Patent GB-948460-A (GB)
Title: Substituted indoles
Filed: 1960-08-30
Abstract: The invention comprises indolyl-acetic acids of the general formula: <FORM:0948460/C2/1> in which the dotted line in the 2(3)-position indicates that a double bond may be present; A represents a substituted benzyl radical, B represents a hydrogen atom or a C1-5-alkyl or C2-5-alkenyl radical; D represents a hydrogen atom or a hydrocarbon radical or a substituted hydrocarbon radical and one or more of the 4, 5, 6 and 7 positions of the indole nucleus may be substituted, together with salts and esters thereof and the preparation of such compounds by reacting together in an alkaline medium an a -(3-indolyl)-aliphatic acid or its ester and an appropriately substituted benzyl ester of a strong acid and optionally reducing the 2(3) bond and/or hydrolysing the ester group. Suitable substituents in the benzyl residue are halogen atoms, hydroxy, hydrocarbonoxy, nitro, mercapto substituted mercapto, cyano, haloalkyl, dialkyl-sulph-amoyl, acyl, haloacyl, carboxy or derivatives thereof such as alkali metal salts, alkyl esters, aldehydes, azides, amides or hydrazides,amino, or substituted amino groups such as acylamino, amino-oxides, urethane, alkyl- and dialkyl-amino amidino, acylamidino, hydrazine, alkoxy amino and sulphonylamino groups; and substituents in the indole ring may be those mentioned above together with hydrocarbon groups such as alkyl alkenyl, aryl and aralkyl group including halo- and alkoxy-aralkyl groups.  The group D may be an aliphatic, cyclo aliphatic, aryl, aralkyl group or a substituted group such as halo alkyl, hydroxyalkyl, halophenyl and alkoxyphenyl.  The methylene group of benzyl radical may also be substituted by an alkyl or alkenyl group. The free acid may be converted into salts such as alkali metal, ammonium, diethylamine, morpholine, glucosamine and choline salts. When the radicals R4 and R5 are such that their presence would interfere with the aralkylation reaction the substituent is elaborated in a succeeding step; thus an amino group is prepared by reduction of a nitro group and the amino group subsequently acylated, alkylated, sulphonylated or converted into a urea group or oxidised to the N-oxide. Similarly a carbobenzoxy group is hydrogenolysed to the free carboxy group which in turn is converted into the carboxy chloride carboxamide, hydrazide or hydroxamo groups or the carboxy group is reduced to the aldehyde group.  Benzyloxy groups are hydrogenolysed to give the free hydroxy group.  Indolyl aliphatic acids used as starting materials are prepared by reacting an appropriately substituted phenyl hydrazine with an b -keto aliphatic acid or by introducing the aliphatic carboxylic acid residue into the 3-position by reacting an appropriately substituted indole under Mannich reaction conditions with formaldehyde and a dialkylamine to produce a substituted gramine, reacting this with an alkali metal cyanide and an alkali metal hydroxide.  2-Ethyl -5- methylindole is prepared from 2,4-dimethylpropionanilide and diethylaniline. p-Bromobenzyl methanesulphonate and p-iodobenzyl toluenesulphonate are prepared from the p-halobenzyl alcohol and mesyl or tosyl chloride.  N,-p-Chloro benzyl -4- methylmercaptophenyl-hydrazine hydrochloride is prepared by reacting p-aminothiophenol with p-chlorobenzaldehyde to give N-p-chlorobenzylidene -4- mercaptoaniline condensing this with methyliodine to give the 4-methylmercapto analogue reducing this to N-p-chlorobenzyl -4- methylmercaptoaniline reacting the amine with nitrous acid to form the nitroso compound and reducing it to the hydrazine. N,-(p-Dimethylamino benzyl)- p-methoxyphenyl hydrazine hydrochloride is similarly prepared through the N-p-dimethylaminobenzylpanisidine.  Pharmaceutical compositions comprise the compounds of the invention together with a compatible pharmaceutical diluent or carrier and may be presented as tablets, capsules, ointments, creams, lotions, solutions for topical administration or sterile aqueous solutions for parenteral administration.  The compositions may be used as antiinflammatory agents and topical compositions may be used as sun-screening agents.  U.S.A. Specification 2,825,734 is referred to.