Synthesis and antihypertensive activity of certain substituted dihydropyridines and pyrimidinones

Abstract

Background and objective Some bulky substituted aromatic aldehydes reacted with urea and ethyl acetoacetate in the presence of acetic acid as a catalyst to yield solely substituted dihydropyridines (Hantzsch-type molecule). In the presence of p-toluene sulfonic acid as a catalyst, the products were only dihydropyrimidines (Biginelli compounds). The same aldehydes yielded dihydropyrimidinones on using acetyl acetone instead of ethyl acetoacetate whatever the catalyst used. These two classes of molecules represent a heterocyclic system of a remarkable antihypertensive effect. The aim of this study was to synthesize certain dihydropyridine and pyrimidinone derivatives with aromatic moiety with bulky substituents to be evaluated for their antihypertensive effect. Methods The aldehydes 3-(substituted-phenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde 3–5, 4-oxo-4H-chromene-3-carbaldehyde (6), and substituted phenylazo-benzaldehyde 7–9 reacted with ethyl acetoacetate and urea in ethanol in the presence of acetic acid to yield dihydropyridines 10–15. Aldehydes 3–9 reacted with ethyl acetoacetate and urea in the presence of p-toluene sulfonic acid to yield dihydropyrimidinones 16–22. Furthermore, the reaction of the aldehydes 3–9 with ethyl acetoacetate and urea in the presence of either acetic acid or p-toluene sulfonic acid yielded the corresponding dihydropyrimidinones 23–29. Results and conclusion The hypotensive activity of compounds 10–14 and 16–20 indicated that the 4-aryl-dihydropyridine derivatives 10–14 showed higher activity than the pyrimidinones 16–20. The most active compound was 4-(1,3-diphenyl-1H-pyrazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (10) at dose levels of 0.6, 1.2, and 2.4 mg/kg. It showed more or less similar hypotensive activity as the reference drug nifedipene at doses of 1.2 and 2.4 mg/kg. Its LD 50 =298 mg/kg body weight.