Prolyl hydroxylase inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-2016009648-A1
Application number	US-201514854080-A
Country	US
Kind code	A1
Filing date	Sep 15, 2015
Priority date	Jun 26, 2006
Publication date	Jan 14, 2016
Grant date	—

Abstract

The present disclosure relates to HIF-1α prolyl hydroxylase inhibitors, compositions which comprise the HIF-1α prolyl hydroxylase inhibitors described herein and to methods for controlling, inter alia, Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, and anemia.

First claim

What is claimed is:

1 . A compound having the formula:

wherein R 2 is chosen from:
i) —OR 6 ; or
ii) —NR 7a R 7b ;
R 6 is hydrogen, methyl, or ethyl;
R 7a and R 7b are each independently:
i) hydrogen; or
ii) methyl;
R 3 is hydrogen or methyl;
R 8a and R 8b are each independently hydrogen, methyl, or ethyl;
R 10 represents from 1 to 5 substitutions for hydrogen, said substitutions independently chosen from:
i) fluoro;
ii) chloro;
iii) trifluoromethyl;
iv) methyl; or
v) two adjacent R 10 units can be taken together to form a 6-member ring having one or two oxygen atoms, provided no two oxygen atoms are adjacent to one another in the ring; and
pharmaceutically acceptable salts thereof.

2 . The compound according to claim 1 , having the formula:

3 . The compound according to claim 2 , wherein R 2 is —OH.

4 . The compound according to claim 2 , wherein R 2 is —OCH 3 or —OCH 2 CH 3 .

5 . The compound according to claim 2 , wherein R 2 is chosen from —NH 2 , —NHCH 3 , or —N(CH 3 ) 2 .

6 . The compound according to claim 2 , wherein R 8a and R 8b are both hydrogen.

7 . The compound according to claim 1 , having the formula:

8 . The compound according to claim 7 , wherein R 2 is —OH.

9 . The compound according to claim 7 , wherein R 2 is —OCH 3 or —OCH 2 CH 3 .

10 . The compound according to claim 7 , wherein R 2 is chosen from —NH 2 , —NHCH 3 , or —N(CH 3 ) 2 .

11 . The compound according to claim 7 , wherein R 8a and R 8b are both hydrogen.

12 . The compound according to claim 1 , having the formula:

13 . The compound according to claim 12 , wherein R 2 is —OH.

14 . The compound according to claim 12 , wherein R 2 is —OCH 3 or —OCH 2 CH 3 .

15 . The compound according to claim 12 , wherein R 2 is chosen from —NH 2 , —NHCH 3 , or —N(CH 3 ) 2 .

16 . The compound according to claim 12 , wherein R 8a and R 8b are both hydrogen.

17 . The compound according to claim 1 , having the formula:

18 . The compound according to claim 17 , wherein R 2 is —OH.

19 . The compound according to claim 17 , wherein R 2 is —OCH 3 or —OCH 2 CH 3 .

20 . The compound according to claim 17 , wherein R 2 is chosen from —NH 2 , —NHCH 3 , or —N(CH 3 ) 2 .

21 . The compound according to claim 17 , wherein R 8a and R 8b are both hydrogen.

22 . The compound according to claim 1 , having the formula:

23 . The compound according to claim 22 , wherein R 2 is —OH.

24 . The compound according to claim 22 , wherein R 2 is —OCH 3 or —OCH 2 CH 3 .

25 . The compound according to claim 22 , wherein R 2 is chosen from —NH 2 , —NHCH 3 , or —N(CH 3 ) 2 .

26 . The compound according to claim 22 , wherein R 8a and R 8b are both hydrogen.

27 . A compound chosen from:
{[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid; {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid methyl ester; {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid ethyl ester; 5-(3-Chlorophenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chlorophenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chlorophenyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid; {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid methyl ester; {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid ethyl ester; 5-(3-Chlorophenyl)-N-(1-methyl-2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chlorophenyl)-N-(1-methyl-2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chlorophenyl)-N-(1-methyl-2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid; {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid methyl ester; {[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid ethyl ester; 5-(3-Chlorophenyl)-N-(1,1-dimethyl-2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chlorophenyl)-N-(1,1-dimethyl-2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Chlorophenyl)-N-(1,1-dimethyl-2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid methyl ester; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid ethyl ester; 5-(4-Fluorophenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Fluorophenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(4-Fluorophenyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid methyl ester; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid ethyl ester; 5-(4-Fluorophenyl)-N-(1-methyl-2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(4-Fluorophenyl)-N-(1-methyl-2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(4-Fluorophenyl)-N-(1-methyl-2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid methyl ester; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-2,2-dimethylacetic acid ethyl ester; 5-(4-Fluorophenyl)-N-(1,1-dimethyl-2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(4-Fluorophenyl)-N-(1,1-dimethyl-2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(4-Fluorophenyl)-N-(1,1-dimethyl-2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(3-Trifluoromethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid; {[5-(3-Trifluoromethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid methyl ester; {[5-(3-Trifluoromethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid ethyl ester; 5-(3-Trifluoromethylphenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Trifluoromethylphenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; 5-(3-Trifluoromethylphenyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; {[5-(3-Trifluoromethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid; {[5-(3-Trifluoromethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylacetic acid methyl ester; {[5-(3-Trifluoromethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-2-methylac

Assignees

• Akebia Therapeutics Inc

Inventors

• Kawamoto Richard Masaru
• Wu Shengde
• Evdokimov Artem G
• Greis Kenneth D
• Boyer Angelique Sun
• Warshakoon Namal C

Classifications

• A61P7/00

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

• A61P7/06

  Antianaemics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P31/04

  Antibacterial agents · CPC title