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Claims for Patent: 6,762,180

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Claims for Patent: 6,762,180

Title: Substituted indolines which inhibit receptor tyrosine kinases
Abstract:Indolinones of the formula ##STR1## having an inhibitory effect on receptor tyrosine kinases and cyclin/CDK complexes, as well as on the proliferation of endothelial cells and various tumor cells. Exemplary are: (a) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycar bonyl-2-indolinone, (b) 3-Z-[(1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoy l-2-indolinone, and (c) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-metboxyca rbonyl-2-indolinone.
Inventor(s): Roth; Gerald Juergen (Biberach, DE), Heckel; Armin (Biberach, DE), Walter; Rainer (Biberach, DE), Van Meel; Jacobus (Moedling, AT), Redemann; Norbert (Biberach, DE), Tontsch-Grunt; Ulrike (Baden, AT), Spevak; Walter (Oberrohrbach, AT), Hilberg; Frank (Vienna, AT)
Assignee: Boehringer Ingelheim Pharma KG (Ingelheim, DE)
Application Number:09/678,682
Patent Claims: 1. A compound of the formula I ##STR10##

wherein: X denotes an oxygen atom, R.sub.1 denotes a hydrogen atom or a C.sub.1-4 -alkoxycarbonyl or C.sub.2-4 -alkanoyl group, R.sub.2 denotes a carboxy group, a straight-chain or branched C.sub.1-6 -alkoxy-carbonyl group, a C.sub.4-7 -cycloalkoxy-carbonyl or an aryloxycarbonyl group, a straight-chain or branched C.sub.1-6 -alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a phenyl, heteroaryl, carboxy, C.sub.1-3 -alkoxy-carbonyl, aminocarbonyl, C.sub.1-3 -alkylamino carbonyl or di-(C.sub.1-3 -alkyl)-aminocarbonyl group, a straight-chain or branched C.sub.2-6 -alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a chlorine atom or a hydroxy, C.sub.1-3 -alkoxy, amino, C.sub.1-3 -alkylamino or di-(C.sub.1-3 -alkyl)-amino group, an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C.sub.1-3 -alkoxy group, R.sub.3 denotes a hydrogen atom, a C.sub.1-6 -alkyl, C.sub.3-7 -cycloalkyl, trifluoromethyl or heteroaryl group, a phenyl or naphthyl group, a phenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C.sub.1-3 -alkyl or C.sub.1-3 -alkoxy group, whilst in the event of disubstitution the substituents may be identical or different and wherein the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted by a hydroxy, hydroxy-C.sub.1-3 -alkyl or C.sub.1-3 -alkoxy-C.sub.1-3 -alkyl group, by a cyano, carboxy, carboxy-C.sub.1-3 -alkyl, C.sub.1-3 -alkoxycarbonyl, aminocarbonyl, C.sub.1-3 -alkylamino-carbonyl or di-(C.sub.1-3 -alkyl)-aminocarbonyl group, by a nitro group, by an amino, C.sub.1-3 -alkylamino, di-(C.sub.1-3 -alkyl)-amino or amino--C.sub.1-3 -alkyl group, by a C.sub.1-3 -alkylcarbonylamino, N--(C.sub.1-3 -alkyl)--C.sub.1-3 -alkylcarbonylamino, C.sub.1-3 -alkylcarbonylamino-C.sub.1-3 -alkyl, N--(C.sub.1-3 -alkyl)--C.sub.1-3 -alkylcarbonylamino-C.sub.1-3 -alkyl, C.sub.1-3 -alkyl-sulphonylamino, C.sub.1-3 -alkylsulphonylamino-C.sub.1-3 -alkyl, N--(C.sub.1-3 -alkyl)--C.sub.1-3 -alkylsulphonylamino-C.sub.1-3 -alkyl or aryl-C.sub.1-3 -alkylsulphonylamino group, by a cycloalkylamino, cycloalkyleneimino, cycloalkyleneiminocarbonyl, cycloalkyleneimino-C.sub.1-3 -alkyl, cycloalkyleneiminocarbonyl-C.sub.1-3 -alkyl or cycloalkyleneiminosulphonyl-C.sub.1-3 -alkyl group having 4 to 7 ring members in each case, whilst in each case the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, --NH or --N(C.sub.1-3 -alkyl) group, or by a heteroaryl or heteroaryl-C.sub.1-3 -alkyl group, R.sub.4 denotes a C.sub.3-7 -cycloalkyl group, whilst the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C.sub.1-3 -alkylamino or di-(C.sub.1-3 -alkyl)-amino group or replaced by an --NH or --N(C.sub.1-3 -alkyl) group, or a phenyl group substituted by the group R.sub.6, which may additionally be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C.sub.1-5 -alkyl, trifluoromethyl, hydroxy, C.sub.1-3 -alkoxy, carboxy, C.sub.1-3 -alkoxycarbonyl, amino, acetylamino, C.sub.1-3 -alkyl-sulphonylamino, aminocarbonyl, C.sub.1-3 -alkyl-aminocarbonyl, di-(C.sub.1-3 -alkyl)-aminocarbonyl, aminosulphonyl, C.sub.1-3 -alkyl-aminosulphonyl, di-(C.sub.1-3 -alkyl)-aminosulphonyl, nitro or cyano groups, wherein the substituents may be identical or different and wherein R.sub.6 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a cyano, nitro, amino, C.sub.1-5 -alkyl, C.sub.3-7 -cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group, the group of formula ##STR11## wherein the hydrogen atoms bound to a nitrogen atom may in each case be replaced independently of one another by a C.sub.1-3 -alkyl group, a C.sub.1-3 -alkoxy group, a C.sub.1-3 -alkoxy-C.sub.1-3 -alkoxy, phenyl-C.sub.1-3 -alkoxy, amino-C.sub.2-3 -alkoxy, C.sub.1-3 -alkylamino-C.sub.2-3 -alkoxy, di-(C.sub.1-3 -alkyl-amino-C.sub.2-3 -alkoxy, phenyl-C.sub.1-3 -alkylamino-C.sub.2-3 -alkoxy, N--(C.sub.1-3 -alkyl)-phenyl-C.sub.1-3 -alkylamino-C.sub.2-3 -alkoxy, C.sub.5-7 -cycloalkyleneimino-C.sub.2-3 -alkoxy or C.sub.1-3 -alkylmercapto group, a carboxy, C.sub.1-4 -alkoxycarbonyl, aminocarbonyl, C.sub.1-3 -alkylamino-carbonyl, N--(C.sub.1-5 -alkyl)--C.sub.1-3 -alkylaminocarbonyl, phenyl-C.sub.1-3 -alkylamino-carbonyl, N--(C.sub.1-3 -alkyl)-phenyl-C.sub.1-3 -alkylamino-carbonyl, piperazinocarbonyl or N--(C.sub.1-3 -alkyl)-piperazinocarbonyl group, a C.sub.1-3 -alkylaminocarbonyl or N--(C.sub.1-5 -alkyl)--C.sub.1-3 -alkylaminocarbonyl group wherein an alkyl moiety is substituted by a carboxy or C.sub.1-3 -alkoxycarbonyl group or in the 2 or 3 position by a di-(C.sub.1-3 -alkyl)-amino, piperazino, N--(C.sub.1-3 -alkyl)-piperazino or a 4- to 7-membered cycloalkyleneimino group, a C.sub.3-7 -cycloalkyl-carbonyl group, wherein the methylene group in the 4 position of the 6- or 7-membered cycloalkyl moiety may be substituted by an amino, C.sub.1-3 -alkylamino or di-(C.sub.1-3 -alkyl)-amino group or replaced by an --NH or --N(C.sub.1-3 -alkyl) group, a 4- to 7-membered cycloalkyleneimino group wherein a methylene group linked to the imino group may be replaced by a carbonyl or sulphonyl group or the cycloalkylene moiety may be fused to a phenyl ring or one or two hydrogen atoms may each be replaced by a C.sub.1-3 -alkyl group and/or in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C.sub.1-3 -alkoxycarbonyl, aminocarbonyl, C.sub.1-3 -alkylaminocarbonyl, di-(C.sub.1-3 -alkyl)-aminocarbonyl, phenyl-C.sub.1-3 -alkylamino or N--(C.sub.1-3 -alkyl)-phenyl-C.sub.1-3 -alkylamino group or may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, --NH, --N(C.sub.1-3 -alkyl), --N(phenyl), --N(C.sub.1-3 -alkyl-carbonyl) or --N(benzoyl) group, a C.sub.1-4 -alkyl group substituted by the group R.sub.7, wherein R.sub.7 denotes a C.sub.3-7 -cycloalkyl group, whilst the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C.sub.1-3 -alkylamino or di-(C.sub.1-3 -alkyl)-amino group or replaced by an --NH or --N(C.sub.1-3 -alkyl) group or in a 5- to 7-membered cycloalkyl group a --(CH.sub.2).sub.2 group may be replaced by a --CO--NH group, a --(CH.sub.2).sub.3 group may be replaced by a --NH--CO--NH or --CO--NH--CO group or a --(CH.sub.2).sub.4 group may be replaced by a --NH--CO--NH--CO group, whilst in each case a hydrogen atom bound to a nitrogen atom may be replaced by a C1-3-alkyl group, an aryl or heteroaryl group, a hydroxy or C.sub.1-3 -alkoxy group, an amino, C.sub.1-7 -alkylamino, di-(C.sub.1-7 -alkyl)-amino, phenylamino, N-phenyl-C.sub.1-3 -alkyl-amino, phenyl-C.sub.1-3 -alkylamino, N--(C.sub.1-3 -alkyl)-phenyl-C.sub.1-3 -alkylamino or di-(phenyl-C.sub.1-3 -alkyl)-amino group, an .omega.-hydroxy-C.sub.2-3 -alkyl-amino, N--(C.sub.1-3 -alkyl)-.omega.-hydroxy-C.sub.2-3 -alkyl-amino, di-(.omega.-hydroxy-C.sub.2-3 -alkyl)-amino, di-(.omega.-(C.sub.1-3 -alkoxy)--C.sub.2-3 -alkyl)-amino or N-(dioxolan-2-yl)--C.sub.1-3 -alkyl-amino group, a C.sub.1-3 -alkylcarbonylamino-C.sub.2-3 -alkyl-amino or C.sub.1-3 -alkylcarbonylamino-C.sub.2-3 -alkyl-N--(C.sub.1-3 -alkyl)-amino group, a C.sub.1-3 -alkylsulphonylamino, N--(C.sub.1-3 -alkyl)--C.sub.1-3 -alkylsulphonylamino, C.sub.1-3 -alkylsulphonylamino-C.sub.2-3 -alkyl-amino or C.sub.1-3 -alkylsulphonylamino-C.sub.2-3 -alkyl-N--(C.sub.1-3 -alkyl)-amino group, a hydroxycarbonyl-C.sub.1-3 -alkylamino or N--(C.sub.1-3 -alkyl)-hydroxycarbonyl-C.sub.1-3 -alkyl-amino group, a guanidino group wherein one or two hydrogen atoms may each be replaced by a C.sub.1-3 -alkyl group, a group of formula

or a tautomer or salt thereof.

2. A compound of the formula I according to claim 1, wherein: R.sub.1 and R.sub.3 are as defined in claim 1, X denotes an oxygen atom, R.sub.2 denotes a carboxy group, a straight-chain or branched C.sub.1-6 -alkoxy-carbonyl group, a C.sub.5-7 -cycloalkoxycarbonyl or a phenoxycarbonyl group, a straight-chain or branched C.sub.1-3 -alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a phenyl, heteroaryl, carboxy, C.sub.1-3 -alkoxycarbonyl, aminocarbonyl, C.sub.1-3 -alkylaminocarbonyl or di-(C.sub.1-3 -alkyl)-aminocarbonyl group, a straight-chain or branched C.sub.2-3 -alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a chlorine atom, by a hydroxy, C.sub.1-3 -alkoxy, amino, C.sub.1-3 -alkylamino or di-(C.sub.1-3 -alkyl)-amino group, an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C.sub.1-3 -alkoxy group, R.sub.4 denotes a C.sub.3-7 -cycloalkyl group, whilst the methylene group in the 4 position of a 6 or 7-membered cycloalkyl group may be substituted by an amino, C.sub.1-3 -alkylamino or di-(C.sub.1-3 -alkyl)-amino group or replaced by an --NH or --N(C.sub.1-3 -alkyl) group, or a phenyl group substituted by the group R.sub.6, which may additionally be mono- or disubstituted by fluorine, chlorine or bromine atoms, by C.sub.1-3 -alkyl, trifluoromethyl, hydroxy, C.sub.1-3 -alkoxy, carboxy, C.sub.1-3 -alkoxycarbonyl, amino, acetylamino, aminocarbonyl, C.sub.1-3 -alkyl-aminocarbonyl, di-(C.sub.1-3 -alkyl)-aminocarbonyl, nitro or cyano groups, wherein the substituents may be identical or different and wherein R.sub.6 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a cyano, nitro, amino, C.sub.1-5 -alkyl, C.sub.3-7 -cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group, the group of formula ##STR12## wherein a hydrogen atom bound to the nitrogen atom may be replaced by a C.sub.1-3 -alkyl group, a C.sub.1-3 -alkoxy group, an amino-C.sub.2-3 -alkoxy, C.sub.1-3 -alkylamino-C.sub.2-3 -alkoxy, di-(C.sub.1-3 -alkyl)-amino-C.sub.2-3 -alkoxy, phenyl-C.sub.1-3 -alkylamino-C.sub.2-3 -alkoxy, N--(C.sub.1-3 -alkyl)-phenyl-C.sub.1-3 -alkylamino-C.sub.2-3 -alkoxy, pyrrolidino-C.sub.2-3 -alkoxy, piperidino-C.sub.2-3 -alkoxy or C.sub.1-3 -alkylmercapto group, a carboxy, C.sub.1-4 -alkoxycarbonyl, aminocarbonyl, C.sub.1-3 -alkylamino-carbonyl, phenyl-C.sub.1-3 -alkylamino-carbonyl or N--(C.sub.1-3 -alkyl)-phenyl-C.sub.1-3 -alkylamino-carbonyl group, a C.sub.3-7 -cycloalkyl-carbonyl group, wherein the methylene group in the 4 position of the 6- or 7-membered cycloalkyl moiety may be replaced by an --NH or --N(C.sub.1-3 -alkyl) group, a 4- to 7-membered cycloalkyleneimino group, wherein a methylene group linked to the imino group may be replaced by a carbonyl or sulphonyl group or one or two hydrogen atoms may each be replaced by a C.sub.1-3 -alkyl group and/or in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C.sub.1-3 -alkoxycarbonyl, aminocarbonyl, C.sub.1-3 -alkylaminocarbonyl, di-(C.sub.1-3 -alkyl)-aminocarbonyl, phenyl-C.sub.1-3 -alkylamino or N--(C.sub.1-3 -alkyl)-phenyl-C.sub.1-3 -alkylamino group or may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, --NH or --N(C.sub.1-3 -alkyl) group, a C.sub.1-4 -alkyl group terminally substituted by the group R.sub.7, wherein R.sub.7 denotes a C.sub.5-7 -cycloalkyl group, whilst the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be replaced by an --NH or --N(C.sub.1-3 -alkyl) group or in a 5- to 7-membered cycloalkyl group a --(CH.sub.2).sub.2 group may be replaced by a --CO--NH group, a --(CH.sub.2).sub.3 group may be replaced by a --NH--CO--NH-- or a --(CH.sub.2).sub.4 group may be replaced by a --NH--CO--NH--CO group, whilst in each case a hydrogen atom bound to a nitrogen atom may be replaced by a C.sub.1-3 -alkyl group, a phenyl or heteroaryl group, a hydroxy or C.sub.1-3 -alkoxy group, an amino, C.sub.1-6 -alkylamino, di-(C.sub.1-6 -alkyl)-amino, phenylamino, N-phenyl-C.sub.1-3 -alkyl-amino, phenyl-C.sub.1-3 -alkylamino, N--(C.sub.1-3 -alkyl)-phenyl-C.sub.1-3 -alkylamino or di-(phenyl-C.sub.1-3 -alkyl)-amino group, a .omega.-hydroxy-C.sub.2-3 -alkyl-amino, N--(C.sub.1-3 -alkyl).omega.-hydroxy-C.sub.2-3 -alkyl-amino, di-(.omega.-hydroxy-C.sub.2-3 -alkyl)-amino, di-(.omega.-(C.sub.1-3 -alkoxy)--C.sub.2-3 -alkyl)-amino or N--(dioxolan-2-yl)--C.sub.1-3 -alkyl-amino group, a C.sub.1-3 -alkylcarbonylamino-C.sub.2-3 -alkyl-amino or C.sub.1-3 -alkylcarbonylamino-C.sub.2-3 -alkyl-N--(C.sub.1-3 -alkyl)-amino group, a C.sub.1-3 -alkylsulphonylamino, N--(C.sub.1-3 -alkyl)--C.sub.1-3 -alkylsulphonylamino, C.sub.1-3 -alkylsulphonylamino-C.sub.2-3 -alkyl-amino or C.sub.1-3 -alkylsulphonylamino-C.sub.2-3 -alkyl-N--(C.sub.1-3 -alkyl)-amino group, a hydroxycarbonyl-C.sub.1-3 -alkylamino or N--(C.sub.1-3 -alkyl)-hydroxycarbonyl-C.sub.1-3 -alkyl-amino group a guanidino group wherein a hydrogen atom may be replaced by a C.sub.1-3 -alkyl group, a group of formula

--N(R.sub.8)--CO--(CH.sub.2).sub.n -R.sub.9 (II), wherein R.sub.8 denotes a hydrogen atom or a C.sub.1-3 -alkyl group, n denotes one of the numbers 0, 1, 2 or 3 and R.sub.9 denotes an amino, C.sub.1-3 -alkylamino, di-(C.sub.1-3 -alkyl)-amino, phenylamino, benzylamino or C.sub.1-4 -alkoxy group, a 5- to 7-membered cycloalkyleneimino group, wherein the methylene group in position 4 of the piperidino group may be replaced by an oxygen or sulphur atom, by an --NH, --N(C.sub.1-3 -alkyl), --N(phenyl), --N(C.sub.1-3 -alkyl-carbonyl) or --N(benzoyl) group, or, if n denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen atom, a group of formula

or a tautomer or salt thereof.

3. A compound of the formula I according to claim 1, wherein: X denotes an oxygen atom, R.sub.1 denotes a hydrogen atom, R.sub.2 denotes a carboxy group, a straight-chain or branched C.sub.1-4 -alkoxycarbonyl group or a phenoxycarbonyl group, a straight-chain or branched C.sub.1-3 -alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a phenyl, carboxy, C.sub.1-3 -alkoxycarbonyl, aminocarbonyl, C.sub.1-3 -alkylaminocarbonyl or di-(C.sub.1-3 -alkyl)-aminocarbonyl group, a straight-chain or branched C.sub.2-3 -alkoxy-carbonyl group which is terminally substituted in the alkyl moiety by a hydroxy, C.sub.1-3 -alkoxy, amino, C.sub.1-3 -alkylamino or di-(C.sub.1-3 -alkyl)-amino group, an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C.sub.1-3 -alkoxy group or, if R.sub.4 does not denote an aminosulphonyl-phenyl or N--(C.sub.1-5 -alkyl)--C.sub.1-3 -alkylaminocarbonyl-phenyl group, it may also denote a di-(C.sub.1-2 -alkyl)-aminocarbonyl group, R.sub.3 denotes a C.sub.1-4 -alkyl group or a phenyl group which may be substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C.sub.1-3 -alkyl, hydroxy or C.sub.1-3 -alkoxy group, R.sub.4 denotes a C.sub.5-6 -cycloalkyl group, wherein the methylene group in position 4 of the cyclohexyl group may be substituted by an amino, C.sub.1-3 -alkylamino or di-(C.sub.1-3 -alkyl)-amino group or replaced by an --NH or --N(C.sub.1-3 -alkyl) group, a phenyl group, a phenyl group disubstituted by C.sub.1-3 -alkyl, C.sub.1-3 -alkoxy or nitro groups, wherein the substituents may be identical or different, or a phenyl group substituted by the group R.sub.6, which may additionally be substituted by a fluorine, chlorine or bromine atom or by an amino or nitro group, wherein R.sub.6 denotes a fluorine, chlorine or bromine atom, a C.sub.1-3 -alkyl, C.sub.1-3 -alkoxy, nitro, amino or C.sub.5-6 -cycloalkyl group, a pyrrolyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl group bound via a carbon atom, wherein the abovementioned heteroaromatic groups in the carbon skeleton may be substituted by a C.sub.1-3 -alkyl group or a hydrogen atom bound to a nitrogen atom may be replaced by a C.sub.1-3 -alkyl or phenyl-C.sub.1-3 -alkyl group, the group of formula ##STR13## a carboxy, C.sub.1-4 -alkoxycarbonyl, phenyl-C.sub.1-3 -alkylamino-carbonyl or C.sub.5-7 -cycloalkyl-carbonyl group, a 5 or 6-membered cycloalkyleneimino group, wherein the methylene group in position 4 of the piperidino group may be replaced by an oxygen or sulphur atom, by an --NH or --N(C.sub.1-3 -alkyl) group, an unbranched C.sub.1-3 -alkyl group terminally substituted by the group R.sub.7, wherein R.sub.7 denotes a C.sub.5-7 -cycloalkyl group, wherein in a 5 or 6-membered cycloalkyl group a --(CH.sub.2).sub.2 group may be replaced by a --CO--NH group, a --CH.sub.2).sub.3 group may be replaced by an --(NH--CO--NH-- or a --(CH.sub.2).sub.4 group may be replaced by an --NH--CO--NH--CO group, whilst in each case a hydrogen atom bound to a nitrogen atom may be replaced by a C.sub.1-3 -alkyl group, a phenyl or pyridinyl group or a pyrrolyl, pyrazolyl, imidazolyl or triazolyl group bound via a carbon or nitrogen atom, wherein the abovementioned heteroaromatic groups in the carbon skeleton may be substituted by a C.sub.1-3 -alkyl group or a hydrogen atom bound to a nitrogen atom may be replaced by a C.sub.1-3 -alkyl group, a hydroxy or C.sub.1-3 -alkoxy group, an amino, C.sub.1-6 -alkylamino, di-(C.sub.1-6 -alkyl)-amino, phenylamino, N-phenyl-C.sub.1-3 -alkylamino, phenyl-C.sub.1-3 -alkylamino or N--(C.sub.1-3 -alkyl)-phenyl-C.sub.1-3 -alkylamino group, a .omega.-hydroxy-C.sub.2-3 -alkyl-amino, N--(C.sub.1-3 -alkyl)-.omega.-hydroxy-C.sub.2-3 -alkylamino, di-(.omega.-hydroxy-C.sub.2-3 -alkyl)-amino or di-(.omega.-(C.sub.1-3 -alkoxy)--C.sub.2-3 -alkyl)-amino group, a C.sub.1- 3-alkylcarbonylamino-C.sub.2-3 -alkyl-amino or C.sub.1-3 -alkylcarbonylamino-C.sub.2-3 -alkyl-N--(C.sub.1-3 -alkyl)-amino group, a C.sub.1-3 -alkylsulphonylamino, N--(C.sub.1-3 -alkyl)--C.sub.1-3 -alkylsulphonylamino, C.sub.1-3 -alkylsulphonylamino-C.sub.2-3 -alkylamino or C.sub.1-3 -alkylsulphonylamino-C.sub.2-3 -alkyl-N--(C.sub.1-3 -alkyl)-amino group, a hydroxycarbonyl-C.sub.1-3 -alkylamino or N--(C.sub.1-3 -alkyl)-hydroxycarbonyl-C.sub.1-3 -alkyl-amino group, a guanidino group wherein a hydrogen atom may be replaced by a C.sub.1-3 -alkyl group, a group of formula

or a tautomer or salt thereof.

4. A compound of the formula I according to claim 1, wherein: X denotes an oxygen atom, R.sub.1 and R.sub.5 each denote a hydrogen atom, R.sub.2 denotes a methoxycarbonyl, ethoxycarbonyl or aminocarbonyl group, R.sub.3 denotes a phenyl group and R.sub.4 denotes a phenyl group monosubstituted by the group R.sub.6, wherein R.sub.6 denotes an N-methyl-imidazol-2-yl group, an unbranched C.sub.1-3 -alkyl group which is terminally substituted by a C.sub.1-4 -alkylamino, di-(C.sub.1-4 -alkyl)-amino, piperidino or 2,6-dimethyl-piperidino group, a group of formula

or a tautomer or salt thereof.

5. A compound selected from the group consisting of: (a) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycar bonyl-2-indolinone, (b) 3-Z-[(1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoy l-2-indolinone, (c) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxyca rbonyl-2-indolinone, (d) 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbo nyl-2-indolinone, (e) 3-Z-[1-(4-((2,6-dimethyl-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methyle ne]-6-ethoxycarbonyl-2-indolinone, (f) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-met hylene]-6-ethoxycarbonyl-2-indolinone, (g) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-me thylene]-6-ethoxycarbonyl-2-indolinone, (h) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-p henyl-methylene]-6-ethoxycarbonyl-2-indolinone, (i) 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarb onyl-2-indolinone, (j) 3-Z-[1-(4-(N-acetyl-N-dimethylaminocarbonylmethyl-amino)-anilino)-1-phenyl -methylene]-6-methoxycarbonyl-2-indolinone, (k) 3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl- 2-indolinone, (l) 3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-methoxyc arbonyl-2-indolinone, (m) 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl -methylene]-6-methoxycarbonyl-2-indolinone, (n) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-p henyl-methylene]-6-methoxycarbonyl-2-indolinone, (o) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1- phenyl-methylene]-6-methoxycarbonyl-2-indolinone, (p) 3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-methylsulphonyl-amino)-anilino) -1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, (q) 3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-methyl-amino)-anilino)-1 -phenyl-methylene]-6-methoxycarbonyl-2-indolinone, (r) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-met hylene]-6-methoxycarbonyl-2-indolinone, (s) 3-Z-[1-(4-methylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl -2-indolinone and (t) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-an ilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,

or a tautomer or salt thereof.

6. A physiologically acceptable salt of a compound according to claims 1, 2, 3, 4 or 5.

7. A pharmaceutical composition containing a compound according to claims 1, 2, 3 or 4, or a physiologically acceptable salt thereof in accordance with claim 5, together with a pharmaceutically acceptable carrier.

8. 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-an ilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone or a pharmaceutically acceptable salt thereof.
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