Patent GB-838748-A (GB)
Title: Heterocyclic compounds
IPC: C07D333/20
Filed: 1958-02-27
Abstract: The invention comprises compounds of the formula <FORM:0838748/IV (b)/1> (wherein R is hydrogen or methyl, Y is -O- or -S- and R1 and R2 are the same or different and are alkyl radicals of at most 4 carbon atoms, or -NR1R2 represents a pyrrolidino or piperidino radical which may be substituted by alkyl groups of at most 4 carbon atoms, or when Y is -S-, R1 and R2 may be hydrogen atoms) and their acid-addition salts.  They may be prepared by the following methods: (a) for compounds wherein neither R1 nor R2 is hydrogen, by reacting the appropriate furan or thiophene 2-magnesium halide with 1-cyano-1-NR1R2-cyclohexane and hydrolysing the product or by reacting a pentamethylene-bis-magnesium halide with an appropriate 2-(CONT1 R2)-furan or -thiophene and hydrolysing the product; (b) for compound wherein R1 is hydrogen and R2 is alkyl, by reacting the appropriate furan or thiophene 2-alkali metal compound with an N-R2-cyclohexylidene-amine and hydrolysing the product, or by reacting the alkali metal compound with a 1-cyano1-NHR2-cyclohexane and hydrolysing the product; (c) for compounds wherein both R1 and R2 are alkyl groups, by alkylation of the N-unsubstituted or N-monosubstituted compounds with, for example, an alkyl halide, a dialkyl sulphate or a mixture of formaldehyde and formic acid; (d) for 2-[1-(1-amino)-cyclohexyl]-thiophenes, by converting the appropriate 2-[1-(1-carboxyl)-cyclohexyl]-thiophenes or functional derivatives thereof such as esters or the corresponding amide or nitrile, to the amino compounds by, for example, converting the amide (which may be obtained by partial hydrolysis of the nitrile) to the isocyanate with an alkali metal hypohalite and hydrolysing the isocyanate with a mineral acid, or by treating an ester with hydrazine, treating the resulting hydrazide with nitrous acid, treating the resulting azide (which may also be prepared directly from the carboxy compound by treatment with hydrazoic acid in a mineral acid or by the action of thionyl chloride to produce the acid chloride and reaction of this with an alkali metal azide) with a lower aliphatic alcohol to produce the carbamic acid alkyl ester and hydrolysing this with mineral acid, or by treating the nitrile with hydroxylamine to give the amido oxime, treating this with benzene sulphonyl chloride to produce the urea compound and hydrolysing this with an alkali.  Examples illustrate the majority of the above processes, the products being isolated as the free bases or as hydrochlorides, sulphate, tartrates, hydrobromides, acetates, sulphamates or p-toluene sulphonates.  The production of succinates and phosphates is also referred to.  1 - Cyanocyclohexylamines are prepared by reacting the bisulphite addition compound of cyclohexanone with an alkali metal cyanide and the appropriate amine in aqueous solution.  N-Cyclohexylidene amines are prepared by reacting cyclohexanone with the appropriate monoalkylamine.  1 - Thienylcyclohexane carboxamides are prepared by reacting 1-thienylcyclohexane carbonitriles with alkali to obtain 1-thienylcyclohexane carboxylic acids, reacting these with thionyl chloride to give 1-thienylcyclohexane carboxylic acid chlorides and reacting these with ammonia.  1 - (2 - Thienyl) - cyclohexane carbonitrile is prepared from 2-thienylacetonitrile and pentamethylene dibromide.  N:N - Dimethyl - 2 - thiophene carboxamide is prepared from 2-thiophene carbonyl chloride and dimethylamine. Furyl magnesium halides are prepared by reacting the furan with butyl lithium to produce the lithium furan and then reacting this with a magnesium halide etherate prepared by the reaction of magnesium with an ether solution of an ethylene halide.ALSO:Pharmaceutical compositions for human or animal use comprise compounds of the formula <FORM:0838748/VI/1> (wherein R is hydrogen or methyl, Y is-O-or -S-and R1 and R2 are the same or different and are alkyl radicals of at most 4 carbon atoms, or -NR1R2 represents a pyrrolidino or piperidino radical which may be substituted by alkyl groups containing at most 4 carbon atoms, or, when Y is-S-, R1 and R2 may be hydrogen atoms) made up in the form of tablets, dragees, capsules, syrups or parenteral solutions.  The active ingredients enhance the effect of anaesthetic agents, especially barbiturates.