Patent GB-997638-A (GB)
Title: Indole derivatives
Inventor: TSUNG-YING SHEN
IPC: C07D209/18
Filed: 1962-03-20
Abstract: The invention comprises compounds of the formula <FORM:0997638/C2/1> wherein R1 is an aromatic radical of one or two fused rings of 5 or 6 atoms each, there being not more than 1 heterocyclic ring and not more than 3 hetero atoms, the hetero atoms being oxygen, nitrogen or sulphur, the aromatic radicals including ketodihydro aromatic radicals and the N-oxides of nitrogen heterocyclic rings, which rings may be substituted by halogen atoms, hydroxy, phenoxy, nitro, mercapto, benzylthio, benzyloxy, phenylthio, cyano, aldehydo or phenyl radicals, alkyl, alkoxy, dialkylamino, alkylthio, haloalkylthio, haloalkyl, haloalkoxy, dialkylsulphonamido, carboalkoxy, dialkylcarboxamido, alkylsulphinyl or alkyl sulphonyl groups containing at most 5 carbon atoms in each alkyl radical, or alkanoaminoalkanoyl, alkanoyloxy, or haloalkanoyl radicals, containing at most 6 carbon atoms; R11 is hydrogen, alkyl or alkenyl of at most 5 carbon atoms, phenyl or benzyl; R* is hydrogen or alkyl or alkenyl of at most 5 carbon atoms and R DEG  is hydrogen, or R* and R DEG  form a methylene group or a cyclopropane ring; R is a hydrogen or fluorine atom, or alkyl, alkoxy, alkenyl or alkylamino of at most 5 carbon atoms, alkanodi-ylamino of at most 6 carbon atoms which may be N-C1- 5 alkyl substituted, di-(C1- 5 alkyl) amino, hydroxy, polyfluoroalkyl, nitro, amino, morpholino, N-methylpiperazino, bis-hydroxyethylamino, 1-pyrrolidinyl, N-azacyclopropyl, cyano, amino-methyl, dimethylaminomethyl, dialkylsulphon-amido, benzylmercapto or mercapto radical; and M is a hydroxy, amino, benzoyloxy, alkoxy of at most 5 carbon atoms or OZ radical, Z being a cation) and their 2,3-dihydro derivatives; and their preparation (1) when M is an alkoxy, benzoloxy or amino radical by contacting in an inert, anhydrous solvent an N1- alkali metal salt of a corresponding N1-unsubstituted 3-indolyl-acetic acid ester or amide with the appropriate acyl halide or acyl ester of p-nitrophenol; or (2) when M is a hydroxy group, by contacting in an inert, anhydrous solvent an N1-alkali metal salt of a corresponding N1-unsubstituted-3-indolyl acetic acid t-butyl or benzyl ester or amide with the appropriate aryl halide, azide or ester of a phenol or thiophenol and hydrogenolysing the benzyl ester product in an inert solvent using a palladium catalyst (other benzyloxy groups, in R1, may be hydrogenolysed in this process or similarly) or heating the t-butyl ester product, preferably in the presence of at least a catalytic amount of an aryl sulphonic acid, or agitating the amide product in an inert solvent with a stoichiometric quantity of nitrous acid; the preparation of the 2,3-dihydro derivatives by catalytic hydrogenation of the compounds of the above general formula; and the preparation of 5-ureido derivatives by reacting the products wherein R is amino or substituted amino with an isocyanate.  Salts with alkali and alkaline earth metals, aluminium, magnesium and organic amines such as dimethylamine, morpholine, methylcyclohexylamine and glycosamine are referred to Products containing a 5-amino or substituted amino group are prepared in general from the 5-nitro compounds, before or after acylation at the 1-position. Reduction of the 5-nitro gives 5-amino, and this can be alkylated, reacted with a dihalo-alkane or oxa-alkane to give an N-heterocycle or acylated. Reduction of the 5-cyano compounds gives the 5-aminomethyl compounds, which can also be alkylated.  The amides of the invention can be hydrolysed to the corresponding acids.  Examples are given. Para-nitro-phenol esters used in process (1) are prepared from the appropriate acids and p-nitrophenol in the presence of dicyclohexyl carbodiimide.  1 - Unsubstituted indoles of the formula <FORM:0997638/C2/2> (wherein Y is alkoxy, benzyloxy or amino) are prepared from R-substituted phenyl hydrazines and compounds of the formula <FORM:0997638/C2/3> or an acetal thereof, via the intermediate hydrazones, and when required, hydrolysis of the product to the free acid, or amidation of the acid or acid chloride to the amide, or esterification of the acid to an alkyl or the benzyl ester (in the case of t-butyl esters, via the acid anhydride), or transesterification; or by reaction of 1,3-unsubstituted-2-R11-5-R-indole with formaldehyde-dialkylamine to produce a substituted gramine, reacting this with an alkali metal cyanide to give a 2-R11-3-cyanomethyl -5-R-indole and hydrolysing this.  The products may be hydrogenated to the 2,3-dihydro derivatives.  Para - methylthiobenzoyl chloride is prepared from the acid and thionyl chloride.  Similarly is prepared 2 - methyl - 4 - methylthiobenzoyl chloride.  Methyl - [1 - p - chlorobenzoyl - 2 - methyl-5 - bis - (p - toluenesulphonyloxyethyl) - amino-3-indolyl]-acetate is prepared from the 5-bis-(b -hydroxyethyl)-amino compound and p-toluenesulphonyl chloride, and is reacted with methylamine to give the 5-(41-methyl-11-piperazinyl) compound.  The 5-(41-morpholinyl) compound is prepared by heating the b -hydroxyethyl compound with p-toluenesulphonyl chloride and pyridine.  Ethyl a -ethyl-laevulinate is prepared from sodio ethyl acetoacetate and ethyl a -bromobutyrate, followed by hydrolysis and decarboxylation to a -ethyl laevulinic acid and then re-esterification.  Ethyl a  - (2 - methyl - 5 - methoxy - 3 - indolyl)-acrylate is prepared by heating ethyl (2-methyl-5-methoxy-3-indolyl)-glyoxylate with n-butyl lithium and triphenyl phosphonium bromide. After 1-benzoylation it is converted to ethyl a  - (1 - benzoyl - 2 - methyl - 5 - methoxy - 3 - indolyl) -cyclopropyl carboxylate by reaction with diazomethane. Para-difluoromethoxy-benzoic acid is prepared from difluorochloromethane and benzyl p-hydroxybenzoate, followed by hydrogenolysis.  2 - Allyl - 5 - methoxy - indole is prepared by reducing 5 - methoxy - 2 - indolyl - acetyl chloride to 5 - methoxy - 2 - indolyl - acetaldehyde and then reacting this with methyl triphenyl-phosphonium iodide and n-butyl lithium.  Para - alkyl - and para - fluoro - phenylhydrazines are obtained by diazotization of the corresponding substituted anilines and reduction of the diazo compounds.  The indole derivatives of the invention, which are stated to have anti-inflammatory and anti-pyretic activity, may be made up into pharmaceutical compositions with suitable carriers.  Tablets and capsules are mentioned.