METHODS FOR THE MANUFACTURE OF CANNABINOID PRODRUGS, PHARMACEUTICAL FORMULATIONS AND THEIR USE

1 . A method for producing a cannabinoid prodrug of Formula Ia or Formula IIa:

comprising the step of contacting a compound according to Formula I or Formula II

with an activated —Y—Z reagent to produce a prodrug according to Formula Ia or Formula IIa;

wherein,

R is —H;

R 1 is —H, —COOH, or —COO(C 1 -C 5 )alkyl;

R 2 is selected from the group consisting of (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkylalkylene, (C 3 -C 10 )aryl, and (C 3 -C 10 )arylalkylene;

R 3 is —H, or (C 1 -C 5 )alkyl;

Z is selected from the group consisting of hemisuccinate, succinate, -oxalate, C(O)—CH 2 —[OCH 2 CH 2 ] n —OR 4 , —C(O)—CH 2 —[OCH 2 CH 2 ] n —NH 2 , —C(O)[CH 2 ] n —NR 4 R 5 , —C(O)O[CH 2 ] n —NR 4 R 5 , —C(O)—NH—[CH 2 ] n —NR 4 R 5 , —C(O)[CH 2 ] n —N + (R 4 )(R 5 ))(R 6 )X − , —C(O)O[CH 2 ] n —N + (R 4 )(R 5 )(R 6 )X − , —C(O)—NH—[CH 2 ] n —N + (R 4 )(R 5 ))(R 6 )X − , and -oligosaccharide;

Y is selected from the group consisting of L-amino acid residue, a D-amino acid residue, a β-amino acid residue, a γ-amino acid residue, —C(O)—CH 2 —[OCH 2 CH 2 ] n —O—, and —C(O)—CH 2 —[OCH 2 CH 2 ] n —NH—; or —Y—Z is an oligosaccharide;

R 4 , R 5 , and R 6 are each independently selected from the group consisting of —H, —OH, formyl, acetyl, pivaloyl, and (C 1 -C 5 )alkyl;

“n” is 1, 2, 3, 4, 5, or 6; and

“X” is a counter ion derived from a pharmaceutically acceptable acid.

2 . The method of claim 1 , wherein the compound according to Formula I or Formula II is obtained by contacting a compound of Formula III

with a cannabinoid synthase, wherein substituents R, R 1 , R 2 , and R 3 are as defined above.

3 . The method of claim 2 , wherein the compound of Formula III is contacted with the cannabinoid synthase in the presence of a solvent selected from the group consisting of water, phosphate buffer, citrate buffer, TRIS buffer, HEPES buffer, a mixture of water and a (C 1 -C 5 )alcohol, and a mixture of buffer and a (C 1 -C 5 )alcohol.

4 . The method of claim 1 , wherein Z is -hemisuccinate, -succinate, —C(O)—CH 2 —[OCH 2 CH 2 ] n —OR 4 , or —C(O)—CH 2 —[OCH 2 CH 2 ] n —NH 2 .

5 . The method of claim 4 , wherein “Y” is an L-amino acid residue selected from the group consisting of glycine, valine, leucine, isoleucine, aspartic acid, glutamic acid, and lysine.

6 . The method of claim 1 , wherein —Y—Z is -valine-C(O)—CH 2 —[OCH 2 CH 2 ] n —OR 4 , R 4 is —H or methyl, and subscript “n” is 1, 2, 3, or 4.

7 . The method of claim 1 , wherein R 1 is —COOH, and R 2 is (C 1 -C 10 )alkyl.

8 . The method of claim 7 , wherein R 2 is propyl or pentyl.

9 . The method of claim 2 , wherein the cannabinoid synthase is selected from the group consisting of tetrahydrocannabivarin acid synthase (THCVA synthase), tetrahydrocannabinolic acid synthase (THCA synthase), cannabidiolic acid synthase, and cannabichromene acid synthase (CBCA synthase).

10 . A method for producing a cannabinoid prodrug of Formula IVa or Formula Va:

comprising

(a) contacting a compound of Formula VI:

with a cannabinoid synthase to obtain a compound according to Formula IV or Formula V:

and

(b) contacting the compound according to Formula IV or Formula V with an activated —Z reagent to obtain the Formula IVa or Formula Va compound;

wherein

R 7 is —H, —COOH, or —COO(C 1 -C 5 )alkyl;

R 8 is selected from the group consisting of (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkylalkylene, (C 3 -C 10 )aryl, and (C 3 -C 10 )arylalkylene;

R 9 is —H, or (C 1 -C 5 )alkyl;

Y is selected from the group consisting of L-amino acid residue, a D-amino acid residue, a β-amino acid residue, a γ-amino acid residue, and —C(O)—CH 2 —[OCH 2 CH 2 ] n —NH—;

Z is selected from the group consisting of hemisuccinate, succinate, oxalate, —C(O)—CH 2 —[OCH 2 CH 2 ] n —OR 10 , —C(O)—CH 2 —[OCH 2 CH 2 ] n —NH 2 , —C(O)[CH 2 ] n —NR 10 R 11 , —C(O)O[CH 2 ] n —NR 10 R 11 , —C(O)—NH—[CH 2 ] n —NR 10 R 11 , —C(O)[CH 2 ] n —N + (R 10 )(R 11 ))(R 12 )X − , —C(O)O[CH 2 ] n —N + (R 10 )(R 11 )(R 12 )X − , and —C(O)—NH—[CH 2 ] n —N + (R 10 )(R 11 ))(R 12 )X − ,

R 10 , R 11 , and R 12 are each independently selected from the group consisting of —H, —OH, formyl, acetyl, pivaloyl, and (C 1 -C 5 )alkyl;

“n” is 1, 2, 3, 4, 5, or 6; and

“X” is a counter ion derived from a pharmaceutically acceptable acid.

11 . The method of claim 10 , wherein the cannabinoid synthase is selected from the group consisting of tetrahydrocannabivarin acid synthase (THCVA synthase), tetrahydrocannabinolic acid synthase (THCA synthase), cannabidiolic acid synthase, and cannabichromene acid synthase (CBCA synthase).

12 . The method of claim 10 , wherein R 7 is —COOH, and R 8 is (C 1 -C 10 )alkyl.

13 . The method of claim 12 , wherein R 8 is propyl or pentyl.

14 . The method of claim 10 , wherein —Y—Z in Formula IVa or Formula Va is selected from the group consisting of —Y-hemisuccinate, —Y-succinate, —Y—C(O)—CH 2 —[OCH 2 CH 2 ] n —OR 4 , and —Y—C(O)—CH 2 —[OCH 2 CH 2 ] n —NH 2 .

15 . The method of claim 14 , wherein —Y—Z in Formula IVa or Formula Va is —Y-hemisuccinate.

16 . A method for producing a cannabinoid prodrug of Formula VIIa or Formula VIIIa:

comprising

(a) contacting a compound of Formula IX:

with a cannabinoid synthase to obtain the Formula VIIa or Formula VIIIa compound;

wherein

R 13 is —H, —COOH, or —COO(C 1 -C 5 )alkyl;

R 14 is selected from the group consisting of (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkylalkylene, (C 3 -C 10 )aryl, and (C 3 -C 10 )arylalkylene;

R 15 is —H, or (C 1 -C 5 )alkyl;

—Y is selected from the group consisting of L-amino acid residue, a D-amino acid residue, a β-amino acid residue, a γ-amino acid residue, —C(O)—CH 2 —[OCH 2 CH 2 ] n —O—, and —C(O)—CH 2 —[OCH 2 CH 2 ] n —NH—;

—Z is selected from the group consisting of hemisuccinate, succinate, oxalate, —C(O)—CH 2 —[OCH 2 CH 2 ] n —OR 4 , —C(O)—CH 2 —[OCH 2 CH 2 ] n —NH 2 , —C(O)[CH 2 ] n —NR 16 R 17 , —C(O)O[CH 2 ] n —NR 16 R 17 , —C(O)—NH—[CH 2 ] n —NR 16 R 17 , —C(O)[CH 2 ] n —N + (R 16 )(R 17 ))(R 18 )X − , —C(O)O[CH 2 ] n —N + (R 16 )(R 17 )(R 18 )X − , and —C(O)—NH—[CH 2 ] n —N + (R 16 )(R 17 ))(R 18 )X − , wherein

R 16 , R 17 , and R 18 are each independently selected from the group consisting of —H, —OH, formyl, acetyl, pivaloyl, and (C 1 -C 5 )alkyl;

“n” is 1, 2, 3, 4, 5, or 6; and

“X” is a counter ion derived from a pharmaceutically acceptable acid.

17 . The method of claim 16 , wherein the cannabinoid synthase is selected from the group consisting of tetrahydrocannabivarin acid synthase (THCVA synthase), tetrahydrocannabinolic acid synthase (THCA synthase), cannabidiolic acid synthase, and cannabichromene acid synthase (CBCA synthase).

18 . The method of claim 16 , further comprising the step of contacting the Formula VIIa or Formula VIIIa compound with an oligosaccharide selected from the group consisting of mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid.

19 . The method of claim 16 , wherein —Y is an L-amino acid or a D-amino acid.

20 . The method of claim 19 , wherein —Y is an L-amino acid selected from the group consisting of valine, lysine, glutamic acid, and aspartic acid.