Novel histamine H-3-receptor antagonists with carbonyl-substituted 4-(3-(phenoxy)propyl)-1H-imidazole structures like ciproxifan and related compounds

Novel histamine H-3-receptor antagonists possessing a 4-(3-(phenoxy)propyl) -1H-imidazole structure generally substituted in the para-position of the p henyl ring have been synthesized according to Mitsunobu or SNAr reactions. With in vitro and in vivo screening for H-3-receptor antagonist potency, th e carbonyl-substituted derivatives proved to be highly active compounds. A number of compounds showed in vitro affinities in the subnanomolar concentr ation range, and the 4-hexanoyl (10) and 4-acetyl-3-methyl (29) substituted derivatives showed in vivo antagonist potencies of about 0.1 mg/kg after p o administration. Many proxifans were also tested for their affinities at o ther histamine receptor subtypes thereby demonstrating their pronounced H-3 -receptor subtype selectivity. Since the cyclopropyl ketone derivative 14 ( ciproxifan) had high affinity in vitro as well as high potency in vivo, it was selected for further studies in monkeys. It showed good oral absorption and long-lasting, dose-dependent plasma levels making it a promising compo und for drug development.