Compounds and uses thereof for the modulation of hemoglobin

Patent metadata

Field	Value
Publication number	US-9458139-B2
Application number	US-201313815776-A
Country	US
Kind code	B2
Filing date	Mar 15, 2013
Priority date	Mar 15, 2013
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

Abstract

Provide herein are compounds and pharmaceutical compositions suitable as modulators of hemoglobin, methods and intermediates for their preparation, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.

First claim

The invention claimed is:

1. A compound selected from the group consisting of

or an N oxide thereof wherein
each Y and Z is independently CR 10 R 11 , O, S, SO, SO 2 or NR 12 ; each R 10 and R 11 independently is hydrogen or C 1 -C 3 alkyl, optionally substituted with halo, OH, or alkoxy, or CR 10 R 11 is C═O; R 12 is hydrogen or C 1 -C 6 alkyl; provided that if one of Y and Z is O, S, SO, SO 2 , then the other is not CO, and provided that and Z are both not heteroatoms or oxidized forms thereof;
x is 0, 1, or 2;
R 14 is C 1 -C 6 alkyl, COR 15 , or COOR 15 ;

and R 15 is optionally substituted C 3 -C 6 alkyl, optionally substituted C 5 -C 10 aryl, optionally substituted 5-10 membered heteroaryl or optionally substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N and/or S and/or oxidized forms of N and S.

2. The compound of claim 1 , wherein the compound is selected from the group consisting of

or an N oxide thereof wherein
x is 0, 1, or 2;
R 14 is C 1 -C 6 alkyl, COR 15 , or COOR 15 ;
and R 15 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5-10 membered heteroaryl or optionally substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S.

3. A compound selected from the group consisting of:

or an N oxide thereof, or a pharmaceutically acceptable salt of each thereof.

4. A composition comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient.

5. A method for increasing oxygen affinity of hemoglobin S in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .

6. A method for treating oxygen deficiency associated with sickle cell anemia or acute respiratory distress syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .

7. The compound of claim 1 , wherein Y—Z is —CH 2 O—, —CH 2 CH 2 —, —CONH— or —NHCO—, wherein the right hand side of the substituent is joined with the substituted phenyl ring.

8. A composition comprising a compound of claim 2 and at least one pharmaceutically acceptable excipient.

9. A method for treating oxygen deficiency associated with sickle cell anemia or acute respiratory distress syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 2 .

10. A composition comprising a compound of claim 3 and at least one pharmaceutically acceptable excipient.

11. A method for increasing oxygen affinity of hemoglobin S in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 3 .

12. A method for treating oxygen deficiency associated with sickle cell anemia or acute respiratory distress syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 3 .

13. A compound of formula

or a pharmaceutically acceptable salt thereof.

14. A compound of formula

or a pharmaceutically acceptable salt thereof.

15. A compound of forumla

or a pharmaceutically acceptable salt thereof.

16. A compound of formula

or a pharmaceutically acceptable salt thereof.

17. A composition comprising a compound of claim 13 and at least one pharmaceutically acceptable excipient.

18. A composition comprising a compound of claim 14 and at least one pharmaceutically acceptable excipient.

19. A composition comprising a compound of claim 15 and at least one pharmaceutically acceptable excipient.

20. A composition comprising a compound of claim 16 and at least one pharmaceutically acceptable excipient.

21. A method for treating oxygen deficiency associated with sickle cell anemia or acute respiratory distress syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 13 .

22. A method for treating oxygen deficiency associated with sickle cell anemia or acute respiratory distress syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 14 .

23. A method for treating oxygen deficiency associated with sickle cell anemia or acute respiratory distress syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 15 .

24. A method for treating oxygen deficiency associated with sickle cell anemia or acute respiratory distress syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 16 .

Assignees

• Global Blood Therapeutics Inc

Inventors

• Xu Qing
• Li Zhe
• Metcalf Brian W

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K8/4906

  with one nitrogen as the only hetero atom · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title