Patent GB-1124972-A (GB)
Title: Alpha-indolyl-aliphatic acids and their derivatives
IPC: C07D209/26
Filed: 1965-12-29
Abstract: Novel compounds of the Formulae (I), (V), (VI), (VIII), (XII), (XIII), (XV) <FORM:1124972/C2/1> (I) <FORM:1124972/C2/2> (V) <FORM:1124972/C2/3> (VI) <FORM:1124972/C2/4> (VIII) <FORM:1124972/C2/5> (XII) <FORM:1124972/C2/6> (XIII) <FORM:1124972/C2/7> (XV) wherein A is aromatic or heteroaromatic carboxylic aryl; R2 is halogen, C1- 5 alkyl, C1- 5 alkylthio, C1- 5 alkoxy, C2- 5 alkenyloxy, CF3, phenoxy, COCF3, COCHF2, COCH2F, di-(C1- 5 alkyl) sulphamoyl, C1- 6 alkanyl, di-(C1- 5\t alkyl) carboxamido, CN, carb C1- 5 alkoxy, SCF3, C1- 5 alkylsulphinyl, C1- 5 alkylsulphonyl benzylthio, SH, NO2, NH2, di-(C1- 5 alkyl) amino, C1- 5 alkylamino, C1- 6 alkanoylamino, OH, C1- 6 alkanoyloxy, OCOCF3, OCOCHF2, benzyloxy, (C1- 5 alkyl) benzyloxy, (C1- 5 alkoxy) benzyloxy or halogenobenzyloxy; R3 is H, C1- 5 alkyl or C2- 5 alkenyl; R31 is H, or R3 + R31 is alkylidene; R4 is H, halogen, C1- 5 alkoxy, C1- 5\t alkyl, NO2 or CF3; R5 is H, halogen, C1- 5 alkyl, C1- 5 alkoxy, NO2, NH2, C1- 5 alkylamino, di-(C1- 5 alkyl) amino, C1- 6 alkanoylamino, C1- 5 alkanoyl, hydroxy C1- 5 alkylamino, bis-(hydroxy C1- 5 alkyl) amino, 1-pyrrolidino, 4-methyl-1-piper-azinyl, 4-morpholinyl, CN, amino C1- 5 alkyl, di-(C1- 5 alkyl) amino C1- 5 alkyl, CF3, di-(C1- 5 alkyl) sulphamoyl, benzylthio, (C1- 5 alkyl) benzylthio, (C1- 5 alkoxy) benzylthio, halogenobenzylthio, the corresponding benzyloxy groups, C2- 5 alkenyl, C2- 5 alkenyloxy, 1-azacyclopropyl, cyclopropylmethyloxy or cyclobutylmethyloxy; R8 is H, halogen or C1- 5 alkyl; and M is OH, C1- 5 alkoxy, C2- 5 alkenyloxy, C2- 5 alkynyloxy, aralkoxy, cycloalkoxy or aryloxy or substituted derivatives of these hydrocarbyloxy groups, or cycloalkoxy in which one or more C atoms have been replaced by hetero atoms) and salts and anhydrides of the free acids, and their acid-addition salts, are prepared (1) by reacting a compound of Formula (V) or an acid-addition salt thereof with one of Formula (VI) (wherein E is OH, C1- 5 alkoxy or aralkoxy) to give a hydrazone product which after cyclization and acylation of the indole N atom, gives a required free acid or its alkyl or aralkyl ester wherein R3 and R31 are each H; or (2) reacting a compound of Formula (VIII) (wherein R6 is C1- 5 alkyl) with a Wittig reagent of the formula (C6H5)3P=C.R1.R11 (wherein R1 and R11 are each H or C1- 5 alkyl) to give a product which, after acylation of the indole N atom, gives a required alkyl ester wherein CR3R31 is C=C.R1R11 (N-acylation can be effected before or after reaction with the Wittig reagent); or (3) pyrolysing a compound of Formula (XII) (wherein R7 and Alk are C1- 5 alkyl), itself prepared from a dialkyloxalate and the appropriate a -unsubstituted indole acetic acid ester, to give a compound of Formula (XIII), alkenylating this to give a corresponding product alkenylated at the a -carbon atom, hydrolysing and decarboxylating this to give a product of the Formula (XV) (wherein R3 is alkenyl and R6 is H) and esterifying and N-acylating this to give a required ester wherein R3 is alkenyl. In the products a 5-nitro group may be reduced or reductively alkylated or acylated to a S-amino, -alkylamino or -acylamino group; a S-amino group alkylated (if necessary via an N - alkyl - N - carbobenzyloxy - amino group) or acylated, or converted to a bis-(b -hydroxyalkyl)-amino group with an alkylene oxide, which group, when bis-(b -hydroxyethyl)-amino, may be converted to 41-methyl-1-piperazinyl or 41-morpholinyl by reaction with tosyl chloride and methylamine or tosyl chloride alone, followed by heating; and free hydroxy groups may be etherified. The anhydrides of the invention may be prepared by reaction of the free acids with a mild dehydrating agent; while esters may be prepared by conversion of the free acids to salts, reaction with alkyl or aryl chloroformates, and reaction of the mixed anhydrides formed or of the symmetrical anhydrides with an alcohol. Tert.-butyl esters may be converted to free acids by heating at above 210 DEG  C., other alkyl esters by hydrolysis, and benzyl esters by hydrogenolysis. N-acylation of the indole ring may precede or follow these processes, and may be followed or preceded by removal of protecting groups, e.g. debenzylation of benzyl ethers, dealkylation of alkyl ethers.  p - Nitrophenyl - p - (N - methyl - N -carbobenzyloxyamino)-benzoate is prepared by reacting carbobenzyloxy chloride with p-aminobenzoic acid to give p-carbobenzyloxyaminobenzoic acid, reacting this with p-nitrophenol to give p - nitrophenyl - p - carbobenzyloxyaminobenzoate and methylating this; and is reacted with methyl a  - [2 - (p - fluorophenyl) - 5-methoxy - 3 - indolyl] acetate to give methyl a  - [1 - (p - N - methyl - N - carbobenzyloxyaminobenzoyl) - 2 - (p - fluorophenyl) - 5 - methoxy - 3 - indolyl] - acetate which is hydrogenated to give the corresponding 1-p-methylaminobenzoyl compound.  2 - (p - Fluorophenyl) - 5,7 - dimethoxy - 3 - indolyl-acetonitril is prepared from 2-(p-fluorophenyl) - 5,7 - dimethoxy - gramine (itself prepared by a Mannich reaction on the 3-unsubstituted indole), and is hydrolysed to the corresponding acid.  The indole derivatives of the invention, which are stated to have anti-inflammatory properties may be incorporated in pharmaceutical compositions for oral administration.