Patent GB-1121722-A (GB)
Title: New carboxylic acid derivatives
Inventor: LEIGH THOMAS
IPC: A61K31/165
Filed: 1966-03-31
Abstract: Novel diphenyl derivatives of the formula <FORM:1121722/C2/1> wherein R1 is hydrogen and R2 is an alkyl radical of at least 2 carbon atoms, or wherein R1 and R2, which may be the same or different, are alkyl radicals; X is an oxygen or sulphur atom or a sulphinyl (-SO-) or sulphonyl (-SO2-) radical; and at least one of the benzene rings A and B bears at least one substituent selected from halogens and alkyl, alkoxy, halogenoalkyl and nitro radicals; and esters, amides and salts thereof; particularly those esters derived from a monohydric alcohol of the formula R3OH, wherein R3 is alkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or alkyleneiminoalkyl, or from a polyhydric alcohol of the formula D(OH)n, wherein D is a straight- or branched-chain alkylene radical and n is an integer from 2 up to the number of carbon atoms in the alkylene radical D, provided that not more than one hydroxyl radical is attached to any one carbon atom of the alkylene radical D; and particularly those amides derived from an amine of the formula R4R5NH, wherein R4 and R5, which may be the same or different, are hydrogen, alkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyleneiminoalkyl, carboxyalkyl or alkoxycarbonylalkyl, or wherein R4 and R5 are joined, together with the adjacent nitrogen atom, to form a heterocyclic ring; are prepared (i) when X is an oxygen or sulphur atom, by reaction of a metal derivative of a diphenyl compound of the formula <FORM:1121722/C2/2> wherein Y is an oxygen or sulphur atom and M is a metal atom, with a carboxylic acid of the formula Z-CR1R2-COOH, wherein Z is a halogen atom, or with an ester, amide or salt thereof, followed by optional conversion of the resulting carboxylic acid or salt thereof into an ester or amide thereof by conventional means, or optional conversion of the resulting ester to an amide by conventional means, or optional conversion of the resulting ester or amide to a carboxylic acid or salt thereof by conventional hydrolysis means; (ii) when X is an oxygen or sulphur atom, by reaction of a phenol or thiophenol derivative of the formula <FORM:1121722/C2/3> with a carbonyl derivative of the formula R1COR2 and a tri- or tetra-halogenated methane derivative, followed by optional conversion of the resulting carboxylic acid or salt thereof to an ester or amide thereof by conventional means; (iii) when X is a sulphinyl or sulphonyl radical, by oxidation of the corresponding carboxylic acid or an ester, amide or salt thereof of the first formula above, wherein X is, respectively, a sulphur atom, or a sulphur atom or sulphinyl radical; or (iv) when the diphenyl derivative is an ester or amide of a carboxylic acid of the first formula above, by reaction of an activated derivative of a carboxylic acid of the first formula above with an alcohol of the formula R3OH or D(OH)n or with an amine of the formula R4R5NH.  The diphenyl derivatives of the invention are useful in the treatment and prophylaxis of coronary artery disease and atherosclerosis, and also possess anti-inflammatory activity. 4-(p-Chlorophenyl)-thiophenol is prepared by reaction of chlorosulphonic acid and 4-chlorobiphenyl to give 4-(p-chlorophenyl)-benzenesulphonyl chloride, which is then reduced. 4-Chloro-3-phenylphenol is prepared by reaction of 4-amino-3-nitroanisole with (a) sodium nitrite and hydrochloric acid and (b) cuprous chloride and hydrochloric acid to give 4-chloro-3-nitroanisole, which is reduced to give 3-amino-4-chloro-anisole hydrochloride, which is reacted with (a) sodium nitrite and hydrochloric acid and (b) benzene to give 4-chloro-3-phenylanisole, which is finally hydrolysed. 4-(p-Ethyl-phenyl)-phenol is prepared by reaction of 4-acetyl-41-methoxy-biphenol with sodium hydroxide, diethylene glycol and hydrazine hydrate.ALSO:Pharmaceutical compositions, useful in the treatment of prophylaxis of coronary artery disease and atherosclerosis and also possessing anti-inflammatory activity, comprise diphenyl derivative(s) of the formula <FORM:1121722/A5-A6/1> wherein R1 is hydrogen and R2 is an alkyl radical of at least 2 carbon atoms, or wherein R1 and R2, which may be the same or different, are alkyl radicals; X is an oxygen or sulphur atom or a sulphinyl or sulphonyl radical, and at least one of the benzene rings A and B bears at least one substituent selected from halogens and alkyl, alkoxy, halogenoalkyl and nitro radicals; or ester(s), amide(s) or salt(s) thereof, in association with a pharmaceutically acceptable diluent or carrier therefor and optional additional active ingredients, e.g. solvent oils, such as maize, cod liver or sunflower seed oils; proteins and carbohydrates, e.g. casein, vitamins, e.g. the tocopherols; salts of glycerophosphoric acid; choline and inositol; amino acids, e.g. methionine; hormones and hormone extracts; steroids, e.g. androsterone or its acetate or propionate; and anti-inflammatory and/or analgesic agents, e.g. acetylsalicylic acid, phenylbutazone, chloroquine, codeine or paracetomol.  The compositions are suitable for oral administration as tablets, capsules, aqueous or oily suspensions, emulsions, aqueous or oily solutions, dispersible powders, syrups or elixirs.