Synthesis and Regioselective Hydrolysis of Novel Dialkyl 4-Imidazolyl-1,4-Dihydropyridine-3,5-dicaroxlates as Potential Dual Acting Angiotensin II Inhibitors and Calcium Channel Blockers

Abstract

Most of the known effects of angiotensin II are mediated via AT(1) receptor by increasing intracellular Ca(2+) by influx of extracellular Ca(2+). Combination therapies of angiotensin receptor blocker (ARB) with calcium channel blocker (CCB) which act through L-type calcium channel have beneficial therapeutic and protective effects on cardiovascular system. Thus, it was hypothesized that merging the key structural elements present in an AT(1) receptor antagonist (telmisartan) with key structural elements in 1,4-dihydropyridine calcium channel blockers (nifedipine) would yield a compound with dual activity for both receptors. This strategy led to the design and synthesis of dialkyl 1,4-dihydro-2,6-dimethyl-4-[2-n-alkyl-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-4(or 5)-yl]-3,5-pyridinedicarboxylates (4 and 6). The synthesis of compounds 4 and 6 was accomplished through the reaction of 2-n-alkyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]imidazole-4(or 5)-carboxaldehydes with alkyl acetoacetate followed by regioselctive hydrolysis of carboethoxybiopheny to carboxybiphenyl that are essential for ARB activity. It is suggested that existence of hindrance by substituted groups prevent hydrolysis of esteric groups on dihydropyridine ring. The structures of the compounds were characterized by (1)H-nuclear magnetic resonance, infrared and mass spectroscopy.