Structure-activity studies on narcotic antagonists. 2. N-substituted ethyl 3-(m- or p-hydroxyphenyl) nipecotates

A number of N-substituted ethyl 3-(n- or p-hydroxyphenyl)nipecotates were synthesized to evaluate the role of a m- or p-hydroxy substituted beta-phenethylamine moiety in narcotic antagonist action. Ethyl m- or p-methoxy-phenylcyanoacetate was alkylated with 1-bromo-3-chloropropane. The resultant chloronitriles were hydrogenated (Raney Ni) to amines and cyclized to yield the N-substituted ethyl 3-(m- or p-methoxyphenyl)nipecotates. These were N-benzylated, O-demethylated using BBr3, N-debenzylated, and then N-alkylated. The following N-substituted derivatives were prepared: methyl, allyl, cyclopropylmethyl, and n-propyl. No significant morphine-like analgesic activity was found in mice by the tail-flick method. The acetic writhing assay showed several compounds to possess analgesic activity. N-n-Propyl and N-(cyclopropylmethyl) m-hydroxy derivatives were marginally active antagonists by the mouse tail-flick method. Surprisingly, the N-methyl m-hydroxy derivative, 11m, was found to be an antagonist.