Patent GB-1087325-A (GB)
Title: Novel 3-substituted-4,7-indoloquinones and methods of preparing the same
IPC: C07C205/37
Filed: 1964-09-09
Abstract: The invention comprises 4, 7-indoloquinones of the general formula <FORM:1087325/C2/1> wherein A represents hydrogen, lower alkyl, o  - halo - lower alkyl, o  - lower - alkylthio-lower alkyl, o -(di-lower alkyl sulphonium) lower alkyl halide, o -hydroxy lower alkyl, o -tetrahydropyranyloxy-lower alkyl, or o -azido lower alkyl; B represents hydrogen, lower alkyl, halomethyl, aminomethyl, hydroxymethyl, lower alkoxymethyl, lower alkanoyloxymethyl, tetrahydropyranyloxymethyl, N - mon oloweralkylcarbamoyloxymethyl, lower alkanoylthiomethyl, lower alkoxycarbonyl, carboxamido, cyano, formyl, hydroxyiminomethyl, lower alkoxyiminomethyl or semicarbazonomethyl; g  represents hydrogen, hydroxy, lower alkoxy, halogen, lower alkyl, lower alkylthio, mono-nuclear arylthio, amino lower alkylamino di-lower alkyl-amino, g -hydroxy lower alkylamino, o - (di - lower alkylamino) mono-lower alkylamino, tri-(lower alkyl) ammonium-lower alkylamino halide, lower cycloalkylamino, phenyl lower alkylamino or polymethyleneimino of 2 to 5 carbon atoms; Z represents hydrogen, lower alkyl, bromine, lower alkoxy, hydroxy, mononuclear arylthio, amino or methylamino, C represents formyl, lower alkanoyl, a -hydroxy lower alkyl, a -(phenoxycarbonyloxy) lower alkyl, a -(lower alkoxycarbonyloxy) lower alkyl, a -(lower alkanoyloxy) lower alkyl, a -(lower cycloalkanoyloxy) lower alkyl, a -(benzoyloxy) lower alkyl, a -(phenyl substituted lower alkanoyloxy) lower alkyl, a -(a -acyloxy (phenyl substituted) lower alkanoyloxy) lower alkyl, a -(phenoxy substituted lower alkanoyloxy)-lower alkyl, a -(a -furoyloxy) lower alkyl, a (lower alkenoyloxy) lower alkyl, a -(phenyl substituted lower alkenoyloxy) lower alkyl, a -(carbamoyloxy) lower alkyl, a -(N-lower alkyl carbamoyloxy) lower alkyl, a -(N-phenycarbamoyloxy) lower alkyl, a -(N-(halo substituted phenyl) carbamoyloxy) lower alkyl, a -(N-(lower alkoxy substituted phenyl) carbamoyloxy) lower alkyl, a -(N-naphthylcarbamoyloxy) lower alkyl, a -(N,N-di phenylcarbamoyloxy) lower alkyl, a -(N,N-dilower alkylcarbamoyloxy) lower alkyl, a -(N-lower alkenyl carbamoyloxy) lower alkyl, a -(N-(phenyl substituted lower alkyl) carbamoyloxy) lower alkyl, a -(N-lower cycloalkyl carbamoyloxy) lower alkyl, a -(N-(o -di-lower alkylamino) lower alkyl carbamoyloxy) lower alkyl, a -(N-methyl-N-(o -di-lower alkylamino) lower alkyl carbamoyloxy) lower alkyl, a -(N-(o -cyano) lower alkyl carbamoyloxy) lower alkyl, a -(N-lower alkyl-N-(o -cyano) lower alkyl carbamoyloxy) lower alkyl, a -(N-lower alkyl-N-(o -lower alkylthio) lower alkyl carbamoyloxy) lower alkyl, a -(N-lower alkyl-N-(o -lower alkoxy) lower alkyl carbamoyloxy) lower alkyl, a  - (N - lower alkyl - N - (o  - hydroxy) lower alkyl carbamoyloxy) lower alkyl, a -(N-lower alkyl-N-(g -hydroxy) lower alkyl carbamoyloxy) lower alkyl or a -(N-aminocarbamoyloxy) lower alkyl or C represents a radical of the formula <F\2> wherein R15 and R16 taken together with the nitrogen atom represent N-lower alkylpiperazino, N-[o -di-lower alkylamino) lower alkyl] piperazino, morpholino, piperidino, cyclopolymethyleneimino of from 2 to 5 carbon atoms, or bis-lower carboalkoxymethyl, and R* represents hydrogen or lower alkyl.  The term "lower" means containing up to 6 carbon atoms.  The main processes for the formation of the above 4,7-dioxo-compounds are by (a) the hydrolysis of the required 4,7-dialkanoyloxy-indoles and oxidation of the resulting 4,7-dihydroxy-indoles; and (b) the oxidation of the required 4-amino (or hydroxy)-7-unsubstitutedindoles. Groups present in the resulting 4,7-dioxo-compounds may then be varied by any of the following processes: (a) a 3-a -hydroxyalkyl group may be formed by reduction of the aldehyde or keto group at the 3-position (an intermediate 4,7-dihydroxy-compound must be oxidized back to the 4,7-quinone structure); (b) treatment of a 3-a -hydroxyalkyl with a chloroformate or an acylating agent to form the corresponding carbonate or ester compound respectively; (c) formation of an a -carbamoyloxyalkyl or a -substituted carbamoyloxy-alkyl group at the 3-position by the treatment of the carbonate compound from (b) with ammonia or an amine or by the treatment of the 3-a -hydroxyalkyl compound from (a) with an isocyanate or a carbamoyl chloride; (d) treatment with ammonia or an amine to convert a suitable group at the 5-position to an amino group; (e) conversion of a 5-amino group to a 5-hydroxy group; (f) a 1-o -hydroxyalkyl or a 2-hydroxymethyl group is formed by hydrolysis of the corresponding tetrahydropyranyloxy ether; (g) a 1-sulphonium or 5-ammonium group is formed by treatment of the required 1- or 5-substituted compound with an organohalide; (h) a 2-ester or 2-carbamoyloxy group is prepared by the treatment of a 2-hydroxy compound with a carboxylic anhydride or isocyanate respectively; (i) oxidation of a 2-hydroxymethyl group to a 2-formyl group; (j) a 2-hydroxyiminomethyl, 2-O-alkylhydroxyiminomethyl or 2-semicarbazonomethyl group is formed by treatment of the 2-formyl compound with hydroxylamine, O-alkylhydroxylamine or semicarbazide respectively; (k) a 2-cyano group is formed by the dehydration of a 2-hydroxyminomethyl group or by the treatment of a 2-formyl compound with O,N-bistrifluoroacetyl hydroxylamine; (1) 2-chloro (and bromo)-methyl compounds are prepared by the halogenation of a 2-hydroxymethyl compound, and the 2-amino-, 2-fluoro-, 2-ether -or 2-thioether compound are prepared by the treatment of the 2-chloromethyl compound with ammonia, silver fluoride, on alkoxide or mercaptide respectively; (m) etherification of a 5- or 6-hydroxy group; (n) formation of a 5-halo- or 5,6-dihalocompound by halogenation of the corresponding 5-hydroxyon 5,6-unsubstituted compound respectively; (o) formation of a 5-thioether group by reaction of a 5-alkoxy group with a mercaptan; (p) conversion of a 5,6-dihalocompound to a 5-hydroxy-6-halo- or 5-halo-6-hydroxy compound (either compound may then be etherified to form a 5- or 6-ether compound); (q) thioetherification of a 5,6-unsubstituted compound to form a 5- or 6-thioether (either compound can be hydrolysed to a 5- or 6-hydroxycompound and then etherified). Pharmaceutical compositions having antibacterial activity contain as the active ingredients indoles of the first formula above.  The compositions may be administered orally or parenterally.  (C) Substituted indoles of the formula <FORM:1087325/C2/2> wherein R1 and R3 are alkyl and R2 is alky or hydroxyalkyl, are prepared by reacting R2NH2 and R3COCH2COOC2H5 to form an amino-acid R3C(NHR2) = CHCOOC2H5, condensing this acid with an R1-substituted quinone to form a substituted indole of the formula <FORM:1087325/C2/3> converting the ester group of the latter compound to free carboxyl and decarboxylating to form the corresponding 3-unsubstituted-5-hydroxy-indole and etherifying the 5-hydroxy group (the etherifying step may also be carried out in the case when R2 is hydrogen).  1 - (b  - Methanesulphonyloxyethyl) - 5 - methoxy - 2,6 - dimethylindole is prepared by the reaction of methanesulphonyl chloride and the required free hydroxy compound.  5 - Methoxy - 6 - methyl - indole is prepared by decarboxylating the corresponding 2-carboxy compound.  2 - Acetoxymethyl - 1 - ethyl - 5 - methoxy - 6-methyl-indole is prepared by methylating 2,5-dimethyl-4-nitrophenol, treating the resulting 2,5 - dimethyl - 4 - nitroanisole with diethyl oxalate and then hydrochloric acid, treating the resulting 5 - methoxy - 4 - methyl - 2 - nitrophenylpyruvic acid with ammonia and ferrous sulphate, treating the resulting 5-methoxy 6-methyl - 2 - indolecarboxylic acid with methanolic hydrogen chloride to form the corresponding methyl ester, N-ethylating this ester to form methyl 1 - ethyl - 5 - methoxy - 6 - methyl - 2-indolecarboxylate, reducing this ester with LiAlH4 and acetylating the resulting corresponding 2-hydroxymethylindole. Substituted indoles of the formula <FORM:1087325/C2/4> wherein R1 is alkyl, R2 is hydrogen, alkyl or methanesulphonyloxyethyl, and R3 is alkyl, acetoxymethyl or methoxycarbonyl, are prepared by reacting the corresponding 3-unsubstituted indoles with dimethylformamide and phosphorus oxychloride (when R2 is hydrogen, the product may be alkylated to convert R2 to alkyl).  These substituted indoles may then be nitrated to form the corresponding 4-nitro-indoles, and when R2 is b -methanesulphonyloxy in the nitro-indole, the product may be treated with sodium acetate in dimethylformamide to form a compound in which R2 is b -acetoxyethyl, and when R3 is methoxycarbonyl in the nitro-indole, the product may be hydrolysed to form a compound in which R3 is carboxy.  All the 4-nitro-indoles thus prepared may be reduced to the corresponding 4-amino-indoles.  1 - Ethyl - 4,5,7 - trihydroxy - 2,6 - dimethyl - 3-indolecarboxaldehyde triacetate is prepared by demethylating 1 - ethyl - 5 - methoxy - 2,6-dimethyl - 3 - indolecarboxaldehyde, oxidizing the resulting corresponding 5-hydroxy compound with potassium nitrosodisulphonate, and acetylating the resulting 1 - ethyl - 2,6 - dimethyl4,5 - dioxo - 3 - indolecarboxaldehyde with acetic anhydride.  4,5,7 - Triacetoxy - 3 - acetyl - 1 - ethyl - 2,6-dimethylindole enol acetate is prepared by reacting 1-ethyl-5-methoxy-2,6-dimethyl-indole with acetic anhydride and sodium acetate, demethylating the resulting 3-acetyl-1-ethyl-5-methoxy - 2,6 - dimethyl - indole with aluminium chloride, oxidizing the resulting corresponding 5-hydroxy compound with potassium nitrosodisulphonate, and reacting the resulting 3-acetyl-1 - ethyl - 2,6 - dimethyl - 4,5 - dioxoindole with acetic anhydride.  Methyl 1 - ethyl - 5 - methoxy - 2,6 - dimethyl-4,7 - dioxo - 3 - indolecarboxylate is prepared by oxidizing ethyl 1-ethyl-5-hydroxy-2,6-dimethyl-3-indolecarboxylate with potassium nitrosodisulphonate, treating the resulting ethyl 1-ethyl - 2,6 - dimethyl - 4,5 - dioxo - 3 - indolecarboxylat