Patent GB-892413-A (GB)
Title: Poly-onium neuromuscular blocking agents
Inventor: EDWARDS DANIEL
Filed: 1957-07-15
Abstract: The invention comprises (1) compounds of the formulae <FORM:0892413/IV (b)/1> (wherein R1 and R2 are alkyl groups, n and m are integers not less than 4, X is <FORM:0892413/IV (b)/2> Z is a non-toxic anion and o is the number of onium groups in the compound divided by the valency of the anion; and (2) bis-5-diethylaminopentyl sulphide; bis(6-diethylaminohexyl)ethylamine; bis (10 - diethylaminodecyl) ethylamine; 1, 20 - bis - (diethylamino) - 7, 14 - diethyl - 7, 14 - diazaeicosane; 1, 32 - bis - (diethylamino) - 11, 22 - diethyl - 11, 22 - diazadotriacontane; bis - (13 - diethylamino - 7 - ethyl - 7 - azatridecyl) sulphide; bis - 8 - diethylaminooctyl sulphide; bis - (8 - diethylaminooctyl) - ethylamine; 1, 28 - bis (diethylamino) - 11,18 - diethyl - 11, 18 - diazaoctacosane and 1,24-bis-(diethylamino)-7,18-diethyl-7,18-diazatetracosane. Compounds (2) are prepared by the following methods in examples (a) for triamines, by reaction of dialkylaminoalkyl halides with trialkylalkylenediamines; (b) for bis-dialkylaminoalkyl sulphides, by reaction of 2 mols of dialkylaminoalkyl halides with 1 mol of sodium sulphide; (c) for bis-[N-(dialkylaminoalkyl)-N-alkyl-aminoalkyl] sulphides, by reaction of 2 mols of N-(dialkylamino alkyl)- N-alkylaminoalkyl halides with 1 mol of sodium sulphide; and (d) for N,N1-dialkyl-N1-dialkylaminoalkyl)-alkylenediamines, by lithium aluminium hydride reduction of suitable di- or tetra-amides. Compounds (1) are prepared from compounds (2) by quaternization, e.g. with alkyl halides.  Hydrochlorides of some of the intermediates (2) are described, and halides and tartrates of the final products (1) are described or referred to.  Examples are given. 5-Diethylaminopentyl chloride is prepared from 5-diethylaminopentanol and thionyl chloride.  8-diethylaminooctyl chloride and 13-diethylamino-7-ethyl-7-azatridecyl chloride are prepared similarly.  6-Diethylaminohexyl bromide is prepared by refluxing 6-diethylaminohexanol with hydrobromic acid and sulphuric acid. 10-Diethylaminodecyl bromide and 8-diethylaminooctyl bromide are prepared similarly.  N, N, N1 - triethylhexamethylenediamine (di - hydrochloride also described) is prepared from 6- diethylaminohexyl bromide and ethylamine.  N, N, N1 - triethyldecamethylenediamine (dihydrochloride also described) is prepared similarly, the reaction also yielding some bis-(10-diethylaminodecyl) ethylamine.  N, N, N1 - triethyloctamethylenediamine (dihydrochloride also described) is also similarly prepared.  8-Diethylaminooctanol (hydrochloride also described) is prepared by reacting 6-diethylaminohexyl chloride with sodiomalonic ester to give 1,1-bisethoxycarbonyl-7-diethylaminoheptane, converting this to ethyl 8-diethylaminocaprylate (ethiodide also described) and reducing this with lithium aluminium hydride.  N, N1 - Diethyl - N, N1 - bis (6 - diethylamino - hexyl) adipamide is prepared from adipoyl chloride and triethylhexanethylenediamine.  Bis - (N - ethyl - N1, N1 - diethyladipamoyl) - hexamethylenediamine is prepared by hydrolysing ethyl N,N-diethyl-adipamate to give N,N1-di-ethyl-adipamic acid, reacting this with thionyl chloride to give the acid chloride, and reacting this with N,N1-diethylhexamethylenediamine.  13 - Diethylamino - 7 - ethyl - 7 - azatridecan - 1 - ol (dihydrochloride also described) is prepared by reacting ethyl adipoyl chloride (from ethyl hydrogen adipate and thionyl chloride) with triethylhexamethylenediamine to give ethyl N-ethyl - N - (6 - diethylaminohexyl) - adipamate and reducing this with lithium aluminium hydride.  The second Provisional Specification describes compounds the cations of which have the formulae <FORM:0892413/IV (b)/3> (wherein the symbols R represent the same or different alkyl or omega-trialkylammonium alkyl groups) and the corresponding compounds wherein one or more of the quaternary ammonium groups is replaced by an equivalent tertiary sulphonium group.