Synthetic cannabinoid analogs, pharmaceutical compositions, and methods of treating anxiety and other disorders

Abstract

Cannabinoid analogs can exhibit anti-inflammatory properties, such as by inhibiting cannabinoid type 2 (CB2) receptors. Pharmaceutical compositions comprising the cannabinoid analogs can be used to treat various diseases and conditions in mammals, including pain, anxiety, sleep disorders, addiction, epilepsy, depression, post-traumatic stress disorder, or Alzheimer's disease. In some examples, the pharmaceutical compositions can be administered for the treatment of cognitive disorders or for the improvement of cognition.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 557,913, filed February 26, 2024, and U.S. Provisional Application No. 63 / 557,934, filed February 26, 2024, pursuant to 35 USC §119(e), the full disclosure of which is incorporated herein by reference. Background Technology

[0003] Extensive research has been conducted in recent years on the therapeutic effects of cannabis and its components tetrahydrocannabinol (THC) and cannabidiol (CBD). There remains a need for improved compounds to treat conditions such as depression, anxiety, substance addiction, sleep disorders, pain, cancer, autoimmune diseases, and other conditions associated with chronic inflammation. In particular, there is a strong desire to develop compounds that can be synthesized and formulated into solid oral dosage forms. Summary of the Invention

[0004] According to one aspect, synthetic cannabinoid analogues have the structure of formula (I):

[0005]

[0006] Formula (I)

[0007] R1 and R2 are each independently selected from the group consisting of: H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; wherein the alkyl, alkenyl, alkynyl, or acyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NR A R B —S-alkyl, —SO-alkyl, —SO2-alkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; wherein R A and R B Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein the aryl or heteroaryl group, whether alone or as part of a substituent, is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C 1-4 Alkyl, —C(O)O—C 1-4 Alkyl, NR C R D —S-alkyl, —SO-alkyl and —SO2-alkyl; wherein R C and R DEach is independently selected from hydrogen and C. 1-4 alkyl;

[0008] R3 is selected from the group consisting of: H, alkyl, acyl, -SO2-alkyl, -SO2-aryl, and -SO2-heteroaryl; wherein the alkyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NR E R F —S-alkyl, —SO-alkyl, —SO2-alkyl, aryl and heteroaryl; and wherein R E and R F Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein the aryl or heteroaryl group, whether alone or as part of a substituent, is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogens, -OH, alkyl, -O-alkyl, NR G R H —S-alkyl, —SO-alkyl and —SO2-alkyl; wherein R G and R H Each is independently selected from hydrogen and C. 1-4 alkyl;

[0009] Each To indicate a single or double bond, the prerequisite is that it is within a pentagonal ring, one or two bonds. It is a double bond, and the rest It is a single bond;

[0010] Or its pharmaceutically acceptable salts or esters.

[0011] According to another aspect, a method for treating cancer, tumors, Alzheimer's disease, addiction, epilepsy, anxiety, sleep disorders, pain, post-traumatic stress disorder (PTSD), or depression, the method comprising administering a pharmaceutical composition to an individual in need, said pharmaceutical composition comprising a therapeutically effective amount of a synthetic cannabinoid analog of formula (I) and a pharmaceutically acceptable carrier for the pharmaceutical composition.

[0012] In some respects, synthetic cannabinoid analogs have the structure of formula (IA):

[0013]

[0014] Formula (IA)

[0015] Where R1, R2, and R3 are as previously defined; and one It is a double bond, and the other one It is a single key.

[0016] According to another aspect, a method of treating cancer, tumors, addiction, epilepsy, anxiety, sleep disorders, pain, PTSD, or depression includes administering a pharmaceutical composition to an individual in need, said pharmaceutical composition comprising a therapeutically effective amount of a synthetic cannabinoid analog of formula (IA) and a pharmaceutically acceptable carrier for use in the pharmaceutical composition.

[0017] According to other factors, synthetic cannabinoid analogues have the structure of formula (II):

[0018]

[0019] Equation (II)

[0020] R2 is as previously defined, or a pharmaceutically acceptable salt or ester thereof. In some examples, R2 is a C1-C4 straight-chain or branched alkyl group, such as propyl. In other examples, R2 is C5-C6. 10 Straight-chain or branched alkyl groups, such as pentyl or heptyl.

[0021] On the other hand, a method for treating anxiety, addiction, depression, sleep disorders, or PTSD includes administering a pharmaceutical composition to an individual in need, said pharmaceutical composition comprising a therapeutically effective amount of a synthetic cannabinoid analog of formula (II) and a pharmaceutically acceptable carrier for use in the pharmaceutical composition.

[0022] On the other hand, the pharmaceutical composition comprises a therapeutically effective amount of a synthetic cannabinoid analog of formula (I), (IA) or (II) or a combination thereof, and a pharmaceutically acceptable carrier for use in the pharmaceutical composition.

[0023] In some embodiments, the compounds disclosed herein have the following structures:

[0024]

[0025]

[0026] or

[0027] ,

[0028] Or its pharmaceutically acceptable salts or esters.

[0029] In one aspect, the pharmaceutical composition comprises a therapeutically effective amount of a compound having the following structure:

[0030]

[0031] Or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable mediator. In some examples, the pharmaceutical composition is administered to an individual in need for the treatment of a sleep disorder. In other examples, the pharmaceutical composition is administered to an individual in need for the treatment of addictions, such as smoking or smokeless tobacco addiction.

[0032] On the other hand, the pharmaceutical composition contains a therapeutically effective amount of a compound having the following structure:

[0033]

[0034] Or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable mediator. In some examples, the pharmaceutical composition is administered to an individual in need for the treatment of cancer, tumors, Alzheimer's disease, addiction, epilepsy, anxiety, sleep disorders, pain, post-traumatic stress disorder (PTSD), or depression. In other examples, the pharmaceutical composition is administered to an individual in need for the treatment of cognitive impairment or to improve cognition.

[0035] On another front, the pharmaceutical composition comprises a therapeutically effective amount of a compound having the following structure:

[0036]

[0037] Or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable mediator. In some examples, the pharmaceutical composition is administered to an individual in need for the treatment of PTSD. Attached Figure Description

[0038] Figure 1 The response curves for increasing concentrations of the test compound 3a-isopropyl-2-methyl-6-propyl-3a,8b-dihydro-1H-cyclopentane[b]benzofuran-8-ol (T-55, circular symbol) and the reference compound R(-)-Deprenyl (square symbol) are shown, as indicated on the x-axis. The MAO-B inhibition percentage is shown on the y-axis.

[0039] Figure 2 Representative monitoring of intermediate 5 cyclization into target compound M-55 is shown, as described in Example 3 and Experiment 7.

[0040] Figure 3 An HPLC chromatogram of M-55 synthesized as in Example 3, Experiment 13 is shown.

[0041] Figure 4 The MS spectrum of M-55 synthesized as in Example 3, Experiment 13 is shown.

[0042] Figure 5 The M-55 synthesized as shown in Example 3, Experiment 13 is illustrated. 1 H-NMR results.

[0043] Figure 6 The M-55 synthesized as shown in Example 3, Experiment 13 is illustrated. 13 C-NMR results.

[0044] Figure 7 An HPLC chromatogram of M-55 synthesized as in Example 3, Experiment 16 is shown.

[0045] Figure 8 The MS spectrum of M-55 synthesized as in Example 3, Experiment 16 is shown.

[0046] Figure 9 The M-55 synthesized as shown in Example 3, Experiment 16 is illustrated. 1 H-NMR results.

[0047] Figure 10 The M-55 synthesized as shown in Example 3, Experiment 16 is illustrated. 13 C-NMR results.

[0048] Figure 11 The group mean (+SEM) effects of M-55 (3 mg / kg, 10 mg / kg, 30 mg / kg, 100 mg / kg, orally) or the catalyst (sesame oil, orally) on inflammation-induced thermal pain (a), mechanical pain (b), and foot swelling (c) are shown; N = 8-10 per sex / dose.

[0049] Figure 12 The group mean (+SEM) effect of M-55 or the mordant on heat pain sensitivity 1 hour after carrageenan application is shown; N = 16–20 per group; sex combination. The p-values ​​shown are obtained by comparing with the mordant using Dunnett's post-hoc test.

[0050] Figure 13 The group mean (+SEM) effects of THC (1 mg / kg, 3 mg / kg and 10 mg / kg, orally) or the catalyst (sesame oil, orally) on inflammation-induced thermal pain (a), mechanical pain (b) and foot swelling (c) are shown; per sex / dose N=8-10.

[0051] Figure 14 The group mean (+SEM) effect of THC (1 mg / kg, 3 mg / kg and 10 mg / kg, orally) or a catalyst (sesame oil, orally) on heat pain sensitivity 1 hour after carrageenan administration is shown. N = 16–20 per group; sex combination.

[0052] Figure 15The group mean (+SEM) effects of ketoprofen (10 mg / kg, 20 mg / kg, intraperitoneal injection) or its mediator (intraperitoneal injection) on inflammation-induced thermal pain (a), mechanical pain (b), and foot swelling (c) are shown; N = 8–12 per sex / dose.

[0053] Figure 16 The mean (+SEM) effect of ketoprofen or its mediator on heat pain sensitivity 5 hours after carrageenan administration is shown; N = 19–23 per group; sex combination.

[0054] Figure 17 The group mean (+SEM) effects of M-55 (3 mg / kg, 10 mg / kg, 30 mg / kg and 100 mg / kg, orally) or the mediator (sesame oil, orally) on acute thermal pain sensitivity (a) and mechanical pain sensitivity (b) are shown; N=6 per sex / dose.

[0055] Figure 18 Peak analgesic effects of M-55 (3 mg / kg, 10 mg / kg, 30 mg / kg and 100 mg / kg, orally) with a mediator (sesame oil, orally) were shown in tests of thermal pain sensitivity (a) at 60 minutes and mechanical pain sensitivity (b) at 30 minutes after drug administration; N=6 per sex / dose. Data are group means (+SEM).

[0056] Figure 19 The results of the M-55 on the Elevated Cross Maze (EPM) anxiety test are shown. Detailed Implementation

[0057] Cannabinoids produced from the cannabis (Cannabis sativa) plant have the potential to treat a variety of diseases and other human ailments. More than 100 different cannabinoids have been isolated from cannabis, and each cannabinoid compound exhibits different effects. For example, THC is well-known for its psychoactive effects, while CBD is known for its non-psychoactive effects. THC and related analogues typically exert their therapeutic effects through cannabinoid receptors present in humans and other mammals. CBD is an isomer of THC. CBD and its derivatives also exhibit antioxidant and anti-inflammatory effects through pathways independent of cannabinoid receptors. Cannabinoid type 1 (CB1) receptors are primarily located in the brain, including the basal ganglia, limbic system, hippocampus, striatum, and cerebellum. CB1 receptors can be found in the anterior eye and retina in humans. Studies indicate that cannabinoid type 2 (CB2) receptors are responsible for cannabinoid-related anti-inflammatory and other therapeutic effects.

[0058] Cannabis plants containing high levels of cannabinoids (such as THC) are generally referred to as "recreational / medical marijuana" plants. Cannabis plants with low cannabinoid content are classified as "industrial hemp" plants. Countries typically determine their own standards for cannabinoid content to distinguish between recreational / medical marijuana and industrial hemp plants. Generally, cannabis plants classified as industrial hemp have a THC content of 0.3% or less on a dry weight basis. Cannabis sativa plants with THC, CBD, and other cannabinoid content exceeding 0.3% are generally considered recreational / medical marijuana plants. Medical marijuana typically contains 5-20% cannabinoids. Other cannabis plants can produce 25%-30% cannabinoid content.

[0059] The biosynthetic pathway for the production of various cannabinoids in the cannabis (Cannabis sativa) plant begins with the precursor cannabinoid acid. THCA synthase and CBDA synthase catalyze the biosynthesis of cannabinoid acid into tetrahydrocannabinol (THCA) and cannabidiol (CBDA), respectively, as well as other cannabinoids. Several other cannabinoids are known to be produced via this pathway. THC, CBD, and other cannabinoid derivatives are artificially generated from THCA and CBDA through non-enzymatic 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 common pathway, including THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiol), CBN (cannabinol), CBG (cannabinol), CBC (cannabinene), CBL (cannabicyclool), CBV (cannabinoid butylphenol), THCV (tetrahydrocannabinoid butylphenol), CBDV (cannabidiol butylphenol), CBCV (cannabinene butylphenol), CBGV (cannabinol butylphenol), CBGM (cannabinol monomethyl ether), CBE (cannabielsoin), and CBT (cannabicitran).

[0060] I. Synthetic cannabinoid analogues

[0061] According to several aspects, synthetic cannabinoid analogues have the structure of formula (I):

[0062]

[0063] Formula (I)

[0064] R1 and R2 are each independently selected from the group consisting of: H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; wherein the alkyl, alkenyl, alkynyl, or acyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NR A R B —S-alkyl, —SO-alkyl, —SO2-alkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; wherein R A and R B Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein the aryl or heteroaryl group, whether alone or as part of a substituent, is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C 1-4 Alkyl, —C(O)O—C 1-4 Alkyl, NR C R D —S-alkyl, —SO-alkyl and —SO2-alkyl; wherein R C and R D Each is independently selected from hydrogen and C. 1-4 alkyl;

[0065] R3 is selected from the group consisting of: H, alkyl, acyl, -SO2-alkyl, -SO2-aryl, and -SO2-heteroaryl; wherein the alkyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NR E R F —S-alkyl, —SO-alkyl, —SO2-alkyl, aryl and heteroaryl; and wherein R E and R F Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein the aryl or heteroaryl group, whether alone or as part of a substituent, is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogens, -OH, alkyl, -O-alkyl, NR G R H—S-alkyl, —SO-alkyl and —SO2-alkyl; wherein R G and R H Each is independently selected from hydrogen and C. 1-4 alkyl;

[0066] Each To indicate a single or double bond, the prerequisite is that it is within a pentagonal ring, one or two bonds. It is a double bond, and the rest It is a single bond;

[0067] Or its pharmaceutically acceptable salts or esters.

[0068] In other examples, synthetic cannabinoid analogs have the structure of formula (IA):

[0069]

[0070] Formula (IA)

[0071] Where R1, R2, and R3 are as previously defined; and one It is a single key, and another It is a double bond;

[0072] Or its pharmaceutically acceptable salts or esters.

[0073] According to other factors, synthetic cannabinoid analogues have the structure of formula (II):

[0074]

[0075] Equation (II)

[0076] R2 is as previously defined, or a pharmaceutically acceptable salt or ester thereof. In some examples, R2 is a C1-C4 straight-chain or branched alkyl group, such as propyl. In some examples, R2 is pentyl. In other examples, R2 is C6-C… 10 Straight-chain or branched alkyl groups, such as hexyl or heptyl.

[0077] As used herein, the term "alkyl" whether alone or as part of a substituent refers to a saturated C1-C2 alkyl group. n A carbon chain, wherein the carbon chain may be straight or branched; wherein n may 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, tert-butyl, n-pentyl, and n-hexyl.

[0078] As used herein, the term "alkenyl," whether alone or as part of a substituent, refers to C2-C nA carbon chain, wherein the carbon chain may be straight or branched, wherein the carbon chain contains at least one carbon-carbon double bond, and wherein n may be 3, 4, 5, 6, 7, 8, 9 or 10.

[0079] As used herein, the term "alkynyl" (whether alone or as part of a substituent) refers to C2-C... n The carbon chain can be straight or branched, and the carbon chain contains at least one carbon-carbon triple bond, and n can be 3, 4, 5, 6, 7, 8, 9 or 10.

[0080] As used herein, the term "aryl," whether alone or as part of a substituent, refers to an unsubstituted carbocyclic aromatic ring containing 6 to 14 carbon atoms. Suitable examples include, but are not limited to, phenyl and naphthyl.

[0081] As used herein, the term "protected hydroxyl" refers to a hydroxyl group substituted with a suitably selected oxygen protecting group. More specifically, "protected hydroxyl" refers to the substituent of formula —OPG1, where PG1 is a suitably selected oxygen protecting group. During any preparation process of the compounds disclosed herein, it may be necessary and / or desired to protect sensitive or reactive groups on the relevant molecule. This can be achieved with conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. JFWMcOmie, Plenum Press, 1973; and TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protecting groups can be removed at a subsequent appropriate stage using existing techniques.

[0082] As used herein, the term "oxygen protecting group" refers to a group that can be attached to an oxygen atom to protect the oxygen atom from participating in the reaction and can be easily removed after the reaction. Suitable oxygen protecting groups include, but are not limited to, acetyl, benzoyl, tert-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, and THP. Other suitable oxygen protecting groups can be found in references such as TWGreene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

[0083] As used herein, the term "nitrogen protecting group" refers to a group that can be attached to a nitrogen atom to protect the nitrogen atom from participating in the reaction and can be easily removed after the reaction. Suitable nitrogen protecting groups include, but are not limited to, urethane groups of the formula —C(O)—OR, where R can be methyl, ethyl, tert-butyl, benzyl, phenethyl, CH2=CH—CH2—, etc.; amide groups of the formula —C(O)—R', where R' can be methyl, phenyl, trifluoromethyl, etc.; and N-sulfonyl derivative groups of the formula —SO2—R'', where R'' can be tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethyltryptane-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, etc. Other suitable nitrogen protecting groups can be found in, for example, TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

[0084] As used herein, the term "acyl" refers to the formula —CO—C n The group, wherein C n This indicates a straight-chain or branched alkyl chain, where n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0085] As used herein, the term "heteroaryl" refers to a five- or six-membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N, and S, and optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N, and S; or a nine- or ten-membered bicyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N, and S, and optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N, and S. The heteroaryl group can be attached to any heteroatom or carbon atom on the ring, resulting in a stable structure. Examples of suitable heteroaryl groups include, but are not limited to: pyrrole, furanyl, thiophene, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyranyl, furazolyl, indoleazinyl, indoleyl, isoindolinel, inzolyl, phenylfuranyl, phenylthiophene, phenylimidazolyl, phenylthiazolyl, purinyl, quinololazinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnamyl, isothiazolyl.

[0086] As used herein, the term "cycloalkyl" refers to a monocyclic structure containing four to six carbon atoms, or a bicyclic structure containing eight to ten carbon atoms. A cycloalkyl group can be attached to any carbon atom on the ring, resulting in a stable structure. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0087] As used herein, the term "heterocycle" refers to a four- to six-membered monocyclic structure containing at least one heteroatom selected from the group consisting of O, N, and S, and optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N, and S; or an eight- to ten-membered bicyclic structure containing at least one heteroatom selected from the group consisting of O, N, and S, and optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N, and S. The heterocyclic group can be attached to any heteroatom or carbon atom on the ring, resulting in a stable structure. Suitable heterocyclic groups include, but are not limited to: aziridine, aziridine, oxadiazine, oxadiazine, thiohexacyclobutane, thiohexacyclobutane, diaziridine, diaziridine, dioxadiazine, dioxadiazine, dithiohexacyclobutane, dithiohexacyclobutane, pyrrolidine, pyrrole, tetrahydrofuran, furan, thioalkyl, thiophene, piperidine, oxadiazine, thioalkyl, pyridine, pyran, and thiopyran.

[0088] The groups described herein may be unsubstituted or substituted as defined herein. Furthermore, substituted groups may be replaced by one or more groups, such as C1-C6 alkyl, C... 1-4 Alkyl, —O—C 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), —SO2—(C 1-4 Alkyl groups, halogens, aryl groups, heteroaryl groups, etc.

[0089] Reference substituents, the term "independently" means that when multiple such substituents are present, these substituents may be the same or different.

[0090] The compounds disclosed herein may contain at least one hydroxyl group. These at least one hydroxyl group may form esters with inorganic or organic acids. Specifically, pharmaceutically acceptable acids. The esters may form chiral carbon atoms. This disclosure relates to all stereochemical forms of the compounds disclosed herein, including forms produced by forming one or more ester groups.

[0091] II. Non-limiting examples of synthetic cannabinoid analogues disclosed herein

[0092] The following are non-limiting examples of synthetic cannabinoid analogues according to Formulas I, IA, and II:

[0093]

[0094] 3a-Isopropyl-2-methyl-6-propyl-3a,8b-dihydro-1H-cyclopentane[b]benzofuran-8-ol

[0095]

[0096] 3a-Isopropyl-2-methyl-6-pentyl-3a,8b-dihydro-1H-cyclopentane[b]benzofuran-8-ol

[0097]

[0098] 6-Heptyl-3a-isopropyl-2-methyl-3a,8b-dihydro-1H-cyclopentan[b]benzofuran-8-ol

[0099] III. Synthesis and purification of cannabinoid compounds

[0100] In some examples, the cannabinoid compounds described herein can form salts that contribute to improved 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 Use, Weinheim / Zürich:Wiley-VCH / VHCA, 2002, including 1-hydroxy-2-naphthyl 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, caproic acid, caprylic acid, and captanoic acid. Acids, carbonic acid, cinnamic acid, citric acid, cyclosulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glucoheponic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutamate, glycerophosphate, glycolic acid, hippuric acid, hydrogen bromide, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, 1,5-disulfonic naphthalene, 2-sulfonic naphthalene, 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), thiocyanate, p-toluenesulfonic acid and undecenoic acid salts.

[0101] The compounds described herein can be synthesized using known techniques, with appropriate modifications to the reactants to form the structures shown herein, or through other suitable means, as will be apparent to those skilled in the art. By way of non-limiting example, the compounds described herein can be synthesized according to one or more of the following routes as described in Razdan, Total Synthesis of Cannabinoids, SISA Incorporated, Cambridge, Massachusetts, with appropriate modifications to the reactants, as will be apparent to those skilled in the art, to produce the structures disclosed herein. Alternatively, the synthetic techniques described in U.S. Patent 10,059,683 B2 to Dialer et al., the disclosure of which is hereby incorporated by reference in its entirety, can be appropriately adapted to synthesize the cannabinoid analogues described herein.

[0102] Compounds intended for use in humans or other mammals should generally possess extremely high purity. For synthetically prepared compounds, purity refers to the ratio of the compound's mass to the total mass of the sample after purification steps. Typically, purity levels are at least about 95%, more commonly at least about 96%, about 97%, about 98%, or higher. For example, purity levels 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 higher.

[0103] If the compounds described herein exist in more than one optical isomer (enantiomer), they may be provided as a racemic mixture or one of the enantiomers may be isolated, in which case the purity may refer to the enantiomer purity as described above.

[0104] IV. Instructions for Use

[0105] As described above, cannabinoids and related cannabinoid analogues typically exert therapeutic and anti-inflammatory activities via the CB2 cannabinoid receptor. While not wishing to be bound by theory, the compounds disclosed herein may also exhibit monoamine oxidase (MAO) activity inhibitors, including MAO-A and / or MAO-B activities. These properties enable the compounds to be effectively used to treat indications associated with MAO activity, such as depression, pain, sleep disorders, substance addiction, and smoking cessation. Therefore, in some embodiments, the compounds disclosed herein can be used for methods of treating diseases and symptoms associated with monoamine oxidase (MAO) activity. In some embodiments, the individual suffers from depression, pain, sleep disorders, or addiction.

[0106] The compounds disclosed herein may also (or alternatively) exhibit anti-inflammatory properties through interactions with inflammatory pathways, including, for example, interleukins IL-1 and IL-6, TNF-α, and cyclooxygenase (COX). The ability of the compounds to inhibit MAO-A and / or MAO-B activity and / or to inhibit COX and / or other inflammation-associated pathways can be assessed using assays well known to those skilled in the art.

[0107] In some respects, the cannabinoid analogues described herein are administered to individuals in need to treat substance addictions such as alcohol, tobacco, opioids, prescription drugs, cocaine, benzodiazepines, amphetamines, hallucinogens, inhalers, phencyclidine, or other drug addictions. Such treatment also includes treatment of withdrawal from benzodiazepine, opioid, or alcohol dependence, as well as symptoms presenting in patients with substance use disorders, such as anxiety, mood symptoms, pain, and sleep disturbances (such as insomnia).

[0108] In addition to anxiety associated with substance use disorders, cannabinoid analogues can also be used to treat other types of anxiety disorders, such as post-traumatic stress disorder (PTSD), generalized anxiety disorder, panic disorder, social anxiety disorder, and obsessive-compulsive disorder.

[0109] In other respects, the cannabinoid analogues described herein can be used to treat multiple sclerosis, fibromyalgia, epilepsy, or epilepsy-related neuropsychiatric disorders such as neurodegenerative diseases, nerve damage, and mental illnesses. Cannabinoid analogues can effectively enhance the anticonvulsant activity of other active agents such as phenytoin and diazepam.

[0110] In other respects, the cannabinoid analogues described herein can be used as antipsychotics to treat patients with schizophrenia. Cannabinoid analogues can also effectively lower intraocular pressure, for example, in the treatment of glaucoma.

[0111] In other respects, cannabinoid analogues, as described herein, can be administered to individuals in need for cancer treatment. Cannabinoid analogues can effectively prevent the spread of cancer cells in the body and their complete invasion of a specific area; they can also inhibit cancer cell growth and / or promote cancer cell death.

[0112] As described in this article, cannabinoid analogues can be used to treat type 1 diabetes, caused by inflammation triggered by the immune system attacking pancreatic cells; they can also be used to treat acne, partly caused by inflammation and overworking sebaceous glands. The anti-inflammatory properties of these compounds can reduce sebum production that leads to acne, including the most common type, acne vulgaris.

[0113] The cannabinoid analogues described herein can be used to treat Alzheimer's disease, and specifically, when administered in the early stages of Alzheimer's disease, can prevent subjects from developing social recognition impairment. In some respects, the compounds can be used to improve cognitive function. Other conditions that cannabinoid analogues described herein can also be used to treat include nausea, vomiting, anorexia, and cachexia. The compounds can produce an appetite-stimulating effect, for example, for use in patients with AIDS or Alzheimer's disease who refuse to eat.

[0114] Cannabinoid analogues, as described in this article, can be used to treat spasticity caused by multiple sclerosis (MS) or spinal cord injury, as well as movement disorders such as Tourette syndrome, dystonia, or tardive dyskinesia. MS patients may benefit from reductions in ataxia and tremor.

[0115] The analgesic properties of cannabinoid analogues may have benefits, such as for treating neuropathic pain caused by multiple sclerosis, brachial plexus injury and HIV infection, as well as rheumatoid arthritis pain, cancer pain, headaches, menstrual pain, chronic intestinal inflammation and neuralgia.

[0116] Cannabinoid analogues, as described in this article, can be used to treat asthma. Experiments on the anti-asthmatic effects of THC or cannabis primarily began in the 1970s and were all acute studies. The effects of cannabis smoke (2% THC) or oral THC (15 mg) are roughly equivalent to therapeutic doses of commonly used bronchodilators (salbutamol, isoproterenol). Because inhaled cannabis products can irritate mucous membranes, oral administration or other alternative delivery systems are preferred. In rare cases, bronchoconstriction occurs after inhaling THC.

[0117] Improved mood has been observed in patients with reactive depression in multiple THC clinical studies. Other case reports indicate that cannabinoids are beneficial for other psychiatric symptoms and disorders, such as sleep disorders, anxiety disorders, bipolar disorder, and dysthymia. Different authors hold differing views on psychiatric syndromes and cannabis. Some emphasize the problems associated with cannabis, while others tout its therapeutic potential. Cannabis products can likely be both beneficial and harmful depending on the specific circumstances. Physicians and patients should approach this topic critically and be open to both possibilities.

[0118] In various pain syndromes triggered by inflammatory processes (such as ulcerative colitis and arthritis), cannabis products not only act as analgesics but also demonstrate anti-inflammatory potential. For example, some cannabis users have reported a reduced need for steroid and nonsteroidal anti-inflammatory drugs. Furthermore, there are reports of positive effects of cannabis self-medication on allergic diseases. It remains unclear whether cannabis products have any impact on the pathogenesis of autoimmune diseases.

[0119] Many patients have also reported positive effects of cannabis on conditions that don't easily fall into the above categories, such as itching, hiccups, attention deficit syndrome (ADS), hypertension, tinnitus, chronic fatigue syndrome, and restless legs syndrome. Different authors have described hundreds of potential indications for cannabis and THC. For example, 2.5 mg to 5 mg of THC was effective in three patients with itching caused by liver disease. Another example is the successful treatment of chronic hiccups that occurred after surgery. No other medication was effective, but smoking one cannabis cigarette completely eliminated the symptoms.

[0120] Cannabis products often work well in diseases with a variety of symptoms that cover the range of THC effects, such as in pain symptoms with an inflammatory origin (e.g., arthritis), or in diseases with increased muscle tone (e.g., menstrual cramps, spinal cord injury), or in diseases with nausea and anorexia, along with pain, anxiety, and depression (e.g., HIV, cancer, hepatitis C).

[0121] COVID-19 spreads through respiratory droplets and enters the human host via the angiotensin-converting enzyme II (ACE2) receptor. ACE2 is expressed in lung tissue, oral and nasal mucosa, kidneys, testes, and the gastrointestinal tract. Modulating ACE2 levels in these entry tissues may reduce susceptibility to the disease. 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 (April 17, 2020), doi:10.20944 / preprints202004.0315.v1. Cannabinoid analogues, as described herein, can modulate ACE2 expression and may be used to treat coronaviruses such as COVID-19.

[0122] V. Dosage and Pharmaceutical Composition

[0123] The appropriate dosage can vary significantly depending on a variety of factors, including the type and / or severity of the disease or condition, prior treatment, individual health status, age and / or weight, treatment frequency, composition release rate, and other comorbidities. This dosage may also vary based on factors such as the subject's disease status, age, and weight. For example, higher doses may be administered for advanced and / or life-threatening conditions. Dosing regimens may also be adjusted to provide the best therapeutic response.

[0124] Pharmaceutical compositions may be formulated with one or more acceptable pharmaceutically or food-grade carriers or excipients. As used herein, the term "acceptable pharmaceutically or food-grade carrier or excipient" means any type of non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation excipient. For example, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; ethylene glycol such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffers; and compatible lubricants such as sodium dodecyl sulfate and magnesium stearate; as well as colorants, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives, and antioxidants may be added to the composition at the formulator's discretion.

[0125] Pharmaceutical compositions can be prepared using any suitable technology and are not limited to any particular manufacturing method. For example, purified cannabinoids can be mixed with excipients and binders and then granulated. The granules can be dry-mixed with the remaining ingredients and compressed into solid forms such as tablets.

[0126] The pharmaceutical composition may be administered via any suitable route. For example, the composition may be taken orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally, via an implanted reservoir, or as a dietary supplement or food. In some embodiments, the composition is provided in an inhaler that can be actuated to administer a vaporized medium inhaled into the lungs. As used herein, the term “parenterical” includes subcutaneous, intradermal, intravenous, intramuscular, and intracranial injection or infusion techniques. Most commonly, the pharmaceutical composition is readily available for oral administration and ingestion.

[0127] Pharmaceutical compositions may contain any conventionally non-toxic, pharmaceutically acceptable carriers, adjuvants, or excipients. In some cases, the pH of the formulation may be adjusted with acceptable pharmaceutical or food-grade acids, bases, or buffers to enhance the stability of the formulated composition or its delivery form.

[0128] Orally administered liquid dosage forms include acceptable pharmaceutically or food-grade emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethyl sulfoxide (DMSO), dimethylformamide, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and fragrances.

[0129] Solid dosage forms for oral administration include capsules, tablets, lozenges, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, acceptable pharmaceutically or food-grade excipient or carrier, such as sodium citrate or calcium hydrogen phosphate, and / or a) fillers or enrichers, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution retarders, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof; j) sweeteners, flavorings, and fragrances, and mixtures thereof. In the case of capsules, lozenges, tablets, and pills, the dosage form may also contain a buffer.

[0130] Solid dosage forms such as tablets, capsules, pills, and granules can be prepared using coatings and shells, enteric coatings, and other coatings well known in the field of pharmaceutical formulation. These dosage forms may optionally contain emulsifiers and may belong to compositions designed to release only one or more active ingredients, or preferably, optionally in a delayed or prolonged manner, in a specific portion of the intestine. Examples of usable encapsulation compositions include polymers and waxes. Delayed-release tablet formulations are described in U.S. Patent No. 5,942,244.

[0131] The composition may contain cannabinoid analogs or compounds, used alone or in combination with other therapeutic compounds. Therapeutic compounds are compounds that provide pharmacological activity or other direct effects during the diagnosis, cure, relief, treatment, or prevention of a disease, or when used to affect the structure or any function of a human or animal body. The therapeutic compounds disclosed herein may be used in the form of pharmaceutically acceptable salts, solvates, or solvates of salts, such as hydrochlorides. Additionally, the therapeutic compounds disclosed herein may be provided as racemic mixtures or as individual enantiomers, including R- or S-enantiomers. Therefore, the therapeutic compounds disclosed herein may comprise only R-enantiomers, only S-enantiomers, or a combination of both R-enantiomers and S-enantiomers of the therapeutic compound. In some aspects, the therapeutic compounds may have anti-inflammatory activity, such as nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are a large number of therapeutic compounds with analgesic, anti-inflammatory, and antipyretic properties. NSAIDs reduce inflammation by blocking cyclooxygenase. Nonsteroidal anti-inflammatory drugs (NSAIDs) include, but are not limited to, aceclofenac, acimetidine, allofenic acid, aminoprofen, azoxystrobin, aminopyrine, antralfenine, aspirin, azaprozilone, benorilate, benoriprofen, benzalkonium chloride, butebufen, celecoxib, chlorpheniramine, choline salicylates, clometasone, dextromethorphan, diclofenac, diflunixazone, emoxadoxon, ipilazole, etoradoxazole, etoricoxib, flucloburazepam, febenazine, fenbufen, fenclofenac, flurbiprofen, granfenidine, and hydroxyethyl. Salicylic acid, ibuprofen, indomethacin, indoprofen, ketoprofen, ketoprofen, phenethylamine lactate, loxoprofen, luminicoxib, mefenamic acid, meloxicam, aminopyrine, methazopiclone, phenylbutazone, nifedipine, naproxen, nifenzodone, niflumiic acid, oxymetazine, phenacetin, piperazine, pranoprofen, propylbenzazole, proquarone, protizine, rofecoxib, salicylamide, thalicylate, sulinda, suprofen, thiabendazole, tenoridone, tofenamic acid, vardicoxib, zometiprazole.

[0132] NSAIDs can be classified based on their chemical structure or mechanism of action. Non-limiting examples of NSAIDs include salicylate derivative NSAIDs, p-aminophenol derivative NSAIDs, propionic acid derivative NSAIDs, acetic acid derivative NSAIDs, enolic acid derivative NSAIDs, fenamic acid derivative NSAIDs, non-selective cyclooxygenase (COX) inhibitors, selective cyclooxygenase-1 (COX-1) inhibitors, and selective cyclooxygenase-2 (COX-2) inhibitors. An NSAID may be ibuprofen. Suitable examples of salicylate derivative NSAIDs include, but are not limited to, acetylsalicylic acid (aspirin), diflunisal, and salicylates. Suitable examples of p-aminophenol derivative NSAIDs include, but are not limited to, acetaminophen and phenacetin. Suitable examples of propionic acid derivative NSAIDs include, but are not limited to, alminoprofen, benoxaprofen, dextrokeprofen, fenoxaprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprazin, pranoprofen, and supprofen. Examples of suitable acetic acid derivative NSAIDs include, but are not limited to, aceclofenac, atalitol, allofenic acid, amifenac, clometasine, diclofenac, etoradola, febenazine, fenclofenac, indomethacin, ketorolac, methaqualone, mofrazol, nalbumime, naproxen, oxmetacin, sulinda, and zometiprazole. Examples of suitable enolic acid (oxacram) derivative NSAIDs include, but are not limited to, deroxicam, isoxoxacin, loxoxicam, meloxicam, piroxicam, and tenoxacin. Examples of suitable fenamine derivative NSAIDs include, but are not limited to, flufenamic acid, mefenamic acid, mefenamic acid, and tofenamic acid. Examples of suitable selective COX-2 inhibitors include, but are not limited to, celecoxib, etoricoxib, phenicoxib, luminicoxib, meloxicam, parecoxib, rofecoxib, and vardicoxib.

[0133] The therapeutically effective dose of the therapeutic compounds disclosed herein is typically from about 0.001 mg / kg / day to about 100 mg / kg / day. Effective doses may 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 examples, the effective dose of the therapeutic compound may be 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, the effective dose of the therapeutic compounds disclosed herein may be, 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.

[0134] In addition to pharmaceutical compositions, the compounds described herein can also be formulated as elixirs, beverages, chewable tablets, tablets, lozenges, chewing gum, etc. According to another aspect, the pharmaceutical compositions can also be formulated as pharmaceutically acceptable mediators, such as capsules, tablets, syrups, lozenges, inhalers, electronic cigarettes, chewing gum, nasal sprays, transdermal patches, liquids, mucosal mediators, hydrogels, nanoliposomes, liposomes, noisomes, nanoparticles, nanospheres, microspheres, microparticles, microemulsions, nanosuspensions, or micelles. The compositions can also be formulated as dietary supplements or nutritional products, etc.

[0135] The description of embodiments of this disclosure is not intended to be exhaustive or to limit this disclosure to the specific forms disclosed. While specific embodiments and examples of this disclosure are described herein for illustrative purposes, those skilled in the art will recognize that various equivalent modifications can be made within the scope of this disclosure. For example, while method steps or functions are presented in a particular order, alternative embodiments may perform functions in a different order or may perform functions substantially simultaneously. The teachings of this disclosure provided herein may be suitably applied to other procedures or methods. The various embodiments described herein may be combined to provide further embodiments. Where necessary, aspects of this disclosure may be modified to employ the compositions, functions, and concepts of the foregoing references and applications, thereby providing further embodiments of this disclosure. Furthermore, given biological functional equivalence, some changes may be made to the protein structure without affecting the type or amount of biological or chemical action. The above and other modifications may be made to this disclosure based on the detailed description. All such modifications are intended to be included within the scope of the appended claims.

[0136] Specific elements of any of the above embodiments may be combined or substituted with elements of other embodiments. Furthermore, while advantages relating to certain embodiments of this disclosure have been described in the context of these embodiments, other embodiments may also exhibit such advantages, and not all embodiments must exhibit such advantages to fall within the scope of this disclosure.

[0137] Example 1

[0138] This example describes the synthesis of 3a-isopropyl-2-methyl-6-propyl-3a,8b-dihydro-1H-cyclopentane[b]benzofuran-8-ol (“T-55”).

[0139]

[0140] Synthesis of 4-bromocyclopentan-2-enone (2):

[0141] Under an argon atmosphere and at room temperature, an anhydrous chloroform solution (1.50 L) of cyclopentan-2-en-1-one (100 g, 1218 mmol) was added in portions to NBS (325 g, 1827 mmol) over 30 minutes. After the addition was complete, the reaction mixture was refluxed at 80 °C (oil bath temperature) for 48 hours. The reaction mixture was cooled to room temperature, diluted with water (2.0 L), and extracted with CH2Cl2 (2 × 1.0 L). The combined organic extracts were washed with ice-cold water (1.0 L) and brine (1.0 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow liquid of 4-bromocyclopentan-2-en-1-one (150 g, 76%).

[0142] 1 HNMR shows the expected signal: 1 H NMR (400 MHz, CDCl3): δ 7.67 (dd, J = 5.52, 2.56Hz, 1H), 6.27 (dd, J = 5.52, 0.95 Hz, 1H), 5.23-5.06 (m, 1H), 3.05 (dd, J =19.5, 6.28 Hz, 1H), 2.72 (dd, J = 19.5, 1.53 Hz, 1H).

[0143] Synthesis of 4-(prop-1-en-2-yl)cyclopent-2-en-1-one (3):

[0144] CuCN (25.0 g, 279 mmol) was added to a stirred solution of LiCl (23.4 g, 558 mmol) in anhydrous THF (500 mL) and stirred at room temperature for 20 min. The reaction mixture was cooled to -40 °C, and isopropenyl magnesium bromide (279.5 mL, 0.5 M in THF, 139.7 mmol) was added dropwise over a 60-minute period, with stirring at -40 °C for an additional 20 min, followed by cooling to -78 °C. Then, 4-bromocyclopentan-2-en-1-one (15 g, 93.1 mmol, 1.0 equivalent) was added dropwise over a 60-minute period, with stirring at -78 °C for 10 min. The reaction mixture was slowly raised to 0 °C and quenched with saturated NH4Cl 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 extract was washed with brine (2 × 1.0 L), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain the crude product. The product was purified by silica gel column chromatography (15%-25% MTBE in hexane). The fractions containing the product were combined and concentrated under reduced pressure to give a colorless oily compound 4-(prop-1-en-2-yl)cyclopent-2-en-1-one (4.0 g, 35%). Note: Compound 3 is volatile; the rotary evaporation bath temperature should be <20°C, and the vacuum should be approximately 600 mbar.

[0145] 1 HNMR showed the expected signal, accompanied by traces of MTBE solvent. 1 H NMR (400 MHz, CDCl3): δ 7.60(dd, J = 5.65, 2.49 Hz, 1H), 6.24 (dd, J = 5.54, 1.98 Hz, 1H), 4.90-4.71 (m,2H), 3.64-3.40 (m, 1H), 2.60 (dd, J = 18.8, 6.75 Hz, 1H), 2.18 (dd, J = 18.8, 2.02 Hz, 1H), 1.71 (s, 3H).

[0146] Synthesis of 1-methyl-4-(prop-1-en-2-yl)cyclopent-2-en-1-ol (4):

[0147] Methyllithium (1.6 M in diethyl ether, 69.1 mL, 73.72 mmol) was added dropwise over a 30-minute period at -78 °C to 4-(prop-1-en-2-yl)cyclopent-2-en-1-one (9.0 g, 73 mmol) in anhydrous THF (100 mL). The reaction mixture was stirred for 10 minutes at -78 °C under an argon atmosphere. The reaction mixture was slowly raised to 0 °C, quenched with NH4Cl solution (130 mL), and extracted with MTBE (2 × 500 mL). The combined MTBE extract was washed with water (500 mL) and brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1-methyl-4-(prop-1-en-2-yl)cyclopent-2-en-1-ol (4.5 g, crude product), a pale yellow liquid, which was used directly in the next step. Note: Compound 4 is also volatile, so the rotary evaporation bath temperature should be below 20°C and the vacuum should be approximately 600 mbar.

[0148] Synthesis of 2-(3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-propylphenyl-1,3-diol (5):

[0149] Over a 20-minute period, boron trifluoride diethyl ether (13.4 mL, 108.6 mmol) was slowly added dropwise at room temperature to a stirred solution of Brockmann I-activated basic alumina (79 g, 782 mmol) in anhydrous CH2Cl2 (300 mL). The reaction mixture was slowly heated to 40 °C and stirred for 10 minutes, followed by the addition of a solution of 1-methyl-4-(prop-1-en-2-yl)cyclopent-2-en-1-ol (6.0 g, 138.1 mmol) and 5-propylphenyl-1,3-diol (4.6 g, 30 mmol) in anhydrous CH2Cl2 (100 mL). The reaction mixture was stirred at 40 °C for 5 minutes. The reaction mixture was cooled to room temperature, diluted with saturated NaHCO3 (300 mL), and extracted with CH2Cl2 (300 mL × 2). The combined organic extracts were washed with water (500 mL) and brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified twice by silica gel column chromatography (6%-10% EtOAc / hexane). The distillates containing the pure product were combined and concentrated under reduced pressure to give 3.0 g (crude) of 2-(3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-propylphenyl-1,3-diol, a brown liquid. 1 1H NMR shows a mixture of compound 5 and compound T-55.

[0150] Synthesis of 3a-isopropyl-2-methyl-6-propyl-3a,8b-dihydro-1H-cyclopentane[b]benzofuran-8-ol (T-55):

[0151] 2-(3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-propylphenyl-1,3-diol (3.0 g, 9.9 mmol) was dissolved in anhydrous CH2Cl2 solution (500 mL), and Fe(OTf)3 (0.99 g, 1.98 mmol) was added. The mixture was stirred at room temperature for 72 hours. The reaction was cooled to 0 °C, quenched with saturated NaHCO3 solution (100 mL), and extracted with CH2Cl2 (2 × 100 mL). The combined CH2Cl2 extract was washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The product was purified twice by silica gel column chromatography (3%–6% EtOAc / hexane). The fractions containing the pure product were combined and concentrated under reduced pressure to give 2,4,4-trimethyl-7-propyl-3,3a,4,9b-tetrahydrocyclopentane[c]chromen-9-ol (0.86 g, 29%), which is a light brown liquid.

[0152] 1 HNMR shows the expected signal: 1 H NMR 1 H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 6.06 (s, 1H), 5.96 (s, 1H), 5.34 (s, 1H), 3.64 (d, J = 6.8 Hz, 1H), 2.66-2.60(m, 1H), 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 / z 273.1 [M + H] + .

[0153] Example 2 – Monoamine oxidase inhibition

[0154] Increased concentrations of the test compound were added to the reaction mixture containing monoamine oxidase (MAO-B or MAO-A) enzymes to generate response curves. The reaction mixture was incubated using 100 mM potassium phosphate at pH 7.4 as an incubation buffer. Fluorescence spectroscopy of 4-hydroxyquinoline was used to determine the activity of either MAO-B or MAO-A enzymes.

[0155] The assays were performed substantially as described in Biochem Pharmacol. 41(2): 155–162 and by Eurofins Panlabs, Inc. If applicable, IC 50 The values ​​were determined using nonlinear least squares regression analysis with MathIQ™ (ID BusinessSolutions Ltd., UK). With the inhibition constant (Ki) present, the equation of Cheng and Prusoff (Cheng, Y., Prusoff, WH, Biochem. Pharmacol. 22:3099-3108, 1973) was used, based on the observed IC50 of the test compound, the concentration of the radioligand used in the analysis, and the Ki of that ligand. D Historical values ​​(obtained from experiments at Eurofins Panlabs, Inc.) were used to calculate K. i The Hill coefficient (nH) is calculated using MathIQ™, as described above. This coefficient defines the slope of the competitive binding curve. A Hill coefficient significantly different from 1.0 indicates that the binding displacement does not follow the mass action law of a single binding site.

[0156] Figure 1 The response curves (x-axis) and MAO-B inhibition percentage (y-axis) for increasing concentrations of 3a-isopropyl-2-methyl-6-propyl-3a,8b-dihydro-1H-cyclopentane[b]benzofuran-8-ol (T-55) are shown. Figure 1 As shown, IC for T-55 suppression of MAO-B 50 The concentration was determined to be 20.1 µM. The IC50 value for inhibition of the reference compound R(-)-Deprenyl against MAO-B was [value missing]. 50 It is 9.69 nM, such as Figure 1 As shown.

[0157] Table 1 below shows further experimental results for T-55 and Delta 9-THC. In the table, NC means "not calculated".

[0158] Table 1

[0159]

[0160]

[0161] Clorgyline and Deprenyl are used as reference compounds, as shown in Table 2 below.

[0162] Table 2: Reference Compounds

[0163]

[0164] Example 3

[0165] This example describes the synthesis of 3a-isopropyl-2-methyl-6-pentyl-3a,8b-dihydro-1H-cyclopentane[b]benzofuran-8-ol (“M-55” or “MIRA-55”). First, compound 5 was prepared according to the following reaction scheme:

[0166]

[0167] The target compound M-55 was prepared by cyclization of structure 5 under strongly acidic conditions, for example, in the presence of trifluoromethanesulfonic acid (TFMS) or trimethylsilyltrifluoromethanesulfonate (TMSOTf). Compound 5 (11.5 g, 38.3 mmol, 1 equivalent) was dissolved in DCM (380 mL, 33 mL / g), and the solution was heated to 25 °C in a water bath. TMSOTf (10.2 g, 46 mmol, 1.2 equivalent) was added in one step, and the reaction mixture was stirred at room temperature and monitored using method #1 below. After 2.5 hours, the impurity profile did not improve. NaHCO3 (400 mL) was added, and the phases were separated. The organic layer was washed with water and brine, dried over Na2SO4, and evaporated to give 12.3 g of crude product, a brown oil. The crude product was filtered through a silica gel pad (30% DCM / hexane (1 L), 50% DCM / hexane (0.5 L)) to give 7.1 g of yellow oil, which was used directly in the next step without further purification.

[0168] A series of experiments were conducted to investigate the effects of cyclization conditions, and the conditions used are shown in Table 2. Experimental progress / conversion rate was monitored using HPLC analysis method #1.

[0169] Table 2

[0170]

[0171]

[0172] M-55 is formed along with other isomers. Initially, a large number of isomers are generated, but most disappear or transform into the target structure after prolonged stirring (see [link to relevant documentation]). Figure 2 It should be noted that the peak intensity of the product did not decrease over time, indicating that there was no product decomposition in the reaction mixture.

[0173] After screening various reaction conditions (equivalence, reaction temperature, and feeding method), the final process was determined and replicated on a large scale. Experiment 5 was terminated when the impurity profile showed no further improvement. The separated crude product was combined with other small batches and purified by column chromatography to obtain the product (Experiment 6) with an HPLC purity of 94.4%. The unknown impurity RRT1.09 was not separated. Since the product and impurity showed significant differences on RT (HPLC) and Rf (TLC), it was speculated that optimizing the purification method could achieve better separation. The cyclization experiment was repeated (Experiment 7), but using a larger silica column and a slower gradient, a mixture of M-55 and impurity RRT1.09 was still obtained (see Table 2 for details). Attempts were made to develop suitable chromatographic methods, including purification with AgNO3-impregnated silica gel, but no significant improvement was observed.

[0174] The fraction containing the high-impurity RRT1.09 was prepared by reverse-phase HPLC, and several milligrams of unknown impurity were separated and analyzed by NMR. The structure of impurity RRT1.09 was successfully resolved and identified as follows:

[0175]

[0176] RRT1.09

[0177] Impurity RRT1.09 was removed by the hydroboration method shown below. The experiments conducted are summarized in Table 3.

[0178]

[0179] Table 3

[0180]

[0181]

[0182]

[0183] Experiments 9-13 used previously purified M-55 containing approximately 6% impurity RRT1.09. After combining all batches, normal-phase chromatography was used for purification, yielding 2.67 g of product with an HPLC purity of 99.41% (impurity RRT1.09 was 0.18%, separation yield approximately 18%). The cyclization of M-5 was repeated (Experiment 16). The crude product was filtered through a silica gel pad and then processed using the developed hydroboration method. Fractions with 97.94% HPLC purity (0.63% RRT1.09) and 97.34% HPLC purity (0.52% RRT1.09) were separated, as summarized in Table 4. The HPLC chromatogram and MS spectrum of Experiment 13 are also shown. 1 H-NMR and 13 The C-NMR results are presented in... Figure 3 , Figure 4 , Figure 5 and Figure 6 middle.

[0184] Table 4

[0185]

[0186] TMS protection

[0187] Previously isolated M-55 (Experiment 16) (7.1 g, 23.7 mmol, 1 equivalent) was dissolved in DCM (90 mL), and Et3N (7.2 g, 71 mmol, 3 equivalents) was added. The solution was cooled to 0-5°C, and TMSCl (3.9 g, 35.5 mmol, 1.5 equivalents) was added dropwise. The resulting reaction mixture was stirred at 0-5°C for 15 minutes, then brought to room temperature and stirred, and monitored using method #2. Complete conversion was detected after 1 hour. The reaction mixture was cooled to 0-5°C, and a white precipitate (Et3N•HCl) was filtered off. The filtrate was evaporated to dryness, dissolved in hexane (100 mL), filtered, and then evaporated to dryness again to obtain protected M-55 (8 g) as a yellow oil.

[0188] Hydroboration

[0189] The previously isolated Experiment 11 (8 g, 21.5 mmol, 1 equivalent) was dissolved in THF (ultra-dry, 80 mL), and 1 M BH3•THF (6.5 mL, 6.5 mmol, 0.3 equivalent) was added dropwise at 0–5 °C. The resulting reaction mixture was stirred at 0–5 °C for 30 min, then brought to room temperature and stirred, and monitored using Method #1. After 1.5 hours, the impurity RRT1.09 decreased from 10% to 3%. An additional 1 M BH3•THF (2 mL, 2 mmol, 0.1 equivalent) was added, and stirring was continued for 1 hour, resulting in a decrease in impurity RRT1.09 from 3% to 1.5%. The peak value of impurity RRT1.09 decreased from 3% to 1.5%. An additional 1 M BH3•THF was added... 3• THF (1 mL, 1 mmol, 0.05 equivalent) was stirred for 1 hour, and the impurity RRT1.09 decreased from 1.5% to 0.7%. The reaction mixture was evaporated to dryness to give 9 g of crude yellow oil.

[0190] To protect

[0191] The previously isolated Experiment 15 (9 g, 24.1 mmol, 1 equivalent) was dissolved in MeOH (100 mL) and TBAF (1 M, 0.5 mL, 0.5 mmol, 0.02 equivalent) was added. The resulting reaction mixture was stirred at room temperature and monitored using method #2 below. Complete conversion was observed after 1 hour, and the solvent was evaporated to dryness. The resulting residue was dissolved in hexane (16 mL) and loaded onto a silica gel column (220 g, 40–60 μ), eluted with 100% hexane (5 min), 0%–30% DCM / hexane (10 min), and 30% DCM / hexane (45 min), yielding 2.9 g of M-55 (HPLC purity 97.94%) and 0.57 g of M-55 (HPLC purity 97.34%), with an overall yield of 30%. HPLC chromatogram and MS spectrum of Experiment 16 are also shown. 1 H-NMR and 13 The C-NMR results are shown below. Figure 7 , Figure 8 , Figure 9 and Figure 10 .

[0192] Method #1 (M-55 analysis)

[0193] Column: Kinetex EVO C18, 1.7 μ, 100x2.1 mm

[0194] Column temperature: 30℃

[0195] Flow rate: 0.5 mL / min

[0196] Injection volume: 1 μL

[0197] UV detection: 220 nm, 250 nm

[0198] Mobile phase A: Acetonitrile / MeOH = 1 / 1

[0199] Mobile phase B: 0.1% H3PO4 in water

[0200] Diluent / Blank Solution: Acetonitrile / Water

[0201] Gradient: See Table 5 below

[0202] Table 5

[0203]

[0204] Method #2 (Monitoring of the hydroboration method)

[0205] Column: XBridge C18, 3.5 μ, 50x3 mm

[0206] Column temperature: 40℃

[0207] Flow rate: 1 mL / min

[0208] Injection volume: 2 μL

[0209] UV detection: 220 nm, 254 nm, 305 nm

[0210] Mobile phase A: Acetonitrile

[0211] Mobile phase B: 10 mM ammonium carbonate in water

[0212] Diluent / Blank Solution: Acetonitrile / Water

[0213] Gradient: See Table 6 below

[0214] Table 6

[0215]

[0216] Example 4 – Evaluation of the anti-hyperalgesic effect of M-55 in an inflammatory pain model

[0217] Inflammatory pain is a complex pain state that remains a significant clinical challenge due to the limited efficacy and / or poor tolerability of current treatments. Inflammatory pain refers to spontaneous pain sensitivity caused by tissue damage and inflammation, including postoperative pain, traumatic pain, and osteoarthritis pain. This type of pathological pain state can be modeled using carrageenan-induced inflammation, where animals receive intraplantar injections of carrageenan. Carrageenan is an irritant that induces transient inflammation and swelling, peaking 3 hours after injection and subsiding after 24 hours. Carrageenan-induced inflammation leads to pain sensitivity (hyperalodynia), typically peaking after 180 minutes. THC has been shown to effectively reduce carrageenan-induced hyperalodynia.

[0218] At the Department of Behavioral Biology, Johns Hopkins University School of Medicine, the effects of M-55 on carrageenan-induced hyperalgesia were investigated in male and female rats. M-55 or a sesame oil mediated agent was administered 1 hour prior to carrageenan injection to assess its effect on blocking or alleviating the induction of inflammatory responses. λ-carrageenan (Sigma Aldrich) was dissolved in physiological saline (1% w / v) and injected at a volume of 0.1 ml into the plantar surface of one hind foot. Foot swelling (swelling) was measured using an electronic digital caliper at carrageenan injection (0:00) and at 1, 3, and 5 hours post-injection. The Hargreaves and von Frey tests were then used to detect carrageenan-induced thermal and mechanical hyperalgesia, respectively. In the Hargreaves test, an infrared light source was placed below the target hind foot (mid-foot), and the withdrawal latency was automatically recorded to an accuracy of 0.1 seconds. The latency after carrageenan injection was compared with the baseline value before treatment on the same day. A decreased foot withdrawal latency indicates hyperalgesia (i.e., increased pain sensitivity / hypersensitivity), while an increased latency indicates analgesia / analgesia (i.e., decreased pain sensitivity).

[0219] In the von Frey test, von Frey threads (9 threads total, 0.6–15.0 g, starting at 2.0 g) were used to stimulate the target hindfoot on the sole for 3 seconds each time. The presence or absence of a response (nociceptive hindfoot flexion reflex) was recorded. If there was no response, a stronger stimulus was applied; otherwise, a weaker stimulus was applied. After the initial change in response direction, this process was repeated 4 times. The 50% threshold for foot withdrawal was determined by the individual's response pattern and the strength of the von Frey thread used in the final test. The threshold after carrageenan injection was compared to the baseline value before treatment on the same day. A decrease in the foot withdrawal threshold indicated hyperalgesia (i.e., increased pain sensitivity / hypersensitivity), while an increase indicated nociceptive / analgesic effects (i.e., decreased pain sensitivity). An additional animal group was given oral THC (3 mg / kg, 10 mg / kg) or sesame oil methylate for comparison with the effects of M-55. As a positive control, an additional animal group was administered the standard nonsteroidal anti-inflammatory drug (NSAID) ketoprofen (10 mg / kg, 20 mg / kg, intraperitoneal injection, ip) or its mediator (1:1:18, ethanol: Cremophor: 0.9% saline; ip) 60 minutes before carrageenan injection.

[0220] Outcome measures were assessed based on changes in baseline test scores. Changes in withdrawal latency (Hargreaves; thermal sensitivity), withdrawal threshold (von Frey; mechanical sensitivity), and foot thickness (swelling; in mm) were evaluated. Results were analyzed using a three-way ANOVA, with time as the within-subjects factor and M-55 dosage and sex as between-subjects factors. Two-way ANOVAs were performed at each time point, pre-planned. Post-hoc comparisons between subjects were performed using the Sidak or Dunnett test.

[0221] The effect of M-55 on carrageenan-induced pain sensitivity and inflammation

[0222] M-55 blocked thermal hyperalgesia (i.e., increased pain sensitivity) that occurred early in the inflammatory pain test. Analysis of the latency changes of M-55 at three time points (three-factor ANOVA: sex, dose, and time factors) Figure 11 a) Both time (F(2,148)=84.69, p<0.001) and gender (F(1,74)=5.50, p=0.022) showed significant main effects. There was also a significant interaction between time and gender (F(1,148)=4.12, p=0.018). The dose effect showed a non-significant trend (F(4,74)=2.21, p=0.076); the time × dose and time × gender × dose interactions were not significant (p>0.2).

[0223] Analysis at each time point showed significant effects from both the first-hour dose (F(4,83)=2.76, p=0.034) and gender (F(1,83)=8.77, p=0.004). Post-hoc tests showed that the 10 mg / kg M-55 treatment group blocked hyperalgesia in the first hour, compared with the carton group (p=0.016; combined with gender). Figure 12 The effect was stronger in females (mean change in latency: mediator: -5.43 s vs. 10 mg / kg M-55: +1.16 s; p < 0.05 vs. mediator); while in males, although not significantly different, the trend was consistent (mediator: -1.48 s vs. 10 mg / kg M-55: 2.61 s). Other doses showed no significant difference from the mediator group (p > 0.05). Analysis at 3 and 5 hours did not show the effect of M-55 on thermal pain sensitivity at these time points. Therefore, treatment with 10 mg / kg M-55 increased the withdrawal latency at 1 hour compared to the control group, suggesting a beneficial effect on inflammatory hyperalgesia.

[0224] Analysis of all time points (3-way ANOVA: sex, dose, and time as factors) showed that M-55 had no significant effect on changes in the von Frey threshold. Figure 11b). The main dose effect was not significant (F(4,74)=0.35, p=0.84), the dose-time interaction was not significant (F(8,148)=0.43, p=0.90), and the dose-sex-time interaction was also not significant (F(8,148)=0.97, p=0.47). A significant dose-sex interaction existed: F(4,74)=2.98, p=0.02, indicating that sex affects M-55 response. Therefore, we determined the effect of M-55 on mechanoreathia in each sex. In males, M-55 had no effect on threshold changes (F(4,38)=1.37, p=0.26); in females, M-55 showed a non-significant trend in threshold changes (F(4,36)=1.83, p=0.14). However, the effect appears to be primarily driven by the increased mechanoreceptive hypersensitivity of 100 mg / kg M-55 at hour 1 compared to the control group.

[0225] Analysis of foot swelling did not show any significant effect of M-55. Analysis at all time points (3-way ANOVA: sex, dose, and time as factors) showed no significant main effect of M-55 on foot swelling (F(4,74)=0.18, p=0.95), no significant dose-time interaction (F(8,148)=0.89, p=0.53), no significant dose-sex interaction (F(4,74)=1.36, p=0.26), and no significant dose-sex-time interaction (F(8,148)=0.20, p=0.88). In the analysis at each time point, dose had no main effect (p>0.05 for all).

[0226] In summary, M-55 effectively blocked thermal hyperalgesia at the 1-hour time point. At the tested dose, M-55 did not significantly enhance mechanical pain sensitivity or inflammation.

[0227] Effects of THC on carrageenan-induced hyperalgesia and inflammation

[0228] Overall, THC produces both thermal and mechanical analgesia at medium to high doses (3–10 mg / kg), while low doses (1 mg / kg) increase carrageenan-induced inflammation. THC increases the foot withdrawal latency in the Hargreaves thermal pain sensitivity test. Figure 13a) Analysis of all time points (3-way ANOVA with sex, dose, and time as factors) showed that THC had a significant main effect of time on changes in foot withdrawal latency (F(2,120)=44.81, p<0.001) and a main effect of dose (F(3,30)=5.75, p=0.002). Sex had no effect (F(1,60)=0.45, p=0.50). The time × sex interaction showed no significant trend (F(2,120)=2.45, p=0.09); the time × dose, sex × dose, and time × sex × dose interactions were all not significant (p>0.3). Post-hoc tests showed that 3 and 10 mg / kg THC increased the latency compared to the control group.

[0229] In the analyses at each time point, the dose at hour 1 (F(3,60)=3.61, p=0.02), hour 3 (F(3,60)=7.12, p<0.001), and hour 5 (F(3,60)=3.78, p=0.02) all had significant main effects. At each time point, sex and the sex × dose interaction had no significant effect. To compare with the maximum effect of M-55 in the Hargreaves test (hour 1), we show the analgesic effect of THC at hour 1 (3 and 10 mg / kg THC vs. control group p<0.02, sex combined) (…). Figure 14 ).

[0230] THC increases the foot withdrawal threshold in the von Frey mechanical pain sensitivity test. Figure 13 b). Analysis of the threshold changes of THC at all time points (3-way ANOVA with sex, dose, and time as factors) showed a main effect of dose (F(3,60)=16.58, p<0.001), a main effect of time (F(2,120)=37.05, p<0.001), and a trend of the main effect of sex (F(1,60)=3.65, p=0.06). Significant interactions were found between sex and dose: F(3,60)=3.67, p=0.02, time and dose (F(6,120)=3.45, p<0.01), and a trend of the interaction between time and sex and dose (F(6,120)=2.06, p=0.07). Post-hoc tests showed that 3 and 10 mg / kg THC increased the threshold compared to the control group (p<0.001). THC effectively increased the threshold at all test time points (1, 3, and 5 hours after carrageenan administration), and the main dose effect was significant at each time point (p < 0.05).

[0231] THC increases foot swelling ( Figure 13c). Analysis of all time points (3-way ANOVA with sex, dose, and time as factors) showed that THC had a significant dose-based main effect (F(3,60)=5.66, p<0.01) and a time-based main effect (F(2,120)=95.35, p<0.001) on changes in foot thickness. Significant interactions existed between time and sex (F(2,120)=5.28, p<0.01) and time and dose (F(6,120)=4.56, p<0.01). Post-hoc tests showed that 1 mg / kg THC tended to increase swelling compared to the control group (p=0.054). In the analysis at each time point, THC showed a trend towards swelling at 1 hour (F(3,60)=2.67, p=0.06), and a significant effect at 3 hours (F(3,60)=3.19, p=0.03) and 5 hours (F(3,60)=6.90, p<0.001).

[0232] Effects of ketoprofen on carrageenan-induced hyperalgesia and inflammation

[0233] Overall, ketoprofen blocked hyperalgesia and reduced swelling in a carrageenan-induced inflammatory pain model. Ketoprofen significantly increased the withdrawal latency in the Hargreaves thermal sensitivity test. Figure 15 a) Analysis of the effects of ketoprofen on the latency of foot contraction at all time points (3-way ANOVA: sex, dose, and time as factors) showed a significant main effect of dose (F(2,58)=6.35, p<0.01) and a main effect of time (F(2,116)=46.68, p<0.001). Significant interactions existed between time × sex (F(2,116)=5.41, p=0.01) and time × dose (F(4,116)=3.40, p=0.01).

[0234] In individual analyses at each time point, the main dose-dependent effects were significant at hour 3 (F(2,58)=5.75, p<0.01) and hour 5 (F(2,58)=11.06, p<0.001). The effect observed at hour 3 was primarily driven by females, with both 10 and 20 mg / kg ketoprofen effectively blocking hyperalgesia (p<0.05). Five hours after carrageenan injection, ketoprofen (10, 20 mg / kg) effectively blocked hyperalgesia in both sexes (p<0.05). To compare with the maximum effect of M-55 in the Hargreaves test (hour 1), we present the maximum effect of ketoprofen (hour 5), combined by sex (…). Figure 16 The main effect of dose was F(2,61)=10.56, p<0.001.

[0235] Ketoprofen has a moderate effect on hyperalgesia observed after carrageenan injection. Figure 15b). Analysis of the effect of ketoprofen on changes in the von Frey threshold (mechanical pain sensitivity) showed a main time effect (F(2,116)=5.23, p=0.01) and a time-sex interaction (F(2,116)=3.76, p=0.03). Among the analyses at each time point, the main dose effect at 3 hours was significant (F(1,58)=3.56, p=0.04), with 10 mg / kg ketoprofen reducing hyperalgesia compared to the control group (p=0.02, sex combined), an effect primarily driven by females.

[0236] Ketoprofen reduces foot swelling ( Figure 15 c). Analysis of the effect of ketoprofen on foot thickness changes at all time points (3-way ANOVA: sex, dose, and time as factors) showed a significant main effect of time (F(2,116)=67.95, p<0.001), and a general trend in the main effect of dose (F(2,58)=2.53, p=0.09). Interactions of time × dose (F(4,116)=7.85, p<0.001) and time × sex × dose (F(4,116)=2.77, p=0.03) were observed. In individual analyses at each time point, only the main effect of dose was significant at hour 5 (F(2,58)=6.16, p<0.01). Post-hoc tests showed that 10 mg / kg (male only) and 20 mg / kg (bisexual) ketoprofen reduced swelling compared to the control group.

[0237] Overall, 10 and 20 mg / kg ketoprofen effectively blocked inflammation-related thermal hyperalgesia at later time points (3-5 hours) and reduced foot swelling at 5 hours.

[0238] in conclusion

[0239] M-55 effectively prevented inflammation-related thermal hyperalgesia in the early stages of a carrageenan model of rodents. The specific effect at early time points suggests that this compound may be short-acting. Future testing should evaluate repeated or chronic dosing to achieve stable plasma concentrations.

[0240] Oral administration of THC at the tested doses in a carrageenan-induced inflammatory pain model effectively produced both thermal and mechanical analgesia. These effects were evident at all time points. Low-dose THC (1 mg / kg) did not modulate hyperalgesia but increased swelling. The antihyperalgesic effects of 10 mg / kg THC and 10 mg / kg M-55 were equivalent (mean differences from control: +5.7s and +5.4s, respectively). However, the duration of the hyperalgesic effect of oral THC was longer, persisting up to the last tested time point (5 hours after carrageenan administration).

[0241] Ketoprofen is an effective analgesic that blocks thermal hyperalgesia 3–5 hours after carrageenan-induced inflammation. At hour 3, ketoprofen moderately reduces hyperalgesia, and this effect is primarily estrogen-driven. Ketoprofen also effectively reduces swelling at hour 5. This is consistent with other reports and its mechanism of action. Compared to M-55, ketoprofen's effect on thermal hyperalgesia occurs in the later stages of inflammatory pain sensitization. Furthermore, ketoprofen (10, 20 mg / kg) showed efficacy in reducing swelling, while M-55 did not.

[0242] Evaluation of M-55's acute analgesia and tetanic effects at multiple time points

[0243] The analgesic effect of a drug is typically determined by testing changes in pain sensitivity. Acute pain sensitivity was measured at baseline (30 minutes before drug administration) and at +30, +60, and +120 minutes after oral administration of M-55 (3 mg / kg, 10 mg / kg, 30 mg / kg, 100 mg / kg) or the control group (sesame oil), using the tail flick and von Frey tests, respectively. The tail flick and von Frey tests are standard tests for assessing acute pain sensitivity and have been proven to be effective against analgesics and anti-hyperalgesics (including cannabinoids). Multiple assessments over 2 hours reveal the time course and duration of drug action. Outcome parameters included the withdrawal latency and threshold in the tail flick and von Frey tests. We also assessed tetany in conjunction with acute pain sensitivity to determine whether M-55 produced the classic effect of cannabinoid 1 receptor (CB1) activation. CB1 agonists, including THC15, can induce typical antinociceptive effects and tetany. Tetany was measured three times using a bar test. In the experiment, the rat's forepaw was placed on a bar with a diameter of 5 cm and a height of 12 cm, assuming an abnormal posture. The result was the time (in seconds) the forepaw remained in contact with the bar, with a maximum test time of 180 seconds. Tetany was tested 150 minutes after oral administration of M-55, as THC-induced tetany was most pronounced at the later time point. Tetany is expressed as the average ln (seconds) of the three experiments.

[0244] Pain sensitivity outcomes were assessed by changes in baseline test scores. We evaluated changes in withdrawal latency (tail flick, thermal pain sensitivity) and withdrawal threshold (von Frey, mechanical pain sensitivity). Tetany was assessed by the total number of seconds of contact with the bar. Results were analyzed using a three-way ANOVA, with time and dose as within-subjects factors and sex as between-subjects factors. Two-way ANOVAs were performed at each time point, pre-planned. Post-hoc comparisons between subjects were performed using the Sidak or Dunnett test.

[0245] Effects of M-55 on acute pain sensitivity and rigidity.

[0246] M-55 produced both thermal and mechanical analgesic effects. M-55 prolonged the latency period in the tail-flicking heat-induced analgesia sensitivity test. Analysis of the change in latency period at all time points (three-way ANOVA) showed a significant main effect of dose (F(4,50)=3.30, p=0.02), and an interaction trend of time × gender × dose (F(8,100)=1.83, p=0.08). Analysis at each time point showed that M-55 significantly prolonged the latency period compared to the control group at 60 minutes after administration (main effect of dose: F(4,50)=4.35, p=0.004). Figure 18 a). Post-hoc tests showed that the latency period of rats tested with 100 mg / kg M-55 was longer than that of the control group (p<0.04). M-55 had no significant effect on thermal pain at 30 minutes (dose-main effect: F(4,50)=1.78, p=0.15), but tended to prolong the latency period at 120 minutes (dose-main effect: F(4,50)=2.26, p=0.08).

[0247] M-55 increased the threshold in the von Frey mechanical pain sensitivity test. Analysis of changes in the von Frey foot withdrawal threshold at all time points (three-way ANOVA) showed a significant interaction between time, sex, and dose (F(8,100)=2.08, p=0.05). Analysis at each time point indicated that M-55 significantly increased the threshold compared to the control group at 30 minutes after administration (dose-based main effect: F(4,50)=3.36, p=0.02). Figure 18 b). M-55 had no effect on mechanical pain sensitivity at 1 hour and 2 hours after application.

[0248] No tetanic state was observed after administration of M-55 or the control group (mean time on bar <10 seconds; mean ± standard error, control group: 4.73 ± 0.32 seconds, 3 mg / kg M-55: 1.18 ± 0.30 seconds; 10 mg / kg M-55: 3.83 ± 2.53 seconds; 30 mg / kg M-55: 3.97 ± 2.87 seconds; 100 mg / kg M-55: 1.58 ± 0.09 seconds, data not shown).

[0249] in conclusion

[0250] Acute administration of 100 mg / kg M-55 effectively produced analgesia in normal rats. These effects were limited to early time points (30 minutes, 60 minutes), suggesting a potentially short duration of action. THC has also been shown to produce analgesia. Compared to the effects of M-55, our previous studies have shown that oral THC produces sustained analgesia, with effects lasting up to 5 hours after administration.

[0251] Based on the findings of studies on inflammatory pain, it can be concluded that M-55 has moderate analgesic and anti-hyperalgesic effects, limited to early time points. Different doses may be effective for both acute and inflammatory pain. Future testing could evaluate repeated or chronic dosing to achieve steady-state plasma concentrations and determine whether stronger or more durable effects can be observed.

[0252] Example 5 – Evaluation of the Anxiety-Rating Effect of M-55

[0253] The elevated cross maze (EPM) is a widely used preclinical behavioral analysis method in rodents and has been validated for assessing the anxiolytic effects of drugs. EPM is also a common tool in neurobiological anxiety research, such as in generalized anxiety disorder or post-traumatic stress disorder, as it serves as a screening method for potential anxiolytic compounds in rodents. The model is based on the aversion response of experimental animals to the open arm space of the maze.

[0254] The anxiolytic effect of the test drug was demonstrated by an increase in the percentage of time animals spent in the open arm compared to placebo. Total walking distance, a measure of overall activation and motor activity in mice during the EPM test, was used to rule out sedative or narcotic effects of the test drug. Several clinically approved pain medications have been shown to delay heat sensitivity in mouse paws when exposed to heat, including opioids.

[0255] This study investigated the effects of acute administration of M-55 on anxiety-related phenotypes in mice to mimic human conditions. Eight to 12-week-old C57Bl / 6 mice (n=5 / group) were intraperitoneally injected (ip) with either a control (saline + 1% DMSO) or a mediator of MIRA-55 (0 mg / kg = placebo [PBO], 50 mg / kg = treatment). Thirty minutes post-injection, anxiety-related markers were measured in the EPM. Figure 19 As shown, at the tested dose, M-55 has a significant anxiolytic effect without sedation or intoxication symptoms.

[0256] Although the present invention has been described in conjunction with specific examples, those skilled in the art will understand that there are numerous variations and combinations of the above systems and techniques, all of which fall within the spirit and scope of the present invention as defined in the appended claims.

Claims

1. A compound having the structure of formula (I): Formula (I) R1 and R2 are each independently selected from the group consisting of: H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; wherein the alkyl, alkenyl, alkynyl, or acyl group is optionally substituted by one or more substituents, wherein the one or more substituents are independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NR A R B —S-alkyl, —SO-alkyl, —SO2-alkyl, alkenyl, ynyl, aryl, heteroaryl, cycloalkyl, and heterocyclic; wherein R A and R B Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein the aryl or heteroaryl group, whether alone or as part of a substituent, is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, -COOH, -C(O)-C 1-4 Alkyl, —C(O)O—C 1-4 Alkyl, NR C R D —S-alkyl, —SO-alkyl and —SO2-alkyl; wherein R C and R D Each is independently selected from hydrogen and C. 1-4 alkyl; R3 is selected from the group consisting of: H, alkyl, acyl, -SO2-alkyl, -SO2-aryl, and -SO2-heteroaryl; wherein the alkyl group is optionally substituted by one or more substituents, which are independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NR E R F —S-alkyl, —SO-alkyl, —SO2-alkyl, aryl and heteroaryl; and wherein R E and R F Each is independently selected from hydrogen and C. 1-4 Alkyl; wherein the aryl or heteroaryl group, whether alone or as part of a substituent, is optionally substituted by one or more substituents, said one or more substituents being independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NR G R H —S-alkyl, —SO-alkyl and —SO2-alkyl; wherein R G and R H Each is independently selected from hydrogen and C. 1-4 alkyl; Each To indicate a single or double bond, the prerequisite is that it is within a pentagonal ring, one or two bonds. It is a double bond, and the rest It is a single bond; Or its pharmaceutically acceptable salts or esters.

2. The compound according to claim 1, wherein R2 is a C1-C4 straight-chain or branched alkyl group.

3. The compound according to claim 1, wherein R2 is C5-C. 10 Straight-chain or branched alkyl groups.

4. The compound according to claim 1, wherein the compound has the structure of formula (IA): Formula (IA) One of them It is a single key, and another It is a double bond; Or its pharmaceutically acceptable salts or esters.

5. The compound according to claim 4, wherein R2 is a C1-C4 straight-chain or branched alkyl group.

6. The compound according to claim 4, wherein R2 is C5-C. 10 Straight-chain or branched alkyl groups.

7. The compound according to claim 1, wherein the compound has the structure of formula (II): Equation (II) Or its pharmaceutically acceptable salts or esters.

8. The compound according to claim 5, wherein R2 is a C1-C4 straight-chain or branched alkyl group.

9. The compound according to claim 5, wherein R2 is C5-C. 10 Straight-chain or branched alkyl groups.

10. The compound according to claim 8, wherein the compound has the following structure: Or its pharmaceutically acceptable salts or esters.

11. The compound according to claim 9, wherein the compound has the following structure: Or its pharmaceutically acceptable salts or esters.

12. A pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable mediator for use in the pharmaceutical composition.

13. Use of the pharmaceutical composition according to claim 12 for the treatment of cancer, tumors, addiction, epilepsy, Alzheimer's disease, pain, or depression.

14. Use of the pharmaceutical composition according to claim 12 for the treatment of anxiety, addiction, depression, sleep disorders or post-traumatic stress disorder (PTSD).

15. Use of the pharmaceutical composition according to claim 12 for treating cognitive impairment or for improving cognition.

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