Patent GB-875845-A (GB)
Title: Improvements in or relating to phenthiazine derivatives
IPC: C07D417/06
Filed: 1959-04-13
Abstract: The invention comprises bases of the general formula <FORM:0875845/IV (b)/1> (wherein X represents a hydrogen or halogen atom or a lower alkoxy, cyano, dimethylsulphamoyl or trifluoromethyl group, A represents a C2-C4 straight or branched alkylene group with at least 2 carbon atoms between the two nitrogen atoms, n is 0 or 1, R represents a hydrogen atom or a methyl group and Z represents a lower acyl, alkoxycarbonyl or alkanesulphonyl group or a group <FORM:0875845/IV (b)/2> wherein B represents CO or SO2 and R1 and R2 represent hydrogen atoms or lower alkyl groups or jointly form with N a pyrrolidino, piperidino or morpholino group, the word "lower" denoting that the groups so qualified contain not more than 4 carbon atoms) and their acid addition and quaternary ammonium salts, pharmaceutical preparations containing these compounds (see Group VI), and the preparation of the bases by (a) reacting a phenthiazine of the general formula <FORM:0875845/IV (b)/3> (wherein Y represents an acid residue of a reactive ester) with a piperidine derivative of the general formula <FORM:0875845/IV (b)/4> or (b) converting the grouping <FORM:0875845/IV (b)/5> in a phenthiazine of the general formula <FORM:0875845/IV (b)/6> into the grouping <FORM:0875845/IV (b)/7> by known methods for the introduction of a lower acyl, lower alkoxycarbonyl, lower alkanesulphonyl, carbamoyl or sulphamoyl group into a primary or secondary amino group.  The bases can also be prepared by: (c) reacting a phenthiazine of the general formula <FORM:0875845/IV (b)/8> with a piperidine derivative of the general formula <FORM:0875845/IV (b)/9> or (d) decarboxylating, by heating above 100 DEG C., a phenthiazine-10-carboxylate of the general formula <FORM:0875845/IV (b)/100> (obtainable by reacting a halide or ester of a phenthiazine-10-carboxylic acid with a compound of the general formula <FORM:0875845/IV (b)/111> or by reacting a haloalkyl phenthiazine-10carboxylate with an appropriately substituted piperidine), or (e) catalytically hydrogenating pyridinium salt of the general formula <FORM:0875845/IV (b)/122> (wherein An represents an anion).  4-Acetamido-, 4-(N-methylacetamido)- and 4 - (N - morpholinocarbonyl-N-methylamino)-piperidine are prepared by catalytic debenzylation of their 1-benzyl derivatives, obtained by appropriate acylation of appropriate 1-benzyl-4-aminopiperidines. 4-Acetamidomethyl- and 4-(N-methylacetamidomethyl)-piperidine hydrochlorides are prepared by catalytic hydrogenation of the corresponding 4-substituted pyridine hydrochlorides.  4 - (N - methylacetamidomethyl)-pyridine is prepared by the action of acetic anhydride on 4-monomethylaminomethylpyridine. 4-Monomethylaminomethylpyridine and 1-benzyl-4-monomethylaminopiperidine are prepared by reductive amination, with monomethylamine in the presence of Adams' platinum, of isonicotinaldehyde and 1-benzyl-4-piperidone respectively.  3 - Chloro - 10-(3-41-aminopiperidinopropyl)phenthiazine, its N-methyl derivative, the 3-methoxy-, 3-cyano-, 3-dimethylsulphamoyl- and 3-trifluoromethyl-compounds corresponding to the latter, and 3-chloro-10-(3-41-aminomethylpiperidinopropyl)-phenthiazine are prepared by acid hydrolysis of the N-acetyl derivatives.  3-Methoxy-, 3-cyano-, 3-dimethylsulphamoyl-and 3-trifluoromethyl-10-(3-41-N-methylaceta midopiperidinopropyl)-phenthiazine are prepared by condensing the corresponding 3-substituted 10-(3-chloropropyl)-phenthiazines with 4-(N-methylacetamido)-piperidine.ALSO:Pharmaceutical preparations, useful as nervous system depressors, potentiators of narcosis, tranquillizers, antiemetics and analgesics, comprise, in admixture with a pharmaceutical carrier, one or more phenthiazine derivatives of the general formula <FORM:0875845/VI/1> (wherein X represents an hydrogen or halogen atom or a lower alkoxy, cyano, dimethylsulphamoyl or trifluoromethyl group, A represents a C2-4 straight or branched alkylene group with at least 2 carbon atoms between the two nitrogen atoms, n is 0 or 1, R represents an hydrogen atom or a methyl group and Z represents a lower acyl, alkoxycycarbonyl or alkanesulphonyl group or a group <FORM:0875845/VI/2> wherein B represents CO or SO2 and R1 and R2 represent hydrogen atoms or lower alkyl groups or jointly form with N a pyrrolidino, piperidino or morpholino group, the word "lower" denoting that the groups so qualified contain not more than 4 carbon atoms) or their acid addition salts (e.g. hydrohalides, phosphates, nitrates, sulphates, acetates, propionates, succinates, benzoates, fumarates, maleates, oxalates, tartrates, methanesulphonates, ethanedisulphonates, theophyllinates, chlorotheophyllinates, salicylates, phenolphthaleinates or methylene-bis-b -hydroxynaphthoates) or quaternary ammonium salts (e.g. halides, alkylsulphates or toluene-p-sulphonates).  They may take the form of tablets, pills, dispersable powders, granules, emulsions, solutions, suspensions, syrups, elixirs or capsules.