Aryl-isoxazol-4-yl-imidazo[1,5-a]pyridine derivatives

• US 20070191421A1
• Filed: 12/18/2006
• Published: 08/16/2007
• Est. Priority Date: 12/27/2005
• Status: Active Grant

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Buettelmann, Bernd, Thomas, Andrew, Knust, Henner, Han, Bo, Dong, Jiaqiang
• Granted Patent: US 7,399,769 B2
• Time in Patent Office: Days
• US Class Current: 514/303
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention is concerned with aryl-isoxazol-4-yl-imidazo[1,5-a]pyridine derivatives of formula wherein:
R¹, R², and R³ are as defined herein and pharmaceutically acceptable acid addition salts thereof. These compounds have high affinity and selectivity for GABA A α5 receptor binding sites. The invention also relates to methods for enhancing cognition and treating cognitive disorders like Alzheimer'"'"'s disease.

Claims

1. An aryl-isoxazol-4-yl-imidazo[1,5-a]pyridine derivative of formula I:

2. The compound of claim 1, wherein R¹ is hydrogen.

3. The compound of claim 2, wherein R² is hydrogen.

4. The compound of claim 1, wherein R² is hydrogen.

5. The compound of claim 1, wherein R³ is hydrogen.

6. The compound of claim 5, which is 3-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,5-a]pyridine.

7. The compound of claim 1, wherein R³ is cyano.

8. The compound of claim 7, which is 3-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,5-a]pyridine-6-carbonitrile.

9. The compound of claim 1, wherein R³ is —

(CO)—

R^a, in which R^a is hydroxy, lower alkoxy, NR′

R″

, wherein R′ and

R″

are each independently hydrogen, cycloalkyl, 5 or 6-membered heterocycloalkyl or is lower alkyl which is optionally substituted by cycloalkyl, cyano, 5 or 6-membered heterocycloalkyl or by 5 or 6-membered heteroaryl;

10. The compound of claim 9, which is 3-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I

12. The composition of claim 11, wherein the compound is 3-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,5-a]pyridine.

13. The composition of claim 11, wherein the compound is 3-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,5-a]pyridine-6-carbonitrile.

14. The composition of claim 11, wherein the compound is 3-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester.