GB1157277A - Cyclopropylpiperazinoalkyl-Phenothiazines and process for preparing the same - Google Patents

Abstract

1,157,277. Phenothiazine derivatives. ELI LILLY & CO. 22 Aug., 1966, No. 37558/66. Heading C2C. Novel phenothiazine derivatives of the general formula wherein R is hydrogen or methyl and R<SP>1</SP> is chloro, trifluoromethyl, methoxy or methylthio, and pharmaceutically acceptable acid addition salts thereof are prepared (a) by heating a phenothiazine derivative of the general formula wherein X is chlorine or bromine, with N-cyclopropyl-piperazine; (b) by reacting a phenothiazine having a chlorine atom or a trifluoromethyl, methoxy or methylthio group in the 2-position with a N-cyclopropyl-piperazine derivative of the general formula wherein X is chlorine or bromine; (c) by heating a 10 - [3 - (N,N - bis - 2 - chloroethyl) - amino - propyl or - 2 - methylpropyl] - phenothiazine having a chlorine atom or a trifluoromethyl, methoxy or methylthio group in the 2-position with cyclopropylamine; or (d) by reacting a phenothiazinyl-10-carbonyl chloride having a chlorine atom or a trifluoromethyl, methoxy or methylthio group in the 2-position with 3-(4- cyclopropylpiperazino) - 1 - propanol or - 2 - methyl - 1 - propanol and heating the carbamate thus formed, followed optionally by conversion of the product to a pharmaceutically acceptable acid addition salt thereof. Pharmaceutical compositions having tranquillizing and anti-emetic properties comprise as active ingredient a phenothiazine of the first general formula above or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutical carrier. N-Cyclopropyl-piperazine derivatives of the general formula wherein R<SP>2</SP> is hydrogen or -CH 2 CHRCH 2 -X and X is chloro or hydroxy, are prepared (a) by hydrolysis of 1-cyclopropyl-4-p-toluenesulphonylpiperazine, obtained by reaction of N,N-bis-(#- chloroethyl) - p - toluenesulphonamide and cyclopropylamine, to yield N-cyclopropyl-piperazine; (b) by reaction of cyclopropylamine with ethylene oxide, conversion of the N,N-bis-(#- hydroxyethyl)-cyclopropylamine thus obtained to the corresponding #-chloroethyl derivative by reaction with a chlorinating agent, followed by cyclization of the N,N-bis-(#-chloroethyl)-cyclopropylamine with an amine of the formula R<SP>2</SP>NH 2 ; or (c) by chlorination of a N-cyclopropyl-piperazine derivative of the fourth general formula above wherein R<SP>2</SP> is -CH 2 - CHR-CH 2 OH to give the corresponding derivative wherein R is -CH 2 -CHR-CH 2 -Cl. 10-(3- Chloropropyl) - 2 - trifluoromethyl - phenothiazine is prepared by reacting 2-trifluoromethylphenothiazine with 1-chloro-3-bromo-propane. Reference has been directed by the Comptroller to Specification 833,473.