Patent GB-895601-A (GB)
Title: N[n-(monocarbocyclic aryl) carbamyl-lower-alkyl] amines and their preparation
Filed: 1958-11-12
Abstract: The invention comprises compounds of the formula <FORM:0895601/IV (b)/1> (wherein R, R1 and R11 are hydrogen or halogen atoms or alkyl or alkoxy radicals of at most 4 carbon atoms, Y is an alkylene radical of at most 5 carbon atoms, n is 1 or 2, and A is CH2, CH(OH), CHCl, CHBr, CH(O-Acyl), C(OH) (COO-C1 to C8-alkyl), C(OH)(C1 to C8-alkyl) or =CH-, the double bond in the last named radical being joined to the 2-carbon atom with elimination of hydrogen to provide a 2,3-double bond) and their acid-addition salts and quaternary ammonium derivatives; and their preparation by reacting the appropriate N-(C6H2RR1R11)-carbamoyl-alkyl halide with the appropriate bicyclic secondary or tertiary amine to give, respectively, a compound of the above formula or a quaternary halide thereof.  In the products or in the amine starting materials one group A may be converted to another.  For example, a hydroxyl group may be esterified or oxidized or replaced by a halogen atom, or water eliminated from a 3-hydroxy compound or hydrogen halide from a 3-halo compound to give a 2,3-double bond which may subsequently be hydrogenated, a keto group may be reduced, or reacted with an alkyl lithium to give a C(OH)(C1 to C8-alkyl) grouping, or reacted with hydrogen cyanide to give a C(OH)(CN) grouping which can then be hydrolysed to give a C(OH)(COOH) group and then esterified to a C(OH)(COOC1 to C8 alkyl) grouping, or an acyloxy group may be saponified. Examples are given and lists of salt-forming organic and inorganic acids and quaternizing agents are provided.  N - (2, 6-dimethyl - 4 - n - butoxyphenyl) carbamoylmethyl chloride is prepared from 2,6-dimethyl - 4 - n - butoxyaniline and chloroacetyl chloride.  1 - Methyl - 2 - [N - (2,6 - dimethylphenyl)carbamoyl]ethyl chloride is prepared from 2, 6 - dimethylaniline and beta - chloro - butyryl chloride.  5 - [N - (2,6 - dimethylphenyl)carbamoyl]-pentyl chloride is prepared from 2,6-dimethylaniline and omega-chloro-caproyl chloride.  3 - Chloro - nortropane and 3 - bromo - nortropane are prepared from nortropine and the appropriate thionyl halide. 3-Benzoyloxynortropane is prepared from nortropine and benzoyl chloride. 3-Hydroxy-3-methylnortropane is prepared from nortropanone and methyl lithium.  Nor-a -ecgonine methyl ester is prepared by hydrolysing nortropinone cyanhydrin to give nor-a -ecgonine and esterifying this. 8 - [N - (2,6 - dimethylphenyl)carbamylmethyl] - nortropinone ethylene glycol ketal is prepared by reacting nortropinone hydrochloride with ethylene glycol to give nortropinone ethylene glycol ketal and then reacting this with N-(2,6-dimethylphenyl) carbamoylmethyl chloride.  8 - [N - (2,6 - dimethylphenyl) carbamoylmethyl]-nortropinone oxime is prepared from the ketone and hydroxylamine hydrochloride.ALSO:Pharmaceutical compositions, useful as local anaesthetics, comprise amides of the formula <FORM:0895601/VI/1> (wherein R, R1 and R11 are hydrogen or halogen atoms or alkyl or alkoxy radicals of at most 4 carbon atoms, Y is an alkylene radical of at most 5 carbon atoms, n is 1 or 2, and A is CH2, CH (OH), CHCl, CHBr, CH(O-Acyl), C(OH)-(COOC1 to C8-alkyl), C(OH)(C1 to C8-alkyl) or =CH-, the double bond in the last-named radical being joined to the 2-carbon atom with elimination of hydrogen to provide a 2,3-double bond) or acid-addition salts or quaternary ammonium derivatives thereof and carriers therefor. Solutions in sterile water may contain stabilizing agents and may also contain other active ingredients such as vasoconstrictors, e.g. epinephrine or phenylephrine. Ointments and creams may also be prepared.  Aqueous preparations, and an ointment containing 8 - [N - (2,6 - dimethylphenyl) - carbamylmethyl]nortropane hydrochloride are described, and other mineral and organic salt-forming acids are referred to.