Synthesis and calcium channel antagonist activity of 1,2-dihydropyridyl analogues of nifedipine

Abstract

Calcium channel antagonist activities of 1,2-dihydropyridines (10), including that (10d) isomeric with nifedipine, were determined using the muscarinic-receptor mediated Ca2+ dependent contraction of guinea pig ileal longitudinal smooth muscle. The effect of the 4-substituent (R) on potency was cyclohexyl and phenyl greater than 2-,3- or 4-trifluoromethyl(nitro)phenyl, although the differences in activity were small. The nature of the 4-substituent (alkyl, cycloalkyl, aryl), and the position (ortho, meta, para) of further substituents (CF3 or NO2) in the case of 4-phenyl substitution, were not major determinants of activity. The weaker calcium channel antagonist activity of these compounds, relative to nifedipine, is attributed to differences in conformation between the 1,2- and 1,4-dihydropyridine ring systems and the orientation of the 4-aryl substituent. In the synthetic work, the required 1,2-dihydropyridines (10), were synthesized by a route involving regiospecific ortho-directed reduction of the 1-oxide analogues (9) using borane. NMR spectrometric studies indicated that the 4-(2-trifluoromethyl) analogue (10a) exists as a single rotamer (10a'), whereas the 4-(2-nitrophenyl) analogue (10d) exists as a 10:3 mixture of rotamers (10d') and (10d") at 25 degrees C in CDCl3 solution.