Cyanoamide compounds useful as malonyl-CoA decarboxylase inhibitors

• US 20050026945A1
• Filed: 07/28/2004
• Published: 02/03/2005
• Est. Priority Date: 08/01/2003
• Status: Active Grant

• Current Assignee: Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG)
• Original Assignee: Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG)
• Inventors: Lopaschuk, Gary D., Dyck, Jason R., Wilson, Mark E., Russell, Anna, Kafka, Mark D.
• Granted Patent: US 7,285,562 B2
• Time in Patent Office: Days
• US Class Current: 514/301
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/12 for electrolyte homeostasis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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
• CPC Class Codes: C07D 277/70 Sulfur atoms
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides methods for the use of compounds as depicted by structure I, pharmaceutical compositions containing the same, and methods for the prophylaxis, management and treatment of metabolic diseases and diseases modulated by MCD inhibition. The compounds disclosed in this invention are useful for the prophylaxis, management and treatment of diseases involving in malonyl-CoA regulated glucose/fatty acid metabolism pathway. In particular, these compounds and pharmaceutical composition containing the same are indicated in the prophylaxis, management and treatment of cardiovascular diseases, diabetes, cancer and obesity.

Claims

1. A pharmaceutical composition useful for inhibiting the enzyme malonyl-CoA decarboxylase which comprises a member selected from the group consisting of compounds of the formula (I):

2. A compound according to claim 1 having the general structure formula (Ia and Ib):

3. A compound according to claims 1 or 2 having the general structure formulae (Ic and Id) wherein R₁ and R₃ are as defined in claim 1.

4. A compound according to claims 1, 2 or 3 selected from the group consisting of:

2-Cyano-3-hydroxy-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-3-(4-trifluoromethyl-phenyl)-acrylamide;

2-Cyano-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-3-(4-trifluoromethyl-phenyl)-acrylamide;

2-Cyano-3-hydroxy-4-methyl-hept-2-enoic acid isopropyl-(2-mercapto-benzothiazol-6-yl)-amide;

2-Cyano-3-hydroxy-5,5-dimethyl-hex-2-enoic acid isopropyl-(2-mercapto-benzothiazol-6-yl)-amide;

2-Cyano-3-hydroxy-4-phenyl-but-2-enoic acid isopropyl-(2-mercapto-benzothiazol-6-yl)-amide;

2-Cyano-3-hydroxy-5-phenyl-pent-2-enoic acid isopropyl-(2-mercapto-benzothiazol-6-yl)-amide;

2-Cyano-3-hydroxy-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-3-(3-trifluoromethyl-phenyl)-acrylamide;

2-Cyano-3-(4-cyano-phenyl)-3-hydroxy-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-acrylamide;

3-(4-Butoxy-phenyl)-2-cyano-3-hydroxy-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-acrylamide;

2-Cyano-3-hydroxy-4-thiophen-2-yl-but-2-enoic acid isopropyl-(2-mercapto-benzothiazol-6-yl)-amide;

2-Cyano-5-methyl-hex-2-enoic acid isopropyl-(2-mercapto-benzothiazol-6-yl)-amide;

2-Cyano-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-3-(3-trifluoromethyl-phenyl)-acrylamide;

9-Cyano-8-hydroxy-9-[isopropyl-(2-mercapto-benzothiazol-6-yl)-carbamoyl]-non-8-enoic acid methyl ester;

9-Cyano-8-hydroxy-9-[isopropyl-(2-mercapto-benzothiazol-6-yl)-carbamoyl]-non-8-enoic acid;

2-Cyano-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-3-thiophen-2-yl-acrylamide;

2-Cyano-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-3-thiophen-3-yl-acrylamide;

2-Cyano-3-(4-cyano-phenyl)-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-acrylamide;

3-(4-Chloro-phenyl)-2-cyano-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-acrylamide;

3-(4-Butoxy-phenyl)-2-cyano-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-acrylamide;

2-Cyano-3-cyclohexyl-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-acrylamide;

2-Cyano-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-3-(tetrahydro-furan-3-yl)-acrylamide;

2-Cyano-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-3-thiazol-2-yl-acrylamide;

2-Cyano-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-3-(1-methyl-1H-imidazol-2-yl)-acrylamide;

3-(4-Bromo-phenyl)-2-cyano-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-acrylamide;

3-(3-Chloro-phenyl)-2-cyano-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-acrylamide;

2-Cyano-3-(3,4-dichloro-phenyl)-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-acrylamide;

2-Cyano-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-3-p-tolyl-acrylamide;

2-Cyano-3-(4-ethyl-phenyl)-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-acrylamide;

2-Cyano-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-3-(4-methoxy-phenyl)-acrylamide;

4-{2-Cyano-2-[isopropyl-(2-mercapto-benzothiazol-6-yl)-carbamoyl]-vinyl}-benzoic acid methyl ester;

2-Cyano-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-3-(4-methylsulfanyl-phenyl)-acrylamide;

2-Cyano-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-3-pyridin-4-yl-acrylamide;

2-Cyano-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-3-pyridin-3-yl-acrylamide;

2-Cyano-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-N-isopropyl-N-(2-mercapto-benzothiazol-6-yl)-acrylamide;

4-{2-Cyano-2-[isopropyl-(2-mercapto-benzothiazol-6-yl)-carbamoyl]-vinyl}-benzoic acid; and

4-{2-Cyano-2-[isopropyl-(2-mercapto-benzothiazol-6-yl)-carbamoyl]-vinyl}-benzoic acid.

5. A method for inhibiting malonyl-CoA decarboxylase in a patient which comprises the administration of a therapeutically effective amount of a composition according to claim 1.

6. A method for shifting fatty acid metabolism to carbohydrate metabolism in a patient by increasing malonyl-CoA concentration which comprises the administration of a therapeutically effective amount of a composition according to claim 1.

7. A method for treating diseases associated with fatty acid and glucose metabolism mediated by malonyl-CoA decarboxylase in a patient which comprises the administration of a therapeutically effective amount of a composition according to claim 1.

8. A method according to claim 7 wherein said disease is a cardiovascular disease.

9. A method according to claim 8 wherein said cardiovascular disease is congestive heart failure.

10. A method according to claim 9 wherein said cardiovascular disease is an ischemic cardiovascular disease.

11. A method according to claim 10 wherein said ischemic cardiovascular disease is angina pectoris.

12. A method according to claim 7 wherein said disease is diabetes.

13. A method according to claim 7 wherein said disease is obesity.

14. A method according to claim 7 wherein said disease is acidosis.

15. A method according to claim 7 wherein said disease is cancer.