New water-soluble salts of cannabinoids, preparation and uses thereof

Abstract

The novel water-soluble salts of cannabinoids with increased bioavailability, their preparation and uses.

Claims

1. A compound of formula (I), including stereoisomers thereof ##STR00017## wherein the combination of A, D and R of moiety C form a cannabinoid and X.sup.+ is selected from the group consisting of NH.sub.4.sup.+, mono, di or trivalent metal cations, organic cations including primary, secondary, tertiary or quaternary organic ammonium ions with up to 48 C-atoms, which can carry even more functional groups, hydrazinium ion (N.sub.2H.sub.5.sup.+), hydroxylammonium ion (NH.sub.3OH.sup.+), guanidinium ion (CN.sub.3H.sub.6.sup.+), and organic derivatives of pyridinium, imidazolinium, imidazolium, tetrahydropyrimidinium and 1,3-diazepan-ylidenium cations, which can carry even more functional groups, and Y is selected from the group consisting of hydrogen or COO.sup.−X.sup.+.

2. A process for the preparation of a compound formula (I) and stereoisomers thereof comprising deprotonation of the phenolic hydroxyl group of phenolic cannabinoid by addition of base.

3. A pharmaceutical composition comprising a compound (I) of claim 1 or an enantiomer, diastereomer, racemate, tautomer, or metabolite thereof, or a pharmaceutically acceptable salt, solvate or hydrate of the compound, enantiomer, diastereomer, racemate, tautomer, or metabolite, together with a pharmaceutically acceptable excipient, diluent, or carrier.

4. A method of treating a medical condition, disease or disorder associated with inflammation comprising administering to a subject in need thereof a therapeutically effective amount of the compound (I) of claim 1 or a composition according to claim 3.

5. The use of a compound (I) as described in claim 1 or a composition according to claim 3, for the preparation of a medicament to prevent as well as treat infection by SARS-CoV-2, for the treatment of a medical condition, wherein the medical condition is selected from the group consisting of: nausea, vomiting, emesis, pain, wasting syndrome, HIV-wasting, chemotherapy induced nausea and vomiting, alcohol use disorders, dystonia, multiple sclerosis, inflammatory bowel disorders, arthritis, dermatitis, Rheumatoid arthritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome (IBS), systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, psoriasis, systemic lupus erythematosus, Type I diabetes (IDDM), Sjogren's disease, autoimmune thyroid disease, acquired immunodeficiency syndrome (AIDS), sarcoidosis, autoimmune uveitis, autoimmune hepatitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, delayed-type hypersensitivity, interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis or other inflammatory diseases), Anti-inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective, anti-cancer, immunomodulatory effects, peripheral neuropathic pain, neuropathic pain associated with post-herpetic neuralgia, diabetic neuropathy, shingles, burns, actinic keratosis, oral cavity sores and ulcers, post-episiotomy pain, psoriasis, pruritis, contact dermatitis, eczema, bullous dermatitis herpetiformis, exfoliative dermatitis, mycosis fungoides, pemphigus, severe erythema multiforme (e.g., Stevens-Johnson syndrome), seborrheic dermatitis, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, gout, chondrocalcinosis, joint pain secondary to dysmenorrhea, fibromyalgia, musculoskeletal pain, neuropathic-postoperative complications, polymyositis, acute nonspecific tenosynovitis, bursitis, epicondylitis, post-traumatic osteoarthritis, synovitis, juvenile rheumatoid arthritis and inhibition of hair growth, Graves ophthalmopathy, amyotrophic lateral sclerosis (ALS), primary biliary cirrhosis, ileitis, chronic inflammatory intestinal disease, celiac disease, Alzheimers's disease, prion associated disease and cancer metastases.

Description

EXAMPLES

[0052] The preparation of the compounds of the disclosure is illustrated further by the following examples, which are not to be construed in any way as limiting the disclosure in scope or spirit to the specific procedures and compounds described in them. These examples are offered to illustrate the invention.

[0053] Choline Salt with CBD (1:1)

[0054] To a 50-mL Erlenmeyer flask equipped with drying tube (CaCl.sub.2) commercially available choline chloride (476 mg, 3.4 mmol), KOH (196 mg, 3.5 mmol) and dry THF (20 mL) were added. The mixture was sonicated in an ultrasonic clean bath for 2 h. On completion of the reaction, the reaction mixture was allowed to stand overnight and filtered through a sintered funnel. The filtrate was concentrated under vacuum affording choline hydroxide as a viscous liquid. The residue was diluted with 10 mL of deionized water and treated by passing through a column charged with Amberlite® IRA910 anion exchange resin in order to remove residual halide. The solution of CBD (1 g, 3.2 mmol) in methanol (50 mL) was added to the obtained aqueous solution under vigorous stirring and heated at 60° C. for 4 h. The solvents were removed using a rotary evaporator. Viscous residue was dried under vacuum at 50° C. for 24 h to eliminate the residual water. The solid was washed with MTBE-heptane and dried in vacuum affording 1.15 g (86%) solid product. Mp 48-50° C. Solubility in water at 20° C.: 6 mg/mL. Structure of the resulting choline salt with CBD (1:1) was confirmed by proton NMR.

[0055] 1 H NMR (400 MHz, DMSO-d6): anion δ 6.0 (s, 2 H), 5.0-4.95 (m, 1 H), 4.4-4.3 (m, 2 H), 3.6-3.3 (br. s., H.sub.2O), 3.1-3.05 (m, 1 H), 2.2-1.9 (m, 3 H), 1.7-1.5 (m, 8 H), 1.4-1.0 (m, 6 H), 0.9-0.8 (m, 3 H); cation δ 3.8-3.7 (m, 2 H), 3.6-3.3 (br. s., H.sub.2O), 3.1 (s, 9 H).

[0056] Choline Salt with CBD (2:1)

[0057] To a 50-mL Erlenmeyer flask equipped with drying tube (CaCl.sub.2) commercially available choline chloride (952 mg, 6.8 mmol), KOH (392 mg, 7 mmol) and dry THF (40 mL) were added. The mixture was sonicated in an ultrasonic clean bath for 2 h. On completion of the reaction, the reaction mixture was allowed to stand overnight and filtered through a sintered funnel. The filtrate was concentrated under vacuum affording choline hydroxide as a viscous liquid. The raw product was diluted with 10 mL of deionized water and treated by passing through a column charged with Amberlite® IRA910 anion exchange resin to remove residual halide. The solution of CBD (1 g, 3.2 mmol) in methanol (50 mL) was added to the obtained aqueous solution under vigorous stirring and heated at 60° C. for 4 h. The solvents were removed using a rotary evaporator. Viscous residue was dried under vacuum at 50° C. for 24 h to eliminate the residual water. The solid was washed with MTBE-heptane and dried in vacuum affording 1.25 g (75% yield) solid product. Mp. 58-60° C. Solubility in water at 20° C.: 19 mg/mL.Structure of the resulting choline salt with CBD (2:1) was confirmed by proton NMR.

[0058] 1 H NMR (400 MHz, DMSO-d6): anion δ 6.0 (s, 2 H), 5.0-4.95 (m, 1 H), 4.4-4.3 (m, 2 H), 3.6-3.3 (br. s., H.sub.2O), 3.1-3.05 (m, 1 H), 2.2-1.9 (m, 3 H), 1.7-1.5 (m, 8 H), 1.4-1.0 (m, 6 H), 0.9-0.8 (m, cation δ 3.8-3.7 (m, 4 H), 3.6-3.3 (br. s., H.sub.2O), 3.1 (s, 18 H).

[0059] Choline Salt with THC (1:1)

[0060] Commercial aqueous 46% choline hydroxide solution (1.4 mL, 5 mmol) was added to a solution of Δ9-tetrahydrocannabinol (1 g, 3.2 mmol) in 20 mL of THF and stirred for 5 h. A mixture isopropanol/hexane (4:1, 20 mL) was added, and the mixture was stirred in dry ice/EtOH bath to induce the crystallization. Solidified product was filtered with suction, washed with 10 ml of chilled isopropanol and dried in vacuum to give the title compound, 1.1 g (82%). Mp. 35-44° C. Solubility in water at 20° C.: 3 mg/mL.Structure of the resulting choline salt with TCA (1:1) was confirmed by proton NMR.

[0061] 1 H NMR (400 MHz, DMSO-d6): anion δ 6: 6.3 (s, 1 H), 6.1-6.0 (m, 2 H), 3.6-3.3 (br. s, H.sub.2O), 3.1-3.0 (m, 1 H), 2.3-1.8 (m, 5 H), 1.6 (s, 3 H), 1.5-1.3 (m, 10 H), 1.0 (s,3 H), 0.9-0.85 (m, 3 H); cation δ 3.8-3.7 (m, 2 H), 3.6-3.3 (br. s., H.sub.2O), 3.1 (s, 9 H).

[0062] Choline Salt with Tetrahydrocannabinolic Acid (2:1)

[0063] Commercial aqueous 46% choline hydroxide solution (1.7 mL, 6 mmol) was added to a solution of tetrahydrocannabinolic acid (1 g, 2.8 mmol) in 50 mL of THF, stirred for 5 h and evaporated in vacuum. Residual oil was triturated with MTBE and solidified product was washed with MTBE and dried in vacuum to give the title compound (1.31 g, 83%). Mp 65-69° C. Solubility in water at 20° C.: 20 mg/mL.

[0064] L-Lysine Salt with CBD (1:1)

[0065] To a 50-mL Erlenmeyer flask equipped with drying tube (CaCl.sub.2) L-lysine hydrochloride (620 mg, 3.4 mmol), KOH (196 mg, 3.5 mmol) and dry THF (20 mL) were added. The mixture was sonicated in an ultrasonic clean bath for 2 h. On completion of the reaction, the reaction mixture was allowed to stand overnight and filtered through a sintered funnel. The filtrate was concentrated under vacuum. The raw product was diluted with 10 mL deionized water and treated by passing through a column charged with Amberlite® IRA910 anion exchange resin to remove residual halide. The solution CBD (1 g, 3.2 mmol) in methanol (50 mL) was added to the obtained aqueous solution under vigorous stirring and heated at 60° C. for 4 h. The solvents were removed using a rotary evaporator. Viscous residue was dried under vacuum at 50° C. for 24 h to eliminate the residual water. The solid was washed with MTBE-heptane and dried in vacuum affording 1.25 g (85%) solid product. Mp. 56-60° C. Solubility in water at 20° C.: 2 mg/mL.Structure of the resulting lysine salt with CBD (1:1) was confirmed by proton NMR.

[0066] 1 H NMR (400 MHz, DMSO-d6): anion δ 6.0 (s, 2 H), 5.0-4.95 (m, 1 H), 4.4-4.3 (m, 2 H), 3.6-3.3 (br. s., H.sub.2O), 3.1-3.05 (m, 1 H), 2.2-1.9 (m, 3 H), 1.7-1.5 (m, 8 H), 1.4-1.0 (m, 6 H), 0.9-0.8 (m, 3 H); cation δ 3.9-3.8 (m, 1 H), 3.2-3.1 (m, 2 H), 1.74-1.65 (m, 4 H), 1.5-1.45 (m, 2 H).

[0067] L-Lysine Salt with CBD (2:1)

[0068] To a 50-mL Erlenmeyer flask equipped with drying tube (CaCl.sub.2) L-lysine hydrochloride (1.24 g, 6.8 mmol), KOH (302 mg, 7 mmol) and dry THF (40 mL) were added. The mixture was sonicated in an ultrasonic clean bath for 2 h. On completion of the reaction, the reaction mixture was allowed to stand overnight and filtered through a sintered funnel. The filtrate was concentrated under vacuum. The residue was diluted with 10 mL of deionized water and treated by passing through a column charged with Amberlite® IRA910 anion exchange resin to remove residual halide. The solution CBD (1 g, 3.2 mmol) in methanol (50 mL) was added to the obtained aqueous solution under vigorous stirring and heated at 60° C. for 4 h. The solvents were removed using a rotary evaporator. The viscous residue was dried under vacuum at 50° C. for 24 h to eliminate the residual water. The solid was washed with MTBE-heptane and dried in vacuum affording 1.45 g (75%) solid product. Mp. 200-210° C. Solubility in water at 20° C.: 4 mg/mL. Structure of the lysine salt with CBD (1:1) was confirmed by proton NMR.

[0069] 1 H NMR (400 MHz, DMSO-d6): anion δ 6.0 (s, 2 H), 5.05-5.0 (m, 1 H), 4.4-4.3 (m, 2 H), 4.2-3.0 (br. s., H.sub.2O), 2.2-1.9 (m, 3 H), 1.7-1.5 (m, 8 H), 1.4-1.0 (m, 6 H), 0.9-0.8 (m, 3 H); cation δ 3.2-3.1 (m, 4 H), 1.74-1.65 (m, 8 H), 1.5-1.45 (m, 4 H).

[0070] L-Lysine Salt with THC (1:1)

[0071] To a 50-mL Erlenmeyer flask equipped with drying tube (CaCl.sub.2) L-lysine hydrochloride (620 mg, 3.4 mmol), KOH (196 mg, 3.5 mmol) and dry THF (20 mL) were added. The mixture was sonicated in an ultrasonic clean bath for 2 h. On completion of the reaction, the reaction mixture was allowed to stand overnight and filtered through a sintered funnel. The filtrate was concentrated under vacuum. The residue was diluted with 10 mL of deionized water and then treated by passing through a column charged with Amberlite® IRA910 anion exchange resin to remove residual halide. The solution Δ.sup.9-tetrahydrocannabinol (1 g, 3.2 mmol) in methanol (50 mL) was added to the obtained aqueous solution under vigorous stirring and heated at 60° C. for 4 h. The solvents were removed using a rotary evaporator. The viscous residue was dried under vacuum at 50° C. for 24 h to eliminate the residual water. The solid was washed with MTBE-heptane and dried in vacuum affording 0.79 g (54%) solid material. Mp. 65-69° C. Solubility in water at 20° C.: 2 mg/mL. Structure of the lysine salt with TCA (1:1) was confirmed by proton NMR.

[0072] 1 H NMR (400 MHz, DMSO-d6): anion δ 6.3 (s, 1 H), 6.1-6.0 (m, 2 H), 4.0-3.3 (br. s, H.sub.2O), 3.1-3.0 (m, 1 H), 2.3-1.8 (m, 5 H), 1.6 (s, 3 H), 1.5-1.3 (m, 10 H), 1.0 (s,3 H), 0.9-0.85 (m, 3 H); cation δ 3.2-3.1 (m, 2 H), 1.74-1.65 (m, 4 H), 1.5-1.4 (m, 2 H).

[0073] Trometamine Salt with CBD (1:1)

[0074] To a 50-mL Erlenmeyer flask equipped with drying tube (CaCl.sub.2) tris(hydroxymethyl)aminomethane hydrochloride (540 mg, 3.4 mmol), KOH (196 mg, 3.5 mmol) and dry THF (20 mL) were added. The mixture was sonicated in an ultrasonic clean bath for 2 h. On completion of the reaction, the reaction mixture was allowed to stand overnight and filtered through a sintered funnel. The filtrate was concentrated under vacuum. The residue was diluted with 10 mL of deionized water and treated by passing through a column charged with Amberlite® IRA910 anion exchange resin to remove residual halide. The solution CBD (1 g, 3.2 mmol) in methanol (50 mL) was added to the obtained aqueous solution under vigorous stirring and heated at 60° C. for 4 h. The solvents were removed using a rotary evaporator. Viscous residue was dried under vacuum at 50° C. for 24 h to eliminate the residual water. The solids were washed with MTBE-heptane and dried in vacuum affording 1.15 g (86%) solid product. Mp. 125-131° C. Solubility in water at 20° C.: 5 mg/mL. Structure of the trometamine salt with CBD (1:1) was confirmed by proton NMR.

[0075] 1 H NMR (400 MHz, DMSO-d6): anion δ 6.1 (s, 2 H), 5.2-5.15 (m, 1 H), 4.5-4.3 (m, 2 H), 3.7-3.0 (br. s., H.sub.2O), 2.2-1.9 (m, 3 H), 1.7-1.5 (m, 8 H), 1.4-1.1 (m, 6 H), 1.0-0.9 (m, 3 H); cation δ 3.35 (s, 6 H).

[0076] Trometamine Salt with CBD (2:1)

[0077] To a 50-mL Erlenmeyer flask equipped with drying tube (CaCl.sub.2) tris(hydroxymethyl)aminomethane hydrochloride (1.08 g, 6.8 mmol), KOH (392 mg, 7 mmol) and dry THF (40 mL) were added. The mixture was sonicated in an ultrasonic clean bath for 2 h. On completion of the reaction, the reaction mixture was allowed to stand overnight and filtered through a sintered funnel. The filtrate was concentrated under vacuum. The raw product was diluted with 10 mL of deionized water and treated by passing through a column charged with Amberlite® IRA910 anion exchange resin to remove residual halide. The solution CBD (1 g, 3.2 mmol) in methanol (50 mL) was added to the obtained aqueous solution under vigorous stirring and heated at 60° C. for 4 h. The solvents were removed using a rotary evaporator. The viscous residue was dried under vacuum at 50° C. for 24 h to eliminate the residual water. The solid was washed with MTBE-heptane and dried in vacuum affording 1.46 g (82%) solid product. Mp 148-150° C. Solubility in water at 20° C.: 6 mg/mL. Structure of the trometamine salt with CBD (2:1) was confirmed by proton NMR.

[0078] 1 H NMR (400 MHz, DMSO-d6): anion δ 6.0 (s, 2 H), 5.0-4.95 (m, 1 H), 4.5-4.4 (m, 2 H), 3.7-3.0 (br. s., H.sub.2O), 2.2-1.9 (m, 3 H), 1.7-1.5 (m, 8 H), 1.4-1.1 (m, 6 H), 1.0-0.9 (m, 3 H); cation δ 3.3 (s, 12 H).

[0079] Meglumine Salt with CBD (1:1)

[0080] To a 50-mL Erlenmeyer flask equipped with drying tube (CaCl.sub.2) N-methyl-D-glucamine hydrochloride (780 mg, 3.4 mmol), KOH (196 mg, 3.5 mmol), and dry THF (20 mL) were added. The mixture was sonicated in an ultrasonic clean bath for 2 h. On completion of the reaction, the reaction mixture was allowed to stand overnight and filtered through a sintered funnel. The filtrate was concentrated under vacuum. The raw product was diluted with 10 mL of deionized water and treated by passing through a column charged with Amberlite® IRA910 anion exchange resin to remove residual halide. The solution CBD (1 g, 3.2 mmol) in methanol (50 mL) was added to the obtained aqueous solution under vigorous stirring and heated at 60° C. for 4 h. The solvents were removed using a rotary evaporator. The viscous residue was dried under vacuum at 50° C. for 24 h to eliminate the residual water. The solid was washed with MTBE-heptane and dried in vacuum affording 1.25 g (77%) solid product. Mp. 50-52° C. Solubility in water at 20° C.: 15 mg/mL. Structure of the meglumine salt with CBD (1:1) was confirmed by proton NMR.

[0081] 1 H NMR (400 MHz, DMSO-d6): anion δ 6.2 (s, 2 H), 5.2-5.1 (m, 1 H), 4.6-4.5 (m, 2 H), 3.8-3.4 br. s., H.sub.2O), 2.4-2.0 (m, 3 H), 1.9-1.7 (m, 8 H), 1.6-1.2 (m, 6 H), 1.1-0.95 (m, 3 H); cation δ 3.8-3.7 (m, 4 H), 2.7-2.6 (m, 5 H).

[0082] Meglumine Salt with CBD (2:1)

[0083] To a 50-mL Erlenmeyer flask equipped with drying tube (CaCl.sub.2) N-methyl-D-glucamine hydrochloride (1.56 g, 6.8 mmol), KOH (392 mg, 7 mmol), and dry THF (40 mL) were added. The mixture was sonicated in an ultrasonic clean bath for 2 h. On completion of the reaction, the reaction mixture was allowed to stand overnight and filtered through a sintered funnel. The filtrate was concentrated under vacuum. The raw product was diluted with 10 mL of deionized water and treated by passing through a column charged with Amberlite® IRA910 anion exchange resin to remove residual halide. The solution CBD (1 g, 3.2 mmol) in methanol (50 mL) was added to the obtained aqueous solution under vigorous stirring and heated at 60° C. for 4 h. The solvents were removed using a rotary evaporator. The viscous residue was dried under vacuum at 50° C. for 24 h to eliminate the residual water. The solid was washed with MTBE-heptane and dried in vacuum affording 1.85 g (82%) solid product. Mp 115-117° C. Solubility in water at 20° C.: 8 mg/mL. Structure of the resulting meglumine salt with CBD (2:1) was confirmed by proton NMR.

[0084] 1 H NMR (400 MHz, DMSO-d6): anion δ 6.4 (s, 2 H), 5.3-5.2 (m, 1 H), 4.7-4.6 (m, 2 H), 3.7-3.3 br. s., H.sub.2O), 2.4-2.0 (m, 3 H), 1.9-1.7 (m, 8 H), 1.6-1.2 (m, 6 H), 1.1-0.95 (m, 3 H); cation δ 3.8-3.7 (m, 8 H), 2.8-2.7 (m, 10 H).

[0085] Meglumine Salt with THC (1:1)

[0086] To a 50-mL Erlenmeyer flask equipped with drying tube (CaCl.sub.2) N-methyl-D-glucamine hydrochloride (780 mg, 3.4 mmol), KOH (196 mg, 3.5 mmol), and dry THF (20 mL) were added. The mixture was sonicated in an ultrasonic clean bath for 2 h. On completion of the reaction, the reaction mixture was allowed to stand overnight and filtered through a sintered funnel. The filtrate was concentrated under vacuum. The raw product was diluted with 10 mL of deionized water and treated by passing through a column charged with Amberlite® IRA910 anion exchange resin to remove residual halide. The solution A.sup.9-tetrahydrocannabinol (1 g, 3.2 mmol) in methanol (50 mL) was added to the obtained aqueous solution under vigorous stirring and heated at 60° C. for 4 h. The solvents were removed using a rotary evaporator. The viscous residue was dried under vacuum at 50° C. for 24 h to eliminate the residual water. The solid was washed with MTBE-heptane and dried in vacuum affording 1.1 g (68%) solid product. Mp. 60-62° C. Solubility in water at 20° C.: 9 mg/mL. Structure of the resulting meglumine salt with THC (1:1) was confirmed by proton NMR.

[0087] 1 H NMR (400 MHz, DMSO-d6): anion δ: 6.3 (s, 1 H), 6.1-6.0 (m, 2 H), 3.8-3.1 (br. s, H.sub.2O), 3.1-3.0 (m, 1 H), 2.3-1.8 (m, 5 H), 1.6 (s, 3 H), 1.5-1.3 (m, 10 H), 1.0 (s,3 H), 0.9-0.85 (m, 3 H); cation δ 3.8-3.7 (m, 4 H), 2.7-2.6 (m, 5 H).

[0088] Meglunine Salt with Tetrahydrocannabinolic Acid (2:1)

[0089] To a 50-mL Erlenmeyer flask equipped with drying tube (CaCl.sub.2) N-methyl-D-glucamine hydrochloride (1.38 g, 6 mmol), KOH (337 mg, 6 mmol), and dry THF (50 mL) were added. The mixture was sonicated in an ultrasonic clean bath for 2 h. On completion of the reaction, the reaction mixture was allowed to stand overnight and filtered through a sintered funnel. The filtrate was concentrated under vacuum. The crude residue was diluted with 10 mL of deionized water and treated by passing through a column charged with Amberlite® IRA910 anion exchange resin in order to remove residual halide. The solution tetrahydrocannabinolic acid (1 g, 2.8 mmol) in methanol (50 mL) was added to the obtained aqueous solution under vigorous stirring and heated at 60° C. for 4 h. The solvents were removed in vacuum using a rotary evaporator. The viscous residue was dried in vacuum at 50° C. for 24 h to eliminate the residual water. The residual viscous oil was triturated with MTBE. The solidified product was washed with MTBE and dried in vacuum affording 1.9 g (91%) desired product. Mp 96-101° C. Solubility in water at 20° C.: 20 mg/mL.

[0090] Procaine Salt with CBD (1:1)

[0091] To a 50-mL Erlenmeyer flask equipped with drying tube (CaCl.sub.2) procaine hydrochloride (920 mg, 3.4 mmol), KOH (196 mg, 3.5 mmol), and dry THF (20 mL) were added. The mixture was sonicated in an ultrasonic clean bath for 2 h. On completion of the reaction, the reaction mixture was allowed to stand overnight and filtered through a sintered funnel. The filtrate was concentrated under vacuum. The residue was diluted with 10 mL of deionized water and treated by passing through a column charged with Amberlite® IRA910 anion exchange resin in order to remove residual halide. The solution CBD (1 g, 3.2 mmol) in methanol (50 mL) was added to the obtained aqueous solution under vigorous stirring and heated at 60° C. for 4 h. The solvents were removed using a rotary evaporator. A viscous residue was dried in vacuum at 50° C. for 24 h to eliminate the water. The solid was washed with MTBE-heptane and dried in vacuum affording 1.46 g (83%) solid product. Mp. 44-43° C. Solubility in water at 20° C.: 5 mg/mL.

[0092] Procaine Salt with CBD (2:1)

[0093] To a 50-mL Erlenmeyer flask equipped with drying tube (CaCl.sub.2) procaine hydrochloride (1.84 mg, 6.8 mmol), KOH (392 mg, 7 mmol) and dry THF (40 mL) were added. The mixture was sonicated in an ultrasonic clean bath for 2 h. On completion of the reaction, the reaction mixture was allowed to stand overnight and filtered through a sintered funnel. The filtrate was concentrated under vacuum. The residue was diluted with 10 mL of deionized water and treated by passing through a column charged with Amberlite® IRA910 anion exchange resin in order to remove residual halide. The solution CBD (1 g, 3.2 mmol) in methanol (50 mL) was added to the obtained aqueous solution under vigorous stirring and heated at 60° C. for 4 h. The solvents were removed using a rotary evaporator. A viscous residue was dried in vacuum at 50° C. for 24 h to eliminate the water. The solid was washed with MTBE-heptane and dried in vacuum affording 1.85 g (74%) solid product. Mp. 48-50° C. Solubility in water at 20° C.: 6 mg/mL.

[0094] Arginine Salt with CBD (1:1)

[0095] Arginine (0.56 g, 3.2 mmol) was added to a solution of CBD (1 g, 3.2 mmol) in 50 mL of ethanol and stirred for 2h. Ethanol was removed in vacuum. The residue was washed with 3×25 ml of hexane/MTBE and dried in vacuum. Yield: 1.25 g (80%). Mp. 148-150° C. Solubility in water at 20° C.: 3 mg/mL.

[0096] Arginine Salt with CBD (2:1)

[0097] Arginine (1.12 g, 6.4 mmol) was added to a solution of CBD (1 g, 3.2 mmol) in 100m1 of ethanol and stirred for 3 h. Ethanol was removed in vacuum. The residue was washed with 3×25 ml of hexane/MTBE and dried in vacuum. Yield: 1.8 g (85%). Mp. 156-158° C. Solubility in water at 20° C.: 2 mg/mL.

[0098] 1-Benzylpyridinium Salt with Cannabigerol (1:1)

[0099] A: 1-Benzylpyridin-1-ium Chloride

[0100] Benzyl chloride (35.7 mL, 0.31 mol) was added drop wise to a solution of pyridine (25.0 mL, 0.31 mol) in toluene (100 mL) in an ice bath and stirred for one hour. Precipitate was filtered with suction and dried in vacuum.

[0101] B: 1-Benzylpyridinium Cannabigerol Salt (1:1)

[0102] Sodium methoxide 25% solution in methanol (37 μL, 0.15 mmol) was added to the solution of 1-benzylpyridin-1-ium chloride (6 mg, 0.3 mmol) and cannabigerol (50 mg, 0.15 mmol) in methanol (10 mL). The reaction mixture stirred for 1 h and evaporated in vacuum. Residue was dispersed in water (2 mL) and extracted with dichloromethane. Organic layer evaporated in vacuum giving a desired product as sticky oil in quantitative yield. Solubility in water at 20° C.: 1 mg/mL.

[0103] Tetraethylammonium Salt with Cannabidiol (2:1)

[0104] An aqueous solution 25% of Me.sub.4NOH (2.4 mL, 6.5 mmol) was added to a solution of cannabidiol (1 g, 3.2 mmol) in 20 mL of MeOH and heated at 50° C. for 2 h. The solvents were evaporated in vacuum. The residue, white solid was dried in vacuum giving the desired salt in quantitative yield. Solubility in water at 20° C.: 0.1 mg/mL.

[0105] Benzyltrimethylammonium Salt with Cannabidiol (1:1)

[0106] Benzyltrimethylammonium methoxide 40 wt. % solution in methanol (1.5 mL, 3.2 mmol) was added to a solution of cannabidiol (1 g, 3.2 mmol) in 20 mL of MeOH. The mixture stirred for 1 h and evaporated in vacuum obtaining desired product as sticky oil in a quantitative yield. Solubility in water at 20° C.: 0.4 mg/mL.

[0107] Agmatine Salt with Δ.sup.9-Tetrahydrocannabinol (1:1)

[0108] Agmatine (417 mg, 3.2 mmol) was added to a solution of Δ.sup.9-tetrahydrocannabinol (1 g, 3.2 mmol) in 20 mL of THF and stirred for 30 min. THF was removed in vacuum affording desired salt in a quantitative yield. Solubility in water at 20° C.: 0.2 mg/mL.

[0109] Tetrakis(2-Hydroxyethyl) Ammonium Salt with Δ.sup.9-Tetrahydrocannabivarin (1:1)

[0110] A. Tetrakis(2-Hydroxyethyl) Ammonium Bromide

[0111] Triethanolamine (1 g, 6.77 mmol) was mixed with 2-bromoethanol (0.84 g, 6.77 mmol) and stirred for 5 days at 70° C. by using a hot plate with a silicon bath. After that the magnetic stirrer was removed from the reaction vial and the vial was placed in an oven at 70° C. for 5 more days. After cooling in a fridge to 5° C. the salt solidified into a waxy-like white solid.

[0112] B. Tetrakis (2-hydroxyethyl) ammonium hydroxide

[0113] Chemical exchange of bromine by hydroxide anions was performed by using a column exchange containing a strongly basic resin (AmberChrom® 1×8, Sigma-Aldrich). The basic resin was first activated with 250 ml of an aqueous solution of 1 M KOH followed by 250 ml of deionized water. The aqueous solution containing 1.8 g of tetrakis(2-hydroxyethyl) ammonium bromide from previous step was flushed three times through the column being activated every time before flushing. The solvent was removed in vacuum. The residue, the hydroxide salt dried at 70° C. in vacuum for 48 hours and stored in a refrigerator at 8° C. until solidified.

[0114] C. Tetrakis(2-Hydroxyethyl) Ammonium Salt with Δ.sup.9-Tetrahydrocannabivarin (1:1)

[0115] Tetrakis (2-hydroxyethyl) ammonium hydroxide (417 mg, 3.2 mmol) obtained from previous step was added to a solution of Δ.sup.9-tetrahydrocannabivarin (100 mg, 0.35 mmol) in 20 mL of dry EtOH and stirred for 30 min. The solvent was removed under reduced pressure. The residue was dried in vacuum at 70° C. for 48 hours affording desired salt in a quantitative yield. Solubility in water at 20° C.: 7 mg/mL.

[0116] Tetrabutylammonium Salt with Δ.sup.9-Tetrahydrocannabivarin (1:1)

[0117] Δ.sup.9-Tetrahydrocannabivarin (100 mg, 0.35 mmol) was dissolved in 20 mL of acetonitrile at room temperature. The tetrabutylammonium hydroxide 30-hydrate (400 mg, 0.5 mmol) was added and the mixture was stirred vigorously for 3 h. The resulting reaction mixture was concentrated in vacuum. The residue was extracted twice with dichloromethane. Combined organic layers were washed with deionized water to remove excess of tetrabutylammonium hydroxide, dried over Na.sub.2SO.sub.4, evaporated in vacuum to afford desired salt as sticky brown oil quantitatively. Solubility in water at 20° C.: 0.2 mg/mL.

[0118] Tetraethylammonium Salt with Cannabinol (1:1)

[0119] A mixture of cannabinol (1 g, 3.2 mmol), anhydrous K2CO3 (5.0 g) and tetraethylammonium bromide (2 g) in benzene (50 mL) was heated under reflux for 5 h. The mixture was filtered off to remove any impurities and non-reacted material. The filtrate was evaporated to almost dryness. The viscous residue was treated with 20 ml methanol and left overnight in a fridge at −20° C. The colorless crystals that formed were filtered off and dried in vacuum. Yield: 90%. Solubility in water at 20° C.: 0.2 mg/mL.

[0120] Quinine Salt with Cannabinol (1:1)

[0121] A mixture of quinine hydrochloride dihydrate (1.35 g) and Ambertlist® A26 (hydroxide form) (10 g) in methanol (50 mL) was stirred at room temperature overnight. The insoluble material was filtered off through celite and washed with methanol (20 ml). To the filtrate, cannabinol (1 g, 3.2 mmol) was added and stirred for 5 h. The solvent was evaporated in vacuum. The oily residue was triturated with diethyl ether. The precipitated solid was collected by filtration, washed with diethyl ether and dried in vacuum to give the title compound. Yield: 1.9 g. Solubility in water at 20° C.: 0.2 mg/mL.

[0122] Acetylcholine Salt with Cannabinol (1:1)

[0123] A mixture of acetylcholine chloride (636 mg) and Ambertlist® A26 (hydroxide form) (10 g) in methanol (50 mL) was stirred at room temperature overnight. The insoluble material was filtered off through celite and washed with methanol (20 ml). To the filtrate, cannabinol (1 g, 3.2 mmol) was added and stirred for 5 h. The solvent was evaporated in vacuum. The oily residue was triturated with diethyl ether. The precipitated solid was collected by filtration, washed with diethyl ether and dried in vacuum to give the title compound. Yield: 1.3 g. Solubility in water at 20° C.: 1 mg/mL.

[0124] Choline Salt with Cannabidiolic Acid (3:1)

[0125] Commercial aqueous 46% choline hydroxide solution (2.6 mL, 9 mmol) was added to a solution of cannabidiolic acid (1 g, 2.8 mmol) in 50 mL of THF, stirred for 6 h and evaporated in vacuum. Residual oil was triturated with diethyl ether. A solidified product was washed with diethyl ether and dried in vacuum to give the title compound (1.70 g, 91%). Mp 78-81° C. Solubility in water at 20° C.: 24 mg/mL.