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CA2493436A1 - Indolinone derivatives, substituted in the 6-position, their preparation and their use as medicaments - Google Patents

Indolinone derivatives, substituted in the 6-position, their preparation and their use as medicaments Download PDF

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CA2493436A1
CA2493436A1 CA002493436A CA2493436A CA2493436A1 CA 2493436 A1 CA2493436 A1 CA 2493436A1 CA 002493436 A CA002493436 A CA 002493436A CA 2493436 A CA2493436 A CA 2493436A CA 2493436 A1 CA2493436 A1 CA 2493436A1
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alkyl
group
amino
carbonyl
phenyl
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CA2493436C (en
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Gerald Juergen Roth
Armin Heckel
Joerg Kley
Thorsten Lehmann-Lintz
Frank Hilberg
Ulrike Tontsch-Grunt
Jacobus Van Meel (Jacques) C.A.
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Boehringer Ingelheim Pharma GmbH and Co KG
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Priority claimed from DE10233366A external-priority patent/DE10233366A1/en
Priority claimed from DE10328533A external-priority patent/DE10328533A1/en
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention relates to indoline derivatives substituted in position 6 of general formula (I) wherein R1 - R6 and X are defined in Claim 1, the tautomers, enantiomers thereof, the mixtures and salts thereof, especially physiologically compatible salts which have valuable pharamaceutical properties, especially an inhibiting effect on various receptor tyrosine kinases and on the proliferation of enthethelial cells and various tumor cells, medicaments containing said compounds, the use thereof and a method for the production thereof.

Claims (10)

  1. Claims A compound of the 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, amino-carbonyl-C1-3-alkyl, (C1-2-alkylamino)-carbonyl-C1-3-alkyl, di-(C1-2-alkyl)-amino-carbonyl-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-[.omega.-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, {.omega.-[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 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, .omega.-[di-(C1-2-alkyl)-amino]-C2-3-alkyl, .omega.-[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, and its tautomers, enantiomers, diastereomers, mixtures thereof and salts thereof.
  2. 2. A compound of the formula I according to Claim 1 in which X, R1, R2, R4, R5 and R6 are as defined in Claim 1 and R3 is a phenyl group which is substituted by a C1-2-alkyl-carbonyl-amino group, by a carboxy-C1-3-alkyl, carboxy-C1-4-alkoxy, C1-4-alkoxy-carbonyl-C1-3-alkyl, C1-4-alkoxy-carbonyl-C1-3-alkoxy, 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, (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 an 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.
  3. 3. A compound of the formula I according to Claim 1 in which X, R1, R2, R4, R5 and R6 are as defined in Claim 1 and R3 is a phenyl group substituted by a carboxy-C1-3-alkyl or C1-4-alkoxy-carbonyl-C1-3-alkyl group.
  4. 4. A compound of the formula I according to any of Claims 1 to 3, in which X, R1, R3, R4, R5 and R6 are as defined in any of Claims 1 to 3 and R2 is a fluorine or chlorine atom.
  5. 5. A compound of the formula I according to Claim 1, selected from the following group:
    (a) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (b) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (c) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (d) 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (e) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (f) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (g) 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (h) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (i) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (j) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (k) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (l) 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (m) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (n) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (o) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (p) 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (q) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)-methylene]-6-bromo-2-indolinone and their salts.
  6. 6. A physiologically acceptable salt of a compound according to any of Claims 1 to 5.
  7. 7. A medicament, comprising a compound of the formula I according to any of Claims 1 to 5 or a physiologically acceptable salt according to Claim 6, if appropriate in addition to one or more inert carrier materials and/or diluents.
  8. 8. The use of a compound of the formula I according to at least one of Claims 1 to 5 or of a physiologically acceptable salt according to Claim 6 for preparing a medicament suitable for treating excessive or abnormal cell proliferation.
  9. 9. A process for preparing a medicament according to Claim 7, characterized in that, by a non-chemical route, a compound of the formula I
    according to at least one of Claims 1 to 5 or a physiologically acceptable salt according to Claim 6 is incorporated into one or more inert carrier materials and/or diluents.
  10. 10. A process for preparing the compounds according to Claims 1 to 5, characterized in that a. a compound of the formula in which the radicals Z1 and R3 may, if appropriate, change their positions, X, R2, R3 and R6 are as defined in Claim 1, R1' has the meanings mentioned at the outset for R1 or is a protective group for the nitrogen atom of the lactam group, where R1 may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, and Z1 is a halogen atom, a hydroxyl, alkoxy or arylalkoxy group, for example a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group, is reacted with an amine of the formula in which R4 and R5 are defined as mentioned at the outset, and, if required, the product is subsequently cleaved from a protective group used for the nitrogen atom of the lactam group or from a solid phase, b. for preparing a compound of the formula I in which R3 is a phenyl or naphthyl group substituted by a carboxy-C2-3-alkenyl, aminocarbonyl-C2-3-alkenyl, (C1-3-alkyl-amino)-carbonyl-C2-3-alkenyl, di-(C1-3-alkylamino)-carbonyl-C2-3-alkenyl or C1-alkoxy-carbonyl-C2-3-alkenyl group, a compound of the formula in which R2, R4, R5, R6 and X are as defined in Claim 1, R1' has the meanings mentioned at the outset for R1 or is a protective group for the nitrogen atom of the lactam group, where R1' may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, and Z3 is a leaving group, for example a halogen atom or an alkyl- or arylsulphonyloxy group, such as a chlorine, bromine or iodine atom or a methylsulphonyloxy, ethylsulphonyloxy, p-toluenesulphonyloxy or trifluoromethanesulphonyloxy group, is reacted with an alkene of the formula in which R3' is an amino, (C1-3-alkylamino), di-(C1-3-alkylamino) or C1-4-alkoxy group and n is the number 0 or 1, c. to prepare a compound of the formula I, in which R3 is a phenyl or naphthyl group substituted by a carboxy-C1-3-alkyl, C1-4-alkoxy-carbonyl-C1-3-alkyl, aminocarbonyl-C1-3-alkyl, (C1-3-alkylamino)-carbonyl-C1-3-alkyl or di-(C1-3-alkyl)aminocarbonyl-C1-3-alkyl group, a compound of the formula in which R2, R4, R5, R6 and X are as defined in claim 1, R1' has the meanings mentioned at the outset for R1 or is a protective group for the nitrogen atom of the lactam group, where R1' may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, A is a C2-3-alkenyl group and R3' is a hydroxyl, C1-4-alkoxy, amino, (C1-3-alkylamino) or di-(C1-3-alkyl)amino group, is hydrogenated and the product is subsequently cleaved from any protective groups used for the nitrogen atom of the lactam group or from a solid phase, as described above under process (a), and an alkoxycarbonyl group is, if appropriate, subsequently converted by hydrolysis into a corresponding carboxyl compound, or an amino or alkylamino group is converted by reductive alkylation into a corresponding alkylamino or dialkylamino compound, or a dialkylamino group is converted by alkylation into a corresponding trialkylammonium compound, or an amino or alkylamino group is converted by acylation or sulphonation into a corresponding acyl or sulphonyl compound, respectively, or a carboxyl group is converted by esterification or amidation into a corresponding ester or aminocarbonyl compound, respectively, or a nitro group is converted by reduction into a corresponding amino compound, or a cyano group is converted by reduction into a corresponding aminomethyl compound, or an arylalkyloxy group is converted with an acid into a corresponding hydroxyl compound, or an alkoxycarbonyl group is converted by hydrolysis into a corresponding carboxyl compound, or a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkyl-amino group is converted by reaction with an appropriate amidino-group-transferring compound or by reaction with an appropriate nitrite into a corresponding guanidine compound of the formula I.
CA2493436A 2002-07-23 2003-07-22 Indolinone derivatives, substituted in the 6-position, their preparation and their use as medicaments Expired - Fee Related CA2493436C (en)

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DE10233366.1 2002-07-23
DE10233366A DE10233366A1 (en) 2002-07-23 2002-07-23 Indolinone derivatives substituted in the 6-position, their preparation and their use as medicaments
DE10328533.4 2003-06-24
DE10328533A DE10328533A1 (en) 2003-06-24 2003-06-24 New 6-amino-substituted indolinone derivatives, useful e.g. for treating tumours and angiogenesis, are inhibitors of receptor tyrosine kinases
PCT/EP2003/007961 WO2004009547A1 (en) 2002-07-23 2003-07-22 Indoline derivatives substituted in position 6, production and use thereof as medicaments

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7514468B2 (en) 2002-07-23 2009-04-07 Boehringer Ingelheim Pharma Gmbh & Co. Kg Indolinone derivatives substituted in the 6 position, the preparation thereof and their use as pharmaceutical compositions
US7547703B2 (en) 2002-07-23 2009-06-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Indoline derivatives substituted in the 6-position, their preparation and their use as medicaments
AU2006239389B2 (en) * 2005-04-28 2012-06-28 Boehringer Ingelheim International Gmbh Novel compounds for treating inflammatory diseases

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060058311A1 (en) * 2004-08-14 2006-03-16 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation
PE20061155A1 (en) * 2004-12-24 2006-12-16 Boehringer Ingelheim Int INDOLINONE DERIVATIVES AS AGENTS FOR THE TREATMENT OR PREVENTION OF FIBROTIC DISEASES
WO2007057399A2 (en) * 2005-11-15 2007-05-24 Boehringer Ingelheim International Gmbh Treatment of cancer with indole derivatives
JP2011510032A (en) * 2008-01-25 2011-03-31 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Salt forms of 6-fluoro-1,2-dihydro-2-oxo-3H-indole-3-ylidene derivatives, processes for their preparation and pharmaceutical compositions containing them
JP2011510031A (en) * 2008-01-25 2011-03-31 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Process for producing 6-fluoro-1,2-dihydro-2-oxo-3H-indole-3-ylidene derivative
UY32010A (en) 2008-07-29 2010-02-26 Boehringer Ingelheim Int NEW INDOLINONES, COMPOSITIONS CONTAINING AND APPLICATIONS
HUE034106T2 (en) 2012-10-17 2018-01-29 Univ Okayama Compound; tautomer and geometric isomer thereof; salt of said compound, tautomer, or geometric isomer; method for manufacturing said compound, tautomer, isomer, or salt; antimicrobial agent; and anti-infective drug
US9642851B2 (en) 2012-12-06 2017-05-09 Kbp Biosciences Co., Ltd. Indolinone derivative as tyrosine kinase inhibitor
CN105461609B (en) * 2015-12-25 2019-08-23 杭州新博思生物医药有限公司 A kind of preparation method of Nintedanib
CN114213396B (en) * 2022-01-27 2023-03-24 深圳市乐土生物医药有限公司 Indole-2-ketone compound and preparation method and application thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1115704B1 (en) * 1998-09-25 2003-06-18 Boehringer Ingelheim Pharma GmbH & Co.KG Novel substituted indolinones with an inhibitory effect on various kinases and cyclin/cdk complexes
GB9904933D0 (en) * 1999-03-04 1999-04-28 Glaxo Group Ltd Compounds
US6559173B1 (en) * 2001-09-27 2003-05-06 Allergan, Inc. 3-(heteroarylamino)methylene-1,3-dihydro-2H-indol-2-ones as kinase inhibitors
AU2002341881B2 (en) * 2001-09-27 2008-05-08 Allergan, Inc. 3-(arylamino)methylene-1, 3-dihydro-2h-indol-2-ones as kinase inhibitors

Cited By (4)

* Cited by examiner, † Cited by third party
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US7514468B2 (en) 2002-07-23 2009-04-07 Boehringer Ingelheim Pharma Gmbh & Co. Kg Indolinone derivatives substituted in the 6 position, the preparation thereof and their use as pharmaceutical compositions
US7547703B2 (en) 2002-07-23 2009-06-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Indoline derivatives substituted in the 6-position, their preparation and their use as medicaments
US7858616B2 (en) 2002-07-23 2010-12-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Indolinone derivatives substituted in the 6 position, their preparation and their use as medicaments
AU2006239389B2 (en) * 2005-04-28 2012-06-28 Boehringer Ingelheim International Gmbh Novel compounds for treating inflammatory diseases

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CA2493436C (en) 2011-11-08
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WO2004009547A1 (en) 2004-01-29
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