Synthesis and Evaluation of Pharmacological Activities of 3, 5‐Dialkyl 1, 4‐Dihydro‐2, 6‐Dimethyl‐4‐Nitroimidazole‐3, 5‐Pyridine Dicarboxylates

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Abstract
New analogues of nifedipine, in which the 2‐nitrophenyl group at position 4 is replaced by a 1‐methyl‐5‐nitro‐2‐imidazolyl substituent, were synthesized. The symmetrical dialkyl 1, 4‐dihydro‐2, 6‐dimethyl‐4‐(1‐methyl‐5‐nitro‐2‐imidazolyl)‐3, 5‐pyridinedicarboxylates were prepared by a classical Hantzsch condensation. The asymmetrical analogues were synthesized using a procedure reported by Iwanami that involved the condensation of alkylacetoacetate with methyl‐, ethyl‐ or isopropyl3‐aminocrotonate and 1‐methyl‐5‐nitroimidazole‐2‐carboxaldehyde. Calcium channel antagonist activities were determined in vitro using a guinea pig ileum longitudinal smooth muscle (GPILSM)assay. Many compounds exhibited superior, or equipotent, calcium antagonist activity (IC50 = 10—10 to 10—13 M range) relative to the reference drug nifedipine (IC50 = 1.09 ± 0.12 × 10—11 M). Antinociceptive effects of some compounds were evaluated by the mouse tail‐flick assay in vivo. Results demonstrate that some of the compounds were active as an antinociceptive.

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