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

• US 10,294,230 B2
• Filed: 08/10/2018
• Issued: 05/21/2019
• 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:
  US16/100,596
• Publication Number:
  US 20180346476A1
• Time in Patent Office: 284 Days
• Field of Search: 544323, 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 chemical entity, which is a compound of formula:

2. A pharmaceutical composition comprising the chemical entity of claim 1 and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition of claim 2, which is suitable for oral administration.

4. The chemical entity of claim 1, wherein R⁵ is —

H, R⁶ is —

H, and R⁷ is —

H.

5. The chemical entity of claim 1, wherein R⁵ is —

CH₃, R⁶ is —

H, and R⁷ is —

H.

6. The chemical entity of claim 1, wherein R⁵ is —

Cl, R⁶ is —

H, and R⁷ is —

H.

7. The chemical entity of claim 1, wherein R⁵ is —

F, R⁶ is —

H, and R⁷ is —

H.

8. The chemical entity of claim 1, wherein R⁵ is —

CH₂CH₃, R⁶ is —

H, and R⁷ is —

H.

9. The chemical entity of claim 1, wherein R⁵ is —

CF₂H, R⁶ is —

H, and R⁷ is —

H.

10. The chemical entity of claim 1, wherein R⁵ is —

CH₂F, R⁶ is —

H, and R⁷ is —

H.

11. The chemical entity of claim 1, wherein R⁵ is —

CF₃, R⁶ is —

H, and R⁷ is —

H.

12. The chemical entity of claim 1, wherein R⁵ is —

CF₂CH₃, R⁶ is —

H, and R⁷ is —

H.

13. The chemical entity of claim 1, wherein R⁵ is —

CH₂CF₃, R⁶ is —

H, and R⁷ is —

H.

14. The chemical entity of claim 1, wherein R⁵ is cyclopropyl, R⁶ is —

H, and R⁷ is —

H.

15. The chemical entity of claim 1, wherein R⁵ is —

OCF₃, R⁶ is —

H, and R⁷ is —

H.

16. The chemical entity of claim 1, wherein R⁵ is —

OCF₂H, R⁶ is —

H, and R⁷ is —

H.

17. The chemical entity of claim 1, wherein R⁵ is —

Cl, R⁶ is —

H, and R⁷ is —

F.

18. The chemical entity of claim 1, wherein R⁵ is —

CH₃, R⁶ is —

H, and R⁷ is —

F.

19. The chemical entity of claim 1, wherein R⁵ is —

CH₃, R⁶ is —

F, and R⁷ is —

H.

20. The chemical entity of claim 1, wherein R⁵ is —

Cl, R⁶ is —

F, and R⁷ is —

H.

21. The chemical entity of claim 1, wherein R⁵ is —

F, R⁶ is —

F, and R⁷ is —

H.

22. The chemical entity of claim 1, wherein R⁵ is —

F, R⁶ is —

H, and R⁷ is —

F.

23. The chemical entity of claim 1, wherein R⁵ is —

F, R⁶ is —

H, and R⁷ is —

Cl.

24. The chemical entity of claim 1, wherein R⁵ is —

F, R⁶ is —

H, and R⁷ is —

CH₃.

25. The chemical entity of claim 1, wherein R⁵ is —

Cl, R⁶ is —

H, and R⁷ is —

CH₃.

26. The chemical entity of claim 1, wherein R⁵ is —

SCH₃, R⁶ is —

H, and R⁷ is —

H.

27. The chemical entity of claim 1, wherein R⁵ is —

SO₂CH₃, R⁶ is —

H, and R⁷ is —

H.

28. The chemical entity of claim 1, wherein R⁵ is ethynyl, R⁶ is —

H, and R⁷ is —

H.