GB1128607A - Indole derivatives - Google Patents

Abstract

1,128,607. lndolyl-3-acetic acid derivatives. MERCK & CO. Inc. 21 Dec., 1965 [31 Dec., 1964], No. 54022/65. Heading C2C. Novel compounds of the formula and their pharmaceutically acceptable acid addition salts in which A is an aromatic carboxylic acyl radical in which there may be two fused rings, preferably a group of the formula ArCO-, wherein Ar is phenyl naphthyl, biphenylyl, furyl, thienyl, pyrryl, thiazolyl, thiadiazolyl, pyrazinyl, pyridinyl, quinolyl, isoquinolyl, pyrazolyl, imidazolyl, oxazolyl, pyrimidyl, benzisoxazolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzotriazolyl, benzoxazolyl, benzothienyl, indazolyl or isoindazolyl; n is 1, 2 or 3, R<SP>0</SP> and R<SP>00</SP> are hydrogen, halogen, C 1-5 alkyl, C 1-5 alkoxy, CF 3 , NO 2 , NH 2 , OH, C 1-5 alkylamino, di-(C 1-5 alkyl) amino, C 1-6 alkanoylamino, bis-(C 1-5 hydroxyalkyl) amino, 1-pyrrolidino, 4-methylpiperazino, morpholino or form a methylenedioxy radical; R<SP>111</SP> is hydrogen, C 1-5 alkyl or C 2-5 alkenyl and R<SP>1111</SP> is hydrogen or R<SP>111</SP> and R<SP>1111</SP> together form a methylene radical; R 4 is hydrogen, halogen, C 1-5 alkyl or CF 3 ; R<SP>*</SP> is hydrogen, C 1-5 alkyl, C 1-5 alkoxy, NO 2 , NH 2 , C 1-5 alkylamino, di-(C 1-5 alkyl) amino, C 1-6 alkanoylamino, C 1-6 alkanoyl, bis-(C 1-5 hydroxyalkyl) amino, pyrrolidino, 4-methylpiperazino, morpholino, CN, aminoalkyl, di-(C 1-5 alkyl) aminoalkyl, CF 3 , halogen, di-(C 1-5 alkyl) sulphamoyl, benzylthio, benzyloxy, C 1-5 alkyl-benzyloxy, C 1-5 - alkoxy - benzyloxy, C 2-5 alkenyl, C 2-5 alkenyloxy, 1 - azacyclopropyl, cyclopropylmethyloxy or cyclobutylmethyloxy; M is OH, NH 2 , substituted amino, C 1-5 alkoxy, C 2-5 alkenyloxy, cyclic C 3-6 alkoxy, aryloxy; or substituted C 1-5 alkoxy, C 2-5 -alkenyloxy, C 2-5 alkynyloxy, quinuclidinyl - 3 - oxy, N - ethylpiperidinyl - 3 - oxy, cyclic C 3-6 alkoxy or aryloxy; or an OZ group wherein Z is a cation or an OY group, wherein Y is a second indolyl-3- acetyl residue of the above general formula, thus forming an acid anhydride, are made by acylating the corresponding 1-unsubstituted indole compounds. Preferably A is a substituted benzoyl radical such as p-chlorobenzoyl or pmethylthiobenzoyl. 1-Unsubstituted indoles corresponding to the 1-acyl indoles of the invention are formed by (a) reacting aniline optionally bearing substituents R<SP>*</SP> and R 4 with an α-halomethyl phenyl - alkyl ketone, e.g. (C 6 H 5 (CH 2 ) n .CO.CH 2 Cl, aminoalkylating the resulting 2-phenylalkyl indole, suitably by the Mannich reaction, to introduce an alkylated aminoalkyl group, e.g. (CH 3 ) 2 . N.CH 2 - in the 3-position, treating with an alkyl halide and alkali-metal cyanide to form a 2 - phenylalkyl - indole - 3 - acetonitrile and hydrolysing to form the corresponding 2-phenylalkyl - indole - 3 - alkanoic acid; (b) reacting an R 4 -R 5 -substituted aniline with an N-methylanilinomethyl phenylalkyl ketone to give a 2-phenylalkyl indole and converting this to the 2 - phenylalkyl - indole - 3 - alkanoic acid as in (a); (c) in the case wherein R<SP>111</SP> and R<SP>1111</SP> together form a radical R<SP>1</SP>(R<SP>11</SP>)C= (wherein R<SP>1</SP> and R<SP>11</SP> are each H or C 1-5 alkyl), reacting a triphenylphosphonium alkene of the formula wherein R<SP>1</SP> and R<SP>11</SP> are H or C 1-5 alkyl, with a 2 - phenylalkyl indole having a group -CO.COOR 6 in which R 6 is a C 1-5 alkyl radical, in the 3-position, or with the corresponding amide; (d) in the case where R<SP>111</SP> is an alkenyl group and R<SP>1111</SP> is hydrogen, reacting a 2- phenylalkyl - indolyl - (3) - acetic ester or amide with a di-alkyl oxalate to form an α-alkoxyoxalyl - indolyl - (3) - acetic ester, pyrolysing to form an indolyl-(3)-malonic ester, alkenylating with an alkenyl halide to form an α-alkenyl indolyl-(3)-malonic ester, hydrolysing and decarboxylating and converting the resulting α - alkenyl - indolyl - (3) - acetic acid to the desired ester or amide, or alternatively alkenylating the α-alkoxy-oxalyl-indolyl-3-acetic ester directly and then removing the oxalyl group by treatment with an alkali-metal alkoxide. Pharmaceutical preparations which have antiinflammatory activity and are active in the prevention and inhibition of granuloma tissue formation, comprise the above compounds of the invention and an inert diluent, carrier or coating.