Patent GB-861779-A (GB)
Title: Piperazino derivatives and methods for their manufacture
IPC: C07D281/16
Filed: 1957-09-16
Abstract: The invention comprises compounds of the general formula <FORM:0861779/IV (b)/1> and their pharmaceutically acceptable acid addition salts (wherein R is a lower alkyl group, R1 is a hydrogen atom or a lower alkyl group, Y is an alkylene group with 2 to 5 carbon atoms, and A is a free, etherified or esterified hydroxy lower alkyl group), and the preparation thereof by reacting a compound of the general formula <FORM:0861779/IV (b)/2> with a compound of the general formula <FORM:0861779/IV (b)/3> preferably in the presence of an acceptor for PQ, and followed, if necessary, by the conversion of A1 into A and Y1 into Y (wherein of P and Q, one is attached directly to the relevant nitrogen atom and the other is connected to the relevant nitrogen atom through a divalent group Y1, A1 being A or a group convertible into A, and Y1 being Y or a group convertible into Y, P and Q being groups of opposite polarity capable of being eliminated as the compound PQ during the course of the reaction).  In the examples, A, when representing an etherified or esterified hydroxy lower alkyl group, may be a hydroxyethoxyethyl group, an acetoxyethyl group, an ethoxycarboxyethyl group, a carbamoylethyl or dimethylcarbamoylethyl group. A lower alkyl group contains less than 6 carbon atoms.  10 - (3 - Chloropropyl) - 2 - acetylphenthiazine is made from 2-acetyl-phenthiazine and 1-bromo-3-chloropropane. Similarly made are 10-(4) - chlorobutyl) - 2 - acetyl - phenthiazine and 10-(3-chloropropyl)-2-propionylphenthiazine.  2 - (2 - Acetyl - 10 - phenthiazinyl) - ethyl chloride is made from 2-acetyl-phenthiazine and 2-chloro-ethyl-p-toluenesulphonate.  2 - Acetyl - phenthiazine is reacted with 1, 2 oxidopropane to give 3 - (2 - acetyl - 10 - phenthiazinyl) - propan - 2 - ol, treatment of which with phosphorus tribromide yields the corresponding bromo compound.  2 - Propionyl - phenthiazine is reacted with 3 - bromo - propan - 1 - ol to give 3 - (2 - propionyl - 10 - phenthiazioyl) - propan - 1 - ol, treatment of which with p-toluenesulphonyl chloride yields the corresponding p-toluene-sulphonic acid ester.  10 - Acetyl - phenthiazine is reacted with butyric anhydride to give 2-butyryl-10-acetyl-phenthiazine, hydrolysis of which yields 2-butyrylphenthiazine.  1 - (2 - Hydroxyethyl) - 4 - [3 - (2 - acetyl - 10-phenthiazinyl)propyl]-piperazine is reacted with thionyl chloride to give the corresponding chloro compound or reacted phenyl chlorocarbonate to yield the corresponding phenyl carbonic ester.  1 - (2 - Hydroxyethyl) - 2,5 - dimethylpiperazine is made from 2,5-dimethyl piperazine and ethylene oxide; and 1 - (2 - hydroxyethyl) - 4 - (3-chloropropyl)-piperazine is made from 1-(2-hydroxyethyl)-piperazine and 1-bromo-3-chloropropane.ALSO:Compounds of the general formula <FORM:0861779/VI/1> (wherein R is a lower alkyl group, R1 is a hydrogen atom or a lower alkyl group, Y is an alkylene group with 2 to 5 carbon atoms, and A is a free, etherified or esterified hydroxy lower alkyl group) are preferably compounded in the form of soluble, pharmaceutically acceptable, acid addition salts, e.g. the dihydrochloride, dicitrate, dimaleate or ditartrate.  They are preferably administered orally in tablets or elixirs in conjunction with suitable carriers and other types of oral, pharmaceutical dosage units.  For parenteral administration, the compounds in the form of non-toxic, acid addition salts are prepared in sterile solutions or suspensions.  The compounds may be used, advantageously in conjunction with barbiturates, to reduce anxiety.