Patent GB-717847-A (GB)
Title: Diamino derivatives of alkane dithiols and their production
IPC: C07D295/088
Filed: 1951-12-11
Abstract: The invention comprises as new compounds having pharmacological uses bis-tertiary bisaminoalkyl thio-alkanes of the general formula Am)N-(CmH2m)-S-(CnH2n) -S-(Cm1H2m1)-N(Am) and their salts with inorganic and organic acids and their diquaternary ammonium salts of the general formula <FORM:0717847/IV (b)/1> wherein N(Am) represents dialkylamino radicals the alkyl radicals of which contain from 1 to 4 carbon atoms and also alkylene imino radicals with 5-6 ring members, Alk represents alkyl or alkenyl radicals which contain from 1 to 6 carbon atoms, X represents monovalent anions in particular of halogen hydracids and of alkyl sulphuric acids and m, m1 and n are whole numbers of at least 2, the total value of n, m and m1 being at least 8, and wherein each two neighbouring hetero atoms, whether they be the same or different, may not be linked to the same carbon atom. The compounds may be unsymmetrical, i.e. both N(Am) groups Alk and X and the groups CmH2m and Cm1 H2m1 can be different from each other.  The piperidino- and pyrrolidino radicals are the preferred alkylene imino radicals with 5-6 ring members.  The ditertiary amines may be produced in two ways: (a) by reacting one mol. of an alkane dithiol of the formula HS-(CnH2n)-SH or a salt thereof with one mol. of a tertiary aminoalkyl halide of the formula (Am)N-(CmH2m)-Hal and one mol. of a tertiary aminoalkyl halide of the general formula (Am)N-(Cm1H2m1)-Hal wherein Hal is chlorine, bromine, or iodine and Am, m, m1 and n are as defined above; and (b) by reacting one mol. of an alkane dihalide of the general formula Hal-(CnH2n)-Hal with 1 mol. of a tertiary amino-alkane thiol of the formula (Am)N-(CmH2m)-SH or salt thereof and 1 mol. of a tertiary amino-alkane thiol of the formula (Am)N-(Cm1H2m1)-SH or salt thereof.  In both cases it is preferred to carry out the reaction in the presence of a solvent and a base which binds the hydrogen halide which is split off.  Suitable bases are sodium amide, lithium amide, sodium ethylate, sodium hydroxide and potassium hydroxide. When using alkali metal amides neutral solvents and those having no hydroxyl groups are suitable such as diethyl ether, dibutyl ether, dioxane, benzene, toluene, xylenes and paraffin hydrocarbons.  When alcoholates are used the solvents may be alcohols such as ethanol or butanol whereas when using alkali metal hydroxides water may be used.  The reactions are generally effected at between 0 and 150 DEG  C.  Examples of alkane dithiols are 1 : 3-dimercapto-propane, 1 : 5-dimercapto-pentane, 2 : 5-dimercaptohexane, 1 : 6-dimercapto-3-methyl-hexane, 1 : 8-dimercaptooctane and 1 : 14-dimercapto tetradecane whilst examples of tertiary aminoalkyl mercaptans are 2-dimethylamino (or -diethylamino-) ethylmercaptan, 2 - (21 : 51 - dimethyl - pyrrolidino)-ethyl mercaptan, 2-dimethylamino-propylmercaptan, 3 - (21 - methylpiperidino) - propylmercaptan, 3 - methyl - ethylamino propylmercaptan, 4 - dibutylamino - butylmercaptan and 6 - piperidino - hexylmercaptan.  Examples of tertiary aminoalkyl halides are 2-dimethylaminoethyl chloride, 2 - (methylethylamino)-ethyl chloride, 2 - dipropyl - aminoethyl chloride, 3-dimethylamino-propyl chloride, and 6-dibutylaminohexyl chloride, whilst examples of dihalogen alkanes are 1 : 4-dibromobutane, 1 : 5 - di - iodo - pentane, 1 : 6 - dichlorohexane, 2 : 5 - dibromohexane, 1 : 7 - dibromoheptane, 1 : 8 - dibromo - octane, 1 : 9 dibromononane, 1 : 10 - dibromodecane, 1 : 11 - dibromoundecane, 1 : 12 - dibromo dodecane, 1 : 13 - dibromo - tridecane, 1 : 14 - dibromotetradecane.  The products form salts with inorganic or organic acids and may be converted into the diquaternary diammonium compounds by reacting one mol. with about 2 mols. of an alkylating agent Alk-X wherein Alk and X are as defined above, e.g. methyl bromide or iodide, dimethyl sulphate, ethyl bromide or iodide, propyl bromide, allyl bromide, butyl bromide and hexyl iodide.  The quaternary salts obtained by direct addition may also be converted to salts with other anions, e.g. sulphates from iodides and silver sulphate, Reinecke's salts from bromides and Reinecke's ammonium salt.  The diquaternary diammonium compounds derived from polymethylene dithiols with 4 to 14 carbon atoms and especially the decamethylene dithiol derivatives are of interest on account of their muscle-relaxing activity.  In examples (1) sodium amide suspended in toluene is added to a mixture of toluene, 1 : 10-dibromodecane and diethylamino ethyl mercaptan in a nitrogen atmosphere at 40-50 DEG C. and the mixture then boiled under reflux to yield 1 : 10-bis - (21 - diethylamino ethyl mercapto)-decane; (2) the compound <FORM:0717847/IV (b)/2> is obtained by heating the corresponding ditertiary amine with ethyl iodide in dry acetone at 50-60 DEG  C; (3) the compound <FORM:0717847/IV (b)/3> is obtained by reacting 1 : 10 dibromodecane and 3-diethylamino propyl mercaptan as in (1) and then stirring with diluted hydrochloric acid (or hydrogen bromide) and cooling; (4) methyl iodide is added to 1 : 6-bis-(31-dimethylaminopropyl mercapto)-hexane in dry acetone to yield the corresponding diquaternary diammonium compound; (5) 1 : 10-decane dithiol is reacted at elevated temperature with 2-piperidino ethyl chloride hydrochloride in a nitrogen atmosphere in the presence of caustic soda lye to yield 1 : 10-bis-(21-piperidino ethyl mercapto)-decane, the raw product is then reacted with oxalic acid (+ 2H2O) in water and the mixture cooled to yield the acid oxalate from which the pure base can be precipitated by dissolving in hot water and adding concentrated caustic soda lye.  The base can be converted into other salts e.g. the hydrochloride, the citrate or ethane disulphonate or into quaternary salts, e.g. the metho-iodide, the etho-bromide or methyl methosulphate.  Several other ditertiary amines and diquaternary ammonium compounds are also specified.