ASYMMETRIC N-(3,3-DIPHENYLPROPYL)AMIMOALKYL ESTERS OF -2,6-DIMETHYL-1,4-DIHYDROPYRIDINE-3,5-DICARBOXYLIC ACIDS WITH ANTIHYPERTENSIVE ACTIVITY

A series of asymmetric 4-aryl-1,4-dihydropyridine-3,5-dicarboxylates c haracterized by the presence of a 3,3-diphenyl-propylamino moiety in o ne of the ester groups were synthesized. They exhibited remarkable ant ihypertensive activity in spontaneously hypertensive rats as well as a ffinity for the 1,4-dihydropyridines binding site labelled by H-3-nitr endipine in the calcium channel. Introduction of this bulky and lipoph ilic amine confers to the whole series an elevated level of antihypert ensive activity and a long duration of action, a structure-dependent m odulation of the activity being found only in the subset characterized by the presence of a branched propylene bridge between the ester and the amino groups. The presence of the amino group is essential for ora l activity. Out of this series, compound 9u (Rec 15/2375-lercanidipine ) was selected for clinical development and obtained marketing authori zation as an antihypertensive in several countries. (C) Elsevier, Pari s.