Patent GB-821012-A (GB)
Title: New phenthiazine derivatives and processes for their preparation
Filed: 1958-01-03
Abstract: The invention comprises compounds of the formula <FORM:0821012/IV (a)/1> and their acid addition and quaternary ammonium salts (wherein A is a straight or branched chain divalent saturated aliphatic hydrocarbon group with 2 to 4 carbon atoms, Y is a sulphur atom or an SO or SO2 group, X is a hydrogen or halogen atom or a lower alkyl or alkoxy group or a cyano, methylthio or dimethylsulphamoyl group, R1 and R2 are the same or different and either each is a hydrogen atom or a lower alkyl, benzyl or cyclo-hexyl group, or R1 and R2 together with the adjacent nitrogen atom collectively represent a pyrrolidino, piperidino or morpholino group, and n is 1 or 2), and the preparation thereof by: (a) reacting a phenthiazine of the formula <FORM:0821012/IV (a)/2> with a piperazine derivative of the formula <FORM:0821012/IV (a)/3> (wherein Z is the acid residue of a reactive ester), (b) reacting a phenthiazine of the formula <FORM:0821012/IV (a)/4> with a piperazine derivative of the formula <FORM:0821012/IV (a)/5> (c) reacting a phenthiazine of the formula <FORM:0821012/IV (a)/6> with a reactive ester of the formula <FORM:0821012/IV (a)/7> (d) reacting a phenthiazine of the formula <FORM:0821012/IV (a)/8> (wherein -COZ1 is a functionally converted carboxyl group such as an acid halide, azide or ester group) with an amine of the formula <FORM:0821012/IV (a)/9> (e) decarboxylating a phenthiazine-10-carboxylate of the formula <FORM:0821012/IV (a)/100> by heating, preferably to a temperature above 100 DEG  C., until evolution of carbon dioxide ceases.  The phenthiazine derivatives in which Y is an SO or SO2 group may also be made by oxidizing the corresponding phenthiazines in which Y is a sulphur atom or SO group. The word "lower" means that the group in question contains not more than four carbon atoms.  Other methods for preparing the compounds of the invention are described. Suitable acid addition salts are the hydrohalides, nitrates, phosphates, sulphates, citrates, fumarates, maleates, oxalates, tartrates, methane sulphonates and ethanedisulphonates. Quaternary ammonium salts may be made from organic halides (e.g. methyl or ethyl bromide, chloride or iodide, or allyl or benzyl bromide or chloride) or other reactive esters (e.g. toluene-p-sulphonates).  The compounds of the invention have therapeutic properties.  The following compounds are made in the examples: 1-[3-(3-chloro - 10 - phenthiazinyl)propyl] - 4 - dimethyl-carbamoylmethyl-piperazine and its hydrochloride, 1 - [3 - (3 - chloro - 10 - phenthiazinyl)-propyl] - 4 - carbamoylmethyl - piperazine, 1-[3 - (3 - chloro - 10 - phenthiazinyl)propyl] - 4 - carbamoylethyl - piperazine, 1 - [3 - (3 - chloro - 10 - phenthiazinyl)propyl] - 4 - dimethylcarbamoylethyl - piperazine and its dimaleate, 1 - [3 - (3 - chloro - 10 - phenthiazinyl)propyl]-4-diethylcarbamoylmethyl - piperazine and its dihydrochloride, 1 - [3 - (3 - chloro - 10 - phethiazinyl)propyl]-4-morpholinocarbonylmethyl-piperazine, 1 - [3 - (3 - chloro - 10 - phenthiazinyl)-propyl] - 4 - piperidinocarbonylmethyl-piperazine and its dihydrochloride, 1-[3-(3-chloro-10-phenthiazinyl)propyl] - 4 - 11 - pyrrolidinylcarbonylmethyl-piperazine and its dihydrochloride and dimethiodide, 1 - [3 - (3 - methoxy - 10 - phenthiazinyl)propyl] - 4 - dimethylcarbamoylmethyl-piperazine and its hydrochloride, 1-[1-(3 - chloro - 10 - phenthiazinyl) - 2 - propyl] - 4 - dimethylcarbamoylmethyl - piperazine and its hydrochloride, 1 - [2 - (10 - phenthiazinyl)ethyl]-4 - dimethylcarbamoylmethyl - piperazine and its dihydrochloride, 1 - [3 - (3 - dimethylsulphamoyl - 10 - phenthiazinyl)propyl] - 4 - dimethyl-carbamoylmethyl-piperazine and its dimethanesulphonate, 1-[3-(3 - chloro - 10 - phenthiazinyl)-propyl]-4- methylcarbamoylmethyl - piperazine and its dihydrochloride, 1-[3-(3-chloro-10-phenthiazinyl)propyl] - 4 - cyclohexylcarbamoylmethyl - piperazine, 1 - [3 - (3 - chloro - 10 - phentiazinyl)propyl] - 4 - benzylcarbamoylmethyl - piperazine, 1 - [3 - (3 - cyano - 10 - phenthiazinyl)propyl] - 4 - 11 - pyrrolidinylcarbonylmethyl-piperazine and its dimaleate, 1-[3 - (3 - methylthio - 10 - phenthiazinyl)propyl] 4 - 11 - pyrrolidinylcarbonylmethyl - piperazine and its dimaleate, 1-[3-(3-chloro-9-oxy-10-phenthiazinyl)propyl] - 4 - carbamoylethyl - piperazine, 1 - [3 - (3 - chloro - 9:9 - dioxy - 10 - phenthiazinyl)propyl] - 4 - 11 - pyrrolidinylcarbonylmethyl-piperazine.  1-Dimethyl carbamoylmethyl-piperazine is made from anhydrous piperazine and N-dimethylchloracetamide; 1 - chloro - propan - 3 - ol is reacted with 1-dimethylcarbamoylmethyl-piperazine to give 1-(3-hydroxypropyl)-4-dimethylcarbamoylmethyl-piperazine, which with thionyl chloride gives 1-(3-chloropropyl)-4-dimethylcarbamoylmethyl-piperazine; 1 - [3 - (3 - chloro - 10 - phenthiazinyl)carbonyloxypropyl] - 4 - dimethylcarbamoylmethyl-piperazine (the dimethyl sulphonate of which is also made) is prepared by reacting 3 - chlorophenthiazinyl - 10 - carbonyl chloride with 1 - (3 - hydroxypropyl) - 4 - dimethylcarbamoylmethyl - piperazine; 1-[3-(3-chloro - 10 - phenthiazinyl)propyl] - 4 - methoxy - carbonylmethyl-piperazine is made from 1-[3-(3-chloro - 10 - phenthiazinyl)propyl] - piperazine and methyl bromoacetate; 1-11-pyrrolidinylcarbonylmethyl-piperazine is made from anhydrous piperazine and chloracetopyrrolidide.