COMPOSITION AND METHODS TO TREAT CARDIAC DISEASES

• US 20070281908A1
• Filed: 05/22/2007
• Published: 12/06/2007
• Est. Priority Date: 05/23/2006
• Status: Active Grant

• Current Assignee: University of Connecticut (State of Connecticut)
• Original Assignee: University of Connecticut (State of Connecticut)
• Inventors: Pappano, Achilles, Shen, Jian-Bing, Liang, Bruce
• Granted Patent: US 8,410,078 B2
• Time in Patent Office: Days
• US Class Current: 514/81
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Disclosed herein are N-methanocarba derivatives of AMP and their use in the treatment of cardiac and vascular diseases and conditions responsive to activation of the cardiac P2X receptor. In one embodiment, the N-methanocarba derivative of AMP is the N-methanocarba derivative of 2-chloro-AMP. Diseases and conditions responsive to activation of the cardiac P2X receptor include, for example, cardiac hypertrophy, cardiac failure resulting from any cause of abnormal Ca²⁺ homeostasis or from myocardial injuries, vascular insufficiency leading to myocardial infarction, post-myocardial infarction conditions, post-myocardial infarction conditions within the short-term post-infarction period, and diastolic heart failure.

Claims

1. A method of treating a mammalian subject in need of treatment for a cardiac or vascular disease or condition responsive to activation of the cardiac P2X receptor, comprising

administering an effective amount of an N-methanocarba derivative of AMP for the treatment of the cardiac or vascular disease or condition responsive to activation of the cardiac P2X receptor.

2. The method of claim 1, wherein the N-methanocarba derivative of AMP is a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein;

R₁ is hydrogen, alkyl, alkoxy, amino, mono- or di-alkylamino, mono or bicyclic cycloalkyl, cycloalkyloxy, aryl, arylalkyl, acyl, sulfonyl, arylsulfonyl, or a mono- or bicyclic thiazolyl group; and

R₂ is hydrogen, halogen, thiol, cyano, alkyl, alkenyl, alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aryl, arylamino, or aryloxy;

R₃ is hydrogen, halogen, methyl, or ethyl; and

R₄ and R₅ are independently hydrogen, methyl, or methoxy.

3. The method of claim 2, wherein

R₁ is hydrogen, C₁-C₄alkyl, C₁-C₄alkoxy, amino, mono- or di-C₁-C₄alkylamino, C₃-C₇cycloalkyl, or C₃-C₇cycloalkyloxy;

R₂ is hydrogen, halogen, thiol, cyano, C₁-C₄alkyl, C₁-C₄alkylthio, C₁-C₄alkylsulfinyl, or C₁-C₄alkylsulfonyl; and

R₃, R₄, and R₅ are all hydrogen.

4. The method of claim 2, wherein

R₁ is NH₂ or CH₃NH;

R₂ is H, Cl, SCH₃ or SOCH₃; and

R₃, R₄, and R₅ are all hydrogen.

5. The method of claim 1, wherein the N-methanocarba derivative of AMP is

6. The method of claim 1, wherein the cardiac or vascular disease or condition responsive to activation of the cardiac P2X receptor is a cardiomyopathy or a disease associated with defects in cardiac contractility.

7. The method of claim 6, wherein the cardiac or vascular disease or condition responsive to activation of the cardiac P2X receptor is cardiac hypertrophy or cardiac failure resulting from abnormal Ca²⁺ homeostasis.

8. The method of claim 7, wherein the cardiac failure resulting from abnormal Ca²⁺ homeostasis is drug-induced cardiac failure, toxin-induced cardiac failure, alcohol-induced cardiac failure, cardiac failure due to congenital heart disease, or cardiac failure due to valvular disease.

9. The method of claim 1, wherein the cardiac or vascular disease or condition responsive to activation of the cardiac P2X receptor is vascular insufficiency leading to myocardial infarction, post-myocardial infarction conditions, and post-myocardial infarction conditions within the short-term post-infarction period.

10. The method of claim 9, wherein the cardiac or vascular disease or condition responsive to activation of the cardiac P2X receptor is diastolic heart failure.

11. The method of claim 1, further comprising administering a beta-adrenergic blocker, an angiotension receptor blocker, or an angiotensin converting enzyme blocker.

12. A method of improving cardiac contractile performance in a mammal in need thereof, comprising

administering an effective amount of an N-methanocarba derivative of AMP for improving cardiac contractile performance.

13. The method of claim 12, wherein the N-methanocarba derivative of AMP is:

or a pharmaceutically acceptable salt thereof, wherein;

R₁ is hydrogen, alkyl, alkoxy, amino, mono- or di-alkylamino, mono or bicyclic cycloalkyl, cycloalkyloxy, aryl, arylalkyl, acyl, sulfonyl, arylsulfonyl, or a mono- or bicyclic thiazolyl group; and

R₂ is hydrogen, halogen, thiol, cyano, alkyl, alkenyl, alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aryl, arylamino, or aryloxy;

R₃ is hydrogen, halogen, methyl, or ethyl; and

R₄ and R₅ are independently hydrogen, methyl, or methoxy.

14. The method of claim 13, wherein

R₁ is hydrogen, C₁-C₄alkyl, C₁-C₄alkoxy, amino, mono- or di-C₁-C₄alkylamino, C₃-C₇cycloalkyl, or C₃-C₇cycloalkyloxy;

R₂ is hydrogen, halogen, thiol, cyano, C₁-C₄alkyl, C₁-C₄alkylthio, C₁-C₄alkylsulfinyl, or C₁-C₄alkylsulfonyl; and

R₃, R₄, and R₅ are all hydrogen.

15. The method of claim 12, wherein the mammal has had or is suspected of having a myocardial infarction.

16. The method of claim 12, wherein administering is performed within the short-term post-infarction period.

17. The method of claim 12, wherein the mammal is in need of treatment for diastolic heart failure.

18. A method of treating a mammalian subject in need of treatment for a cardiac hypertrophy, comprising

administering an effective amount of a cardiac P2X receptor agonist.

19. The method of claim 18, wherein the cardiac P2X receptor agonist is an N-methanocarba derivative of AMP.

20. The method of claim 19, wherein the N-methanocarba derivative of AMP is a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein;

R₁ is hydrogen, alkyl, alkoxy, amino, mono- or di-alkylamino, mono or bicyclic cycloalkyl, cycloalkyloxy, aryl, arylalkyl, acyl, sulfonyl, arylsulfonyl, or a mono- or bicyclic thiazolyl group; and

R₂ is hydrogen, halogen, thiol, cyano, alkyl, alkenyl, alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aryl, arylamino, or aryloxy;

R₃ is hydrogen, halogen, methyl, or ethyl; and

R₄ and R₅ are independently hydrogen, methyl, or methoxy.