RIGID CANNABIDIOL ANALOGUES AS POTENT MODULATORS OF CANNABINOID RECEPTORS AND USES THEREOF

Abstract

Disclosed herein are novel rigid cannabidiol (CBD) analogues and their formulations that modulate cannabinoid receptors, method(s) of preparation, methods of modulating cannabinoid receptors, and methods of treating various conditions related to the modulation of cannabinoid receptors, such as, pain and inflammation, cancer, glaucoma, neurodegenerative disorders, multiple sclerosis, renal fibrosis, fibrotic disorders, addiction, anxiety, insomnia, motor function disorders and gastrointestinal and metabolic disorders.

Claims

1. A compound of formula I: ##STR00025## wherein: X = C, S, O, or N; and R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are independently selected from the group consisting of: CH.sub.3, CH.sub.2OH, OH, CCH.sub.2CH.sub.3, a halogen, methoxy, ethoxy, nitrile, amino, nitro, halogenated or cyanated alkyl groups, aromatic, heteroaromatic, and cyclic or acyclic aliphatic chains; and wherein at least one of R.sub.1, R.sub.2, R.sub.3, or R.sub.4 is an aromatic, heteroaromatic, cyclic or acyclic aliphatic chain. wherein if X = O, R.sub.1 is a substituted or unsubstituted aromatic or heteroaromatic.

2. The compound of claim 1, wherein one or both of ring A and ring C contain a heteroatom.

3. The compound of claim 2, wherein the heteroatom of one or both of ring A and ring C is, independently, N, O, or S.

4. The compound of claim 1, wherein R.sub.2 is a hydrogen donor group.

5. The compound of claim 4, wherein R.sub.2 is selected from the group consisting of: OH, SH, NH, NH.sub.2, SO.sub.2NH.sub.2.

6. The compound of claim 5, wherein R.sub.3 is an aromatic, heteroaromatic, or unsaturated ring.

7. The compound of claim 6, wherein R.sub.4 is a one to three-carbon alkyl chain.

8. The compound of claim 7, wherein the R.sub.4 alkyl chain is substituted with a hydrogen donor group.

9. The compound of claim 8, wherein R.sub.1 is a substituted or unsubstituted aromatic or heteroaromatic.

10. The compound of claim 9, wherein R.sub.1 is substituted with a group selected from the group consisting of: methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, sec-butyl, isobutyl, cyclobutyl, pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl, heptyl, cycloheptyl, 4,4-dimethylpentyl, 1,1-dimethylpentyl, 1,2-dimethylheptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, adamantly and their cyclic and alicyclic analogues.

11. The compound of claim 10, wherein one or more of R.sub.1-R.sub.4 are substituted by a heteroatom or a halogen.

12. The compound of claim 11, wherein one or more of R.sub.1-R.sub.4 are selected from the group consisting of: an alkene, alkyne, alcohol, carbonyl, amine, nitro, ether, acid, sulfonyl, sulfonamide, amide, ester, cyano, and a substituted or unsubstituted aryl group.

13. The compound of claim 1, wherein the compound is. ##STR00026##

14. The compound of claim 1, wherein the compound is. ##STR00027##

15. The compound of claim 1, wherein the compound is. ##STR00028##

16. The compound of claim 1, wherein the compound is. ##STR00029##

17. The compound of claim 1, wherein the compound is. ##STR00030##

18. The compound of claim 1, wherein the compound is. ##STR00031##

19. The compound of claim 1, wherein the compound is. ##STR00032##

20. The compound of claim 1, wherein the compound is. ##STR00033##

21. The compound of claim 1, wherein the compound is. ##STR00034##

22. The compound of claim 1, wherein the compound is. ##STR00035##

23. The compound of claim 1, wherein the compound is. ##STR00036##

24. The compound of claim 1, wherein the compound is. ##STR00037##

25. The compound of claim 1, wherein the compound is. ##STR00038##

26. The compound of claim 1, wherein the compound is. ##STR00039##

27. The compound of claim 1, wherein the compound is. ##STR00040##

28. The compound of claim 1, wherein the compound is. ##STR00041##

29. The compound of claim 1, wherein the compound is. ##STR00042##

30. A compound comprising a tricyclic heterocycle having a ring A and a ring C fused on either side of a ring B, wherein ring A and ring C are individually selected from the group consisting of: alicyclic, heterocyclic, aromatic and heteroaromatic rings, and wherein ring B is a three to five atom ring with a C, S, O, or N atom; wherein each of ring A and ring C have at least two side groups individually selected from the group consisting of: CH.sub.3, CH.sub.2OH, OH, CCH.sub.2CH.sub.3, a halogen, methoxy, ethoxy, nitrile, amino, nitro, halogenated or cyanated alkyl groups, substituted or unsubstituted aromatic, heteroaromatic, and cyclic or acyclic aliphatic chains; wherein at least one of ring A and ring C have a side group selected from the group consisting of: a substituted or unsubstituted aromatic, heteroaromatic, and cyclic or acyclic aliphatic chain; and wherein ring C has an O atom, at least one of the side groups on ring A or ring C is a substituted or unsubstituted aromatic or heteroaromatic group.

31. The compound of claim 30, wherein each of ring A and ring C is a three to eight atom ring.

32. The compound of claim 31, wherein at least one of ring A and ring C is an aromatic, heteroaromatic, or unsaturated ring.

33. The compound of claim 32, wherein the two side groups on ring A have a 1,3-relationship and the two side groups on ring C have a 1,4-relationship.

34. The compound of claim 33, wherein one or more of ring A or C contains a basic nitrogen.

35. The compound of claim 33, wherein at least one of ring A and ring C has a hydrogen donor side group.

36. The compound of claim 35, wherein the hydrogen donor side group is selected from the group consisting of: OH, SH, NH, NH.sub.2, SO.sub.2NH.sub.2.

37. The compound of claim 36, wherein at least one of ring A and ring C has a one to three-carbon cyclic or acyclic alkyl chain side group.

38. The compound of claim 37, wherein the alkyl chain side group is substituted with a hydrogen donor group.

39. The compound of claim 38, wherein at least one of ring A and ring C has a cyclic or acyclic aliphatic side chain.

40. The compound of claim 39, wherein the aliphatic side chain is selected from the group consisting of: methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, sec-butyl, isobutyl, cyclobutyl, pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl, heptyl, cycloheptyl, 4,4-dimethylpentyl, 1,1-dimethylpentyl, 1,2-dimethylheptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, adamantly and their cyclic and alicyclic analogues.

41. The compound of claim 40, wherein one or more of the side groups on ring A and ring C are substituted by a heteroatom or a halogen.

42. The compound of claim 41, wherein one or more of the side groups on ring A and ring C are selected from the group consisting of: an alkene, alkyne, alcohol, carbonyl, amine, nitro, ether, acid, sulfonyl, sulfonamide, amide, ester, cyano, and a substituted or unsubstituted aryl group.

43. The use of a compound of claim 1 to treat one or more conditions selected from pain and inflammation, cancer, glaucoma, neurodegenerative disorders, multiple sclerosis, renal fibrosis, fibrotic disorders, addiction, anxiety, insomnia, motor function disorders and gastrointestinal and metabolic disorders.

44. A pharmaceutical formulation, comprising a compound of claim 1 or physiologically acceptable isomers, salts, derivatives, or pro-drugs and mixtures thereof.

45. The pharmaceutical formulation of claim 44, comprising a synergistic compound selected from the group consisting of: delta-9-tetrahydrocannabinol (THC); delta-8-tetrahydrocannabinol (THC); cannabidiol (CBD); cannabinodiol (CBND); cannabinol (CBN); cannabigerol (CBG); cannabichromene (CBC); cannabicyclol (CBL); canabivarol (CBV); tetrahydrocannabivarin (THCV); cannabidivarin (CBDV); cannabichromevarin (CBCV); cannabigerol monoethyl ether (CBGM); cannabielsoin (CBE); cannabitriol (CBT); Boswellia sp . extracts, including Boswellia carterii and Boswellia serrata; ginger; capsaicin; camphor; polyphenols, including quercetin, ellagic acid, curcumin, and resveratrol; phytosterols; carbohydrates, including mannose-6-phosphate; essential oils, including thymol and carvacrol; terpenoids, including squalene, lycopene, p-cymene and linalool.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order that the invention may be more clearly understood, a preferred embodiment thereof will now be described in detail by way of example, with reference to the accompanying drawings, in which:

[0028] FIG. 1 is a molecular docking schematic view of a compound, according to the present invention, compared to a potent agonist. Example compound EX-1 (green) selectively lies in the agonist region and is aligned with the potent crystallized agonist (red) in CB1 binding site (PDB code = 5TGZ). EX-1 is away from TRP 356 and interacts with the other toggle switch PHE200 to further enhance the induced fit initiated by TRP356.

[0029] FIG. 2 is a molecular docking schematic view of the compound of FIG. 1, compared with THC. EX-1 (green) showed better conformation than THC (red) in CB1 binding site (PDB code = 5XR8). EX-1 is better oriented in the agonist site and showed conformations that keep its pentyl side chain away from TRP356.

[0030] FIG. 3 is a molecular docking schematic view of the compound of FIG. 1, compared with an antagonist (red) in CB2 (PDB code = 5ZTY). EX-1 (green) selectively occupied the agonist binding region and away from TRP256.

DETAILED DESCRIPTION OF THE INVENTION

[0031] This disclosure relates to compounds that can modulate cannabinoids receptors, to methods of their synthesis, to pharmaceutical formulations of these compounds, to methods of modulating CB1 and CB2 and to methods of treating pain, inflammation, neurodegenerative disorders, cancer, renal fibrosis, epilepsy and other motor dysfunction, obesity and other metabolic disorder, addiction, sleep disorders, anxiety, multiple sclerosis, anorexia and others.

[0032] The term “target compounds” in the present disclosure include any, and all possible isomers, including isomers, stereoisomers, enantiomers, diastereomers, tautomers, salts, and pro-drugs thereof. They can include derivatives and analogues of a rigid pharmacophore with the general formula I. Preferably they are derivatives and analogues of a fused tricyclic system. More preferably, they are derivatives and analogues of a carbazole heterocycle. Examples of the target compounds include the compounds of formula I:

##STR00005##

TABLE-US-00002 Rings A and C Ring B Arms (R.sub.1-R.sub.4) alicyclic, heterocyclic, aromatic and heteroaromatic rings of any size, fused or non- fused small size ring (3-5 atoms); X = C, S, O, or N Aromatic, heteroaromatic, aliphatic chain, straight or branched, cyclic or acyclic, with/without heteroatoms, alkene, alkyne, sulfonyl, sulfonamides, basic, acidic functional group or their isosteres

[0033] The term “a fused tricyclic system” relates to rings A, B and C with a fused relationship. The terms “substituents” relates to substituents R.sub.1-R.sub.4 on the peripheral carbon skeleton at C3, C5, C6 and C9.

[0034] Unless otherwise specifically defined, the term “Rings A and C” refers to alicyclic (e.g. cyclohexane), heterocyclic (e.g. tetrahydropyridine), aromatic (e.g. benzene) or heteroaromatic (e.g. pyridine) rings of any size. Preferably, of 3 to 8 atoms. Preferably, ring A is an aromatic or heteroaromatic with six atoms size, while ring C is an alicyclic ring, optionally saturated or unsaturated, optionally aromatic or heteroaromatic. The rings A and C could be fused (e.g. naphthalene or indole) or non-fused systems (e.g. benzene or pyrrole). Preferably, rings A and C are not fused systems. The rings A and C may be optionally substituted by one or more substituents at any point of attachment. Preferably, rings A and C are substituted. Preferably, the substituents on ring A have a 1,3-relationship and a 1,4-relationship on ring C. The substituents can themselves be optionally substituted and modified to include hydrogen, hydroxyl, hydroxymethyl, halogens (F, Cl, Br, I), methoxy, ethoxy, nitrile, amino, nitro and halogenated or cyanated alkyl groups (e.g. CF.sub.3, -CH2CN). The rings A and C may optionally contain a hetero atom including, N, O, S. Preferably, ring A and C may contain nitrogen. When rings A or C contain a basic nitrogen, the target compounds are protonated at physiological pH, and may show decreased ability to cross the blood brain barrier. As a result, they exert their actions peripherally without any psychotropic effects.

[0035] In order to enforce rigidity of the target molecules, ring B is a small size ring of 3-5 atoms of any nature, including aliphatic, aromatic, heteroaromatic, saturated or unsaturated. Preferably, ring B is composed of five atoms with at least one carbon-carbon single bond. At least one atom (atom X) of ring B is a heteroatom including S, O and N. Preferably, ring B contain a basic NH to act as a H-bond donor group. This atom (X) is in a meta relation to substituents R.sub.1 and R.sub.2.

[0036] The substituents R.sub.1-R.sub.4 could be of any nature including aromatic, aliphatic, saturated or unsaturated, linear or branched chain, cyclic or acyclic hydrocarbon, halogen or hetero based functionality, saturated or unsaturated heterocyclic ring, as defined for rings A-C. Preferably, C3 substituent (R.sub.1) is an aliphatic chain, optionally substituted with a hydrogen donor or acceptor group. Examples include, methyl (“Me”), ethyl (“Et”), propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, sec-butyl, isobutyl, cyclobutyl, pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl, heptyl, cycloheptyl, 4,4-dimethylpentyl, 1,1-dimethylpentyl, 1,2-dimethylheptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, adamantly and their cyclic and alicyclic analogues and the like. C5 substituent (R.sub.2) is a hydrogen donor group (e.g. OH, SH, NH, NH.sub.2, SO.sub.2NH.sub.2). C6 substituent (R.sub.3) is an aromatic or heteroaromatic or unsaturated ring, optionally substituted or unsubstituted. C9 substituent (R4) is a small alkyl chain (e.g. methyl, ethyl, propyl), optionally substituted with a hydrogen donor group (e.g. OH, SH, NH, NH.sub.2, SO.sub.2NH.sub.2). The substituents R.sub.1-R.sub.4 may be optionally substituted by a hetero atom or a halogen, including F, Cl, Br, I, O, N, and S and may contain aromatic or heteroaromatic rings. The substituents R.sub.1-R.sub.4 may contain other functional groups, including alkene, alkyne, alcohol, carbonyl, amine, nitro, ether, acid, sulfonyl, sulfonamides, amide, ester, cyano and a substituted or unsubstituted aryl group.

[0037] In a preferred embodiment, the selective cannabinoid ligands of the present invention are represented by the following examples (EX-1 to EX-18):

##STR00006##

##STR00007##

##STR00008##

##STR00009##

##STR00010##

##STR00011##

##STR00012##

##STR00013##

##STR00014##

##STR00015##

##STR00016##

##STR00017##

##STR00018##

##STR00019##

##STR00020##

##STR00021##

##STR00022##

##STR00023##

[0038] The compounds may be prepared according to the reaction below, where modification of the reaction can produce other derivatives and analogues. This reaction is presented as an example; however, other possible routes will become apparent to those skilled in the art.

##STR00024##

[0039] The term “pharmaceutical formulation”, as used herein, refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, or other synergistic compounds along with other physiologically acceptable carriers and excipients. The purpose of a pharmaceutical formulation (e.g. solid or liquid dosage forms) is to facilitate administration of a compound to a subject animal or human. Preferably, the formulation is a solid dosage form for oral and oromucosal applications.

[0040] The formulation may contain synergistic ingredients, in addition to active ingredients, which may include: delta-9-tetrahydrocannabinol (THC); delta-8-tetrahydrocannabinol (THC); cannabidiol (CBD); cannabinodiol (CBND); cannabinol (CBN); cannabigerol (CBG); cannabichromene (CBC); cannabicyclol (CBL); canabivarol (CBV); tetrahydrocannabivarin (THCV); cannabidivarin (CBDV); cannabichromevarin (CBCV); cannabigerol monoethyl ether (CBGM); cannabielsoin (CBE); cannabitriol (CBT); Boswellia sp. extracts, including Boswellia carterii and Boswellia serrata; ginger; capsaicin; camphor; polyphenols, including quercetin, ellagic acid, curcumin, and resveratrol; phytosterols; carbohydrates, including mannose-6-phosphate; essential oils, including thymol and carvacrol; terpenoids, including squalene, lycopene, p-cymene and linalool; or mixtures or combinations thereof. Preferably, the formulation contains only one active ingredient, being the target compound, without any synergistic ingredients.

[0041] The term “salt” is intended to include salts derived from inorganic (e.g. hydrochloric) or organic acids (e.g. tartaric acid).

[0042] The term “pro-drugs” is intended to include derivatives of the target compounds that may require activation within the human body (e.g. carbohydrate and ester derivatives).

[0043] Certain exemplary compounds, according to the present invention, can be delivered by oromucosal, nasal, oral, ophthalmic, transdermal and parenteral routes. They can be used for the treatment of inflammation and pain and other related conditions. They have an improved pharmacokinetic/pharmacodynamic profile, compared to some other related analogues. This is useful in the treatment of inflammation, pain, and related conditions to quickly alleviate the symptoms and provide long-lasting relief to the patient.

[0044] The term “subject” in the present disclosure refers to human patients but may include animals.

Example 1: Preparation of EX-18

[0045] A solution of [Pd(OAc).sub.2] (11.2 mg, 0.05 mmol, 5.0 mol%), PCy.sub.3 (28.9 mg, 0.10 mmol, 10 mol%), K.sub.3PO.sub.4 (636.8 mg, 3.00 mmol), aryl halide 1 (263.1 mg, 1.00 mmol) and aniline derivative 2 (329 mg, 1.20 mmol) in dry NMP (10.0 mL) was stirred for 15 h at 130° C. under N.sub.2. Et.sub.2O (25 mL) and H.sub.2O (25 mL) were added to the mixture at r.t. and the separated aqueous phase was extracted with Et.sub.2O (2 × 70 mL). The combined organic layers were washed with brine (50 mL), dried (sodium sulfate), and concentrated in vacuo. The residue was purified by column chromatography (silica gel, pentane) to give EX-18.

Example 2: Molecular Docking Studies of EX-1 Compared to Potent Ligands

[0046] As shown in FIG. 1, EX-1 selectively lies in the agonist region and is aligned with the potent crystallized agonist. EX-1 is away from TRP356 and interacts with the other toggle switch PHE200 to further enhance the induced fit initiated by TRP356.

[0047] As shown in FIG. 2, EX-1 showed better conformation than THC in the CB1 binding site. EX-1 is better oriented in the agonist site and showed conformations that keep its pentyl side chain away from TRP356.

[0048] As shown in FIG. 3, compared to an antagonist shown in red, EX-1 selectively occupied the agonist binding region and is positioned away from TRP256, which is labeled as magenta sticks.

[0049] The present invention has been described and illustrated with reference to an exemplary embodiment; however, it will be understood by those skilled in the art that various changes may be made, and equivalents may be substituted for elements thereof without departing from the scope of the invention as set out in the following claims. Therefore, it is intended that the invention is not limited to the embodiments disclosed herein.