Substituted imidazol[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 formula I wherein R 1 is hydrogen, halogen, lower alkyl, lower alkynyl, cycloalkyl, heterocycloalkyl, benzyl, cyano, lower alkoxy, OCF 3 , —NHR, —NHC(O)R or —NHSO 2 R; R 2 is lower alkyl substituted by halogen; R 3 is hydrogen, methyl or aryl; R is lower alkyl, cycloalkyl or aryl; and pharmaceutically acceptable acid addition salts thereof.
1. A compound of formula I
wherein
R 1 is hydrogen, halogen, lower alkyl lower alkynyl, cycloalkyl, heterocycloalkyl, benzyl, cyano, lower alkoxy, OCF 3 , —NHR, —NHC(O)R or —NHSO 2 R;
R 2 is lower alkyl substituted by halogen;
R 3 is hydrogen, methyl or aryl;
R is lower alkyl, cycloalkyl or aryl;
or a pharmaceutically acceptable acid addition salt thereof.
2. A compound of claim 1 having formula I-A
wherein
R 1 is hydrogen, halogen, lower alkyl, lower alkynyl, cycloalkyl, benzyl, cyano, lower alkoxy, OCF 3 , —NHR, —NHC(O)R or —NHSO 2 R;
R 2 is lower alkyl substituted by halogen;
R is lower alkyl, cycloalkyl or aryl;
and their pharmaceutically acceptable acid addition salts.
3. A compound of claim 1 in which R 2 is CH 2 F.
4. A compound of claim 3 , selected from the group consisting of
3-chloro-10-fluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-fluoro-10-fluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-bromo-10-fluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-cyclopropyl-10-fluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine and
3-chloro-10-fluoromethyl-6-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.
5. A compound of claim 1 in which R 2 is CHF 2 .
6. A compound of claim 5 , selected from the group consisting of
3-chloro-10-difluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-fluoro-10-difluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-bromo-10-difluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-cyclopropyl-10-difluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
10-difluoromethyl-3-ethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-benzyl-10-difluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
10-difluoromethyl-3-ethynyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
3-cyano-10-difluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine and
10-difluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.
7. A compound of claim 1 in which R 2 is CF 3 .
8. A compound of claim 7 , which is
3-fluoro-10-trifluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.
9. A compound of claim 1 in which R 2 is CF 2 CH 3 or CF 2 CH 2 CH 3 .
10. A compound of claim 9 , selected from the group consisting of
10-(1,1-difluoro-ethyl)-3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,
10-(1,1-difluoro-propyl)-3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine, and
3-bromo-10-(1,1-difluoro-propyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d ][1,4]benzodiazepine.
11. A compound of claim 1 , which is
3-chloro-6-(3,4-dimethoxyphenyl)-10-fluoromethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I
wherein
R 1 is hydrogen, halogen, lower alkyl, lower alkynyl, cycloalkyl, heterocycloalkyl, benzyl, cyano, lower alkoxy, OCF 3 , —NHR, —NHC(O)R or —NHSO 2 R;
R 2 is lower alkyl substituted by halogen;
R 3 is hydrogen, methyl or aryl;
R is lower alkyl, cycloalkyl or aryl;
or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.
13. A process for preparation of a compound of formula I
wherein
R 1 is hydrogen, halogen, lower alkyl, lower alkynyl, cycloalkyl, heterocycloalkyl, benzyl, cyano, lower alkoxy, OCF 3 , —NHR, —NHC(O)R or —NHSO 2 R;
R 2 is lower alkyl substituted by halogen;
R 3 is hydrogen, methyl or aryl;
R is lower alkyl, cycloalkyl or aryl;
or a pharmaceutically acceptable acid addition salt thereof wherein the process is selected from the group consisting of
a) reacting a compound of formula
with a suitable halogen-transfer-reagent to produce a compound of formula
wherein R 2 is lower alkyl substituted by halogen;
b) reacting a compound of formula
with a suitable halogen-transfer-reagent to produce a compound of formula
c) reacting a compound of formula
with sulfur tetrafluoride in the presence of a hydrogen halogenide to produce a compound of formula
14. A method for enhancing cognition or treating a disorder selected from the group consisting of cognitive disorders, schizophrenia, anxiety and Alzheimer's disease comprising administering to an individual a therapeutically effective amount of a compound of formula I
wherein
R 1 is hydrogen, halogen, lower alkyl, lower alkynyl, cycloalkyl, heterocycloalkyl, benzyl, cyano, lower alkoxy, OCF 3 , —NHR, —NHC(O)R or —NHSO 2 R;
R 2 is lower alkyl substituted by halogen;
R 3 is hydrogen, methyl or aryl;
R is lower alkyl, cycloalkyl or aryl;
or a pharmaceutically acceptable acid addition salt thereof.
15. The method of claim 14 , wherein the disorder is Alzheimer's disease.