ABSTRACT
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.
Subject(s)
Antihypertensive Agents/chemical synthesis , Blood Pressure/drug effects , Calcium Channel Blockers/chemical synthesis , Heart Rate/drug effects , Pyrimidines/chemical synthesis , Receptors, Nicotinic/metabolism , Vasodilator Agents/chemical synthesis , Animals , Calcium Channel Blockers/pharmacology , Calcium Channels , Cerebral Cortex/metabolism , Dogs , Female , Indicators and Reagents , Male , Molecular Structure , Pyrimidines/pharmacology , Rats , Rats, Inbred SHR , Structure-Activity RelationshipABSTRACT
Several 7a-substituted benzoylaminoalkyl-hexahydro-1 H-pyrrolizines were synthesized by acylations of 7a-aminoalkyl-hexahydro-1 H-pyrrolizines. All compounds synthesized were evaluated for their antiarrhythmic activities using the chloroform-mouse method, and some of them were found to have significant antiarrhythmic activities, comparable to that of procainamide.
Subject(s)
Arrhythmias, Cardiac/prevention & control , Pyrroles/therapeutic use , Animals , Arrhythmias, Cardiac/chemically induced , Benzamides/chemical synthesis , Benzamides/therapeutic use , Benzamides/toxicity , Chemical Phenomena , Chemistry , Chloroform , Lethal Dose 50 , Male , Mice , Procainamide/therapeutic use , Pyrroles/chemical synthesis , Pyrroles/toxicity , Structure-Activity RelationshipABSTRACT
The synthesis and antiarrhythmic activity of N-aryl-8-pyrrolizidinealkanamides are described. The target compounds were evaluated for their ability to protect against chloroform-induced fibrillation in mice. Many of them were found to have antifibrillatory activity comparable to that of lidocaine; several are more potent than lidocaine. N-(2,6-Dimethylphenyl)-8-pyrrolizidineacetamide which was found to be more potent and less toxic (LD50) than lidocaine, also showed a long duration of action in dogs with ventricular arrhythmias after oral administration.
