Phenoxy and phenylthio alkanoic acids and esters and amides thereof

摘要

Novel phenoxyalkanoic and phenylthioalkanoic acid derivatives of the formula wherein A is oxygen or sulphur; R is C3- 5 alkyl, cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, cycloalkylalkyl, e.g. cyclopentylmethyl or cyclohexylmethyl, or aralkyl, e.g. benzyl, phenylethyl or phenylpropyl; X is OH, -OM (where M is an equivalent of a non-toxic cation), alkoxy or in which R1 and R2 are H or C1- 5 alkyl; X1 is H, halogen, C1- 5 alkyl or -NO2; X2 is halogen, C1- 5 alkyl, -CF3, CH3CONH- or carboxyalkoxy, e.g. -O.CH2.COOH; X3 and X4 are H, halogen, or C1- 5 alkyl and n is 1-5, are made by (a) reacting an alkanoyl halide R.CO.Halogen with the appropriate phenoxy- or phenylthioalkanoic acid, in the presence of a metallic halide; (b) reacting a 4-alkanoylphenol with a haloalkanoic acid, Halogen.CnH2n.COOH, or an ester thereof in the presence of a base and, if necessary, saponifying the product and/or acidifying to form the free acid or (c) hydrogenating a 4-(2-alkylidenealkanoyl) phenoxy- or 4 - (2 - alkylidenealkanoyl) phenylthio-alkanoic acid to its saturated derivative, thus giving products of the invention wherein R has an alkyl side chain in the a -position. The ester and amide derivatives, i.e. products, wherein X is alkoxy or may be made by conventional methods of esterification or amidation, e.g. by reacting the free acid with an alcohol or converting the acid to an acid halide and reacting with an alcohol or with ammonia or an amine. 4-Alkanoyl-phenols bearing substituents corresponding to X1, X2, X3 and X4 on the ring are made by treating an appropriately substituted anisole, phenetole or similar ether with an alkanoyl halide R.CO.Halogen in the presence of a metal halide, e.g. AlCl3 and splitting off the ether group by treating with an additional amount of AlCl3. 4 - (2 - Alkylideneacyl) - phenoxy- and 4 - (2-alkylideneacyl) - phenylthio - alkanoic acids, e.g. compounds having the structure R.C(=CH2).CO.C6H4.A.CnH2n.COOH bearing substituents X1, X2, X3 and X4 on the phenyl nucleus are made by (a) reacting a 4-alkanoylphenoxy- or 4-alkanoylphenylthio-alkanoic acid with the acid addition salt of a secondary amine and formaldehyde or paraformaldehyde to form a 2-secondaryaminomethyl-alkanoyl derivative, and treating this with a weak base such as sodium bicarbonate, or (b) acylating a phenoxy-or phenylthio-alkanoic acid with a 2-methylenealkanoic halide. Pharmaceutical preparations having diuretic activity comprise the above compounds of the invention in admixture with a carrier or excipient preferably in the form of a tablet, capsule, orally administrable or injectable solution or suspension, pill or powder.