GB796305A - Derivatives of oxopiperazinoalkylhalophenothiazines - Google Patents

Abstract

The invention comprises phenthiazine derivatives of the general formula <FORM:0796305/IV (b)/1> and non-toxic acid addition and quaternary salts thereof, wherein n is 0, 1 or 2, X is fluorine or chlorine and is preferably a chlorine substituent in the 2-position of the phenthiazine ring, Alk is an alkylene radical separating the two nitrogen atoms by at least two carbon atoms and R is hydrogen or an alkyl, aralkyl, acyl, hydroxyalkyl, alkoxyalkyl, alkenyloxyalkyl or acyloxyalkyl radical. The compounds are prepared by condensing a fluorine or chlorine substituted phenthiazyl-alkyl halide with the corresponding keto-piperazine or by treating a fluoro- or chloro-phenthiazine with a piperazinoalkyl halide. Derivatives containing a substituent in the 4-position of the piperazine ring may also be prepared by alkylation or acylation of the corresponding unsubstituted compounds. The products which are useful therapeutically as anti-emetic and ataractic agents may be converted into their acid addition salts with acids such as sulphuric, phosphoric, hydrochloric, hydrobromic, sulphamic, citric or ascorbic or into their quaternary salts with organic esters such as halides, sulphates and aromatic sulphonates. Examples describe the preparation of 10-(ketopiperazinyl) alkylhalophenthiazines of the general formula I in which the halo-substituent is a 2- or 3-chloro or a 2-fluoro substituent, the radical "Alk" is an ethyl, propyl or butyl residue and R is chosen from hydrogen or methyl, ethyl, benzyl, phenethyl, m-tolylmethyl, acetyl, propionyl, b - hydroxyethyl, b - acetoxyethyl, b - acrylyloxyethyl, b - ethoxyethyl, allyloxyethyl or propoxypropyl groups. Acid addition and quaternary salts and compounds containing methyl substituents on the piperazine ring are also described. Starting materials. 2-Fluoro-10-(d -chlorobutyl)-phenthiazine is made by heating N-phenyl - 4 - fluoroanthranilic acid to give m - fluoro - diphenylamine, heating this with sulphur in the presence of iodine to form 2-fluorophenthiazine and treating this with butyl lithium, followed by d -chlorobutyl p-toluene-sulphonate. 1 - Methyl - 3 - piperazinone is made by methylating 2-piperazinone with formic acid and formaldehyde. 2-Chloro-10-[g - (41 - tetrahydropyranyloxyethyl - 31 - ketopiperazinyl) - propyl] - phenthiazine is made by the action of 2-(b -bromoethoxy) tetrahydropyran on 2-chloro-10-[g -(1-ketopiperazinyl) propyl] phenthiazine (sodium compound). Cleavage of the pyranyl ether by distillation in vacuum gives the corresponding 41-hydroxyethyl compound.