Patent GB-1012480-A (GB)
Title: Anti-inflammatory agents
Inventor: NICHOLSON JOHN STUART
IPC: C07C29/147
Filed: 1962-07-26
Abstract: The invention comprises compounds of general formula <FORM:1012480/C2/1> wherein R1 represents cycloalkyloxy (C3-C5), cycloalkylthio (C3-C5), alkylthio (C2-C3), when R2 is hydrogen; or R1 represents ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, branched alkyl (C6-C7), cycloalkyl (C3-C5), alkoxy (C3-C4), alkenyloxy (C3-C4), alkylthio (C1-C5), alkenylthio (C3-C5), cycloalkyloxy (C3-C7), cycloalkylthio (C3-C7), phenoxy, phenylthio, alkenyl (C2-C4), when R2 is methyl; X represents CH2OH, COOR3 where R3 is hydrogen or alkyl (C1-C4) or, when R2 is methyl, dialkylamino substituted alkyl (C1-C4), CONH2, CH2NH2; and the non-toxic organic and inorganic salts of the acids, basic esters and amines; provided that X is not CH2OH when R1 is ethyl; and their preparation by methods described, these being analogous to known methods.  Processes and intermediate and final compounds in examples are as follows:- 4-Substituted phenyl acetic acids are esterified to form ethyl esters which on treatment with ethyl carbonate yield ethyl 4-substituted phenylmalonates; methyl iodide yields the C-methyl compounds which are hydrolysed to form the malonic acids and these decarboxylated yielding 2-(4-substituted phenyl)-propionic acids.  Ethyl esters thereof are obtained and reduced with lithium aluminium hydride to form 2-(4-n-propyl, -n-butyl, and -allyloxy phenyl)-propanols. 2-(4-Propyl and -butyl phenyl)-propionamides are prepared by reacting the acids with thionyl chloride and the acid chlorides with ammonia. 2-(4-Propoxy and -butoxy phenyl)-propionic acids are prepared by hydrogenation of the allyloxy and but-2-enyloxy compounds. 4-Cyclopentyloxyphenyl acetic acid is prepared by hydrolysis of the ethyl ester, obtained from the 4-hydroxy compound by reaction with cyclopentyl iodide.  4-Ethylthioacetophenone, obtained by Friedel-Crafts reaction of thiophenetole and acetyl chloride, yields on reaction with sulphur and morpholine the intermediate thioacetmorpholide which may be hydrolysed to 4-ethylthiophenylacetic acid; 4-n-propyl and -isopropyl thio compounds are similarly obtained.  2-(4-Propylphenyl)-propylamine is obtained by lithium aluminium hydride reduction of the amide.ALSO:Therapeutic compositions comprise compounds of general formula <FORM:1012480/A5-A6/1> wherein R4 represents n-butyl, cycloalkyloxy (C3-C5), cycloalkylthio (C3-C5) or alkylthio (C1-C3) when R2 is hydrogen; or R4 represents n-butyl, n-pentyl, cycloalkyl (C3-C4), alkenyloxy (C4), alkoxy (C4), branched alkyl (C6-C7), alkylthio (C1-C5), alkenylthio (C3-C5), cycloalkyloxy (C3-C7), or cycloalkylthio (C3-C7) when R2 is methyl; and X is CH2OH, COOR3 where R3 is hydrogen or alkyl (C1-C4) or, when R2 is methyl, dialkylamino substituted alkyl (C1-4), CONH2, CH2NH2; and the nontoxic organic and inorganic salts of the acids and amines, in association with a pharmaceutically acceptable diluent or carrier; also solid compositions of 2-41-n-propylphenylpropionic acid its salts and ethyl ester.  Forms are described for oral (capsules, tablets, lozenges, granules, mixtures elixirs, syrups, solutions, suspensions), topical (ointments, creams, lotions) and parenteral administration.  The compounds have anti-inflammatory, antipyretic and analgesic properties.