Patent GB-842995-A (GB)
Title: Therapeutic bis-quaternary compounds
IPC: C07D401/06
Filed: 1956-11-12
Abstract: The invention comprises bis-quaternary amines in which a polycarbon lower alkane is substituted at one carbon atom by an N- attached quaternary ammonium grouping having a radical weight not in excess of 118, in which the nitrogen atom bears three alkyl substituents, e.g. methyl, of which two may be linked directly or through a hetero-atom to form a ring, e.g. pyrrolidine, piperidine; and another carbon atom of the alkane is attached to a quaternary nitrogen atom of a substituted C5N ring e.g. pyridine or piperidine, having a radical weight of at least 150, but in the case of a pyridine ring not bearing substituents in both the 2- and 6- positions; the quaternary groups being neutralized by two anions, e.g. bromide or chloride. The compounds are made by (a) quaternizing a C5N ring compound with an o -halo-alkyammonium salt, e.g. by refluxing in a solvent at a temperature of up to 150 DEG C; (b) in the preparation of products wherein the larger quaternary moiety is to be a substituted pyridinium radical, by treating a 1-quaternaryammoniumalkyl pyridinium bis-salt in which the pyridinium residue bears a methylene function attached to the pyridine ring (e.g. picolinium, butidinium, ethylpyridinium), with an aldehyde or ketone, preferably in the presence of a basic catalyst; or (c) by first forming a di-tertiary base by treating a piperidine compound with a dialkylaminoalkyl halide and thereafter diquaternising the di-base.  Examples describe the preparation of many compounds according to the invention and especially 1-pyridinium or 1-(1-methylpiperidinium) 3-trimethylammonium-propane dibromides in which the pyridine or piperidine rings bear such substituents as phenylthioethyl, propylthioethyl, butylthioethyl, indolylethyl, diphenylaminoethyl, benzotriazolylethyl, phthalimidoethyl, tetrachlorophthalimidoethyl benzyl, benzoxypropyl, benzyloxycarbonyl, 2-oxocyclohexylethyl, benzoyl, hydroxypropyl, indenylethyl, benzothiazolethioethyl, bicyclo- 2:2:1-hepten-(2)-yl, phenylcarbomoyl, benzyloxycarbonyl, piperidino, 2-oxo-3-methylpentyl, 2-oxy-3-carbethoxypentyl, diphenylmethyl, 1:2-diphenylethenyl triphenylmethyl, naphthyl-ethyl, fluorene, carboxypropyl spiro-fluorene, phenylethylamino, 2-pyridyl-amino, 1-methyl-indolylethyl, 1-benzylindolylethyl, 1-methylindolylpropyl, 1-methyloxindolylethyl, benzyloxyethyl, benzylthioethyl, fluorenethioethyl, b -1-methylindolyla -cyclohexyl (or 4-ethylcyclohexyl)-ethyl, indolyl, di-indolylmethyl, 1-methylindolyalkyl, hydroxyacetoxy- and benzoxy-alkyl (octyl, decyl, undecyl, dodecyl), g -hydroxy-g -benzyl-n-butyl, bicycloheptylmethyl, spiro-1-methyloxindole, phenyl-hydroxyalkyl, benzoxypropyl, fluorenecarboxymethyl, diphenylmethoxy-methyl, stilbazolium, naphthylethenyl, indolylethenyl and b -methylindolyl-a -benzylidene-ethyl groups.  Substituted pyridine bases used as starting materials are prepared by the following methods: (a) treating 2- or 4-vinyl-pyridines with nucleophila reagents having a labile hydrogen atom such as amines, alcohols, mercaptans, secondary amides or imides, diphenylmethane, phenylacetonitrile, ethyl phenylacetate or benzotriazole to give corresponding substituted ethyl-pyridines; (b) treating 2,- 3- or 4-vinyl pyridines with conjugated dienes by the Diels Alder synthesis to give, for example, with cyclopentadiene, a bicycloheptenyl pyridine; (c) esterifying pyridine alkanols to give for example benzoxyalkyl or fluorenecarboxy alkyl derivatives; (d) esterifying pyridinecarboxylic acids; (e) treating 2- or 4-substituted pyridines with an alkyl or aralkyl halide to give substituted products such as 3:4-dichlorophenylethylpyridine; (f) reacting pyridine alkanols with alkyl or aralkyl halides to give ethers; (g) converting an arylhydrazone of an acylpyridine to an indolyl pyridine by the Fischer indole synthesis; (h) condensing a pyridine aldehyde with an indole derivative to give for example 4-(3:31-di-indolylmethyl)-pyridine and (i) reacting an alkyl, aryl or aralkyl Grignard reagent with a carbonyl substituted pyridine base. The products may be converted to acid addition or quaternary salts. Substituted piperidine bases are made by methods analogous to those of (c) and (i) above and also by (j) N-alkylating a piperidine base by a tertiaryaminoalkyl halide to give a di-tertiary base; (k) reacting a piperidine base with an epoxide to give a 2-hydroxyalkyl piperidine which may bear further substituents e.g. 1-(2:11-dihydroxyundecyl)-piperidine; (l) by N-alkylating a piperidine base by an alkyl or aralkyl halide and also (m) reducing the corresponding pyridine compound.  The products may be converted into acid addition and quaternary salts. Specifications 733,566, 764,232, 781,502 and 842,996 are referred to.ALSO:Pharmaceutical preparations having hypotensive activity and ganglionic blocking properties are prepared by admixture of a bis-quaternary amine comprising a polycarbon lower alkane substituted at one carbon atom by an N-attached quaternary ammonium grouping, having a radical weight not in excess of 118, in which the nitrogen atom bears three alkyl substituents, of which two may be linked directly or through a hetero atom to form a ring, e.g. piperidine or pyrrolidine, and another carbon atom of the alkane is attached to a quaternary nitrogen atom of a substituted C5N ring e.g. piperidine or pyridine, having a radical weight of at least 150, but in the case of a pyridine ring not containing substituents in both the 2- and 6- positions, the quaternary groups being neutralised by two anions e.g. bromide or chloride (see Group IV(b)) with a pharmaceutical diluent or carrier.  Specifications 764,832, 773,566, 781,502 and 842,996 are referred to.