3,3-difluoro-piperidine derivatives as NR2B NMDA receptor antagonists

• US 10,221,182 B2
• Filed: 02/03/2016
• Issued: 03/05/2019
• Est. Priority Date: 02/04/2015
• Status: Active Grant

• Current Assignee: Rugen Holdings (Cayman) Limited
• Original Assignee: Rugen Holdings (Cayman) Limited
• Inventors: Shapiro, Gideon
• Primary Examiner(s): Davis, Zinna Northington
• Application Number:
  US15/548,594
• Publication Number:
  US 20180030055A1
• Time in Patent Office: 1,126 Days
• Field of Search: None
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• 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 487/04 Ortho-condensed systems

Abstract

Disclosed are chemical entities of Formula (I): wherein X, Y, Z, R¹, R³, R⁴ and R⁵ 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 I:

2. The chemical entity of claim 1, wherein:

X is —

H;

—

F;

—

Cl;

C₁-C₄ alkyl;

C₁-C₃ alkyl substituted with 1 to 6 fluoro;

cyclopropyl;

C₁-C₄ alkoxy;

C₁-C₂ alkoxy substituted with 1 to 3 fluoro;

—

CN;

—

NO₂;

—

N(R⁷)(R⁸);

—

SR⁷;

or —

S(O)₂R⁶;

Y is C(R²) or N;

Z is C(H) or N;

R¹ is —

H;

—

F;

—

Cl;

C₁-C₄ alkyl;

C₁-C₂ alkyl substituted with 1 to 3 fluoro;

cyclopropyl;

C₁-C₄ alkoxy;

C₁-C₂ alkoxy substituted with 1 to 3 fluoro;

—

CN;

—

NO₂;

—

N(R⁷)(R⁸);

—

CO₂R⁷;

or —

C(O)N(R⁷)(R⁸);

R² is —

H;

—

F;

—

Cl;

C₁-C₄ alkyl;

C₁-C₂ alkyl substituted with 1 to 3 fluoro;

cyclopropyl;

C₁-C₄ alkoxy;

C₁-C₂ alkoxy substituted with 1 to 3 fluoro;

R³ is —

H, —

F, —

Cl, —

CH₃, —

CF₃ or —

OCH₃;

R⁴ is —

H, —

F, —

Cl, —

CH₃, —

CF₃, or cyclopropyl;

R⁵ is —

H or —

CH₃;

each instance of R⁶ independently is C₁-C₂ alkyl optionally substituted with 1 to 3 fluoro;

each instance of R⁷ independently is C₁-C₂ alkyl; and

each instance of R⁸ independently is —

H or C₁-C₂ alkyl.

3. The chemical entity of claim 1, wherein:

X is —

H;

—

F;

—

Cl;

C₁-C₂ alkyl optionally substituted with 1 to 3 fluoro;

or C₁-C₂ alkoxy optionally substituted with 1 to 3 fluoro;

Y is C(R²) or N;

Z is C(H) or N;

R¹ is —

H, halo or —

CH₃;

R² is —

H, —

F, —

Cl or —

CH₃;

R³ is —

H, —

F, —

Cl, —

CH₃ or —

CF₃;

R⁴ is —

H, —

F, —

CH₃ or —

CF₃; and

R⁵ is —

H or —

CH₃.

4. The chemical entity of claim 1, wherein:

X is —

H, —

F, —

Cl, —

CH₃, —

CH₂F, —

CHF₂, —

CF₃, —

OCHF₂ or —

OCF₃;

Y is C(R²) or N;

Z is C(H) or N;

R¹ is —

H or —

F;

R² is —

H;

R³ is —

H, —

F or —

CF₃;

R⁴ is —

H or —

CH₃; and

R⁵ is —

H or —

CH₃.

5. The chemical entity of claim 1 of formula (II):

6. The chemical entity of claim 5, wherein:

X is —

H, —

F, —

Cl, —

CH₃, —

CH₂CH₃, —

CH(CH₃)₂, —

CF₃, —

CH₂F, —

CF₂CF₃, —

CH(CF₃)₂, —

CH₂CF₂CF₃, cyclopropyl, —

OCH₃, —

OCF₃, —

OCHF₂, —

OCFH₂, —

CN, —

NO₂, —

N(CH₃)₂, —

SCH₃, —

SO₂CH₃ or —

SO₂CF₃;

R¹ is —

H, —

F, —

Cl, —

CH₃, —

CH₂CH₃, —

CH(CH₃)₂, —

CF₃, cyclopropyl, —

OCH₃, —

OCF₃, —

OCHF₂, —

OCFH₂,

—

CN, —

NO₂, —

CO₂CH₃, —

CO₂CH₂CH₃, —

C(O)N(CH₃)₂ or —

C(O)NH(CH₃);

R³ is —

H, —

F, —

Cl, —

CH₃, —

CF₃ or —

OCH₃;

R⁴ is —

H, —

F;

—

Cl;

C₁-C₃ alkyl optionally substituted with 1 to 3 fluoro;

or cyclopropyl; and

R⁵ is —

H or —

CH₃.

7. The chemical entity of claim 5, wherein:

X is —

H, —

F, —

Cl, —

CH₃, —

CH₂F, —

CHF₂, —

CF₃, —

OCHF₂ or —

OCF₃;

R¹ is —

H or —

F;

R³ is —

H, —

F or —

CF₃;

R⁴ is —

H or —

CH₃; and

R⁵ is —

H or —

CH₃.

8. The chemical entity of claim 5 of formula (IIa):

9. The chemical entity of claim 1 of formula (III):

10. The chemical entity of claim 9, wherein:

X is —

H, —

F, —

Cl, —

CH₃, —

CH₂CH₃, —

CH(CH₃)₂, —

CF₃, —

CHF₂, —

CH₂F, —

CF₂CF₃, —

CH(CF₃)₂, —

CH₂CF₂CF₃, cyclopropyl, —

OCH₃, —

OCF₃, —

OCHF₂, —

OCFH₂, —

CN, —

NO₂, —

N(CH₃)₂, —

SCH₃, —

SO₂CH₃ or —

SO₂CF₃;

R¹ is —

H, —

F, —

Cl, —

CH₃, —

CH₂CH₃, —

CH(CH₃)₂, —

CF₃, cyclopropyl, —

OCH₃, —

OCF₃, —

OCHF₂, —

OCFH₂, —

CN, —

NO₂, —

CO₂CH₃, —

CO₂CH₂CH₃, —

C(O)N(CH₃)₂ or —

C(O)NH(CH₃);

R³ is —

H, —

F, —

Cl, —

CH₃, —

CF₃ or —

OCH₃;

R⁴ is —

H, —

F;

—

Cl;

C₁-C₃ alkyl optionally substituted with 1 to 3 fluoro;

or cyclopropyl; and

R⁵ is —

H or —

CH₃.

11. The chemical entity of claim 9, wherein:

X is —

H, —

F, —

Cl, —

CH₃, —

CH₂F, —

CHF₂, —

CF₃, —

OCHF₂ or —

OCF₃;

R¹ is —

H or —

F;

R³ is —

H, —

F or —

CF₃;

R⁴ is —

H or —

CH₃; and

R⁵ is —

H or —

CH₃.

12. The chemical entity of claim 9 of formula (Ma):

13. The chemical entity of claim 1 of formula (IV):

14. The chemical entity of claim 1 of formula (V):

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

16. The pharmaceutical composition of claim 15, which is suitable for oral administration.

17. A method of treating a disease or disorder responsive to NR2B antagonism in a subject in need of such treatment, comprising administering an effective amount of the chemical entity of claim 1.

18. The method of claim 17, wherein the disease or disorder is depression, pain, Parkinson'"'"'s disease, Huntington'"'"'s disease, Alzheimer'"'"'s disease, cerebral ischaemia, traumatic brain injury, epilepsy or migraine.

19. The method of claim 18, wherein the disease or disorder is depression.