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Synthesis and cardiotonic activity of esters of 2-substituted 5-cyano-1,6-dihydro-6-oxo-3-pyridinecar☐ylic acids. Crystal structure of 2-methyl, 2-t-butyl and 2-phenyl esters

1989; Elsevier BV; Volume: 24; Issue: 5 Linguagem: Inglês

10.1016/0223-5234(89)90057-3

1768-3254

Luisa Mosti, Giulia Menozzi, P. SCHENONE, P. Dorigo, R.M. Gaion, F. Benetollo, G. Bombieri,

Synthesis of heterocyclic compounds

The synthesis of ethyl and methyl esters of 2-substituted 5-cyano-1,6-dihydro-6-oxo-3-pyridinecar☐ylic acids by reaction of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates with sodium cyanoacetamide is described. These esters gave by alkaline hydrolysis the corresponding car☐ylic acids, which were decar☐ylated to 6-substituted 1,2-dihydro-2-oxo-3-pyridinecarbonitriles. As milrinone analogues, nearly all the above compounds were tested on contractile activity and frequency rate of spontaneously beating atria and electrically driven left atria from guinea pigs. Among the esters, ethyl 5-cyano-1,6-dihydro-2-methyl-6-oxo-3-pyridinecar☐ylate induced positive inotropic and chronotropic effects superior to those caused by milrinone. By increasing or branching the 2-substitutent, the activity decreased until faded or even reversed. Car☐ylic acids and nitriles were less active than milrinone. Some aspects of the structure-activity relationship of these compounds are discussed on the basis of X-ray structural analyses of 2-methyl, 2-t-butyl and 2-phenyl esters. On a synthe´tise´une se´rie d'esterse´thyliques et me´thyliques de cyano-5 dihydro-1,6 oxo-6 pyridine-3 acides car☐yliques substitue´s en 2 par re´action des dime´thylaminome´thyle`ne-2 oxo-3 alkanoates correspondants avec le cyanoace´tamide sode´. Les esters onte´te´saponifie´s et les acides obtenus de´car☐yle´s pour donner les dihydro-1,2 oxo-2 pyridine-3 carbonitriles respectifs substitue´s en 2. Les re´sultats pharmacologiques re´alise´s sur presque tous ces compose´s apparente´s au milrinone ont re´ve´le´que l'estere´thylique du cyano-5 dihydro-1,6 me´thyl-2 oxo-6 pyridine-3 acide car☐ylique a pre´sente´une activite´inotrope et chronotrope supe´rieure au milrinone. La substitution du groupe me´thyl-2 avec des groupes plus lourds ou plus ramifie´s entraiˆne une baisse ou une inversion de l'activite´. La structure aux rayons X des esters me´thyl-2,t-butyl-2 et phe´nyl-2 est rapporte´e et pour ces compose´s des relations structure-activite´onte´te´discute´es.