Patent GB-1369542-A (GB)
Title: Substituted indenylalkanoic acids
IPC: C07C317/14
Filed: 1972-01-17
Abstract: 1369542 Indenyl acetic acid derivatives MERCK & CO Inc 17 Jan 1972 [21 Jan 1971] 2193/72 Heading C2C  Novel compounds of the Formula I: wherein each of Rα and R# is hydrogen, halogen, alkyl, alkenyl, alkoxy or amino; n is 1 or 2; X is alkylene, alkenylene, alkynylene, oxygen, sulphur, carbonyl, imino, alkylimino or alkenyloxy; R 1  is hydrogen, alkyl, haloalkyl, alkenyl or alkynyl; each of R 2 , R 3 , R 4  and R 5  is a hydrogen or halogen atom or an alkyl, acyloxy, alkoxy, nitro, amino, acylamino, alkylamino, dialkylamino, dialkylaminoalkyl, sulphamoyl, alkylthio, mercapto, hydroxy, hydroxyalkyl, alkylsulphonyl, cyano, carboxy, carboalkoxy, carbamido, halogenoalkyl, cycloalkyl, cycloalkoxy, alkenyloxy or acyl radical; Ar is an aryl or heteroaryl radical; R 6  is an alkylsulphinyl or alkylsulphonyl radical; R 7  is a hydrogen or halogen atom or a hydroxy, alkoxy, hydroxyalkoxy or haloalkyl radical; and M is a hydroxy, C 1-6  alkoxy, substituted C 1-6  alkoxy, amino, alkylamino, dialkylamino, N-morpholino, piperidino, pyrrolidino, piperazino, N- methylpiperazino, N-phenylpiperazino, N-hydroxyethylpiperazino, aralkylamino, dibenzylamino, anilino, p-ethoxyanilino, p-chloroanilino, p-fluoranilino, p-trifluoromethylanilino, cyclohexylamino, tetra - O - acetyl - d - glucosamino, N,N - dialkylcarbonylmethylamino, benzyloxycarbonylmethylamino, hydroxyalkylamino, bis- (hydroxyalkyl)amino, polyhydroxyalkylamino, alkoxyalkylamino, bis-(alkoxyalkyl)amino, dialkylaminoalkylamino or aminoalkylamino radical or a radical of formula OMe in which Me is a cation; provided that when X is alkylene or alkenylene, R 7  is not hydrogen, may be prepared (a) by oxidation of a thio ether group to sulphoxide; (b) oxidation of sulphoxide to sulphone; (c) where X is oxygen condensation of the sodium salt of an appropriate t-butyl ester of 1-hydroxymethylene-indene acetic acid with an iodoaryl-sulphoxide; (d) formation of an amide group, ester group or salt at -COM from the free acid, (e) separation of racemic mixtures into their (+) and ( - ) forms and isomerization into a cis or trans isomer; and (f) resolution of racemic mixtures into their (+) and ( -) forms. Thioethers of the Formula I wherein R 6  is thiomethyl may be prepared by reaction of an appropriate 1-unsubstituted indene acetic acid ester derivative with a thiomethyl-R 7 -substituted Ar-X-CHO. 3 - Chloro - 4 - methylthiophenylacetaldehyde may be prepared by reaction of ethyl α,#-epoxy- 3-chloro-4-methylthiocinnamate with ethanolic sodium ethoxide, the epoxy compound in turn being prepared by reaction in the presence of sodamide of ethyl chloroacetate and 3-chloro-4- methylthiobenzaldehyde, which then is prepared by reaction of O-chlorothioanisole with dichloromethyl methyl ether in the presence of aluminium chloride. The ethyl esters of the 1-unsubstituted indene acetic acid used above may be prepared by Reforuntsky reaction of a 1-indanone with an ethyl bromo acetate. 3 - Chloro - 4 - methylthiocinnamaldehyde may be prepared by reaction of 3-chloro-4-methylthiobenzaldehyde with acetaldehyde in the presence of calcium oxide. (3<SP>1</SP> - Chloro - 4<SP>1</SP> - methylthio) phenylpropargaldehyde may be prepared from the above cinnamaldehyde by bromination to yield 3-chloro- 4 - methylthio - α - bromocinnamaldehyde which on treatment with methyl orthoformate yields 1,1 - dimethoxy - 2 - bromo - 3 - (3<SP>1</SP> - chloro - 4<SP>1</SP>- methylthiophenyl) - 2 - propene which on dehydrohalogenation gives 1,1-dimethoxy - (3<SP>1</SP>- chloro - 4<SP>1</SP> - methylthiophenyl) - 2 - propyne which on hydrolysis yields the required aldehyde. The sodium salts of appropriate t-butyl esters of 1-hydroxymethylene indene acetic acids may be prepared by reaction of the appropriate t-butyl ester of indene acetic acid with ethyl formate and sodium hydride, the starting t-butyl ester being in turn prepared by transesterification of the ethyl ester or methyl ester. Various o - hydroxyalkoxy - thioanisoles may be prepared by reaction of o-hydroxythioanisole with an hydroxyalkylchloride in the presence of sodium ethoxide. Also various alkoxythioanisoles may be prepared by reaction of o-chlorothioanisole with sodium alkoxide. Pharmaceutical compositions of the compounds I show antiinflammatory, antipyretic and analgesic activity when administered topically, orally, rectally or parenterally with the usual excipients.