Patent GB-1080470-A (GB)
Title: Indole derivatives
IPC: C07D209/08
Filed: 1964-12-21
Abstract: Novel compounds of the formula <FORM:1080470/C2/1> (wherein R2 is H, C2- 5 alkenyl, C2- 5 alkenyloxy or C1- 5 alkyl; R3 is amino, C1- 5 alkylamino, C2- 10 dialkylamino, benzylamino, C1- 5 alkylbenzylamino, cyclohexylamino, N-pyrrolidino, N-piperidino, N-tetrahydropyridino, N-morpholino, N-piperazino, acetyl-N-piperazino, b -di-(C1- 5 alkyl)-amino-ethylamino or N-diethanolamino; R4 is H, F, C1- 5 alkyl, C1- 5 alkoxy or CF3; R5 is H, halogen, OH, C1- 5 alkyl, C1- 5 alkoxy, C2- 5 alkenyloxy, NO2, amino, C1- 5 alkylamino, di-(C1- 5 alkyl)-amino, C1- 6 alkanoylamino, C1- 6 alkanoyl, bis-(hydroxy-C1- 5 alkyl) amino, 1-pyrrolidino, 4-methyl-1-piperazinyl, 4-morpholinyl, CN, amino-C1- 5 alkyl, CF3, di-(C1- 5 alkyl)-sulphamoyl, benzylthio, C1- 5 alkylbenzylthio, C1- 5 alkoxy benzylthio, halogenobenzylthio, benzyloxy, C1- 5 alkyl benzyloxy, C1- 5 alkoxy benzyloxy, halogenobenzyloxy, C2- 5 alkenyl, C2- 5 alkenyloxy, 1-azacyclopropyl, cyclopropylalkoxy, cyclobutyl (C1- 5 alkoxy)-methyloxy or dimethylcarbamoyl; R6 is phenyl, naphthyl or biphenylyl which may contain halogen, C1- 5 alkyl, C1- 5 alkythio, C1- 5 alkoxy, CF3, phenoxy, C1- 5-alkyl-phenoxy, C1- 5 alkoxyphenoxy, halogenophenoxy, tri-, di- or monofluoroacetyl, di-(C1- 5 alkyl)-sulphamoyl, C1- 6 alkanoyl, di-(C1- 5 alkyl) carboxamido, cyano, carb-(C1- 5 alkoxy), CHO, SCF3, C1- 5 alkyl)-sulphinyl, C1- 5 alkylsulphonyl, benzylthio, C1- 5 alkylbenzylthio, C1- 5 alkoxybenzylthio, halogenobenzylthio, SH, NO2, NH2, di-(C1- 5 alkylamino, C1- 5 alkylamino, C1- 6 alkanoylamino, OH, C1- 6 alkanoyloxy, mono-, di or tri-fluoroacetoxy benzyloxy, C1- 5 alkylbenzyloxy, C1- 5 alkoxybenzyloxy and/or halogenobenzyloxy; M is OH, NH2, NHCH3, NHC2H5, NHC3H7, NHC4H9, N(CH3)2, N(C2H5)2, NCH3.CH2H5, NCH3.C4H9, N(C4H9)2, glucosamino, allylamino, phenethylamino, N -e thylphenethylamino, p-chloranilino, 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-hydroxyethyl - piperazino, N,N - dimethylcarboxamido - methylamino, N,N - diethylaminoethylamino, benzyloxy, C1- 5 alkylbenzyloxy, C1- 5 alkoxy or OY or OZ where Z is a cation and Y is another a -amino-3-indolylacetyl residue; with the proviso that when M is OY, R3 is tertiary amino) are prepared by the methods outlined below; <FORM:1080470/C2/2> <FORM:1080470/C2/3> <FORM:1080470/C2/4> <FORM:1080470/C2/5> <FORM:1080470/C2/6> <FORM:1080470/C2/7> <FORM:1080470/C2/8> <FORM:1080470/C2/9> the starting materials for process G being prepared by reacting the starting materials for process C with oxalyl chloride and reacting the acid chloride thus formed with a C1- 5 alkanol, benzyl alcohol, ammonia or a primary or secondary amine; and the starting materials for processes A and B being prepared by N-acylation, the free acids and their salts being prepared by pyrolysis of the t-butyl esters and conversion to salts when required.  In the above flow sheet R can have all the values of M except OY; R3 to R6 are as previously defined but exclude all primary and secondary amino groups in processes B and C; R7 has all the values of R except OH, glucosamino, N-hydroxyethylpiperazino and OZ; R8 is di-(C1- 5 alkyl)-amino, N-pyrrolidino, N-piperidino, N-tetrahydro-pyridino, N-morpholino or acetyl-N-piperazino; R1 is mono- or di-alkylamino; R2 to R6 in process F are as previously defined but exclude primary and secondary amino, hydroxy and carboxyl substituents; R2, R4 and R5 in process G cannot be groups that will be affected by reduction; R6 has the substantive values given above but with a restricted list of optional substituents and R7 is as R except OH, OZ, benzyloxy and C1- 5 alkyl benzyloxy.  Process B is effected with ammonia or an amine and a glyoxalic acid compound. 5-Nitro compounds of the invention can be converted to other 5-substituted compounds, before or after 1-acylation.  The indole compounds of the invention, which are stated to have anti-inflammatory and anti-pyretic activity, may be made up into pharmaceutical compositions, e.g. for oral or parenteral use, with suitable carriers.