Substituted imidazo [1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine derivatives
The present invention is concerned with a method of treating a disease selected from the group consisting of cognitive disorders, anxiety, Alzheimer's disease, and schizophrenia comprising administering a therapeutically effective amount of a substituted imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine derivatives of the following formula wherein R 1 is halogen, lower alkyl, lower alkynyl, cycloalkyl, lower alkoxy, OCF 3 , —NHR, —NHC(O)R or —NHSO 2 R; R 2 is hydrogen, methyl or aryl which is unsubstituted or substituted by one or two substituents selected from the group consisting of halogen and lower alkoxy; R 3 is hydrogen, lower alkyl, lower alkenyl, cycloalkyl, lower alkoxy, —O(CH 2 ) n+1 —O-lower alkyl, —(CH 2 ) n -aryl which is optionally substituted by lower alkyl or halogen, heteroaryl, —NHR, —N(R) 2 , wherein each R can be the same or different, —NHCH 2 C≡CH, or pyrrolidin-1-one; R is hydrogen, lower alkyl, lower alkyl substituted by halogen, heteroaryl, —(CH 2 ) n O-lower alkyl, —NH-lower alkyl, cycloalkyl or aryl, and n is 0, 1, 2 or 3; and with their pharmaceutically acceptable acid addition salts. The invention also provides novel compounds of formula I-A and pharmaceutical compositions containing them. The most preferred indication is Alzheimer's disease.
1. A method of treating a disease selected from the group consisting of cognitive disorders, anxiety, Alzheimer's disease, and schizophrenia comprising administering a therapeutically effective amount of a substituted imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine of the formula I
wherein
R 1 is halogen, lower alkyl, lower alkynyl, cycloalkyl, lower alkoxy, OCF 3 , —NHR, —NHC(O)R or —NHSO 2 R;
R 2 is hydrogen, methyl or aryl which is unsubstituted or substituted by one or two substituents selected from the group consisting of halogen and lower alkoxy;
R 3 is lower alkenyl, cycloalkyl, —O(CH 2 ) n+1 —O-lower alkyl, —(CH 2 ) n -aryl which is optionally substituted by lower alkyl or halogen, heteroaryl, —NHR, —N(R) 2 , wherein each R can be the same or different, —NHCH 2 C≡CH, or pyrrolidin-1-one;
R is lower alkyl, lower alkyl substituted by halogen, heteroaryl, —(CH 2 ) n O-lower alkyl, —NH-lower alkyl, cycloalkyl or aryl, and
n is 0, 1, 2 or 3;
or a pharmaceutically acceptable acid addition salt thereof.
2. The method of claim 1 , wherein the disease is Alzheimer's disease.
3. The method of claim 1 , wherein R 3 is cycloalkyl, —(CH 2 ) 2 -phenyl, or —(CH 2 ) 3 -phenyl.
4. The method of claim 3 , wherein the compound is selected from the group consisting of
cyclopropyl-[3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-10-yl]-methanone,
cyclopropyl-[3-chloro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-10-yl]-methanone,
cyclopropyl-[3-bromo-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-10-yl]-methanone,
1-[3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-10-yl]-4-phenyl-butan-1-one, and
1-[3-bromo-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-10-yl]-3-phenyl-propan-1-one.
5. The method of claim 1 , wherein R 3 is NHCH 2 C≡CH.
6. The method of claim 5 , wherein the compound is 3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine-10-carboxylic acid prop-2-ynylamide.
7. A compound of formula I-A
wherein
R 1 is halogen, lower alkyl, lower alkynyl, cycloalkyl, lower alkoxy, OCF 3 , —NHR, —NHC(O)R or —NHSO 2 R;
R 2 is hydrogen, methyl or aryl which is unsubstituted or substituted by one or two substituents selected from the group consisting of halogen and lower alkoxy;
R 3 is lower alkenyl, cycloalkyl, —O(CH 2 ) n+1 —O-lower alkyl, —(CH 2 ) n -aryl which is optionally substituted by lower alkyl or halogen, heteroaryl, —NHR, —N(R) 2 , wherein each R can be the same or different, —NHCH 2 C≡CH, or pyrrolidin-1-one;
R is lower alkyl, lower alkyl substituted by halogen, heteroaryl, —(CH 2 ) n O-lower alkyl, —NH-lower alkyl, cycloalkyl or aryl; and
n is 0, 1, 2 or 3;
or a pharmaceutically acceptable acid addition salt thereof.
8. A compound of claim 7 , selected from the group consisting of
2-methoxy-ethyl 3-bromo-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine-10-carboxylate,
1-[3-bromo-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-10-yl]-but-2(E)-en-1-one,
[3-bromo-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-10-yl]-o-tolyl-methanone,
1-[3-bromo-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-10-yl]-2-phenyl-ethanone,
[3-bromo-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-10-yl]-phenyl-methanone,
[3-bromo-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-10-yl]-thiophen-2-yl-methanone,
1-[3-bromo-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-10-yl]-2-(3-chloro-phenyl)-ethanone and
3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine-10-carboxylic acid cyclopropyl-amide.
9. The compound of claim 7 , wherein R 3 is cycloalkyl.
10. The compound of claim 9 , selected from the group consisting of
cyclopropyl-[3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-10-yl]-methanone,
cyclopropyl-[3-chloro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-10-yl]-methanone and
cyclopropyl-[3-bromo-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-10-yl]-methanone.
11. The compound of claim 7 , wherein R 3 is (CH 2 ) n -phenyl or NHCH 2 C≡CH.
12. The compound of claim 11 , selected from the group consisting of
1-[3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-10-yl]-4-phenyl-butan-1-one,
1-[3-bromo-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-10-yl]-3-phenyl-propan-1-one; and
3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine-10-carboxylic acid prop-2-ynylamide.
13. A compound of claim 7 , wherein R 1 is halogen.
14. A compound of claim 13 , wherein R 3 is cycloalkyl.
15. A compound of claim 7 , wherein R 3 —NHCH 2 C≡CH.
16. A compound of claim 7 , wherein R 1 is cycloalkyl.
17. A compound of claim 7 , wherein R 2 is hydrogen.
18. A composition comprising a therapeutically effective amount of compound of formula I-A
wherein
R 1 is halogen, lower alkyl, lower alkynyl, cycloalkyl, lower alkoxy, OCF 3 , —NHR, —NHC(O)R or —NHSO 2 R;
R 2 is hydrogen, methyl or aryl which is unsubstituted or substituted by one or two substituents selected from the group consisting of halogen and lower alkoxy;
R 3 is lower alkenyl, cycloalkyl, —O(CH 2 ) n+1 —O-lower alkyl, —(CH 2 ) n -aryl which is optionally substituted by lower alkyl or halogen, heteroaryl, —NHR, —N(R) 2 , wherein each R can be the same or different, —NHCH 2 C≡CH, or pyrrolidin-1-one;
R is lower alkyl, lower alkyl substituted by halogen, heteroaryl, —(CH 2 ) n O-lower alkyl, —NH-lower alkyl, cycloalkyl or aryl; and
n is 0, 1, 2 or 3;
or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.