Synthesis and calcium channel antagonist activity of nifedipine analogues containing 1-oxido-2-pyridyl in place of the 2-nitrophenyl moiety

Abstract

Analogues (5) of nifedipine (1a), in which the 2-nitrophenyl at position 4 is replaced by 1-oxido-2-pyridyl, were synthesized and evaluated as calcium channel antagonists using the muscarinic receptor-mediated Ca2+-dependent contraction of guinea pig ileal longitudinal smooth muscle. The replacement resulted in a significant loss of activity. In the case of the symmetrical dialkyl esters (5a-e), activity was enhanced by increasing the size of the alkyl ester substituents, the relative order of potency being i-Bu congruent to t-Bu greater than i-Pr greater than Et and Me. Our results show that the 1-oxido-2-pyridyl substituent is not a useful isostere of the 2-nitrophenyl moiety of nifedipine. In the synthetic work, Hantzsch condensation of 2-pyridinecarboxaldehyde 1-oxide (4) with equimolar quantities of alkyl acetoacetates (2) and alkyl 3-aminocrotonates (3) afforded dialkyl 1,4-dihydro-2,6-dimethyl-4-(1-oxido-2-pyridyl)-3,5-pyridinedicarboxylate s (5).