Collect. Czech. Chem. Commun. 1984, 49, 1009-1020

1-[2-(2-Hydroxymethylphenylthio)benzyl]-4-methylpiperzine and related compounds as potential antidepressants: Synthesis and pharmacological acreening

Irena Červená and Miroslav Protiva

Research Institute for Pharmacy and Biochemistry, 130 60 Prague 3


Heating of 1-(2-iodobenzoyl)-4-methylpiperazine (II) with thiophenol and its 2-methyl, 4-methyl, 4-chloro and 2-hydroxymethyl derivatives in dimethylformamide in the presence of potassium carbonate, copper and cuprous iodide gave the piperazides IV-VIII; compound VIII was transformed by reduction with lithium aluminium hydride to the title compound I. The acid IX, obtained by a reaction of 5-chloro-2-iodobenzoic acid with 2-methylthiophenol, was reduced to the alcohol X, which was transformed via the chloride XI to 1-[5-chloro-2-(2-methylphenylthio)-benzyl]-4-methylpiperazine (XII), an open model of the neuroleptic agent clorothepin. Heating of 2,5-dichloroacetophenone with thiosalicylic acid afforded the keto acid XIII whose reaction with 1-methylpiperazine was carried out with the help of N,N"-carbonyldiimidazole. The piperazide XIV obtained was reduced on the one hand with sodium borohydride to the secondary alcohol XV, and with lithium aluminium hydride to 1-(2-[4-chloro-2-(1-hydroxyethyl)phenylthio]benzyl)-4-methylpiperazine (XVI) on the other. None of the dibasic piperazines (I, XII, XVI) did show antireserpine activity. In the general screening, some of the piperazides displayed a mild hypotensive (II, VIII, XIV, XV), adrenolytic (VIII), mild stimulating and antitussic (V), and spasmolytic, antiinflammatory and negatively ino- and chronotropic (XIV) activities.