Left ventricular diastolic function improving agent

Patent metadata

Field	Value
Publication number	US-9682065-B2
Application number	US-201214236474-A
Country	US
Kind code	B2
Filing date	Aug 1, 2012
Priority date	Aug 2, 2011
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

An agent for treating heart failure, which improves left ventricular diastolic function itself without depending on the diuretic effect or vasodilation effect; controls the pathological condition of diastolic functional failure; and prevents the recurrence, and can prevent dyspnea and death from the pathological condition, is provided.
By directly acting on a heart, 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid improves left ventricular diastolic function, and can effectively treat diastolic functional failure among heart failure types. Accordingly, by present invention, a new agent for treating heart failure that can relieve diastolic functional failure, for which no effective therapeutic method has been established, can be provided.

First claim

The invention claimed is:

1. A method for treating heart failure, wherein an effective amount of 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof is administered to a mammal in need thereof.

2. The method according to claim 1 , wherein the heart failure is acute heart failure or chronic heart failure.

3. The method according to claim 1 , wherein the heart failure is diastolic heart failure.

4. The method of claim 1 , wherein the method comprises improving left ventricular diastolic function.

5. The method of claim 4 , wherein the heart failure is diastolic heart failure.

6. The method of claim 2 , wherein the method comprises improving left ventricular diastolic function.

7. A method for treating heart failure by administering an effective amount of 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof to a mammal in need thereof, which changes Peak positive dP/dt and Peak negative dP/dt of a mammal having a pathological condition of heart failure, wherein the change ratio of the Peak negative dP/dt calculated from the values before and after the administration of the agent is larger than the change ratio of the Peak positive dP/dt.

8. The method according to claim 7 , which is a method for treating diastolic heart failure.

9. A method for improving the survival rate of heart failure, wherein an effective amount of 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof is administered to a mammal in need thereof.

10. A method for treating heart failure in which diastolic function is impaired, wherein an effective amount of 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof is administered to a mammal in need thereof.

11. A method for reducing the dose of an existing agent for treating heart failure, wherein an effective amount of 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof is administered to a mammal in need thereof.

12. A method for reducing the side effect of an existing agent for treating heart failure, wherein an effective amount of 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof is administered to a mammal in need thereof.

13. The method according to claim 11 or 12 , wherein the existing agent is one or more compounds selected from an angiotensin-converting enzyme inhibitor, an angiotensin II receptor antagonist, a β-blocker, a digitalis preparation, a diuretic agent, a natriuretic peptide, a vasodilator, a phosphodiesterase III inhibitor and/or an aldosterone antagonist.

14. A method for improving the survival rate of patients with heart failure associated with hypertension, wherein an effective amount of 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof is administered to a mammal in need thereof.

15. A method for improving left ventricular diastolic function and/or treating systolic heart failure, wherein an effective amount of 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof is administered to a mammal in need thereof.

16. A method for improving left ventricular diastolic function and/or improving left ventricular systolic function, wherein an effective amount of 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof is administered to a mammal in need thereof.

17. A method for treating systolic heart failure, wherein an effective amount of 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof is administered to a mammal in need thereof.

18. A method for improving left ventricular distensibility, wherein an effective amount of 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof is administered to a mammal in need thereof.

19. A method for selectively improving left ventricular diastolic function, wherein an effective amount of 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof is administered to a mammal in need thereof, which selectively improves left ventricular diastolic function in comparison with left ventricular systolic function.

20. A method for treating diastolic heart failure, wherein an effective amount of 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof is administered to a mammal in need thereof, which selectively improves left ventricular diastolic function in comparison with left ventricular systolic function.

21. A method for treating and/or improving diastolic functional failure, wherein an effective amount of 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof is administered to a mammal in need thereof.

22. A method for treating and/or improving diastolic functional disorderdysfunction, wherein an effective amount of 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof is administered to a mammal in need thereof.

23. A method for treating diastolic heart failure, wherein an effective amount of 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof is administered to a mammal in need thereof.

24. The method according to claim 16 , which is a method for improving left ventricular diastolic function and for improving left ventricular systolic function.

25. The method of claim 16 , which is a method for improving left ventricular diastolic function.

26. A method for treating and/or relieving dyspnea associated with heart failure, wherein 4-[(2-{(2R)-2-[(1E,3S)-4-(4-fluorophenyl)-3-hydroxy-1-buten-1-yl]-5-oxo-1-pyrrolidinyl}ethyl)thio]butanoic acid, a salt thereof, a solvate thereof or a cyclodextrin clathrate thereof is administered to a mammal.

Assignees

• Kanaji Toshiya
• Fuchibe Kazuhiro
• Takahashi Masaya
• Ono Pharmaceutical Co

Inventors

• Kanaji Toshiya
• Fuchibe Kazuhiro
• Takahashi Masaya

Classifications

• A61P9/06

  Antiarrhythmics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P43/00

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

• A61P7/10

  Antioedematous agents; Diuretics · CPC title