Compounds and uses thereof for the modulation of hemoglobin

Patent metadata

Field	Value
Publication number	US-9422279-B2
Application number	US-201313815770-A
Country	US
Kind code	B2
Filing date	Mar 15, 2013
Priority date	Mar 15, 2013
Publication date	Aug 23, 2016
Grant date	Aug 23, 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

What is claimed is:

1. A compound of formula (I):

or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein
ring A is phenyl optionally substituted with 1-3 halo and/or C 1 -C 6 alkoxy, or is a 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, optionally substituted, or is

 wherein R 7 is C 1 -C 6 alkyl, optionally substituted with 3-5 fluoro groups, or is C 3 -C 6 cycloalkyl;
ring B is selected from the group consisting of

 wherein R 8 is C 1 -C 6 alkyl, —CO—C 1 -C 6 alkyl or a prodrug moiety;
X is 0, S, SO, or SO 2 ;
is a single or a double bond;
ring C is phenyl or a 6 membered nitrogen-containing heteroaryl, each of which is optionally substituted with 1-4: halo, oxo, —OR 1 , C 1 -C 6 alkyl and/or C 1 -C 6 alkoxy, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo, C 1 -C 6 alkoxy and/or 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; and
each R 1 is hydrogen or a prodrug moiety;
V 1 and V 2 independently are C 1 -C 6 alkoxy; or V 1 and V 2 together with the carbon atom they are attached to form a ring of formula:

wherein each V 3 and V 4 are independently O, S, or NH, provided that when one of V 3 and V 4 is S, the other is NH, and provided that V 3 and V 4 are both not NH; q is 1 or 2; each V 5 is independently C 1 -C 6 alkyl or CO 2 R 60 , where each R 60 independently is C 1 -C 6 alkyl or hydrogen; t is 1, 2, or 4; or CV 1 V 2 is C═V, wherein V is O, NOR 80 , or NNR 81 R 82 ;
wherein R 80 is optionally substituted C 1 -C 6 alkyl;
R 81 and R 82 independently are selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, COR 83 , or CO 2 R 84 ;
R 83 is hydrogen or optionally substituted C 1 -C 6 alkyl;
R 84 is optionally substituted C 1 -C 6 alkyl;
provided that when ring C is C 6 -C 10 aryl;
and ring B is optionally substituted 4-10 membered heterocyclyl;
then ring A excludes optionally substituted 5-10 membered heteroaryl.

2. The compound of claim 1 , wherein V 1 and V 2 independently are C 1 -C 6 alkoxy; or V 1 and V 2 together with the carbon atom they are attached to form a ring of formula:

wherein each V 3 and V 4 are independently O, S, or NH, provided that when one or V 3 and V 4 is S the other is NH, and provided that V 3 and V 4 are both not NH; q is 1 or 2; each V 5 is independently C 1 -C 6 alkyl or CO 2 R 60 , where each R 60 independently is C 1 -C 6 alkyl or hydrogen; t is 1, 2, or 4; or CV 1 V 2 is C═V, wherein V is O, and wherein the remaining variables are defined as in claim.

3. The compound of claim 2 , of formula:

wherein the remaining variables are defined as in claim 2 .

4. A compound of claim 2 selected from formulas (IIA), (IIB) and (IIC):

wherein
R 9 is hydrogen, —OR 1 , C 1 -C 6 alkoxy optionally substituted with 1-3 C 1 -C 6 alkoxy or 4-10 membered heterocycle containing up to 5 ring heteroatoms selected from N, O, S or oxidized forms thereof;
R 10 is hydrogen, halo or C 1 -C 6 alkoxy;
R 11 is hydrogen or C 1 -C 6 alkyl; and
R 12 is —OR 1 ;
wherein R 1 is hydrogen or the prodrug moiety.

5. The compound of claim 3 , wherein ring A is
phenyl substituted with 1-3 halo or C 1 -C 6 alkoxy, or
C 3 -C 8 heterocyclyl containing 1-3 heteroatoms, wherein the heterocycle is optionally substituted with 1-3 halo.

6. The compound of claim 3 , wherein

is selected from the group consisting of:

7. The compound of claim 3 , wherein

8. A compound selected from the group consisting of:

or an N oxides thereof, or a pharmaceutically acceptable salt of each thereof, wherein is a single or a double bond.

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

10. 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 .

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

12. The method of claim 11 , wherein oxygen affinity of the subject's hemoglobin S is increased.

13. The compound of claim 1 , wherein ring B is

14. The compound of claim 1 , wherein ring B is

wherein R 8 is C 1 -C 6 alkyl, —CO—C 1 -C 6 alkyl or a prodrug moiety.

15. The compound of claim 1 , wherein ring B is

wherein R 8 is C 1 -C 6 alkyl, —CO—C 1 -C 6 alkyl or a prodrug moiety.

16. The compound of claim 1 , wherein ring B is

17. The compound of claim 13 , wherein ring A is selected from:

wherein R 7 is C 1 -C 6 alkyl, optionally substituted with 3-5 fluoro groups, or is C 3 -C 6 cycloalkyl.

18. The compound of claim 14 , wherein ring A is selected from:

wherein R 7 is C 1 -C 6 alkyl, optionally substituted with 3-5 fluoro groups, or is C 3 -C 6 cycloalkyl.

19. The compound of claim 15 , wherein ring A is selected from:

Assignees

• Global Blood Therapeutics Inc

Inventors

• Metcalf Brian W
• Li Zhe

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K31/445

  Non condensed piperidines, e.g. piperocaine · CPC title

• C07D227/08

  Oxygen atoms · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title