Patent GB-770411-A (GB)
Title: Improvements in aminophenoxyalkane derivatives
Inventor: RAISON CLIFFORD GORDON
IPC: C07C275/34
Filed: 1954-02-18
Abstract: The invention comprises compounds of the formula <FORM:0770411/IV(b)/1> and acid addition salts thereof, in which R1 is a straight or branched chain alkyl group having from 1 to 6 carbon atoms, or a cycloalkyl group, or a group of the general formula <FORM:0770411/IV(b)/2> wherein R4 is hydrogen or an alkyl group of 1 to 3 carbon atoms which may carry an amino group as a substituent, an alkoxy group of 1 to 3 carbon atoms, or a benzyloxy, acyl, carboxy, alkoxycarbonyl, carbamoyl, cyano, nitro, halogen, hydroxy, alkylsulphonyl or N-nitroso-N-alkylamino group or a group NR5R6 in which R5 is an acyl, alkoxycarbonyl, alkylsulphonyl or carbamoyl group and R6 is hydrogen or an alkyl group of 1 to 4 carbon atoms which may optionally carry at least one hydroxyl group on carbon atoms other than that adjacent the nitrogen atom; R2 and R3 are the same or different and are hydrogen or alkyl groups of 1 to 4 carbon atoms which may optionally carry one or more hydroxyl groups on carbon atoms other than that adjacent the nitrogen atom, and M is an aliphatic hydrocarbon chain of 1 to 8 carbon atoms which optionally contains one double or triple bond.  Preferred products comprise compounds wherein the group NR5R6 is in the para position and R5 is a methoxy- or ethoxycarbonyl group or an acetyl group, R6 is hydrogen or methyl; NR2R3 is amino, methylamino or dimethylamino and -CH2-M-CH2- is a butane, butene, pentane, hexane, heptane or octane residue.  The products are prepared by converting a compound of the formula <FORM:0770411/IV(b)/3> in which R8 is a group convertible into the group NR2R3 and R7 is a group as defined for R1 to give the desired compound.  In the above process R7 may or may not be identical with the desired group R1 and in the latter case the synthesis includes the step, for example, of converting one of the groups defined for R4 into another such group.  Conversion of the group R8 into the group NR2R3 may be effected by the following methods; (A) when NR2R3 is to be a primary amino group; reduction of nitro, aldimine or azo groups, for example the reduction of a nitro group by means of iron and a dilute acid; removal of a protecting group W from a group -NHW, for example an acyl, toluene-p-sulphonyl or alkoxycarbonyl group may be removed by hydrolysis; and the amination of a halogen atom; (B) when NR2R3 is to be a secondary amino group; the removal of a protecting group W from a group -NR2W, and (C) where NR2R3 is to be a tertiary amino group; pyrolysis or hydrolysis of the corresponding quaternary amino compound.  The intermediate compound of the formula III may be made by reacting an a : o -disubstituted compound of the formula <FORM:0770411/IV(b)/4> successively in either order with a compound R7Y and a disubstituted benzene of the formula <FORM:0770411/IV(b)/5> wherein X and Y are groups capable of reacting together to form an ether linkage, for example Y may be a hydroxy group and -X may be halogen, e.g. bromine, alkanesulphonyloxy, such as methanesulphonyloxy, arenesulphonyloxy, such as p-toluene sulphonyloxy or aralkanesulphonyloxy, such as benzylsulphonyloxy. Where the group NR2R3 is to be a tertiary amino group, this group may already be present as the group R1 in the formula V, in which case the desired product is obtained directly by reacting the compound of formula IV successively with the compound R7Y and the compound of formula V.  The products are used as therapeutic agents, preferred compounds having therapeutic activity being 1-(4-methoxycarbonylmethylaminophenoxy) - 4 - (4 - methylaminophenoxy) but-2-ene, 1-(4-cyanophenoxy)-4 - (4 - methylaminophenoxy) butane, 1 - (4 - cyanophenoxy) - 4 - (4 - aminophenoxy) butane and 1 - cyclohexyloxy - 5 - (4 - aminophenoxy) pentane.  Examples are given of the preparation of many compounds of the formula I wherein R1 is chosen from phenyl, p-acetamidophenyl, p-tolyl, p-chlorophenyl, p-methoxyphenyl, p - carbethoxyphenyl, p - carbamoylphenyl, p - methylsulphonylphenyl, p - valeramidophenyl, p - nitrophenyl, p - cyanophenyl, p - benzyloxyphenyl, p - hydroxyphenyl, hexyl cyclohexyl, p - ethoxycarbonamidophenyl, o-, m- and p-ethoxycarbonmethylamidophenyl, p-pentyloxycarbonamidophenyl, p-bromophenyl, p - acetylphenyl, p - ureidophenyl, methyl, propyl, p - acetmethylamidophenyl, p - N - nitrosomethylaminophenyl, p - carboxyphenyl and p-methanesulphonamidophenyl groups.  Starting materials.  Phenoxyalkyl bromides, for example p-nitro-, p-acetamido-, p-acetmethylamido-, p - ethoxycarbonamido-, p - ethoxycarbonmethylamido-, p - nitrosomethylamino- and p-cyano-, phenoxyalkyl bromides are made by the reaction of the appropriate substituted phenol with an a  : o -dibromoalkane; similarly phenoxyalkenyl bromides such as the p-ethoxycarbonamido-, p-acetamido- and p - N - nitrosomethylamino - derivatives of 1 - bromo-4-phenoxy - but - 2 - ene; 1 - bromo - 6 - (p - ethoxycarbonamidophenoxy) hex - 3 - ene and 1 - bromo - 7 - (p - acetamidophenoxy) hept-3 (or (4)-ene are prepared.  By reaction of these bromo compounds with compounds of the formula R7Y or compounds of the formula V as defined above, and more especially with hydroxy derivatives corresponding to the groups specified for R1 in the examples, corresponding intermediate compounds of the formula III are obtained. Intermediates of the formula III, wherein R8 is a quaternary ammonium group are also described.  Specifications 749,907, 749,923, 758,382, 765,957 and 770,410 are referred to in the first Provisional Specification.