Potential antipsychotic agents: 2-Chloro- and 2-methyl-11-(2-piperazinoethoxy)-6,11-dihydrodibenzo[b,e]thiepins and some related compounds; Synthesis and pharmacology

Abstract

Reactions of 2-chloro- and 2-methyl-6,11-dihydrodibenzo[b,e]thiepin-11-ol with 2-bromoethanol in the presence of sulfuric acid in boiling benzene afforded the 2-bromoethyl ethers VIa and VIb which were transformed by substitution reactions with 1-methylpiperazine, 1-(2-hydroxyethyl)-piperazine and 1-(ethoxycarbonyl)piperazine to the title compounds. Alkaline hydrolysis of the carbamate IVa gave the secondary amine IIIa. Treatment of the bromo ether VIa with 4-(4-chloro-3-trifluoromethylphenyl)piperidin-4-ol resulted in the piperidine derivative VIIa. Substitution reaction of 11-chloro-6,11-dihydrodibenzo[b,e]thiepin with 1-(2-methoxyethyl)piperazine and 1-(2-ethoxyethyl)piperazine led to the amino ethers VIII and IX. Reaction of 11-chloro-11-phenyl-6,11-dihydrodibenzo[b,e]thiepin with 2-dimethylaminoethanethiol in dimethylformamide at 90°C gave a mixture of two isomeric bases which was separated to the expected sulfide X and the base XII, resulting evidently after the rearrangement of the primary carbocation. A similar reaction of 3-dimethylaminopropanethiol afforded a single product of structure XI. Out of the compounds prepared, the ether VIII was found most interesting: it is little toxic and has significant antireserpine activity in two tests (is considered a potential antidepressant). The ethers Iab, Iab, IIIa and VIIa did not reveal the expected neuroleptic activity.