GB1370028A - Substituted indenyl acetic acid derivatives - Google Patents

Abstract

1370028 Indene acetic acid derivatives MERCK & CO Inc 17 Jan 1972 [21 Jan 1971] 2196/72 Heading C2C Novel compounds of the general Formula I wherein (Ar) is aryl or heteroaryl; R 1 is hydro- gen, alkyl or haloalkyl; R 2 is hydrogen, alkyl, haloalkyl, alkenyl or alkynyl; R 3 , R 4 , R 5 and R 6 each may be hydrogen, halogen, acyl, cyano, alkylsulphinyl or alkylsulphonyl; R 7 is alkylsulphinyl or alkylsulphonyl; R 8 is hydrogen, halogen, trifluoromethyl, hydroxy, cyano, alkoxy, haloalkoxy, hydroxyalkoxy, alkylsulphinyl or alkylsulphonyl; and M is 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-fluoroanilino, 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 at least one of R 3 , R 4 , R 5 and R 6 is other than hydrogen, halogen, cyano or alkylsulphonyl when R 8 is hydrogen, halogen, trifluoromethyl, hydroxy or alkoxy, are prepared by reacting an ester of indenylacetic acid of the formula in which E is hydrogen or an esterifying group with an aldehyde of the formula in which R is an alkyl group and R 8 has the above significance and oxidizing the resulting ester of the formula i.e., oxidizing the thioalkyl group to alkylsulphinyl and then, if necessary, to alkylsulphonyl and, when E is an esterifying group, hydrolysing the oxidation product to form compounds I in which M is OH. The final products may then be converted into esters, amides or salts as required. It is also possible to modify the R 3 to R 6 groups, to isomerize into a cis or trans isomer and to resolve racemic mixtures into their (+) and ( - ) forms. Intermediates of the Formula I wherein R 7 and optionally R 8 is methyl thio, M is hydroxy, R 2 is methyl, and Ar is phenyl, may be prepared by (1) reaction of the 1-unsubstituted indene acetic acid ester with a methylthiobenzaldehyde in the presence of a strong base; and (2) demethylation of R 4 to hydroxyl followed by separation of cis and trans isomers. Methyl 5 - (α,α - dichloroethyl) - 2 - methyl indenyl - 3 - acetate may be prepared by reaction of p-acetyl benzaldehyde with propionic acid in the form of its anhydride and sodium salt to yield p-acetyl-α-methyl cinnamic acid which is reduced to p-acetyl-α-methylhydrocinnamic acid which on treatment with phosphorous pentachloride yields p-(α<SP>1</SP>,α<SP>1</SP>-dichloromethyl)-α-methylhydrocinnamic acid which is cyclized with polyphosphoric acid to 6-(α,α-dichloroethyl)-2-methyl- 1-indanone which on Reformatsky reaction with methylbromoacetate yields the required product. 3,4 - Dimethylthiobenzaldehyde may be prepared by treatment of 1,2-bis-methylthiobenzene with phosphorous oxychloride and N- methyl-N-phenyl formamide. Also, 3-hydroxy- 4-methylthiobenzaldehyde may be prepared by reaction of o-hydroxythioanisole with dichloromethylmethyl ether in the presence of aluminium chloride. o - C 1-4 - Alkoxythioanisoles are prepared by reaction of o-chlorothioanisole with sodium C 1-4 alkoxide in the presence of copper. o - C 1-4 - Hydroxyalkoxythioanisoles are pre- pared by reaction of o-hydroxythioanisole with a C 1-4 hydroxyalkyl chloride. This is optionally followed by halogenation to yield o-C 1-4 haloalkoxythioanisoles. Pharmaceutical compositions of the compounds I show antiinflammatory, analgesic and antipyretic activity when administered orally, parenterally, topically or rectally with the usual excipients.