STUDIES ON NILVADIPINE .1. SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 1,4-DIHYDROPYRIDINES CONTAINING NOVEL SUBSTITUENTS AT THE 2-POSITION

The synthesis of new 1,4-dihydropyridine derivatives containing novel substituent at the 2-position of the nucleus via the key intermediate 2-formyl-1,4-dihydropyridines (X), is described. The aldehydes (X) were prepared by hydrolysis of the acetals (IX) which were obtained from aryl aldehyde (V) and alkyl 4,4-dialkoxyacetoacetate (VI) by the Knoevenagel reaction and treatment with alkyl 3-aminocrotonate (VIII) according to the modified Hantzsch method. The formyl group of the aldehydes (X) was reactive enough to be converted to a variety of functional groups such as hydroxymethyl, cyano, substituted iminomethyl, carbamoyl, semicarbazone, substituted vinyl, ethynyl, and so on. In all of the novel compounds we prepared, 2-hydroxymethyl- and 2-cyano-1,4-dihydropyridines (IV and XXII) were found to possess potent activities in preliminary biological evaluations on hypotension in normotensive rats and on an increase in coronary blood flow in pentobarbital-anesthetized dogs. Optimization research in order to obtain a more potent compound was accomplished in the 2-hydroxymethyl- and 2-cyano-1,4-dihydropyridine series. We selected isopropyl 2-cyano-3-methoxycarbonyl-4-(3-nitrophenyl)-6-methyl-1,4-dihydropyridine-5-carboxylate (XXIIj) as a candidate compound for further biological evaluation studies. Fortunately, XXIIj (nilvadipine) has been accepted in clinical use for the treatment of hypertension.