Patent GB-1373262-A (GB)
Title: Indenyl-alkanoic acids and their derivatives
IPC: C07C45/29
Filed: 1972-01-17
Abstract: 1373262 Sulphoxides and sulphones of arylidene indene derivatives MERCK & CO Inc 17 Jan 1972 [21 Jan 1971] 2195/72 Heading C2C Novel cmpounds of the general Formula I wherein R 1  is (CH 2 ) p COM where p is 2, 3 or 4, or -(CH 2 ) m C(R<SP>1</SP>R)(CH 2 ) n COM where R and R<SP>1</SP> are each hydrogen, alkyl, aryl or halogen, m is 2, 1 or 0 and n is 1 or 0 provided that m+n is not 0; (Ar) is aryl or heteroaryl; R 2  is hydrogen, alkyl or haloalkyl; R 3 , R 4 , R 5  and R 6  each are hydrogen, alkyl, acyloxy, alkoxy, amino, acylamino, alkylamino, dialkylamino, dialkylaminoalkyl, sulphamyl, hydroxy, hydroxyalkyl, alkylsulphonyl, halogen, cyano, carboxyl, carboalkoxy, carbamido, haloalkyl, cycloalkyl, cycloalkoxy, alkenyloxy or acyl; R 7  is alkylsulphinyl or alkylsulphonyl; R 8  is hydrogen or halogen atom or a methyl sulphinyl, cyano, hydroxy, alkoxy, hydroxyalkoxy or haloalkoxy 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, pchloroanilino, p-fluoroanilino, p-trifluoromethylanilino, cyclohexylamino, tetra-O-acetyl-dglucosamino, 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, may be prepared by (1) oxidation of the corresponding compound I in which R 7  is thioalkyl; (2) interconversion of the substituted alkyl in R 1 ; (3) formation of esters and amides at COM; (4) separation of racemic mixtures into their (+) and (-) forms and isomerization into a cis or trans isomer. The intermediates I in which R 7  is thioalkyl and COM is the free acid may be prepared by condensation of a thioalkyl substituted aryl aldehyde with an appropriately substituted indene ester optionally followed by intereonversion of the substituted alkyl in the R 1  grouping and/or separation into isomers. The intermediate indene esters may be prepared by introduction of the R 1  group into the appropriate 1-indanone by a Wittig reaction with an α-triphenyl phosphinyl ester followed by rearrangement to the indene. 6-Fluoroindanone may be prepared by reaction of p-fluorobenzaldehyde with acetic anhydride and sodium acetate. Methyl 5 - fluoro - 2 - methyl - 3 - indenyl - γ- (#-hydroxybutyrate) may be prepared by reduction of methyl 5-fluoro-2-methyl indenyl-3- acetate to 5 - -fluoro - 2 - methyl - indenyl - 3- (#-ethanol) followed by oxidation to 5-fluoro-2- methyl - indenyl - 3 - acetaldehyde followed by condensation with methyl bromoacetate in the presence of zinc. o-C 1-4 -Alkoxythioanisoles may be prepared by reaction of o-chloroanisole with the appropriate sodium alkoxide in the presence of copper. Similarly various hydroxy- and halo-C 1-4  alkoxy thioanisoles may be prepared by condensation of the hydroxyalkylhalides with ohydroxythioanisole followed by halogenation of the free hydroxy group.  3 - Hydroxy - 4 - methylthiobenzaldehyde may be prepared by reaction of o-hydroxythioanisole with dichloromethyl methyl ether in the presence of aluminium chloride. Pharmaceutical compositions of the compounds I show anti-inflammatory, analgesic and antipyretic activity when administered topically, orally, parenterally or rectally with the-usual excipients.