Patent GB-1081134-A (GB)
Title: 1,3,4,5-tetrahydrobenz-[c,d]-indole-3-carboxylic acids and derivatives thereof
IPC: C07D209/18
Filed: 1964-08-19
Abstract: Novel compounds of Formula I <FORM:1081134/C2/1> where X is a methylene or carbonyl group, A is an aromatic or heteroaromatic carboxylic acyl radical containing one ring or two fused rings; R2 is a hydrogen atom, a C1- 8 hydrocarbon radical or a halogenated or alkoxylated C6- 8 aryl radical; R6 is a hydrogen or halogen atom, or a C1- 5 alkyl, C1- 5 alkoxy, C2- 5 alkenyloxy, nitro, amino, substituted amino, aryl, aralkoxy, hydroxy, mercapto, haloalkyl, cyano, sulphamoyl, sulphoxide, aminomethyl, substituted aminomethyl, pyrrolidino, morpholino, ureido, carboxy, N,N-dialkylcarbamyl, dialkylsulphamoyl, or carboalkoxy radical; and M is a hydroxyl, amino, alkylamino, dialkylamino, allylamino, phenethylamino, N-ethyl-phenethylamino, benzylamino, anilino, p-chloroanilino, p-methoxyanilino, diethanolamino, piperidino, pyrrolidino, morpholino, N - methylpiperazino, N - phenylpiperazino, N - b  - hydroxyethylpiperazino, 1 - methyl - 2-aminomethylpyrrolidino, 1 - ethyl - 2 aminomethylpiperidino, tetrahydrofurfurylamino, 1,2,5,6 - tetrahydropyridino, alkoxy, alkoxyalkoxy, aryloxy, aralkoxy, alkaryloxy, cycloalkoxy, morpholino, b -dialkylaminoethoxy, b  - morpholinoethoxy, tetrahydrofurfuryloxy, cyclohexylamino, glycino, alkenyloxy, ethanolamino, cycloalkylalkoxy, or -OY radical, where Y is a cation or a radical of formula <FORM:1081134/C2/2> are prepared by aroylation or hetero-aroylation of compounds of Formula I in which A is a hydrogen atom, X, R2 and M are as defined above, and R6 is as defined above except that it is not a group which will interfere in the acylation reaction.  The acylation is preferably carried out on the ester or amide derivative of the carboxylic acid.  The esters may then be converted to the free acid, e.g. by hydrolysis, by hydrogenolysis of a benzyl ester, or by heating a t-butyl ester alone or in the presence of a catalytic amount of an acid.  The amides may be converted to the free acids by reaction with a stoichiometric quantity of nitrous acid in an inert solvent.  The free acids may be converted to esters, amides or salts by known methods.  The synthesis of the compounds in which the 6-substituent has a nitrogen atom attached to the ring is generally based on the 6-nitro substituent. The nitro group may be reduced to amino, which may be converted to mono- or di-alkylamino by treatment with an alkyl halide, or to a heterocyclic group if a dihaloalkylene or a dihalo-ether is used. The amino group may also be acylated or converted to a ureido group. Compounds where R6 is a hydroxy group may be prepared from the corresponding benzyloxy derivatives.  The 1,3,4,5 - tetrahydrobenz[c,d] - indole - 3 - carboxylic acids and the corresponding 5-oxo compounds are prepared from an indole which may be obtained, e.g. by treating a phenylhydrazine with a ketone and cyclizing the phenylhydrazone obtained, by reacting the indole with maleic anhydride or maleic acid, dehydrating the indolyl succinic acid obtained to give the corresponding anhydride, e.g. by reacting the acid with an isopropenyl alkanoate in the presence of an acid, during which reaction the nitrogen atom of the indole ring is acylated to give an N-alkanoyl-indole-succinic anhydride, cyclizing this compound to produce a 1-acyl-1,3,4,5 - tetrahydro - 5 - oxobenz[c,d] - indole - 3 - carboxylic acid and either removing the 1-acyl group by hydrolysis to give the corresponding 1,3,4,5 - tetrahydro - 5- oxobenz[c,d] - indole - 3 - carboxylic acid, or reducing the compound to obtain a 1,3,4,5 - tetrahydrobenz[c,d] - indole - 3 - carboxylic acid.  The indolyl-succinic acid may also be prepared by condensation of a 3-indole-carboxaldehyde, prepared by reacting indole with dimethylformamide in the presence of phosphorus oxychloride, with ethyl cyanoacetate or diethyl malonate followed by reaction with potassium cyanide in ethanol and hydrolysing the cyano derivative obtained.  The 1,3,4,5 - tetrahydrobenz[c,d] - indole - 3 - carboxylic acids may be converted to esters or amides by known methods.  The aroylation or heteroaroylation reaction may be performed using the p-nitrophenyl esters of the appropriate acids. These esters are obtained by esterification of the corresponding acid. p-Difluoromethoxy-benzoic acid may be obtained by the action of difluorochloromethane on the p-hydroxybenzoate of benzyl alcohol, followed by removal of the benzyl group by hydrogenation. Therapeutic compositions, which have antiinflammatory, antipyretic and analgesic activity and which may be administered, e.g. orally, contain as active ingredient a compound of Formula I above.