Potential antidepressants: 2-(Methoxy- and hydroxyphenylthio)benzylamines as selective inhibitors of 5-hydroxytryptamine re-uptake in the brain

Abstract

2-, 3- and 4Methoxythiophenol, and 2,4-, 2,5- and 3,4-dimethoxythiophenol were transformed in two steps to the corresponding 2-(methoxyphenylthio)benzoyl chlorides XIII which were reacted with ammonia, methylamine, diethylamine, dipropylamine, and di(2-propyl)amine to give the amides XIV-XIX. These were reduced mostly with lithium aluminium hydride to the amines II-VII. These methoxylated amines were demethylated mostly either by heating with pyridine hydrochloride or by treatment with boron tribromide. Some of the 2-(methoxy- and hydroxy-phenylthio)benzylamines prepared, especially compounds II, III, XXI, and XXII, indicated properties of potential antidepressants being highly active and selective inhibitors of 5-hydroxytryptamine re-uptake in the brain structures and having the typical antireserpine activity. The most interesting compound of the series is XXIb (hydrogen maleate VUFB-15 468) which is undergoing preclinical studies. On the basis of its structure, some further compounds (XXVII–XXIX, XXXIX-XLI) were prepared by various methods.