Bicycloheteroaryl-heteroaryl-benzoic acid compounds as retinoic acid receptor beta (RARβ) agonists

• US 10,385,044 B2
• Filed: 06/05/2018
• Issued: 08/20/2019
• Est. Priority Date: 12/17/2014
• Status: Active Grant

• Current Assignee: Kings College London (University of London)
• Original Assignee: Kings College London (University of London)
• Inventors: Borthwick, Alan David, Mills, Mark Trevor, Brown, Jane Theresa, Corcoran, Jonathan Patrick Thomas, De Castro Vasconcelos Goncalves, Maria Beatriz, Kalindjian, Sarkis Barret
• Primary Examiner(s): Aguirre, Amanda L
• Application Number:
  US15/997,796
• Publication Number:
  US 20190010146A1
• Time in Patent Office: 441 Days
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond

Abstract

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain bicycloheteroaryl-heteroaryl-benzoic acid compounds of the following formula (for convenience, collectively referred to herein as “BHBA compounds”), which, inter alia, are (selective) retinoic acid receptor beta (RARβ) (e.g., RARβ2) agonists. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to (selectively) activate RARβ (e.g., RARPβ2), to cause or promote neurite development, neurite outgrowth, and/or neurite regeneration, and in the treatment of diseases and conditions that are mediated by RARβ (e.g., RARβ2), that are ameliorated by the activation of RARβ (e.g., RARβ2), etc., including, e.g., neurological injuries such as spinal cord injuries.

Claims

1. A method of treatment of a nerve injury, comprising administering to a subject having nerve injury a therapeutically-effective amount of a compound selected from compounds of the following formula, and pharmaceutically acceptable salts thereof:

2. A method according to claim 1, wherein —

R^A is —

H.

3. A method according to claim 2, wherein:

X¹ is O, X² is N, and X³ is N;

or

X¹ is S, X² is N, and X³ is N;

or

X¹ is N, X² is S, and X³ is N.

4. A method according to claim 2, wherein:

X¹ is O;

X² is N; and

X³ is N.

5. A method according to claim 3, wherein:

Y¹ is O and Y² is CH;

or

Y¹ is O and Y² is CR^Y;

or

Y¹ is O and Y² is N; and

—

R^Y is -Me.

6. A method according to claim 4, wherein:

Y¹ is O and Y² is CH;

or

Y¹ is O and Y² is CR^Y;

or

Y¹ is O and Y² is N; and

—

R^Y is -Me.

7. A method according to claim 3, wherein:

Y¹ is O; and

Y² is CH.

8. A method according to claim 4, wherein:

Y¹ is O; and

Y² is CH.

9. A method according to claim 5, wherein:

—

R^Q1 is independently —

R^Q1A or —

R^Q1B;

—

R^Q1A is -Me;

—

R^Q1B is —

F or —

Cl;

—

R^Q2 is independently —

R^Q2A or —

R^Q2B;

—

R^Q2A is -Me;

—

R^Q2B is —

F or —

Cl;

—

R^Q3 is —

H; and

—

R^Q4 is —

H.

10. A method according to claim 6, wherein:

—

R^Q1 is independently —

R^Q1A or —

R^Q1B;

—

R^Q1A is -Me;

—

R^Q1B is —

F or —

Cl;

—

R^Q2 is independently —

R^Q2A or —

R^Q2B;

—

R^Q2A is -Me;

—

R^Q2B is —

F or —

Cl;

—

R^Q3 is —

H; and

—

R^Q4 is —

H.

11. A method according to claim 7, wherein:

—

R^Q1 is independently —

R^Q1A or —

R^Q1B;

—

R^Q1A is -Me;

—

R^Q1B is —

F or —

Cl;

—

R^Q2 is independently —

R^Q2A or —

R^Q2B;

—

R^Q2A is -Me;

—

R^Q2B is —

F or —

Cl;

—

R^Q3 is —

H; and

—

R^Q4 is —

H.

12. A method according to claim 8, wherein:

—

R^Q1 is independently —

R^Q1A or —

R^Q1B;

—

R^Q1A is -Me;

—

R^Q1B is —

F or —

Cl;

—

R^Q2 is independently —

R^Q2A or —

R^Q2B;

—

R^Q2A is -Me;

—

R^Q2B is —

F or —

Cl;

—

R^Q3 is —

H; and

—

R^Q4 is —

H.

13. A method according to claim 5, wherein:

—

R^Q1 is —

R^Q1A;

—

R^Q1A is -Me;

—

R^Q2 is —

R^Q2A;

—

R^Q2A is -Me;

—

R^Q3 is —

H; and

—

R^Q4 is —

H.

14. A method according to claim 6, wherein:

—

R^Q1 is —

R^Q1A;

—

R^Q1A is -Me;

—

R^Q2 is —

R^Q2A;

—

R^Q2A is -Me;

—

R^Q3 is —

H; and

—

R^Q4 is —

H.

15. A method according to claim 7, wherein:

—

R^Q1 is —

R^Q1A;

—

R^Q1A is -Me;

—

R^Q2 is —

R^Q2A;

—

R^Q2A is -Me;

—

R^Q3 is —

H; and

—

R^Q4 is —

H.

16. A method according to claim 8, wherein:

—

R^Q1 is —

R^Q1A;

—

R^Q1A is -Me;

—

R^Q2 is —

R^Q2A;

—

R^Q2A is -Me;

—

R^Q3 is —

H; and

—

R^Q4 is —

H.

17. A method according to claim 9, wherein:

—

R^P is independently —

R^PA or —

R^PB;

—

R^PA is -Me; and

—

R^PB is independently —

F or —

Cl.

18. A method according to claim 10, wherein:

—

R^P is independently —

R^PA or —

R^PB;

—

R^PA is -Me; and

—

R^PB is independently —

F or —

Cl.

19. A method according to claim 11, wherein:

—

R^P is independently —

R^PA or —

R^PB;

—

R^PA is -Me; and

—

R^PB is independently —

F or —

Cl.

20. A method according to claim 12, wherein:

—

R^P is independently —

R^PA or —

R^PB;

—

R^PA is -Me; and

—

R^PB is independently —

F or —

Cl.

21. A method according to claim 13, wherein:

—

R^P is independently —

R^PA or —

R^PB;

—

R^PA is -Me; and

—

R^PB is independently —

F or —

Cl.

22. A method according to claim 14, wherein:

—

R^P is independently —

R^PA or —

R^PB;

—

R^PA is -Me; and

—

R^PB is independently —

F or —

Cl.

23. A method according to claim 15, wherein:

—

R^P is independently —

R^PA or —

R^PB;

—

R^PA is -Me; and

—

R^PB is independently —

F or —

Cl.

24. A method according to claim 16, wherein:

—

R^P is independently —

R^PA or —

R^PB;

—

R^PA is -Me; and

—

R^PB is independently —

F or —

Cl.

25. A method according to claim 1, wherein the compound is a compound of one of the following formulae, or a pharmaceutically acceptable salt thereof:

26. A method according to claim 1, wherein the nerve injury is a peripheral nervous system (PNS) nerve injury.

27. A method according to claim 1, wherein the nerve injury is a central nervous system (CNS) nerve injury.

28. A method according to claim 1, wherein the nerve injury is a spinal cord injury.

29. A method according to claim 1, wherein the nerve injury is a spinal cord injury caused by trauma.

30. A method according to claim 1, wherein the nerve injury is an optic nerve injury.

31. A method according to claim 1, wherein the nerve injury is an optic nerve injury caused by glaucoma.

32. A method of treatment of a nerve injury, comprising administering to a subject having nerve injury a therapeutically-effective amount of a compound of the following formula, or a pharmaceutically acceptable salt thereof:

33. A method according to claim 32, wherein the nerve injury is a peripheral nervous system (PNS) nerve injury.

34. A method according to claim 32, wherein the nerve injury is a central nervous system (CNS) nerve injury.

35. A method according to claim 32, wherein the nerve injury is a spinal cord injury.

36. A method according to claim 32, wherein the nerve injury is a spinal cord injury caused by trauma.

37. A method according to claim 32, wherein the nerve injury is an optic nerve injury.

38. A method according to claim 32, wherein the nerve injury is an optic nerve injury caused by glaucoma.