Various diester ANALOGUES of NIFEDIPINE in which the ortho nitrophenyl group at position 4 were replaced by 3-chloro-1H-2-indolyl substituent, were synthesized and evaluated as CALCIUM ANTAGONISTs on guinea-pig ileal smooth muscle. NIFEDIPINE was used as a standard. Compound 6f was found to be the most active

2-monobromomethyl 1,4-dihydropyridines is selectively synthesized by bromination of the parent compound by 1.1 equivalents of pyridinium bromide perbromide in dichloromethane/pyridine at -20 degrees C. The same reagent in dichloromethane at 0 degrees C produce the 2,6-bis(bromomethyl) 1,4-dihydropyridines.

The new ANALOGUES of NIFEDIPINE, in which 2-nitrophenyl group at position 4 is replaced by phenylisoxazolyl substituent, were synthesized. The symmetrical dialkyl 1,4-dihydro-2,6-dimethyl-4-(5-phenylisoxazol-3-yl) pyridine-3,5-dicarboxylates were prepared by classical Hantzsch condensation, and the asymmetrical ANALOGUES were synthesized using a procedure reported by Dagnino that involved the condensation of alkyl acetoacetate with alkyl 3-aminocrotonate and 5-phenylisoxazole-3-carboxaldehyde. The structure of all compounds was confirmed by IR, 1H NMR and Mass spectra. In vitro CALCIUM CHANNEL ANTAGONIST activities were evaluated as CALCIUM CHANNEL ANTAGONISTs using the high K+ concentration of guinea-pig ileum longitudinal smooth muscle (GPILSM) assay. These compounds exhibited moderate CALCIUM ANTAGONIST activity (IC50=10-7 to 10-5 M range) relative to the reference drug NIFEDIPINE (IC50=1.10±0.40×10-8 M).  

The discovery that 1,4-dihydropyridine (DHP) class of CALCIUM CHANNEL ANTAGONIST inhibits the Ca+2 influx represented a major therapeutic advance in the treatment of cardiovascular diseases such as hypertension, angina pectoris and other spastic smooth muscle disorders. A novel class of CALCIUM CHANNEL ANTAGONIST of flunarizine containing arylpiperazinyl moiety has recently been reported. It was therefore of interest to determine the effect that selected C-3 substituents contained amino alkyl and arylpiperazine, in conjunction with a C-4 1-methyl-5-nitro-2-imidazolyl substituents on CALCIUM CHANNEL ANTAGONIST activity. The unsymmetrical ANALOGUES were prepared by a procedure reported by Meyer in which 1-methyl-5-nitro-imidazol-2-carboxaldehyde was reacted with acetoacetic esters and alkyl 3-aminocrotonate. In vitro CALCIUM CHANNEL ANTAGONIST activities were determined by the use of high K+ contraction of guinea pig ileal longitudinal smooth muscle. All compounds exhibited comparable CALCIUM CHANNEL ANTAGONIST activity (IC-950=10 to 10 -11M) against reference drug NIFEDIPINE (IC50= 2.75±0.36x 10-10 M).