Claims
- 1. A compound represented by Formula I:
- 2. The compound of claim 1 where m is 2, n is 2, and p is 0.
- 3. The compound of claim 2 where X is C(H)— or S═.
- 4. The compound of claim 3 where R1 is substituted aryl or substituted heteroaryl.
- 5. The compound of claim 4 where R1 is 4-alkoxyphenyl, 4-bromo-2-fluorophenyl, 4-bromophenyl, 4-chlorophenyl, 4-chloro-2-methylphenyl, 4-cyanophenyl, 4-fluorophenyl, 3-methylphenyl, 4-methylphenyl, 4-nitrophenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 5-bromo-thiophen-2-yl or 5-chloro-thiophen-2-yl.
- 6. The compound of claim 5 where R1 is 4-chlorophenyl.
- 7. The compound of claim 1 where R2 is lower alkyl, alkoxycarbonyl, halo or hydroxy.
- 8. The compound of claim 1 where R3 is methyl, hydrogen, or a valence bond of S═ when X is S═.
- 9. The compound of claim 8 where R3 is hydrogen, or a valence bond of S═ when X is S═.
- 10. The compound of any of claims 1, 2, 3, 4, 5, 6 or 9 where R4 is optionally substituted aryl or optionally substituted heteroaryl.
- 11. The compound of claim 10 where:
R4 is phenyl optionally substituted with one or more of the following: acetyl, acyl, acyloxy, optionally substituted alkoxy, alkoxycarbonyl, optionally substituted alkyl, optionally substituted amino, aminocarbonyl, azido, cyano, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkoxy, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, halo, hydroxy, nitro, sulfanyl, sulfonamido, sulfonyl and trifluoromethyl, or R4 is benzodioxineyl, benzodioxolyl, benzothiazolyl, furanyl, pyrazolyl, pyridinyl, pyrrolyl or thiophenyl, optionally substituted with one or more of the following: optionally substituted alkyl, alkoxy, alkoxycarbonyl, halo, optionally substituted heteroaryl, optionally substituted heteroaryloxy and oxo.
- 12. The compound of claim 10 where R4 is 4-(1-aminoethyl)-phenyl, 4-(2-cyanoethoxymethyl)-phenyl, 4-(1-hydroxyethyl)-phenyl, 4-(2-hydroxyethyl)-phenyl, 4-(1-hydroxy-2-methoxyethyl)-phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-methoxymethoxyphenyl, 4-methoxymethoxymethylphenyl, 4-methoxymethylphenyl, 4-(pyrazin-2-yloxymethyl)-phenyl, 4-(pyrazol-1-yl)-phenyl, 4-(pyridin-3-ylmethoxy)-phenyl, 4-[(pyridin-2-ylmethyl)-amino]-phenyl, 4-(pyridin-2-yloxy)-phenyl, 4-(2-hydroxy-thiazol-5-ylmethoxy)-phenyl, 4-([1,2,3]triazol-1-yl)-phenyl, 4-([1,2,4]triazol-1-yl)-phenyl, 5-(thiadiazol-5-yl)-thiophen-2-yl, 5-(isoxazol-3-yl)-thiophen-2-yl, 5-(pyridin-2-yl)-thiophen-2-yl, or 5-(5-methoxy-[1,2,4]thiadiazol-3-yl)-thiophen-2-yl.
- 13. The compound of claim 2 where R1 is 4-chlorophenyl, and R3 is hydrogen or a valence bond of S═ when X is S═, wherein:
X is C(H)— and R4 is 4-(1-aminoethyl)-phenyl, 4-(1-hydroxyethyl)-phenyl, 4-(1-hydroxy-2-methoxyethyl)-phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-methoxymethoxyphenyl, 4-(pyridin-3-ylmethoxy)-phenyl or 4-(pyridin-2-yloxy)-phenyl; or X is S═ and R4 is 4-(2-cyanoethoxymethyl)-phenyl, 4-(1-hydroxyethyl)-phenyl, 4-(2-hydroxyethyl)-phenyl, 4-methoxymethoxyphenyl, 4-methoxymethoxymethylphenyl, 4-methoxymethylphenyl, 4-(pyrazin-2-yloxymethyl)-phenyl, 4-(pyrazol-1-yl)-phenyl, 4-(pyrimidin-2-yloxy)-phenyl, 4-(pyridin-3-ylmethoxy)-phenyl, 4-[(pyridin-2-ylmethyl)-amino]-phenyl, 4-(pyridin-2-yloxy)-phenyl, 4-(2-hydroxy-thiazol-5-ylmethoxy)-phenyl, 4-([1,2,3]triazol-1-yl)-phenyl, 4-([1,2,4]triazol-1-yl)-phenyl, 5-(thiadiazol-5-yl)-thiophen-2-yl, 5-(isoxazol-3-yl)-thiophen-2-yl, 5-(pyridin-2-yl)-thiophen-2-yl or 5-(5-methoxy-[1,2,4]thiadiazol-3-yl)-thiophen-2-yl.
- 14. A method of treatment for heart failure, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound represented by Formula I:
- 15. The method of claim 14 where m is 2, n is 2, and p is 0.
- 16. The method of claim 15 where X is C(H)— or S═.
- 17. The method of claim 16 where R1 is substituted aryl or substituted heteroaryl.
- 18. The method of claim 17 where R1 is 4-alkoxyphenyl, 4-bromo-2-fluorophenyl, 4-bromophenyl, 4-chlorophenyl, 4-chloro-2-methylphenyl, 4-cyanophenyl, 4-fluorophenyl, 3-methylphenyl, 4-methylphenyl, 4-nitrophenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 5-bromo-thiophen-2-yl or 5-chloro-thiophen-2-yl.
- 19. The method of claim 18 where R1 is 4-chlorophenyl.
- 20. The method of claim 14 where R2 is lower alkyl, alkoxycarbonyl, halo or hydroxy.
- 21. The method of claim 14 where R3 is methyl, hydrogen, or a valence bond of S═ when X is S═.
- 22. The method of claim 21 where R3 is hydrogen, or a valence bond of S═ when X is S═.
- 23. The method of any of claims 14, 15, 16, 19, or 22 where R4 is optionally substituted aryl or optionally substituted heteroaryl.
- 24. The method of claim 23 where:
R4 is phenyl optionally substituted with one or more of the following: acetyl, acyl, acyloxy, optionally substituted alkoxy, alkoxycarbonyl, optionally substituted alkyl, optionally substituted amino, aminocarbonyl, azido, cyano, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkoxy, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, halo, hydroxy, nitro, sulfanyl, sulfonamido, sulfonyl and trifluoromethyl, or R4 is benzodioxineyl, benzodioxolyl, benzothiazolyl, furanyl, pyrazolyl, pyridinyl, pyrrolyl or thiophenyl, optionally substituted with one or more of the following: optionally substituted alkyl, alkoxy, alkoxycarbonyl, halo, optionally substituted heteroaryl, optionally substituted heteroaryloxy and oxo.
- 25. The method of claim 23 where R4 is 4-(1-aminoethyl)-phenyl, 4-(2-cyanoethoxymethyl)-phenyl, 4-(1-hydroxyethyl)-phenyl, 4-(2-hydroxyethyl)-phenyl, 4-(1-hydroxy-2-methoxyethyl)-phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-methoxymethoxyphenyl, 4-methoxymethoxymethylphenyl, 4-methoxymethylphenyl, 4-(pyrazin-2-yloxymethyl)-phenyl, 4-(pyrazol-1-yl)-phenyl, 4-(pyridin-3-ylmethoxy)-phenyl, 4-[(pyridin-2-ylmethyl)-amino]-phenyl, 4-(pyridin-2-yloxy)-phenyl, 4-(2-hydroxy-thiazol-5-ylmethoxy)-phenyl, 4-([1,2,3]triazol-1-yl)-phenyl, 4-([1,2,4]triazol-1-yl)-phenyl, 5-(thiadiazol-5-yl)-thiophen-2-yl, 5-(isoxazol-3-yl)-thiophen-2-yl, 5-(pyridin-2-yl)-thiophen-2-yl, or 5-(5-methoxy-[1,2,4]thiadiazol-3-yl)-thiophen-2-yl.
- 26. The method of claim 15 where R1 is 4-chlorophenyl, and R3 is hydrogen or a valence bond of S═ when X is S═, wherein:
X is C(H)— and R4 is 4-(1-aminoethyl)-phenyl, 4-(1-hydroxyethyl)-phenyl, 4-(1-hydroxy-2-methoxyethyl)-phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-methoxymethoxyphenyl, 4-(pyridin-3-ylmethoxy)-phenyl or 4-(pyridin-2-yloxy)-phenyl; or X is S═ and R4 is 4-(2-cyanoethoxymethyl)-phenyl, 4-(1-hydroxyethyl)-phenyl, 4-(2-hydroxyethyl)-phenyl, 4-methoxyphenyl, 4-methoxymethoxyphenyl, 4-methoxymethoxymethylphenyl, 4-methoxymethylphenyl, 4-(pyrazin-2-yloxymethyl)-phenyl, 4-(pyrazol-1-yl)-phenyl, 4-(pyrimidin-2-yloxy)-phenyl, 4-(pyridin-3-ylmethoxy)-phenyl, 4-[(pyridin-2-ylmethyl)-amino]-phenyl, 4-(pyridin-2-yloxy)-phenyl, 4-(2-hydroxy-thiazol-5-ylmethoxy)-phenyl, 4-([1,2,3]triazol-1-yl)-phenyl, 4-([1,2,4]triazol-1-yl)-phenyl, 5-(thiadiazol-5-yl)-thiophen-2-yl, 5-(isoxazol-3-yl)-thiophen-2-yl, 5-(pyridin-2-yl)-thiophen-2-yl or 5-(5-methoxy-[1,2,4]thiadiazol-3-yl)-thiophen-2-yl.
- 27. The method of claim 14 comprising a method of treating a heart disease that is associated with systolic dysfunction.
- 28. A pharmaceutical formulation comprising a pharmaceutically accepted excipient and a therapeutically effective amount of a compound represented by Formula I:
- 29. The pharmaceutical formulation of claim 28 where m is 2, n is 2, and p is 0.
- 30. The pharmaceutical formulation of claim 29 where X is C(H)— or S═.
- 31. The pharmaceutical formulation of claim 30 where R1 is substituted aryl or substituted heteroaryl.
- 32. The pharmaceutical formulation of claim 31 where R1 is 4-alkoxyphenyl, 4-bromo-2-fluorophenyl, 4-bromophenyl, 4-chlorophenyl, 4-chloro-2-methylphenyl, 4-cyanophenyl, 4-fluorophenyl, 3-methylphenyl, 4-methylphenyl, 4-nitrophenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 5-bromo-thiophen-2-yl or 5-chloro-thiophen-2-yl.
- 33. The pharmaceutical formulation of claim 32 where R1 is 4-chlorophenyl.
- 34. The pharmaceutical formulation of claim 28 where R2 is lower alkyl, alkoxycarbonyl, halo or hydroxy.
- 35. The pharmaceutical formulation of claim 28 where R3 is methyl, hydrogen, or a valence bond of S═ when X is S═.
- 36. The pharmaceutical formulation of claim 35 where R3 is hydrogen, or a valence bond of S═ when X is S═.
- 37. The pharmaceutical formulation of any of claims 28, 29, 30, 33, or 36 where R4 is optionally substituted aryl or optionally substituted heteroaryl.
- 38. The pharmaceutical formulation of claim 37 where:
R4 is phenyl optionally substituted with one or more of the following: acetyl, acyl, acyloxy, optionally substituted alkoxy, alkoxycarbonyl, optionally substituted alkyl, optionally substituted amino, aminocarbonyl, azido, cyano, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroaralkoxy, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, halo, hydroxy, nitro, sulfanyl, sulfonamido, sulfonyl and trifluoromethyl, or R4 is benzodioxineyl, benzodioxolyl, benzothiazolyl, furanyl, pyrazolyl, pyridinyl, pyrrolyl or thiophenyl, optionally substituted with one or more of the following: optionally substituted alkyl, alkoxy, alkoxycarbonyl, halo, optionally substituted heteroaryl, optionally substituted heteroaryloxy and oxo.
- 39. The pharmaceutical formulation of claim 37 where R4 is 4-(1-aminoethyl)-phenyl, 4-(2-cyanoethoxymethyl)-phenyl, 4-(1-hydroxyethyl)-phenyl, 4-(2-hydroxyethyl)-phenyl, 4-(1-hydroxy-2-methoxyethyl)-phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-methoxymethoxyphenyl, 4-methoxymethoxymethylphenyl, 4-methoxymethylphenyl, 4-(pyrazin-2-yloxymethyl)-phenyl, 4-(pyrazol-1-yl)-phenyl, 4-(pyridin-3-ylmethoxy)-phenyl, 4-[(pyridin-2-ylmethyl)-amino]-phenyl, 4-(pyridin-2-yloxy)-phenyl, 4-(2-hydroxy-thiazol-5-ylmethoxy)-phenyl, 4-([1,2,3]triazol-1-yl)-phenyl, 4-([1,2,4]triazol-1-yl)-phenyl, 5-(thiadiazol-5-yl)-thiophen-2-yl, 5-(isoxazol-3-yl)-thiophen-2-yl, 5-(pyridin-2-yl)-thiophen-2-yl, or 5-(5-methoxy-[1,2,4]thiadiazol-3-yl)-thiophen-2-yl.
- 40. The pharmaceutical formulation of claim 29 where R1 is 4-chlorophenyl, and R3 is hydrogen or a valence bond of S═ when X is S═, wherein:
X is C(H)— and R4 is 4-(1-aminoethyl)-phenyl, 4-(1-hydroxyethyl)-phenyl, 4-(1-hydroxy-2-methoxyethyl)-phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-methoxymethoxyphenyl, 4-(pyridin-3-ylmethoxy)-phenyl or 4-(pyridin-2-yloxy)-phenyl; or X is S═ and R4 is 4-(2-cyanoethoxymethyl)-phenyl, 4-(1-hydroxyethyl)-phenyl, 4-(2-hydroxyethyl)-phenyl, 4-methoxyphenyl, 4-methoxymethoxyphenyl, 4-methoxymethoxymethylphenyl, 4-methoxymethylphenyl, 4-(pyrazin-2-yloxymethyl)-phenyl, 4-(pyrazol-1-yl)-phenyl, 4-(pyrimidin-2-yloxy)-phenyl, 4-(pyridin-3-ylmethoxy)-phenyl, 4-[(pyridin-2-ylmethyl)-amino]-phenyl, 4-(pyridin-2-yloxy)-phenyl, 4-(2-hydroxy-thiazol-5-ylmethoxy)-phenyl, 4-([1,2,3]triazol-1-yl)-phenyl, 4-([1,2,4]triazol-1-yl)-phenyl, 5-(thiadiazol-5-yl)-thiophen-2-yl, 5-(isoxazol-3-yl)-thiophen-2-yl, 5-(pyridin-2-yl)-thiophen-2-yl or 5-(5-methoxy-[1,2,4]thiadiazol-3-yl)-thiophen-2-yl.
CROSS-REFERENCE TO RELATED APPLICATONS
[0001] This application claims the benefit of co-pending provisional U.S. Application Serial No. 60/343,092, filed Dec. 21, 2001, incorporated herein by reference.
STATEMENT OF GOVERNMENT INTEREST
[0002] This invention was made with government support under NIH Grant Number 1 R43 HL66647-01. Accordingly, the United States Government may have certain rights in this invention.
Provisional Applications (1)
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Number |
Date |
Country |
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60343092 |
Dec 2001 |
US |