Patent GB-769706-A (GB)
Title: Improvements in or relating to amines and to processes for their preparation
Inventor: BARBER HARRY JAMES
IPC: C07D213/81
Filed: 1954-04-30
Abstract: The invention comprises p-aminophenoxyalkyl- and aminophenoxyalkenyl-amides of the formula <FORM:0769706/IV(b)/1> and their acid addition salts, where R1 and R2 are hydrogen atoms, alkyl, hydroxyalkyl (including polyhydroxyalkyl) or alkoxyalkyl groups of not more than 6 carbon atoms, A is an unbranched saturated or ethylenicallyunsaturated hydrocarbon chain of 5 to 9 carbon atoms and R is a mono- or di-acylamido group.  The invention also comprises formaldehydesodium bisulphite compounds of the primary amines of the above general formula.  The mono- or di-acylamido groups may suitably be derived from aliphatic, aromatic or heterocyclic acids including dicarboxylic acids (which may give imides, monoamides or diamides), sulphonic acids and mixed sulphonic-carboxylic acids. These acids may bear substituents such as chlorine atoms or methoxy groups.  The compounds are made by condensing a compound of the formula <FORM:0769706/IV(b)/2> with a compound of the formula Z2Y, wherein X is a tertiary amino group or an atom or group capable of being replaced by or converted into a primary, secondary or tertiary amino group, Y represents the group R or an atom (e.g. a halogen atom) or group which may be converted into the group R and Z1 and Z2 are atoms or groups capable of reacting together to form the -O-A1- linkage in which A1 represents the group A or a corresponding less-saturated hydrocarbon linkage.  If necessary, the groups X and Y are then converted into the groups NR1R2 and R respectively and also, if necessary the group A1 is reduced to form the group A.  Groups which may be represented by X include: (a) groups convertible into primary amino groups; acylamido, carbonamido, nitro, nitroso, alkoxycarbonylamido, anil and arylazo groups; (b) groups convertible into secondary amino groups; anil, alkoxycarbonylamido and acylamido groups (by reduction) and acylalkylamido groups (by hydrolysis) and (c) tertiary amino groups or groups convertible thereto, e.g. quaternary ammonium groups (by pyrolysis) and acylalkylamido groups (by reduction).  Groups which may be represented by Y include: (a) acetamido, benzamido, diacetamido, succinimido, phthalimido and benzenesulphonamido groups, wherein one acylamido may be converted to another, if desired, by hydrolysis (or in the case of a phthalimido group by treatment with hydrazine) and subsequent acylation and (b) nitro groups which may be converted by reduction and acylation.  The products may be used in pharmaceutical preparations for treatment of bilharziasis.  Preferred products are a  - p - aminophenoxy - o  - phthalimido - pentane, -hexane, -heptane and -octane and a  - p - aminophenoxy - o  - benzamido - pentane and -octane and their salts with pharmaceutically acceptable anions.  In examples, the preparation of many compounds of the formula I is described wherein R and R1 are chosen from hydrogen atoms and 2-hydroxyethyl, methyl, 2 - methoxyethyl, 2 - hydroxypropyl, 2 : 3 - dihydroxypropyl and n-propyl groups; A is a straight-chain alkylene radical of 5 to 9 carbon atoms or a cyclohexene residue and R is chosen from phthalimido-, succinimido-, o-sulphobenzoic imido-, benzamido-, benzenesulphonamido-, methanesulphonamido-, methoxybenzamido-, chlorobenzamido-, phenylacetamido-, phenoxyacetamido -, p - chlorophenoxyacetamido -, naphthoylamino -, nicotinamido -, isonicotinamido -, diacetamido -, hexahydrophthalimido -, o - carboxybenzamido -, 21 - furoylamino -, 21 - thenoylamino - and cinnamoylaminogroups.  1 : 2-Di-[N-(5-p-aminophenoxypentyl) carbamoyl] benzene is prepared as exemplifying a phthalic acid diamide of the formula I.  The products may be isolated as salts such as the methanesulphonates or picrates or converted to sodium formaldehyde bisulphite compounds.  p - Nitrophenoxyalkyl amides corresponding to the p-aminophenoxyalkyl amides of the general formula I are made (a) by treating the corresponding o  - p - nitrophenoxyalkyl bromide with potassium phthalimide or potassium succimide; (b) by treating an o -phthalimidoalkyl bromide with potassium p-nitrophenoxide; (c) by treating an o -p-nitrophenoxy-a -aminopentane or octane with acid chlorides or anhydrides to give corresponding benzamido-, benzenesulphonamido-, o-, m- and p-methoxybenzamido-, methanesulphonamido-, p-chlorobenzamido-, phenylacetamido-, phenoxyacetamido-, p - chlorophenoxyacetamido -, diacetamido-, 21 - furoylamino -, 21 - thenoylaminoand cinnamoylamino -, o  - b  - nitrophenoxyalkanes or to give a diamide such as 1 : 2-di-[N - (5 - p - nitrophenoxypentyl) carbamyl] benzene; and (d) nitrating 1-phenoxy-5-phthalimidopentane.  Starting materials.  1 - p - Dimethylaminophenoxy - 5 - phthalimidopentane methiodide and 1 - p - dimethylaminophenoxy - 5 - benzamidopentane methiodide are made by the action of methyl iodide on the corresponding primary aminophenoxypentane. The former compound is also made by the reaction of p-hydroxyphenyltrimethylammonium iodide and 5-phthalimidopentyl bromide.  N - Formyl - p - methylaminophenol is made by treating p-methylaminophenol sulphate with formamide and potassium acetate in acetic acid.  Reaction of this product with 5-phthalimidopentyl bromide gives N - formyl - 1 - p - methylamino - phenoxy - 5 - phthalimidopentane.  1 - p - Benzylideneaminophenoxy - 5 - phthalimidopentane is made by reaction of p-benzylideneaminophenol with 5-phthalimidopentyl bromide.  The benzylidene derivative of 1-p-aminophenoxy-5-hexahydrophthalimidopentane is also referred to. 1 - Methanesulphonyloxy - 5 - phthalimidopentane is made by treating 1 : 5-dimethanesulphonyloxypentane with potassium phthalimide.  The product is treated with potassium p-nitrophenoxide to give 1-p-nitrophenoxy-5-phthalimidopentane.  1 - p - (2 - Chloroethoxycarbonamidophenoxy) - 5 - benzamidopentane is made by treating 1 - p - aminophenoxy - 5 - benzamidopentane with 2-chloroethyl chloroformate in the presence of sodium acetate.  1 - Toluene - p - sulphonyloxyhex - 3 - ene - 6 - ol is made by treating hex-3-ene-1 : 6-diol with toluene-p-sulphonyl chloride in pyridine. By treating this with potassium phthalimide 1 - Phthalimido - 6 - hydroxyhex - 3 - ene is obtained which is treated with toluene-p-sulphonyl chloride to give 1-p-phthalimido-6-toluene - p - sulphonyloxyhex - 3 - ene and reacted with p-acetamidophenol to give 1-phthalimido-6-p-acetamidophenoxy hex-3-ene.ALSO:Therapeutic compositions for the treatment of bilharziasis comprises compounds of the formula <FORM:0769706/VI/1> where R1 and R2 represent hydrogen or alkyl, hydroxyalkyl (including polyhydroxyalkyl) or alkoxyalkyl groups of not more than 6 carbon atoms, A is an unbranched, saturated or ethylenically unsaturated hydrocarbon chain of 5 to 9 carbon atoms and R is a mono- or di-acylamido group, acid addition salts of these compounds and formaldehyde-sodium bisulphite compounds of the primary amines of the above general formula, admixed with a pharmaceutical diluent.  The mono- or diacylamido group R may be derived from aliphatic, aromatic or heterocyclic acids, including mono- and di-carboxylic acids (which may give imides, monoamides and diamides), sulphonic acids and mixed sulphonic-carboxylic acids.  These acids may bear substituents such as chlorine atoms or methoxy groups. Preferred therapeutic compounds of the above general formula together with their acid addition salts containing pharmaceutically acceptable diluents are those wherein R1 and R2 are the same or different and are hydrogen atoms or methyl, ethyl, propyl, hydroxyethyl or hydroxypropyl groups, A is a polymethylene chain of 5 to 8 carbon atoms and R is a phthalimido or benzamido group or less preferably a succinimido, o-, m- or p-methoxybenzamido, 1-naphthoylamino, acetamido, 2-thenoylamino or benzenesulphonamido group. Specified preferred products are a -p-aminophenoxy-o -phthalimido-pentane, hexane, heptane and octane, a -p-aminophenoxy-o -benzamido-pentane and a -p - amino - phenoxy - o  - benzamido-octane.  Many other specific products are exemplified (see Group IV(b)).  The active compounds are suitably employed as elixirs tablets, powders, capsules or injectable solutions.  The compositions may contain the active material in a liquid diluent such as water or admixed with solid diluents such as starch, lactose, talc, stearic acid, magnesium stearate or gums.  Examples describe compositions suitable for tablet formation comprising (a) 1-p-aminophenoxy-5-phthalimidopentane, starch, dextrin, magnesium stearate, stearic acid and sodium carboxymethyl cellulose and (b) 1-p - aminophenoxy - 5 - benzamidopentane, starch, dextrin, magnesium stearate, stearic acid, alginic acid and sodium lauryl sulphate.