5-(Phenyl)-1,6-naphthyridin-2(1H)-ones, their cardiotonic use and preparation

• US 4,560,691 A
• Filed: 07/13/1984
• Issued: 12/24/1985
• Est. Priority Date: 07/13/1984
• Status: Expired due to Fees

• Current Assignee: Sanofi S.A. (Sanofi )
• Original Assignee: Sterling Drug, Inc. (GSK plc)
• Inventors: Singh, Baldev, Lesher, George Y.
• Primary Examiner(s): Jiles, Henry R.
• Assistant Examiner(s): Cassatt, Barbara
• Application Number:
  US06/630,810
• Time in Patent Office: 529 Days
• Field of Search: 546/122, 546/298, 514/300, 514/350, 424/263, 424/256
• US Class Current: 514/300
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

1-R-5-Ar-1,6-naphthyridin-2(1H)-ones (I) or salts thereof, where R is hydrogen or methyl, and Ar is phenyl or phenyl substituted by methyl, ethyl, methoxy, ethoxy, hydroxy, amino, acetylamino, methanesulfonylamino, bromo, chloro, fluoro, cyano or carbamyl are useful as cardiotonic agents and corresponding compounds where Ar is nitrophenyl are useful as intermediates. Also shown as intermediates, are 5-(Ar--CO)-6-[2-(di-lower-alkylamino)-ethenyl]-2(1H)-pyridinones (II) or salts thereof, where Ar is phenyl or phenyl substituted by methyl, ethyl, methoxy, ethoxy, bromo, chloro, fluoro, cyano or nitro and 5-(Ar--CO)-6-methyl-2(1H)-pyridinones (III) where Ar is phenyl or phenyl substituted by methyl, ethyl, methoxy, ethoxy, bromo, chloro, fluoro, hydroxy, cyano or nitro; said compounds (III) where Ar is phenyl or hydroxyphenyl also are useful as cardiotonic agents. Processes for preparing the compounds of formulas I, II and III are shown.

Claims

1. 1-R-5-Ar-1,6-naphthyridin-2(1H)-one having the formula ##STR4## or acid-addition or cationic salt thereof, where R is hydrogen or methyl and Ar is phenyl or phenyl substituted by a member selected from methyl, ethyl, methoxy, ethoxy, hydroxy, amino, acetylamino, methanesulfonylamino, bromo, chloro, fluoro, nitro, cyano or carbamyl.

2. A compound according to claim 1 where R is hydrogen and Ar is phenyl, 4-hydroxyphenyl, 4-carbamylphenyl, 4-aminophenyl, 4-bromophenyl or 4-chlorophenyl.

3. 5-Phenyl-1,6-naphthyridin-2(1H)-one according to claim 1.

4. 5-(4-Hydroxyphenyl)-1,6-naphthyridin-2(1H)-one according to claim 1.

5. 5-(4-Carbamylphenyl)-1,6-naphthyridin-2(1H)-one according to claim 1.

6. 5-(4-Aminophenyl)-1,6-naphthyridin-2(1H)-one according to claim 1.

7. 5-(4-Bromophenyl)-1,6-naphthyridin-2(1H)-one according to claim 1.

8. 5-(4-Chlorophenyl)-1,6-naphthyridin-2(1H)-one according to claim 1.

24. A cardiotonic composition for increasing cardiac contractility which comprises a pharmaceutically acceptable carrier and, as the active component thereof, a cardiotonically effective amount of the 1-R-5-Ar-1,6-naphthyridin-2(1H)-one of claim 1 or pharmaceutically acceptable acid-addition or cationic salt thereof, where R is hydrogen or methyl and Ar is phenyl or phenyl substituted by a member selected from methyl, ethyl, methoxy, ethoxy, hydroxy, amino, acetylamino, methanesulfonylamino, bromo, chloro, fluoro, cyano or carbamyl.

25. A cardiotonic composition according to claim 24 where in in the active component R is hydrogen and Ar is phenyl, 4-hydroxyphenyl, 4-carbamylphenyl, 4-aminophenyl, 4-bromophenyl or 4-chlorophenyl.

26. A cardiotonic composition according to claim 24 where the active component is 5-phenyl-1,6-naphthyridine-2(1H)-one.

27. A method for increasing cardiac contractility in a patient requiring such treatment which comprises administering orally or parenterally in a solid or liquid dosage form to such patient a cardiotonically effective amount of the 1-R-5-Ar-1,6-naphthyridin-2(1H)-one of claim 1 or pharmaceutically acceptable acid-addition or cationic salt thereof, where R is hydrogen or methyl and Ar is phenyl or phenyl substituted by a member selected from methyl, ethyl, methoxy, ethoxy, hydroxy, amino, acetylamino, methanesulfonylamino, bromo, chloro, fluoro, cyano or carbamyl.

28. A method according to claim 27 where in the active component R is hydrogen and Ar is phenyl, 4-hydroxyphenyl, 4-carbamylphenyl, 4-aminophenyl, 4-bromophenyl or 4-chlorophenyl.

29. A method according to claim 27 where the active component is 5-phenyl-1,6-naphthyridin-2(1H)-one.

9. 5-(Ar--CO)-6-[2-(di-lower-alkylamino)ethenyl]-2(1H)-pyridinone having the formula ##STR5## or acid-addition salt thereof, where Ar is phenyl or phenyl substituted by a member selected from methyl, ethyl, methoxy, ethoxy, bromo, chloro, fluoro, cyano or nitro, and R₁ and R₂ are each lower-alkyl.

10. A compound according to claim 9 where R₁ and R₂ are each methyl and Ar is phenyl, 4-methoxyphenyl, 4-bromophenyl, 4-chlorophenyl or 4-nitrophenyl.

11. 5-Benzoyl-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone according to claim 9.

12. 6-(2-Dimethylaminoethenyl)-5-(4-methoxybenzoyl)-2(1H)-pyridinone according to claim 9.

13. 5-(4-Bromobenzoyl)-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone according to claim 9.

14. 5-(4-Chlorobenzoyl)-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone according to claim 9.

15. 6-(2-Dimethylaminoethenyl)-5-(4-nitrobenzoyl)-2(1H)pyridinone according to claim 9.

16. 5-(Ar--CO)-6-methyl-2(1H)-pyridinone having the formula ##STR6## where Ar is phenyl or phenyl substituted by a member selected from methyl, ethyl, methoxy, ethoxy, bromo, chloro, fluoro, hydroxy, cyano or nitro.

17. A compound according to claim 16 where Ar is phenyl, 4-methoxyphenyl, 4-bromophenyl, 4-chlorophenyl, 4-hydroxyphenyl or 4-nitrophenyl.

18. 5-Benzoyl-6-methyl-2(1H)-pyridinone according to claim 16.

19. 5-(4-Methoxybenzoyl)-6-methyl-2(1H)-pyridinone according to claim 16.

20. 5-(4-Bromobenzoyl)-6-methyl-2(1H)-pyridinone according to claim 16.

21. 5-(4-Chlorobenzoyl)-6-methyl-2(1H)-pyridinone according to claim 16.

22. 6-Methyl-5-(4-nitrobenzoyl)-2(1H)-pyridinone according to claim 16.

23. 5-(4-Hydroxybenzyol)-6-methyl-2(1H)-pyridinone according to claim 16.

30. A cardiotonic composition for increasing cardiac contractility which comprises a pharmaceutically acceptable carrier and, as the active component thereof, a cardiotonically effective amount of 5-benzoyl-6-methyl-2(1H)-pyridinone or 5-(4-hydroxybenzoyl)-6-methyl-2(1H)-pyridinone according to claim 16.

31. A method for increasing cardiac contractility in a patient requiring such treatment which comprises administering orally or parenterally in a solid or liquid dosage form to such patient a cardiotonically effective amount of 5-benzoyl-6-methyl-2(1H)-pyridinone or 5-(4-hydroxyphenyl)-6-methyl-2(1H)-pyridinone of claim 16.