Synthesis and antihypertensive activity of certain substituted dihydropyridines and pyrimidinones

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 -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 –, 4-oxo-4H-chromene-3-carbaldehyde (), and substituted phenylazo-benzaldehyde – reacted with ethyl acetoacetate and urea in ethanol in the presence of acetic acid to yield dihydropyridines –. Aldehydes – reacted with ethyl acetoacetate and urea in the presence of -toluene sulfonic acid to yield dihydropyrimidinones –. Furthermore, the reaction of the aldehydes – with ethyl acetoacetate and urea in the presence of either acetic acid or -toluene sulfonic acid yielded the corresponding dihydropyrimidinones –.
Results and conclusion
The hypotensive activity of compounds – and – indicated that the 4-aryl-dihydropyridine derivatives – showed higher activity than the pyrimidinones –. 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 () 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=298 mg/kg body weight.