Collect. Czech. Chem. Commun. 1983, 48, 906-927

8-Chloro and 8-methylthio derivatives of 10-piperazino-10,11-dihydrodibenzo[b,f]thiepins; New compounds and new procedures

Jiří Jílek, Josef Pomykáček, Zdeněk Prošek, Jiří Holubek, Emil Svátek, Jiřina Metyšová, Antonín Dlabač and Miroslav Protiva

Research Institute for Pharmacy and Biochemistry, 130 60 Prague 3


The resolution of racemic clorothepin (Ia) was repeated and the water-soluble methanesulfonates of (S)(+)-clorothepin and (R)(-)-clorothepin were prepared which were used in recent studies of the stereoselectivity of action of this neuroleptic agent. Alkylation of the secondary amine VIa with 2-chloroethyl decanoate resulted in noroxyclothepin decanoate IVa whose basically catalyzed ethanolysis afforded smoothly the amino alcohol IIa. Reactions of amines VIa and VIb with 1,2-butene oxide gave the amino alcohols VIIab. Alkylation of the amine VIa with 5-bromopentan-2-one and the following reduction of the amino ketone IXa formed gave the amino alcohol VIIIa. Amino alcohols IIa and IIIb were transformed by treatment with thionyl chloride to the chloroalkylamines Xa and XIb which were used for the synthesis of mandelates XIIa, XIIIb and benzilates XIVa, XVb derived from noroxyclothepin IIa and oxyprothepin IIIb. A substitution reaction of 2,11-dichloro-10,11-dihydrodibenzo[b,f]thiepin with 1,4-diazabicyclo[4,3,0]nonane led to the clorothepin analogue XVI. From 2-chlorodibenzo[b,f]thiepin-10(11H)-one XVII via the 11-bromo derivative XVIII the amino ketone XIX was prepared. While its reduction with sodium borohydride gave the cis-amino alcohol XXI, the reduction with diborane gave the trans-amino alcohol XXII. The pharmacological properties of the new piperazine derivatives are described; some of them showed a high degree of neuroleptic activity of various profile.