Composition and methods to treat cardiac diseases

• US 8,410,078 B2
• Filed: 05/22/2007
• Issued: 04/02/2013
• 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 Tsan
• Primary Examiner(s): Gembeh, Shirley V
• Application Number:
  US11/751,699
• Publication Number:
  US 20070281908A1
• Time in Patent Office: 2,142 Days
• Field of Search: 514/81, 514/269, 514/263.4, 514/263.3, 544/244, 544/277
• 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 that activates a cardiac P2X receptor for the treatment of the cardiac or vascular disease or condition responsive to activation of the cardiac P2X receptor,

wherein the N-methanocarba derivative of AMP that activates the cardiac P2X receptor is of the formula:

2. The method of claim 1, 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.

3. The method of claim 1, wherein

R₁ is NH₂ or CH₃NH;

R₂ is H, Cl, SCH₃ or SOCH₃; and

R₃, R₄, and R₅ are all hydrogen.

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

5. The method of claim 1, wherein the post-myocardial infarction condition is post-myocardial infarction conditions within the short-term post-infarction period.

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

7. The method of claim 1, wherein the post-myocardial infarction condition is ischemic cardiomyopathy.

8. 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 that activates a cardiac P2X receptor for improving cardiac contractile performance, wherein the N-methanocarba derivative of AMP that activates a cardiac P2X receptor is of the formula:

9. The method of claim 8, 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.

10. The method of claim 8, wherein administering is performed within the short-term post-infarction period.

11. The method of claim 8, wherein the N-methanocarba derivative of AMP is a compound of the formula:

12. The method of claim 8, wherein the post-myocardial infarction condition is ischemic cardiomyopathy.

13. 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,

wherein the N-methanocarba derivative of AMP is a compound of the formula:

14. The method of claim 13, wherein the N-methanocarba derivative of AMP is a compound of the formula: