Patent GB-800632-A (GB)
Title: New derivatives of phenthiazine and processes for their production
Inventor: HORCLOIS RAYMOND JACQUES
Filed: 1954-11-09
Abstract: The invention comprises phenthiazine derivatives of the general formula: <FORM:0800632/IV (b)/1> and their salts, including quaternary ammonium derivatives (wherein Y represents a sulphur atom or an SO or SO2 group, X represents one or more hydrogen or halogen atoms or acyl groups containing not more than four carbon atoms, which may be present in one or both carbocyclic nuclei, A represents the trivalent hydrocarbon group: <FORM:0800632/IV (b)/2> in which A1 represents a single bond or a divalent hydrocarbon group containing not more than three carbon atoms and in which the three valencies are each attached to a nitrogen atom, and the groups R are the same or different and, when individual atoms or groups, represent either hydrogen atoms or lower alkyl groups (i.e. containing not more than four carbon atoms), or, when pairs are linked together, form with the adjacent nitrogen atom a heterocyclic ring such as a pyrrolidino, piperidino or morpholino group) excluding those compounds in which simultaneously Y represents a sulphur atom, A represents a trivalent aliphatic chain of three carbon atoms and the R groups are alike and represent either methyl or ethyl groups.  Such compounds are obtained by the interaction of a phenthiazine compound of the formula: <FORM:0800632/IV (b)/3> with a halogenodiamine of the formula: <FORM:0800632/IV (b)/4> or an acid addition salt thereof (wherein Hal represents a halogen atom and A1 either represents the group A as defined above or a group convertible by reduction into the group A) and, where A1 is other than A, reduction of the group A1 into the trivalent hydrocarbon group A.  Alternatively, products of the first formula above in which Y represents an SO or SO2 group are obtained by oxidation of the corresponding phenthiazine compound in which Y represents a sulphur atom.  The first reaction is preferably effected in e.g. toluene or xylene solution in the presence of a condensing agent such as an alkali metal, or the metal alkyl, metal aryl or the hydride, amide, hydroxide or alcoholate.  As a result of isomerization during the reaction, a mixture of isomers is obtained having at the 10 position the groups: <FORM:0800632/IV (b)/5> and <FORM:0800632/IV (b)/6> respectively.  The mixed isomers can be used therapeutically, or they can be separated by fractional crystallization of their dihydrochlorides from alcohol. Hydrohalides, 8-chloro-theophyllinates and methiodides of the products are mentioned.  In Example (1) phenthiazine and 1 - dimethylamino - 2 - dimethylaminomethyl-3-chlorobutane are reacted in xylene in the presence of sodamide to give 10-[1-bis-(dimethylaminomethyl) - 2 - propyl] - phenthiazine (and its dihydrochloride).  Similarly prepared are (2) 10 - [1 - bis - (diethylaminomethyl) - 2 - propyl] phenthiazine; (5) 10-(2 : 3-bispiperidino-1-propyl) phenthiazine; 3-chloro-10-(2 : 3-bispiperidino - 1 - propyl) phenthiazine, and 3-acetyl - 10 - (2 : 3 - bispiperidino - 1 - propyl)-phenthiazine (as its acid ditartrate).; (6) 9 : 9-dioxy - 10 - [2 : 3 - bis - (dimethylamino) 1-propyl]-phenthiazine.  In further examples: (3) 10 - [2 : 3 - bis - (dimethylamino) - 1 - propyl]-phenthiazine in acetic acid is treated with sulphuric acid and hydrogen peroxide at 10 DEG  to 20 DEG  C. to give 9-oxy-10-[2 : 3-bis-(dimethylamino)-1-propyl] phenthiazine which is then converted (Example (4)) to its ethiodide.  3-Chloro - 9 - oxy - 10 - (2 : 3 - bispiperidino - 1-propyl) phenthiazine is prepared similarly.  In preparing starting materials piperidine and epichlorhydrin are reacted at 60 DEG  C. to give 1 : 3-bispiperidino - 2 - propanol which on treatment in chloroform with hydrogen chloride and thionyl chloride gives 1 : 3-bispiperidino-2-chloropropane dihydrochloride.  Specification 800,635 is referred to.