Patent GB-871412-A (GB)
Title: Improvements in or relating to phenthiazine derivatives
IPC: C07D417/06
Filed: 1959-04-15
Abstract: The invention comprises compounds of the general formula: <FORM:0871412/IV (b)/1> (wherein X represents a C1-4 alkoxy, acyl, alkylthio or alkanesulphonyl group or a cyano or trifluoromethyl group, A represents a straight or branched aliphatic hydrocarbon group containing 2-4 carbon atoms with at least 2 carbon atoms between the two nitrogen atoms, and R1 and R2 are the same or different and each represent a hydrogen atom or a C1-4 alkyl group or R1 and R2 together form with the adjacent nitrogen atom an unsubstituted saturated mononuclear heterocyclic group) and their acid addition and quaternary ammonium salts; the preparation thereof by reacting a compound of the general formula:  <FORM:0871412/IV (b)/2> (wherein Y represents the acid residue of a reactive ester) with a compound of the general formula:  <FORM:0871412/IV (b)/3> or (when R1 and R2 are both hydrogen) by the action of ammonia on a compound of the general formula:  <FORM:0871412/IV (b)/4> (wherein Z represents an alkoxy group); and pharmaceutical compositions containing the products (see Group VI).  The compounds of the invention can also be made by catalytic hydrogenation of a pyridinium salt of the general formula:  <FORM:0871412/IV (b)/5> (wherein An represents an anion). 3-Methoxy-10-(3-41-ethoxycarbonylpiperidinopropyl) -phenthiazine (characterized as its acid oxalate) is prepared by refluxing 3-methoxy-10-(3-chloropropyl)-phenthiazine with ethyl isonipecotate in xylene.  3-Cyano, 3-methanesulphonyl-, 3-acetyl-, 3-trifluoromethyl-, 3-methylthio- and 3-methoxy-10-(3-chloropropyl)-phenthiazine are prepared by condensing the appropriate 3-substituted 10-unsubstituted phenthiazines with 1-chloro-3-bromopropane in liquid ammonia in the presence of sodamide prepared in situ.  3-Methoxy- 10-(3-chloro- 2-methylpropyl)-phenthiazine is similarly prepared from 3-methoxyphenthiazine and 1-chloro-2-methyl-3-  bromopropane. 4-(N,N-Diethylcarbamoyl)-piperidine and 4-(morpholinocarbonyl)-piperidine (characterized as their hydrochlorides) are prepared by hydrogenating the corresponding pyridine derivatives in dioxan in the presence of Raney nickel. 4-Morpholinocarbonylpyridine is prepared by refluxing morpholine with isonicotinoyl chloride hydrochloride in chloroform.ALSO:Pharmaceutical preparations, useful as depressors of the nervous sytem, potentiators of narcosis, tranquillizers, antiemetics and analgesics, comprise, in association with a significant amount of a pharmaceutical carrier, at least one compound of the general formula, <FORM:0871412/VI/1> (wherein X represents a C1-4 alkoxy, acyl, alkylthio or alkanesulphonyl group or a cyano or trifluoromethyl group, A represents a straight or branched aliphatic hydrocarbon group containing 2-4 carbon atoms with at least 2 carbon atoms between the two nitrogen atoms, and R1 and R2 are the same or different and each represent a hydrogen atom or a C1-4 alkyl group or R1 and R2 together form with the adjacent nitrogen atom an unsubstituted saturated mononuclear heterocyclic group) or an acid addition salt (e.g. hydrohalide, phosphate, nitrate, sulphate, acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, tartrate, methanesulphonate, ethanedisulphonate, chlorotheophyllinate, theophyllineacetate, salicylate, phenolphthaleinate or methylene - bis-b -hydroxynaphthoate) or quaternary ammonium salt (e.g. halide, alkylsulphate or arylsulphonate) thereof.  They may be in the form of tablets, pills, dispersible powders, granules, emulsions, solutions, suspensions, syrups, elixirs or capsules. p