European Journal of Medicinal Chemistry p. 517 - 529 (1989)
Update date:2022-08-05
Topics:
Mosti
Menozzi
Schenone
Dorigo
Gaion
Benetollo
Bombieri
The synthesis of ethyl and methyl esters of 2-substituted 5-cyano-1,6-dihydro-6-oxo-3-pyridinecarboxylic acids by reaction of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates with sodium cyanoacetamide is described. These esters gave by alkaline hydrolysis the corresponding carboxylic acids, which were decarboxylated 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-pyridinecarboxylate induced positive inotropic and chronotropic effects superior to those caused by milrinone. By increasing or branching the 2-substituent, the activity decreased until faded or even reversed. Carboxylic 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.
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(1989)