Patent GB-1170620-A (GB)
Title: Indole Derivatives
IPC: C07D209/26
Filed: 1967-06-12
Abstract: 1,170,620. Substituted 3-indolyl aliphatic acids. SUMITOMO CHEMICAL CO. Ltd. 12 June, 1967 [10 June, 1966; 30 June, 1966], No. 26965/67. Heading C2C. Novel 1-aryloxyalkylcarbonyl- or 1-arylthioalkylcarbonyl - 3 - indolyl aliphatic acids or derivatives thereof the formula wherein R<SP>1</SP> is an unsubstituted or a C 1-4  alkyl., C 1-4  alkoxy-, C 1-4  alkylthio-, or halogen-substituted carbocyclic aromatic ring; R<SP>2</SP> and R<SP>3</SP> are independently H, or C 1-3  alkyl; R 4  is H or C 2-4  alkoxycarbonyl; R 5  is OH, C 1-4  alkoxy, benzyloxy, tetrahydropyranyloxy, or NH 2 ; R<SP>6</SP> is halogen, C 1-4  alkyl, C 1-4  alkoxy or C 1-4  alkylthio; A is an unsubstituted, saturated or unsaturated, straight or branched hydrocarbon chain containing up to 5 carbon atoms; X is O or S; m and p are independently 0 or 1; and n is 0, 1, 2 or 3, are prepared by any one of the following methods: (a) Heating a keto-aliphatic acid of the formula R<SP>2</SP>CO.CH<SP>2</SP>(CHR<SP>3</SP>) m .(CH 2 ) n .(CHR<SP>4</SP>) p .COR<SP>5</SP> with either a phenylhydrazine of the formula R<SP>6</SP>C 6 H 4 .N.(C = NH.A.X.R<SP>1</SP>).NH 2  or an acid addition salt thereof or a N<SP>1</SP>-acylatedphenylhydrazine of the formula R<SP>6</SP>.C 6 H 4 .N(CO.A.x.R<SP>1</SP>).NH 2  or acid addition salt thereof, which is obtained either by reacting corresponding N<SP>1</SP>-unsubstituted phenylhydrazine in an inert solvent in the presence of a hydrogen halide acceptor with a compound of the formula Y-CO-A-X-R<SP>1</SP>, wherein Y is a halogen atom, or by the acid hydrolysis of the corresponding N<SP>1</SP>-acylated phenylhydrazone of the formula R<SP>6</SP>-C 6 H4-N(CO-A-X-R<SP>1</SP>)-N = B wherein B is a ketone or aldehyde residue. This latter compound is made by reacting the appropriate phenylhydrazone with Y-CO-A-X-R<SP>1</SP>. (b) Compounds in which R<SP>5</SP> is H by hydrolysing the corresponding esters or amides, by hydrogenolysing the corresponding benzyl esters; or by thermally decomposing the corresponding tert.-butyl esters. (c) Compounds wherein R<SP>5</SP> is H, m = 1 and n and p are O by heating the corresponding N<SP>1</SP>-acylated phenylhydrazine or an acid addition salt thereof with an acid either of the formula R<SP>2</SP>.CO.CH 2 .C.R<SP>3</SP>.(COOH) 2  or of the formula R<SP>2</SP>.CO.CH(COOH).CHR<SP>3</SP>COOH; or by oxidizing the appropriate indole-3-aldehyde or indole-3-alcohol; or by dehydrogenating the corresponding 2,3-dihydro-3-indolyl aliphatic acid; or by the ring closure of the corresponding γ-(N-acylanilino)-aliphatic acid. (d) Compounds wherein m and p are 0, n = 1 and R<SP>5</SP> is H by dehydrating the corresponding 2,3 - dihydro - 3 - hydroxy - 3 - indolylacetic acid or alkyl ester thereof, followed by, if desired or necessary, hydrolysis. t - Butyl 1 - phenoxyacetyl - 2 - methyl - 3- hydroxy - 5 - methoxy - 2,3 - dihydro - 3 - indolylacetate is prepared by reacting the corresponding 3-oxo-2,3-dihydro-indole with t-butyl bromoacetate. 4 - {N - (p - Methoxyphenyl) - N - phenoxyacetyl}amino - 3 - oxovaleric acid is made by the hydrolysis of the corresponding butyl ester, resulting from the reaction of t-butyl γ-bromo- # - ketovaleriate with N - phenoxyacetyl panisidine, obtained from p-anisidine and phenoxyacetyl chloride. Pharmaceutical compositions, having antiinflammatory and anti-cholesterolemic activity contain the above novel indolyl aliphatic acids or derivatives thereof and pharmaceutically acceptable carriers.