Patent ES-350640-A1 (ES)
Title: Novel bis-phenoxy-acetic acid derivatives, the preparation thereof and compositions containing the same
IPC: A61K31/19
Filed: 1968-02-19
Abstract: Novel bis-phenoxy-acetic acid derivatives of the general formula wherein each Y is the same and is a 4-biphenylyl, 4 - (4 - chlorophenyl) phenyl or 4 - trifluoromethylphenyl radical and R 1 is a hydrogen atom, a C 1-4 alkyl radical or a heterocyclic radical of the formula in which n is 0 or a whole number from 1 to 4, n1 is 4 or 5 and R 2 is a C 1-4 alkyl radical, and salts thereof are prepared (a) when R 1 is a heterocyclic radical as defined above, (i) by reaction of a bis-phenoxy-acetic acid alkyl ester derivative of the general formula wherein R11 1 is a C 1-4 alkyl radical and Z is a hydrogen atom or a -COOR111 radical, with an alcohol of the general formula R 1 OH, in which R 1 is a heterocyclic radical as defined above, at a temperature sufficiently high for a partial decarboxylation to occur when Z is a -COOR111 radical or (ii) by reaction of a bis-phenoxyacetyl halide derivative of the general formula wherein X is a chlorine or bromine atom, with an alcohol or salt thereof of the general formula R 1 OP, in which R 1 is a heterocyclic radical as defined above and P is a hydrogen atom or an alkali metal atom (b) when R 1 is a C 1-4 alkyl radical, (i) by reaction of an alkali metal phenolate of the general formula Y-O-M, in which M is an alkali metal atom, with a dihaloacetic acid ester of the general formula X 2 CHCOOR 1 , wherein R 1 is a C 1-4 , alkyl radical (ii) by partial decarboxylation of a bis-phenoxymalonic acid alkyl ester of the second general formula above, wherein Z is a -COOR111 radical or (iii) by reaction of a bis-phenoxyacetic acid derivative of the fourth general formula above, wherein X is a chlorine or bromine atom or a hydroxyl radical with an alcohol or salt thereof of the fifth general formula above, wherein R 1 is a C 1-4 alkyl radical, with the proviso that when X is a hydroxyl radical, P is a hydrogen atom and the reaction is carried out in the presence of a conventional esterification catalyst or (c) when R 1 is a hydrogen atom, (i) by partial decarboxylation of a bis-phenoxy-malonic acid derivative of the general formula (ii) by saponification of a bis-phenoxy-acetic acid alkyl ester of the second general formula above, the temperature being sufficiently high for a partial decarboxylation to occur when Z is a -COOR111 radical or (iii) by reaction of a dihaloacetic acid salt of the general formula X 2 CHCOOM with an alkali metal phenolate of the sixth general formula above followed optionally by salt-formation. Bis-phenoxy-malonic acid derivatives of the eighth general formula above are prepared by saponification of the corresponding bis-phenoxyacetic acid dialkyl ester of the second general formula above, wherein Z is a -COOR11 1 radical, which in turn is prepared by reaction of a dihalomalonic acid ester of the general formula with an alkali metal phenolate of the sixth general formula at a temperature not exceeding 80 C. Bis-phenoxy-acetyl halide derivatives of the fourth general formula above are prepared by reaction of a bis-phenoxy-acetic acid derivative of the first general formula above, wherein R 1 is a hydrogen atom with a chlorinating or brominating agent. Pharmaceutical compositions having hypocholesteremic activity comprise as active ingredient a bis-phenoxy-acetic acid derivative of the first general formula above or a non-toxic, pharmaceutically acceptable salt thereof in association with a physiologically acceptable carrier or diluent.