Patent GB-860303-A (GB)
Title: Pharmaceutical compositions comprising ª‡-aryloxy-aliphatic carboxylic acids and/or ª
Inventor: GLYNNE WILLIAM
IPC: A61K31/215
Filed: 1958-06-20
Abstract: Compounds of general formula <FORM:0860303/IV (b)/1> wherein R1 and R2, which may be the same or different, represent hydrogen or an alkyl radical or may be joined, together with the adjacent carbon atom, to form a cycloalkyl ring, B is an oxygen atom and Y represents a dihalogenated phenyl radical or a phenyl radical containing at least one substituent selected from the following; alkyl of at least two carbon atoms, alkenyl, aryl, aralkyl, arylamino radicals; or for a naphthyl radical optionally substituted by one, two or three substituents selected from halogen atoms, alkyl, alkenyl, alkoxy, aryl, aralkyl, aralkoxy and arylamino radicals, or B represents an imino radical and Y a phenyl or naphthyl radical likewise optionally substituted, are prepared by the following methods: (a) by the interaction of a phenol or naphthol Y-OH (Y being as above) and a ketone of formula R3.CO.R4 (R3 and R4=R1 and R2 above) in the presence of a tri- or tetrahalogenated methane derivative and a strong base; (b) by the interaction of a metal (e.g. alkali metal) derivative of said phenol or naphthol Y-OH with a compound of general formula <FORM:0860303/IV (b)/2> wherein Hal represents a halogen atom and R5 an alkyl radical, R3 and R4 being as stated in (a) above, in an inert solvent; (c) by hydrolysis of a compound of general formula <FORM:0860303/IV (b)/3> wherein R3 and R4 are as before, Y is a phenyl or naphthyl radical optionally substituted and R6 is a carboxy amide radical or a functional derivative or a precursor therefor, e.g. nitrile, the hydrolysis being carried out preferably by means of aqueous hydrochloric acid and heat.  The preparation of the above carboxy amides may be achieved by the hydrolysis of the corresponding nitrile in the presence of sulphuric acid at normal temperature, the nitriles themselves being conveniently obtained by the addition of an aqueous solution of an alkali or metal cyanide to a mixture of the corresponding ketone R3.CO.R4 and a primary aromatic amine Y-NH2. By method (a) are obtained: p-chlorophenoxy isobutyric acid; 4-ethylphenoxyisobutyric acid; 4-t-butyl-phenoxyisobutyric acid; 4-phenylphenoxyisobutyric acid; 4-t-octylphenoxyisobutyric acid; 3-methyl 4-chlorophenoxyisobutyric acid; 2-methoxyphenoxyisobutyric acid.  By method (a) followed by esterification of the crude acid with ethanol in the presence of sulphuric acid are obtained: ethyl (2 - methoxy - 4 - allylphenoxy) isobutyrate; ethyl (o-benzylphenoxy) isobutyrate; ethyl 3 : 4-dichlorophenoxyisobutyrate; ethyl 2 - methoxy - 4 - propenylphenoxyisobutyrate; ethyl 4 - (a a  - dimethyl - n - butyl) phenoxyisobutyrate.  By method (b) are obtained: ethyl (4 - benzylphenoxy) isobutyrate; ethyl (2 - phenylphenoxy) isobutyrate; ethyl (4-anilinophenoxy)-isobutyrate; and ethyl 4-benzyloxyphenoxyisobutyrate which is converted to the free acid by hydrolysis with methanolic potassium hydroxide.  By method (c) are prepared: 4-chloranilinoisobutyric acid from a -p-chloroanilino - isobutyramide (preparation described); 1 - p - chloroanilinocyclohexane carboxylic acid from 1 - p p  - chloroanilinocyclohexane carboxamide (preparation described); and 2-chloroanilinoisobutyric acid, the last by analogous reactions starting with o-chloroaniline and sodium cyanide, the intermediates not being obtained solid.  Also described are: the esterification reactions (alcohol and sulphuric acid) whereby n-butyl- and n-propyl-4-chloro-phenoxyisobutyrate are produced; the preparation of methyl 4-chlorophenoxyisobutyrate by reaction of the parent acid with diazo-methane; ethyl p-chlorophenoxyisobutyrate from the parent acid, ethanol and sulphuric acid.ALSO:Compositions for reducing the blood cholesterol level comprise a non-toxic, pharmaceutically inert diluent or carrier and at least one compound of general formula <FORM:0860303/VI/1> wherein A represents an oxygen atom or an imino radical, R1 and R2 which may be the same or different represent hydrogen or alkyl radicals or, together with the adjacent carbon atom form a cycloalkyl ring X represents a phenyl or naphthyl radical which may optionally be substituted by one, two or three halogen atoms, alkyl, alkenyl, alkoxy, aryl, aralkyl or arylamino radicals and the esters and salts thereof, e.g. with alkali and alkaline earth metals.  Specified active compounds are the following iso-butyric acid derivatives; phenoxy-, 2-methylphenoxy-, 3-methylphenoxy-, 4-methylphenoxy-, 2-chlorophenoxy-, 3:4-dimethylphenoxy, 4-methoxyphenoxy-,  -naphthoxy-, b -naphthoxy-,  -(r -chloroanilino)-, 4-ethylphenoxy-, 4-tert.-butylphenoxy-, 4-phenylphenoxy-, 4-tert.-octylphenoxy-, 2 - methoxyphenoxy-, 3-methyl-4-chlorophenoxy-, 4 - benzyloxyphenoxy-, 2 - chloroanilo-; the following derivatives of ethyl iso-butyrate: 2-methoxy-4-allyphhenoxy-, 2-benzylphenoxy-, 3:4 - dichlorophenoxy-, 2 - methoxyl - 4- propenylphenoxy-, 4 - ( ,  - di-methyl - n - butyl) - phenoxy -, 4 - benzyl - phenoxy-, 2 - phenyl - phenoxy -, 4 - anilino - phenoxy-, 4 - benzyloxy - phenoxy-; the esters methyl 4-chloro-phenoxyisobutyrate, n-butyl 4-chlorophenoxyisobutyrate, n-propyl 4-chlorophenoxyisobutyrate; the acids  -(r -chlorophenoxy) -methyl-n-butyric acid,  -(r -chlorophenoxy) propionic acid, 1-anilinccyclohexane carboxylic acid, 1-r -chloroanilo-cyclohexane carboxylic acid. The compositions may be in forms suitable for oral administration, e.g. tablets, capsules, suspensions, emulsions, solutions, dispersable powders, syrups, elixirs, effervescent tablets, which contain conventional diluents, carriers, preservatives, flavours, sweetening, emulsifying, disintegrating agents, wetting agents and antioxidants.  They may also be in the form of a nutritive preparation in which the active ingredient is mixed with proteins, e.g. casein and carbohydrates and, additionally, the above-mentioned compositions may contain dietary supplements, e.g. vitamins, e.g. nicotinic acid, riboflavin, pyridoscine hydrochloride, ascorbic acid, calcium pantothenate, glycerophosphates, choline, inositol, amino acids, e.g. methionine and hormones or hormone extracts useful in the treatment of conditions associated with old age.  Reference is also made to the use, as a solvent or carrier, of an oil, e.g. sunflower oil, which is itself useful in the treatment of atherosclerosis.