Selective NR2B antagonists

• US 10,501,451 B2
• Filed: 10/13/2016
• Issued: 12/10/2019
• Est. Priority Date: 10/14/2015
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Islam, Imadul, Thangathirupathy, Srinivasan, Warrier, Jayakumar Sankara, Cheruku, Srinivas, Shetty, Poornima, Macor, John E.
• Primary Examiner(s): McDowell, Brian E
• Application Number:
  US15/767,385
• Publication Number:
  US 20180312495A1
• Time in Patent Office: 1,153 Days
• CPC Class Codes: A61K 31/4523 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: C07B 2200/09 Geometrical isomers
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

The present disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof. The Formula (I) compounds are ligands for NR2B N-Methyl-D-aspartate (NMD A) receptor and thereby making them useful for the treatment of various disorders of the central nervous system.

Claims

1. A compound of the formula I

2. A compound of claim 1 where Ar¹ is phenyl and is substituted with 0-1 substituent selected from halo and alkyl;

Ar² is phenyl, pyridinyl or pyrimidinyl, and is substituted with 1 OR substituent and with 0-2 halo or alkyl substituents;

R is hydrogen;

X is a bond or C₁-C₃ alkylene;

n is 1 or 2;

ring A is piperidine or piperazine and is substituted with 0-1 halo substituents;

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 2 where Ar¹ is phenyl and is substituted with 0-1 substituent selected from halo and alkyl;

Ar² is phenyl or pyridinyl, and is substituted with 1 OR substituent and with 0-1 halo substituents;

R is hydrogen;

X is a methylene;

n is 1 or 2;

ring A is piperidine or piperazine and is substituted with 0-1 halo substituents;

or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 where n is 1 and ring A is piperazine or piperidine substituted with 0-1 fluoro.

5. A compound of claim 1 where Ar¹ is phenyl substituted with 0-1 substituents selected from chloro, fluoro and methyl.

6. A compound of claim 1 where Ar² is selected from

7. A compound of claim 1 where X is methylene.

8. A compound of claim 1 selected from the group consisting of

9. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

10. A method for the treatment of depression, Alzheimer'"'"'s disease, neuropathic pain, or Parkinson'"'"'s disease, which comprises administering to a patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 directed to the treatment of depression.

12. The method of claim 10 directed to the treatment of Alzheimer'"'"'s disease.

13. The method of claim 10 directed to the treatment of neuropathic pain.

14. A compound:

15. A pharmaceutical composition comprising a compound of claim 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

16. A method for the treatment of depression, Alzheimer'"'"'s disease, neuropathic pain, or Parkinson'"'"'s disease, which comprises administering to a patient a therapeutically effective amount of a compound of claim 14.

17. A compound:

18. A pharmaceutical composition comprising a compound of claim 17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

19. A method for the treatment of depression, Alzheimer'"'"'s disease, neuropathic pain, or Parkinson'"'"'s disease, which comprises administering to a patient a therapeutically effective amount of a compound of claim 17.