3,3-difluoropiperidine carbamate heterocyclic compounds as NR2B NMDA receptor antagonists

• US 10,584,127 B2
• Filed: 05/31/2016
• Issued: 03/10/2020
• Est. Priority Date: 06/01/2015
• Status: Active Grant

• Current Assignee: Rugen Holdings (Cayman) Limited
• Original Assignee: Rugen Holdings (Cayman) Limited
• Inventors: Shapiro, Gideon
• Primary Examiner(s): Morris, Patricia L
• Application Number:
  US15/578,460
• Publication Number:
  US 20180170935A1
• Time in Patent Office: 1,379 Days
• Field of Search: 514275
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/24 Antidepressants
• 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: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Disclosed are chemical entities of Formula (I), wherein R¹ and Z are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of Formula (I), and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of Formula (I).

Claims

1. A method of treating a disease or disorder responsive to NR2B antagonism, wherein the disease or disorder is depression, in a subject in need of such treatment, comprising administering an effective amount of a chemical entity which is a compound of formula:

2. The method of claim 1, wherein the chemical entity is selected from the group consisting of:

3. The method of claim 1, wherein R⁵ is —

H, R⁶ is —

H, and R⁷ is —

H.

4. The method of claim 1, wherein R⁵ is —

CH₃, R⁶ is —

H, and R⁷ is —

H.

5. The method of claim 1, wherein R⁵ is —

Cl, R⁶ is —

H, and R⁷ is —

H.

6. The method of claim 1, wherein R⁵ is —

F, R⁶ is —

H, and R⁷ is —

H.

7. The method of claim 1, wherein R⁵ is —

CH₂CH₃, R⁶ is —

H, and R⁷ is —

H.

8. The method of claim 1, wherein R⁵ is —

CF₂H, R⁶ is —

H, and R⁷ is —

H.

9. The method of claim 1, wherein R⁵ is —

CH₂F, R⁶ is —

H, and R⁷ is —

H.

10. The method of claim 1, wherein R⁵ is —

CF₃, R⁶ is —

H, and R⁷ is —

H.

11. The method of claim 1, wherein R⁵ is —

CF₂CH₃, R⁶ is —

H, and R⁷ is —

H.

12. The method of claim 1, wherein R⁵ is —

CH₂CF₃, R⁶ is —

H, and R⁷ is —

H.

13. The method of claim 1, wherein R⁵ is cyclopropyl, R⁶ is —

H, and R⁷ is —

H.

14. The method of claim 1, wherein R⁵ is —

OCF₃, R⁶ is —

H, and R⁷ is —

H.

15. The method of claim 1, wherein R⁵ is —

OCF₂H, R⁶ is —

H, and R⁷ is —

H.

16. The method of claim 1, wherein R⁵ is —

Cl, R⁶ is —

H, and R⁷ is —

F.

17. The method of claim 1, wherein R⁵ is —

CH₃, R⁶ is —

H, and R⁷ is —

F.

18. The method of claim 1, wherein R⁵ is —

CH₃, R⁶ is —

F, and R⁷ is —

H.

19. The method of claim 1, wherein R⁵ is —

Cl, R⁶ is —

F, and R⁷ is —

H.

20. The method of claim 1, wherein R⁵ is —

F, R⁶ is —

F, and R⁷ is —

H.

21. The method of claim 1, wherein R⁵ is —

F, R⁶ is —

H, and R⁷ is —

F.

22. The method of claim 1, wherein R⁵ is —

F, R⁶ is —

H, and R⁷ is —

Cl.

23. The method of claim 1, wherein R⁵ is —

F, R⁶ is —

H, and R⁷ is —

CH₃.

24. The method of claim 1, wherein R⁵ is —

Cl, R⁶ is —

H, and R⁷ is —

CH₃.

25. The method of claim 1, wherein R⁵ is —

SCH₃, R⁶ is —

H, and R⁷ is —

H.

26. The method of claim 1, wherein R⁵ is —

SO₂CH₃, R⁶ is —

H, and R⁷ is —

H.

27. The method of claim 1, wherein R⁵ is ethynyl, R⁶ is —

H, and R⁷ is —

H.