BIOSYNTHESIS OF CANNABINOID PRODRUGS AND THEIR USE AS THERAPEUTIC AGENTS
The present invention provides methods for producing cannabinoid prodrugs. Also described are pharmaceuticals acceptable compositions of the prodrugs and a system for the large-scale production of the prodrugs.
1 . A method for producing a cannabinoid prodrug of Formula II or Formula III:
comprising
(i) contacting a compound according to Formula I
with a cannabinoid synthase to produce a compound according to Formula II or Formula III; and
(ii) optionally decarboxylating the Formula II or Formula III compound;
wherein
R and R 3 are each independently selected from the group consisting of —H, acetyl, propionyl, 3-hydroxy-2-methylpropionyl, TMS, TBDMS, benzyl, tetrahydropyran, —C(O)[CH 2 ] x —C(O)OH, —C(O)[CH 2 ] x —OR 4 , —C(O)[CHR 4 ] x —C(O)OH, —C(O)[CHR 4 ] x —OR 5 , —C(O)[CR 4 R 5 ] x —OR 6 , —C(O)O[CH 2 ] x —OR 4 , —C(O)—CH 2 [OCH 2 CH 2 ] x —OR 4 , —C(O)—C(O)—[OCH 2 CH 2 ] x —OR 4 , —C(O)[CH 2 ] x —NR 4 R 5 , —C(O)O[CH 2 ] x —NR 4 R 5 , —C(O)—NH—[CH 2 ] x —NR 4 R 5 , —C(O)[CH 2 ] x —N + (R 4 )(R 5 ) )(R 6 )X − , —C(O)[CH 2 ] x —N + (R 4 )(R 5 )(R 6 )X − , —C(O)—NH—[CH 2 ] x —(R 4 )(R 5 ) )(R 6 )X − , a L-amino acid residue, a D-amino acid residue, a β-amino acid residue, a γ-amino acid residue, —P(O)[OY](OZ), and —P(O)[NR 4 NR 5 9 [OY](OZ);
R 1 is —H, —COOH, —COOR a , or —(CH 2 ) n COOH;
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 )cycioalkyl, (C 3 -C 10 )cycloalkylalkylene, (C 3 -C 10 )aryl, and (C 3 -C 10 )arylalkylene;
R 4 , R 5 , and R 6 are each independently selected from the group consisting of —H, —OH, formyl, acetyl, pivaloyl, —NH 2 , —NH(CH 3 ), —NH(CH 2 CH 3 ), N(CH 3 ), —NH[C(O)H], —NH[C(O)CH 3 ], and (C 1 -C 5 )alkyl;
R a is (C 1 -C 10 )alkyl;
“X” is a counter ion derived from a pharmaceutically acceptable acid;
“Y” and “Z” are each independently selected from the group consisting of —H, (C 1 -C 5 )alkyl, alkali metal cations, alkaline earth metal cations, ammonium cation, methyl ammonium cation, and pharmaceutically acceptable bases; and
subscripts “x” and “n” are independently selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6.
2 . The method of claim 1 , wherein R 1 is —COOH, and R 2 is (C 1 -C 10 )alkyl.
3 . The method of claim 2 , wherein R 2 is propyl or pentyl.
4 . The method of claim 2 , wherein R is selected from the group consisting of —C(O)[CH 2 ] x —C(O)H, —C(O)[CH 2 ] x —OR 4 , —C(O)[CH 2 ] x —NR 4 R 5 , and —C(O)—CH 2 [OCH 2 CH 2 ] x —OR 4 .
5 . The method of claim 4 , wherein R is —C(O)[CH 2 ] x —OR 4 , subscript “x” is 1, 2, 3, or 4, and R 4 is —H, or (C 1 -C 5 )alkyl.
6 . The method of claim 4 , wherein R is —C(O)—CH 2 —[OCH 2 CH 2 ] x —OR 4 , R 4 is methyl, and subscript “x” is 1, 2, 3, or 4.
7 . The method of claim 4 , wherein R is —C(O)[CH 2 ] x —NR 4 R 5 and subscript “x” is 1, 2, 3, or 4.
8 . The method of claim 7 , wherein R 4 and R 5 are each independently —H, or (C 1 -C 5 )alkyl.
9 . A cannabinoid prodrug according to Formula IV or Formula V
wherein
R 7 and R 10 are each independently selected from the group consisting of —H, acetyl, propionyl, 3-hydroxy-2-methylpropionyl, tetrahydropyranyl, —C(O)[CH 2 ] x —C(O)OH, —C(O)[CH 2 ] x —OR 11 , —C(O)[CHR 11 ] x —C(O)OH, —C(O)[CHR 11 ] x —OR 12 , —C(O)[CR 11 R 12 ] x —OR 13 , —C(O)O[CH 2 ] x —OR 11 , —C(O)—CH 2 —[OCH 2 CH 2 ] x —OR 11 , —C(O)—C(O)—[OCH 2 CH 2 ] x —OR 11 , —C(O)[CH 2 ] x —NR 11 R 12 , —C(O)O[CH 2 —NR 11 R 12 , —C(O)—NH—[CH 2 ] x —NR 11 R 12 , —C(O)[CH 2 ] x —N + (R 11 )(R 12 ) )(R 13 )X − , —C(O)O[CH 2 ] x —N + (R 11 )(R 12 ) )(R 13 )X − , —C(O)—NH—[CH 2 ] x —N + (R 11 )(R 12 ) )(R 13 )X − , a L-amino acid residue, a D-amino acid residue, a β-amino acid residue, a γ-amino acid residue, —P(O)[OY](OZ), and —P(O)[NR 11 NR 12 ][OY](OZ);
R 8 is —H, —COOH, —COOR a , or —(CH 2 ) n ,COOH;
R 9 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 11 , R 12 and R 13 are each independently selected from the group consisting of —H, —OH, formyl, acetyl, pivaloyl, —NH 2 , —NH(CH 3 ), —NH(CH 2 CH 3 ), N(CH 3 ) 2 , —NH[C(O)H], —NH[C(O)CH 3 ], and (C 3 -C 5 )alkyl;
R a is (C 1 -C 10 )alkyl;
“X” is a counter ion derived from a pharmaceutically acceptable acid;
“Y” and “Z” are each independently selected from the group consisting of —H, (C 1 -C 5 )alkyl, alkali metal cations, alkaline earth metal cations, ammonium cation, methyl ammonium cation, and pharmaceutically acceptable bases; and
subscripts “x” and “n” are independently selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6.
10 . The cannabinoid prodrug of claim 9 , wherein R 7 is selected from the group consisting of —C(O)[CH 2 ] x —C(O)OH, —C(O)[CH 2 ] x —OR 11 , —C(O)[CH 2 ] x —NR 11 R 12 , —C(O)—CH 2 [OCH 2 CH 2 ] x —OR 11 , and —C(O)[CH 2 ] x —N + (R 11 )(R 12 )(R 13 )X − .
11 . The cannabinoid prodrug of claim 9 , wherein R 8 is —H or —COOH, and R 9 is propyl, butyl, or pentyl.
12 . The cannabinoid prodrug of claim 9 , wherein R 8 is —H and R 9 is propyl, or pentyl.
13 . The cannabinoid prodrug according to Formula IV of claim 9 , selected from the following table:
14 . The cannabinoid prodrug according to Formula V of claim 9 , selected from the following table:
15 . A system for producing a cannabinoid prodrug according to Formula VII or Formula VIII:
comprising
(i) a bioreactor containing a reactant according to Formula VI, a solvent, and a cannabinoid synthase;
(ii) a control mechanism configured to control at least one condition of the bioreactor, wherein the compound according to Formula VI interacts with the cannabinoid synthase to produce a compound according to Formula VII or Formula VIII, and
(iii) optionally decarboxylating the Formula VII or Formula VIII compound;
wherein
R 14 and R 17 are each independently selected from the group consisting of —H, acetyl, propionyl, 3-hydroxy-2-methylpropionyl, benzyl, tetrahydropyranyl, —C(O)[CH 2 ] x —C(O)OH, —C(O)[CH 2 ] x —OR 18 , —C(O)[CHR 18 ] x —C(O)OH, —C(O)[CHR 18 ] x —OR 19 , —C(O)[CR 18 R 19 ] x —OR 20 , —C(O)O[CH 2 ] x —OR 18 , —C(O)—CH 2 [OCH 2 CH 2 ] x —OR 18 , —C(O)—C(O)—[OCH 2 CH 2 ] x —OR 18 , —C(O)[CH 2 ] x —NR 18 R 19 , —C(O)O[CH 2 ] x —NR 18 R 19 , —C(O)—NH—[CH 2 ] x —NR 18 R 19 , —C(O)[CH 2 ] x —N + (R 18 )(R 19 )(R 20 )X − , —C(O)O[CH 2 ] x —N + (R 18 )(R 19 ) )(R 20 )X − , —C(O)—NH—[CH 2 ] x —N + (R 18 )(R 19 ) )(R 20 )X − , a L-amino acid residue, a D-amino acid residue, a β-amino acid residue, a γ-amino acid residue, —P(O)[OY](OZ), and —P(O)[NR 18 NR 19 ][OY](OZ);
R 15 is —H, —COOH, —COOR a , or —(CH 2 ) n COOH;
R 16 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 18 , R 19 , and R 20 are each independently selected from the group consisting of —H, —OH, formyl, acetyl, pivaloyl, —NH 2 , —NH(CH 3 ), —NH(CH 2 CH 3 ), N(CH 3 ) 2 , —NH[C(O)H], —NH[C(O)CH 3 ], and (C 1 -C 5 )alkyl;
R a is (C 1 -C 10 )alkyl;
“X” is a counter ion derived from a pharmaceutically acceptable acid;
“Y” and “Z” are each independently selected from the group consisting of —H, (C 1 -C 5 )alkyl, alkali metal cations, alkaline earth metal cations, ammonium cation, methyl ammonium cation, and pharmaceutically acceptable bases; and
subscripts “x” and “n” are independently selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6.
16 . The system of claim 15 , wherein the cannabinoid synthase is a natural enzyme or a recombinant enzyme.
17 . The system of claim 15 , wherein the cannabinoid synthase is selected from the group consisting of tetrahydrocannabinol acid synthase (THCA synthase), tetrahydrocannabivarin acid synthase (THCVA synthase), cannabidiolic acid synthase (CBDA synthase), and cannabichromene acid synthase (CBCA synthase).
18 . The system of claim 15 , wherein the condition of the bioreactor is selected from the group consisting of temperature, solvent, pressure, and pH.
19 . The system of claim 18 , wherein the condition of the bioreactor is pH, and the control mechanism is configured to control the pH in the range from about 4.0 to about 8.0.