WO1999062882A1 - Indolinones substituees, leur production et leur utilisation comme medicaments - Google Patents

Indolinones substituees, leur production et leur utilisation comme medicaments Download PDF

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Publication number
WO1999062882A1
WO1999062882A1 PCT/EP1999/003692 EP9903692W WO9962882A1 WO 1999062882 A1 WO1999062882 A1 WO 1999062882A1 EP 9903692 W EP9903692 W EP 9903692W WO 9962882 A1 WO9962882 A1 WO 9962882A1
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Prior art keywords
group
methyl
substituted
alkyl
indolinone
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PCT/EP1999/003692
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German (de)
English (en)
Inventor
Armin Heckel
Rainer Walter
Wolfgang Grell
Jacobus C. A. Van Meel
Norbert Redemann
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Boehringer Ingelheim Pharma Kg
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Priority to CA002328291A priority Critical patent/CA2328291A1/fr
Priority to EA200100001A priority patent/EA003514B1/ru
Application filed by Boehringer Ingelheim Pharma Kg filed Critical Boehringer Ingelheim Pharma Kg
Priority to PL99344467A priority patent/PL344467A1/xx
Priority to KR1020007013597A priority patent/KR20010043973A/ko
Priority to BR9910898-4A priority patent/BR9910898A/pt
Priority to AU43707/99A priority patent/AU764782B2/en
Priority to SK1822-2000A priority patent/SK18222000A3/sk
Priority to IL13870299A priority patent/IL138702A0/xx
Priority to HU0102210A priority patent/HUP0102210A3/hu
Priority to EP99926454A priority patent/EP1100779A1/fr
Priority to EEP200000723A priority patent/EE200000723A/xx
Priority to JP2000552094A priority patent/JP2002516906A/ja
Publication of WO1999062882A1 publication Critical patent/WO1999062882A1/fr
Priority to BG104938A priority patent/BG104938A/xx
Priority to NO20006138A priority patent/NO20006138L/no
Priority to HR20000831A priority patent/HRP20000831A2/hr

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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
    • A61P35/00—Antineoplastic agents
    • 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
  • the above compounds of general formula I in which R 2 represents a hydrogen atom or a prodrug residue, have valuable pharmacological properties, in particular an inhibitory effect on various kinases, especially on complexes of CDK's (CDK1, 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 (see L. Mengtao in J Virology ZI (3), 1984-1991 (1997)) and the other compounds of the general formula I above, in which R represents no hydrogen atom and no prodrug residue, are valuable intermediates for the preparation of the compounds mentioned above.
  • the present invention thus relates to the above compounds of the general formula I, the compounds in which R x represents a hydrogen atom or a prodrug residue provides valuable pharmacological properties, the pharmacologically active compounds containing drugs, their use and methods for their preparation.
  • X is an oxygen or sulfur atom
  • R x is a hydrogen atom, a C 1 _ 4 -alkoxy-carbonyl or C 2 _ 4 -alkanoyl group,
  • R 2 is a carboxy or C 1 _ 4 alkoxy-carbonyl group or an aminocarbonyl group which is optionally substituted by one or two C 1 _ 3 alkyl groups, it being possible for the substituents to be the same or different,
  • a C 2 . 3 alkoxy group in the 2- or 3-position by a C 1 _ 3 alkylamino, di- (C 1. 3, alkyl) -amino or 5- to 7-membered cycloalkyleneimino group may be substituted in each case additionally an alkyl part in the above-mentioned alkylamino and dialkylamino groups may be substituted by a phenyl group,
  • a carbonyl group which is substituted by a hydroxy, C ⁇ alkoxy, amino, C - ⁇ - alkylamino or N- (C ⁇ alkyl) - C ⁇ alkylamino group, each additionally having an alkyl part in the above groups mentioned by a carboxy, C ⁇ alkoxycarbonyl or phenyl group or in the 2- or 3-position by a di- (C ⁇ alkyl) amino, piperazino, N- (C ⁇ alkyl) - piperazino or 5- to 7-membered cycloalkyleneimino group can be substituted,
  • C 1-3 alkyl group which is replaced by an amino, C 1 . 7- alkylamino-, C s _ 7 -cycloalkylamino-, C 5 . 7- cycloalkyl-C 1 . 3 -alkylamino or phenyl-C ⁇ 3 -alkylamino group, each of which is additionally substituted on the amine nitrogen atom by a C ⁇ -alkyl group in which the hydrogen atoms are partially or completely replaced by fluorine atoms, by a C 5 .
  • C 2 _ 4 -alkenyl or C x _ 4 -alkyl group may be substituted, where the C 1-4 alkyl substituent mentioned above is in each case additionally substituted by a cyano, carboxy, , Pyridyl, imidazolyl, benzo [1, 3] dioxole or phenyl group, the phenyl group being mono-, di.
  • fluorine, chlorine or bromine atoms by methyl, methoxy, trifluoromethyl, cyano or nitro group - or can be trisubstituted and the substituents can be the same or different, or can be substituted in the 2-, 3- or 4-position by a hydroxyl 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 s is a hydrogen atom or a C ⁇ alkyl group.
  • 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.
  • residues which can be split off in vivo such as an acyl group such as the benzoyl, pyridinoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C 1 .
  • 16 -alkoxycarbonyl group such as the pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl -C 1-6 -alkoxycarbonyl group such as the benzylethoxycarbonyl, phenyl or phenylpropoxycarbonyl group, a C 1-3 alkylsulfonyl -C 2 _ 4 alkoxycarbonyl, C 1 . 3 -alkoxy-C 2 .
  • R c is C ⁇ alkyl, C 5 . 7- cycloalkyl, phenyl or phenyl-C 1 _ 3 -alkyl 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 _ 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 is an aminocarbonyl group
  • a phenyl group that by a fluorine, chlorine, bromine or iodine atom
  • 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
  • C x _ 3 alkyl group which is replaced by an amino, C ⁇ alkylamino, C 5 . 7- cycloalkylamino-, C 5 . 7- Cycloalkyl-C 1 _ 3 alkylamino or phenyl C _ 3 alkylamino group, each of which is additionally substituted on the amine nitrogen atom by a C 1 . 3 -alkyl group, in which the hydrogen atoms are partially or completely replaced by fluorine atoms, by a C 5 . 7- cycloalkyl-, C 2 . 4 -alkenyl- or C x . 4 alkyl group may be substituted, wherein the above-mentioned C 1 .
  • a C 1 . 3 -alkyl group which is replaced by a hydroxyl, carboxy, thiomorpholino, 1-oxidothiomorpholino, 1,1-dioxidothiomorpholino, 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 abovementioned 5- to 7-membered cycloalkyleneimino groups being substituted by one or two C 1 .
  • a pyridyl group optionally substituted by a chlorine or bromine atom or by a methyl group
  • R 5 represents a hydrogen atom, a C x _ 3 alkyl group
  • R 4 is a hydrogen atom, a C 1-4 alkyl group or a C 5 optionally substituted by a C 1-4 alkyl group.
  • 7- cycloalkyl group in which a methylene group in the 3- or 4-position, based on the carbon atom of the R 3 -C (R 4 NR 5 ) group, can be replaced by an imino group which is optionally substituted by a C 1-4 -alkyl group,
  • a phenyl or naphthyl group by a fluorine, chlorine, bromine or iodine atom, by a C ⁇ - j alkoxy, amino, C. 1 3- alkylamino-, di- (C x _ 3 -alkyl) -amino-, C 2 _ 5 -alkanoylamino-, N- (C ⁇ -alkylamino) -C 2 _ 5 -alkanoylamino-, C 1 _ 5- alkylsulfonylamino-, N- (C - ⁇ - alkyl) -C 1 .
  • Particularly preferred compounds of the general formula I are those in which R x to R 5 are defined as mentioned above and R 2 is in position 5,
  • X is an oxygen atom
  • R ⁇ is a hydrogen atom
  • R 2 in the 5-position is an aminocarbonyl group
  • R 3 is a hydrogen atom or a C 1 . 4 -alkyl group, which may be terminally substituted by a chlorine or bromine atom or by a phenylsulfonyl group,
  • 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 atom, monosubstituted by a methyl, methoxy, cyano, trifluoromethyl or nitro group or by fluorine, chlorine or bromine atoms, by methyl or methoxy groups may be di- or tri-substituted and the substituents may be the same or different
  • phenyl groups may be substituted, in addition the above-mentioned monosubstituted phenyl groups 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 1-4 alkyl group
  • Very particularly preferred compounds of general formula I are those in which X is an oxygen atom,
  • R ⁇ is a hydrogen atom
  • R 2 in the 5-position is an aminocarbonyl group
  • R 3 is a hydrogen atom or a C 1-4 alkyl group
  • R 4 is a phenyl group which
  • a methyl or ethyl group each by a phenyl group which is substituted in the 4-position 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 group and in which the phenyl part by a fluorine, chlorine or bromine atom, by a methyl -, Methoxy, cyano, trifluoromethyl or nitro group monosubstituted, disubstituted by methyl or methoxy groups or by Methyl or methoxy groups can be trisubstituted and the substituents can be the same or different,
  • phenyl groups may be substituted, in addition the above-mentioned monosubstituted phenyl groups 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 1-4 alkyl group
  • the new compounds are obtained, for example, by the following processes which are known in principle from the literature:
  • R 2 ' has the meanings mentioned for R 2 at the outset
  • R 6 is a hydrogen atom or a protective group for the nitrogen atom of the lactam group
  • one of the radicals R 2 ' or R can also represent a bond to a solid phase which may be formed via a spacer and the other of the radicals R 2 'or R 6 has the meanings mentioned above
  • Z represents a halogen atom, a hydroxyl, alkoxy or aralkoxy group, for example a chlorine or bromine atom , a methoxy, ethoxy or benzyloxy group,
  • 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' -dimethoxyphenylamino-methyl) -phenoxy resin, the binding advantageously taking place 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 conveniently carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, diethyl sulfoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such as triethylamine, N-ethyldiisopropylamine or sodium hydrogen carbonate at temperatures between 20 and 175 ° C. , where a 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, dirnethylformamide / 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.
  • the cleavage from a solid phase used is preferably carried out using tri luoroacetic acid and water at temperatures between 0 and 35 ° C., preferably at room temperature.
  • R x and R 3 to R 5 are defined as mentioned above, or their reactive derivatives with an amine of the general formula
  • R 7 and R 8 which may be the same or different, are hydrogen atoms or C 1 . 3 -alkyl groups.
  • 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.
  • a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulfoxide or dimethylformamide
  • the amidation with a corresponding 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, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus trichloride , N '-dicyclohexylcarbodiimide, N, N' -dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N '-Di- cyclohexylcarbodiimide / l-hydroxy-benzotriazole, 2- (1H-benzotriazol-1-yl) -1, 1, 3,3-ramethyluronium-t rafluoroborate, 2- (1H-benzotriazol-1-yl) -1,1,3, 3-
  • the subsequent hydrolysis is preferably carried out in an aqueous solvent, for example in water, isopropanol / water, tetra- hydrofuran / 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, tetra- hydrofuran / 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.
  • 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, e.g. of 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 e.g. of hydrogen
  • the subsequent alkylation is carried out using an alkylating agent such as an alkyl halide or dialkyl sulfate such as methyl iodide, dimethyl sulfate or propyl bromide, preferably in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or dimethylaminopyridine, preferably at temperatures between 20 ° C and the boiling point of the solvent used.
  • an alkylating agent such as an alkyl halide or dialkyl sulfate such as methyl iodide, dimethyl sulfate or propyl bromide
  • a solvent such as methanol, ethanol, methylene chloride,
  • 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 .
  • 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 water pulling agent, for example in the presence of chloroformate isobutyl ester, orthocarbonic acid tetraethyl ester, orthoacetic acid trimethyl ester, 2, 2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-hexodimodiodicyclide - carbodiimide / N-hydroxysuccinimide, N, N '-dicyclohexylcarbodimide / l-hydroxy-benzotriazole, 2- (IH-benzotriazol-l-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate, 2- (IH -Benzotriazol-l-yl) - 1,1,3,3-tetramethyluron
  • 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, for example 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.
  • 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, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group in addition the phthalyl group into consideration.
  • the subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. 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 e.g. in water, isopropanol / water, tetrahydrofuran / water or dioxane / water
  • an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
  • 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
  • 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 Solvents 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 Solvents 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 methylamine, 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 separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as esters or amides, with the racemic compound, 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.
  • 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.
  • Suitable optically active alcohols are, for example, (+) - or (-) menthol and optically active acyl radicals in amides are, for example, the (+) - or (-) menthyloxycarbonyl radicals.
  • 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, 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 ⁇ represents a hydrogen atom or a prodrug residue, have valuable pharmacological properties, in particular inhibitory effects on various kinases and cyclin / CDK complexes, on the proliferation of cultured human tumor Cells and after oral administration for the growth of tumors in nude mice that had been infected with human tumor cells.
  • 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 combined with radioactively labeled ATP in the presence of a suitable substrate with various concentrations of the inhibitor in a 1% DMSO solution (dimethyl sulfoxide) 45 Incubated for minutes at 30 ° C.
  • 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; IC50 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 (ATCC)
  • ATCC 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 (Amersham) was added to each well and incubation was continued for 24 hours.
  • the amount of 14 C-thymidine which was incorporated into the tumor cells in the presence of the inhibitor and which represents the number of cells in the S phase was measured in a Wallace 1450 Microbeta liquid scintillation counter.
  • SK-UT-IB 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.
  • Such 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 (e.g. hair, intestinal, blood and progenitor cells) against DNA damage from radiation, UV treatment and / or cytostatic treatment.
  • 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 optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, e.g.
  • Rink resin (MBHA resin, Novobiochem) is allowed to swell in 330 ml of dimethylformamide. Then 330 ml of 30% piperidine in dimethylformamide are added and the mixture is shaken for 7 minutes in order to remove the 9H-fluoren-9-yl-methoxycarbonyl group. Then the resin is washed several times with dimethylformamide. Finally, 7.3 g of 10.5 g of 2-indolinone-5-carboxylic acid (preparation analogous to Ogawa, Hidenori et al. Chem. Pharm.
  • Example IV The following coated resins are produced analogously to Example IV: (1) Resin coated with 3-Z- (1-ethoxy-methylene] -5-amido-2-indolinone by reaction of the product from Example I and triethyl orthoformate

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne des indolinones substituées correspondant à la formule générale (I), dans laquelle les groupes R1 à R5 et X correspondent à la définition donnée dans la revendication 1, leurs isomères et leurs sels, en particulier leurs sels physiologiquement compatibles, qui présentent des caractéristiques pharmacologiques précieuses, en particulier un effet inhibiteur sur différentes kinases et sur différents complexes cycline/CDK, ainsi que sur la prolifération de différentes cellules tumorales, des médicaments contenant ces composés, leur utilisation et leur procédé de production.
PCT/EP1999/003692 1998-06-04 1999-05-28 Indolinones substituees, leur production et leur utilisation comme medicaments WO1999062882A1 (fr)

Priority Applications (15)

Application Number Priority Date Filing Date Title
HU0102210A HUP0102210A3 (en) 1998-06-04 1999-05-28 Substituted indolinones, the production thereof and their use for producing medicaments and medicaments containing same
IL13870299A IL138702A0 (en) 1998-06-04 1999-05-28 Substituted indolinones, the production thereof and their use as medicaments
PL99344467A PL344467A1 (en) 1998-06-04 1999-05-28 Substituted indolinones, the production thereof and their use as medicaments
EA200100001A EA003514B1 (ru) 1998-06-04 1999-05-28 Замещенные индолиноны, их получение и их применение в качестве лекарственных средств
BR9910898-4A BR9910898A (pt) 1998-06-04 1999-05-28 Indolinonas sibstituìdas, preparação e utilização das mesmas como composições farmacêuticas
AU43707/99A AU764782B2 (en) 1998-06-04 1999-05-28 Substituted indolinones, the production thereof and their use as medicaments
EP99926454A EP1100779A1 (fr) 1998-06-04 1999-05-28 Indolinones substituees, leur production et leur utilisation comme medicaments
CA002328291A CA2328291A1 (fr) 1998-06-04 1999-05-28 Indolinones substituees, leur preparation et leur utilisation comme medicaments
KR1020007013597A KR20010043973A (ko) 1998-06-04 1999-05-28 치환된 인돌리논, 이의 제조방법 및 약제로서의 이의 용도
SK1822-2000A SK18222000A3 (sk) 1998-06-04 1999-05-28 Substituované indolinóny, spôsob ich prípravy, farmaceutický prostriedok s ich obsahom a ich použitie
EEP200000723A EE200000723A (et) 1998-06-04 1999-05-28 Asendatud indolinoonid, nende valmistamine ja nende kasutamine ravimitena
JP2000552094A JP2002516906A (ja) 1998-06-04 1999-05-28 新規置換インドリノン、それらの調製及び医薬組成物としてのそれらの使用
BG104938A BG104938A (en) 1998-06-04 2000-11-13 Substituted indolinones, the production thereof and their use as medicaments
NO20006138A NO20006138L (no) 1998-06-04 2000-12-01 Substituerte indolinoner, fremstilling og anvendelse derav som medikamenter
HR20000831A HRP20000831A2 (en) 1998-06-04 2000-12-01 New substituted indolinones, the preparation thereof and their use as pharmaceutical compositions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19824922A DE19824922A1 (de) 1998-06-04 1998-06-04 Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
DE19824922.5 1998-06-04

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JP (1) JP2002516906A (fr)
KR (1) KR20010043973A (fr)
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DE (1) DE19824922A1 (fr)
EA (1) EA003514B1 (fr)
EE (1) EE200000723A (fr)
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HU (1) HUP0102210A3 (fr)
ID (1) ID27035A (fr)
IL (1) IL138702A0 (fr)
NO (1) NO20006138L (fr)
PL (1) PL344467A1 (fr)
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001027081A1 (fr) * 1999-10-13 2001-04-19 Boehringer Ingelheim Pharma Kg Indolinones substituees en position 6, leur preparation et leur utilisation en tant que medicaments
EP1165514A1 (fr) * 1999-03-04 2002-01-02 Glaxo Group Limited Oxindoles 3-(anilinomethylene) faisant office proteine tyrosine kinase et de la proteine serine/threonine kinase
US6624171B1 (en) 1999-03-04 2003-09-23 Smithkline Beecham Corporation Substituted aza-oxindole derivatives
JP2004508366A (ja) * 2000-09-01 2004-03-18 グラクソ　グループ　リミテッド オキシインドール誘導体
US6762180B1 (en) 1999-10-13 2004-07-13 Boehringer Ingelheim Pharma Kg Substituted indolines which inhibit receptor tyrosine kinases
US6858641B2 (en) 2001-04-06 2005-02-22 Boehringer Ingelheim Pharma Kg Substituted indolinones
WO2006067165A2 (fr) * 2004-12-24 2006-06-29 Boehringer Ingelheim International Gmbh Medicaments pour le traitement ou la prevention de maladies fibrotiques
WO2008117061A2 (fr) * 2007-03-28 2008-10-02 Sterix Limited Composé
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
US10105323B2 (en) 2008-06-06 2018-10-23 Boehringer Ingelheim International Gmbh Pharmaceutical dosage form for immediate release of an indolinone derivative
WO2024050297A1 (fr) * 2022-09-02 2024-03-07 Deciphera Pharmaceuticals, Llc Inhibiteurs d'ulk et leurs procédés d'utilisation

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19816624A1 (de) * 1998-04-15 1999-10-21 Boehringer Ingelheim Pharma Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
AU2001288374A1 (en) 2000-09-01 2002-03-22 Glaxo Group Limited Substituted oxindole derivatives as tyrosine kinase inhibitors
ES2274075T3 (es) 2001-06-29 2007-05-16 Ab Science Utilizacion de inhibidores de c-kit para tratar enfermedades inflamatorias intestinales (eii).
ES2266553T3 (es) 2001-06-29 2007-03-01 Ab Science Utilizacion de derivados de la n-fenil-2-pirimidina-amina para tratar las enfermedades inflamatorias.
EP1401413B1 (fr) 2001-06-29 2006-11-22 AB Science Utilisation d'inhibiteurs de tyrosine kinase dans le traitement de maladies allergiques
ATE401079T1 (de) * 2001-06-29 2008-08-15 Ab Science Die verwendung von c-kithemmern zur behandlung von autoimmunerkrankungen
DE60223063T2 (de) 2001-06-29 2008-07-17 Ab Science C-kit inhibitoren
CA2461812C (fr) 2001-09-27 2011-09-20 Allergan, Inc. L'utilisation de 3-(arylamino)methylene-1, 3-dihydro-2h-indol-2-ones en tant qu'inhibiteurs de kinases
JP4879492B2 (ja) * 2002-11-27 2012-02-22 アラーガン、インコーポレイテッド 疾患の治療のためのキナーゼ阻害剤
DE102004012070A1 (de) * 2004-03-12 2005-09-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue cycloalkyl-haltige 5-Acylindolinone, deren Herstellung und deren Verwendung als Arzneimittel
SG177128A1 (en) * 2006-12-05 2012-01-30 Arena Pharm Inc Processes for preparing (r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine and intermediates thereof
CN101735071A (zh) * 2009-12-04 2010-06-16 大连凯飞精细化工有限公司 一种生产4-n,n-二甲胺基甲基苯胺的方法
CN103102352B (zh) * 2011-11-15 2015-08-12 山东亨利医药科技有限责任公司 酪氨酸激酶抑制剂吲哚满酮衍生物
CN103130775B (zh) * 2011-11-22 2015-09-30 山东亨利医药科技有限责任公司 作为酪氨酸激酶抑制剂的吲哚满酮衍生物
GB201208775D0 (en) * 2012-05-18 2012-07-04 Uni I Oslo Chemical compounds
CN103848814B (zh) * 2012-12-06 2016-08-17 山东亨利医药科技有限责任公司 作为酪氨酸激酶抑制剂的取代吲哚满酮衍生物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE838623A (fr) * 1976-02-16 1976-06-16 Derives de 3-hydroxymethylene-2-indolinone et procede pour leur production
US4145422A (en) * 1977-09-06 1979-03-20 Abbott Laboratories Aminomethylene oxindoles
WO1996040116A1 (fr) * 1995-06-07 1996-12-19 Sugen, Inc. Composes d'indolinone pour le traitement de maladies
WO1998007695A1 (fr) * 1996-08-23 1998-02-26 Sugen, Inc. Banques combinatoires d'indolinone, produits et procedes associes pour traiter des maladies
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

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE838623A (fr) * 1976-02-16 1976-06-16 Derives de 3-hydroxymethylene-2-indolinone et procede pour leur production
US4145422A (en) * 1977-09-06 1979-03-20 Abbott Laboratories Aminomethylene oxindoles
WO1996040116A1 (fr) * 1995-06-07 1996-12-19 Sugen, Inc. Composes d'indolinone pour le traitement de maladies
WO1998007695A1 (fr) * 1996-08-23 1998-02-26 Sugen, Inc. Banques combinatoires d'indolinone, produits et procedes associes pour traiter des maladies
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

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6815439B2 (en) 1999-03-04 2004-11-09 Smithkline Beecham Corporation Substituted aza-oxindole derivatives
EP1165514A1 (fr) * 1999-03-04 2002-01-02 Glaxo Group Limited Oxindoles 3-(anilinomethylene) faisant office proteine tyrosine kinase et de la proteine serine/threonine kinase
US6350747B1 (en) 1999-03-04 2002-02-26 Glaxo Wellcome Inc. 3-(anilinomethylene) oxindoles
US6624171B1 (en) 1999-03-04 2003-09-23 Smithkline Beecham Corporation Substituted aza-oxindole derivatives
US7129253B2 (en) 1999-03-04 2006-10-31 Smithkline Beecham Corporation Compounds
US6818632B2 (en) 1999-03-04 2004-11-16 Smithkline Beecham Corporation 3-(anilinomethylene)oxindoles
EP2157081A1 (fr) * 1999-10-13 2010-02-24 Boehringer Ingelheim Pharma GmbH & Co. KG Indolinones substitués en position 6, leur fabrication et leur utilisation comme médicament
WO2001027081A1 (fr) * 1999-10-13 2001-04-19 Boehringer Ingelheim Pharma Kg Indolinones substituees en position 6, leur preparation et leur utilisation en tant que medicaments
US6762180B1 (en) 1999-10-13 2004-07-13 Boehringer Ingelheim Pharma Kg Substituted indolines which inhibit receptor tyrosine kinases
HRP20020306B1 (en) * 1999-10-13 2010-09-30 Boehringer Ingelheim Pharma Gmbh & Co. Kg. 6-position substituted indole, production and use thereof as a medicament
JP2004508366A (ja) * 2000-09-01 2004-03-18 グラクソ　グループ　リミテッド オキシインドール誘導体
US6858641B2 (en) 2001-04-06 2005-02-22 Boehringer Ingelheim Pharma Kg Substituted indolinones
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
EP2878297A1 (fr) * 2004-12-24 2015-06-03 Boehringer Ingelheim International GmbH Médicaments pour le traitement ou la prévention des maladies fibrogènes
NO341591B1 (no) * 2004-12-24 2017-12-11 Boehringer Ingelheim Int 3-Z-[1-(4-(N-((4-metyl-piperazin-1-yl)-metylkarbonyl)-N-metyl-amino)-anilino)-1-fenyl-metylen]-6-metoksykarbonyl-2-indolinon, tautomerene, diastereomerene, enantiomerene, blandinger derav og saltene derav, og i kombinasjon med en ytterligere farmakologisk aktiv substans, for anvendelse i forebygging eller behandling av fibrose ved revmatoid artritt
EP3643309A1 (fr) * 2004-12-24 2020-04-29 Boehringer Ingelheim International GmbH Médicaments pour le traitement ou la prévention des maladies fibrogènes
WO2006067165A3 (fr) * 2004-12-24 2007-04-26 Boehringer Ingelheim Int Medicaments pour le traitement ou la prevention de maladies fibrotiques
EA015011B1 (ru) * 2004-12-24 2011-04-29 Бёрингер Ингельхайм Интернациональ Гмбх Применение 3-z-[1-(4-(n-((4-метилпиперазин-1-ил)метилкарбонил)-n-метиламино)анилино)-1-фенилметилен]-6-метоксикарбонил-2-индолинона для лечения или предупреждения фиброзных заболеваний
EP2384751A1 (fr) * 2004-12-24 2011-11-09 Boehringer Ingelheim International Gmbh Médicaments pour le traitement ou la prévention des maladies fibrogènes
AU2005318126B2 (en) * 2004-12-24 2011-11-24 Boehringer Ingelheim International Gmbh Indolidone derivatives for the treatment or prevention of fibrotic diseases
US10154990B2 (en) 2004-12-24 2018-12-18 Boehringer Ingelheim International Gmbh Medicaments for the treatment or prevention of fibrotic diseases
WO2006067165A2 (fr) * 2004-12-24 2006-06-29 Boehringer Ingelheim International Gmbh Medicaments pour le traitement ou la prevention de maladies fibrotiques
RU2505532C2 (ru) * 2007-03-28 2014-01-27 Стерикс Лимитед Соединение
WO2008117061A3 (fr) * 2007-03-28 2009-05-14 Sterix Ltd Composé
US8394825B2 (en) 2007-03-28 2013-03-12 Sterix Limited Compound
WO2008117061A2 (fr) * 2007-03-28 2008-10-02 Sterix Limited Composé
US10105323B2 (en) 2008-06-06 2018-10-23 Boehringer Ingelheim International Gmbh Pharmaceutical dosage form for immediate release of an indolinone derivative
WO2024050297A1 (fr) * 2022-09-02 2024-03-07 Deciphera Pharmaceuticals, Llc Inhibiteurs d'ulk et leurs procédés d'utilisation

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DE19824922A1 (de) 1999-12-09
CA2328291A1 (fr) 1999-12-09
HUP0102210A2 (hu) 2001-11-28
CO5050294A1 (es) 2001-06-27
AU4370799A (en) 1999-12-20
IL138702A0 (en) 2001-10-31
EE200000723A (et) 2002-04-15
BG104938A (en) 2001-06-29
PL344467A1 (en) 2001-11-05
AU764782B2 (en) 2003-08-28
HRP20000831A2 (en) 2001-12-31
HUP0102210A3 (en) 2002-12-28
CN1303374A (zh) 2001-07-11
EA003514B1 (ru) 2003-06-26
NO20006138L (no) 2001-02-01
EP1100779A1 (fr) 2001-05-23
ID27035A (id) 2001-02-22
ZA200005435B (en) 2002-01-07
NO20006138D0 (no) 2000-12-01
YU73900A (sh) 2003-04-30
KR20010043973A (ko) 2001-05-25
TR200003515T2 (tr) 2001-06-21
SK18222000A3 (sk) 2001-08-06
BR9910898A (pt) 2001-02-13
EA200100001A1 (ru) 2001-08-27

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