Cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation
The present invention relates to novel cannabinoid receptor modulators, in particular cannabinoid 1 (CB1) or cannabinoid 2 (CB2) receptor modulators, and uses thereof for treating diseases, conditions and/or disorders modulated by a cannabinoid receptor.
1. A method of treating pain associated with diabetic neuropathy in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (IA):
or an analog thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable ester thereof, tautomer thereof, stereoisomer thereof, enantiomer thereof, or diastereomer thereof,
wherein
each occurrence of R is independently substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R 1 is hydrogen;
R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heteroarylalkyl, or NR 3 R 4 ;
or R 1 and R 2 may be joined together to form an optionally substituted piperidinyl
R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted cycloalkyl and R 4 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyl;
or R 3 and R 4 may be joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR 3 or S;
p is 1; and
A is
wherein
each of the dotted lines in A independently represents an optional bond, and
each occurrence of R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is the same or different and selected from hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
with the proviso that the compound does not have the formula:
wherein R 1 and R 2 are as defined above.
2. The method according to claim 1 , wherein the compound of Formula (1A) is
3. The method according to claim 1 , wherein the compound of formula (IA) is (4S,7R) N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
4. The method according to claim 1 , which comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the compound (4S,7R) N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
5. The method according to claim 1 , wherein the subject is human.
6. The method according to claim 3 , wherein the subject is human.
7. The method according to claim 4 , wherein the subject is human.
8. A method of treating Alzheimer's disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (IA):
or an analog thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable ester thereof, tautomer thereof, stereoisomer thereof, enantiomer thereof, or diastereomer thereof,
wherein
each occurrence of R is independently substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R 1 is hydrogen;
R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heteroarylalkyl, or NR 3 R 4 ;
or R 1 and R 2 may be joined together to form an optionally substituted piperidinyl
R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted cycloalkyl and R 4 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyl;
or R 3 and R 4 may be joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR 3 or S;
p is 1; and
A is
wherein
each of the dotted lines in A independently represents an optional bond, and
each occurrence of R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is the same or different and selected from hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
with the proviso that the compound does not have the formula:
wherein R 1 and R 2 are as defined above.
9. The method according to claim 8 , wherein the compound of Formula (1A) is
10. The method according to claim 8 , wherein the compound of formula (IA) is (4S,7R) N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-H-4,7-methano-indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
11. The method according to claim 8 , which comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the compound (4S,7R) N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
12. The method according to claim 8 , wherein the subject is human.
13. The method according to claim 10 , wherein the subject is human.
14. The method according to claim 11 , wherein the subject is human.
15. A method of treating psoriasis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (IA):
or an analog thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable ester thereof, tautomer thereof, stereoisomer thereof, enantiomer thereof, or diastereomer thereof,
wherein
each occurrence of R is independently substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R 1 is hydrogen;
R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heteroarylalkyl, or NR 3 R 4 ;
or R 1 and R 2 may be joined together to form an optionally substituted piperidinyl
R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted cycloalkyl and R 4 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyl;
or R 3 and R 4 may be joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR 3 or S;
p is 1; and
A is
wherein
each of the dotted lines in A independently represents an optional bond, and
each occurrence of R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is the same or different and selected from hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
with the proviso that the compound does not have the formula:
wherein R 1 and R 2 are as defined above.
16. The method according to claim 15 , wherein the compound of Formula (1A) is
17. The method according to claim 15 , wherein the compound of formula (IA) is (4S,7R) N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
18. The method according to claim 15 , which comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of the compound (4S,7R) N(3)-(tert-Butyl)-1-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-4,7-methano-indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.
19. The method according to claim 15 , wherein the subject is human
20. The method according to claim 17 , wherein the subject is human.
21. The method according to claim 18 , wherein the subject is human.