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WO2000073297A1 - Indolinones substituees, utilisees comme inhibiteurs de la tyrosine kinase - Google Patents

Indolinones substituees, utilisees comme inhibiteurs de la tyrosine kinase Download PDF

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Publication number
WO2000073297A1
WO2000073297A1 PCT/EP2000/004685 EP0004685W WO0073297A1 WO 2000073297 A1 WO2000073297 A1 WO 2000073297A1 EP 0004685 W EP0004685 W EP 0004685W WO 0073297 A1 WO0073297 A1 WO 0073297A1
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group
alkyl
substituted
phenyl
amino
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PCT/EP2000/004685
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German (de)
English (en)
Inventor
Armin Heckel
Rainer Walter
Gerald Roth
Jacobus C. A. Van Meel
Norbert Redemann
Ulrike Tontsch-Grunt
Walter Spevak
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Boehringer Ingelheim Pharma Kg
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Priority to AU52157/00A priority Critical patent/AU5215700A/en
Publication of WO2000073297A1 publication Critical patent/WO2000073297A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • 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
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2

Definitions

  • the present invention relates to new substituted indolines of the general formula
  • R x represents a hydrogen atom or a prodrug residue
  • R x represents a hydrogen atom or a prodrug residue
  • CDK's Cyclin Dependent Kinases
  • the present invention thus relates to the above compounds of the general formula I, where the compounds in which R ⁇ represents a hydrogen atom or a prodrug residue have valuable pharmacological properties, the medicaments containing the pharmacologically active compounds, their use and process for their preparation.
  • X is an oxygen or sulfur atom
  • R x is a hydrogen atom, a C - ⁇ - alkoxycarbonyl or C 2 . 4 -alkanoyl group,
  • R 2 is one on the amide nitrogen atom by a Substituted aminocarbonyl or C- L .g-alkylaminocarbonyl group, in which one or both of the alkyl parts present in each case by a carboxy group or from position 2 by a hydroxy, C- 3 alkoxy, amino, C- ⁇ -Alkylamino- or di- (C ⁇ alkyl) - amino group can be substituted, but in a C 1 _ 3 alkylaminocarbonyl or di- (C 1 - 3 alkyl) aminocarbonyl group at least one alkyl part by a carboxy group or ab Position 2 must be substituted by an amino, C 1 _ 3 alkylamino or di (C 1. 3 alkyl) amino group,
  • 3- alkyl-carbonyl-substituted imino group can be replaced,
  • R 3 is a hydrogen atom, a C 1 . 6 alkyl group or a j is optionally substituted by a fluorine, chlorine or bromine atom, by a Ci alkyl, hydroxy, C 1 _ 3 alkoxy, C 1 _ 3 -Alkylsulfenyl-, C 1 _ 3 alkylsulfinyl -, C - ⁇ - Alkylsulfonyl-, Phenylsulfenyl-, Phenylsulfinyl-, Phenylsulfonyl-, Amino-, C - ⁇ - Alkylamino-, Di- (C 1 _ 3 -Alkyl) -amino-, C 2 . 5 -alkanoylamino or N- (C - ⁇ - alkylamino) -C 2 _ 5 -alkanoylamino group substituted phenyl group,
  • thiophenyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C 1-4 alkyl group,
  • a phenyl or naphthyl group the by a fluorine, chlorine, bromine or iodine atom,
  • a C 2 _ 3 alkoxy group which can be substituted in the 2- or 3-position by a C - ⁇ - alkylamino, di- (C - ⁇ - alkyl) -amino or 5- to 7-membered cycloalkyleneimino group, where in each case an alkyl part in the above-mentioned alkylamino and dialkylamino groups can be substituted by a phenyl group
  • a C 2 _ 4 -alkylamino group which is terminally substituted in the 2-, 3- or 4-position by a di- (C 1 _ 3 -alkyl) -amino group and in which the hydrogen amine atom is additionally substituted by a C 2 . 5 -alkanoyl or C - ⁇ - alkylsulfonyl group can be replaced,
  • C 1 _ 4 -alkyl substituent each additionally by a cyano, carboxy, C 1 _ 3 -alkoxycarbonyl, pyridyl, imidazolyl, benzo [1, 3] dioxole or phenyl group, the phenyl group being substituted by fluorine , Chlorine or bromine atoms, may be mono-, di- or tri-substituted by methyl, methoxy, trifluoromethyl, cyano or nitro group and the substituents may be the same or different, or in 2-, 3- or 4- Position can be substituted by a hydroxy group,
  • a C - ⁇ - alkyl group which by a hydroxy, carboxy, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, piperazino, N- (C - ⁇ - alkyl) -piperazino - or N-phenyl-piperazino group, by a 5- to 7-membered cycloalkenyleneimino group or by a 4- to 7-membered cycloalkyleneimino group, the above-mentioned 5- to 7-membered cycloalkyleneimino groups being substituted by one or two C - ⁇ - alkyl groups, through a C 5 _ 7 cycloalkyl or phenyl group, through a C 1 _ 3 alkyl, C 5 _ 7 cycloalkyl, phenyl, carboxy or C - ⁇ - alkoxy-car- bonyl group and can be
  • phenyl groups mentioned above may be substituted, in addition the monosubstituted phenyl groups mentioned above may be substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy or nitro group,
  • a 5-membered heteroaromatic group which contains an imino group, an oxygen or sulfur atom or an imino group, an oxygen or sulfur atom and one or two nitrogen atoms, or
  • a 6-membered heteroaromatic group which contains one, two or three nitrogen atoms, it being possible for the abovementioned 5- and 6-membered heteroaromatic groups to be additionally substituted by a chlorine or bromine atom or by a methyl group or to which the above-mentioned 5- and 6-membered heteroaromatic groups can be fused to a phenyl ring via 2 adjacent carbon atoms, and
  • R 5 is a Wassersto fatom or a C 1-3 alkyl group, wherein R 2 is preferably in position 5 or 6 represents
  • R 4 with the exception of a thiophenyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C 1 _ 3 alkyl group, one on the amide nitrogen atom by a C 5 _ 7 cycloalkyl, phenyl-C - ⁇ - alkyl-, C 5 _ 7- cycloalkyl-C 1 _ 3 -alkyl and naphthyl-C 1 _ 3 -alkyl group substituted aminocarbonyl and C 7 -alkylaminocarbonyl groups and the radicals containing a phenyl group substituted by three methoxy groups has the meanings mentioned for R 4 and
  • R 5 with the exception of one by a C 2 - 4 -alkylamino group which is terminally substituted in the 2-, 3- or 4-position by a di- (C - ⁇ - alkyl) - amino group and in which the amine hydrogen atom is additionally substituted by a C 2 _ 5 alkanoyl or C - ⁇ - alkylsulfonyl group can be replaced, and that by a di (C 2 _ 4 alkylamino) -C - ⁇ - alkyl group in which the C 2 . 4 -alkyl parts each in the 2-, 3- or 4-position are substituted by a hydroxyl group, substituted phenyl and naphthyl groups have the meanings mentioned for R 5 at the outset,
  • carboxy, amino or imino groups present in a compound of the above general formula I can be substituted by residues which can be split off in vivo.
  • in-cleavable residues such as an acyl group such as the benzoyl, pyridinoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a c ⁇ -i 6 ⁇ alkoxycarbonyl group such as the pentoxycarbonyl, hexyloxy - Carbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C 1 _-- alkoxycarbonyl group such as benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a -Alkylsulfonyl-C 2 _ 4 -
  • R c a kyl group
  • R e is a hydrogen atom, a C 1 _ 3 alkyl, C 5 _ 7 cycloalkyl or phenyl group and
  • R d represents a hydrogen atom or a C 1 _ 3 alkyl group or the R c CO-0- (R d CR e ) -O radical,
  • ester residues can also be used as a group which can be converted into a carboxy group in vivo.
  • Preferred compounds of general formula I are those in which
  • X is an oxygen atom
  • R x is a hydrogen atom
  • R 2 in position 5 or 6 is one on the amide nitrogen atom by a C 1 . 6 -alkyl group substituted aminocarbonyl or C- L .g-alkyl aminocarbonyl group in which one of the alkyl parts present by a carboxy group or from position 2 by an amino, C - ⁇ - alkylamino or di- (C ⁇ alkyl) -amino group can be substituted, but in a C - ⁇ - alkylaminocarbonyl or di (C ⁇ alkyl) aminocarbonyl group at least one alkyl part by a carboxy or C - ⁇ - alkoxycarbonyl group or from position 2 by an amino, C 1st 3 -Alkylamino- or di- (C - ⁇ - Alkyl) - amino group must be substituted,
  • R 3 is a C 1-4 alkyl group or a phenyl group which is optionally substituted by a fluorine, chlorine or bromine atom, by a C 1 _ 3 -alkyl, hydroxy or C 1 _ 3 -alkoxy group,
  • thiophenyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C 1-4 alkyl group,
  • a methoxy group optionally substituted by 1 to 3 fluorine atoms by a C 2 _ 3 alkoxy group which is substituted in the 2- or 3-position by a methylamino, dimethylamino or 5- to 7-membered cycloalkyleneimino group, in each case additionally a methyl group in the above-mentioned amino groups by a phenyl group can be substituted
  • a carbonyl group which is substituted by a hydroxy, C 1 _ 3 alkoxy, amino, C ⁇ alkylamino or N- (C- . - 5 alkyl) - C ⁇ alkylamino group, each having an alkyl part of the groups mentioned above additionally by a carboxy, C 1 . 3 alkoxycarbonyl or phenyl group or in the 2 or 3 position by a di- (c._ 3 alkyl) -amino, piperazino, N- (C- ⁇ - j alkyl) or 5- -piperazino- can be substituted to 7-membered cycloalkyleneimino group,
  • a C - ⁇ - alkyl group which is substituted by an amino, C - ⁇ - alkylamino, C 5.7 -cycloalkylamino or phenyl-C 1 _ 3 -alkylamino group, each of which is additionally on the amine nitrogen atom by a C ⁇ -Alkyl distr, in which the hydrogen atoms are partially or completely replaced by fluorine atoms, can be substituted by a cyclohexyl, C 2 _ 4 alkenyl or C - ⁇ - alkyl group, wherein the aforementioned C 1 _ 4 alkyl substituent each additionally by a cyano, carboxy, C 1 _ 3 alkoxycarbonyl, pyridyl, imidazolyl, benzo [1, 3] dioxole or phenyl group, the phenyl group being substituted by a fluorine -, Chlorine or bromine atom, may be monosubstitute
  • a C 1 _ 3 alkyl group which is replaced by a hydroxy, carboxy, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxothiomorpholino, piperazino, N- (C 1 _ 3 -alkyl) -piperazino or N-phenyl-piperazino group, by a 5- to 7-membered cycloalkenyleneimino group or by a 4- to 7-membered cycloalkyleneimino group, the above-mentioned 5- to 7-membered cycloalkyleneimino groups being substituted by one or two C 1 _ 3 alkyl groups, by a cyclohexyl or phenyl group, by a C 1 _ 3 alkyl, cyclohexyl, phenyl, carboxy or C 1 _ 4 alkoxy-carbonyl group and substituted by a hydroxy group and in the cycloalkyleneimin
  • a C 1 _ 3 -alkyl group which is substituted by a 5- to 7-membered cycloalkyleneimino group
  • the abovementioned 5- to 7-membered cycloalkyleneimino groups having 2 adjacent carbon atoms, optionally by fluorine, chlorine or bromine atoms, by Methyl or methoxy groups mono- or disubstituted phenyl group, where the substituents can be the same or different, or a pyrazino or thiazole group optionally substituted by an amino group is fused on, or by a di- (C 2 _ 4 -alkylamino) -C - ⁇ - alkyl group, in which the C 2.4 -alkyl parts are each substituted in the 2-, 3- or 4-position by a hydroxy group,
  • phenyl groups mentioned above may be substituted, in addition the monosubstituted phenyl groups mentioned above may be substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy or nitro group,
  • a pyridyl group optionally substituted by a chlorine or bromine atom or by a methyl group
  • R 5 represents a hydrogen atom a C - ⁇ - alkyl group
  • a C 2 _ 4 -alkylamino group which is terminally substituted in the 2-, 3- or 4-position by a di- (C 1 _ 3 -alkyl) -amino group and in which the hydrogen amine atom is additionally substituted by a C 2 . 5 -alkanoyl or C 1 _ 5 -alkylsulfonyl group can be replaced,
  • C 1 _ 3 alkyl group which by a C 1 _ 5 alkylamino, di (C - ⁇ - alkyl) amino, thiomorpholino, 1-oxo-thiomorpholino-, 1, 1-dioxo -thiomorpholino-, piperazino-, N- (C - ⁇ - alkyl) - piperazino-, N-phenyl -piperazino-, C 5 _ 7 -cycloalkenyleneimino or C 4 _ 7 -cycloalkyleneimino group, where the above-mentioned C 5 _ 7 cycloalkyleneimino groups through one or two C 1 _ 3 alkyl groups, through a C 5 .
  • X is an oxygen atom
  • R x is a hydrogen atom
  • R 2 in position 5 or 6 is an aminocarbonyl or C - ⁇ - alkyl substituted on the amide nitrogen atom by a C - ⁇ - alkyl group aminocarbonyl group in which one of the alkyl parts present can be substituted by a carboxy or methoxycarbonyl group or from position 2 by a di (C 1, 3 alkyl) amino group, but in a C 1 _ 3 alkyl aminocarbonyl or di (C x _ 3 alkyl) aminocarbonyl group at least one alkyl part must be substituted by a carboxy or methoxycarbonyl group or from position 2 by a di (C 1 _ 3 alkyl) amino group,
  • a 6-membered cycloalkyleneiminocarbonyl group optionally substituted by a C 1 _ 3 -alkyl group, in which a methylene group in the 4-position can be replaced by an oxygen atom,
  • R 3 is a C 1-4 alkyl group or a phenyl group which is optionally substituted by a fluorine, chlorine or bromine atom, by a C 1 _ 3 alkyl or C 1 _ 3 alkoxy group,
  • a phenyl group that by a fluorine, chlorine, bromine or iodine atom
  • a methyl or ethyl group each by a phenyl group which is substituted by a 5 to 7-membered cycloalkyleneimino group, a phenyl ring being additionally fused to the above-mentioned cycloalkyleneimino groups via 2 adjacent carbon atoms,
  • a methyl or ethyl group which are substituted by an amino, methylamino or ethylamino group, each of which is additionally substituted on the amine nitrogen atom by a benzyl or phenylethyl group
  • the phenyl part of the above-mentioned groups in each case by a fluorine, chlorine or Bromine may be monosubstituted by a methyl, methoxy, cyano, trifluoromethyl or nitro group or may be di- or trisubstituted by fluorine, chlorine or bromine atoms, by methyl or methoxy groups and the substituents may be the same or different,
  • a C 2 . 4 alkylamino group which is terminally substituted in the 2-, 3- or 4-position by a di- (C 1. 3 -alkyl) -amino group and in which the hydrogen amine atom is additionally substituted by a C 2 _ s -alkanoyl or C 1 -C 4 -Alkylsulfonyl distr can be replaced, may be substituted, in addition the monosubstituted phenyl groups mentioned above may be substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy or nitro group, and
  • R 5 represents a hydrogen atom or a C - ⁇ - alkyl group
  • X is an oxygen atom
  • R ⁇ is a hydrogen atom
  • R 2 in position 5 or 6 is an aminocarbonyl or C - ⁇ - alkyl aminocarbonyl group substituted on the amide nitrogen atom in which one of the alkyl parts present is substituted by a carboxy or methoxycarbonyl group or from position 2 by a di ( C x _ 3 alkyl) amino group may be substituted, but in a C 1 _ 3 alkylaminocarbonyl or di (C - ⁇ - alkyl) aminocarbonyl group at least one alkyl part by a carboxy or methoxycarbonyl group or from position 2 by a di (C 1-4 alkyl) amino group must be substituted,
  • R 3 is a C - ⁇ - alkyl group or a phenyl group which is optionally substituted by a fluorine, chlorine or bromine atom, by a C 1 _ 3 -alkyl or C 1 - 3 -alkoxy group,
  • X is an oxygen atom
  • R x is a hydrogen atom
  • R 2 in position 5 or 6 is an aminocarbonyl or C 1 _ 4 alkyl aminocarbonyl group substituted on the amide nitrogen atom by a C 1 _ 4 alkyl group, in which one of the alkyl parts present is replaced by a methoxycarbonyl group or from position 2 by a di (C 1 _ 3 alkyl) amino group can be substituted, but in a C 1.3 alkylaminocarbonyl or di (C - ⁇ - alkyl) aminocarbonyl group at least one alkyl part by a methoxycarbonyl group or from position 2 by a di (C 1 _ 3- alkyl) -amino group must be substituted,
  • 2- alkyl group substituted aminocarbonyl or C 1 , 4 -alkylaminocarbonyl group, in each of which the phenyl part is substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy, C 1 _ 3 alkoxycarbonyl, cyano or nitro group can be or
  • R 3 is a phenyl group
  • R 4 is a phenyl group through
  • a methyl or ethyl group each represented by a C - ⁇ - alkylamino, di (C -__ 3 alkyl) amino, diethanolamino, N- (phenyl- C 1 _ 3 alkyl) -C 1 _ 3 alkylamino or piperidino group may be substituted, or by a C 2 . 4 alkylamino group, the amino group terminal in the 2-, 3- or 4-position by a di- (C ⁇ j alkyl) and additionally the amine hydrogen atom by a C. 2 5 -alkanoyl or C 1 _ 3 -alkylsulfonyl group is replaced, is substituted,
  • R 5 represents a hydrogen atom
  • the new compounds are obtained, for example, by the following processes which are known in principle from the literature:
  • R 6 is a hydrogen atom or a protective group for the nitrogen atom of the lactam group, where R 6 can also represent a bond to a solid phase which may be formed via a spacer, and
  • Z x represents a halogen atom, a hydroxyl, alkoxy or aralkoxy group, for example a 'chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group, with an amine of the general formula
  • R 4 and R 5 are defined as mentioned at the beginning, and if necessary subsequent cleavage of a protective group used for the nitrogen atom of the lactam group or from a solid phase.
  • a protective group for the nitrogen atom of the lactam group is, for example, an acetyl, benzoyl, ethoxycarbonyl, tert. - Butyloxycarbonyl or benzyloxycarbonyl group and
  • a resin such as a 4- (2 ', 4' -Dirnethoxyphenylamino-methyl) -phenoxy resin, where the binding is advantageously carried out via the amino group, or a p-benzyloxybenzyl alcohol resin, the binding advantageously via an intermediate member such as a 2, 5-Dimethoxy-4-hydroxy-benzyl derivative is considered.
  • the reaction is advantageously carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such as triethylamine, N-ethyl-diisopropylamine or sodium hydrogen carbonate at temperatures between 20 and 175 ° C, one protective group used can be split off simultaneously as a result of transamidation.
  • a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, methylene chloride or mixtures thereof
  • an inert base such as triethylamine, N-ethyl-diisopropylamine or sodium hydrogen carbonate at temperatures between 20 and 175 ° C
  • one protective group used can be split off simultaneously as a result of transamidation.
  • Z x in a compound of the general formula II denotes a halogen atom
  • the reaction is preferably carried out in the presence of an inert base at temperatures between 20 and 120 ° C.
  • Z ] _ in a compound of the general formula II denotes a hydroxyl, alkoxy or aralkoxy group
  • the reaction is preferably carried out at temperatures between 20 and 200 ° C.
  • the subsequent splitting off of a protective group that may be required is advantageously carried out either hydrolytically in an aqueous or alcoholic solvent, e.g. in methanol / water, ethanol / water, isopropanol / water, tetrahydrofuran / water, dioxane / water, dimethylformamide / - water, methanol or ethanol in the presence of an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at Temperatures between 10 and 50 ° C,
  • Umamidierung with an organic base such as ammonia, methylamine, butylamine, dimethylamine or piperidine in a solvent such as methanol, ethanol, dimethylformamide and mixtures thereof or in an excess of the amine used at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C performed.
  • organic base such as ammonia, methylamine, butylamine, dimethylamine or piperidine
  • solvent such as methanol, ethanol, dimethylformamide and mixtures thereof or in an excess of the amine used at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C performed.
  • a solid phase used is preferably cleaved off using trifluoroacetic acid and water at temperatures between 0 and 35 ° C., preferably at room temperature.
  • R- L and R 3 to R 5 are defined as mentioned at the outset, or their reactive derivatives with an amine of the general formula
  • R 7 is a hydrogen atom or and R 8 is a C - ⁇ - alkyl group, at least one of the C - ⁇ - alkyl groups contained in the radicals R 7 and R B being represented by a carboxy group or from position 2 by a hydroxy-, C 1 _ 3 -alkoxy-, amino- , C - ⁇ - Alkyl- amino- or di- (C ⁇ alkyl) amino group can be substituted with the proviso that at least one C ⁇ alkyl group present in the above-mentioned groups by a carboxy group or from position 2 by an amino , C. 3 -Alkylamino- or di- (C. ⁇ - alkyl) amino group is substituted, or
  • R 7 is a C 3 .g-alkyl, C 5 . 7- cycloalkyl, phenyl, phenyl-C ⁇ alkyl, C s _ 7 -cycloalkyl-C 1 _ 3 alkyl or naphthyl-C 1 _ 3 alkyl group, in each of which the phenyl part by fluorine, chlorine - or bromine atoms, mono- or di- substituted by C - ⁇ - alkyl or C - ⁇ - alkoxy groups, where the substituents can be the same or different, by three methoxy groups or by one trifluoromethyl, carboxy, C 1 _ 3 -alkoxycarbonyl-, cyano-, aminocarbonyl-, C - ⁇ - alkylaminocarbonyl-, di- (C - ⁇ - alkyl) -aminocarbonyl-, C 3 .
  • R 8 is a hydrogen atom or a the above mentioned C 1 _ 7 alkyl group additionally by a carboxy group or from position 2 by a hydroxy, C 1 _ 3 alkoxy, amino, C-. 3 -Alkylamino- or di- (C 1 _ 3 -alkyl) -amino group may be substituted, or
  • R 7 and R 8 together with the nitrogen atom in between represent a 3- to 7-membered cycloalkyleneimino carbonyl group which is optionally substituted by a C x _ 3 alkyl group, a methylene group in a 6 or 7 membered cycloalkyleneimino group in the 4-position by an oxygen or sulfur atom, can be replaced by a sulfinyl or sulfonyl group or by an imino group which is optionally substituted by a C 1-4 alkyl, formyl or C 1-4 alkyl carbonyl group.
  • the amidation is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulfoxide or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20 ° C. and the boiling point of the solvent used, carried out.
  • a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulfoxide or dimethylformamide
  • the amidation with an appropriate acid is preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarboxylate, trimethyl orthoacetic acid, 2, 2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus trichloride '-Dicyclohexylcarbodiimide, N, N' -dicyclohexyl-carbodiimide / N-hydroxysuccinimide, N, N '-dicyclohexylcarbodimide / l-hydroxy-benzotriazole, 2- (1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl) - 1,1,3, 3-tetramethyluron
  • the subsequent hydrolysis is preferably carried out in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide Temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.
  • an aqueous solvent for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
  • the subsequent reductive alkylation is preferably carried out in a suitable solvent such as methanol, methanol / water, methanol / water / ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide, optionally with the addition of an acid such as hydrochloric acid in the presence of catalytically excited hydrogen, for example from Hydrogen in the presence of Raney nickel, platinum or palladium / carbon, or in the presence of a metal hydride such as sodium borohydride, lithium borohydride or lithium aluminum hydride at temperatures between 0 and 100 ° C, preferably at temperatures between 20 and 80 ° C.
  • a suitable solvent such as methanol, methanol / water, methanol / water / ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide
  • an acid such as hydrochloric acid
  • catalytically excited hydrogen for example from Hydrogen in the presence of
  • the subsequent acylation is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulfoxide or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20 ° C. and the boiling point of the solvent used , carried out.
  • a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulfoxide or dimethylformamide
  • the acylation with an appropriate acid is preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2, 2-dimethoxypropane, tetra-methoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus trichloride '-Dicyclohexylcarbodiimide, N, N' -dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N '-Di- cyclohexylcarbodiimide / 1-hydroxy-benzotriazole, 2 - (lH-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1,1,3, 3-tetra
  • the subsequent esterification or amidation is advantageously carried out by reacting a reactive corresponding carboxylic acid derivative with a corresponding alcohol or amine as described above.
  • the subsequent reduction of a nitro group is preferably carried out hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon or Raney nickel in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50 ° C. , but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • a catalyst such as palladium / carbon or Raney nickel
  • a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid
  • an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50 ° C. , but preferably at room temperature, and at
  • any reactive groups present such as carboxy, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.
  • the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group comes as a protective radical for a carboxyl group
  • a protective radical for an amino, alkylamino or imino group the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert. Butoxycarbonyl-, Benzyloxycarbonyl -, Benzyl-, Methoxy- benzyl- or 2, -Dimethoxybenzyl distr and for the amino group additionally the phthalyl group into consideration.
  • a protective radical used takes place, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide , Sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.
  • an aqueous solvent for example in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide , Sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.
  • a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50 ° C., but preferably at Room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • a catalyst such as palladium / carbon
  • a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid
  • an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50 ° C., but preferably at Room
  • a methoxybenzyl group can also be split off in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
  • an oxidizing agent such as cerium (IV) ammonium nitrate
  • a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
  • a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane, ethyl acetate or ether.
  • a phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methyl a in, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.
  • chiral compounds of the general formula I obtained can be separated into their enantiomers and / or diastereomers.
  • the compounds of general formula I obtained which occur in racemates can be converted into their optical / antipodes by methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) and compounds of the general formula I with at least 2 asymmetric carbon atoms on the basis of their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.
  • the enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives with the racemic compound, such as esters or amides, in particular acids and their activated derivatives or alcohols, and separating the mixture of diastereomeric salts or derivatives obtained in this way, for example due to different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • an optically active substance which forms salts or derivatives with the racemic compound such as esters or amides, in particular acids and their activated derivatives or alcohols
  • optically active acids are, for example, the D and L forms of tartaric acid, dibenzoyl tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, N-acetylglutamic acid, aspartic acid, N-acetyl-aspartic acid or quinic acid.
  • an optically active alcohol for example (+) - or (-) menthol and the optically active acyl radical in amides, for example the (+) - or (-) menthyloxycarbonyl radical.
  • the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
  • suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid or methanesulfonic acid.
  • the new compounds of the formula I obtained in this way if they contain a carboxy group, can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
  • Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the new compounds of the general formula I in which R x represents a hydrogen atom or a prodrug residue, have valuable pharmacological properties, in particular an inhibitory effect on various kinases, especially on receptor tyrosine kinases such as VEGFR2, PDGFR, FGFR1 , EGFR, HER2, IGFIR and HGFR, and on complexes of CDK's (Cyclin Dependent Kinases) such as CDKl, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins (A, Bl, B2, C, Dl, D2, D3, E, F, Gl, G2, H, I and K) and on viral cyclin the proliferation of cultured human cells, in particular that of endothelial cells, for example in angiogenesis, but also on the proliferation of other cells, in particular tumor cells.
  • CDK's Cyclin Dependent Kinases
  • High Five TM insect cells (BTI-TN-5B1-4), which were infected with a high titer of recombinant baculovirus, were used for the production of active human cyclin / CDK holoenzymes.
  • a baculovirus vector that contained two promoters (polyhedrin enhancer promoter, P10 enhancer promoter), GST-tagged cyclins (eg Cyclin Dl or Cyclin D3) with the corresponding Hisg-tagged CDK subunit (eg for CDK4 or CDK6) expressed in the same cell.
  • the active holoenzyme was isolated by affinity chromatography on glutathione-Sepharose.
  • Recombinant GST-tagged pRB (aa 379-928) was produced in E. coli and purified by affinity chromatography on glutathione-Sepharose.
  • the substrates used for the kinase assays depended on the specific kinases.
  • Histone Hl Sigma was used as a substrate for Cyclin E / CDK2, Cyclin A / CDK2, Cyclin B / CDK1 and for v-Cyclin / CDK6.
  • GST-tagged pRB (aa 379-928) was used as a substrate for Cyclin D1 / CDK4, Cyclin D3 / CDK4, Cyclin D1 / CDK6 and for Cyclin D3 / CDK6.
  • Lysates of the insect cells infected with recombinant baculovirus or also recombinant kinases were mixed with radioactive labeled ATP in the presence of a suitable substrate Concentrations of the inhibitor in a 1% DMSO solution (dimethyl sulfoxide) incubated at 30 ° C for 45 minutes.
  • the substrate proteins with associated radioactivity were precipitated with 5% TCA (trichloroacetic acid) in hydrophobic PVDF multi-well microtiter plates (Millipore) or with 0.5% phosphoric acid solution on Whatman P81 filters. After adding scintillation fluid, the radioactivity was measured in a Wallace 1450 Microbeta liquid scintillation counter. Double measurements were carried out per concentration of the substance; IC5 Q values for enzyme inhibition were calculated.
  • SK-UT-1B obtained from the American Type Culture Collection (ATCC)
  • ATCC American Type Culture Collection
  • SK-UT-1B obtained from the American Type Culture Collection
  • the SK-UT-IB cells were then introduced into Cytostar® multi-well plates (Amersham) with a density of 4000 cells per well and incubated overnight in an incubator.
  • Different concentrations of the compounds dissolved in DMSO; final concentration: ⁇ 1%
  • 14 C-thymidine was added to each well and incubation was continued for 24 hours.
  • the amount of the compounds dissolved in DMSO; final concentration: ⁇ 1%
  • SK-UT-1B or non-small cell lung tumor NCI-H460 (obtained from ATCC)
  • a kinase inhibitor was administered orally (by gavage) for a period of 2 to 4 weeks.
  • the tumor size was measured three times a week with a digital caliper.
  • the effect of a kinase inhibitor on tumor growth was determined as a percent inhibition compared to a control group treated with placebo.
  • the new compounds of general formula I, their isomers and their physiologically tolerable salts are suitable for the treatment of diseases which are characterized by excessive or abnormal cell proliferation.
  • diseases include (without claim to completeness): viral infections (eg HIV and Kaposi's sarcoma); Inflammation and autoimmune diseases (eg colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and / or parasitic infections; Leukemia, lymphoma and solid tumors; Skin diseases (eg psoriasis); Bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy). They are also useful as protection of proliferating cells (eg hair, intestinal, blood and progenitor cells) against DNA damage by radiation, UV treatment and / or cytostatic treatment.
  • proliferating cells eg hair, intestinal, blood and progenitor cells
  • the new compounds can also be used for the short-term or long-term treatment of the abovementioned diseases, if appropriate in combination with other "state-of-art” compounds such as other cytostatics.
  • the dosage required to achieve a corresponding effect is expediently 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg for intravenous administration, and 0.1 to 100 mg / kg, preferably 0.3 to for oral administration 30 mg / kg, 1 to 4 times a day.
  • the compounds of the formula I prepared according to the invention cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, Tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures, in conventional pharmaceutical preparations such as tablets, dragees, capsules, Incorporate powders, suspensions, suppositories or as solutions for injections or infusions.
  • Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for injections. Be i ⁇ pi el 6.
  • Active ingredient and mannitol are dissolved in water. After filling, freeze-drying.
  • the ready-to-use solution is dissolved with water for injections.
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing. This powder mixture is filled into size 3 hard gelatin capsules on a capsule filling machine.
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
  • This powder mixture is filled on a capsule filling machine into hard gelatin capsules Gr6Be 0.
  • 1 suppository contains:
  • Polyethylene glycol (M.G. 1500) 600.0 mg Polyethylene glycol (M.G. 6000) 460.0 mg Polyethylene sorbitan monostearate 840.0 mg
  • the polyethylene glycol is melted together with polyethylene sorbitan monostearate.
  • the milled active substance is homogeneously dispersed in the melt at 40 ° C. It gets to 38 ° C cooled and poured into weakly pre-cooled suppository molds.

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Abstract

L'invention concerne des indolinones substituées de formule générale (I) dans laquelle R1 à R5 et X sont définis dans la revendication 1, leurs isomères et leurs sels, notamment leurs sels physiologiquement tolérables, qui présentent des propriétés pharmacologiques intéressantes, notamment un effet inhibiteur sur différentes kinases et différents complexes cycline/CDK, ainsi que sur la prolifération de différentes cellules tumorales. L'invention concerne également des médicaments contenant ces composés, l'utilisation de ces derniers ainsi que leur préparation.
PCT/EP2000/004685 1999-05-27 2000-05-23 Indolinones substituees, utilisees comme inhibiteurs de la tyrosine kinase WO2000073297A1 (fr)

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AU52157/00A AU5215700A (en) 1999-05-27 2000-05-23 Substituted indolinone as tyrosine kinase inhibitors

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DE19924401A DE19924401A1 (de) 1999-05-27 1999-05-27 Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
DE19924401.4 1999-05-27

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Cited By (15)

* Cited by examiner, † Cited by third party
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US6686362B2 (en) 2001-12-27 2004-02-03 Theravance, Inc. Indolinone derivatives
WO2004017948A3 (fr) * 2002-08-16 2004-04-22 Boehringer Ingelheim Pharma Utilisation d'inhibiteur lck pour le traitement d'affections immunologiques
WO2003035049A3 (fr) * 2001-09-20 2004-06-10 Ab Science Utilisation d'inhibiteurs de c-kit puissants selectifs et non toxiques pour traiter des infections bacteriennes
US6858641B2 (en) 2001-04-06 2005-02-22 Boehringer Ingelheim Pharma Kg Substituted indolinones
WO2007057399A2 (fr) * 2005-11-15 2007-05-24 Boehringer Ingelheim International Gmbh Traitement du cancer
US7678805B2 (en) 2001-06-29 2010-03-16 Ab Science Use of tyrosine kinase inhibitors for treating inflammatory bowel diseases (IBD)
US7727731B2 (en) 2001-06-29 2010-06-01 Ab Science Potent, selective and non toxic c-kit inhibitors
US7741335B2 (en) 2001-06-29 2010-06-22 Ab Science Use of tyrosine kinase inhibitors for treating inflammatory diseases
US7989474B2 (en) 2002-08-16 2011-08-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of Lck inhibitors for treatment of immunologic diseases
EP2359829A1 (fr) 2003-04-29 2011-08-24 Boehringer Ingelheim International Gmbh Combinaisons pour traiter des maladies impliquant la prolifération cellulaire, la migration ou l'apoptose de cellules du myélome ou l'angiogènes
JP2011529470A (ja) * 2008-07-29 2011-12-08 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 新規化合物
EP2837626A1 (fr) * 2013-08-16 2015-02-18 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Dérivés d'indolinone comme modulateurs GRK5
EP3056202A1 (fr) * 2015-02-16 2016-08-17 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Derives de la benzopyrrolidone possédant des propriétés antivirales et anticancéreuses
US10105323B2 (en) 2008-06-06 2018-10-23 Boehringer Ingelheim International Gmbh Pharmaceutical dosage form for immediate release of an indolinone derivative
US10154990B2 (en) 2004-12-24 2018-12-18 Boehringer Ingelheim International Gmbh Medicaments for the treatment or prevention of fibrotic diseases

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DE10147088A1 (de) * 2001-09-25 2003-04-17 Medinnova Ges Med Innovationen Verwendung von Wirksubstanzen zur Prophylaxe und/oder Therapie von Erkrankungen, die mit Zellwachstumsstörungen einhergehen und Testsystem zum Auffinden solcher Wirksubstanzen
US7005444B2 (en) 2001-09-27 2006-02-28 Allergan, Inc. 3-(heteroarylamino)methylene-1, 3-dihydro-2H-indol-2-ones as kinase inhibitors
WO2007057397A1 (fr) * 2005-11-15 2007-05-24 Boehringer Ingelheim International Gmbh Traitement du cancer

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DE19816624A1 (de) * 1998-04-15 1999-10-21 Boehringer Ingelheim Pharma Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel

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WO1999015500A1 (fr) * 1997-09-05 1999-04-01 Glaxo Group Limited Derives substitues d'oxindole en tant qu'inhibiteurs de la tyrosine kinase et de la serine/threonine kinase
DE19816624A1 (de) * 1998-04-15 1999-10-21 Boehringer Ingelheim Pharma Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6858641B2 (en) 2001-04-06 2005-02-22 Boehringer Ingelheim Pharma Kg Substituted indolinones
US7727731B2 (en) 2001-06-29 2010-06-01 Ab Science Potent, selective and non toxic c-kit inhibitors
US7741335B2 (en) 2001-06-29 2010-06-22 Ab Science Use of tyrosine kinase inhibitors for treating inflammatory diseases
US7678805B2 (en) 2001-06-29 2010-03-16 Ab Science Use of tyrosine kinase inhibitors for treating inflammatory bowel diseases (IBD)
WO2003035049A3 (fr) * 2001-09-20 2004-06-10 Ab Science Utilisation d'inhibiteurs de c-kit puissants selectifs et non toxiques pour traiter des infections bacteriennes
US6686362B2 (en) 2001-12-27 2004-02-03 Theravance, Inc. Indolinone derivatives
US7223783B2 (en) 2001-12-27 2007-05-29 Theravance, Inc. Indolinone derivatives
US7060703B2 (en) 2001-12-27 2006-06-13 Theravance, Inc. Indolinone derivatives
WO2004017948A3 (fr) * 2002-08-16 2004-04-22 Boehringer Ingelheim Pharma Utilisation d'inhibiteur lck pour le traitement d'affections immunologiques
EP2281561A2 (fr) 2002-08-16 2011-02-09 Boehringer Ingelheim Pharma GmbH & Co. KG Utilisation d'inhibiteur LCK pour le traitement d'affectations immunologiques
US7989474B2 (en) 2002-08-16 2011-08-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of Lck inhibitors for treatment of immunologic diseases
EP2826480A1 (fr) 2003-04-29 2015-01-21 Boehringer Ingelheim International GmbH Combinaisons pour le traitement des maladies impliquant une prolifération cellulaire, migration ou apoptose des cellules de myélome, ou angiogenèse
EP2359829A1 (fr) 2003-04-29 2011-08-24 Boehringer Ingelheim International Gmbh Combinaisons pour traiter des maladies impliquant la prolifération cellulaire, la migration ou l'apoptose de cellules du myélome ou l'angiogènes
EP2361626A1 (fr) 2003-04-29 2011-08-31 Boehringer Ingelheim International Gmbh Combinaisons pour le traitement des maladies impliquant une prolifération cellulaire, migration ou apoptose des cellules de myélome, ou angiogenèse
US10154990B2 (en) 2004-12-24 2018-12-18 Boehringer Ingelheim International Gmbh Medicaments for the treatment or prevention of fibrotic diseases
WO2007057399A2 (fr) * 2005-11-15 2007-05-24 Boehringer Ingelheim International Gmbh Traitement du cancer
WO2007057399A3 (fr) * 2005-11-15 2007-08-30 Boehringer Ingelheim Int Traitement du cancer
US10105323B2 (en) 2008-06-06 2018-10-23 Boehringer Ingelheim International Gmbh Pharmaceutical dosage form for immediate release of an indolinone derivative
US8853420B2 (en) 2008-07-29 2014-10-07 Boehringer Ingelheim International Gmbh Compounds
JP2011529470A (ja) * 2008-07-29 2011-12-08 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 新規化合物
EP2837626A1 (fr) * 2013-08-16 2015-02-18 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Dérivés d'indolinone comme modulateurs GRK5
EP3056202A1 (fr) * 2015-02-16 2016-08-17 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Derives de la benzopyrrolidone possédant des propriétés antivirales et anticancéreuses
WO2016131789A1 (fr) * 2015-02-16 2016-08-25 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Dérivés de benzopyrrolidone possédant des propriétés antivirales et anticancéreuses

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DE19924401A1 (de) 2000-11-30
AU5215700A (en) 2000-12-18

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