Substitued imidazo [1,5-A][1,2,4]triazolo[1,5-D][1,4]benzodiazepine derivatives
The present invention is concerned with substituted imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine derivatives of the formula I wherein R 1 is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, nitro, cycloalkyl, —O(CH 2 ) m O(CH 2 ) m OH or —C≡C—R′; R 2 is hydrogen or methyl; R 3 is lower alkyl, lower alkyl substituted by halogen, lower alkenyl, lower alkenyl substituted by halogen, lower alkynyl, —(CH 2 ) n -cycloalkyl, —(CR′R″) m —CH 3 , phenyl that is unsubstituted or substituted by halogen, pyridinyl or thienyl each of which is unsubstituted or substituted by lower alkyl, —(CH 2 ) n —NH-cycloalkyl, lower alkenyl-cycloalkyl, lower alkynyl-(CR′R″) m OH, or lower alkynyl-phenyl wherein the phenyl ring is unsubstituited or substituted by halogen, CF 3 , lower alkyl or lower alkoxy; R′ is hydrogen or lower alkyl; R″ is hydrogen, hydroxy or lower alkyl; n is 0, 1 or 2; m is 1, 2 or 3; and o is 1 or 2; and pharmaceutically acceptable acid addition salts thereof. This class of compounds have high affinity and selectivity for GABA A α5 receptor binding sites. Thus, the invention also relates to methods of enhancing cognition and treating cognitive disorders like Alzheimer's disease.
1. A compound of formula I
wherein
R 1 is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, nitro, cycloalkyl, —O(CH 2 ) m O(CH 2 ) m OH or —C≡C—R′;
R 2 is hydrogen or methyl;
R 3 is lower alkyl, lower alkyl substituted by halogen, lower alkenyl, lower alkenyl substituted by halogen, lower alkynyl, —(CH 2 ) n -cycloalkyl, —(CR′R″) m —CH 3 , phenyl that is unsubstituted or substituted by halogen, pyridinyl or thienyl each of which is unsubstituted or substituted by lower alkyl, —(CH 2 ) n —NH-cycloalkyl, lower alkenyl-cycloalkyl, lower alkynyl-(CR′R″) m OH, or lower alkynyl-phenyl wherein the phenyl ring is unsubstituited or substituted by halogen, CF 3 , lower alkyl or lower alkoxy;
R′ is hydrogen or lower alkyl;
R″ is hydrogen, hydroxy or lower alkyl;
n is 0, 1 or 2;
m is 1, 2 or 3; and
o is 1 or 2;
or a pharmaceutically acceptable acid addition salt thereof.
2. A compound of formula I in accordance with claim 1 , wherein R 3 is lower alkyl.
3. A compound of formula I in accordance with claim 2 , selected from the group consisting of
10-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-fluoro-10-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-chloro-10-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
10-ethyl-3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-chloro-10-ethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
10-ethyl-3-methoxy-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-chloro-10-propyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-bromo-10-propyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-iodo-10-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
4-chloro-3-fluoro-10-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
4-fluoro-10-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine and
4-chloro-10-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.
4. A compound of formula I in accordance with claim 1 , wherein R 3 is —(CH 2 ) n -cycloalkyl.
5. A compound of formula I in accordance with claim 4 , which is 3-chloro-10-cyclopropylmethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.
6. A compound of formula I in accordance with claim 1 , wherein R 3 is lower alkenyl.
7. A compound of formula I in accordance with claim 6 , selected from the group consisting of
10-vinyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-fluoro-10-vinyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-chloro-10-vinyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-chloro-10-(E)-propenyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine and
3-chloro-10-(Z)-propenyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.
8. A compound of formula I in accordance with claim 1 , wherein R 3 is lower alkenyl-cycloalkyl.
9. A compound of formula I in accordance with claim 8 , selected from the group consisting of
3-chloro-10-((E)-2-cyclopropyl-vinyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine and
3-chloro-10-((Z)-2-cyclopropyl-vinyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.
10. A compound of formula I in accordance with claim 1 , wherein R 3 is lower alkynyl.
11. A compound of formula I in accordance with claim 10 , selected from the group consisting of
10-ethynyl-3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-chloro-10-ethynyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine and
3-bromo-10-ethynyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.
12. A compound of formula I in accordance with claim 1 , wherein R 3 is optionally substituted lower alkynyl-phenyl.
13. A compound of formula I in accordance with claim 12 , selected from the group consisting of
3-fluoro-10-phenylethynyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-chloro-10-phenylethynyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-fluoro-10-(3-fluoro-phenylethynyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-fluoro-10-(3-chloro-phenylethynyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-fluoro-10-(3-trifluoromethyl-phenylethynyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-fluoro-10-(3-methoxy-phenylethynyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-fluoro-10-(3-methyl-phenylethynyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine and
3-fluoro-10-(3-isopropyl-phenylethynyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.
14. A compound of formula I in accordance with claim 1 , wherein R 3 is lower alkynyl-(CR′R″) m OH.
15. A compound of formula I in accordance with claim 14 , which is
3-chloro-10-(3-hydroxy-3-methyl-but-1-ynyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.
16. A compound of formula I in accordance with claim 1 , wherein R 3 is lower alkenyl substituted by halogen or is lower alkyl substituted by halogen.
17. A compound of formula I in accordance with claim 16 , selected from the group consisting of
10-(2,2-difluoro-vinyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine and
10-(2,2-difluoro-ethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.
18. A compound of formula I in accordance with claim 1 , wherein R 2 is hydrogen.
19. A compound of formula I in accordance with claim 1 , wherein R 2 is methyl.
20. A compound of formula I in accordance with claim 1 , wherein R 1 is lower alkyl, lower alkyl substituted by halogen, or cycloalkyl.
21. A compound of formula I in accordance with claim 1 , wherein R 1 is lower alkoxy, lower alkoxy substituted by halogen, or —O(CH 2 ) m O(CH 2 ) m OH.
22. A compound of formula I in accordance with claim 1 , wherein R 1 is hydrogen, halogen, nitro, or —C≡C—R′.
23. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I
wherein
R 1 is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, nitro, cycloalkyl, —O(CH 2 ) m O(CH 2 ) m OH or —C≡C—R′;
R 2 is hydrogen or methyl;
R 3 is lower alkyl, lower alkyl substituted by halogen, lower alkenyl, lower alkenyl substituted by halogen, lower alkynyl, —(CH 2 ) n -cycloalkyl, —(CR′R″) m —CH 3 , phenyl that is unsubstituted or substituted by halogen, pyridinyl or thienyl each of which is unsubstituted or substituted by lower alkyl, —(CH 2 ) n —NH-cycloalkyl, lower alkenyl-cycloalkyl, lower alkynyl-(CR′R″) m OH, or lower alkynyl-phenyl wherein the phenyl ring is unsubstituited or substituted by halogen, CF 3 , lower alkyl or lower alkoxy;
R′ is hydrogen or lower alkyl;
R″ is hydrogen, hydroxy or lower alkyl;
n is 0, 1 or 2;
m is 1, 2 or 3; and
o is 1 or 2;
or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.
24. A method of treating Alzhemier's disease or enhancing cognition comprising administering to an individual a therapeutically effective amount of a compound of formula I
wherein
R 1 is hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, nitro, cycloalkyl, —O(CH 2 ) m O(CH 2 ) m OH or —C≡C—R′;
R 2 is hydrogen or methyl;
R 3 is lower alkyl, lower alkyl substituted by halogen, lower alkenyl, lower alkenyl substituted by halogen, lower alkynyl, —(CH 2 ) n -cycloalkyl, —(CR′R″) m —CH 3 , phenyl that is unsubstituted or substituted by halogen, pyridinyl or thienyl each of which is unsubstituted or substituted by lower alkyl, —(CH 2 ) n —NH-cycloalkyl, lower alkenyl-cycloalkyl, lower alkynyl-(CR′R″) m OH, or lower alkynyl-phenyl wherein the phenyl ring is unsubstituited or substituted by halogen, CF 3 , lower alkyl or lower alkoxy;
R′ is hydrogen or lower alkyl;
R″ is hydrogen, hydroxy or lower alkyl;
n is 0, 1 or 2;
m is 1, 2 or 3; and
0 is 1 or 2;
or a pharmaceutically acceptable acid addition salt thereof.