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Last Updated: March 28, 2024

Claims for Patent: 4,313,951


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Summary for Patent: 4,313,951
Title: 3-Substituted-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones, their cardiotonic use and intermediates therefor
Abstract:1-R.sub.1 -3-[amino, cyano, carbamyl, halo, lower-alkylamino, di-(lower-alkyl)amino or lower-acylamino]-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones or pharmaceutically-acceptable acid-addition or cationic salts thereof are useful as cardiotonic agents, where R.sub.1 is hydrogen, lower-alkyl or lower-hydroxyalkyl. 1-R.sub.1 -3-amino-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones are prepared by hydrolyzing the corresponding 3-cyano compounds to produce the corresponding 3-carbamyl compounds and reacting the latter with a reagent capable of converting carbamyl to amino. The 1-R.sub.1 -3-cyano-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones are prepared by reacting (pyridinylmethyl) lower-alkyl ketones with dimethylformamide di-(lower-alkyl) acetal to produce 1-(pyridinyl)-2-(dimethylamino)ethenyl lower-alkyl ketone and reacting said ketones with N-R.sub.1 -.alpha.-cyanoacetamide to produce the 1-R.sub.1 -3-cyano-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones. Also shown are the conversions: of the 3-cyano compounds to the 3-H compounds; of the 3-H compounds to the 3-halo compounds; of the 3-halo compounds to the 3-[mono-(lower-alkyl)- or di-(lower-alkyl)-amino]compounds; and, of the 3-amino compounds to the 3-lower-acylamino or 3-[mono-(lower-alkyl)- or di-(lower-alkyl)amino] compounds.
Inventor(s): Lesher; George Y. (Schodack, NY), Philion; Richard E. (Schodack, NY)
Assignee: Sterling Drug Inc. (New York, NY)
Application Number:06/198,461
Patent Claims: 1. A 1-R.sub.1 -3-Q-5-PY-6-R-2(1H)-pyridinone having the formula ##STR3## where Q is amino, cyano, carbamyl, halo, lower-alkylamino, di-(lower-alkyl)amino or lower-acylamino, R.sub.1 is hydrogen, lower-alkyl or lower-hydroxyalkyl, R is lower-alkyl and PY is 4-, 3- or 2-pyridinyl or 4-, 3- or 2-pyridinyl having one or two lower-alkyl substituents, or pharmaceutically-acceptable acid-addition or cationic salt thereof.

2. A compound according to claim 1 where Q is amino.

3. A compound according to claim 1 where Q is cyano.

4. A compound according to claim 1 where Q is carbamyl.

5. A compound according to claim 1 where Q is halo.

6. A compound according to claim 1 where Q is lower-alkylamino.

7. A compound according to claim 1 where Q is di-(lower-alkyl)amino.

8. A compound according to claim 1 where Q is lower-acylamino.

9. 3-Amino-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone or pharmaceutically-acceptable acid-addition salt thereof.

10. 3-Amino-6-ethyl-5-(4-pyridinyl)-2(1H)-pyridinone or pharmaceutically-acceptable acid-addition salt thereof.

11. 3-Amino-6-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone or pharmaceutically-acceptable acid-addition salt thereof.

12. 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile or pharmaceutically-acceptable acid-addition salt thereof.

13. 6-Methyl-3-methylamino-5-(4-pyridinyl)-2(1H)-pyridinone or pharmaceutically-acceptable acid-addition salt thereof.

14. 3-Bromo-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone or pharmaceutically-acceptable acid-addition salt thereof.

15. 6-Ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile according to claim 3.

16. 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinamide according to claim 4.

17. 6-Ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide according to claim 4.

18. 3-Ethylamino-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone according to claim 6.

19. 3-Dimethylamino-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone according to claim 7.

20. A cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically-acceptable inert carrier and, as the active component thereof, an effective amount of a cardiotonic 1-R.sub.1 -3-Q-5-PY-6-R-2(1H)pyridinone having the formula ##STR4## where Q is amino, cyano, carbamyl, halo, lower-alkylamino, di-(lower-alkyl)amino or lower-acylamino, R.sub.1 is hydrogen, lower-alkyl or lower-hydroxyalkyl, R is lower-alkyl and PY is 4-, 3- or 2-pyridinyl or 4-, 3- or 2-pyridinyl having one or two lower-alkyl substituents, or pharmaceutically-acceptable acid-addition or cationic salt thereof.

21. A composition according to claim 20 where the active component is 3-amino-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone or pharmaceutically-acceptable acid-addition salt thereof.

22. A composition according to claim 20 where the active component is 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile or pharmaceutically-acceptable acid-addition salt thereof.

23. A composition according to claim 20 where the active component is 3-amino-6-ethyl-5-(4-pyridinyl)-2(1H)-pyridinone or pharmaceutically-acceptable acid-addition salt thereof.

24. The 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 an effective amount of a cardiotonic 1-R.sub.1 -3-Q-5-PY-6-R-2(1H)-pyridinone having the formula ##STR5## where Q is amino, cyano, carbamyl, halo, lower-alkylamino, di-(lower-alkyl)amino or lower-acylamino, R.sub.1 is hydrogen, lower-alkyl or lower-hydroxyalkyl, R is lower-alkyl and PY is 4-, 3- or 2-pyridinyl or 4-, 3- or 2-pyridinyl having one or two lower-alkyl substitutents, or pharmaceutically-acceptable acid-addition or cationic salt thereof.

25. The method according to claim 24 where Q is amino, R is methyl or ethyl, and PY is 4-pyridinyl.

26. The method according to claim 24 where Q is cyano, R is methyl or ethyl, and PY is 4-pyridinyl.

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