Dihydropyrimidine calcium channel blockers. 4. Basic 3-substituted-4-aryl-1,4-dihydropyrimidine-5-carboxylic acid esters. Potent antihypertensive agents.

摘要: We have examined a series of novel dihydropyrimidine calcium channel blockers that contain basic group attached to either C5 or N3 the heterocyclic ring. Structure-activity studies show 1-(phenylmethyl)-4-piperidinyl carbamate moiety at and sulfur C2 are optimal for vasorelaxant activity in vitro impart potent long-acting antihypertensive vivo. One these compounds (11) was identified as lead, individual enantiomers 12a (R) 12b (S) were synthesized. Two key steps synthesis (1) efficient separation diastereomeric ureido derivatives 29a/29b (2) high-yield transformation 2-methoxy intermediates 30a/30b (p-methoxybenzyl)thio 31a/31b. Chirality demonstrated be significant determinant biological activity, with dihydropyridine receptor recognizing enamino ester (12a) but not (12b). Dihydropyrimidine is equipotent nifedipine amlodipine vitro. In spontaneously hypertensive rat, both more longer acting than compares most favorably derivative amlodipine. has potential advantage being single enantiomer.