Dihydropyrimidines: novel calcium antagonists with potent and long-lasting vasodilative and antihypertensive activity

• Published in: Journal of medicinal chemistry 1989-10, Vol.32 (10), p.2399-2406
• Main Authors: CHO, H, UEDA, M, KAWAI, M, TAKEDA, M, ISHIHARA, T, FUNAHASHI, K, SATOH, F, MORITA, M, NOGUCHI, T, SHIMA, K, MIZUNO, A, HAYASHIMATSU, M, OHNAKA, Y, TAKEUCHI, Y, HAMAGUCHI, M, AISAKA, K, HIDAKA, T
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive Agents - chemical synthesis; blood pressure; Blood Pressure - drug effects; calcium; Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - pharmacology; Calcium Channels; Cerebral Cortex - metabolism; Chemistry; Dogs; Exact sciences and technology; Female; Heart Rate - drug effects; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Indicators and Reagents; Male; Molecular Structure; Organic chemistry; Preparations and properties; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Rats; Rats, Inbred SHR; Receptors, Nicotinic - metabolism; Structure-Activity Relationship; vasodilation; Vasodilator Agents - chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00130a029

The novel calcium antagonists 3-N-substituted-3,4-dihydropyrimidines 1 and 9 and 3-N-substituted-dihydro-pyrimidin-2(1H)-ones 8 were regioselectively synthesized in good yields. Compounds 1 [especially 1s [R1 = (CH2)2N(benzyl)(2-naphthylmethyl), R2 = i-Pr, X = 0-NO2] and 1t [R1 = (CH2)2N(benzyl)(3,4-dichlorobenzyl), R2 = i-Pr, X = 0-NO2]] exhibited not only more potent and longer lasting vasodilative action but also a hypotensive activity with slow onset as compared with dihydropyridines. Moreover, some dihydropyrimidines [1q [R1 = (CH2)2N(benzyl)(3-phenylpropyl), R2 = CH2(cyclopropyl), X = 0-NO2], 1s, and 1t] were weaker in blocking atrioventricular conduction in anesthetized open-chest dogs and less toxic than the dihydropyridines.