Dihydropyridinone Derivatives

• US 20080045541A1
• Filed: 02/05/2005
• Published: 02/21/2008
• Est. Priority Date: 02/19/2004
• Status: Active Grant

• Current Assignee: Bayer Intellectual Property GmbH (Bayer AG)
• Original Assignee: Bayer Healthcare AG (Bayer AG)
• Inventors: Bauser, Marcus, Pernerstorfer, Josef, Schlemmer, Karl-Heinz, Telan, Leila, Li, Volkhart, Albrecht, Barbara, Gielen-Haertwig, Heike, Keldenich, Jorg
• Granted Patent: US 8,097,629 B2
• Time in Patent Office: Days
• US Class Current: 514/253.12
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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 211/90 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The invention relates to novel dihydropyridinone derivatives, processes for their preparation, and their use in medicaments, especially for the treatment of chronic obstructive pulmonary diseases, acute coronary syndrome, acute myocardial infarction and heart failure development.

Claims

1. Compounds of the general formula (I)

2. Compounds of general formula (I) according to claim 1, wherein

A represents an aryl or heteroaryl ring,

R¹, R² and R³ independently from each other represent hydrogen, halogen, nitro, cyano, trifluoromethyl, C₁-C₆-alkyl, hydroxy, C₁-C₆-alkoxy or trifluoromethoxy, wherein C₁-C₆-alkyl and C₁-C₆-alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of hydroxy and C₁-C₄-alkoxy,

R⁴ represents C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono- or di-C₁-C₄-alkylaminocarbonyl or cyano, wherein C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, mono- and di-C₁-C₄-alkylaminocarbonyl can be substituted with one to three identical or different radicals selected from the group consisting of hydroxy, C₁-C₄-alkoxy, hydroxycarbonyl, C₁-C₄-alkoxycarbonyl, amino, mono- and di-C₁-C₄-alkylamino, aminocarbonyl, mono- and di-C₁-C₄-alkylaminocarbonyl, C₁-C₄-alkylcarbonylamino and heteroaryl,

R⁵ represents C₁-C₄-alkyl,

R⁶ represents

a group of the formula

3. Compounds of general formula (I) according to claim 1 or 2, wherein

A represents a phenyl or pyridyl ring,

R¹, R² and R³ independently from each other represent hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, trifluoromethyl or trifluoromethoxy,

R⁴ represents C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl or cyano, wherein C₁-C₆-alkylcarbonyl and C₁-C₆-alkoxycarbonyl can be substituted with one to two identical or different radicals selected from the group consisting of hydroxy, methoxy, hydroxycarbonyl, methoxycarbonyl, amino, mono- and di-C₁-C₄-alkylamino,

R⁵ represents methyl,

R⁶ represents

a group of the formula

4. Compounds of general formula (I) according to claim 1, 2 or 3, wherein

A represents a phenyl ring,

R¹ represents hydrogen,

R² represents cyano, bromo or nitro,

R³ represents hydrogen,

R⁴ represents C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxycarbonyl or cyano, wherein C₁-C₄-alkylcarbonyl and C₁-C₄-alkoxycarbonyl can be substituted with hydroxycarbonyl or C₁-C₄-alkoxycarbonyl,

R⁵ represents methyl,

R⁶ represents

a group of the formula

5. Compounds of general formula (I) according to at least one of claims 1 to 4, wherein A is phenyl.

6. Compounds of general formula (I) according to at least one of claims 1 to 5, wherein R¹ is hydrogen.

7. Compounds of general formula (I) according to at least one of claims 1 to 6, wherein R² is cyano.

8. Compounds of general formula (I) according to at least one of claims 1 to 7, wherein R³ is hydrogen.

9. Compounds of general formula (I) according to at least one of claims 1 to 8, wherein R⁴ is acetyl, methoxycarbonyl, ethoxycarbonyl or cyano.

10. Compounds of general formula (I) according to at least one of claims 1 to 9, wherein R⁵ is methyl.

11. Compounds of general formula (I) according to at least one of claims 1 to 10, wherein R⁷ is trifluoromethyl or nitro.

12. Compounds of general formula (IA)

13. Processes for synthesizing the compounds of general formula (I) or (IA), respectively, as defined in claims 1 to 12, characterized in that

[A] compounds of general formula (II)

14. The composition containing at least one compound of general formula (I) or (IA), as defined in claims 1 to 12, and a pharmacologically acceptable diluent.

15. A composition according to claim 14 for the treatment of acute and chronic inflammatory, ischaemic and/or remodelling processes.

16. The process for the preparation of compositions according to claim 14 and 15 characterized in that the compounds of general formula (I) or (IA), as defined in claims 1 to 12, together with customary auxiliaries are brought into a suitable application form.

17. Use of the compounds of general formula (I) or (IA), as defined in claims 1 to 12, for the preparation of medicaments.

18. Use according to claim 17 for the preparation of medicaments for the treatment of acute and chronic inflammatory, ischaemic and/or remodelling processes.

19. Use according to claim 18, wherein the process is chronic obstructive pulmonary disease, acute coronary syndrome, acute myocardial infarction or development of heart failure.

20. Process for controlling chronic obstructive pulmonary disease, acute coronary syndrome, acute myocardial infarction or development of heart failure in humans and animals by administration of an neutrophil elastase inhibitory amount of at least one compound according to any of claims 1 to 12.