Patent GB-1087359-A (GB)
Title: ª-amino-3-indolylacetic acids
IPC: C07D209/08
Filed: 1964-11-11
Abstract: The invention comprises indoles of the general formula <FORM:1087359/C2/1> wherein R6 is a halogen atom or an alkyl, acyloxy, alkyl-substituted benzyloxy, hydroxy, C1- 5 alkoxy, monocyclic six-membered carbocyclic aryloxy, monocyclic six-membered carbocyclic aryl-substituted C1- 5 alkoxy, halogenated or C1- 5 alkoxylated monocyclic six-membered carbocyclic aryl-substituted C1- 5 alkoxy, nitro, amino, C1- 6 alkanoylamino, monocyclic six-membered carbocyclic aroylamino, C1- 5 alkylamino, di (C1- 5 alkyl) amino, C1- 6 alkanoylamino, mercapto, C1- 5 alkylthio, monocyclic six-membered carbocyclic arylthio, monocyclic six-membered carbocyclic aryl-substituted C1- 5 alkylthio C1- 5 halo-alkyl, C1- 5 alkanoyl halogenated C1- 5 alkanoyl, monocyclic six-membered carbocyclic aryl C1- 5 alkanoyl, halogenated C1- 5 alkoxy, halogenated C1- 5 alkylthio sulphamoyl, benzylthiomethyl, cyano, di-(C1- 5 alkyl)sulphamoyl, carboxy, carb-C1- 5 alkoxy or carboxamide radical, or a C1- 5 alkyl acetal of an aldehyde or a C1- 5 alkylthio acetal of an aldehyde; b is 1, 2 or 3; R3 is an amino, mono (C1- 5 alkyl) amino, di (C1- 5 alkyl) amino, benzylamino, C1- 5 alkyl benzylamino, cyclohexylamino, N-pyrrolidino, N-piperidino, N-1,2,5,6-tetrahydropyridino, N-morpholino, N-piperazino, acetyl-N-piperazino, b -di (C1- 5 alkyl) amino-ethylamino or N-diethanolamino radical; R2 is a hydrogen atom or a C2- 5 alkenyl or C1- 5 alkyl radical; R4 is a hydrogen or fluorin atom or a C1- 5 alkyl, C1- 5 alkoxy or trifluoromethyl radical; R5 is a hydrogen or halogen atom, or a hydroxy, C1- 5 alkoxy, C1- 5 alkyl, nitro, amino, C1- 5 alkylamino, di (C1- 5 alkyl) amino, C1- 5 alkanoylamino, C1- 5 alkanoyl bis (hydroxy C1- 5 alkyl) amino, 1-pyrrolidino, 4-methyl-1-piperazinyl, bis (benzyloxy alkyl), amino, 4-morpholinyl, cyano, amino C1- 5 alkyl, trifluoromethyl, di (C1- 5 alkyl) sulphamoyl, benzylthio, (C1- 5 alkyl) benzylthio, (C1- 5 alkoxy) benzylthio, halogenobenzylthio, benzyloxy, (C1- 5 alkyl) benzyloxy, (C1- 5 alkoxy) benzyloxy, halogenobenzyloxy, C2- 5 alkenyl, C2- 5 alkenyloxy, 1-azacyclopropyl, N,N-dimethylcarbamoyl, cyclopropyl (C1- 5 alkoxy)-methyloxy or cyclobutyl (C1- 5 alkoxy) methyloxy radical; P represents a hydrogen atom or a C1- 8 alkyl or C2- 5 alkenyl radical; M is a hydroxy, amino, methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, methylethylamino, methylbutylamino, dibutylamino, glucosamino, glycosylamino, glucosylamino, allylamino, phenethylamino, N - ethylphenethylamino, p - chloroamilino, 1 - ethyl - 2 - aminomethyl - piperidino, tetrahydrofurfurylamino 1,2,5,6 - tetrahydropyridino, morpholino, N-methylpiperazino, piperazino, N-phenylpiperazino, piperidino, benzylamino, anilino, p-ethoxyanilino, cyclohexylamino, pyrrolidino, N-(1-hydroxyethyl) piperazino, N,N - dimethylcarboxamidomethylamino, N,N - diethylaminoethylamino, benzyloxy, C1- 5 alkoxy, OZ (where Z is a cation) or OY where Y represents a radical of the formula <FORM:1087359/C2/2> wherein all the symbols have the above significance (thus when M is OY the compound is a carboxylic anhydride), are prepared by the following general methods (certain substituents are excluded for each method):- (a) indolyl compounds having the -CH(NH2)COR group at the 3-position, where the -COR group is a carboxylic group or the required salt, ester or amide thereof, are prepared by reacting the required indolyl compounds having the -(CO) (COR) group attached to the 3-position (the COR group having the previous significance) to form an indolyl compound having at the 3-position the group -C(NOH)COR and reducing these compounds with hydrogen (a nitro or benzyloxy group present in a definition above is converted to an amino or hydroxy group respectively by this process) and, when required, converting the amino group in the 3-substituent to a C1- 5 monoalkylamino or di (C1- 5 alkyl) amino radical by reaction with an alkyl halide; (b) indolyl compounds unsubstituted at the 3-position are mixed with (i) glyoxylic acid or an alkali metal salt, or a C1- 5 alkyl or benzyl ester thereof, or glyoxalamide or a glyoxal substituted amide, and (ii) ammononia, C1- 5 monoalkylamine, di (C1- 5 alkyl) amine, benzylamine, (C1- 5 alkyl) benzylamine, pyrrolidine, piperidine, morpholine, piperazine, acetyl-N-piperazine, b -di (C1- 5 alkyl) aminoethylamine, diethanolamine, 1,2,5,6 - tetrahydropyridine or cyclohexylamine, at a temperature between 30 DEG  and 80 DEG  C.; and (c) the anhydrides referred to above are prepared by treating the free acids with dicyclohexylcarbodiimide (substituents that may interfere with this reaction should not be present elsewhere in the molecule namely a primary or secondary amino, hydroxy or carboxy group).  A nitro group in the 5-position of the indole products may be reduced to an amino group, or the amino group may be reacted with an alkyl halide to form a mono- or di-alkylamino group or with a dihaloalkylene group to form a heterocyclic group such as a pyrrolidino or N-morpholino group.  Reduction and alkylation of the amino group may be carried out simultaneously, for example with formaldehyde, and Raney nickel and hydrogen. Acylation may be carried out on the 5-amino group or on the 5-nitro group (in the latter case with simultaneous reduction to form 5-acylamino indole compounds). The 5-amino group may also be reacted with isocyanates to form 5-ureido indole compounds.  Therapeutic compositions having anti-inflammatory and anti-pyretic activity and useful in the treatment of arthritic and dermatological disorders contain as the active ingredient substituted indoles of the first general formula above.  The compositions may be administered orally in the form of tablets or capsules.  Substituted indoles used in process (a) above having the required 1-aralkyl group and 3-(CO)COR group, R having the same significance as M above but excluding OY, are prepared from the corresponding 1,3-di-unsubstituted indoles with (i) oxalyl chloride and then the required alcohol, water, ammonia, alkali metal base or amine; and (ii) the required aralkylating agent, steps (i) and (ii) being carried out in either order thereby forming 1 - unsubstituted - 3 - (CO)COR substituted and 1 - aralkyl - 3 - unsubstituted indoles as intermediate compounds.  1 - p - Chlorobenzyl - 2 - methyl - 5 - methoxy-3-indolyl acetic anhydride is obtained by dehydrating the corresponding free acid with dicyclohexylcarbodiimide.