IP Library › Granted Patent US 8,323,671

Granted Patent B2

US 8,323,671 · App. 12/860,136 · Granted Dec 4, 2012

Prolyl hydroxylase inhibitors and methods of use

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Quick Facts

Patent No.: US 8,323,671
App. No.: 12/860,136
Granted: Dec 4, 2012
Kind: B2

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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.

Claims (245)

1. A method for treating anemia comprising administering to a human or mammal in need of treatment an effective amount of one or more compounds having the formula:

wherein R is a unit chosen from:

i) substituted or unsubstituted phenyl; or

ii) substituted or unsubstituted heteroaryl;

said substitutions chosen from:

i) C 1 -C 4 linear, branched, or cyclic alkyl;

ii) C 1 -C 4 linear, branched, or cyclic alkoxy;

iii) C 1 -C 4 linear, branched, or cyclic haloalkyl;

iv) halogen;

v) —CN;

vi) —NHC(O)R 4

vii) —C(O)NR 5a R 5b ;

viii) heteroaryl; or

ix) two substitutions can be taken together to form a fused ring having from 5 to 7 atoms;

R 4 is C 1 -C 4 linear, branched, or cyclic alkyl;

R 5a and R 5b are each independently:

i) hydrogen;

ii) C 1 -C 4 linear, branched, or cyclic alkyl; or

iii) R 5a and R 5b can be taken together to form a ring having from 3 to 7 atoms;

R 2 is chosen from:

i) —OR 6 ; or

ii) —NR 7a R 7b ;

R 6 is hydrogen or C 1 -C 4 linear, branched, or cyclic alkyl;

R 7a and R 7b are each independently:

i) hydrogen;

ii) C 1 -C 4 linear, branched, or cyclic alkyl; or

iii) R 7a and R 7b can be taken together to form a ring having from 3 to 7 ring atoms;

R 3 is hydrogen, methyl, or ethyl;

L is a linking unit having the formula:

—[C(R 8a R 8b )] n —

R 8a and R 8b are each independently hydrogen, methyl, or ethyl;

the index n is from 1 to 3;

R 9 is hydrogen or methyl; or

a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein R is substituted or unsubstituted phenyl.

3. The method according to claim 1 , wherein R is chosen from 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, and 4-chlorophenyl.

4. The method according to claim 1 , wherein R is chosen from 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-iso-propoxyphenyl, 3-iso-propoxyphenyl, 4-iso-propoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, and 4-cyanophenyl.

5. The method according to claim 1 , wherein R is a unit having the formula:

wherein R 10 has the formula —C(O)NR 5a R 5b ; R 5a and R 5b are each hydrogen or R 5a and R 5b are taken together to form a ring having 5 or 6 atoms.

6. The method according to claim 1 , wherein R 5a and R 5b are taken together to form a pyrrolidin-1-yl ring.

7. The method according to claim 1 , wherein R is a unit having the formula:

wherein R 10 has the formula —NHC(O)R 4 ; R 4 is a unit chosen from methyl, ethyl, n-propyl, iso-propyl, and cyclopropyl.

8. The method according to claim 1 , wherein R is a unit having the formula:

wherein R 10 is a heteroaryl unit chosen from 1,2,3,4-tetrazol-5-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, and thiophene-3-yl.

9. The method according to claim 1 , wherein R is substituted or unsubstituted heteroaryl.

10. The method according to claim 1 , wherein R is a unit chosen from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, isoquinolin-1-yl, isoquinolin-3-yl, and isoquinolin-4-yl.

11. The method according to claim 1 , wherein R is a unit chosen from thiazol-2-yl, thiazol-4-yl, 1,2,3,4-tetrazol-5-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, and thiophene-3-yl.

12. The method according to claim 1 , wherein R 2 is —OH.

13. The method according to claim 1 , wherein R 2 is —OCH 3 .

14. The method according to claim 1 , wherein R 2 is —NR 7a R 7b ; R 7a and R 7b are each independently hydrogen, methyl, or ethyl.

15. The method according to claim 1 , wherein R 2 is chosen from:

i) —NH 2 ;

ii) —NHCH 3 ; or

iii) —N(CH 3 ) 2 .

16. The method according to claim 1 , wherein R 3 is hydrogen.

17. The method according to claim 1 , wherein L has the formula chosen from:

i) —CH 2 CH 2 —; or

ii) —C(CH 3 ) 2 —.

18. The method according to claim 1 , wherein L has the formula —CH 2 —.

19. The method according to claim 1 , wherein the compound has 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.

20. The method according to claim 19 , wherein the compound has the formula:

21. The method according to claim 20 , wherein R 2 is —OH.

22. The method according to claim 20 , wherein R 2 is —OCH 3 or —OCH 2 CH 3 .

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

24. The method according to claim 20 , wherein R 8a and R 8b are both hydrogen.

25. The method according to claim 19 , wherein the compound has the formula:

26. The method according to claim 25 , wherein R 2 is —OH.

27. The method according to claim 25 , wherein R 2 is —OCH 3 or —OCH 2 CH 3 .

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

29. The method according to claim 25 , wherein R 8a and R 8b are both hydrogen.

30. The method according to claim 19 , wherein the compound has the formula:

31. The method according to claim 30 , wherein R 2 is —OH.

32. The method according to claim 30 , wherein R 2 is —OCH 3 or —OCH 2 CH 3 .

33. The method according to claim 30 , wherein R 2 is chosen from —NH 2 , —NHCH 3 , or —N(CH 3 ) 2 .

34. The method according to claim 30 , wherein R 8a and R 8b are both hydrogen.

35. The method according to claim 19 , wherein the compound has the formula:

36. The method according to claim 35 , wherein R 2 is —OH.

37. The method according to claim 35 , wherein R 2 is —OCH 3 or —OCH 2 CH 3 .

38. The method according to claim 35 , wherein R 2 is chosen from —NH 2 , —NHCH 3 , or —N(CH 3 ) 2 .

39. The method according to claim 35 , wherein R 8a and R 8b are both hydrogen.

40. A method for treating anemia comprising administering to a human or mammal in need of treatment an effective amount of one or more compounds chosen from:

{[5-(3-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;

{[5-(4-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;

{[5-(2-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;

{[5-(4-Fluoro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;

[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-acetic acid methyl ester;

{[3-Hydroxy-5-(4-isopropyl-phenyl)-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;

{[5-(4-Ethyl-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;

{[3-Hydroxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;

{[5-(4-Cyano-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;

{[5-(3-Cyano-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;

{[5-(3-Carbamoyl-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester;

({3-Hydroxy-5-[3-(pyrrolidine-1-carbonyl)-phenyl]-pyridine-2-carbonyl}-amino)-acetic acid methyl ester;

({5-[3-(Cyclopropanecarbonyl-amino)-phenyl]-3-hydroxy-pyridine-2-carbonyl}-amino)-acetic acid methyl ester;

({3-Hydroxy-5-[3-(2H-tetrazol-5-yl)-phenyl]-pyridine-2-carbonyl}-amino)-acetic acid methyl ester;

[(5-Hydroxy-[3,3′]bipyridinyl-6-carbonyl)-amino]-acetic acid methyl ester

[(5′-Hydroxy-[2,3′]bipyridinyl-6′-carbonyl)-amino]-acetic acid methyl ester;

[(3-Hydroxy-5-pyrimidin-5-yl-pyridine-2-carbonyl)-amino]-acetic acid methyl ester;

[(3-Hydroxy-5-isoquinolin-4-yl-pyridine-2-carbonyl)-amino]-acetic acid methyl ester;

[(3-Hydroxy-5-thiazol-2-yl-pyridine-2-carbonyl)-amino]-acetic acid methyl ester;

{[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;

{[5-(4-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;

{[5-(2-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;

{[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;

[(3-Hydroxy-5-(4-methylphenyl)pyridine-2-carbonyl)amino]-acetic acid;

{[5-(4-Ethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;

{[3-Hydroxy-5-(4-isopropylphenyl)pyridine-2-carbonyl]amino}-acetic acid;

{[3-Hydroxy-5-(3-trifluoromethylphenyl)pyridine-2-carbonyl]amino}-acetic acid;

{[5-(4-Cyanophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;

{[5-(3-Cyanophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;

{[5-(5-Chloro-2-methylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-acetic acid;

{[3-Hydroxy-5-(4-isopropoxyphenyl)pyridine-2-carbonyl]amino}-acetic acid;

({5-[3-(Cyclopropanecarbonylamino)phenyl]-3-hydroxy-pyridine-2-carbonyl}-amino)-acetic acid;

({3-Hydroxy-5-[3-(pyrrolidine-1-carbonyl)phenyl]-pyridine-2-carbonyl}amino)-acetic acid;

({3-Hydroxy-5-[3-(2H-tetrazol-5-yl)phenyl]-pyridine-2-carbonyl}-amino)-acetic acid;

[(5′-Hydroxy-[2,3′]bipyridinyl-6′-carbonyl)-amino]-acetic acid;

[(5-Hydroxy-[3,3′]bipyridinyl-6-carbonyl)-amino]-acetic acid;

[(3-Hydroxy-5-pyrimidin-5-yl-pyridine-2-carbonyl)-amino]-acetic acid;

[(3-Hydroxy-5-isoquinolin-4-yl-pyridine-2-carbonyl)-amino]-acetic acid;

[(3-Hydroxy-5-thiazol-2-yl-pyridine-2-carbonyl)-amino]-acetic acid;

{[5-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid;

5-(3-Chlorophenyl)-N-(2-amino-2-oxo-1,1-dimethylethyl)-3-hydroxylpyridin-2-yl amide;

5-(3-Chlorophenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide;

5-(3-Chlorophenyl)-N-(2-amino-2-oxo-1-methylethyl)-3-hydroxylpyridin-2-yl amide;

5-(4-Methylphenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide;

5-(3-Chlorophenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide;

2-{[5-(3-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester;

2-{[5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid

3[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-propionic acid ethyl ester;

3[(3-Hydroxy-5-(3-chlorophenyl)-pyridine-2-carbonyl)-amino]-propionic acid ethyl ester;

3-{[5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-propionic acid;

3[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino]-propionic acid;

5-(3-Chlorophenyl)-N-(3-amino-3-oxo-1,1-dimethylpropyl)-3-hydroxylpyridin-2-yl amide; and

5-(3-Chlorophenyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide; or

a pharmaceutically acceptable salt thereof.

41. A method for promoting wound healing comprising administering to a human or mammal in need of treatment an effective amount of one or more compounds having the formula:

wherein R is a unit chosen from:

i) substituted or unsubstituted phenyl; or

ii) substituted or unsubstituted heteroaryl;

said substitutions chosen from:

i) C 1 -C 4 linear, branched, or cyclic alkyl;

ii) C 1 -C 4 linear, branched, or cyclic alkoxy;

iii) C 1 -C 4 linear, branched, or cyclic haloalkyl;

iv) halogen;

v) —CN;

vi) —NHC(O)R 4

vii) —C(O)NR 5a R 5b ;

viii) heteroaryl; or

ix) two substitutions can be taken together to form a fused ring having from 5 to 7 atoms;

R 4 is C 1 -C 4 linear, branched, or cyclic alkyl;

R 5a and R 5b are each independently:

i) hydrogen;

ii) C 1 -C 4 linear, branched, or cyclic alkyl; or

iii) R 5a and R 5b can be taken together to form a ring having from 3 to 7 atoms;

R 2 is chosen from:

i) —OR 6 ; or

ii) —NR 7a R 7b ;

R 6 is hydrogen or C 1 -C 4 linear, branched, or cyclic alkyl;

R 7a and R 7b are each independently:

i) hydrogen;

ii) C 1 -C 4 linear, branched, or cyclic alkyl; or

iii) R 7a and R 7b can be taken together to form a ring having from 3 to 7 ring atoms;

R 3 is hydrogen, methyl, or ethyl;

L is a linking unit having the formula:

—[C(R 8a R 8b )] n —

R 8a and R 8b are each independently hydrogen, methyl, or ethyl;

the index n is from 1 to 3;

R 9 is hydrogen or methyl; or

a pharmaceutically acceptable salt thereof.

42. The method according to claim 41 , wherein the compound has the formula:

43. The method according to claim 41 , wherein R 2 is —OH.

44. The method according to claim 41 , wherein R 2 is —OCH 3 or —OCH 2 CH 3 .

45. The method according to claim 41 , wherein R 2 is chosen from —NH 2 , —NHCH 3 , or —N(CH 3 ) 2 .

46. The method according to claim 41 , wherein R 8a and R 8b are both hydrogen.

47. A method for promoting wound healing comprising administering to a human or mammal in need of treatment an effective amount of one or more compounds chosen from: