Patent GB-1446239-A (GB)
Title: Aroyl-substituted phenylacetic acid derivatives
IPC: C07C57/32
Filed: 1973-10-24
Abstract: 1446239 Aroyl-substituted-phenyl acetic acid derivatives JANSSEN PHARMACEUTICA NV 24 Oct 1973 [24 Oct 1972 10 Sept 1973] 49580/73 Heading C2C Novel compounds of the Formula I ArCO is an aroyl-substituent the Ar function of which is a 2-thienyl, 5-alkyl-2-thienyl, 5-halo-2- thienyl, 2 - naphthyl or 3 - pyridyl group, said ArCO being in the meta- or para-position relative to the acetic acid function; R is a hydrogen atom, a halogen atom or an alkyl group, provided that when said R is a halogen atom or an alkyl group, then R 1  is a hydrogen atom and said ArCO is in the aforementioned para-position, and provided that when said R is a halogen atom, then said Ar is a 2-thienyl, 5- alkyl-2-thienyl or 5-halo-2-thienyl group; R 1  is a hydrogen atom, a halogen atom or an alkyl group, provided that, when said R 1  is a halogen atom or an alkyl group, then R is a hydrogenatom and said ArCO is in the aforementioned meta position, and provided that when said R 1  is a halogen atom, then said Ar is a 2-thienyl, 5- alkyl-2-thienyl or 5-halo-2-thienyl group; R 2  is a hydrogen atom, an allyl or alkyl group; R 3  is a hydrogen atom or an alkyl group, provided that when said R 2  is an allyl group, then said R 3  is a hydrogen atom; R 2  and R 3  may also form together an alkylene bridge, having from 2 to 5 carbon atoms; Y is a hydroxy, alkoxy, having from 1 to 8 carbon atoms; dialkylamino-alkyloxy, or an amino containing group which is an amino, anilino, halo-substituted anilino, alkylanilino, alkyloxyanilino, piperidino, 2 - hydroxyethylamino, 2 - (2 - thiazolinyl)-amino or hydroxyamino group, wherein unless otherwise stated alkyl groups contain from 1 to 5 carbon atoms, may be prepared by (1) hydrolysing a compound of the Formula IV to produce a compound of the Formula Ia (b) hydrolysing a compound of the Formula VI (c) subjecting a compound of the Formula XVIa to a Willgerodt reaction in the presence of sulphur and morpholine to form a compound of the Formula Id (d) subjecting a compound XVIa to a modified Willgerodt in the presence of rhodamine to prepare a compound of the Formula Ie (e) mono or dialkylating free acids or esters of the Formula I in which one or both of R 2  and R 3  are hydrogen to introduce alkyl groups at R 2  and R 3  (f) reacting a compound of the Formula XXI with ArH under Friedel-Crafts conditions to prepare a compound of the Formula Ij (g) hydrolysing and decarboxylating a compound of the Formula XXIII to produce a free acid of the Formula I in which R 3  is hydrogen, (h) reacting a compound of the Formula XXX with ArCOCl under Friedel-Crafts conditions to yield a free acid of the Formula I, optionally followed by esterification or amidation of compounds I in which Y is hydroxy and/or hydrolysis to form the free acid and/or forming salts thereof. Intermediates of the Formula IV are prepared by reacting ArH with a halobenzoyl chloride in a Friedel-Crafts reaction to form a halophenylarylketone which is reacted with a diethyl malonate derivative in the presence of strong base to yield the required compound. Nitriles of the Formula VI are prepared by reacting ArH with an alkyl benzoyl chloride in a Friedel-Crafts reaction to form an alkylphenylketone; which is brominated under free radical conditions to form a bromoalkylphenylarylketone which is converted to the cyanoalkylphenylarylketone and optionally when the alkyl is -CH 2 -, mono or dimethylating the methylene group. Several α - chloroalkylphenyl - 2 - thienylketones are prepared by reacting an appropriate bromo benzonitrile with an alkylmagnesium halide to form a bromophenylalkylketone which is reacted with ethylene glycol to form a 2- bromphenyl - 2 - alkyl - 1,3 - dioxolane which is reacted with magnesium and then 2-thenonitrile and the intermediate ketimine hydrolysed to form a 2-thenoylphenylalkylketone which is reduced to a α-hydroxyalkylphenyl-2-thienylketone which is chlorinated to give the required compound. Several p(α - hydroxyalkyl)phenyl- 2 - thienylketones are prepared by reacting a p-(α-hydroxyalkyl)bromobenzene with 2H-3,4-dihydropyran to form a 2 - (p - bromo - benzyloxy) - tetrahydropyran which yields the required compound on reaction with magnesium and then 2-thio phenecarbonitrile. Pharmaceutical compositions of the compounds I with the usual excipients show antiinflammatory activity and inhibit platelet aggregation when administered orally or parenterally.