Patent GB-815205-A (GB)
Title: New phenthiazine derivatives and their preparation
Filed: 1957-07-05
Abstract: The invention comprises phenothiazines of the formula (I) <FORM:0815205/IV (b)/1> and their acid addition and quaternary ammonium salts (wherein R1 is a hydrogen atom or alkyl group; R2 is an alkyl group; R3 and R4 are the same or different and either each is an alkyl group or one is a hydrogen atom and the other an alkyl group, or NR3R4 forms a heterocyclic group; and B is a straight or branched divalent aliphatic group containing two to four carbon atoms, unsubstituted or substituted by a group <FORM:0815205/IV (b)/2> where A is a single bond or methylene group), and their preparation by one of the following methods.  (1) Alkylation of a 3-hydroxyalkylphenothiazine (I) in which R2 is a hydrogen atom, e.g. by replacing the hydroxy group with a halogen atom followed by reaction with an alcohol or metal alcoholate; when -NR2R4 is a 4-hydroxyalkylpiperazinyl group this may be protected, e.g. by tetrahydropyranylation.  (2) Interaction of a phenothiazine (II) <FORM:0815205/IV (b)/3> with a halogenoamine <FORM:0815205/IV (b)/4> (wherein Hal is a halogen atom).  (3) Thermal decarboxylation (above 100 DEG  C.) of a phenothiazine (III), which may be prepared, e.g. by <FORM:0815205/IV (b)/5> reacting a halide (or ester) of the corresponding phenothiazine - 10 - carboxylic acid with the appropriate amino-alcohol, or by the action of a halogenoalkyl ester of such an acid on the appropriate secondary amine.  (4) Interaction of an amine HNR3R4 with a phenothiazine (IV). <FORM:0815205/IV (b)/6> wherein Y is the residue of a reactive ester such as a halogen atom or a sulphonic ester residue, and B1 is a straight or branched divalent aliphatic hydrocarbon group containing two to four carbon atoms, unsubstituted or substituted by -A-Y1 where Y1 is the residue of a reactive ester, or a grouping -NR3R4.  (5) When NR3R4 is a 4-acyloxyalkylpiperazino group, acylation of the corresponding 4-hydroxyalkyl-piperazino compound.  When B is an asymmetric branched chain, methods (2) and (3) may cause isomerization; if B contains an asymmetric carbon atom the products may exist in optically active forms.  Examples describe the preparation of the following phenothiazine derivatives by the methods indicated by numerals in brackets: 3-(1-methoxyethyl)- and 3 - (1 - ethoxyethyl) - 10 - (3 - dimethylaminopropyl) - phenothiazine (1) as oxalates; 3 - (1 - methoxyethyl) - 10 - (3 - di - methylaminopropyl) - phenothiazine (2) and its hydrochloride; 3 - methoxymethyl - 10 - (3-41-methyl - 11 - piperazinylpropyl) - phenothiazine (2) and its dihydrochloride; 3-methoxymethyl-10 - (3 - dimethylamino - 2 - methylpropyl) - phenothiazine (2) and its acid oxalate; 3-methoxymethyl - 10 - [2:3 - bis - (dimethyl - amino)propyl]phenothiazine (2) and its acid oxalate and acid maleate; 3-methoxymethyl-10 - (3 - diethylaminopropyl) - phenothiazine (3) and its acid oxalate; 3-methoxymethyl-10-(3 - 41 - b  - hydroxyethyl - 11 - piperazinylpropyl)-phenothiazine (4) and its acid dimaleate; and 3 - methoxymethyl - 10 - (3 - 41 - b  - acetoxyethyl - 11 - piperazinylpropyl) - phenothiazine (5) and its acid dimaleate.  3 - (1 - Chloroethyl) - 10 - (3 - dimethylamino - propyl)-phenothiazine hydrochloride is obtained by the action of thionyl chloride on 3-(1-hydroxyethyl) - 10 - (3 - dimethylaminopropyl) - phenothiazine.  3 - Methoxy - and 3 - ethoxy - methylphenothiazine are prepared by the action of methyl iodide and ethyl iodide, respectively, on the sodium derivative of 3-hydroxymethylphenothiazine.  3 - Diethylaminopropyl 3 - methoxymethyl - phenothiazine-10-carboxylate is obtained by reacting 3-diethylamino-1-propanol with 3-methoxymethylphenothiazine-10-carbonyl chloride.  Other esters of formula (III) are obtainable similarly, or by using an ester instead of a halide of the acid, or by reacting a haloalkyl ester of the acid with the appropriate secondary amine.