Substituted benzo[f]imidazo[1,5-a][1,4]diazepines as GABA(a) receptor modulators

Patent metadata

Field	Value
Publication number	US-11447495-B2
Application number	US-201716325080-A
Country	US
Kind code	B2
Filing date	Aug 16, 2017
Priority date	Aug 16, 2016
Publication date	Sep 20, 2022
Grant date	Sep 20, 2022

Abstract

Substituted benzo[f]imidazo[1,5-α][1,4]diazepines of formula (I′) target alpha-4 and alpha-5 GABAA receptors for use in the treatment of airway hyperresponsiveness and inflammation in asthma. Compounds selectively partition to the peripheral compartment and have reduced CNS effects.

First claim

We claim:

1. A compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R 1 is COOH;
R 2 is C 1-4 alkyl, CF 3 , or CCl 3 ;
R 2 ′ is H, C 1-4 alkyl, or CCl 3 ;
R 3 is Cl, Br, or cyclopropyl; and
X is CF, CCl, CBr, CI, or N.

2. The stereoisomer of the compound of claim 1 , wherein the stereoisomer of the compound is of formula (I-A):

or a pharmaceutically acceptable salt thereof.

3. The stereoisomer of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is CH 3 , CF 3 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 2 is C 1-4 alkyl; and
R 2 ′ is H or C 1-4 alkyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 2 is CH 3 or CH 2 CH 3 ; and
R 2′ is H, CH 3 , or CH 2 CH 3 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 2 is CH 3 ; and
R 2′ is H.

7. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is Cl or Br.

8. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is cyclopropyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is CF, CCl, CBr, or CI.

10. The compound of claim 9 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is CCl or CBr.

11. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 2 is C 1-4 alkyl;
R 2′ is H;
R 3 is Cl or Br; and
X is CF, CCl, or CBr.

12. The compound of claim 11 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
R 2 is CH 3 or CH 2 CH 3 .

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.

14. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 14 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 14 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 14 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 14 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Assignees

• Uwm Res Foundation Inc
• Univ Columbia

Inventors

• Arnold Alexander E
• Stafford Douglas C
• Cook James M
• Emala Charles W
• Forkuo Gloria
• Jahan Rajwana
• Kodali Revathi
• Li Guanguan
• Stephen Michael Rajesh

Classifications

• A61P11/06

  Antiasthmatics · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D487/14 Primary

  Ortho-condensed systems · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P11/08

  Bronchodilators · CPC title