BIO-STABLE CANNABINOID COMPOUNDS AND METHODS FOR ENHANCING THEIR PHYSIOLOGICAL CONCENTRATION
The present disclosure provides biostable cannabinoid compounds according to Formula and methods for synthesizing and enhancing the biological concentrations of the compounds, where R 1 , R 2 , and R 3 are defined as set forth in the disclosure.
1 . A pharmaceutical composition comprising a compound according to Formula I or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein
R 1 is —H, —COOR 4 , or —(CH 2 ) n COOH;
R 2 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl;
R 3 is (C 1 -C 10 )halo alkyl, (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyl-(C 1 -C 10 )alkylene, —CH 2 —CH 2 —[O—CH 2 —CH 2 —] m O—CH 2 —CH 2 —R b , —(CHR a ) q —NH 2 , and —(CHR a ) q —NH + 3 X − ;
R a is selected from the group consisting of —H, —OH, halogen, (C 1 -C 5 ) alkyl, and alkoxy;
R b is selected from the group consisting of —OH, —O(C 1 -C 5 ) alkyl, —(C 2 -C 6 ) alkene, azide, and —(C 2 -C 6 ) alkyne;
R 4 is —H or (C 1 -C 10 )
X is a counter ion derived from a pharmaceutically acceptable acid; and
n, m and q are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 and a pharmaceutically acceptable carrier.
2 . The pharmaceutical composition according to claim 1 , wherein R 1 is —H and R 2 is propyl or pentyl.
3 . The pharmaceutical composition according to claim 1 , wherein R 3 is (C 1 -C 10 )haloalkyl, —CH 2 —CH 2 —[O—CH 2 —CH 2 —] m O—CH 2 —CH 2 —OH, —(CH 2 ) q —NH 2 , or —(CH 2 ) q —NH + 3 X − .
4 . The pharmaceutical composition according to claim 3 , wherein R 3 is (C 1 -C 10 )haloalkyl.
5 . The pharmaceutical composition according to claim 4 , wherein R 3 is fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, fluoro-t-butyl, 1,1-difluoro-t-butyl, 1,2-difluoro-t-butyl, 1,2,3-trifluoro-t-butyl, and 1,1,2-trifluoro-t-butyl.
6 . The pharmaceutical composition according to claim 3 , wherein R 3 is —(CH 2 ) 2 —[O—CH 2 —CH 2 —] m O—(CH 2 ) 2 —OH and m is 2 or 3.
7 . The pharmaceutical composition according to claim 3 , wherein R 3 is —(CHR a ) q —NH + 3 X − and R a is —H.
8 . The pharmaceutical composition according to claim 7 , wherein R 3 is —(CH 2 ) 4 —NH + 3 X − , —(CH 2 ) 5 —NH + 3 X − , —(CH 2 ) 6 —NH + 3 X − , or —(CH 2 ) 7 —NH + 3 X − .
9 . The pharmaceutical composition according to claim 1 , wherein the compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is one selected from the following table:
10 . A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the following table:
11 . The compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, according to claim 10 , selected from the following table:
12 . A method for producing a compound according to Formula IIa or a pharmaceutically acceptable salt, solvate, or stereoisorner thereof,
comprising:
(i) contacting a compound of Formula III
with a recombinant cannabinoid synthase in the presence of a solvent to produce a compound according to Formula II
and then
(ii) contacting the Formula II compound with a suitable Y—R 8 group to produce a compound according to Formula IIa;
wherein
R 5 is —COOR 9 , or
(CH 2 ) n COOH;
R 6 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl;
R 7 is —H;
R 8 is is optionally substituted (C 1 -C 10 ) alkyl, (C 1 -C 10 )haloalkyl, optionally substituted (C 3 -C 10 )aryl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted (C 3 -C 10 )aryl-(C 1 -C 10 )alkylene, optionally substituted (C 3 -C 10 )cycloalkyl-(C 1 -C 10 )alkylene, optionally substituted —CH 2 —CH 2 —[O—CH 2 —CH 2 —] m O—CH 2 —CH 2 —R b , optionally substituted. —(CHR a ) q —NH 2 , and optionally substituted —(CHR a ) q —NH + 3 X − ;
R a is selected from the group consisting of —H,
OH, halogen, (C 1 -C 5 ) alkyl, and alkoxy;
R b is selected from the group consisting of
OH, -O(C 1 -C 5 ) alkyl,
(C 2 -C 6 ) alkene, azide, and —(C 2 -C 6 ) alkyne;
R 9 is —H or (C 1 -C 10 ) alkyl;
X is a counter ion derived from a pharmaceutically acceptable acid;
Y is a leaving group; and
n, m and q are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
13 . The method of claim 9 , wherein the recombinant cannabinoid synthase is a recombinant cannabidiolic acid synthase (CBDA synthase).