Synthetic cannabinoid compounds, pharmaceutical compositions, and methods of treatment

Abstract

Cannabinoid derivatives may exhibit anti-inflammatory properties, such as by inhibition of the cannabinoid type 2 (CB2) receptor. Pharmaceutical compositions containing cannabinoid derivatives may be used to treat a variety of diseases and conditions in mammals, including pain, anxiety, sleep disorders, addiction, epilepsy, depression, or Alzheimer's disease.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119 to U.S. Provisional Patent Application No. 63 / 403,544, filed September 2, 2022, and U.S. Provisional Patent Application No. 63 / 283,431, filed November 27, 2021, the entire contents of which are incorporated by reference herein. [Background technology]

[0002] In recent years, much research has been conducted on the therapeutic effects of cannabis, including its components tetrahydrocannabinol (THC) and cannabidiol (CBD). There remains a need for improved compounds for treating disorders such as depression, anxiety, substance addiction, sleep disorders, pain, cancer, autoimmune disorders, and other disorders associated with chronic inflammation. It would be particularly desirable to develop compounds that can be synthetically prepared and formulated as solid oral dosage forms. Summary of the Invention

[0003] According to one embodiment, the synthetic cannabinoid derivative has the structure of formula (I): [ka] (In the formula, R 1 and R 2 are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle, where alkyl, alkenyl, alkynyl, or acyl is optionally selected from halogen, -OH, alkyl, -O-alkyl, NR A R B , -S-alkyl, -SO-alkyl, -SO 2 - substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle, where R A and R B is hydrogen and C1~4 alkyl, where aryl or heteroaryl, alone or as part of a substituent, are optionally selected from halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C 1~4 Alkyl, -C(O)OC 1~4 Alkyl, NR C R D , -S-alkyl, -SO-alkyl, and -SO 2 -alkyl, where R C and R D is hydrogen and C 1~4 are each independently selected from alkyl, R 3 is H, alkyl, acyl, -SO 2 -Alkyl, -SO 2 -aryl and -SO 2 -heteroaryl, where alkyl is optionally selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, NR E R F , -S-alkyl, -SO-alkyl, -SO 2 - substituted with one or more substituents independently selected from the group consisting of alkyl, aryl, and heteroaryl, where R E and R F is hydrogen and C 1~4 alkyl, where aryl or heteroaryl, alone or as part of a substituent, are optionally selected from halogen, —OH, alkyl, —O-alkyl, NR G R H , -S-alkyl, -SO-alkyl, and -SO 2 -alkyl, where R G and R H is hydrogen and C 1~4 are each independently selected from alkyl, each --------- represents a single bond or a double bond, provided that within a five-membered ring, --------- is a double bond, and the other four ---------is a single bond), or a pharma- ceutically acceptable salt or ester thereof.

[0004] According to another aspect, a method for treating cancer, a tumor, an addiction, epilepsy, anxiety, or depression comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic cannabinoid derivative of formula (I) and a pharma- ceutically acceptable carrier therefor.

[0005] In some embodiments, the synthetic cannabinoid derivative has the structure of formula (IA): [ka] (In the formula, R 1 , R 2 , and R 3 is as defined above).

[0006] According to another aspect, a method for treating cancer, a tumor, an addiction, epilepsy, anxiety, or depression comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic cannabinoid derivative of formula (IA) and a pharma- ceutically acceptable carrier therefor.

[0007] According to another embodiment, the synthetic cannabinoid derivative has the structure of formula (II): [ka] (In the formula, R 1 , R 2 , R 3 , and --------- is as defined above), or a pharma- ceutically acceptable salt or ester thereof.

[0008] In another aspect, a method for treating anxiety, addiction, depression, or Alzheimer's disease comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic cannabinoid derivative of formula (II) and a pharma- ceutically acceptable carrier therefor.

[0009] According to another embodiment, the synthetic cannabinoid derivative has the structure of formula (II): [ka] (In the formula, R 1 , R 2 , and R 3 is as defined above), or a pharma- ceutically acceptable salt or ester thereof.

[0010] In another aspect, a method for treating anxiety, addiction, depression, or Alzheimer's disease comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic cannabinoid derivative of formula (IIA) and a pharma- ceutically acceptable carrier therefor.

[0011] In another aspect, a pharmaceutical composition comprises a therapeutically effective amount of a synthetic cannabinoid derivative of formula (I), (IA), (II), or (IIA), or a combination thereof, and a pharma- ceutically acceptable carrier therefor.

[0012] According to another aspect, the synthetic cannabinoid derivative has the structure of formula (III): [ka] (In the formula, R 1 , R 2 , R 3 , and --------- is as defined above), or a pharma- ceutically acceptable salt or ester thereof.

[0013] According to another aspect, a method for treating cancer, tumors, addiction, epilepsy, anxiety, or depression comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic cannabinoid derivative of formula (III) and a pharma- ceutically acceptable carrier therefor.

[0014] In some embodiments, the synthetic cannabinoid derivative has the structure of formula (IIIA): [ka] (In the formula, R 1 , R 2 , and R 3 is as defined above).

[0015] According to another aspect, a method for treating cancer, tumors, addiction, epilepsy, anxiety, or depression comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic cannabinoid derivative of formula (IIIA) and a pharma- ceutically acceptable carrier therefor.

[0016] According to another embodiment, the synthetic cannabinoid derivative has the structure of formula (IV): [ka] (In the formula, R 1 , R 2 , R 3 , and --------- is as defined above), or a pharma- ceutically acceptable salt or ester thereof.

[0017] In another aspect, a method for treating anxiety, addiction, depression, or Alzheimer's disease comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic cannabinoid derivative of formula (IV) and a pharma- ceutically acceptable carrier therefor.

[0018] In other aspects, the synthetic cannabinoid derivative has the structure of formula (IVA): [ka] (In the formula, R 1 , R 2 , and R 3 is as defined above), or a pharma- ceutically acceptable salt or ester thereof.

[0019] In another aspect, a method for treating anxiety, addiction, depression, or Alzheimer's disease comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic cannabinoid derivative of formula (IVA) and a pharma- ceutically acceptable carrier therefor.

[0020] In another aspect, a pharmaceutical composition comprises a therapeutically effective amount of a synthetic cannabinoid derivative of formula (III), (IIIA), (IV), or (IVA), or a combination thereof, and a pharma- ceutically acceptable carrier therefor.

[0021] In another embodiment, the synthetic cannabinoid derivative has the structure of formula (V): [ka] (In the formula, R 1 , R 2 , and R 3 is as defined above), or a pharma- ceutically acceptable salt or ester thereof.

[0022] According to another aspect, a method for treating cancer, tumors, addiction, epilepsy, anxiety, or depression comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic cannabinoid derivative of formula (V) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier therefor.

[0023] According to another aspect, the synthetic cannabinoid derivative has the structure of formula (VI): [ka] (In the formula, R 1 , R 2 , and R 3 is as defined above), or a pharma- ceutically acceptable salt or ester thereof.

[0024] In another aspect, a method for treating anxiety, addiction, depression, or Alzheimer's disease comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic cannabinoid derivative of formula (VI) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier therefor.

[0025] In another aspect, a pharmaceutical composition comprises a therapeutically effective amount of a synthetic cannabinoid derivative of formula (V) or formula (VI) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier therefor.

[0026] In some embodiments, the compounds disclosed herein can be used in a method for treating diseases and conditions associated with monoamine oxidase (MAO) activity. In some embodiments, the individual suffers from depression, pain, or addiction. In some embodiments, the method for treating diseases and conditions associated with monoamine oxidase (MAO) activity comprises administering to an individual in need thereof a pharmaceutical composition, the pharmaceutical composition comprising a compound of formula (VI): [ka] wherein R1 and R2 are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle, where alkyl, alkenyl, alkynyl, or acyl is optionally selected from one or more independently selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, NRARB, -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle. Substituted by a substituent, where R A and R B are each independently selected from hydrogen and C1-4 alkyl, and where the aryl or heteroaryl, alone or as part of a substituent, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C1-4 alkyl, -C(O)O-C1-4 alkyl, NRCRD, -S-alkyl, -SO-alkyl, and -SO2-alkyl, where R C and R D are each independently selected from hydrogen and C1-4 alkyl. R3 is selected from the group consisting of H, alkyl, acyl, -SO2-alkyl, -SO2-aryl, and -SO2-heteroaryl, where alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, NRERF, -S-alkyl, -SO2-alkyl, -SO2-alkyl, aryl, and heteroaryl, where RE and RF are each independently selected from hydrogen and C1-4 alkyl, where aryl or heteroaryl may be independently selected from the group consisting of H, alkyl, acyl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl, -S-alkyl, -SO2-alkyl, -S-alkyl, -S-alkyl, aryl, and heteroaryl, where RE and RF are each independently selected from hydrogen and C1-4 alkyl, where aryl or heteroaryl may be independently selected from the group consisting of H, alkyl, acyl, -SO2-alkyl, -SO2-aryl, -S-alkyl, -S-alkyl, -S-alkyl, aryl, and heteroaryl, and optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, NRGRH, -S-alkyl, -SO-alkyl, and -SO2-alkyl, where RG and RH are each independently selected from hydrogen and C1-4 alkyl, or a pharma- ceutically acceptable salt or ester thereof, with the proviso that the compound is not 2,4,4-trimethyl-7-pentyl-3,3a,4,9b-tetrahydrocyclopenta[c]chromen-9-ol.

[0027] In some embodiments, the pharmaceutical composition for treating a MOA-related disease or condition comprises 2,4,4-trimethyl-7-propyl-3,3a,4,9b-tetrahydrocyclopenta[c]chromen-9-ol.

[0028] In some embodiments, the compounds disclosed herein are [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt or ester thereof.

[0029] In some embodiments, the present disclosure relates to a method of treating a sleep disorder, the method comprising administering an effective amount of a compound or pharmaceutical composition disclosed herein. In some embodiments, the method of treating a sleep disorder comprises: [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt or ester thereof to a subject in need thereof. [Brief description of the drawings]

[0030] [Figure 1]Response curves of increasing concentrations of test compound 2,4,4-trimethyl-7-propyl-3,3a,4,9b-tetrahydrocyclopenta[c]chromen-9-ol (T-101, circle symbols) and reference compound R(-)-deprenyl (square symbols) are shown as indicated on the x-axis. Percent inhibition of MAO-B is shown on the y-axis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] Cannabinoids produced by the Cannabis sativa plant have the potential to treat a wide variety of diseases and other human ailments. Over 100 different cannabinoids have been isolated from cannabis, with each cannabinoid compound exhibiting a variety of effects. For example, THC is well known for its psychological effects, while CBD is known for its non-psychoactive effects. THC and related derivatives typically exert their therapeutic activity through cannabinoid receptors found in humans and other mammals. CBD is an isomer of THC. CBD and CBD derivatives also exhibit antioxidant and anti-inflammatory effects through pathways not related to cannabinoid receptors. Cannabinoid type 1 (CB1) 1 CB receptors are found primarily in the brain, including the basal ganglia and limbic system, as well as the hippocampus and striatum, as well as the cerebellum. 1 Receptors can be found in the anterior segment of the human eye and in the retina. Research has shown that cannabinoid type 2 (CB 2 ) receptor is responsible for the anti-inflammatory and other therapeutic effects associated with cannabinoids.

[0032] For example, cannabis plants that contain high levels of cannabinoids such as THC are typically known as "marijuana" plants. Cannabis plants with low cannabinoid content are classified as "hemp" plants. Typically, individual countries determine the levels of cannabinoids that distinguish cannabis plants classified as marijuana plants or hemp plants. Generally, cannabis plants classified as hemp plants have a THC content of 0.3% or less on a dry weight basis. Cannabis sativa plants with THC, CBD, and other cannabinoid content levels above 0.3% are typically considered marijuana plants. Medical marijuana typically contains levels of cannabinoids between 5-20%. Other Cannabis sativa plants may produce levels of cannabinoids between 25-30%.

[0033] The biosynthetic pathway in Cannabis sativa plants that produces various cannabinoids starts with the precursor cannabigerolic acid. The enzymes THCA synthase and CBDA synthase catalyze the biosynthesis of cannabigerolic acid to tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), respectively, as well as other cannabinoids. Various other cannabinoids are known to be produced via this pathway. THC, CBD, and other cannabinoid derivatives are artificially produced from THCA and CBDA by nonenzymatic decarboxylation. Aizpurua-Olaizola et al., "Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes," J.Natural Prods.2016 79(2),324-331. Various classes of cannabinoids are biosynthesized via this general pathway, including THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiol acid), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclol), CBV (cannabivarin), THCV (tetrahydrocannabivarin), CBDV (cannabidivarin), CBCV (cannabichromevarin), CBGV (cannabigerovarin), CBGM (cannabigerol monomethyl ether), CBE (cannabiersoin), and CBT (cannabicitran).

[0034] I. Synthetic cannabinoid derivatives According to some embodiments, the synthetic cannabinoid derivative has the structure of formula (I): [ka] (In the formula, R 1 and R 2are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle, where alkyl, alkenyl, alkynyl, or acyl is optionally selected from halogen, -OH, alkyl, -O-alkyl, NR A R B , -S-alkyl, -SO-alkyl, -SO 2 - substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle, where R A and R B is hydrogen and C 1~4 alkyl, where aryl or heteroaryl, alone or as part of a substituent, are optionally selected from halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C 1~4 Alkyl, -C(O)OC 1~4 Alkyl, NR C R D , -S-alkyl, -SO-alkyl, and -SO 2 -alkyl, where R C and R D is hydrogen and C 1~4 are each independently selected from alkyl, R 3 is H, alkyl, acyl, -SO 2 -Alkyl, -SO 2 -aryl and -SO 2 -heteroaryl, where alkyl is optionally selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, NR E R F , -S-alkyl, -SO-alkyl, -SO 2 - substituted with one or more substituents independently selected from the group consisting of alkyl, aryl, and heteroaryl, where R E and R F is hydrogen and C 1~4alkyl, where aryl or heteroaryl, alone or as part of a substituent, are optionally selected from halogen, —OH, alkyl, —O-alkyl, NR G R H , -S-alkyl, -SO-alkyl, and -SO 2 -alkyl, where R G and R H is hydrogen and C 1~4 are each independently selected from alkyl, each --------- represents a single bond or a double bond, provided that within a five-membered ring, --------- is a double bond, and the other four --------- is a single bond), or a pharma- ceutically acceptable salt or ester thereof.

[0035] In some embodiments, the synthetic cannabinoid derivative has the structure of formula (IA): [ka] (In the formula, R 1 , R 2 , and R 3 is as defined above).

[0036] In other embodiments, the synthetic cannabinoid derivative has the structure of formula (II): [ka] (In the formula, R 1 , R 2 , R 3 , and --------- is as defined above), or a pharma- ceutically acceptable salt or ester thereof.

[0037] According to another embodiment, the synthetic cannabinoid derivative has the structure of formula (II): [ka] (In the formula, R1 , R 2 , and R 3 is as defined above), or a pharma- ceutically acceptable salt or ester thereof.

[0038] In some embodiments, the synthetic cannabinoid derivative has the structure of formula (III): [ka] (In the formula, R 1 , R 2 , R 3 , and --------- is as defined above), or a pharma- ceutically acceptable salt or ester thereof.

[0039] In some embodiments, the synthetic cannabinoid derivative has the structure of formula (IIIA): [ka] (In the formula, R 1 , R 2 , and R 3 is as defined above).

[0040] In other embodiments, the synthetic cannabinoid derivative has the structure of formula (IV): [ka] (In the formula, R 1 , R 2 , R 3 , and --------- is as defined above), or a pharma- ceutically acceptable salt or ester thereof.

[0041] According to another embodiment, the synthetic cannabinoid derivative has the structure of formula (IVA): [ka] (In the formula, R 1 , R 2 , and R 3is as defined above), or a pharma- ceutically acceptable salt or ester thereof.

[0042] According to some embodiments, the synthetic cannabinoid derivative has the structure of formula (V): [ka] (In the formula, R 1 and R 2 are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle, where alkyl, alkenyl, alkynyl, or acyl is optionally selected from halogen, -OH, alkyl, -O-alkyl, NR A R B , -S-alkyl, -SO-alkyl, -SO 2 - substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle, where R A and R B is hydrogen and C 1~4 alkyl, where aryl or heteroaryl, alone or as part of a substituent, are optionally selected from halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C 1~4 Alkyl, -C(O)OC 1~4 Alkyl, NR C R D , -S-alkyl, -SO-alkyl, and -SO 2 -alkyl, where R C and R D is hydrogen and C 1~4 are each independently selected from alkyl, R 3 is H, alkyl, acyl, -SO 2 -Alkyl, -SO 2 -aryl and -SO 2-heteroaryl, where alkyl is optionally selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, NR E R F , -S-alkyl, -SO-alkyl, -SO 2 - substituted with one or more substituents independently selected from the group consisting of alkyl, aryl, and heteroaryl, where R E and R F is hydrogen and C 1~4 alkyl, where aryl or heteroaryl, alone or as part of a substituent, are optionally selected from halogen, —OH, alkyl, —O-alkyl, NR G R H , -S-alkyl, -SO-alkyl, and -SO 2 -alkyl, where R G and R H is hydrogen and C 1~4 alkyl), or a pharma- ceutically acceptable salt or ester thereof, with the proviso that the compound is not 2-(3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol.

[0043] According to another embodiment, the synthetic cannabinoid derivative has the structure of formula (VI): [ka] (In the formula, R 1 R 2 , and R 3 is as defined above) or a pharma- ceutically acceptable salt or ester thereof, with the proviso that the compound is not 2,4,4-trimethyl-7-pentyl-3,3a,4,9b-tetrahydrocyclopenta[c]chromen-9-ol.

[0044] According to another aspect, the synthetic cannabinoid derivative has the structure: [ka]

[0045] As used herein, the term “alkyl” alone or as part of a substituent refers to a saturated C 1 ~C n refers to a carbon chain, where the carbon chain can be straight or branched, and where n can be 2, 3, 4, 5, 6, 7, 8, 9, or 10. Suitable examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl.

[0046] As used herein, the term “alkenyl” alone or as part of a substituent means any of the following: 2 ~C n refers to a carbon chain, where the carbon chain may be straight or branched, where the carbon chain contains at least one carbon-carbon double bond, and where n can be 3, 4, 5, 6, 7, 8, 9, or 10.

[0047] As used herein, the term “alkynyl” alone or as part of a substituent means C 2 ~C n wherein the carbon chain can be straight or branched, and wherein the carbon chain contains at least one carbon-carbon triple bond, and wherein n can be 3, 4, 5, 6, 7, 8, 9, or 10.

[0048] As used herein, the term "aryl" alone or as part of a substituent refers to an unsubstituted carboxylic acid aromatic ring containing 6 to 14 carbon atoms. Suitable examples include, but are not limited to, phenyl and naphthyl.

[0049] As used herein, the term "protected hydroxyl" refers to a hydroxyl group substituted with an appropriately selected oxygen protecting group. More specifically, a "protected hydroxyl" is a group of the formula -OPG 1In the formula, PG 1 is an appropriately selected oxygen protecting group. During any of the processes for preparing the compounds of the present disclosure, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be accomplished using conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. MacOmie, Plenum Press, 1973; and TW Greene & P. ​​G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups can be removed at a later convenient stage using methods known in the art.

[0050] As used herein, the term "oxygen protecting group" refers to a group that can be attached to an oxygen atom to prevent the oxygen atom from participating in a reaction, and can be easily removed after the reaction. Suitable oxygen protecting groups include, but are not limited to, acetyl, benzoyl, t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, and THP. Other suitable oxygen protecting groups can be found in literature such as TW Greene & P. ​​GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

[0051] As used herein, the term "nitrogen protecting group" refers to a group that can be attached to a nitrogen atom to prevent the nitrogen atom from participating in a reaction and that can be easily removed after the reaction. Suitable nitrogen protecting groups include carbamate groups of the formula -C(O)-OR, where R is methyl, ethyl, t-butyl, benzyl, phenylethyl, CH 2 =CH-CH 2 -, etc.), amide groups of the formula -C(O)-R', where R' can be methyl, phenyl, trifluoromethyl, etc., 2-R" N-sulfonyl derivative groups, where R" can be tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, etc. Other suitable nitrogen protecting groups can be found in references such as TW Greene & P. ​​GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

[0052] As used herein, the term "acyl" refers to a group of the formula -CO-C n In the formula, C n represents a straight or branched alkyl chain, and n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0053] As used herein, the term "heteroaryl" refers to any 5- or 6-membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N, and S, and optionally containing 1 to 3 additional heteroatoms independently selected from the group consisting of O, N, and S, or a 9- or 10-membered bicyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N, and S, and optionally containing 1 to 4 additional heteroatoms independently selected from the group consisting of O, N, and S. The heteroaryl group may be attached at any heteroatom or carbon atom of the ring that results in a stable structure. Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolidinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and pteridinyl.

[0054] As used herein, the term "cycloalkyl" refers to any monocyclic ring containing 4 to 6 carbon atoms, or a bicyclic ring containing 8 to 10 carbon atoms. The cycloalkyl group may be attached to any carbon atom of the ring that results in a stable structure. Examples of suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0055] As used herein, the term "heterocycle" refers to any 4- to 6-membered monocyclic ring structure containing at least one heteroatom selected from the group consisting of O, N, and S, and optionally containing 1-3 additional heteroatoms independently selected from the group consisting of O, N, and S, or an 8- to 10-membered bicyclic ring structure containing at least one heteroatom selected from the group consisting of O, N, and S, and optionally containing 1-4 additional heteroatoms independently selected from the group consisting of O, N, and S. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring that results in a stable structure. Examples of suitable heterocyclic groups include, but are not limited to, azetidine, azeto, oxetane, oxeto, thietane, thiet, diazetidine, diazeto, dioxetane, dioxetate, dithietane, dithiet, pyrrolidine, pyrrole, tetrahydrofuran, furan, thiolane, thiophene, piperidine, oxane, thiane, pyridine, pyran, and thiopyran.

[0056] The groups described herein may be unsubstituted or substituted as defined herein. Further, the substituents may be any of the following: C 1 ~C 6 Alkyl, C 1~4 Alkyl, -OC 1~4 Alkyl, hydroxyl, amino, (C 1~4 Alkyl)amino, di(C 1~4 Alkyl)amino, -S-(C 1~4 alkyl), -SO-(C 1~4 Alkyl), -SO 2 -(C1~4 The alkyl group may be substituted with one or more groups such as alkyl, halogen, aryl, heteroaryl, etc.

[0057] With reference to substituents, the term "independently" means that when more than one of such substituents may be present, such substituents may be the same or different from each other.

[0058] The compounds of the present disclosure may contain at least one hydroxyl group. The at least one hydroxyl group may form an ester with an inorganic or organic acid. In particular, a pharma-ceutically acceptable acid. The ester(s) may form a chiral carbon. The present disclosure covers all stereochemical forms of the compounds of the present disclosure, including those formed by forming one or more ester groups.

[0059] II. NON-LIMITING EXAMPLES OF SYNTHETIC CANNABINOID DERIVATIVES ACCORDING TO THE DISCLOSURE Non-limiting examples of synthetic cannabinoid derivatives according to Formulas I, IA, II, and IIA are shown below. [ka] [ka] [ka] [ka] [ka] [ka]

[0060] Non-limiting examples of synthetic cannabinoid derivatives according to formulas III, IIIA, IV, and IVA are shown below. [ka] [ka] [ka] [ka] [ka] [ka]

[0061] Non-limiting examples of synthetic cannabinoid derivatives according to Formulas V and VI are shown below. [ka] [ka] [ka] [ka] [ka] [ka] 5-Methyl-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)benzene-1,3-diol [ka] 2-((1R,5R)-3-Methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-propylbenzene-1,3-diol [ka] 5-Butyl-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)benzene-1,3-diol [ka] 2,4-Dihydroxy-3-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-6-pentylbenzoic acid [ka] 2,4-Dihydroxy-3-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-6-propylbenzoic acid [ka] 3-Methoxy-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylphenol [ka] 5-Butyl-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)benzene-1,3-diol [ka] (3R,4R)-3-(2,6-dihydroxy-4-pentylphenyl)-4-(prop-1-en-2-yl)cyclopent-1-ene-1-carboxylic acid [ka] 2-((1R,5R)-3-(hydroxymethyl)-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol [ka] (2S,3S,4S,5R)-3,4,5-trihydroxy-6-(3-hydroxy-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylphenoxy)tetrahydro-2H-pyran-2-carboxylic acid [ka] 6-((1S,2S)-2-(2,6-dihydroxy-4-methylphenyl)-4-methylcyclopent-3-en-1-yl)-3-hydroxyhept-6-en-2-one [ka] 3-Phenyl-1-(2,4,6-trihydroxy-3-((1S,5S)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)phenyl)propan-1-one [ka] 2-((1S,5S)-5-isopropyl-3-methylcyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol [ka] 5-Butyl-2-((1R,2S)-2-isopropyl-4-methylcyclopentyl)benzene-1,3-diol [ka] 2-((1S,5S)-3-(hydroxymethyl)-5-isopropylcyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol [ka] 2-((1R)-3-(hydroxymethyl)-5-isopropylcyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol [ka] 2-((1R,5R)-3-Methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-(2-methyloctan-2-yl)benzene-1,3-diol [ka] (3R,4R)-3-(2,6-dihydroxy-4-(2-methyloctan-2-yl)phenyl)-4-(prop-1-en-2-yl)cyclopent-1-ene-1-carboxylic acid [ka] 2-((1R,5R)-3-(hydroxymethyl)-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-(2-methyloctan-2-yl)benzene-1,3-diol [ka] 1,3-Dimethoxy-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-(2-methyloctan-2-yl)benzene [ka] 2-((1S,5S)-5-isopropyl-3-methylcyclopent-2-en-1-yl)-5-(2-methyloctan-2-yl)benzene-1,3-diol [ka] 2-((1R,2S)-2-isopropyl-4-methylcyclopentyl)-5-(2-methyloctan-2-yl)benzene-1,3-diol [ka] (S)-(3-(2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl)-4,4-dimethylcyclopent-1-en-1-yl)methanol [ka] (R)-(3-(2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl)-5,5-dimethylcyclopent-1-en-1-yl)methanol [ka] 1-(3-(3,5-dihydroxy-4-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)benzyl)azetidin-1-yl)ethan-1-one [ka] 5-(2-(1H-1,2,3-triazol-1-yl)ethyl)-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)benzene-1,3-diol [ka] 2-(3,5-dihydroxy-4-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)phenyl)-1-morpholinoethan-1-one [ka] 2-(3,5-dihydroxy-4-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)phenyl)-1-morpholinoethan-1-one [ka] 5-(4-hydroxybutyl)-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)benzene-1,3-diol [ka] 4-(3,5-dihydroxy-4-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)phenyl)butanoic acid [ka] 5-(2-ethoxyethyl)-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)benzene-1,3-diol [ka] 4-Chloro-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol [ka] 4,6-Dichloro-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol [ka] 4-Bromo-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol [ka] 4,6-Dibromo-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol [ka] 4-Iodo-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol [ka] 4,6-Diiodo-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol [ka] 4-Fluoro-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol [ka] 2-((1R,5R)-5-(1-fluorovinyl)-3-methylcyclopent-2-en-1-yl)-5-pentyl-1,3-phenylenediacetate [ka] 2-((1R,5R)-3-(fluoromethyl)-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol [ka] 1,3-Dimethoxy-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene [ka] 2-((1R,5R)-3-Methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylphenol [ka] (3S,4S)-3-(2,6-diacetoxy-4-pentylphenyl)-4-isopropylcyclopent-1-ene-1-carboxylic acid [ka] (3R,4R)-3-(2-(carboxymethoxy)-6-hydroxy-4-pentylphenyl)-4-(prop-1-en-2-yl)cyclopent-1-ene-1-carboxylic acid [ka] 3-(3-aminopropoxy)-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylphenol [ka] 2,2'-((2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentyl-1,3-phenylene)bis(oxy))diacetonitrile [ka] Bis((diethylamino)methyl)(2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentyl-1,3-phenylene)bis(carbonate) [ka] 2-((1R,5R)-3-Methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentyl-1,3-phenylenebis(2-((tert-butyldimethylsilyl)oxy)acetate) [ka] 2-((1R,5R)-3-Methyl-5-(3-oxoprop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentyl-1,3-phenylenediacetate [ka] 2-((1R,5R)-3-Methyl-4-oxo-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentyl-1,3-phenylenediacetate [ka] 2-((1R,5R)-4-acetoxy-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentyl-1,3-phenylenediacetate [ka] 2-((1R,5R)-5-(3-acetoxyprop-1-en-2-yl)-3-methylcyclopent-2-en-1-yl)-5-pentyl-1,3-phenylenediacetate [ka] 3-Hydroxy-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylcyclohexa-2,5-diene-1,4-dione [ka] 2-(Butylamino)-5-hydroxy-6-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-3-pentylcyclohexa-2,5-diene-1,4-dione [ka] 2-(Benzylamino)-5-hydroxy-6-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-3-pentylcyclohexa-2,5-diene-1,4-dione [ka] 5-Methyl-4-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)benzene-1,3-diol [ka] 4-((1R,5R)-3-Methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol [ka] (Z)-2-(3,6-dimethylhepta-2,5-dien-1-yl)-5-pentylbenzene-1,3-diol [ka] (3aR,9bR)-9-Hydroxy-4,4-dimethyl-7-(2-methyloctan-2-yl)-1,3a,4,9b-tetrahydrocyclopenta[c]chromene-2-carboxylic acid [ka] 2-(Benzylamino)-5-hydroxy-6-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-3-pentylcyclohexa-2,5-diene-1,4-dione [ka] 4-((3-methyl-1-oxo-1-(((3aR,9bR)-2,4,4-trimethyl-7-pentyl-3,3a,4,9b-tetrahydrocyclopenta[c]chromen-9-yl)oxy)butan-2-yl)amino)-4-oxobutanoic acid [ka] 4-((1-((3-hydroxy-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylcyclohexa-2,5-dien-1-yl)oxy)-3-methyl-1-oxobutan-2-yl)amino)-4-oxobutanoic acid [ka] 1-(3-(3,5-dihydroxy-4-((1R,5R)-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)benzyl)azetidin-1-yl)ethan-1-one [ka] [ka]

[0062] III. Synthesis and Purification of Cannabinoid Compounds In some examples, the cannabinoid compounds described herein may be formed as salts, which may serve to improve chemical purity, stability, solubility, and / or bioavailability. Non-limiting examples of possible salts are described in PH Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection and In the Journal of Chemical Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002, it is described that 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, Includes salts of gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid.

[0063] The compounds described herein can be synthetically prepared using known techniques with appropriate modification of reactants to form the structures shown herein, or by other suitable routes that are obvious to those skilled in the art.As a non-limiting example, the compounds described herein can be synthesized according to one or more of the following routes described in Razdan, Total Synthesis of Cannabinoids, SISA Incorporated, Cambridge, Massachusetts, with appropriate modification of reactants, as would be obvious to those skilled in the art, to obtain the structures disclosed herein.Alternatively, the synthetic techniques described in U.S. Patent No. 10,059,683 B2 to Dialer et al. (the entire disclosure of which is incorporated herein by reference) can be appropriately adapted to synthesize the cannabinoid derivatives described herein.

[0064] Example 1 herein provides an exemplary synthesis process for 2,4,4-trimethyl-7-propyl-3,3a,4,9b-tetrahydrocyclopenta[c]chromen-9-ol (compound T-101).

[0065] Compounds intended for administration to humans or other mammals generally need to have a very high purity. For synthetically prepared compounds, purity refers to the ratio of the mass of the compound after any purification steps to the total mass of the sample. Typically, the level of purity is at least about 95%, more typically at least about 96%, about 97%, about 98%, or more. For example, the level of purity can be about 98.5%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or more.

[0066] Compounds described herein that exist in two or more optical isomeric forms (enantiomers) can be provided either as a racemic mixture or by isolating one of the enantiomers, in which case purity as described above may refer to enantiomeric purity.

[0067] IV.How to use As mentioned above, cannabinoids and related cannabinoid derivatives are typically derived from CB 2 They exert therapeutic and anti-inflammatory activities via cannabinoid receptors. Without wishing to be bound by theory, the compounds disclosed herein may also exhibit properties as inhibitors of monoamine oxidase (MAO) activity, including either or both of MAO-A and MAO-B activity. These properties may make the compounds effective in treating indications associated with MAO activity, such as depression, pain, sleep disorders, substance addiction, smoking cessation, etc. 3. Thus, in some embodiments, the compounds disclosed herein can be used in methods of treating diseases and conditions associated with monoamine oxidase (MAO) activity. In some embodiments, the individual suffers from depression, pain, sleep disorders, or addiction. In some embodiments, the method of treating diseases and conditions associated with monoamine oxidase (MAO) activity comprises administering to an individual in need thereof a pharmaceutical composition, the pharmaceutical composition comprising a compound having the structure of formula (VI): [ka] wherein R1 and R2 are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle, where alkyl, alkenyl, alkynyl, or acyl is optionally independently selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, NRARB, -S-alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle. or more substituents, R A and R B are each independently selected from hydrogen and C1-4 alkyl, where the aryl or heteroaryl, alone or as part of a substituent, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C1-4 alkyl, -C(O)O-C1-4 alkyl, NRCRD, -S-alkyl, -SO-alkyl, and -SO2-alkyl, and R C and R D are each independently selected from hydrogen and C1-4 alkyl. R3 is selected from the group consisting of H, alkyl, acyl, -SO2-alkyl, -SO2-aryl, and -SO2-heteroaryl, where alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, NRERF, -S-alkyl, -SO2-alkyl, -SO2-alkyl, aryl, and heteroaryl, where RE and RF are each independently selected from hydrogen and C1-4 alkyl, where aryl or heteroaryl is and optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, NRGRH, -S-alkyl, -SO-alkyl, and -SO2-alkyl, where RG and RH are each independently selected from hydrogen and C1-4 alkyl), either alone or as part of a substituent, or a pharma- ceutically acceptable salt or ester thereof, with the proviso that the compound is not 2,4,4-trimethyl-7-pentyl-3,3a,4,9b-tetrahydrocyclopenta[c]chromen-9-ol.

[0068] In some embodiments, the pharmaceutical composition for treating a MOA-related disease or condition comprises 2,4,4-trimethyl-7-propyl-3,3a,4,9b-tetrahydrocyclopenta[c]chromen-9-ol.

[0069] Compounds disclosed herein may also (or alternatively) exhibit anti-inflammatory properties due to the interaction of the compounds with inflammatory pathways including, by way of example, interleukins such as IL-1 and IL-6, TNF-α, cyclooxygenase (COX), etc. The ability of a compound to inhibit MAO-A and / or MAO-B activity, and / or its ability to inhibit COX and / or other pathways associated with inflammation, may be assessed using assays well known to those of skill in the art.

[0070] In some aspects, the cannabinoid derivatives described herein are administered to an individual in need thereof for the treatment of a substance addiction, such as alcohol, tobacco, opioid, prescription drug, cocaine, benzodiazepine, amphetamine, hallucinogen, inhalant, phencyclidine, or other drug addiction. Such treatments include the treatment of withdrawal symptoms of benzodiazepine, opiate, or alcohol addiction, as well as symptoms experienced by patients with substance use disorders, such as anxiety, mood symptoms, pain, and sleep disorders, such as insomnia.

[0071] In addition to anxiety associated with substance use disorders, cannabinoid derivatives may also be effective in treating other types of anxiety disorders, such as post-traumatic stress disorder, generalized anxiety disorder, panic disorder, social anxiety disorder, and obsessive-compulsive disorder.

[0072] In other aspects, the cannabinoid derivatives described herein may be administered to an individual in need thereof for the treatment of multiple sclerosis, fibromyalgia, epilepsy, or epilepsy-related neuropsychiatric disorders such as neurodegenerative, neurological injury, and psychiatric disorders. The cannabinoid derivatives may be effective in enhancing the anticonvulsant activity of other active agents such as phenytoin and diazepam.

[0073] In yet another aspect, the cannabinoid derivatives described herein may be used as antipsychotics to treat patients with schizophrenia. The cannabinoid derivatives may also be effective in reducing intraocular pressure, such as in the treatment of glaucoma.

[0074] In yet another aspect, the cannabinoid derivatives described herein may be administered to an individual in need thereof for the treatment of cancer. The cannabinoid derivatives may be effective in blocking the spread of cancer cells throughout the body and invading entire regions to inhibit the growth of cancer cells and / or promote the death of cancer cells.

[0075] The cannabinoid derivatives described herein can be useful in treating type 1 diabetes, which is caused by inflammation when the immune system attacks cells in the pancreas, and acne, which is caused in part by inflammation in the body and overworked sebaceous glands.The anti-inflammatory properties of the compounds can reduce the production of sebum, which leads to acne, including acne vulgaris, the most common form of acne.

[0076] The cannabinoid derivatives described herein can be used to treat Alzheimer's disease, and particularly when administered at the early stage of Alzheimer's disease, to prevent the onset of social cognitive impairment in subjects.Other examples of disorders that can be treated by the cannabinoid derivatives described herein include nausea, vomiting, anorexia, and cachexia.The compound can produce an appetite-enhancing effect, for example, in AIDS patients who refuse food or individuals with Alzheimer's disease.

[0077] The cannabinoid derivatives described herein may be useful in treating spasticity caused by multiple sclerosis (MS) or movement disorders such as spinal cord injury, Tourette's syndrome, dystonia, or tardive dyskinesia. MS patients may experience benefits with regard to reduced ataxia and tremors.

[0078] The analgesic properties of cannabinoid derivatives may prove beneficial in the treatment of, for example, neuropathic pain due to multiple sclerosis, brachial plexus injuries and HIV infection, rheumatoid arthritis pain, cancer pain, headaches, menstrual pain, chronic enteritis, and neuralgia.

[0079] The cannabinoid derivatives described herein may be useful in the treatment of asthma. Experiments investigating the anti-asthmatic effects of THC or cannabis date mainly back to the 1970s and are all acute studies. The effects of cannabis cigarettes (2% THC) or oral THC (15 mg), respectively, are roughly equivalent to those obtained with therapeutic doses of common bronchodilators (salbutamol, isoprenaline). Inhalation of cannabis products may irritate mucous membranes, so oral administration or another alternative delivery system would be preferable. Very few patients developed bronchoconstriction after inhalation of THC.

[0080] In some clinical studies with THC, mood improvement in reactive depression has been observed. Further case reports exist claiming the benefit of cannabinoids in other psychiatric conditions and diseases, such as sleep disorders, anxiety disorders, bipolar disorder, and dysthymia. Regarding psychiatric syndromes and cannabis, different authors express different views. Some emphasize the problems caused by cannabis, while others encourage its therapeutic potential. It is highly likely that cannabis products can be beneficial or harmful, depending on the specific case. The attending physician and the patient should be open to a critical review of this topic, and an openness to both possibilities.

[0081] In many painful syndromes secondary to inflammatory processes (e.g. ulcerative colitis, arthritis), cannabis products may not only act as analgesics but also show anti-inflammatory capabilities. For example, some patients using cannabis report a reduced need for steroidal and non-steroidal anti-inflammatory drugs. Furthermore, there are some reports of the positive effects of cannabis self-medication in allergic symptoms. It is still unclear whether cannabis products can have a relevant impact on the causative processes of autoimmune diseases.

[0082] There are many positive patient reports of conditions that cannot be easily classified into the above categories, such as pruritus, hiccups, ADS (attention deficit syndrome), hypertension, tinnitus, chronic fatigue syndrome, restless legs syndrome, etc. Various authors have described hundreds of possible indications for cannabis and THC. For example, 2.5-5 mg of THC was effective in three patients with pruritus caused by liver disease. Another example is the successful treatment of chronic hiccups that developed after surgery. No medication was effective, but smoking cannabis cigarettes completely eliminated the symptoms.

[0083] Cannabis products often have a very positive effect in diseases with multiple symptoms that fall within the spectrum of THC's effects, such as pain conditions caused by inflammation (e.g. arthritis) or accompanied by increased muscle tone (e.g. menstrual cramps, spinal cord injuries), or diseases in which there is nausea and loss of appetite accompanied by pain, anxiety and depression, respectively (e.g. AIDS, cancer, Hepatitis C).

[0084] COVID-19 is transmitted via respiratory droplets and uses receptor-mediated entry into the human host via angiotensin-converting enzyme II (ACE2), which is expressed in lung tissues as well as oral and nasal mucosa, kidneys, testes, and the gastrointestinal tract. Modulating ACE2 levels in these gateway tissues may reduce disease susceptibility. See Wang et al., In Search of Preventative Strategies: Novel Anti-Inflammatory High-CBD Cannabis Sativa Extracts Modulate ACE2 Expression in COVID-19 Gateway Tissues (17 April 2020), doi:10.20944 / preprints202004.0315.v1. The cannabinoid derivatives described herein can modulate ACE2 expression and may be useful in treating coronaviruses such as COVID-19.

[0085] In some embodiments, the present disclosure relates to a method of treating a sleep disorder, the method comprising administering an effective amount of [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt or ester thereof.

[0086] V. Dosage and Pharmaceutical Compositions Suitable doses can vary over a wide range depending on various factors, including type and / or severity of disease or disorder, previous treatment, overall health, age, and / or weight of the individual, frequency of treatment, release rate from the composition, and other diseases present.This dose can vary depending on factors such as the disease state, age, and weight of the subject.For example, higher doses can be administered for treatment with advanced and / or life-threatening conditions.Dosage regimes can also be adjusted to provide optimal therapeutic response.

[0087] Pharmaceutical compositions can be formulated with one or more acceptable pharmaceutical or food grade carriers or excipients.As used herein, the term "acceptable pharmaceutical or food grade carriers or excipients" refers to any type of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary. For example, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; excipients such as powdered tragacanth, malt, gelatin, talc, cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate, and the like; buffers such as agar-agar, magnesium hydroxide, and aluminum hydroxide; alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and phosphate buffers; and compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants can also be present in the composition according to the judgment of the formulator.

[0088] The pharmaceutical composition can be prepared by any suitable technique and is not limited by any particular method for its manufacture. For example, purified cannabinoids may be combined with excipients and binders and then granulated. The granules may be dry blended with the remaining ingredients and compressed into a solid form such as a tablet.

[0089] The pharmaceutical composition may be administered by any suitable route. For example, the composition may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, via an implanted reservoir, or taken as a dietary supplement or food. In some embodiments, the composition is provided in an inhaler, which may be actuated to administer a vaporized medium that is inhaled into the lungs. The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, and intracranial injection or infusion techniques. Most often, the pharmaceutical composition is easily administered and taken orally.

[0090] Pharmaceutical compositions can contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle.In some cases, the pH of the formulation can be adjusted with acceptable pharmaceutical or food grade acid, base or buffer to enhance the stability of the formulated composition or its delivery form.

[0091] Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs of acceptable pharmaceutical or food grade.In addition to active compounds, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylsulfoxide (DMSO) dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and aromatic agents.

[0092] The solid dosage form for oral administration includes capsules, tablets, lozenges, pills, powders, and granules.In these solid dosage forms, the active compound is mixed with sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) glycerol, d ... ) a solution retarder such as paraffin, f) an absorption enhancer such as a quaternary ammonium compound, g) a wetting agent such as cetyl alcohol and glycerol monostearate, h) an absorbent such as kaolin and bentonite clay, i) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, and j) mixed with at least one inert acceptable pharmaceutical or food grade excipient or carrier such as a sweetener, a flavoring agent, a perfuming agent, and mixtures thereof. In the case of capsules, lozenges, tablets, and pills, the dosage form may also include a buffering agent.

[0093] The solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They can optionally contain opacifying agents and can be of a composition that releases the active ingredient(s) only, or preferably in a certain part of the intestinal tract, or optionally in a delayed or sustained release manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Tablet formulations for sustained release are also described in U.S. Patent No. 5,942,244.

[0094] The composition may contain the cannabinoid derivative or compound alone or in combination with other therapeutic compound(s). A therapeutic compound is a compound that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or affects the structure or any function of the human or animal body. The therapeutic compounds disclosed herein may be used in the form of a pharmaceutically acceptable salt, solvate, or solvate of a salt, such as a hydrochloride salt. Additionally, the therapeutic compounds disclosed herein may be provided as racemates or as individual enantiomers, including R- or S-enantiomers. Thus, the therapeutic compounds disclosed herein may include only the R-enantiomer, only the S-enantiomer, or a combination of both the R-enantiomer and the S-enantiomer of the therapeutic compound. In some embodiments, the therapeutic compounds may have anti-inflammatory activity, such as nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are a large group of therapeutic compounds that have analgesic, anti-inflammatory, and antipyretic properties. NSAIDs reduce inflammation by blocking cyclooxygenase.NSAIDs include aceclofenac, acemetacin, actarit, alcofenac, alminoprofen, amfenac, aloxipirin, aminophenazone, anthraphenine, aspirin, azapropazone, benorylate, benoxaprofen, benzydamine, butibufen, celecoxib, chlortenoxacin, choline salicylate, clometacin, dexketoprofen, diclofenac, diflunisal, emorfazone, epirizole, etodolac, etoricoxib, feclobuzone, felbinac, fenbufen, fenclofenac, flurbiprofen, glafenine, hydroxyethyl salicylate, These include, but are not limited to, ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac, lactylphenetidine, loxoprofen, lumiracoxib, mefenamic acid, meloxicam, metamizole, methazinic acid, mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, niflumic acid, oxametacin, phenacetin, pipebuzone, pranoprofen, propyphenazone, proquazone, protizinic acid, rofecoxib, salicylamide, salsalate, sulindac, suprofen, tiaramide, tinoridine, tolfenamic acid, valdecoxib, and zomepirac.

[0095] NSAIDs can be classified based on their chemical structure or mechanism of action. Non-limiting examples of NSAIDs include salicylic acid derivatives NSAIDs, p-aminophenol derivatives NSAIDs, propionic acid derivatives NSAIDs, acetic acid derivatives NSAIDs, enolic acid derivatives NSAIDs, fenamic acid derivatives NSAIDs, non-selective cyclooxygenase (COX) inhibitors, selective cyclooxygenase-1 (COX-1) inhibitors, and selective cyclooxygenase-2 (COX-2) inhibitors. The NSAID can be a profen. Examples of suitable salicylic acid derivatives NSAIDs include, but are not limited to, acetylsalicylic acid (aspirin), diflunisal, and salsalate. Examples of suitable p-aminophenol derivatives NSAIDs include, but are not limited to, paracetamol and phenacetin. Examples of suitable propionic acid derivatives NSAIDs include, but are not limited to, aluminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, and suprofen. Examples of suitable acetic acid derivatives NSAIDs include, but are not limited to, aceclofenac, acemetacin, actarit, alcofenac, amfenac, clometacin, diclofenac, etodolac, felbinac, fenclofenac, indomethacin, ketorolac, metiazinic acid, mofezolac, nabumetone, naproxen, oxametacin, sulindac, and zomepirac. Examples of suitable enolic acid (oxicam) derivative NSAIDs include, but are not limited to, droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, and tenoxicam. Examples of suitable fenamic acid derivative NSAIDs include, but are not limited to, flufenamic acid, mefenamic acid, meclofenamic acid, and tolfenamic acid. Examples of suitable selective COX-2 inhibitors include, but are not limited to, celecoxib, etoricoxib, firocoxib, lumiracoxib, meloxicam, parecoxib, rofecoxib, and valdecoxib.

[0096] The therapeutically effective amount of the therapeutic compounds disclosed herein generally ranges from about 0.001 mg / kg / day to about 100 mg / kg / day. An effective amount can be, for example, at least 0.001 mg / kg / day, at least 0.01 mg / kg / day, at least 0.1 mg / kg / day, at least 1.0 mg / kg / day, at least 5.0 mg / kg / day, at least 10 mg / kg / day, at least 15 mg / kg / day, at least 20 mg / kg / day, at least 25 mg / kg / day, at least 30 mg / kg / day, at least 35 mg / kg / day, at least 40 mg / kg / day, at least 45 mg / kg / day, or at least 50 mg / kg / day. In some embodiments, an effective amount of a therapeutic compound may be within the range of about 0.001 mg / kg / day to about 10 mg / kg / day, about 0.001 mg / kg / day to about 15 mg / kg / day, about 0.001 mg / kg / day to about 20 mg / kg / day, about 0.001 mg / kg / day to about 25 mg / kg / day, about 0.001 mg / kg / day to about 30 mg / kg / day, about 0.001 mg / kg / day to about 35 mg / kg / day, about 0.001 mg / kg / day to about 40 mg / kg / day, about 0.001 mg / kg / day to about 45 mg / kg / day, about 0.001 mg / kg / day to about 50 mg / kg / day, about 0.001 mg / kg / day to about 75 mg / kg / day, or about 0.001 mg / kg / day to about 100 mg / kg / day. In other examples, an effective amount of a therapeutic compound disclosed herein can be in the range of, for example, about 0.01 mg / kg / day to about 10 mg / kg / day, about 0.01 mg / kg / day to about 15 mg / kg / day, about 0.01 mg / kg / day to about 20 mg / kg / day, about 0.01 mg / kg / day to about 25 mg / kg / day, about 0.01 mg / kg / day to about 30 mg / kg / day, about 0.01 mg / kg / day to about 35 mg / kg / day, about 0.01 mg / kg / day to about 40 mg / kg / day, about 0.01 mg / kg / day to about 45 mg / kg / day, about 0.01 mg / kg / day to about 50 mg / kg / day, about 0.01 mg / kg / day to about 75 mg / kg / day, or about 0.01 mg / kg / day to about 100 mg / kg / day.

[0097] In addition to pharmaceutical compositions, the compounds described herein can be formulated as elixirs, beverages, chewables, tablets, lozenges, gums, etc. According to another embodiment, the pharmaceutical compositions can also be formulated as pharma- ceutically acceptable vehicles, such as capsules, tablets, syrups, lozenges, inhalants, e-cigarettes, chewable gums, nasal sprays, transdermal patches, liquids, transmucosal vehicles, hydrogels, nanosomes, liposomes, noisomes, nanoparticles, nanospheres, microspheres, microparticles, microemulsions, nanosuspensions, or micelles. The compositions can also be formulated, for example, as dietary supplements or nutraceuticals.

[0098] The description of the embodiments of the present disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. Although specific embodiments and examples of the present disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the present disclosure, as will be recognized by those skilled in the relevant art. For example, while method steps or functions are presented in a given order, alternative embodiments may perform the functions in a different order, or may perform the functions substantially simultaneously. The teachings of the present disclosure provided herein may be applied to other procedures or methods as appropriate. The various embodiments described herein may be combined to provide further embodiments. Aspects of the present disclosure may be modified as appropriate to provide still further embodiments of the present disclosure, using the compositions, functions, and concepts of the above references and applications. Furthermore, some changes may be made to the structure of a protein without affecting the type or amount of biological or chemical activity, due to considerations of biological functional equivalence. These and other changes may be made to the present disclosure in light of the detailed description. All such modifications are intended to be within the scope of the appended claims.

[0099] Particular elements of any of the foregoing embodiments may be combined with or substituted for elements of other embodiments. Additionally, although advantages associated with certain embodiments of the present disclosure have been described in connection with those embodiments, other embodiments may also exhibit such advantages, and not all embodiments necessarily must exhibit such advantages, to fall within the scope of the present disclosure.

[0100] While the present invention has been described in terms of specific embodiments, those skilled in the art will recognize that there are numerous variations and permutations of the above-described systems and techniques that fall within the spirit and scope of the present invention as set forth in the appended claims. EXAMPLES

[0101] Example 1 - Synthesis of 2,4,4-trimethyl-7-propyl-3,3a,4,9b-tetrahydrocyclopenta[c]chromen-9-ol (Compound T-101): [ka]

[0102] Synthesis of 4-bromocyclopent-2-enone (2): To a solution of cyclopent-2-en-1-one (100 g, 1218 mmol) in anhydrous chloroform (1.50 L) at room temperature under an argon atmosphere, NBS (325 g, 1827 mmol) was added in small portions over 30 min. After the addition was complete, the reaction mixture was refluxed at 80° C. (oil bath temperature) for 48 h. The reaction mixture was cooled to room temperature, diluted with water (2.0 L) and dissolved in CH 2 Cl 2 (2×1.0 L). The combined organic extracts were washed with ice-cold water (1.0 L), brine (1.0 L) and added Na 2 SO 4 The mixture was evaporated in vacuo, dried at 40° C., filtered and concentrated under reduced pressure to give 4-bromocyclopent-2-en-1-one (150 g, 76%) as a yellow liquid.

[0103] 1 H NMR showed the desired signals: 1H NMR (400 MHz, CDCl 3 ):δ 7.67(dd,J=5.52,2.56Hz,1H),6.27(dd,J=5.52,0.95Hz,1H),5.23-5.06(m,1H),3.05(dd,J=19.5,6.28Hz,1H),2.72(dd,J=19.5,1.53Hz,1H).

[0104] Synthesis of 4-(prop-1-en-2-yl)cyclopent-2-en-1-one (3): To a stirred solution of LiCl (23.4 g, 558 mmol) in anhydrous THF (500 mL) was added CuCN (25.0 g, 279 mmol) and stirred at room temperature for 20 min. The reaction mixture was cooled to -40°C and isopropenylmagnesium bromide (279.5 mL, 0.5 M in THF, 139.7 mmol) was added dropwise over 60 min, stirred at -40°C for an additional 20 min, and then cooled to -78°C. Next, 4-bromocyclopent-2-en-1-one (15 g, 93.1 mmol, 1.0 equiv) in anhydrous THF (100 mL) was added dropwise over 60 min and the reaction mixture was stirred at -78°C for 10 min. The reaction mixture was slowly brought to 0°C and saturated NH 4 The mixture was quenched with Cl solution (500 mL) and stirred at room temperature for 30 min. The reaction mixture was filtered and the filtrate was extracted with MTBE (2×1.0 L). The combined MTBE extracts were washed with brine (2×1.0 L) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under vacuum to give the crude product. The product was purified by silica gel chromatography (15-25% MTBE in hexanes). Fractions containing the product were combined and concentrated under reduced pressure to give 4-(prop-1-en-2-yl)cyclopent-2-en-1-one (4.0 g, 35%) as a colorless oil. NOTE: Compound 3 is inherently volatile, so the bath temperature of the rotary evaporator should be <20° C. and the vacuum ~600 mbar. 1 1 H NMR showed the desired signals with a trace of MTBE solvent. 1 H NMR (400 MHz, CDCl 3):δ 7.60(dd,J=5.65,2.49Hz,1H),6.24(dd,J=5.54,1.98Hz,1H),4.90-4.71(m,2H),3.64- 3.40(m,1H),2.60(dd,J=18.8,6.75Hz,1H),2.18(dd,J=18.8,2.02Hz,1H),1.71(s,3H).

[0105] Synthesis of 1-methyl-4-(prop-1-en-2-yl)cyclopent-2-en-1-ol (4): A solution of methyllithium (1.6 M in diethyl ether, 69.1 mL, 73.72 mmol) was added dropwise over 30 min to a solution of 4-(prop-1-en-2-yl)cyclopent-2-en-1-one (9.0 g, 73 mmol) in anhydrous THF (100 mL) under argon atmosphere at -78 °C, and the reaction mixture was stirred at -78 °C for 10 min. The reaction mixture was slowly brought to 0 °C and NH 4 The mixture was quenched with Cl solution (130 mL) and extracted with MTBE (2×500 mL). The combined MTBE extracts were washed with water (500 mL), brine (500 mL) and diluted with Na 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure afforded 1-methyl-4-(prop-1-en-2-yl)cyclopent-2-en-1-ol (4.5 g, crude) as a pale yellow liquid which was used directly in the next step.

[0106] NOTE: Compound 4 is also volatile in nature, therefore the bath temperature of the rotary evaporator should be <20 °C and the vacuum ~600 mbar.

[0107] Synthesis of 2-(3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-propylbenzene-1,3-diol (5): Anhydrous CH 2 Cl 2To a stirred solution of Brockmann 1 activated basic alumina (79 g, 782 mmol) in 1H2O (300 mL) was added boron trifluoride diethyl etherate (13.4 mL, 108.6 mmol) dropwise over 20 min at room temperature. The reaction mixture was slowly heated to 40 °C and stirred for an additional 10 min, followed by addition of anhydrous CH 2 Cl 2 A solution of 1-methyl-4-(prop-1-en-2-yl)cyclopent-2-en-1-ol (6.0 g, 138.1 mmol), 5-propylbenzene-1,3-diol (4.6 g, 30 mmol) in 100 mL of ethyl acetate was added dropwise. The reaction mixture was stirred at 40° C. for 5 min. The reaction mixture was cooled to room temperature and saturated NaHCO 3 (300 mL) and dilute with CH 2 Cl 2 (300 mL x 2). The combined organic extracts were washed with water (500 mL), brine (500 mL) and added Na 2 SO 4 The crude residue was purified twice by silica gel chromatography (6-10% EtOAc in hexanes). Fractions containing pure product were combined and concentrated under reduced pressure to give 2-(3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-propylbenzene-1,3-diol (3.0 g, crude) as a brown liquid. 1 1 H NMR showed a mixture of compound 5 and compound T-101.

[0108] Synthesis of 2,4,4-trimethyl-7-propyl-3,3a,4,9b-tetrahydrocyclopenta[c]chromen-9-ol (T-101): Anhydrous CH 2 Cl 2 To a solution of 2-(3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-propylbenzene-1,3-diol (3.0 g, 9.9 mmol) in 1,2-dimethylformamide (500 mL), Fe(OTf) 3 (0.99 g, 1.98 mmol) was added and stirred at room temperature for 72 h. The reaction mixture was cooled to 0 °C and saturated NaHCO 3solution (100 mL) and quenched with CH 2 Cl 2 (2×100 mL). The combined CH 2 Cl 2 The extract was washed with water (100 mL), brine (100 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo to give the crude product. The product was purified twice by silica gel chromatography (3-6% EtOAc in hexanes). Fractions containing pure product were combined and concentrated in vacuo to give 2,4,4-trimethyl-7-propyl-3,3a,4,9b-tetrahydrocyclopenta[c]chromen-9-ol (0.86 g, 29%) as a light brown liquid.

[0109] 1 H NMR showed the desired signals: 1 H NMR 1 H NMR (400MHz, DMSO-d 6 ):9.20(s,1H),6.06(s,1H),5.96(s,1H),5.34(s,1H),3.64(d,J=6.8Hz,1H),2.66-2.60(m,1 H),2.40-2.33(m,3H),2.02-1.95(m,1H),1.70(s,3H),1.53-1.44(m,2H),0.90-0.84(m,9H). MS(MM)m / z273.1[M+H] + .

[0110] Example 2 - Inhibition of Monoamine Oxidase Response curves were generated by adding increasing concentrations of test compound to a reaction mixture containing monoamine oxidase (MAO-B or MAO-A) enzyme, using 100 mM potassium phosphate, pH 7.4 as the incubation buffer.

[0111] Spectrofluorimetric quantification of 4-hydroxyquinoline was used to determine MAO-B or MAO-A enzyme activity.

[0112] The assay was carried out essentially as described in Biochem Pharmacol. 41(2):155-162, which was carried out by Eurofins Panlabs, Inc. Where presented, IC50 values ​​were determined by nonlinear least squares regression analysis using MathIQ™ (ID Business Solutions Ltd., UK). Where inhibition constants (Ki) are presented, Ki values ​​were calculated using the Cheng-Prusoff equation (Cheng, Y., Prusoff, WH, Biochem. Pharmacol. 22:3099-3108, 1973) using the observed IC50 of the test compound, the concentration of radioligand used in the assay, and the historical value of the KD of the ligand (obtained experimentally at Eurofins Panlabs, Inc.). Where presented, the Hill coefficient (nH), which defines the slope of the competitive binding curve, was calculated using MathIQ™. A Hill coefficient that differs significantly from 1.0 may suggest that bond displacement does not follow the laws of mass action at a single binding site.

[0113] Figure 1 shows the response curve of 2,4,4-trimethyl-7-propyl-3,3a,4,9b-tetrahydrocyclopenta[c]chromen-9-ol (T-101) with increasing concentrations as shown on the x-axis, and the percent inhibition of MAO-B is shown on the y-axis. As shown in Figure 1, the IC 50 was determined to be 20.1 μM. The IC for MAO-B inhibition by the reference compound R(-)-deprenyl 50 was determined to be 9.69 nM as shown in FIG.

[0114] The following table shows further experimental results. NC shown in the table means "not calculated". [Table 1]

[0115] Clorgyline and deprenyl were used as reference compounds, as shown in Table 2 below.

Table 2

Claims

1. A compound having a structure selected from the group consisting of: or a pharmaceutically acceptable salt or ester thereof. 2,4-dihydroxy-3-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-6-pentylbenzoic acid, 2,4-dihydroxy-3-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-6-propylbenzoic acid, (3R,4R)-3-(2,6-dihydroxy-4-pentylphenyl)-4-(prop-1-en-2-yl)cyclopent-1-ene-1-carboxylic acid (2S,3S,4S,5R)-3,4,5-trihydroxy-6-(3-hydroxy-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylphenoxy)tetrahydro-2H-pyran-2-carboxylic acid, (3R,4R)-3-(2,6-dihydroxy-4-(2-methyloctan-2-yl)phenyl)-4-(prop-1-en-2-yl)cyclopent-1-ene-1-carboxylic acid, 4-(3,5-dihydroxy-4-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)phenyl)butanoic acid, 2-((1R,5R)-5-(1-fluorovinyl)-3-methylcyclopent-2-en-1-yl)-5-pentyl-1,3-phenylenediacetate, (3S,4S)-3-(2,6-diacetoxy-4-pentylphenyl)-4-isopropylcyclopent-1-ene-1-carboxylic acid, (3R,4R)-3-(2-(carboxymethoxy)-6-hydroxy-4-pentylphenyl)-4-(prop-1-en-2-yl)cyclopent-1-ene-1-carboxylic acid, 2-((1R,5R)-3-methyl-5-(3-oxoprop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentyl-1,3-phenylenediacetate, 2-((1R,5R)-3-methyl-4-oxo-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentyl-1,3-phenylenediacetate, 2-((1R,5R)-4-acetoxy-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentyl-1,3-phenylenediacetate, 2-((1R,5R)-5-(3-acetoxyprop-1-en-2-yl)-3-methylcyclopent-2-en-1-yl)-5-pentyl-1,3-phenylenediacetate, (3aR,9bR)-9-hydroxy-4,4-dimethyl-7-(2-methyloctan-2-yl)-1,3a,4,9b-tetrahydrocyclopenta[c]chromene-2-carboxylic acid, 4-((3-methyl-1-oxo-1-(((3aR,9bR)-2,4,4-trimethyl-7-pentyl-3,3a,4,9b-tetrahydrocyclopenta[c]chromen-9-yl)oxy)butan-2-yl)amino)-4-oxobutanoic acid, 4-((1-((3-hydroxy-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylcyclohexa-2,5-dien-1-yl)oxy)-3-methyl-1-oxobutan-2-yl)amino)-4-oxobutanoic acid, 1-(3-(3,5-dihydroxy-4-((1R,5R)-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)benzyl)azetidin-1-yl)ethan-1-one, and

2. 10. A pharmaceutical composition comprising an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier therefor.

Images