Medicaments for the Treatment or Prevention of Fibrotic Diseases

Abstract

The present invention relates to the use of indolinones of general formula substituted in the 6 position, wherein R 1 to R 5 and X are defined as in claim 1, the isomers and the salts thereof, particularly the physiologically acceptable salts thereof, as a medicament for the prevention or treatment of specific fibrotic diseases.

1 . A method for preventing or treating a fibrotic disease selected from the group consisting of fibrosis and remodeling of lung tissue in chronic obstructive pulmonary disease, fibrosis and remodeling of lung tissue in chronic bronchitis, fibrosis and remodeling of lung tissue in emphysema, lung fibrosis and pulmonary diseases with a fibrotic component, fibrosis and remodeling in asthma, fibrosis in rheumatoid arthritis, virally induced hepatic cirrhosis, radiation-induced fibrosis, post angioplasty restenosis, chronic glomerulonephritis, renal fibrosis in patients receiving cyclosporine and renal fibrosis due to high blood pressure, diseases of the skin with a fibrotic component, and excessive scarring, which comprises administering a therapeutically effective amount of an indolinone of formula  
     
       
         
         
             
             
         
       
       substituted in the 6 position, wherein  
       X denotes an oxygen or sulphur atom,  
       R 1  denotes a hydrogen atom or a prodrug group,  
       R 2  denotes a carboxy group, a straight-chain or branched C 1-6 -alkoxy-carbonyl group, a C 4-7 -cycloalkoxy-carbonyl or an aryloxycarbonyl group,  
       a straight-chain or branched C 1-6 -alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a phenyl, heteroaryl, carboxy, C 1-3 -alkoxy-carbonyl, aminocarbonyl, C 1-3 -alkylamino-carbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group,  
       a straight-chain or branched C 2-6 -alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a chlorine atom or a hydroxy, C 1-3 -alkoxy, amino, C 1-3 -alkylamino or di-(C 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 1-3 -alkoxy group or a di-(C 1-2 -alkyl)-aminocarbonyl group,  
       R 3  denotes a hydrogen atom, a C 1-6 -alkyl, C 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 1-3 -alkyl or C 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 1-3 -alkyl or C 1-3 -alkoxy-C 1-3 -alkyl group,  
       by a cyano, carboxy, carboxy-C 1-3 -alkyl, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylamino-carbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group,  
       by a nitro group,  
       by an amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino or amino-C 1-3 -alkyl group,  
       by a C 1-3 -alkylcarbonylamino, N—(C 1-3 -alkyl)-C 1-3 -alkylcarbonylamino, C 1-3 -alkylcarbonylamino-C 1-3 -alkyl, N—(C 1-3 -alkyl)-C 1-3 -alkylcarbonylamino-C 1-3 -alkyl, C 1-3 -alkyl-sulphonylamino, C 13 -alkylsulphonylamino-C 1-3 -alkyl, N—(C 1-3 -alkyl)-C 1-3 -alkylsulphonylamino-C 1-3 -alkyl or aryl-C 1-3 -alkylsulphonylamino group,  
       by a cycloalkylamino, cycloalkyleneimino, cycloalkyleneiminocarbonyl, cycloalkyleneimino-C 1-3 -alkyl, cycloalkyleneiminocarbonyl-C 1-3 -alkyl or cycloalkyleneiminosulphonyl-C 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 1-3 -alkyl) group,  
       or by a heteroaryl or heteroaryl-C 1-3 -alkyl group,  
       R 4  denotes a C 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 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino group or replaced by an —NH or —N(C 1-3 -alkyl) group,  
       or a phenyl group substituted by the group R 6 , which may additionally be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C 1-5 -alkyl, trifluoromethyl, hydroxy, C 1-3 -alkoxy, carboxy, C 1-3 -alkoxycarbonyl, amino, acetylamino, C 1-3 -alkyl-sulphonylamino, aminocarbonyl, C 1-3 -alkyl-aminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, aminosulphonyl, C 1-3 -alkyl-aminosulphonyl, di-(C 1-3 -alkyl)-aminosulphonyl, nitro or cyano groups, wherein the substituents may be identical or different and wherein  
       R 6  denotes a hydrogen, fluorine, chlorine, bromine or iodine atom,  
       a cyano, nitro, amino, C 1-5 -alkyl, C 3-7 -cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group,  
       the group of formula  
       
         
           
           
               
               
           
         
       
       wherein the hydrogen atoms bound to a nitrogen atom may in each case be replaced independently of one another by a C 1-3 -alkyl group,  
       a C 1-3 -alkoxy group, a C 1-3 -alkoxy-C 1-3 -alkoxy, phenyl-C 1-3 -alkoxy, amino-C 2-3 -alkoxy, C 1-3 -alkylamino-C 2-3 -alkoxy, di-(C 1-3 -alkyl)-amino-C 2-3 -alkoxy, phenyl-C 1-3 -alkylamino-C 2-3 -alkoxy, N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino-C 2-3 -alkoxy, C 5-7 -cycloalkyleneimino-C 2-3 -alkoxy or C 1-3 -alkylmercapto group,  
       a carboxy, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylamino-carbonyl, N—(C 1-5 -alkyl)-C 1-3 -alkylaminocarbonyl, phenyl-C 1-3 -alkylamino-carbonyl, N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino-carbonyl, piperazinocarbonyl or N—(C 1-3 -alkyl)-piperazinocarbonyl group,  
       a C 1-3 -alkylaminocarbonyl or N—(C 1-5 -alkyl)-C 1-3 -alkylaminocarbonyl group wherein an alkyl moiety is substituted by a carboxy or C 1-3 -alkoxycarbonyl group or in the 2 or 3 position by a di-(C 1-3 -alkyl)-amino, piperazino, N—(C 1-3 -alkyl)-piperazino or a 4- to 7-membered cycloalkyleneimino group,  
       a C 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 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino group or replaced by an —NH or —N(C 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 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 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, phenyl-C 1-3 -alkylamino or N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino group or  
       may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH, —N(C 1-3 -alkyl), —N(phenyl), —N(C 1-3 -alkyl-carbonyl) or —N(benzoyl) group,  
       a C 1-4 -alkyl group substituted by the group R 7 , wherein  
       R 7  denotes a C 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 1-3 -alkylamino or di-(C 1-3 -alkyl)-amino group or replaced by an —NH or —N(C 1-3 -alkyl) group or  
       in a 5- to 7-membered cycloalkyl group a —(CH 2 ) 2  group may be replaced by a —CO—NH group, a —(CH 2 ) 3  group may be replaced by a —NH—CO—NH or —CO—NH—CO group or a —(CH 2 ) 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 1 -3-alkyl group,  
       an aryl or heteroaryl group,  
       a hydroxy or C 1-3 -alkoxy group,  
       an amino, C 1-7 -alkylamino, di-(C 1-7 -alkyl)-amino, phenylamino, N-phenyl-C 1-3 -alkyl-amino, phenyl-C 1-3 -alkylamino, N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkylamino or di-(phenyl-C 1-3 -alkyl)-amino group,  
       an ω-hydroxy-C 2-3 -alkyl-amino, N—(C 1-3 -alkyl)-ω-hydroxy-C 2-3 -alkyl-amino, di-(ω-hydroxy-C 2-3 -alkyl)-amino,  
       di-(ω-(C 1-3 -alkoxy)-C 2-3 -alkyl)-amino or N-(dioxolan-2-yl)-C 1-3 -alkyl-amino group,  
       a C 1-3 -alkylcarbonylamino-C 2-3 -alkyl-amino or C 1-3 -alkylcarbonylamino-C 2-3 -alkyl-N—(C 1-3 -alkyl)-amino group,  
       a C 1-3 -alkylsulphonylamino, N—(C 1-3 -alkyl)-C 1-3 -alkyl-sulphonylamino, C 1-3 -alkylsulphonylamino-C 2-3 -alkyl-amino or C 1-3 -alkylsulphonylamino-C 2-3 -alkyl-N—(C 1-3 -alkyl)-amino group,  
       a hydroxycarbonyl-C 1-3 -alkylamino or N—(C 1-3 -alkyl)-hydroxycarbonyl-C 1-3 -alkyl-amino group,  
       a guanidino group wherein one or two hydrogen atoms may each be replaced by a C 1-3 -alkyl group,  
       a group of formula  
         —N(R 8 )—CO—(CH 2 ) n —R 9    (II),  
       wherein  
       R 8  denotes a hydrogen atom or a C 1-3 -alkyl group,  
       n denotes one of the numbers 0, 1, 2 or 3 and  
       R 9  denotes an amino, C 1-4 -alkylamino, di-(C 1-4 -alkyl)-amino, phenylamino, N—(C 1-4 -alkyl)-phenylamino, benzylamino, N—(C 1-4 -alkyl)-benzylamino or C 1-4 -alkoxy group, a 4- to 7-membered cycloalkyleneimino group, whilst in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl,  
       sulphonyl, —NH, —N(C 1-3 -alkyl), —N(phenyl), —N(C 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  
         —N(R 10 )—(CH 2 ) m —(CO) o —R 11    (III),  
       wherein  
       R 10  denotes a hydrogen atom, a C 1-3 -alkyl group, a C 1-3 -alkylcarbonyl, arylcarbonyl, phenyl-C 1-3 -alkyl-carbonyl, C 1-3 -alkylsulphonyl, arylsulphonyl or phenyl-C 1-3 -alkylsulphonyl group,  
       m denotes one of the numbers 1, 2, 3 or 4,  
       o denotes the number 1 or, if m denotes one of the numbers 2, 3 or 4, o may also denote the number 0 and  
       R 11  denotes an amino, C 1-4 -alkylamino, di-(C 1-4 -alkyl)-amino, phenylamino, N—(C 1-4 -alkyl)-phenylamino, benzylamino, N—(C 1-4 -alkyl)-benzylamino, C 1-4 -alkoxy or C 1-3 -alkoxy-C 1-3 -alkoxy group, a di-(C 1-4 -alkyl)-amino-C 1-3 -alkylamino group optionally substituted in the 1 position by a C 1-3 -alkyl group or a 4- to 7-membered cycloalkyleneimino group, wherein the cycloalkylene moiety may be fused to a phenyl ring or in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH, —N(C 1-3 -alkyl), —N(phenyl), —N(C 1-3 -alkyl-carbonyl) or —N(benzoyl) group,  
       a C 4-7 -cycloalkylamino, C 4-17 -cycloalkyl-C 1-3 -alkylamino or C 4-7 -cycloalkenylamino group wherein position 1 of the ring is not involved in the double bond and wherein the abovementioned groups may each additionally be substituted at the amino-nitrogen atom by a C 5-7 -cycloalkyl, C 2-4 -alkenyl or C 1-4 -alkyl group,  
       a 4- to 7-membered cycloalkyleneimino group, wherein  
       the cycloalkylene moiety may be fused to a phenyl group or to an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidino group optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a nitro, C 1-3 -alkyl, C 1-3 -alkoxy or amino group, and/or  
       one or two hydrogen atoms may each be replaced by a C 1-3 -alkyl, C 5-7 -cycloalkyl or phenyl group and/or  
       the methylene group in the 3 position of a 5-membered cycloalkyleneimino group may be substituted by a hydroxy, hydroxy-C 1-3 -alkyl, C 1-3 -alkoxy or C 1-3 -alkoxy-C 1-3 -alkyl group,  
       the methylene group in the 3 or 4 position of a 6- or 7-membered cycloalkyleneimino group may in each case be substituted by a hydroxy, hydroxy-C 1-3 -alkyl, C 1-3 -alkoxy, C 1-3 -alkoxy-C 1-3 -alkyl, carboxy, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, di-(C 1-3 -alkyl)-aminocarbonyl, phenyl-C 1-3 -alkylamino or N—(C 1-3 -alkyl)-phenyl-C 1-3 -alkyl-amino group or  
       may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, —NH, —N(C 1-3 -alkyl-), —N(phenyl), —N(phenyl-C 1-3 -alkyl-), —N(C 1-3 -alkyl-carbonyl-), —N(C 1-4 -alkyl-hydroxy-carbonyl-), N(C 1-4 -alkoxy-carbonyl-), —N(benzoyl-) or —N(phenyl-C 1-3 -alkyl-carbonyl-) group,  
       wherein a methylene group linked to an imino-nitrogen atom of the cycloalkyleneimino group may be replaced by a carbonyl or sulphonyl group or in a 5- to 7-membered monocyclic cycloalkyleneimino group or a cycloalkyleneimino group fused to a phenyl group the two methylene groups linked to the imino-nitrogen atom may each be replaced by a carbonyl group,  
       or R 6  denotes a C 1-4 -alkyl group which is substituted by a carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl or di-(C 1-3 -alkyl)-aminocarbonyl group or by a 4- to 7-membered cycloalkyleneiminocarbonyl group,  
       an N—(C 1-3 -alkyl)-C 2-4 -alkanoylamino group which is additionally substituted in the alkyl moiety by a carboxy or C 1-3 -alkoxycarbonyl group,  
       a group of formula  
         —N(R 12 )—CO—(CH 2 ) p —R 1-3    (IV),  
       wherein  
       R 12  denotes a hydrogen atom, a C 1-6 -alkyl or C 3-7 -cycloalkyl group or a C 1-3 -alkyl group terminally substituted by a phenyl, heteroaryl, trifluoromethyl, hydroxy, C 1-3 -alkoxy, aminocarbonyl, C 1-4 -alkylamino-carbonyl, di-(C 1-4 -alkyl)-amino-carbonyl, C 1-3 -alkyl-carbonyl, C 1-3 -alkyl-sulphonylamino, N—(C 1-3 -alkyl)-C 1-3 -alkyl-sulphonylamino, C 1-3 -alkyl-aminosulphonyl or di-(C 1-3 -alkyl)-aminosulphonyl group and  
       p denotes one of the numbers 0, 1, 2 or 3 and  
       R 13  assumes the meanings of the abovementioned group R 7 , or, if p denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen atom,  
       a group of formula  
         —N(R 14 )—(CH 2 ) q —(CO) r —R 15    (V),  
       wherein  
       R 14  denotes a hydrogen atom, a C 1-4 -alkyl group, a C 1-3 -alkylcarbonyl, arylcarbonyl, phenyl-C 1-3 -alkylcarbonyl, heteroarylcarbonyl, heteroaryl-C 1-3 -alkylcarbonyl, C 1-4 -alkylsulphonyl, arylsulphonyl, phenyl-C 1-3 -alkylsulphonyl, heteroarylsulphonyl or heteroaryl-C 1-3 -alkyl-sulphonyl group,  
       q denotes one of the numbers 1, 2, 3 or 4,  
       r denotes the number 1 or, if q is one of the numbers 2, 3 or 4, it may also denote the number 0 and  
       R 15  assumes the meanings of the abovementioned group R 7 ,  
       a group of formula  
         —N(R 16 )—SO 2 —R 17    (VI),  
       wherein  
       R 16  denotes a hydrogen atom or a C 1-4 -alkyl group optionally terminally substituted by a cyano, trifluoromethyl-carbonylamino or N—(C 1-3 -alkyl)-trifluoromethyl-carbonyl-amino group and  
       R 17  denotes a C 1-3 -alkyl group,  
       an amino group substituted by a di-(C 1-3 -alkyl)-amino-C 1-3 -alkyl-carbonyl or di-(C 1-3 -alkyl)-amino-C 1-3 -alkyl-sulphonyl group and a di-(C 1-3 -alkyl)-aminocarbonyl-C 1-3 -alkyl group,  
       or an N—(C 1-3 -alkyl)-C 1-5 -alkylsulphonylamino or N—(C 1-3 -alkyl)-phenylsulphonylamino group wherein the alkyl moiety is additionally substituted by a cyano or carboxy group,  
       wherein all the single-bonded or fused phenyl groups contained in the groups mentioned under R 6  may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C 1-5 -alkyl, trifluoromethyl, hydroxy, C 1-3 -alkoxy, carboxy, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-4 -alkylamino-carbonyl, di-(C 1-4 -alkyl)-amino-carbonyl, aminosulphonyl, C 1-3 -alkyl-aminosulphonyl, di-(C 1-3 -alkyl)-aminosulphonyl, C 1-3 -alkyl-sulphonylamino, nitro or cyano groups, wherein the substituents may be identical or different, or two adjacent hydrogen atoms of the phenyl groups may be replaced by a methylenedioxy group,  
       and  
       R 5  denotes a hydrogen atom or a C 1-3 -alkyl group,  
       wherein by an aryl group is meant a phenyl or naphthyl group optionally mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a cyano, trifluoromethyl, nitro, carboxy, aminocarbonyl, C 1-3 -alkyl or C 1-3 -alkoxy group and  
       by a heteroaryl group is meant a monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C 1-3 -alkyl group in the carbon skeleton, wherein  
       the 6-membered heteroaryl group contains one, two or three nitrogen atoms and  
       the 5-membered heteroaryl group contains an imino group optionally substituted by a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group, an oxygen or sulphur atom or  
       an imino group optionally substituted by a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or  
       an imino group optionally substituted by a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group and two nitrogen atoms,  
       and moreover a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused phenyl ring,  
       some or all of the hydrogen atoms in the abovementioned alkyl and alkoxy groups or in the alkyl moieties contained in the above-defined groups of formula I may be replaced by fluorine atoms,  
       and the hydrogen atom of any carboxy group present or a hydrogen atom bound to a nitrogen atom may each be replaced by a group which can be cleaved in viva,  
       or a salt thereof.  
     
   
   
       2 . The method as recited in  claim 1  wherein the substituent in the 6 position of the substituted indolinone of formula I comprises a substituted amido group.  
   
   
       3 . The method as recited in  claim 1  wherein the indolinone of formula I is selected from the group consisting of: 
 (a) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,    (b) 3-Z-[(1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone,    (c) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,    (d) 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,    (e) 3-Z-[1-(4-((2,6-dimethyl-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,    (f) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,    (g) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,    (h) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,    (i) 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-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-methoxycarbonyl-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-phenyl-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-methylene]-6-methoxycarbonyl-2-indolinone and    (s) 3-Z-[1-(4-methylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,    or a salt of any of the above recited indolines.    
   
   
       4 . The method as recited in  claim 1  wherein the indolinone of formula I is selected from the group consisting of: 
 (t) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (u) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,    (v) 3-Z-[1-(3-cyano-4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (w) 3-Z-[1-(3-methoxy-4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (x) 3-Z-[1-(4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (y) 3-Z-[1-(4-(N-(N-(2-dimethylamino-ethyl)-N-methyl-aminomethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (z) 3-Z-[1-(4-(N-(di-(2-hydroxy-ethyl)-amino-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (aa) 3-Z-[1-(4-(N-(imidazol-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (ab) 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (ac) 3-Z-[1-(4-(N-((4-methyl-[1,4]diazepan-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (ad) 3-Z-[1-(4-(N-((1-methyl-piperidin-4-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (ae) 3-Z-[1-(2,3-dimethyl-4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (af) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (ag) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (ah) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (ai) 3-Z-[1-(4-(N-((3-dimethylamino-propyl)-aminocarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (aj) 3-Z-[1-anilino-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (ak) 3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (al) 3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone    (am) 3-Z-[1-(4-(4-methylpiperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone    (an) 3-Z-[1-(4-methylaminomethyl-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone    (ao) 3-Z-[1-(4-(morpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone    (ap) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone    (aq) 3-Z-[1-(4-(di-(2-hydroxy-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone    (ar) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone    (as) 3-Z-[1-(4-(N-(morpholin-4-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone    (at) 3-Z-[1-(4-(N-(N-(2-dimethylamino-ethyl)-N-methyl-aminomethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone    (au) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone    (av) 3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-carboxy-2-indolinone    (aw) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone    (ax) 3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone    (ay) 3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone    (az) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone    (ba) 3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bb) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bc) 3-Z-[1-((1-methyl-piperidin-4-yl)-amino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bd) 3-Z-[1-(trans-4-dimethylamino-cyclohexylamino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (be) 3-Z-[1-(4-(2-diethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bf) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-propionyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bg) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bh) 3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bi) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bj) 3-Z-[1-(3-diethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bk) 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bl) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bm) 3-Z-[1-anilino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bn) 3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (ba) 3-Z-[1-(4-((2-diethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bp) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bq) 3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (br) 3-Z-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bs) 3-Z-[1-(4-carboxy-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bt) 3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (bu) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone    (bv) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone    (bw) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone    (bx) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (by) 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone    (bz) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone    (ca) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone    (cb) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone    (cc) 3-Z-[1-(4-carbamoyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (cd) 3-Z-[1-(4-(N-(2-diethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (ce) 3-Z-[1-(4-((4-methyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (cf) 3-Z-[1-(4-((4-methyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone    (cg) 3-Z-[1-(4-((4-ethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (ch) 3-Z-[1-(4-(N-ethyl-N-(2-dimethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (ci) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-diethylcarbamoyl-2-indolinone    (cj) 3-Z-[1-(4-((cis-3,5-dimethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (ck) 3-Z-[1-(4-((4-ethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone    (cl) 3-Z-[1-(4-(N-(2-diethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone    (cm) 3-Z-[1-(4-((cis-3,5-dimethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone    (cn) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone    (co) 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-methylene]-6-methoxycarbonyl-2-indolinone    (cp) 3-Z-[1-(4-dimethylaminomethyl-anilino)-methylene]-6-methoxycarbonyl-2-indolinone    (cq) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-methylene]-6-methoxycarbonyl-2-indolinone    (cr) 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone    (cs) 3-Z-[1-(4-dimethylaminomethyl-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone    (ct) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone, and    (cu) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone,    or a salt of any of the above recited indolines.    
   
   
       5 . The method as recited in  claim 1  wherein the indolinone of formula I is selected from 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone or the monoethanesulfonate salt thereof  
   
   
       6 . The method as recited in  claim 1  wherein the disease is selected from the group consisting of the lung fibrosis and pulmonary diseases with a fibrotic component selected from idiopathic pulmonary fibrosis, giant cell interstitial pneumonia, sarcodosis, cystic fibrosis, respiratory distress syndrome, drug-induced lung fibrosis, granulomatosis, silicosis, asbestosis, systemic scleroderma, the virally induced hepatic cirrhosis selected from hepatitis C induced hepatic cirrhosis, and the diseases of the skin with a fibrotic component selected from scleroderma, sarcodosis and systemic lupus erythematosus.  
   
   
       7 . The method as recited in  claim 6  wherein the disease is idiopathic pulmonary fibrosis.  
   
   
       8 . The method as recited in  claim 1  further comprising administering an additional pharmacologically active substance selected from the group consisting of anticholinergic agents, beta-2 mimetics, steroids, PDE-IV inhibitors, p38 MAP kinase inhibitors, NK 1  antagonists, LTD4 antagonists, EGFR inhibitors and endothelin-antagonists in combination with the indoline of formula I.  
   
   
       9 . A pharmaceutical composition comprising a substituted indolinone of formula I as recited in  claim 1 , an additional pharmacologically active substance selected from the group consisting of anticholinergic agents, beta-2 mimetics, PDE-IV inhibitors, p38 MAP kinase inhibitors, NK 1  antagonists, LTD4 antagonists and endothelin-antagonists, and one or more pharmaceutically acceptable carriers or excipients.