Potential antidepressants: 2-(fluoro-, chloro-, bromo- and cyanophenylthio)benzylamines as inhibitors of 5-hydroxytryptamine and noradrenaline re-uptake in brain

Abstract

2-, 3- and 4-Fluorothiophenol, 2-, 3- and 4-chlorothiophenol, and 2-bromothiophenol were converted in two steps into the corresponding 2-(halogenphenylthio)benzoyl chlorides IV which afforded amides V and VI by reaction with dimethylamine and N,N,N’-trimethylethylenediamine. The amides were reduced either by lithium aluminium hydride or by diborane to benzylamines Ia-Ig and IIa-IIc. The reaction of 2-chlorobenzaldehyde with 3-bromothiophenol or 4-bromothiophenol afforded aldehydes VIIh and VIIi yielding subsequently benzylamines Ih and Ii by subsequent reducing amination. Cyano analogs Ij and Il were obtained from the bromo derivatives Ig and Ii by their reaction with cuprous cyanide in hexamethylphosphoric triamide. The synthesis of compound Ik was effected via aldehyde acid VIIm affording amino acid Im on reducing amination. The conversion of the latter to amide In and its dehydration yielded nitrile Ik. Some of the compounds synthesized, especially Ic, Id, Ie and If, are efficient and selective inhibitors of re-uptake of 5-hydroxytryptamine in brain structures. The most interesting from this aspect is compound If(hydrochloride VUFB-17649) of this series which was chosen for detailed pharmacological testing.