Fatty acid ester derivatives of cannabinoid, methods of preparation thereof, and uses thereof

Abstract

A fatty acid ester of cannabinoid, wherein the fatty acid is an unsaturated acid, with an ester linkage consisting of an aryloxy oxygen directly bonded to an aromatic ring of the cannabinoid and a carbonyl group attached to the fatty acid unsaturated carbon chain.

Description

[0001] FATTY ACID ESTER DERIVATIVES OF CANNABINOID, METHODS OF PREPARATION THEREOF, AND USES THEREOF

[0002] Background of the invention

[0003] Cannabinoids have received considerable attention in recent years as possible therapeutic agents for treatment of a wide variety of conditions such as inflammation and pain associated therewith, eye diseases, nausea arising from chemotherapy, and various cancers. To this end, topical and transdermal applications of cannabinoids were designed. Examples of cannabinoids that are of current therapeutic interest include psychoactive cannabinoids such as tetrahydrocannabinol (THC, compound of Formula 1) and cannabinol (CBN, compound of Formula 2) and non-psychoactive cannabinoids such as cannabigerol (CBG, compound of Formula 3) and cannabidiol (CBD, compound of Formula 4).

[0004] Formula 3 As an example of a cannabinoid that has been of particular pharmaceutical, medical, and cosmetic interest, the anti-inflammatory properties of the non-psychoactive cannabinoid CBG (compound of Formula 3) are well-known in the art. A large number of medical, therapeutic, and cosmetic uses have been suggested for CBG. For example, U.S. Pat. Appl. Pub. No. 2018 / 0263952 discloses the use of CBG in treatment of inflammatory skin diseases; U.S. Pat. No. 10098867 discloses the use ofCBG in treatment of ovarian cancer; U.S. Pat. No. 10272051 discloses the use of CBG in treatment of atopic dermatitis; U.S. Pat. No. 11484510 discloses the use of CBG in the treatment of vitiligo; PCT Pat. Appl. Pub. No. WO2019 / 227167 discloses the use of CBG in treatment of mesothelioma; PCT Pat. Appl. Pub. No. WO2021 / 248207 discloses the use of CBG in treatment of chronic pain; PCT Pat. Appl. Pub. No. WO2021 / 248251 discloses the use of CBG in treatment of multiple myeloma; and a topical anti-aging formulation containing CBG as its active ingredient has been the subject of an experimental study (Perez, E.; Fernandez, J.R.; Fitzgerald, C.; Rouzard, K.; Tamura, M.; Savile, C., "In Vitro and Clinical Evaluation of Cannabigerol (CBG) Produced via Yeast Biosynthesis: A Cannabinoid with a Broad Range of Anti-Inflammatory and Skin Health- Boosting Properties," Molecules 2022, 27, 491. )

[0005] One approach that has been taken for increasing the bioavailability of cannabinoids in topical formulations has been to prepare topical compositions that comprise a cannabinoid such as CBG and a penetration enhancer dispersed in a carrier. Examples of permeation enhancers known in the art for topical application of CBG include terpenes (disclosed in, for example, U.S. Pat. No. 10,588,979), micellar encapsulation of CBG (disclosed in, for example, U.S. Pat. No. 10,709,748), and water-insoluble polymers (disclosed in, for example, U.S. Pat. Appl. Pub. No. 2003 / 0232101).

[0006] A different approach to enhancement of the skin permeability of topically-applied pharmaceutical and cosmetic compounds has been by chemical modification of the molecule itself to a form that penetrates the skin more efficiently, typically by increasing its lipophilicity. After topical administration, the chemically modified molecule decomposes under subcutaneous physiological conditions to provide the pharmaceutically active compound. An example of this approach is the enhancement of the skin permeability of anti-wrinkle peptides by addition of a hydrophobic moiety (Mortazavi, S. M.; Moghimi, H R. "Skin Permeability, a Dismissed Necessity for Anti -Wrinkle Peptide Performance," Ini. J. Cosmet. Sci. 2022, 44, 232). Further examples are described in PCT Pat. Appl. Pub. Nos. WO2019 / 046491 and WO2020 / 191477, which disclose lipid conjugates for therapeutic substances. While derivatives of compounds related to CBG such as cannabigerolic acid (compound of

[0007] Formula 5), are well-known in the art, (see, for example, PCT Pat. Appl. Pub. No. W02021 / 034403), pharmaceutically useful derivatives of CBG itself are less known.

[0008] Examples of CBG derivatives that incorporate substitution at one or both of the phenolic H atoms have been reported. Kogan et al. reported a morpholino ester of CBG and a method for its preparation (Kogan, N. M.; Lavi, Y.; Topping, L. M.; Williams, R. O.; McCann, F. E.; Yekhtin, Z.; Feldmann, M.; Galily, R.; Mechoulam, R., "Novel CBG Derivatives Can Reduce Inflammation, Pain, and Obesity," Molecules 2021, 26, 5601), and U.S. Pat. No. 11,097,204 discloses acetylated CBG and a method for its preparation from cannabis extract and acetic anhydride.

[0009] Examples known in the prior art of fatty acid ester derivatives of a cannabinoid in which the ester linkage to the cannabinoid is through a phenolic oxygen of the cannabinoid are a palmitate ester of the psychotropic cannabinoid THC (compound of Formula 6), and a palmitate diester of 11-hydroxy-THC (compound of Formula 7) (Kraemer, M.; Broecker, S.; Diehl, B. W. K.; Madea, B.; Hess, C., "Palmitic Acid Ester of Tetrahydrocannabinol (THC) and Palmitic Acid Diester of 11 -hydroxy-THC --- Unsuccessful Search for Additional THC Metabolites in Human Body Fluids and Tissues," Forensic Sei. Int. 2019, 294, 86).

[0010] Formula 6 Formula 7 The invention

[0011] The inventors synthesized new compounds by reacting an unsaturated fatty acid (in the form of the corresponding acyl chloride) with a cannabinoid - more precisely, through one or more of the phenol groups of the cannabinoid -to produce the corresponding esters. With appropriate selection of the unsaturated fatty acid - for example, C12-C24 fatty acids, in particular C18-C22, mono- and poly- unsaturated fatty acids - the resultant fatty acid ester of the cannabinoid - in particular CBG - are suitable for topical application owing to their miscibility and compatibility with acceptable carriers, in particular with Jojoba oil. For example, experimental results reported below show that the new esters of the invention dissolve well in Jojoba oil, showing stability against phase separation even at high concentration, affording topically administrable formulations (Jojoba oil consists of -98% waxes, -1% free alcohols and -1% free fatty acids; the most abundant of these fatty acids is gondoic acid, which comprises -70% of the total fatty acid content).

[0012] Accordingly, the invention is primarily directed to a fatty acid ester of cannabinoid, wherein the fatty acid is an unsaturated acid, with an ester linkage consisting of an aryloxy oxygen (namely, the oxygen is directly bonded to an aromatic ring of the cannabinoid) and a carbonyl group attached to the chain of the unsaturated fatty acid. As pointed out above, C12-C24, and in particular C18-C22, mono- and poly- unsaturated fatty acids esters of cannabinoids, e.g., gondoic acid, oleic acid and linolenic acid esters, are preferred. In some embodiments, suitable fatty acids include common naturally occurring monounsaturated and polyunsaturated fatty acids that have anti-inflammatory properties.

[0013] When the cannabinoid used to form the ester possesses two hydroxyl groups (with one or both directly attached to an aromatic ring), then the corresponding diester is also provided by the present invention. The diester is usually "symmetric" (the two ester groups are the same, i.e., the fatty acid moieties are identical). "Asymmetric diesters "(the two ester groups are different) can also be obtained upon isolation of a monoester and subsequent reaction with a different fatty acid, which may be an unsaturated fatty acid or a saturated fatty acid. The resultant "asymmetric diesters" may possess two unsaturated ester groups; or one unsaturated and one saturated ester group.

[0014] More specifically, preferred esters of the invention have the general Formula (I):

[0015] X- [O*-C(O)R' ]nFormula (I) wherein X is a cannabinoid moiety; the ester oxygen (marked by an asterisk) is directly bonded to an aromatic ring carbon atom of the cannabinoid moiety and the carbonyl group of the ester linkage is attached to the unsaturated carbon chain, namely, R' is an unsaturated linear C12-C24 alkenyl having one or more C=C bonds, which may be the same or different in the two ester groups, and n=l or 2.

[0016] In the preferred fatty acid esters of cannabinoids provided by the invention, the ester oxygen is directly bonded to a non-fused six-membered aromatic ring, i.e., cannabigerol- (CBG-) and cannabidiol- (CBD-) based esters are most preferred.

[0017] Specifically, in one aspect the present invention provides mono- or diester- of CBG of general Formula (II): Formula (II) including the stereoisomers, and mixtures thereof, wherein each of R1and R2is independently selected from hydrogen and fatty acid ester residue selected from -C(O)-R' and -C(O)-R", wherein R' and R" are as defined hereinafter; and wherein R1and R2are not both hydrogen. In preferred diesters of general Formula (II), R1and R2are the same.

[0018] The invention also relates to processes for preparing a compound of general Formula (II) according to the invention, comprising reacting acyl chloride of one or more unsaturated C12- C24 fatty acids with a cannabinoid having one or more phenoxy rings in an alkaline environment, and isolating the fatty acid ester of cannabinoid.

[0019] Compounds of general Formula (II), as defined hereinafter, were found to be highly soluble in jojoba oil and are suitable for inclusion in compositions with Jojoba oil (JO). Such composition can be useful for topical skin cosmetic and dermatological formulations. Thus, the invention is further directed to compositions containing a compound of Formulae (I) and (II) according to the invention and a topically acceptable carrier, such as JO. Other aspects and embodiments of the present invention will become apparent to the skilled person from the following detailed description.

[0020] BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 shows GC traces of: a sample of CBG (FIG. 1 A); a reaction mixture comprising CBG and acid chlorides of fatty acids, sampled after 1 hour of reaction (FIG. IB); and a sample of fatty acid mixture extracted from jojoba oil, as described in Preparation 1 below (FIG. 1C).

[0022] Figure 2 shows a TLC plate comparing CBG (left) with a reaction mixture comprising CBG and acid chlorides of fatty acids sampled after 1 hour of reaction (right).

[0023] Figures 3A and 3B present 'H-NMR and °C-NMR spectra, respectively, of a CBG-gondoate monoester (compound of Formula 12).

[0024] Figures 4A and 4B show 'H-NMR and °C-NMR spectra, respectively, of a CBG-gondoate diester (compound of Formula 13).

[0025] Figures 5 A and 5B show 'H-NMR and °C-NMR spectra, respectively, of CBG (compound of Formula 3).

[0026] Figure 6 shows the 'H-NMR spectra of: CBG (compound of Formula 3, FIG. 6A), CBG- monooleate (compound of Formula 8, FIG. 6B), and CBG-di oleate (compound of Formula 9, FIG. 6C).

[0027] Figure 7 shows the13C-NMR spectra of: CBG (compound of Formula 3, FIG. 7A), CBG- monooleate (compound of Formula 8, FIG. 7B), and CBG-di oleate (compound of Formula 9, FIG. 7C).

[0028] Figure 8 shows the 'H-NMR spectra of: CBG (compound of Formula 3, FIG. 8A), CBG-mono- a-linolenate (compound of Formula 10, FIG. 8B), and CBG-di-a-linolenate (compound of Formula 11, FIG. 8C).

[0029] Figure 9 shows the13C-NMR spectra of: CBG (compound of Formula 3, FIG. 9A), CBG- mono-a-linolenate (compound of Formula 10, FIG. 9B), and CBG-di-a-linolenate (compound of Formula 11, FIG. 9C). The present invention is primarily directed to mono- and di- fatty acid esters of cannabinoid, wherein the fatty acid is an unsaturated acid, with an ester linkage consisting of an aryloxy oxygen (i.e., the oxygen is directly bonded to an aromatic ring of the cannabinoid) and a carbonyl group attached to the fatty acid unsaturated carbon chain featuring one or more double carbon bonds ( C=C). As pointed out above, C12-C24, and in particular C18-C22, mono- and poly- unsaturated fatty acids esters of cannabinoids, e.g., gondoic acid, oleic acid and linolenic acid esters, are preferred.

[0030] More specifically, preferred esters of the invention have the general Formula (I):

[0031] X-[O*-C(O)R' ]nFormula (I) wherein X is a cannabinoid moiety; wherein O* is directly bonded to aromatic ring carbon atom of the cannabinoid moiety; wherein n=l or 2, and whererin R' is independently an unsaturated linear C12 to C24 alkenyl, having one or more C=C bonds.

[0032] In some embodiments of the esters of the invention of the general Formula (I), R' is a C16-C22 linear alkenyl (, i.e. having a chain length of 16-22 carbon atoms, inclusive), having one or more (namely, 2, 3, etc.) double carbon bonds. In some embodiments of the esters of the invention of the general Formula (I), R' is a C18-C22 linear alkenyl (, i.e. having a chain length of 18-22 carbon atoms, inclusive), having one or more double carbon bonds. In other embodiments of the esters of the invention of the general Formula (I), R' is a C18-C20 (inclusive) linear alkenyl, having one or more double carbon bonds.

[0033] In some embodiments of the invention n=l and the compound of general Formula (I) is a mono-ester. In other embodiments of the invention n=2 and the compound of general Formula (I) is a di-ester, in which the fatty acid carbon chains R' may be the same or different in the two esters. In preferred embodiments of the diesters of general Formula (I) (i.e., n=2), the fatty acid ester residues are the same.

[0034] In some embodiments of the compound of general Formula (I), the fatty acid ester residue - [O*-C(O)R' ] is derived from an unsaturated fatty acid that is present in Jojoba oil. In some embodiments of the compound of general Formula (I), the fatty acid ester residue -[O*-C(O)R' ] is selected from gondoate, oleate, linolenate (e.g. a-linolenate), and mixtures thereof. In preferred embodiments of the compound of general Formula (I), the aromatic ring of the cannabinoid moiety is a non -fused six-membered ring.

[0035] In particularly preferred fatty acid esters of general Formula (I), X is a cannabinoid moiety having a non-fused aromatic ring selected from cannabigerol (CBG, compound of formula 3) and cannabidiol (CBD, compound of formula 4).

[0036] Certain embodiments of such fatty acid esters of general Formula (I) are compounds having the general structure: Formula (II) including the stereoisomers, and mixtures thereof, wherein each of R1and R2is independently selected from hydrogen and fatty acid ester residue selected from -C(O)-R' and -C(O)-R", wherein each of R' and R" is independently selected from a linear C12 to C24 alkenyl, comprising one or more carbon double bonds, wherein R' and R" may be the same or different, and wherein at least one of R1and R2is different from hydrogen.

[0037] CBG-derivatives of general Formulae (I) and (II) according to the invention include monoesters, diesters, and mixtures thereof; including all possible geometrical stereoisomers (namely, cis / trans isomers) with respect to a carbon-carbon doublebond of the fatty acid ester residue(s), and mixtures thereof.

[0038] The fatty acid ester residue — C(O)-R' and -C(O)-R" of compounds of general Formula (II) can be formed by chemically conjugating a fatty acid having a C14 to C24 (14- to 24- carbons, inclusive) aliphatic chain to cannabigerol (CBG). In some embodiments, suitable fatty acids include common naturally occurring monounsaturated and polyunsaturated fatty acids that exert anti-inflammatory effects. In some embodiments, suitable fatty acids include monounsaturated and polyunsaturated fatty acids naturally occurring in jojoba oil. Nonlimiting examples of suitable fatty acids include myristoleic acid (IUPAC name: (9Z)-tetradec- 9-enoic acid), palmitoleic acid ((9Z)-hexadec-9-enoic acid), sapienic acid ((6Z)-hexadec-6- enoic acid), stearidonic acid ((6Z,9Z,12Z,15Z)-octadeca-6,9,12,15-tetraenoic acid), a-linolenic acid ((9Z,12Z,15Z)octadeca-9,12,15-trienoic acid), y-linolenic acid ((6Z,9Z,12Z)-octadeca- 6,9,12-trienoic acid), linoleic acid ((9Z,12Z)-octadeca-9,12-dienoic acid), linolelaidic acid ((9£,,12£)-octadeca-9,12-dienoic acid), oleic acid ((9Z)-octadec-9-enoic acid), vaccenic acid ((l l£)-octadec-l l-enoic acid), eicosapentaenoic acid ((5E,8E,l lE,14E,17E)-icosa- 5,8,11,14,17-pentaenoic acid), arachidonic acid ((5Z,8Z,l lZ,14Z)-Icosa-5,8,l l,14-tetraenoic acid), gondoic acid ((HZ)-icos-l 1-enoic acid), paullinic acid ((13Z)-Icos-13-enoic acid), docosahexaenoic acid ((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid), erucic acid ((13Z)-docos-13-enoic acid) and nervonic acid ((Z)-tetracos-l 5-enoic acid).

[0039] In certain embodiments of the CBG-derivatives having the general structure of Formula (II), R' and R" of the fatty acid ester residues -C(O)-R' and -C(O)-R" is independently selected from a linear alkenyl, having one or several double carbon bonds, and having a chain length selected from C16-C22 (namely, having 16- to 22- carbons, inclusive), from C18-C22 (namely, having 18- to 22- carbons, inclusive), for example from C18-C20, inclusive. In exemplary embodiments of the CBG-derivatives of the invention having the general structure of Formula (II), the fatty acid residue -C(O)-R' and -C(O)-R" is derived from a fatty acid selected from gondoic acid (IUPAC name: (HZ)-Icos-l 1-enoic acid), oleic acid (IUPAC name: (9Z)- O\octadec-9-enoic acid), a-linolenic acid (IUPAC name: (9Z,12Z,15Z)-Octadeca-9,12,15- trienoic acid), and mixtures thereof.

[0040] In some embodiments of the CBG-derivatives of the invention, R' and R" are different. Certain embodiments of such CBG-derivatives of general Formula (II) are compounds having the general structure: Formula (Ila) including the stereoisomers, and mixtures thereof, wherein each of R1and R2is independently selected from hydrogen and fatty acid ester residue selected from -C(O)-R' and -C(O)-R", wherein each of R' and R" is independently selected from a linear C12 to C24 alkenyl, comprising one or more double carbon bonds, wherein R' and R" are different; and wherein at least one of R1and R2is different from hydrogen.

[0041] In other embodiments of the CBG-derivatives of the invention, R' and R" are the same. Certain embodiments of such CBG-derivatives of general Formula (II) are compounds having the general structure: Formula (lib) including the stereoisomers, and mixtures thereof, wherein each of R1and R2is independently selected from hydrogen and fatty acid ester residue -C(O)-R', wherein R' is selected from a linear C12 to C24 alkenyl, comprising one or more double carbon bonds, and wherein at least one of R1and R2is different from hydrogen.

[0042] In some embodiments of the CBG mono- and di- esters having the general structure of Formula (lib), the fatty acid ester residue -C(O)-R' is selected from a linear alkenyl, having one or several double carbon bonds, and having a chain length selected from C14 to C24 (12- to 24- carbon atoms, inclusive). In some preferred embodiments of the CBG mono- and di- esters having the general structure of Formula (lib), the fatty acid ester residue -C(O)-R' is selected from a linear alkenyl, having one or more (i.e., 2, 3, etc.) double carbon bonds, and having a chain length selected from Cis to C22, inclusive, for example Cis to C20, inclusive. In some embodiments the fatty acid residue is extracted from jojoba oil.

[0043] Non-limiting examples of compounds of general Formula (lib) include CBG-monooleate, CBG-dioleate, CBG- mono-a-linolenate, CBG-di-a-linolenate, CBG-monogondoate and CBG-digondoate. The structures of these compounds are presented in Table 1. Table 1 The present disclosure also relates to methods for preparing a fatty acid ester of cannabinoid, such as compounds of general Formulae (I) and (II), the method comprising: adding a chloride of a fatty acid to a solution comprising a cannabinoid and a base; and reacting the fatty acid chloride with the cannabinoid, thereby forming a fatty acid ester of cannabinoid. The preparative methods according to the present invention are illustrated by the Examples described below.

[0044] The terms "fatty acid chloride", " fatty acid acyl chloride", "chloride of a fatty acid" are used interchangeably to mean a derivative of a fatty acid formed by replacing the hydroxyl group of a fatty acid with a chlorine atom thereby creating a functional group -C(O)-C1.

[0045] For cannabinoids that comprise only a single phenolic hydroxide, such as, tetrahydrocannabinol (THC, compound of Formula 1) and cannabinol (CBN, compound of Formula 2), the esters of the instant invention are necessarily monoesters. For cannabinoids that comprise two phenolic hydroxide groups, such as, cannabigerol (CBG, compound of Formula 3) and cannabidiol (CBD, compound of Formula 4), monoesters, diesters, and mixtures thereof can be produced by the methods disclosed herein.

[0046] In some embodiments of the disclosed method, the fatty acid ester of cannabinoid is a CBG- derivative of general Formula (lib). Specifically, the present disclosure provides a method for preparing a CBG-derivative of general Formula (lib), the method comprising: adding a chloride of an unsaturated fatty acid having the general structure:

[0047] C1-C(O)-R' Formula (III) wherein R1is selected from a linear C12 to C24 alkenyl, comprising one or more double carbon bonds, to a reaction vessel that was previously charged with an organic solvent, a non-nucleophilic organic base and a cannabinoid of Formula 3: Formula 3 to form a product mixture; and separating a compound of general Formula (lib), or a mixture thereof, from the product mixture.

[0048] Fatty acid chlorides of general Formula (III) are commercially obtainable or may be prepared by using known methods of synthesis, e.g. based on a literature procedure described by Lin et al. (Lin, H.; Long, J. Z.; Roche, A. M.; Svensson, K. J.; Dou, F. Y Chang, M. R.; Strutzenberg, T.; Ruiz, C.; Cameron, M. D.; Novick, S. J.; Berdan, C. A.; Louie, S. M.; Nomura, D. K.; Spiegelman, B. M.; Griffin, P. R.; Kamenecka, T. M., "Discovery of Hydrolysis-Resistant Isoindoline N-Acyl Amino Acid Analogues That Stimulate Mitochondrial Respiration," J. Med. Chem. 2018, 67, 3224), wherein fatty acid chloride is prepared via reacting a fatty acid with oxalyl chloride. In some embodiments of the present method, fatty acid chlorides are prepared, e.g. as described by Lin et al., from a fatty acid mixture extracted from Jojoba oil.

[0049] Cannabigerol (compound of Formula 3) is available from various suppliers, e.g. Merck.

[0050] The disclosed method for preparing a CBG-derivative of general Formula (lib) comprises reacting cannabigerol (compound of Formula 3) with a fatty acid chloride of Formula (III) in a presence of a solvent and a non-nucleophilic organic base to form a reaction mixture.

[0051] As used herein, the term “solvent” means a substance that dissolves a solute (e.g. one or more reagents). In an embodiment of a method for preparing a CBG-derivative of general Formula (lb), the solvent is an aprotic organic solvent. Volatile aprotic organic solvents are preferred. In exemplary embodiments of the present method, the solvent is selected from chloroform, dichloromethane, acetonitrile, tetrahydrofuran, or any combination thereof. In a particular embodiment, the solvent is dichloromethane.

[0052] As used herein, the term "non-nucleophilic organic base" refers to a substance that is useful as a moderate base while at the same time being a poor nucleophile. In various embodiments of the present method, the non-nucleophilic organic base is selected from pyridine, tri ethyl amine, NA-diisopropylethylamine (DIPEA), or any combination thereof. In a particular embodiment, the non-nucleophilic organic base is NA-diisopropylethylamine (DIPEA). The reacting of cannabigerol (compound of Formula 3) with a fatty acid chloride of Formula (III) may be done by combining a solution of a fatty acid chloride with a solution containing cannabigerol, a solvent and a non-nucleophilic organic base, and allowing a reaction to proceed under reaction conditions to form a product mixture comprising the CBG-derivative of general Formula (lib). The combining may be done by any suitable means such as, but not limited to, stirring in a reaction vessel.

[0053] In some embodiments, combining cannabigerol (compound of Formula 3) with a fatty acid chloride of Formula (III) comprises a cannabigerol : fatty acid chloride molar ratio of between about 1 : 0.5 and about 1 : 3, more particularly between about 1 : 0.5 and about 1 : 2.5. In a particular embodiment, the cannabigerol : fatty acid chloride molar ratio is about 1 : 1.

[0054] The reacting of cannabigerol (compound of Formula 3) with a fatty acid chloride of Formula (III) is carried out in the presence of a solvent and a non-nucleophilic organic base. In some embodiments, cannabigerol : non-nucleophilic organic base molar ratio of between about 1 : 1 and about 1 : 3 is used, more particularly between about 1 : 1 and about 1 : 2. In a particular embodiment, the cannabigerol : non-nucleophilic organic base molar ratio is about 1 : 1.

[0055] The reacting of cannabigerol (compound of Formula 3) with a fatty acid chloride of Formula (III) is carried out under reaction conditions to form a product mixture comprising the CBG- derivative of general Formula (lib), or a mixture thereof. In general, the progress of the reaction can be followed using thin layer chromatography (TLC) and an appropriate solvent systems. In an embodiment of the method, completion of the reaction is determined by TLC.

[0056] As used herein, the term “reaction conditions” is intended to refer to conditions, such as, temperature, pressure, and time, used in the methods of the present invention. In an embodiment of the method, the pressure is atmospheric pressure. In an embodiment of the method, the temperature is between about 15° C and about 35° C, more particularly between about 18° C and about 30° C, also identified herein by the term "room temperature". In an embodiment of the method, the time is between about 1 hour and about 20 hours (overnight), more particularly between about 2 hours and about 3 hours.

[0057] In a particular embodiment, the reacting of cannabigerol (compound of Formula 3) with a fatty acid chloride of Formula (III) is performed under an atmospheric pressure, at a temperature between about 15° C and about 30° C and for a time of between about 2 hours and about 5 hours, more particularly at about 18° C and for about 3 hours.

[0058] The present method for preparing a CBG-derivative of general Formula (lib) comprises separating the CBG-derivative of general Formula (lib) or a mixture thereof from the product mixture. Separating can be accomplished by a variety of methods, as known to those skilled in the art. In an embodiment of the present method, the CBG-derivative of general Formula (lib), or a mixture thereof, is extracted from the product mixture with an organic solvent.

[0059] In various embodiments, the methods of the present disclosure further comprise a step of purifying the CBG-derivative of general Formula (lib) or separating the mixture of CBG- derivative of general Formula (lib), by, for instance, chromatography. In a particular embodiment, the present method comprises a step of separating a mixture of CBG-derivatives of general Formula (lib) into individual mono- and di-esters by chromatography.

[0060] The fatty acid esters of cannabinoid according to the invention are suitable for topical application owing to their miscibility and compatibility with acceptable carriers, in particular with Jojoba oil. For example, experimental results reported below show that the new esters of the invention dissolve well in Jojoba oil, showing stability against phase separation even at high concentration, affording topically administrable formulations. Accordingly, another aspect of the invention relates to a composition comprising a fatty acid ester of cannabinoid according to the invention, such as a compound of general Formulae (I) and (II), or mixtures thereof, and topically acceptable carrier. Preferably the topically acceptable carrier is oil. Even more preferably, the oil is Jojoba oil (JO).

[0061] As used herein, "topically acceptable" means that the carrier is suitable for use in contact with the skin without undue toxicity, incompatibility, instability, irritation, allergic response, and the like.

[0062] More specifically, the present disclosure provides a composition comprising a CBG-derivative of general Formula (lib) Formula (lib) including the stereoisomers, and mixtures thereof, wherein each of R1and R2is independently selected from hydrogen and fatty acid ester residue

[0063] -C(O)-R', wherein R1is selected from a linear C12 to C24 alkenyl, preferably a linear Cis to C22 alkenyl, comprising one or more double carbon bonds, and wherein at least one of R1and R2is different from hydrogen; and a topically acceptable carrier.

[0064] The composition according to the present invention may be used in any current application of Jojoba oil (JO), to enhance or supplement the effect thereof. Jojoba oil is widely used in the cosmetic and pharmaceutical industries, especially in cosmetics for topical, transdermal, and parenteral preparations. Traditionally, JO is used for many skin and scalp disorders. Extensive studies on Jojoba oil showed a wide range of pharmacological applications, including antioxidant, anti-acne and antipsoriasis, anti-inflammatory, antifungal, antipyretic, analgesic, antimicrobial, and anti -hyperglycemia activities (see Gad HA et al. Jojoba Oil: An Updated Comprehensive Review on Chemistry, Pharmaceutical Uses, and Toxicity. Polymers 2021, 13, 1711). Without being bound by theory, it is believed that the inclusion of a fatty acid ester of cannabinoid in the composition may enhance or supplement the effects of Jojoba oil, due to the known benefits of the cannabinoid and the fatty acid.

[0065] The composition according to the present invention may also be used in any current application of the cannabinoid, especially for increasing the bioavailability of the cannabinoid, e.g. CBG, in topical formulations, due to the presence of the lipophilic fatty acid residue in the fatty acid esters of cannabinoid according to the invention. Once the esters have been absorbed into the body, they may be hydrolyzed back to cannabinoid and free fatty acid, thus delivering two independent therapeutically useful agents from a single applied compound. In some embodiments the composition comprises up to 50% by weight of a CBG-derivative of general Formula (lib). In some embodiments the composition comprises up to 20% by weight, e.g. about 0.1 - 20% by weight, preferably about 2 - 20 % by weight, especially about 3 - 20 % by weight, of the CBG-derivative of general Formula (lib). In other embodiments, the composition comprises up to 10% by weight, especially, about 2 - 10% by weight of the CBG- derivative of general Formula (lib). In an embodiment of the invention, the composition comprises about 5% by weight of the CBG-derivative of general Formula (lib).

[0066] The composition according to the present invention may be prepared by combining the CBG- derivative of general Formula (lib) with Jojoba oil to form a clear solution. The combining of the CBG-derivative of general Formula (lib) with Jojoba oil may be done in any order. For example, the combining may comprise adding the CBG-derivative of general Formula (lib) to the Jojoba oil. In other embodiments, the Jojoba oil may be added to the CBG-derivative of general Formula (lib). The combining may be done by any suitable means such as mixing or stirring in a reaction vessel.

[0067] EXAMPLES

[0068] Materials

[0069] Materials used in the Examples are tabulated in Table 2.

[0070] Table 2

[0071]

[0072] Methods

[0073] Purity and characterization of compounds were established by a combination of TLC, mass spectrometry, and NMR analyses. HSQC) NMR spectra were recorded on a Bruker Avance III, 500 MHz spectrometer and were determined in chloroform-d with solvent peaks as the internal reference. Chemical shifts are reported in ppm relative to the reference signal and coupling constant (J) values are reported in hertz (Hz).

[0074] Thin layer chromatography (TLC) was performed on Silica gel 60 F254 Aluminum sheets plates using 9: 1 hexane: ethyl -acetate eluent, and spots were visualized with iodine staining.

[0075] GC (Gas Chromatography) was performed on Agilent model 8860 GC system with FID detector.

[0076] GC-MS (Gas Chromatography-Mass Spectrometry) was performed on Agilent model 6890 GC coupled to Agilent model 5973 MS (El mode).

[0077] Preparation 1 - Extraction of a Fatty Acid Fraction from Jojoba A fatty acid fraction was extracted from Jojoba oil according to the following method, based on a literature procedure described by V. K. Bhatia et al. in an Indian patent No. 178981 :

[0078] 1000 g Ethanol were placed in a 31iter double jacket reactor followed by 132 g KOH 85% (2mole). The temperature was set to 50°C while stirring for 35 min. To this solution 840g (1.4mole) Jojoba oil (JO) were slowly added within 1.5 hours at 50°C. The reaction mixture was stirred at 50°C for 1 hour then heated to 75 °C and stirring continued for another 1 hour. Reaction mixture was then cooled to room temperature, and the product was collected by filtration. The solid cake was washed tree times with ethanol (~ 500 g each) and dried at 80°C under reduced pressure (20 mmHg) to afford 320 g (0.9mole) of fatty acid potassium salt mixture (FAPS). The product (identified herein as "fatty acid fraction") was analyzed by GC.

[0079] Figure 1C shows GC chromatogram of the fatty acid fraction.

[0080] The main fatty acids in the isolated fraction were at retention time 9.37' minutes and 10.08' minutes, identified as C20: l (ca. 84%) and C22:l (ca. 6%), respectively. Residual peaks from jojoba oil appeared at 16.3' minutes, 18.1' minutes and 20.5' minutes.

[0081] The fatty acid fraction was used in the following Example 1 for reaction with cannabigerol (CBG).

[0082] Example 1 -Synthesis of cannabigerol (CBG) monogondoate (Formula 12) and cannabigerol (CBG) digondoate (Formula 13)

[0083] A mixture of fatty acids was extracted from JO as described in Preparation 1 above. The fatty acids mixture was converted to the respective acid chlorides according to the following method, based on a literature procedure described by Lin et al. :

[0084] A DCM solution of the fatty acids mixture (product of Preparation 1) was prepared by, combining 10ml DCM (dried over molecular sieves) with 0.5g (~1.6mmole) of fatty acids mixture and cooling the fatty acid solution to 0 °C, under Argon atmosphere.

[0085] Next, 1.2 equivalents of oxalyl chloride (0.24g, 1.9mmole) were added to the cooled fatty acid solution along with one drop of DMF. The reaction mixture was then left at room temperature for two hours, followed by removal of the excess reagents by evaporation. The product acid chlorides mixture was re-dissolved in DCM. The resulting acid chloride solution was then added dropwise using an addition funnel to a solution containing 0.5 g cannabigerol (CBG) (1.5mmole) and 0.27 ml DIPEA (1.6mmole) in 10 ml DCM, with stirring.

[0086] The progress of the reaction was followed using thin layer chromatography (TLC) and 9: 1 hexane:ethyl-acetate eluent.

[0087] Reference is now made to Figure 1, which shows GC traces of: a sample of CBG (FIG. 1A); the CBG - fatty acid chloride reaction mixture after 1 hour of reaction (FIG. IB); and a sample of fatty acids mixture extracted from JO as described in Preparation 1 (FIG. 1C, which also shows peaks from residual JO). The GC trace from the reaction mixture shows two new peaks (retention times 20.8' min and 24.3' min), indicated by arrows in FIG. IB. These peaks were assigned to CBG gondoate (CBG-C20:l) and CBG erucate (CBG-C22: 1) monoesters, respectively. The difference in the retention times of these two new peaks is similar to that between the C40:2 and C42:2 wax esters found in JO, as reported in literature. The failure to observe the CBG-digondoate in FIG. IB may have been due to its high molecular weight (MW = 901) precluding it from being entrained in the gas phase under the GC operating conditions.

[0088] Reference is now made to Figure 2, which shows a TLC plate comparing CBG at Rf 0.45 (left) with the CBG-fatty acid chloride reaction mixture after 1 hour of reaction (right). New spots at Rf ~ 0.65 and Rf ~ 1 (designated by a vertical line) can be seen in the reaction mixture (right). The new spots were assigned to the CBG- monogondoate (Rf ~ 0.65)and digondoate (Rf ~ 1), respectively. The CBG-C22: 1 is not traceable in the TLC.

[0089] The reaction mixture was then left at room temperature overnight before being quenched by addition of 20ml water. The lower organic phase was collected, washed with brine and dried over anhydrous sodium sulphate. The DCM was removed by vacuum evaporation.

[0090] The final reaction mixture was then separated by extraction on a silica gel column (10mm 15cm packed with 13g of silica gel. Eluent was 100% hexane then hexane:ethyl acetate (99: 1)).

[0091] The fractions that did not contain CBG but did show two TLC spots at Rf ~ 0.65 and Rf ~ 1, were isolated in this manner and combined respectively, to obtain a fraction of an isolated CBG-gondoate monoester and a fraction of isolated CBG-gondoate monoester. The isolated CBG-gondoate monoester was analyzed using GC-MS, and presented a peak having M / z=608.5, corresponding to the calculated molecular mass of compound of Formula 12.

[0092] The isolated CBG-gondoate monoester (compound of Formula 12) and CBG-gondoate diester (compound of Formula 13) were further analyzed by1H- and13C- NMR.

[0093] Reference is now made to Figures 3 A and 3B, which present 'H-NMR and °C-NMR spectra, respectively, of a chloroform-t / solution of the isolated CBG-monogondoate (compound of Formula 12);

[0094] Figures 4A and 4B, which present 'H-NMR and °C-NMR spectra, respectively, of a chloroform-t / solution of the isolated CBG-digondoate (compound of Formula 13); and

[0095] Figures 5A and 5B, which present for comparison 'H-NMR and °C-NMR spectra of CBG (compound of Formula 3).

[0096] As can be seen from a comparison of the spectra, no peaks due to CBG are present in the products.

[0097] The following discussion of the NMR spectra is with reference to the numbering of the positions of the atoms given in structures of compounds of Formulae 3, 12 and 13 in Scheme 1.

[0098] Scheme 1

[0099]

[0100] Compound of Formula 13

[0101] Assignments of the peaks in the NMR spectra are given in Tables 3 ( 'H-NMR spectra) and 4 (13C-NMR spectra), respectively.

[0102] Table 3

[0103]

[0104] Table 4

[0105]

[0106] The assignments for CBG (in Tables 3 and 4) are consistent with those reported in the literature by Choi et al., Marchetti et al. and Barthlott et al. (Choi, Y. H.; Hazekamp, A.; Peltenberg- Looman, A. M. G.; Frederich, M.; Erkelens, C.; Lefeber, A. W. M.; Verpoorte, R., "NMR Assignments of the Major Cannabinoids and Cannabiflavonoids Isolated from Flowers of Cannabis sativa," Phytochem. Anal. 2004, 75, 345; Marchetti, L.; Brighenti, V.; Rossi, M. C.; Sperlea, J.; Pellati, F.; Bertelli, D., "Use of °C-qNMR Spectroscopy for the Analysis of NonPsychoactive Cannabinoids in Fibre-Type Cannabis sativa L. (Hemp)," Molecules 2019, 24, 1138; Barthlott, I.; Scharinger, A.; Golombek, P.; Kuballa, T.; Lachenmeier, D. W ., "A Quantitative 'H NMR Method for Screening Cannabinoids in CBD Oils," Toxics, 2021, 9, 136). Reference is now made to carbon atoms at the 3' and 5' positions in the CBG, CBG-gondoate monoester and CBG-gondoate diester (see Scheme 1). In CBG, the signals due to the chemically equivalent protons and carbon atoms at the 3' and 5' positions (see Scheme 1) appear as a single peak at 56.24 in the 'H-NMR spectrum (Fig. 5A) and 5108.3 in the13C-NMR spectrum (Fig. 5B), respectively. In contrast, in CBG-gondoate monoester, due to lack of chemical equivalence of protons and carbon atoms at the 3' and 5' positions the signals appear as two peaks, having resonances separated by 0.1 ppm in the 'H-NMR spectrum (56.54 and 56.44 in Fig. 3A ), and by 0.6 ppm in the13C-NMR spectrum (5114.36 and 5113.77 in Fig. 3B), respectively; and the signals are shifted down as indicated by an arrow in FIG. 3A. The assignments of the peaks in the 'H-NMR spectrum were confirmed by Two-Dimensional Heteronuclear Single Quantum Coherence (2D-HSQC) NMR.

[0107] Reference is now made to Figures 4A and 4B, which show 'H-NMR and °C-NMR spectra, respectively, of a chloroform-t / solution of the isolated CBG-gondoate diester. The restoration of the symmetry of the molecules by addition of a gondoate chain at the 6' position renders the 3' and 5' chemically equivalent as in CBG, leading to a single peak in the NMR spectra (56.77 in the 'H-NMR spectrum and 5119.87 in the13C-NMR spectrum).

[0108] Example 2 - Synthesis of Cannabigerol (CBG) monooleate (Formula 8) and

[0109] Cannabigerol (CBG) dioleate (Formula 9)

[0110] Oleic acid (OA) was converted to the respective acid chloride according to the following method, based on a literature procedure described by Lin et al. :

[0111] A DCM solution of oleic acid (OA) was prepared by, combining 10ml DCM (dried over molecular sieves) with 0.5g (~1.6mmole) of oleic acid and cooling the solution to 0 °C, under Argon atmosphere.

[0112] Next, 1.2 equivalents of oxalyl chloride (0.24g, 1.9mmole) was added to the cooled OA solution along with one drop of DMF. The reaction mixture was then left at room temperature for two hours, followed by removal of the excess reagents by evaporation.

[0113] The product oleic acid chloride was then re-dissolved in DCM. The resulting oleic acid chloride solution was then added dropwise to a solution containing 0.5 g cannabigerol (CBG) (1.6mmole) and 0.27 ml DIPEA (1.6mmole) in 10 ml DCM, while stirring. The reaction was allowed to proceed overnight. Completion of the reaction was confirmed by TLC, as described in Example 1.

[0114] Next, the reaction mixture was quenched with water (20 ml), and the lower organic phase was collected. The aqueous upper phase (pH=3.5-4) was extracted with 4mL DCM. The organic phases was washed with brine (10 ml), dried by anhydrous sodium sulfate, and evaporated to obtain 0.47g of a crude product, also identified as "crude CBG oleate mixture", that had an appearance of a colored oil.

[0115] A portion of the crude product was then separated by silica gel column chromatography in a similar manner to CBG mono- and di- gondoate, as described in Example 1. Two fractions were collected and analyzed by GC-MS and1H- and13C- NMR.

[0116] The following chemical shifts were observed in the1H- and13C- NMR spectra:

[0117] 'H NMR spectrum of the first fraction: 3.12 d 2H, 5.06 t 1H, 2.02, 1.95, 5.04 t 1H, 1.68 s, 1.5 s, 1.57 s, 6.75 s 1H, 6.75 s 1H, 2.56 t 2H, 0.88 t 3H, 2.53 t 4H, 1.27 b, 2.02, 5.35 m 2H, 5.35 m 2H, 2.02, 1.27 b, 0.88 t 6H

[0118] 13C NMR spectrum of the first fraction: 13.98, 14.1, 16.26, 17.66, 22.46, 22.67 (2C) 23.61, 24.88, 25.63 26.57, 27.14, 27.2, 29.09, 29.14, 29.19, 29.31, 29.51, 29.69, 29.75, 30.56, 31.47, 31.89 34.23, 35.32, 39.51, 119.9 (2C), 121.43, 123.5, 124.1, 129.7, 130, 131.32, 135, 141.99, 149.5 (2C), 171.9

[0119] 'H NMR spectrum of the second fraction: 3.21 d 2H, 2.03. 2.08, 5.041 1H. 1.77 s, 1.67 s, 1.58 s, 6.43 s 1H, 6.53 s 1H, 2.55 t 2H, 0.88 t 3H, 2.49 t 2H, 1.27 b, 2.02, 5.35 m 1H, 5.35 m 1H, 2.02, 1.27 b, 0.88 t 3H

[0120] 13C NMR spectrum of the second fraction: 13.9, 14.09, 16.1, 17.66, 22.5, 22.6, 22.66, 23.4, 25, 26.3, 27.14, 27.2, 29.09, 29.19, 29.16, 29.3, 29.51, 29.67, 29.74, 30.63, 31.5, 31.88, 34.3, 35.4, 39.6, 113.8, 114.3, 116.7, 121.2, 123.7, 129.7, 130, 131.9, 138.5, 142.6, 149.1, 155.4, 172.4

[0121] Figures 6A and 7A show1H- and13C- NMR spectra, respectively, for CBG (compound of Formula 3).

[0122] Figures 6B and 7B show1H- and13C- NMR spectra, respectively, for the second fraction. Figures 6C and 7C show the3H and13C NMR spectra, respectively, for the first fraction. The following discussion of the NMR spectra is with reference to the numbering of the positions of the atoms given for structures in Scheme 1, whereas the numbering of the positions for CBG mono- and di- oleate is similar to the corresponding positions in CBG-mono and di- gondoate.

[0123] Reference is now made to carbon atoms at the 3' and 5' positions, and 2' and 6' positions, in CBG, CBG-moonooleate and CBG-dioleate (see Scheme 1), and to the discussion of1H- and13C-NMR spectra interpretation for CBG-monogondoate and CBG-digondoate in Example 1 above. Based on the comparison to theXH and13C NMR spectra, the first fraction was attributed to CBG-dioleate (compound of Formula 9) and the second fraction was attributed to CBG- mono-gondoate (compound of Formula 13).

[0124] In CBG, the signals due to the chemically equivalent protons and carbon atoms at the 3' and 5' positions (see Scheme 1) appear as a single peak at 56.24 in the 'H-NMR spectrum (Fig. 6A) and carbon atoms at the 2' and 6' appear as a single peak at 5154.78 ppm in the13C-NMR spectrum (Fig. 7A), respectively.

[0125] In contrast, in 'H-NMR and13C-NMR spectra of a chloroform-t / solution of the isolated second fraction (Figures 6B and 7B, respectively), due to lack of chemical equivalence of protons atoms at the 3' and 5' positions in the NMR spectrum, and 2' and 6' in the13C NMR spectrum, respectively, these signals appear as two separate peaks, of protons atoms at the 3' and 5' positions having resonances separated by 0.1 ppm in the 'H-NMR spectrum (56.53 and 56.43 in Fig. 6B), and of carbon atoms at the 2' and 6' positions separated by 7.33 ppm in the13C-NMR spectrum (5156.43 and 5149.10 in Fig 7B). Accordingly, the isolated second fraction was attributed to CBG-monooleate.

[0126] Reference is now made to Figures 6C and 7C, which show 'H-NMR and13C-NMR spectra, respectively, of a chloroform-t / solution of the isolated first fraction, attributed to CBG- dioleate. The restoration of the symmetry of the molecule by addition of an oleate chain at the 6' position renders the atoms at positions 3' and 5' and positions 2' and 6' chemically equivalent, as in CBG-digondoate, leading to a single peak in the NMR spectra (56.75 in the 'H-NMR spectrum for protons in positions 3' and 5' and 5149.48 in the13C-NMR spectrum for carbon atomes in positions 2' and 6').

[0127] The first fraction was further analyzed by GC and no peak was observed. This is believed to be due to the high molecular weight of CBG-dioleate (MW = 845), precluding it from being entrained in the gas phase under the GC operating conditions. The second fraction was further analyzed using GC-MS, and presented a peak having M / z=580.4 corresponding to the CDB-mono-oleate (compound of Formula 8).

[0128] Example 3 - Synthesis of Cannabigerol (CBG)-mono-a-linolenate (compound of Formula 10) and Cannabigerol (CBG)-di-a-linolenate (compound of Formula 11) a-Linolenic acid (ALA) was converted to the respective acid chloride according to the following method, based on a literature procedure described by Lin et al .

[0129] A DCM solution of the ALA (0.38 g, 1.4mmole) was prepared by combining 10ml DCM (dried over molecular sieves) with 0.5g (~1.6mmole) of a-linolenic acid and cooling the solution to 0 °C, under Argon atmosphere.

[0130] Next, 1.2 equivalents of oxalyl chloride (0.21g, 1.9mmole) were added to the cooled ALA solution along with one drop of DMF. The reaction mixture was then left at room temperature for two hours, followed by removal of the excess reagents by evaporation.

[0131] The product a-linolenic acid chloride was then re-dissolved in DCM. The resulting a-linolenic acid chloride solution was then added dropwise using an addition funnel into a solution containing 0.44 g cannabigerol (CBG) (1.4mmole), 0.23 ml DIPEA (1.4mmole) in 10 ml DCM, while stirring. The reaction mixture was allowed to stand for 3 hours at room temperature with stirring. No further reaction was observed to have taken place, as determined by GC and TLC (TLC eluent Hexane; ethyl acetate, 9: 1).

[0132] The reaction mixture was quenched by water (20 ml) and the lower organic phase was collected. The upper aqueous phase was extracted again with DCM (5ml). The combined organic phases were washed with brine (10 ml), dried by anhydrous sodium sulfate, and evaporated to obtain 0.72 g of a crude product, also identified as "crude CBG linolenate mixture", that had an appearance of a colored oil.

[0133] The crude product was then separated by silica gel column chromatography in a similar manner to CBG-mono and di-gondoate. Two fractions were collected and analyzed by GC-MS and 'H- and °C- NMR.

[0134] The following chemical shifts were observed in the 'H- and13C- NMR spectra: 'H NMR spectrum of the first fraction: 0.88 t, 0.98 t, 1.34m, 1.57 s, 1.65 s, 1.68s, 1.73 t, 1.94 m, 2.07m, 2.53 m, 2.81 1, 3.11 d, 3.41 d, 5.04 m, 5.37 m, 6.75 s

[0135] °C NMR spectrum of the first fraction: 13.99, 14.27, 16.28, 17.66, 20.54, 22.46, 23.63, 24.89,

[0136] 25.52, 25.61, 25.65, 26.61, 27.20, 29.11, 29.16, 29.21, 29.59, 29.69, 30.56, 31.48, 34.26, 35.33,

[0137] 39.53, 119.89, 121.45, 123.52, 124.12, 127.08, 127.74, 128.21, 128.28, 130.21, 131.37, 131.94, 135.35,142.03, 149.51, 171.91

[0138] 'H NMR spectrum of the second fraction: 0.88 t, 0.97 t, 1.31 m, 1.34 m, 1.57 m, 1.58 s, 1.67 s, 1.75 m, 1.77 s, 2.08 m, 2.5 t, 2.55 t, 2.81 t, 3.21 d, 5.04 t, 5.19 t, 5.37 m, 6.43 s, 6.53 s

[0139] °C NMR spectrum of the second fraction: 13.98, 14.25, 16.14, 17.66, 20.53, 22.48, 22.52, 23.30, 24.96, 25.50, 25.59, 25.63, 26.36, 27.18, 29.09, 29.14, 29.16, 29.56, 30.63, 30.80, 31.45,

[0140] 34.26, 35.40, 39.60, 108.22, 113.76, 114.31, 116.7, 121.20, 123.73, 127.07, 127.73, 128.19,

[0141] 128.26, 130.18, 131.92, 138.49,142.58, 149.09, 155.43, 172.32

[0142] Figures 8A and 9A show1H- and13C- NMR spectra, respectively, for CBG (compound of Formula 3).

[0143] Figures 8B and 9B show1H- and13C- NMR spectra, respectively, for the second fraction. Figures 8C and 9C show the1H- and13C- NMR spectra, respectively, for the first fraction.

[0144] Interpretation of the1H- and13C- NMR spectra was carried out as explained previously in Examples 1 and 2. The following discussion of the NMR spectra is with reference to the numbering of the positions of the atoms given for structures in Scheme 1, whereas the numbering of the positions for CBG mono-a- and di-a- linolenate is similar to the corresponding positions in CBG-mono and di-gondoate, respectively.

[0145] In CBG, the signals due to the chemically equivalent protons atoms at the 3' and 5' positions (see Scheme 1) appear as a single peak at 56.25 in the 'H-NMR spectrum (Fig. 8A) and carbon atoms at the 2' and 6' at 5154.9 in the13C-NMR spectrum (Fig. 9A), respectively.

[0146] In contrast, in 'H-NMR and13C-NMR spectra of a chloroform-t / solution of the isolated second fraction (Figures 8B and 9B, respectively), due to lack of chemical equivalence of proton atoms at the 3' and 5' positions, the signals appear as two peaks, having resonances separated by 0.1 ppm in the 'H-NMR spectrum (56.53 and 56.43 in Fig. 8B), and carbon atoms at the 2' and 6' and by 6.3 ppm in the13C-NMR spectrum (5155.4 and 5149.1 in Fig 9B). Accordingly, the isolated second fraction was attributed to CBG-mono-a-linolenate (compound of Formula 10). The restoration of the symmetry of the molecule by addition of an a-linolenate chain at the 6' position renders the 3' and 5' chemically equivalent as in CBG-digondoate, leading to a single peak in the NMR spectra (56.75 in the 'H-NMR spectrum and 5149.51 in the °C-NMR spectrum).

[0147] Reference is now made to Figures 8C and 9C that show 'H-NMR and °C-NMR spectra, respectively, of a chloroform-t / solution of the isolated first fraction, attributed to CBG-di-a- linolenate (compound of Formula 11). The restoration of the symmetry of the molecule by addition of an a-linolenate chain at the 6' position renders the 3' and 5' positions, and the 2' and 6' positions, respectively, chemically equivalent as in CBG-digondoate, leading to a single peak in the NMR spectra (56.75 in the 'H-NMR spectrum and 5149.5 for 2' and 6' carbon atoms in the13C-NMR spectrum).

[0148] The first fraction, attributed to CBG-di-a-linolenate, was further analyzed by GC and no peak was observed. This is believed to be due to its high molecular weight CBG-di-a-linolenate (MW = 839), precluding it from being entrained in the gas phase under the GC operating conditions.

[0149] The second fraction was further analyzed using GC-MS, and presented a peak having M / z=576.1 corresponding to the CDB-mono-a-linolenate (compound of Formula 10).

[0150] Example 4 - Testing the Solubility in Oil of a Crude Oleate Mixture of Cannabigerol (CBG)-monooleate (compound of Formula 8) and Cannabigerol (CBG)-dioleate (compound of Formula 9)

[0151] 100 mg of jojoba oil (JO) were placed in a 1 dram vial. Crude CBG oleate mixture of Cannabigerol (CBG)-monooleate (compound of Formula 8) and Cannabigerol (CBG)-dioleate (compound of Formula 9) was prepared as described in Example 2 above and added stepwise in 25mg portions to the JO. After each addition the dissolution of the crude CBG oleate mixture in JO was carefully examined visually to show clear solution with no solid particles or oil drops. Total of 100 mg CBG oleate mixture were added to form a 50% (w / w) solution of the crude oleate mixture in JO. Example 5: Preparation of CBD-monooleate (compound of Formula 8) Solution in Jojoba Oil

[0152] 72 mg CBG-monooleate (prepared as described in Example 2 above) were placed in a 1 dram vial. 70 mg of jojoba oil (JO) were first added, demonstrated complete dissolution, examined visually as explained in Example 4, of the two materials in 1 : 1 ratio. 10 mg of this mixture were used to prepare a sample for GC analysis that showed ca 1 : 1 ration of the CBG- monooleate to JO.

[0153] Next, extra 1160 mg of JO were added to get 5% CBG-monooleate in JO solution. This solution remained clear for at least 3 days after its preparation (no further examination of the appearance was performed).

[0154] Example 6: Preparation of CBD-dioleate (compound of Formula 9) Solution in Jojoba Oil

[0155] 77 mg of CBG-dioleate (prepared as described in Example 2 above) were placed in a 1 dram vial. 75 mg of jojoba oil (JO) were first added, demonstrated complete dissolution, examined visually as explained in Example 4, of the two materials in 1 : 1 ratio.

[0156] Next, extra 1462 mg of JO were added to get 5% CBG-dioleate in JO solution. This solution remained clear for at least 3 days after its preparation (no further examination of the appearance was performed).

[0157] Example 7: Application to back-hand skin

[0158] A drop of a 5% CBG-monooleate in JO solution (prepared as described in Example 5 above) was applied on the back-hand skin of four individuals and their reactions were recorded.

[0159] All the individuals reported that the solution feels smooth and that it absorbed quickly, leaving a nice soft texture. No adverse effect was reported.

[0160] A drop of a 5% CBG-dioleate in JO solution (prepared as described in Example 6 above) was applied on the back-hand skin of four individuals and their reactions were recorded.

[0161] All the individuals reported that the solution feels smooth and that it absorbed quickly, leaving a nice soft texture. No adverse effect was reported.

Claims

CLAIMS1. A fatty acid ester of cannabinoid, wherein the fatty acid is an unsaturated acid, with an ester linkage consisting of an aryloxy oxygen directly bonded to an aromatic ring of the cannabinoid and a carbonyl group attached to the fatty acid unsaturated carbon chain.

2. The fatty acid ester of cannabinoid according to claim 1, wherein the fatty acid carbon chain is C12 to C24 linear alkenyl having one or more C=C bonds.

3. The fatty acid ester of cannabinoid according to claim 1, wherein the fatty acid carbon chain is Cis to C22 linear alkenyl having one or more C=C bonds.

4. The fatty acid ester of cannabinoid according to claim 1, having the general structure:X- [O*-C(O)R' ]nFormula (I) wherein X is a cannabinoid moiety; wherein the aryloxy oxygen (O*) is directly bonded to an aromatic ring carbon atom of the cannabinoid moiety and a carbonyl group attached to the fatty acid unsaturated carbon chain (R')> wherein n=l or 2, and wherein R' is independently a linear C18-C22 alkenyl having one or more C=C bonds.

5. The fatty acid ester of cannabinoid according to any one of claims 1 - 4, wherein the fatty acid is an acid that is present in Jojoba oil.

6. The fatty acid ester of cannabinoid according to claim 5, wherein the fatty acid is selected from gondoic acid, oleic acid, linolenic acid and mixtures thereof.

7. The fatty acid ester according to any one of the preceding claims, which is a monoester.

8. The fatty acid ester according to any one of claims 1 - 6 which is a di-ester, wherein the two fatty acid carbon chains may be the same or different.

9. The fatty acid ester according to claim 8, wherein the two fatty acid carbon chains are the same.

10. The fatty acid ester according to any one of the preceding claims, wherein the aromatic ring of the cannabinoid is a non-fused six-membered ring.

11. The fatty acid ester according to claim 10, which is a fatty ester acid of cannabigerol (CBG) or a fatty ester acid of cannabidiol (CBD).

12. The compound according to claim 11, which is a fatty acid ester of CBG, having the general structure:Formula (II) including the stereoisomers, and mixtures thereof, wherein each of R1and R2is independently selected from hydrogen and fatty acid ester residue selected from -C(O)-R' and -C(O)-R", wherein each of R' and R" is independently selected from a linear C12 to C24 alkenyl, comprising one or more double carbon bonds, wherein R' and R" are the same or different, and wherein at least one of R1and R2is different from hydrogen.

13. The compound according to claim 12, having the general structure:Formula (lib) including the stereoisomers, and mixtures thereof, wherein each of R1and R2is independently selected from hydrogen and fatty acid ester residue -C(O)-R', wherein R' is linear C12 to C24 alkenyl comprising one or more double carbon bonds, and wherein at least one of R1and R2is different from hydrogen.

14. The compound according to claim 12 or 13, wherein R' and R" are selected from a linear Cis to C22 alkenyl comprising one or more C=C bonds.

15. The compound according to any one of claims 12-14, wherein one of R1and R2is hydrogen.

16. The compound according to any one of claims 12 - 14, wherein both R1and R2are different from hydrogen.

17. The compound according to any one of claims 12 - 16, wherein the fatty acid is an acid that is present in Jojoba oil.

18. The compound according to claim 17, wherein the fatty acid is selected from gondoic acid, oleic acid, linolenic acid and mixture thereof.

19. The compound according to claim 18, wherein the compound is selected from CBG- monooleate, CBG-dioleate, CBG-mono-a-linolenate, CBG-di-a-linolenate, CBG- monogondoate and CBG-digondoate and mixtures thereof.

20. The compound according to claim 19, wherein the compound is of Formula 8:including the stereoisomers, and mixtures thereof.

21. The compound according to claim 19, wherein the compound is of Formula 9:including the stereoisomers, and mixtures thereof.

22. The compound according to claim 19, wherein the compound is of Formula 10:Formula 10 including the stereoisomers, and mixtures thereof.

23. The compound according to claim 19, wherein the compound is of Formula 11 :Formula 11 including the stereoisomers, and mixtures thereof.

24. The compound according to claim 19, wherein the compound is of Formula 12:Formula 12 including the stereoisomers, and mixtures thereof.

25. The compound according to claim 19, wherein the compound is of Formula 13:Formula 13 including the stereoisomers, and mixtures thereof.

26. A method for preparing a compound according to any one of claims 1 - 25, the method comprising: combining in an organic solvent a cannabinoid, a base and a chloride of an unsaturated fatty acid; and reacting the chloride of an unsaturated fatty acid with the cannabinoid, thereby forming the fatty acid ester of cannabinoid.

27. The method according to claim 26, the method comprising: adding a chloride of an unsaturated fatty acid having the general structure:C1-C(O)-R' Formula (III) wherein R1is selected from a linear C12 to C24 alkenyl, comprising one or several double carbon bonds, to a reaction vessel that was previously charged with an organic solvent, a non-nucleophilic organic base and a cannabinoid of Formula 3:Formula 3 to form a product mixture; and separating a compound of general Formula (lib), or a mixture thereof, from the product mixture.

28. The method according to claim 27, wherein R', in the chloride of an unsaturated fatty acid of general Formula (III), is selected from a linear Cis to C22 alkenyl comprising one or more double carbon bonds.

29. The method according to claim 27, wherein the solvent is an aprotic organic solvent selected from chloroform, dichloromethane, acetonitrile, tetrahydrofuran, or any combination thereof.

30. The method according to claim 29, wherein the solvent is dichloromethane.

31. The method according to claim any one of claims 27 - 30, wherein the non-nucleophilic organic base is selected from pyridine, tri ethyl amine, A,A-diisopropylethylamine (DIPEA), or any combination thereof.

32. The method according to claim 31, wherein the non-nucleophilic organic base is N,N- diisopropylethylamine (DIPEA).

33. A composition comprising a compound according to any one of claims 1 - 25, and a topically acceptable carrier.

34. The composition according to claim 33, wherein the topically acceptable carrier is Jojoba oil.

35. The composition according to claim 33 or 34, wherein the composition comprises up to 50% by weight of a compound of general Formula (lib) :Formula (lib) including the stereoisomers, and mixtures thereof, wherein each of R1and R2is independently selected from hydrogen and fatty acid ester residue -C(O)-R', wherein R' is linear C12 to C24 alkenyl comprising one or more double carbon bonds, and wherein at least one of R1and R2is different from hydrogen.

36. The composition according to claim 35, wherein R' and R" in the compound of general Formula (lib) are selected from a linear Cis to C22 alkenyl comprising one or more double carbon bonds.

37. The composition according to claim 35, wherein one of R1and R2in the compound of general Formula (lib) is different from hydrogen.

38. The composition according to claim 35, wherein both R1and R2in the compound of general Formula (lib) are different from hydrogen.

39. The composition according to any one of claims 35 - 38, wherein the composition comprises about 2 - 10% by weight of the compound of general Formula (lib).

40. The composition according to any one of claims 35 - 38, wherein the composition comprises about 5% by weight of the compound of general Formula (lib).

41. The composition according to any one of claims 35 - 40, wherein the compound of general Formula (lib) is selected from CBG-monooleate, CBG-dioleate, CBG- mono-a-linolenate, CBG-di-a-linolenate, CBG-monogondoate and CBG-digondoate, and mixtures thereof.

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