Patent GB-797172-A (GB)
Title: New phenthiazine derivatives and process for their preparation
Filed: 1956-07-13
Abstract: The invention comprises phenthiazines of the formula <FORM:0797172/IV (b)/1> and acid addition and quaternary salts thereof (Y represents an alkyl or alkoxy group containing not more than four carbon atoms, R1 is a methyl or ethyl group, and -N(R)2 represents a dialkylamino group in which the alkyl groups each contain not more than four carbon atoms, or represents a heterocyclic group such as pyrrolidino, piperidino or morpholino), and also processes for their preparation (a) by reacting phenthiazine substituted at position 3 by a group Y with an aminohalogenoalkane ZCH2-CH2CH(R1)N(R)2 or ZCH(R1)CH2CH2N(R)2, (in which Z is a halogen atom) optionally in the presence of a solvent and/or an alkaline condensing agent, or (b) by condensing an amine HN(R)2 with phenthiazine substituted at position 3 by a group Y and at position 10 by the group -CH2CH2CH(R1)X, where X is the residue of a reactive ester.  Specified salts include hydrohalides, 8 - chlorotheophyllinates, phosphates, nitrates, sulphates, maleates, fumarates, citrates, tartrates, oxalates, methane sulphonates, ethane disulphonates, and quaternary derivatives with methyl or ethyl chloride, bromide or iodide, and allyl or benzyl chloride or bromide.  In examples: (1) 3-ethyl-phenthiazine in boiling xylene is treated with sodamide and then with 1-dimethylamino-3-chlorobutane to yield 3 - ethyl - 10 - (3 - dimethylaminobutyl) phenthiazine characterized as its hydrochloride; similarly (2) to (6) are prepared 3-methyl-10-(3-dimethylaminobutyl)-; 3 - methyl - 10 - (3 - diethylaminobutyl) -; 3 - methoxy - 10 - (3 - diethylaminobutyl) -; 3 - ethyl - 10 - (3 - diethylaminobutyl)-; and 3-methoxy-10-(3-pyrrolidinobutyl) - phenthiazine; (7) 3 - methyl - 10 - (3 - chlorobutyl) - phenthiazine and dimethylamine are autoclaved in ethanol, the cooled mixture evaporated to dryness, treated with aqueous NaOH and 3-methyl-10-(3-dimethylaminobutyl) - phenthiazine extracted with ether, purified by re-extraction with acid and by distillation and characterized as its hydrochloride; similarly (8) and (9) are prepared 3 - ethyl - 10 - (3 - dimethylaminobutyl) - and 3 - ethyl - 10 - (3 - dimethylaminopentyl) - phenthiazines and their hydrochlorides and the iodomethylate of the former; (10) 3-methylphenthiazine in boiling xylene is treated with sodamide and then with 1-chloro-3-dimethylaminobutane to give 3-methyl-10-(3-dimethylaminobutyl) phenthiazine and its hydrochloride; (11) as in (10) using 3-methoxy-phenthiazine to yield 3 - methoxy - 10 - (3 - dimethylaminobutyl) - phenthiazine.  The starting materials 3-methyl-10-(3-chlorobutyl) phenthiazine and 3-ethyl-10-(3-chloropentyl) phenthiazine are prepared by the action of thionyl chloride on 3-methyl-10-(3-hydroxybutyl)- and 3-ethyl-10-(3-hydroxypentyl) phenthiazine respectively, these compounds being obtained by the action of 1-chloro-3-tetrahydropyranyloxybutane (from 1-chlorobutan-3-ol and dihydropyran) on 3-methylphenthiazine, and 1 - chloro - 3 - tetrahydropyranyloxypentane (from 1-chloropentan-3-ol and dihydropyran) on 3-ethylphenthiazine.  Reference has been directed by the Comptroller to Specifications 608,208, 632,277 and 701,741.