiers to predict potential therapeutic utility.
Compound 001 was active (>90%) at all doses tested (1, 3 and 10 mg/kg). Class analysis showed that all doses showed antidepressant-like signature. Subclass analysis found an anxiolytic/benzodiazepine signature and a NMDA antagonist-like signature.
Compound 220 was active at 10 and 30 mg/kg and produced an identical phenotype to Compound 001. Class analysis showed antidepressant-like signature, and subclass analysis found an anxiolytic/benzodiazepine signature and a NMDA antagonist-like signature.
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In-vitro metabolism and Metabolite ID of test compounds was carried out in human hepatocyte culture. Cells were treated with 10 mM concentration of test compound and then incubated at 37° C. for 4 hr. Incubations were quenched with acetonitrile containing 0.1% formic acid followed by centrifugation. Aliquots of the supernatant were mixed with water and used for LC-MS/MS analysis. Results are shown in the table below:
In vitro metabolism studies in human hepatocytes show that Compound 001 is quickly metabolized (CLint human 40 mL/min/106 cells), and primarily converts to Compound 018 (94% abundance). To retain the behavioral phenotype of Compound 001, analogs were developed to identify metabolically stable compounds that conserve the behavioral phenotype of Compound 001. Compound 220 is two-times more stable in human hepatocytes while maintaining the behavioral phenotype classification of Compound 001. Potentially resulting in a longer lasting therapeutic for depression or anxiety compared to Compound 001.
This application claims the benefit of and priority to U.S. Provisional Patent Application Nos. 63/424,675, filed Nov. 11, 2022; 63/462,784, filed Apr. 28, 2023; and 63/533,191, filed Aug. 17, 2023.
| Number | Date | Country | |
|---|---|---|---|
| 63424675 | Nov 2022 | US | |
| 63462784 | Apr 2023 | US | |
| 63533191 | Aug 2023 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US23/79358 | Nov 2023 | WO |
| Child | 18799037 | US |
