Medicaments for the Treatment or Prevention of Fibrotic Diseases
First Claim
Patent Images
1. A method for preventing or treating 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 an effective amount of an indolinone of formula in which X is an oxygen atom, R1 is a hydrogen atom, R2 is a fluorine, chlorine or bromine atom or a cyano group, R3 is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a C1-3-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyl groups may additionally be substituted in the 3- or 4-position by a fluorine, chlorine or bromine atom, by a cyano group, by a C1-3-alkoxy or C1-2-alkyl-carbonyl-amino group, by a cyano-C1-3-alkyl, carboxy-C1-3-alkyl, carboxy-C1-4-alkoxy, carboxy-C1-3-alkylamino, carboxy-C1-3-alkyl-N—
- (C1-3-alkyl)-amino, C1-4-alkoxy-carbonyl-C1-3-alkyl, C1-4-alkoxy-carbonyl-C1-3-alkoxy, C1-4-alkoxy-carbonyl-C1-3-alkylamino, C1-4-alkoxy-carbonyl-C1-3-alkyl-N—
(C1-3-alkyl)-amino, amino-C1-3-alkyl, aminocarbonyl-C1-3-alkyl, (C1-2-alkylamino)-carbonyl-C1-3 -alkyl, di-(C1-2-alkyl)-aminocarbonyl-C1-3-alkyl, (C1-2-alkyl-carbonyl)-amino-C1-3-alkyl, (C1-4-alkoxy-carbonyl)-amino-C1-3-alkyl, (C3-6 -alkyl-carbonyl)-amino-C1-3-alkyl, (phenyl-carbonyl)-amino-C1-3-alkyl, (C3-6-cycloalkyl-carbonyl)-amino-C1-3-alkyl, (C3-6-cycloalkyl-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, (thiophen-2-yl-carbonyl)-amino-C1-3-alkyl, (furan-2-yl-carbonyl)-amino-C1-3-alkyl, (phenyl-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, (2-(C1-4-alkoxy)-benzoyl-carbonyl)-amino-C1-3-alkyl, (pyridin-2-yl-carbonyl)-amino-C1-3-alkyl, (pyridin-3-yl-carbonyl)-amino-C1-3-alkyl-, (pyridin-4-yl-carbonyl)-amino-C1-3-alkyl- or C1-3-alkyl-piperazin-1-yl-carbonyl-C1-3-alkyl group, by a carboxy-C2-3-alkenyl, aminocarbonyl-C2-3-alkenyl, (C1-3-alkylamino)-carbonyl-C2-3-alkenyl, di-(C1-3-alkyl)-amino-carbonyl-C2-3-alkenyl or C1-4-alkoxy-carbonyl-C2-3-alkenyl group, where the substituents may be identical or different, R4 is a phenyl group or a phenyl group which is monosubstituted by a C1-3-alkyl group which is terminally substituted by an amino, guanidino, mono- or di-(C1-2-alkyl)-amino-, N-[ω
-di-(C1-3-alkyl)-amino-C2-3-alkyl]-N—
(C1-3-alkyl)-amino, N-methyl-(C3-4-alkyl)-amino, N—
(C1-3-alkyl)-N-benzylamino, N—
(C1-4-alkoxycarbonyl)-amino, N—
(C1-4-alkoxycarbonyl)-C1-4-alkylamino, 4-(C1-3-alkyl)-piperazin-1-yl, imidazol-1-yl, pyrrolidin-1-yl, azetidin-1-yl, morpholin-4-yl, piperazin-1-yl, thiomorpholin-4-yl group, by a di-(C1-3-alkyl)-amino-(C1-3-alkyl)-sulphonyl, 2-[di-(C1-3-alkyl)-amino]-ethoxy, 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl, {ω
-[di-(C1-3-alkyl)-amino]-(C2-3-alkyl)}-N-—
C1-3-alkyl)-amino-carbonyl, 1-(C1-3-alkyl)imidazol-2-yl, (C1-3-alkyl)-sulphonyl group, or by a group of the formulain which R7 is a C1-2-alkyl, C1-2-alkyl-carbonyl, di-(C1-2-alkyl)-amino-carbonyl-C1-3-alkyl or C1-3-alkylsulphonyl group and R8 is C1-3-alkyl, ω
-[di-(C1-2-alkyl)-amino]-C2-3-alkyl, ω
-[mono-(C1-2-alkyl)-amino]-C2-3-alkyl group, or a (C1-3-alkyl)-carbonyl, (C4-6-alkyl)-carbonyl or carbonyl-(C1-3-alkyl) group which is terminally substituted by a di-(C1-2-alkyl)-amino, piperazin-1-yl or 4-(C1-3-alkyl)-piperazin-1-yl group, where all dialkylamino groups present in the radical R4 may also be present in quaternized form, for example as an N-methyl-(N,N-dialkyl)-ammonium group, where the counterion is preferably selected from the group consisting of iodide, chloride, bromide, methylsulphonate, para-toluenesulphonate and trifluoroacetate, R5 is a hydrogen atom and R6 is a hydrogen atom, where the abovementioned alkyl groups include linear and branched alkyl groups in which additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, where additionally a carboxyl, amino or imino group present may be substituted by an in vivo cleavable radical or may be present in the form of a prodrug radical, for example in the form of a group which can be converted in vivo into a carboxyl group or in the form of a group which can be converted in vivo into an imino or amino group, or a salt thereof,
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Abstract
The present invention relates to the use of indolinones of general formula
R1 to R6 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.
18 Citations
6 Claims
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1. A method for preventing or treating 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 an effective amount of an indolinone of formula
in which X is an oxygen atom, R1 is a hydrogen atom, R2 is a fluorine, chlorine or bromine atom or a cyano group, R3 is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a C1-3-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyl groups may additionally be substituted in the 3- or 4-position by a fluorine, chlorine or bromine atom, by a cyano group, by a C1-3-alkoxy or C1-2-alkyl-carbonyl-amino group, by a cyano-C1-3-alkyl, carboxy-C1-3-alkyl, carboxy-C1-4-alkoxy, carboxy-C1-3-alkylamino, carboxy-C1-3-alkyl-N— - (C1-3-alkyl)-amino, C1-4-alkoxy-carbonyl-C1-3-alkyl, C1-4-alkoxy-carbonyl-C1-3-alkoxy, C1-4-alkoxy-carbonyl-C1-3-alkylamino, C1-4-alkoxy-carbonyl-C1-3-alkyl-N—
(C1-3-alkyl)-amino, amino-C1-3-alkyl, aminocarbonyl-C1-3-alkyl, (C1-2-alkylamino)-carbonyl-C1-3 -alkyl, di-(C1-2-alkyl)-aminocarbonyl-C1-3-alkyl, (C1-2-alkyl-carbonyl)-amino-C1-3-alkyl, (C1-4-alkoxy-carbonyl)-amino-C1-3-alkyl, (C3-6 -alkyl-carbonyl)-amino-C1-3-alkyl, (phenyl-carbonyl)-amino-C1-3-alkyl, (C3-6-cycloalkyl-carbonyl)-amino-C1-3-alkyl, (C3-6-cycloalkyl-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, (thiophen-2-yl-carbonyl)-amino-C1-3-alkyl, (furan-2-yl-carbonyl)-amino-C1-3-alkyl, (phenyl-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, (2-(C1-4-alkoxy)-benzoyl-carbonyl)-amino-C1-3-alkyl, (pyridin-2-yl-carbonyl)-amino-C1-3-alkyl, (pyridin-3-yl-carbonyl)-amino-C1-3-alkyl-, (pyridin-4-yl-carbonyl)-amino-C1-3-alkyl- or C1-3-alkyl-piperazin-1-yl-carbonyl-C1-3-alkyl group,by a carboxy-C2-3-alkenyl, aminocarbonyl-C2-3-alkenyl, (C1-3-alkylamino)-carbonyl-C2-3-alkenyl, di-(C1-3-alkyl)-amino-carbonyl-C2-3-alkenyl or C1-4-alkoxy-carbonyl-C2-3-alkenyl group, where the substituents may be identical or different, R4 is a phenyl group or a phenyl group which is monosubstituted by a C1-3-alkyl group which is terminally substituted by an amino, guanidino, mono- or di-(C1-2-alkyl)-amino-, N-[ω
-di-(C1-3-alkyl)-amino-C2-3-alkyl]-N—
(C1-3-alkyl)-amino, N-methyl-(C3-4-alkyl)-amino, N—
(C1-3-alkyl)-N-benzylamino, N—
(C1-4-alkoxycarbonyl)-amino, N—
(C1-4-alkoxycarbonyl)-C1-4-alkylamino, 4-(C1-3-alkyl)-piperazin-1-yl, imidazol-1-yl, pyrrolidin-1-yl, azetidin-1-yl, morpholin-4-yl, piperazin-1-yl, thiomorpholin-4-yl group,by a di-(C1-3-alkyl)-amino-(C1-3-alkyl)-sulphonyl, 2-[di-(C1-3-alkyl)-amino]-ethoxy, 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl, {ω
-[di-(C1-3-alkyl)-amino]-(C2-3-alkyl)}-N-—
C1-3-alkyl)-amino-carbonyl, 1-(C1-3-alkyl)imidazol-2-yl, (C1-3-alkyl)-sulphonyl group, orby a group of the formula in which R7 is a C1-2-alkyl, C1-2-alkyl-carbonyl, di-(C1-2-alkyl)-amino-carbonyl-C1-3-alkyl or C1-3-alkylsulphonyl group and R8 is C1-3-alkyl, ω
-[di-(C1-2-alkyl)-amino]-C2-3-alkyl, ω
-[mono-(C1-2-alkyl)-amino]-C2-3-alkyl group, ora (C1-3-alkyl)-carbonyl, (C4-6-alkyl)-carbonyl or carbonyl-(C1-3-alkyl) group which is terminally substituted by a di-(C1-2-alkyl)-amino, piperazin-1-yl or 4-(C1-3-alkyl)-piperazin-1-yl group, where all dialkylamino groups present in the radical R4 may also be present in quaternized form, for example as an N-methyl-(N,N-dialkyl)-ammonium group, where the counterion is preferably selected from the group consisting of iodide, chloride, bromide, methylsulphonate, para-toluenesulphonate and trifluoroacetate, R5 is a hydrogen atom and R6 is a hydrogen atom, where the abovementioned alkyl groups include linear and branched alkyl groups in which additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, where additionally a carboxyl, amino or imino group present may be substituted by an in vivo cleavable radical or may be present in the form of a prodrug radical, for example in the form of a group which can be converted in vivo into a carboxyl group or in the form of a group which can be converted in vivo into an imino or amino group, or a salt thereof, - View Dependent Claims (2, 3, 4, 5, 6)
- (C1-3-alkyl)-amino, C1-4-alkoxy-carbonyl-C1-3-alkyl, C1-4-alkoxy-carbonyl-C1-3-alkoxy, C1-4-alkoxy-carbonyl-C1-3-alkylamino, C1-4-alkoxy-carbonyl-C1-3-alkyl-N—
Specification
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Current AssigneeBoehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
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Original AssigneeBoehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
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InventorsHeckel, Armin, Roth, Gerald Juergen, Lehmann-Lintz, Thorsten, Kley, Joerg, Chaudhary, Nveed, Park, John Edward
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Application NumberUS11/275,226Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/418CPC Class CodesA61K 31/404 Indoles, e.g. pindololA61K 31/4178 not condensed 1,3-diazoles ...A61K 31/496 Non-condensed piperazines c...A61P 1/16 for liver or gallbladder di...A61P 11/00 Drugs for disorders of the ...A61P 11/06 AntiasthmaticsA61P 13/12 of the kidneysA61P 17/00 Drugs for dermatological di...A61P 19/02 for joint disorders, e.g. a...A61P 29/00 Non-central analgesic, anti...A61P 43/00 Drugs for specific purposes...A61P 9/00 Drugs for disorders of the ...C07D 209/34 in position 2C07D 403/06 linked by a carbon chain co...
