Efange_1993_J.Med.Chem_36_985

Introduction of a nitrogen atom into the cyclohexane ring of 2-(4-phenylpiperidinyl)cyclohexanol (vesamicol, AH5183) yielded two positional isomers, 5-azavesamicol (5, prezamicol) and 4-azavesamicol (6, trozamicol). As inhibitors of vesicular acetylcholine transport, 5 and 6 were found to be 147 and 85 times less potent than vesamicol. N-Benzoylation of 5 (to yield 9a) increased the potency 3-fold. In contrast, 10a, a compound derived from N-benzoylation of 6, was 50 times more potent than the latter and almost equipotent with vesamicol, thereby suggesting a preference for the 4-azavesamicol series. Although (-)-vesamicol is more potent than its dextrorotary isomer, (+)-10a was found to be 3 times more potent than (-)-10a, suggesting a reversal of the sign of rotation in the azavesamicol series. Reduction of 9a and 10a (to yield the corresponding N-benzyl derivatives 11a and 12a) increased potency 20- and 2-fold, respectively, indicating a preference for a basic nitrogen. The reaction of 5 or 6 with substituted benzyl halides yielded several potent inhibitors of vesicular acetylcholine transport, including N-(p-fluorobenzyl)trozamicol, 12d, which is twice as potent as vesamicol. Thus the introduction of a nitrogen atom into the cyclohexane ring of vesamicol provides opportunities for developing a new class of anticholinergic agents.