Patent DE-10328533-A1 (DE)
Title: New 6-amino-substituted indolinone derivatives, useful e.g. for treating tumours and angiogenesis, are inhibitors of receptor tyrosine kinases
IPC: C07D401/12
Filed: 2003-06-24
Abstract: 6-amino-substituted indolinone derivatives (I) and their tautomers, enantiomers, stereoisomers, or mixtures, and salts are new. 6-amino-substituted indolinone derivatives of formula (I) and their tautomers, enantiomers, stereoisomers, or mixtures, and salts are new. [Image] X : O; R 1>H; R 2>fluoro, chloro, bromo or cyano; R 3>phenyl, optionally substituted once with fluoro, chloro, bromo, iodo or 1-3C alkoxy, optionally also substituted, at 3 or 4 position, with a wide range of other substituents Y; Y : cyano, fluoro, chloro, bromo, cyano, 1-3C alkoxy or 1-3C alkylcarbonyl, 1-3C alkyl (substituted by cyano or carboxy), carboxy(1-4C)alkoxy, carboxy-(1-3C)alkylamino (optionally N-substituted by 1-3C alkyl); 1-3C alkyl, alkoxy or alkylamino (substituted by 1-4C alkoxycarbonyl); 1-4C alkoxycarbonyl-(1-3C) alkyl-N-(1-3C alkyl)amino,1-3C alkyl substituted by amino, aminocarbonyl (optionally substituted by 1 or 2 1-2C alkyl), 1-6C alkylcarbonylamino, 1-4C alkoxycarbonylamino, phenylcarbonylamino, 3-6C cycloalkylcarbonyl, 3-6C cycloalkyl(1-3C)alkylcarbonylamino, phenylcarbonylamino, thiophen-2-ylcarbonylamino, furan-2-ylcarbonylamino, phenyl(1-3C)alkylcarbonylamino, 2-(1-4C alkoxy)benzoylcarbonylamino, pyridin-2, 3 or 4-ylcarbonylamino,1-3C alkylpiperazin-1-ylcarbonyl; or 2-3C alkenyl substituted by carboxy, aminocarbonyl (optionally substituted by 1 or 2 1-3C alkyl) or 1-4C alkoxycarbonyl; R 4>phenyl or a wide range of other substituents Y'; Y' : 1-3C alkyl end-substituted by amino (optionally substituted by 1 or 2 1-2C alkyl), guanidinio, N-[omega -di(1-3C alkyl)amino-(2-3C)alkyl]-N-(1-3C alkyl)amino, N-Me-(3-4C)alkylamino, N-(1-3C alkyl)-N-benzylamino, N-(1-4C alkoxycarbonyl)amino, N-(1-4C alkoxycarbonyl)-(1-4C)alkylamino, 4-(1-3C alkyl)piperazin-1-yl, imidazol-1-yl, pyrrolidin-1-yl, azetidin-1-yl, (thio)morpholin-4-yl, piperazin-1-yl; di(1-3C alkyl)amino(1-3C)alkylsulfonyl, 2-[di(1-3C alkyl)amino]ethoxy, 4-(1-3C alkyl)piperazin-1-ylcarbonyl, {omega -[di(1-3C alkyl)amino](2-3C)alkyl)}-N-(1-3C alkyl)aminocarbonyl, 1-(1-3C alkyl)-imidazol-2-yl or 1-3C alkylsulfonyl; or phenyl substituted once by -NR 8>R 7>; R 7>1-2C alkyl, 1-2C alkylcarbonyl, di(1-2C alkyl)aminocarbonyl(1-3C)alkyl or 1-3C alkylsulfonyl; R 8>1-3C alkyl, omega -[mono- or di-(1-2C alkyl)amino](2-3C) alkyl, or any of 1-6C alkylcarbonyl or carbonyl(1-3C)alkyl, end-substituted by di(1-2C alkyl)amino, piperazin-1-yl, or 4-(1-3C)alkyl-piperazin-1-yl; or all dialkylamino groups in R 4> may be in quaternized form, e.g. as N-methyl-N,N-dialkylammonium, where preferred counter anions are iodide, chloride, bromide, methanesulfonate, p-toluenesulfionate or trifluoroacetate; all linear or branched alkyl may have 1-3 hydrogen replaced by fluoro; and any carboxy, amino or imino groups may be substituted by a group that can be released in vivo. An independent claim is also included for several methods for preparing (I). ACTIVITY : Cytostatic; Antipsoriatic; Antirheumatic; Antiarthritic; Ophthalmological; Antidiabetic; Nephrotropic; Immunosuppressive; Antiarteriosclerotic; Vasotropic. Test methods are described but no results are given for specified compounds. Typically (I) have IC 5 0 against proliferation of human umbilical vein endothelial cells induced by 5 ng/ml vascular endothelial growth factor and 10 Microg/ml heparin of 50 MicroM to 1 nM. MECHANISM OF ACTION : Inhibition of kinases, especially receptor tyrosine kinases, e.g. vascular endothelial, platelet-derived or fibroblast growth factors, and thus proliferation of endothelial cells (angiogenesis) and tumor cells.