Dihydropyrimidines: novel calcium antagonists with potent and long-lasting vasodilative and antihypertensive activity.
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.
Cho
H
H
Suntory Institute for Biomedical Research, Osaka, Japan.
Ueda
M
M
Shima
K
K
Mizuno
A
A
Hayashimatsu
M
M
Ohnaka
Y
Y
Takeuchi
Y
Y
Hamaguchi
M
M
Aisaka
K
K
Hidaka
T
T
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis*; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D015220:Calcium Channels; D002540:Cerebral Cortex / Q000378:metabolism; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D007202:Indicators and Reagents; D008297:Male; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis*
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007202:Indicators and Reagents; D011743:Pyrimidines; D011978:Receptors, Nicotinic; D014665:Vasodilator Agents