Patent GB-1369543-A (GB)
Title: Indenylalkanoic acid compounds
IPC: C07C317/14
Filed: 1972-01-17
Abstract: 1369543 Indene derivatives MERCK & CO Inc 17 Jan 1972 [21 Jan 1971] 2194/72 Heading C2C Novel compounds of the Formula I wherein X is O, S or -NR, where R is hydrogen, alkyl, aryl or aralkyl, n is 1 or 2, R 1  is hydrogen, alkyl, haloalkyl, alkenyl or alkynyl; R 2 , R 3 , R 4  and R 5  each are hydrogen, alkyl, acyloxy, alkoxy, nitro, amino, acylamino, alkylamino, dialkylamino, dialkylaminoalkyl, sulphamyl, hydroxy, hydroxyalkyl, alkylsulphonyl, halogen, cyano, carboxyl, carboalkoxy, carbamido, haloalkyl, cycloalkyl, cycloalkoxy, alkenyloxy, acyl, alkenyl or alkynyl; (Ar) is aryl or heteroaryl; R 7  is alkylsulphinyl or alkylsulphonyl; R 6  is hydrogen, halogen, hydroxy, alkoxy or haloalkyl; 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-ethoxy. anilino, 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 or a radical of the formula OMe in which Me is a cation, may be prepared by (a) oxidation of a thioalkyl to a sulphinyl alkyl or sulphonyl alkyl at R 7 ; (b) condensation of an appropriate 3-chloroindene with a thioalkyl ester or an amino-alkyl ester to introduce the X-(CH 2 ) n COM group and optionally where an N-benzyl group is present at X, reduction of this to -NH-; (c) formation of the esters, amides or salts at -COM; (d) isomerization into a cis or trans isomer; and (e) resolution of racemic mixtures into their (+) and ( -) forms. cis - 5,6 - Difluoro - 2 - methyl - 1 - (4<SP>1</SP> - methylthiobenzylidene) - 3 - indenylacetic acid and cis- 5,6 - difluoro - 2 - methyl - 1 - (31 - hydroxy - 4<SP>1</SP>- methylthiobenzylidene)- 3 - indenyloxyacetic acid may be prepared by reaction of dimethyl-4,5- difluorophthalate with ethyl propionate in presence of base to yield 5,6-difluoro-2-methylindane-1,3-dione in which one of the keto groups is protected with ethylene glycol to yield 5,6 - difluoro - 3,3 - ethylenedioxy - 2 - methyl - 1- indanone which is reacted with 4-methylthiobenzylmagnesium bromide or 3-hydroxy-4- methylthiobenzylmagnesium bromide to yield cis- and trans - 5,6 - difluoro - 3,3 - ethylenedioxy - 2 - methyl - 1 - (4<SP>1</SP> - methylthiobenzylidene)- indene and cis- and trans - 5,6 - difluoro - 3,3- ethylenedioxy - 2 - methyl - 1 - (3<SP>1</SP> - hydroxy - 4<SP>1</SP>- methylthiobenzylidene)-indene respectively, which may be separated into cis and trans isomers. The cis isomers of the above compounds are hydrolysed to convert the 3,3-ethylenedioxy group to the keto group followed by reaction with sodium hydride and ethyl bromoacetate to yield ethyl - cis - 5,6 - difluoro - 2 - methyl - 1 - (4<SP>1</SP>- methylthiobenzylidene)- 3 - indenyl oxyacetate and the corresponding 3<SP>1</SP>-hydroxy compound, respectively, which are hydrolysed to the free acids required. 3 - Hydroxy - 4 - methylthiobenzaldehyde may be prepared by reaction of o-hydroxythioanisole with dichloromethyl methyl ether in the presence of aluminium chloride. Several o-hydroxyalkoxythioanisoles (alkyl= C 1-4 ) may be prepared by condensation of ohydroxythioanisole with hydroxyalkyl chloride compounds in the presence of base. The hydroxyl group of these products may be halogenated to o-haloalkoxythioanisoles. Several o-alkoxythioanisoles (alkyl = C 1-4 ) were prepared by reaction of o-chlorothioanisole with sodium alkoxide in the presence of copper. Pharmaceutical compositions of the compounds I show anti-inflammatory, antipyretic, and analgesic activity when administered topically, orally, rectally or parenterally with the usual excipients.