Synthesis and calcium channel antagonist activities of 3-nitrooxyalkyl, 5-alkyl 1,4-dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazolyl)-3,5-pyridinedicarboxylates

Abstract

A group of racemic 3-[(2-nitrooxyethyl), (3-nitrooxypropyl), (4-nitrooxybutyl) or (1,3-dinitrooxy-2-propyl)], 5-methyl (ethyl or propyl) 1,4-dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazolyl)-3,5-pyridinedicarboxylates ( 18– 29) were synthesized using modified Hantzsch reaction that involved the condensation of 2-nitrooxyethyl ( 8), 3-nitrooxypropyl ( 9), 4-nitrooxybutyl ( 10) or 1,3-dinitrooxy-2-propyl ( 13) acetoacetate with methyl ( 14), ethyl ( 15) or isopropyl ( 16) 3-aminocrotonate and 1-methyl-5-nitroimidazole-2-carboxaldehyde ( 17). In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. Compounds 18– 29 exhibited superior, or equipotent, calcium antagonist activity (IC 50=10 −11–10 −13 M range) relative to the reference drug nifedipine (IC 50=1.07±0.12×10 −11 M), which could serve as potential probes to investigate the in vivo release of nitric oxide which induces vascular muscle relaxation.