WO2020198874A1

WO2020198874A1 - Cannabidiolic acid monoglycerides, derivatives, and uses thereof

Info

Publication number: WO2020198874A1
Application number: PCT/CA2020/050443
Authority: WO
Inventors: Samuel C. Fortin
Original assignee: Scf Pharma Inc.
Priority date: 2019-04-04
Filing date: 2020-04-03
Publication date: 2020-10-08

Abstract

There are provided various cannabidiolic acid monoglycerides and derivatives thereof. These compounds can be useful as an inflammation resolution agent, anti-inflammatory agent, cancer chemopreventive agent, mitochondrial modulator agent, life-span enhancer agent and prebiotic agent.

Description

CANNABIDIOLIC ACID MONOGLYCERIDES,

DERIVATIVES, AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

G0011 The present application claims priority to US application No. 62/829,427 filed on April 4, 2019. This document is hereby incorporated by reference in its entirety.

FIELD OF THE DISCLOSURE

G0021 The present disclosure relates to the field of medicinal chemistry. More particularly it relates to the field of active agents used as an inflammation resolution agent, anti-inflammatory agent, cancer chemopreventive agent, mitochondrial modulator agent, life-span enhancer agent and prebiotic agent.

BACKGROUND OF THE DISCLOSURE

G0031 Cannabidiolic acid (CBDA) is a chemical compound found in the resin glands (trichomes) of raw cannabis or hemp plants (unheated and uncured) and CBDA is the precursor of cannabidiol (CBD). In fresh cannabis or hemp, it is estimated that 95 percent of the CBD exists as CBDA and only 5 percent as CBD. In a preclinical model of inflammation, CBD have a bell shaped response but a crude extract containing CBDA didn’t have this effect and was found to be more active than CBD (L.Hanus and a/., Pharmacology & Pharmacy, 2015, 6, 75-85). It was also be found that CBDA is more potent and selective inhibitor for COX-2 than CBD (K. Watanabe and al. DRUG METABOLISM AND DISPOSITION, Vol. 36, No. 9).

G0041 One drawback of the CBDA is the instability of the carboxylic acid who is prone to decarboxylation on heating (G. Cannazza and al. Journal of Pharmaceutical and Biomedical Analysis 149 (2018) 532-540). SUMMARY OF THE DISCLOSURE

G0051 According to one aspect there are provided compounds of formula (I):

wherein

Xi is O, NH, or S;

X₂ is O, NH, or S;

X₃ is O, NH, or S;

Ri and R2 each independently represents -H, -C(0)NH2, - Sec nd, -S(0)2NH₂, -C1-C22 (oxy)alkyl, -C1-C22 alkyl, -C1-C22

(hydroxy)alkyl, -C1-C22 (amino)alkyl, -C1 -C22 (halo)alkyl, -C3-C22 alkenyl, - C3-C22 alkynyl, ,-(C3-C7) cycloalkyl unsubstituted or substituted with at least one substituent chosen from C1-C22 alkyl, -C2-C22 alkenyl, and -C2-C22 alkynyl, -C6-C12 aryl, -C7-C22 (aryl)alkyl, -C8-C22 (aryl)alkenyl, -C8-C22 (aryl)alkynyl, three- to seven-mem bered non-aromatic heterocycle unsubstituted or substituted with at least one substituent chosen from -C1-C22 alkyl, -C2-C22 alkenyl, and -C2-C22 alkynyl, five- to seven-membered aromatic heterocycle unsubstituted or substituted with at least one substituent chosen from -C1-C22 alkyl, -C2-C22 alkenyl, and -C2-C22 alkynyl, -(CH2)_namino acid wherein the amino acid is connected through its alpha carbon atom, - (CH2)_npeptide wherein the peptide is connected through the alpha carbon atom of one of its amino acids, -CH2OR5, -C(0)Rs, -C(0)0Rs, -C(0)NRs, - P(0)(0R₅)2, -S(0)₂NHR₅, -SOR5, -S(0)₂R₅, -arylP(0)(0R₅)2, a sugar, or a sugar phosphate or Ri and R2 are joigned together so as to form a five- to seven- mem bered non-aromatic heterocycle unsubstituted or substituted with at least one substituent chosen from -C1 -C22 alkyl, -C2-C22 alkenyl, and -C2-C22 alkynyl, a phosphate, sulfate carbonyl group, or a thiocarbonyl imine;

Rs is -H, -C1 -C22 alkyl, -(C3-C7) cycloalkyl, -C1-C22 (halo)alkyl, - C6-C12 aryl, -C2- C22 alkenyl, -C2-C22 alkynyl, -C7-C22 (aryl)alkyl, -C8-C22 (aryl)alkenyl, -C8-C22 (aryl)alkynyl, -C1 -C22 (hydroxy)alkyl, -C1-C22 alkoxy, - C1-C22 (amino)alkyl, a -(C3-C7) cycloalkyl unsubstituted or substituted with at least one substituent chosen from -C1-C22 alkyl, -C2-C22 alkenyl, and -C2- C22 alkynyl, a three- to seven-membered non-aromatic heterocycle unsubstituted or substituted at least one substituent chosen from -C1-C22 alkyl, -C2-C22 alkenyl, and -C2-C22 alkynyl, a three- to seven-membered aromatic heterocycle unsubstituted or substituted with at least one susbtituent chosen from -C1 -C22 alkyl, -C2-C22 alkenyl, and -C2-C22 alkynyl, a - (CH2)_namino acid wherein the amino acid is connected to the compound through its alpha carbon atom, a -(CH2)_npeptide wherein the peptide is connected to the compound through the alpha carbon atom of one of its amino acids, a sugar or a sugar phosphate; and n is an integer having a value of 0, 1 , 2, 3, or 4, and pharmaceutically acceptable salts thereof.

G0061 It was found that such compounds can be used so as to reduce or inhibit tumor growth, or inhibit tumor cell proliferation in vitro as well as in vivo. It was also found that the compounds previously mentioned can be useful as cancer chemopreventive agents (for example breast cancer, prostate cancer, colon cancer and lung cancer). The compounds of the present disclosure can be used as a composition which also includes a pharmaceutically acceptable carrier.

G0071 It was also found that the compounds previously mentioned can provide effective pharmaceutical compositions for chemoprevention of cancer.

G0081 These compounds can also be effective in combination with a pharmaceutically active ingredient in chemotherapy of cancer.

G0091 These compounds can be effective for chemoprevention of various types of cancers (such as breast cancer, lung cancer, prostate cancer, colon cancer). Tumors growth of such types of cancer can be inhibited or reduced with these compounds.

G00101 These compounds can also be effective in resolution of the inflammation or as an anti-inflammatory agent.

G001 P These compounds can also be effective in modulation of the mitochondrial functions.

G00121 These compounds can also be effective to increase the lifespan.

G00131 According to another aspect there is provided a method for chemopreventing cancer comprising administering to a subject at least one compound chosen from compounds of formula (I).

G00141 According to another aspect there is provided a method for inhibiting tumor growth, inhibiting tumor cell proliferation, or reducing tumor growth, in vitro or in vivo , comprising contacting the tumor with an effective amount of a at least one compound chosen from compounds of formula (I).

G00151 According to another aspect there is provided a method of reducing tumor growth in a subject comprising administering to the subject at least one compound chosen from compounds of formula (I). G00161 According to another aspect there is provided a method for chemopreventing cancer comprising administering to a subject at least one compound chosen from compounds of formula (I).

G00171 The term "aryl" as used herein refers to a cyclic or polycyclic aromatic ring. For example, the aryl group can be phenyl or napthyl.

G00181 The expression "aromatic heterocycle" as used herein refers to an aromatic cyclic or fused polycyclic ring system having at least one heteroatom selected from the group consisting of N, O, S and P. Non-limitative examples include heteroaryl groups are furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, and so on.

G00191 The expression "non-aromatic heterocycle" includes non-aromatic rings or ring systems that contain at least one ring having at least one hetero atom (such as nitrogen, oxygen, sulfur or phosphorus). This term includes, in a non-limitative manner all of the fully saturated and partially unsaturated derivatives of the above mentioned aromatic heterocycles groups. Examples of non-aromatic heterocycle groups include, in a non-limitative manner, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, isothiazolidinyl, and imidazolidinyl.

G00201 The sugar can be chosen from 5-carbon sugars and 6-carbon sugars. Non-limiting examples of 5-carbon sugar include ribose, arabinose, xylose, and lyxose. Non-limiting examples of 6-carbon sugar include glucose, galactose, mannose, allose, gulose, idose, talose, and altrose.

G00211 The sugar phosphate can be chosen from monosaccharides (such as mannose-6-phosphate, glucose-6-phosphate, galactose-6-phosphate, mannose-l-phosphate, glucose-l-phosphate and galactose-l-phosphate), disaccharides (such as 6-0-phosphoryl-a-D-mannopyranosyl-(1 -2)-D- mannopyranose,6-0-phosphoryl-a-D-mannopyranosyl-(1 -3)-mannopyranose, 6-0-phosphoryl-a-D-mannopyranosyl-(1-6)-D-mannopyranose), trisaccharides (such as 6-0-phosphoryl-a-D-mannopyranosyl-(1 -2)-D-mannopyranosyl-(l-2)- D-mannopyranose), and higher linear or branched oligosaccharides (such as pentamannose-6-phosphate).

G00221 The amino acid can be chosen from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

G00231 The peptide can be chosen from any possible combination of the amino acids previously described.

G00241 For example, the compounds of the present disclosure can be of formula:

BRIEF DESCRIPTION OF THE FIGURES

G00251 Further features and advantages will become more readily apparent from the following description of specific embodiments as illustrated by way of examples in the appended figures wherein:

Figure 1 represents the fragmentation spectra of pure compound 3 in negative ionization mode. The parent ion (m/z=431.3) was fragmented to daughter ions (m/z=357.2) corresponding to Cannabidiolic acid (compound 1) and daughter ions (m/z=339.3) corresponding to the elimination of a glycerol molecule.

Figure 2 represents the fragmentation spectra of pure compound 3 in positive ionization mode. The parent ion (m/z=433.3) was fragmented to daughter ions (m/z=415.0) corresponding to the elimination of a water molecule and daughter ions (m/z=341.2) corresponding to the elimination of a glycerol molecule.

DETAILLED DESCRIPTION OF THE DISCLOSURE

G00261 Further features and advantages of the previously-mentioned compounds will become more readily apparent from the following description of non-limiting examples.

EXAMPLE 1

Preparation of cannabidiolic acid monoglyceride 2

G00271 Cannabidiolic acid (compound 1) (1 mg) and solketal (1 ml) were mixed together and heated at a temperature of 60°C. The enzyme (10mg) was added and the reaction mixture was stirred at 60°C under nitrogen for 5 h. The reaction mixture was filtered and the enzyme was washed with ethanol 95% (5ml). The acidic resin (50mg) or organic acid was added to the ethanol solution and heated to reflux for 18h. The resin was removed by filtration and the ethanol was evaporated in vacuo. The resulting crude product was dissolved in a mixture of hexanes/ethyl acetate 90:10 (1 ml) and silica gel (1 g) was added. The slurry was put on a fritted funnel and eluted with hexanes/ethyl acetate 90:10 (1 ml) to remove unreacted solketal. A second elution with ethyl acetate (3ml) give, after evaporation in vacuo, the pure compound 2 (1 mg). EXAMPLE 2

Preparation of protected cannabidiolic acid monoglyceride 3

G00281 Cannabidiolic acid (compound 1 ) (550mg) and solketal (0.4 ml) were mixed together at 0°C. DMAP (cat. amount) was added followed by DCC (1.7ml of 1 M solution). The reaction mixture was stirred at 0°C under nitrogen for 0.5 h and heated up to room temperature for 1 h. The reaction mixture was filtered through a silica gel pad and washed with 10 ml of 9:1 Hex/AcOEt. The solvents was removed in vacuo to give crude compound 3.

EXAMPLE 3

Preparation of cannabidiolic acid monoglyceride 2

G00291 Crude protected cannabidiolic acid (compound 3) was dissolved in 95% Ethanol and an acidic resin (200mg) was added and heated to reflux for 6h. The resin was removed by filtration and the ethanol was evaporated in vacuo. The resulting crude product was dissolved in a mixture of hexanes/ethyl acetate 90:10 (1 ml) and silica gel (1 g) was added. The slurry was put on a fritted funnel and eluted with hexanes/ethyl acetate 90:10 (1 ml) to remove unreacted solketal. Compound 2 was purified by flash chromatography (hexanes/ethyl acetate 90:10) to give pure compound 2.

G00301 While a description was made with particular reference to the illustrated embodiments, it will be understood that numerous modifications thereto will appear to those skilled in the art. Accordingly, the above description and accompanying drawings should be taken as specific examples and not in a limiting sense.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I):

wherein

Xi is O, NH, or S;

X₂ is O, NH, or S;

X₃ is O, NH, or S;

Ri and R₂ each independently represents -H, -C(0)NH₂, -S(0)NH₂, -S(0)₂NH₂, -C1 -C22 (oxy)alkyl, -C1 -C22 alkyl, -C1-C22

(hydroxy)alkyl, -C1-C22 (amino)alkyl, -C1 -C22 (halo)alkyl, -C3-C22 alkenyl, - C3-C22 alkynyl, ,-(C3-C7) cycloalkyl unsubstituted or substituted with at least one substituent chosen from C1-C22 alkyl, -C2-C22 alkenyl, and -C2-C22 alkynyl, -C6-C12 aryl, -C7-C22 (aryl)alkyl, -C8-C22 (aryl)alkenyl, -C8-C22 (aryl)alkynyl, three- to seven-mem bered non-aromatic heterocycle unsubstituted or substituted with at least one substituent chosen from -C1-C22 alkyl, -C2-C22 alkenyl, and -C2-C22 alkynyl, five- to seven-membered aromatic heterocycle unsubstituted or substituted with at least one substituent chosen from -C1-C22 alkyl, -C2-C22 alkenyl, and -C2-C22 alkynyl,

-(CH₂)_namino acid wherein the amino acid is connected through its alpha carbon atom, -(CH₂)_npeptide wherein the peptide is connected through the alpha carbon atom of one of its amino acids, -CH₂ORs, -C(0)Rs, -C(0)0Rs, -C(0)NRs, -P(0)(0R₅)2, -S(0)2NHRS, -SORS, -S(0)₂R5, -arylP(0)(0R₅)2, a sugar, or a sugar phosphate or Ri and R2 are joigned together so as to form a five- to seven- mem bered non-aromatic heterocycle unsubstituted or substituted with at least one substituent chosen from -C1 -C22 alkyl, -C2-C22 alkenyl, and -C2-C22 alkynyl, a phosphate, sulfate carbonyl group, or a thiocarbonyl imine;

Rs is -H, -C1 -C22 alkyl, -(C3-C7) cycloalkyl, -C1-C22 (halo)alkyl, - C6-C12 aryl, -C2- C22 alkenyl, -C2-C22 alkynyl, -C7-C22 (aryl)alkyl, -C8-C22 (aryl)alkenyl, -C8-C22 (aryl)alkynyl, -C1 -C22 (hydroxy)alkyl, -C1-C22 alkoxy, - C1-C22 (amino)alkyl, a -(C3-C7) cycloalkyl unsubstituted or substituted with at least one substituent chosen from -C1-C22 alkyl, -C2-C22 alkenyl, and -C2- C22 alkynyl, a three- to seven-membered non-aromatic heterocycle unsubstituted or substituted at least one substituent chosen from -C1-C22 alkyl, -C2-C22 alkenyl, and -C2-C22 alkynyl, a three- to seven-membered aromatic heterocycle unsubstituted or substituted with at least one susbtituent chosen from -C1 -C22 alkyl, -C2-C22 alkenyl, and -C2-C22 alkynyl, a - (CH2)_namino acid wherein the amino acid is connected to the compound through its alpha carbon atom, a -(CH2)_npeptide wherein the peptide is connected to the compound through the alpha carbon atom of one of its amino acids, a sugar or a sugar phosphate; and n is an integer having a value of 0, 1 , 2, 3, or 4, or pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein said sugar is chosen from 5-carbon sugars and 6-carbon sugars.

3. The compound of claim 1 , wherein said sugar is a 5-carbon sugar chosen from ribose, arabinose, xylose, and lyxose.

4. The compound of claim 1 , wherein said sugar is a 6-carbon sugar chosen from glucose, galactose, mannose, allose, gulose, idose, talose, and altrose.

5. The compound of claim 1 , wherein said sugar phosphate is chosen from monosaccharides (such as mannose-6-phosphate, glucose-6- phosphate, galactose-6-phosphate, mannose-l-phosphate, glucose-l- phosphate and galactose-l-phosphate), disaccharides (such as 6-0- phosphoryl-a-D-mannopyranosyl-(1-2)-D-mannopyranose,6-0- phosphoryl-a-D-mannopyranosyl-(1 -3)-mannopyranose, 6-0- phosphoryl-a-D-mannopyranosyl-(1-6)-D-mannopyranose),

trisaccharides (such as 6-0-phosphoryl-a-D-mannopyranosyl-(1-2)-D- mannopyranosyl-(l-2)-D-mannopyranose), and higher linear or branched oligosaccharides (such as pentamannose-6-phosphate).

6. The compound of any one of claims 1 to 5, wherein

Xi is O;

X2 is O; and

X₃ is O.

7. The compound of any one of claims 1 to 6, wherein Ri is H.

8. The compound of any one of claims 1 to 7, wherein R2 is H.

9. The compound of claim 1 , wherein said compound is a compound of formula:

10. The compound of claim 1 , wherein said compound is a compound of formula:

1 1 . The compound of claim 1 , wherein said compound is a compound of formula:

a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein said compound is a compound of formula:

pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein said compound is a compound of formula:

pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein said compound is a compound of formula:

pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein said compound is a compound of formula:

pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein said compound is a compound of formula:

a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 1 to 16, wherein said compound is in an isolated form.

18. A composition comprising at least two compounds as defined in any one of claims 1 to 17.

19. A composition comprising at least one compound as defined in any one of claims 1 to 17 and a pharmaceutically acceptable carrier.

20. Use of a compound or composition as defined in any one of claims 1 to 19 as a cancer chemopreventive agent.

21 . Use of a compound or composition as defined in any one of claims 1 to 19 for treating cancer, inhibiting tumor growth or reducing tumor growth.

22. Use of a compound or composition as defined in any one of claims 1 to 19 in combinaiton with a pharmaceutically active ingredient in chemotherapy of cancer.

23. Use of a compound or composition as defined in any one of claims 1 to 19 as an inflammation resolution agent.

24. Use of a compound or composition as defined in any one of claims 1 to 19 as an anti-inflammatory agent.

25. Use of a compound or composition as defined in any one of claims 1 to 19 as a mitochondrial modulator agent.

26. Use of a compound or composition as defined in any one of claims 1 to 19 as a life-span enhancer agent.

27. Use of a compound or composition as defined in any one of claims 1 to 19 as a prebiotic agent

28. The use of any one of claims 20 to 22, wherein said cancer is breast cancer.

29. The use of any one of claims 20 to 22, wherein said cancer is lung cancer.

30. The use of any one of claims 20 to 22, wherein said cancer is prostate cancer.

31 . The use of any one of claims 20 to 22, wherein said cancer is colon cancer.

32. The use of any one of claims 23 and 24 wherein said inflammation is caused by arthritis.

33. The use of any one of claims 23 and 24, wherein said inflammation is caused by colitis.

34. The use of any one of claims 23 and 24, wherein said inflammation is caused by ageing.

35. The use of any one of claims 23 and 24, wherein said inflammation is caused by Alzheimer disease.

36. A method for chemopreventing cancer comprising administering to a subject at least one compound or composition as defined in any one of claims 1 to 19.

37. A method for treatment of inflammation comprising administering to a subject at least one compound or composition as defined in any one of claims 1 to 19.

38. A method for resolving the inflammation comprising administering to a subject at least one compound or composition as defined in any one of claims 1 to 19.

39. A method for enhancing the lifespan comprising administering to a subject at least one compound or composition as defined in any one of claims 1 to 19.

40. A method for modulating the mitochondria function comprising administering to a subject at least one compound or composition as defined in any one of claims 1 to 19.

41 . A method for modulating the microbiote comprising administering to a subject at least one compound or composition as defined in any one of claims 1 to 19.