EP1379501A1 - In 6-stellung substituierte indoline und ihre verwendung als kinase-inhibitoren - Google Patents

In 6-stellung substituierte indoline und ihre verwendung als kinase-inhibitoren

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Publication number
EP1379501A1
EP1379501A1 EP02735201A EP02735201A EP1379501A1 EP 1379501 A1 EP1379501 A1 EP 1379501A1 EP 02735201 A EP02735201 A EP 02735201A EP 02735201 A EP02735201 A EP 02735201A EP 1379501 A1 EP1379501 A1 EP 1379501A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
group
amino
phenyl
carbonyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02735201A
Other languages
German (de)
English (en)
French (fr)
Inventor
Frank Hilberg
Armin Heckel
Thorsten Lehmann-Lintz
Gerald Jürgen Roth
Jörg Kley
Jacobus Van Meel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1379501A1 publication Critical patent/EP1379501A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to novel 6-substituted indolinones of the general formula
  • Rt represents a hydrogen atom or a prodrug residue
  • Rt 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, the compounds in which R 1 represents a hydrogen atom or a prodrug residue have valuable pharmacological properties, the medicaments containing the pharmacologically active compounds, their use and processes for their preparation.
  • X is an oxygen or sulfur atom
  • Ri is a hydrogen atom or a prodrug group such as a C 1- alkoxycarbonyl or C 2-4 alkanoyl group,
  • R 2 is a carboxy group, a linear or branched C ⁇ . 6 alkoxycarbonyl group, a C 4 - 7 -Cycloalkoxycarbonyl- or an aryloxycarbonyl group,
  • R 3 is a hydrogen atom, a C ⁇ . 6 alkyl, C 3-7 cycloalkyl, trifluoromethyl or heteroaryl group,
  • a phenyl or naphthyl group or a mono- or disubstituted phenyl or naphthyl group by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C- ⁇ - 3 alkyl or C ⁇ - 3 alkoxy group, where in the case of disubstitution, the substituents can be the same or different,
  • R 4 is a phenyl, pyrrolyl or furanyl group substituted by the group R 6 , which is additionally substituted by fluorine, chlorine, bromine or iodine atoms, by C -5 alkyl, trifluoromethyl, hydroxy, C 1-3 - alkoxy, carboxy, C ⁇ -3 alkoxycarbonyl, amino, acetyl amino, C ⁇ -3-alkyl-sulfonylamino, aminocarbonyl, d- C3 alkyl-aminocarbonyl, di- (C -3 alkyl ) aminocarbonyl, aminosulfonyl, C 3 alkyl alkyl aminosulfonyl, Di- (C ⁇ - 3 alkyl) aminosulfonyl, nitro or cyano groups can be mono- or disubstituted, where the substituents can be the same or different and where
  • R an aminocarbonyl, C ⁇ -4 -alkylamino-carbonyl-, N- (C ⁇ -5 -alkyl) -C ⁇ -3 -alkylamino- carbonyl-, C 3-7 -cycloalkylamino-carbonyl-, N- (C ⁇ - 5th -Alkyl) -C 3 - 7 -cycloalkylamino-carbonyl-, (phenyl-C ⁇ -3 -alkyl) amino-carbonyl-, N- (C 1-3 -alkyl) -phenyl-C ⁇ -3 -alkylamino- carbonyl group .
  • a C ⁇ . 3 -Alkylaminocarbonyl- or N- ⁇ is-alkyl -ds-alkylaminocarbonyl group in which one or two alkyl parts independently of one another by a nitro, cyano, carbamoyl, N- (C ⁇ - 3 alkyl) carbamoyl, di- N- (-C 3 alkyl) carbamoyl, carboxy or C f .
  • the cycloalkylene part can be condensed with a phenyl ring via two adjacent ring atoms or can be bridged with a methylene or ethylene group via two non-adjacent ring atoms or
  • one or two hydrogen atoms can each be replaced by a C ⁇ -3 alkyl group or / and
  • Di- (-C 3 alkyl) aminosulfonyl, C 3 alkyl sulfonylamino, nitro or cyano groups can be mono- or disubstituted, where the substituents can be the same or different, or two adjacent hydrogen atoms of the phenyl groups by a methylenedioxy group can be replaced,
  • R 5 is a hydrogen atom or a C -3 alkyl group
  • an aryl group optionally by a fluorine, chlorine, bromine or iodine atom, by a cyano, trifluoromethyl, nitro, carboxy, aminocarbonyl, C 1 -C 3 alkyl or C ⁇ alkoxy group mono- or disubstituted phenyl or naphthyl group and
  • heteroaryl group a monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C 1-3 alkyl group in the carbon skeleton, where
  • the 6-membered heteroaryl group has one, two or three nitrogen atoms and
  • the 5-membered heteroaryl group is an imino group optionally substituted by a C 3 alkyl or phenyl C 3 C 3 alkyl group, an oxygen or sulfur atom or an imino group optionally substituted by a C 3 alkyl or phenyl C 3 alkyl group or an oxygen or sulfur atom and additionally a nitrogen atom or
  • a phenyl ring may be fused to the above-mentioned monocyclic heterocyclic groups via two adjacent carbon atoms and the binding takes place via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,
  • saturated alkyl and alkoxy parts present in the groups defined above which contain more than 2 carbon atoms, including their branched isomers, such as, for example, the isopropyl, tert-butyl, isobutyl group, unless stated otherwise, and
  • hydrogen atom of an existing carboxy group or a hydrogen atom bonded to a nitrogen atom for example an amino, alkylamino or imino group or a saturated N-heterocycle such as the piperidinyl group, can in each case be replaced by a radical which can be split off in vivo,
  • a group that can be split off from an imino or amino group in vivo is, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a C ⁇ . ⁇ 6 alkanoyl group such as the formyl, acetyl, propionyl, butanoyl -, Pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C- ⁇ - 16 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, Octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyl
  • R e is a Cig-alkyl, C 5 - 7 cycloalkyl, phenyl or phenyl-C- ⁇ - 3 alkyl group,
  • R f is a hydrogen atom, a C -3 alkyl, C 5 . 7- cycloalkyl or phenyl group and
  • R g represents a hydrogen atom, a C -3 alkyl or R e CO-O- (R f CR g ) -O group, in which R e to R g are as defined above,
  • the ester radicals mentioned above also being able to be used as a group which can be converted into a carboxy group in vivo.
  • R ⁇ denotes an unsubstituted or substituted aminocarbonyl group as defined above or below.
  • Preferred compounds of general formula I are those in which
  • X is an oxygen atom
  • Ri is a hydrogen atom, a C ⁇ -4-Alkoxycarbony -.! Or C 2-4 alkanoyl
  • R 2 is a carboxy group or a linear or branched C -4 alkoxycarbonyl group
  • R 3 is a hydrogen atom, a Ci- ⁇ -alkyl or C 3-7 cycloalkyl group,
  • a phenyl or naphthyl group or by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C ⁇ . 3 -alkyl or C- ⁇ . 3 -alkoxy group mono- or disubstituted phenyl or naphthyl group, where in the case of disubstitution the substituents can be the same or different,
  • R 4 is a furanyl group substituted by an aminocarbonyl, C 1 -C -alkylaminocarbonyl or N- (C 4 alkyl) - C 3 alkylaminocarbonyl group, the C 1 -C 4 -alkyl aminocarbonyl or N- (C 4 alkyl) ) -C ⁇ -3 -alkylaminocarbonyl distr in one or both alkyl parts from position 2 can be substituted by an amino, C- ⁇ _ 3 alkylamino or di- (C- ⁇ - 3 - alkyl) amino group,
  • a phenyl group substituted by the group R 6 additionally by fluorine, chlorine or bromine atoms, by C ⁇ . 5 -Alkyl-, trifluoromethyl-, hydroxy-, C ⁇ -3 -alkoxy-, carboxy-, C- ⁇ -3-alkoxycarbonyl-, amino-, acetylamino-, C ⁇ .
  • a C ⁇ -3-alkylaminocarbonyl or N- (C ⁇ - 3 alkyl) -C ⁇ ⁇ alkylaminocarbonyl group in which one or two alkyl parts independently of one another by a nitro, cyano, carbamoyl, N- (C ⁇ " 3 alkyl ) -carbamoyl-, di-N- (C ⁇ -3 -alkyl) -carbamoyl, carboxy or C ⁇ - 3 alkoxycarbonyl group or in 2- or 3-position by an amino-, (C ⁇ -3- alkyl) -amino- , Di- (C ⁇ . 3 -alkyl) -amino-, (C ⁇ - 4 -alkoxycarbonyl) -amino-, N-
  • the cycloalkylene part can be condensed with a phenyl ring via two adjacent ring atoms or can be bridged with a methylene or ethylene group via two non-adjacent ring atoms or
  • one or two hydrogen atoms can each be replaced by a d-3-alkyl group or / and
  • R 5 is a hydrogen atom or a C ⁇ . 3 -alkyl group
  • saturated alkyl and alkoxy parts present in the groups defined above which contain more than 2 carbon atoms, including their branched isomers, such as, for example, the isopropyl, tert-butyl, isobutyl group, unless stated otherwise, and
  • hydrogen atom of an existing carboxy group or a hydrogen atom bonded to a nitrogen atom for example an amino, alkylamino or imino group or a saturated N-heterocycle such as the piperidinyl group, can in each case be replaced by a radical which can be split off in vivo,
  • a preferred subgroup relates to compounds of the general formula I in which
  • X is an oxygen atom
  • Ri is a hydrogen atom
  • R 2 is a carboxy group or a C ⁇ . alkoxycarbonyl group
  • R 3 is a phenyl or naphthyl group, or a phenyl group monosubstituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C 3 alkyl or C 3 alkoxy group,
  • R 4 is a pyrrolyl group which is substituted by an aminocarbonyl, C 4 alkylaminocarbonyl or N (C 4 alkyl) C 3 alkylaminocarbonyl group, the C 4 alkyl aminocarbonyl or N (C 4 - 4 - Alkyl) -C ⁇ - 3 -alkylaminocarbonyl distr in one or both alkyl parts from position 2 can be substituted by an amino, C ⁇ - 3 alkylamino or di- (C ⁇ -3 - alkyl) amino group and the nitrogen atom of the pyrrolyl ring optionally by a C ⁇ _ 3 alkyl group is substituted, or
  • R ⁇ is an aminocarbonyl, C 4 alkylamino carbonyl, N (C 3 alkyl) C 3 alkylamino carbonyl, Cs ⁇ cycloalkylamino carbonyl, N (C 5 alkyl) ) -C 5 - 6 -cycloalkylamino-carbonyl group,
  • a C ⁇ . 3 -Alkylaminocarbonyl- or N- (-C ⁇ - 3 -alkyl) -C ⁇ - 3 -alkylaminocarbonyl in which one or two alkyl parts independently of one another by a carbamoyl, N- (-C ⁇ . 3 -alkyl) carbamoyl, di-N- (C ⁇ - 3 -alkyl) -carbamoyl, C ⁇ - 3 alkoxycarbonyl group or in 2- or 3-position by an amino, (C ⁇ .
  • R 5 is a hydrogen atom or a C 3 alkyl group
  • the saturated alkyl and alkoxy parts present in the groups defined above which contain more than 2 carbon atoms including their branched isomers, such as, for example, the isopropyl, tert-butyl, isobutyl group,
  • X is an oxygen atom
  • Ri and R 5 each represent a hydrogen atom
  • R 2 is a methoxycarbonyl group
  • R 3 is a phenyl group and R 4 is a phenyl group which is monosubstituted in the 3- or 4-position by the Re group, where
  • the new compounds are obtained, for example, by the following processes which are known in principle from the literature:
  • X and R 3 are defined as mentioned at the beginning,
  • R 2 ' has the meanings mentioned above for R 2 ,
  • Ris is a hydrogen atom or a protecting group for the nitrogen atom of the
  • Lactam group where one of the radicals R 2 'and R- ⁇ 8 can also represent a bond to a solid phase which may be formed via a spacer and the other of the radicals R 2 ' and Ris has the meanings mentioned above, and Z 1
  • Halogen atom a hydroxy, alkoxy or arylalkoxy group, e.g. a chlorine or
  • 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 or imino 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'-dimethoxyphenylaminomethyl) phenoxy resin, the binding advantageously taking place via the amino group, or a p- Benzyloxybenzyl alcohol resin, the binding advantageously taking place via an intermediate member such as a 2,5-dimethoxy-4-hydroxy-benzyl derivative.
  • 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. carried out, a 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.
  • a protective group used can be split off simultaneously as a result of transamidation.
  • the reaction is preferably carried out in the presence of an inert base at temperatures between 20 and 120 ° C.
  • Zi in a compound of the general formula VII denotes a hydroxyl, alkoxy or arylalkoxy 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, 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.
  • a solid phase used is preferably cleaved off using trifluoroacetic acid and water at temperatures between 0 and 35 ° C., preferably at room temperature.
  • Ri and R 3 to R 5 are defined as mentioned above, or their reactive
  • Rt 9 is a Ytnearer or branched C ⁇ - 6 alkanol, a C 4-7 cycloalkanol or an aromatic alcohol.
  • the esterification 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 reaction with a corresponding 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-di- methoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N.N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N.N'-dicyclohexylcarbol diimide (N.N'-dicyclohexylcarbodiimide 1 H-benzotriazol-1 -yl) -1, 1, 3,3-tetramethyluronium tetrafluoroborate, 2- (1 H-benzotriazol-1 -yl) -1,
  • the subsequent hydrolysis is preferably carried out in an aqueous solvent, e.g. in water, methanol / water, ethanol / 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, methanol / water, ethanol / 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
  • 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 hydrogen Presence of Raney nickel, platinum or palladium / carbon, or in the presence of a metal hydride such as sodium borohydride, Lithium borohydride, sodium cyanoborohydride 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
  • an acid such as hydrochloric
  • the subsequent acylation or sulfonylation is advantageously carried out with the corresponding free acid or a corresponding reactive compound such as its anhydride, ester, imidazolide or halide, preferably in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulfoxide or dimethylformamide, optionally in the presence of a inorganic or a tertiary organic base at temperatures between -20 and 200 ° C, 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 reaction with the free acid may optionally be in the presence of an acid activating agent or a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonic acid, trimethyl orthoacetic acid, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylnodimidodimidodimidium carbodiimide, nododicyclide, carbodiimide, nodoxydimide, carbodiimide, carbodiimide, carbodiimide, carbodiimide, carbodiimide, nodicyclide, carbodiimide, carbodiimide, carbodiimide, nodicyclide, carbodiimide, carbodiimide, carbodiimide, nodi
  • the reaction with a corresponding reactive compound can optionally in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine or when using an anhydride in the presence of the corresponding acid at temperatures between 0 and 150 ° C. preferably at temperatures between 50 and 100 ° C.
  • a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine
  • the subsequent esterification or amidation is advantageously carried out by reacting a reactive corresponding carboxylic acid derivative with an appropriate 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
  • a corresponding urea compound of the general formula I is advantageously carried out with an inorganic cyanate or a corresponding isocyanate or carbamoyl chloride, preferably in a solvent such as dimethylformamide and optionally in the presence of a tertiary organic base such as triethylamine at temperatures between 0 and 50 ° C., preferably at Room temperature.
  • a solvent such as dimethylformamide
  • a tertiary organic base such as triethylamine
  • Amide / nogroup compound such as 3,5-dimethylpyrazole-1-carboxylic acid amidine preferably in a solvent such as dimethylformamide and optionally in the presence of a tertiary organic base such as triethylamine at temperatures between 0 and 50 ° C, preferably at room temperature ,
  • any reactive groups present such as carboxy, hydroxyl, 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 carboxy group as a protective radical for a hydroxyl, 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 additionally 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 cleaved 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 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
  • 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.
  • Butyloxycarbonylrest.es is preferably carried out 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.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • 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 and by known methods (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)
  • 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, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols, and Separation of 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 such as esters or amides, for example 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.
  • optically more active Alcohol is, for example, (+) - or (-) - menthol
  • the optically active acyl radical in amides is, 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, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid or methanesulfonic acid.
  • the new compounds of formula I thus obtained contain a carboxy group, they 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.
  • Bases which can be used here are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the new compounds of the general formula I in which Ri 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, VEGFR3, PDGFR, PDGFRß, FGFR1, FGFR3, EGFR, HER2, IGF1R and HGFR, as well as on complexes of CDKs (Cyclin Dependent Kinases) such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific
  • Cyclins (A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K) and on viral cyclin, on the proliferation of cultured human cells, especially those of endothelial cells Rows, for example in angiogenesis, but also on the proliferation of other cells, especially tumor cells.
  • Human umbilical cord endothelial cells were in IMDM (Gibco BRL), supplemented with 10% fetal bovine serum (FBS) (Sigma), 50 ⁇ M ß-mercaptoeethanol (Fluka), standard antibiotics, 15 ⁇ g / ml endothelial cell growth factor (ECGS, Collaborative Biomedical Products) and 100 ⁇ g / ml heparin (Sigma) on gelatin-coated culture bottles (0.2% gelatin, Sigma) at 37 ° C, 5% CO2 in a water-saturated atmosphere.
  • FBS fetal bovine serum
  • Fluka ß-mercaptoeethanol
  • standard antibiotics 15 ⁇ g / ml endothelial cell growth factor
  • ECGS Endothelial cell growth factor
  • heparin 100 ⁇ g / ml heparin
  • the cells were "starved” for 16 hours, ie kept in culture medium without growth factors (ECGS + heparin).
  • the cells were detached from the culture bottles using trypsin / EDTA and washed once in serum-containing medium. Then 2.5 ⁇ 10 3 cells were sown per well.
  • VEGF165 vascular endothelial growth factor
  • the compounds according to the invention were dissolved in 100% dimethyl sulfoxide and added to the cultures as triple determinations in various dilutions, the maximum dimethyl sulfoxide concentration being 0.3%.
  • the cells were incubated for 76 hours at 37 ° C., then 3 H-thymidine (0.1 ⁇ Ci / well, Amersham) was added for a further 16 hours in order to determine the DNA synthesis.
  • the radioactively labeled cells were then immobilized on filter mats and the radioactivity incorporated was determined in a ß-counter.
  • the mean value of the non-stimulated cells was determined from the mean value of the Factor-stimulated cells (in the presence or absence of the compounds of the invention) subtracted.
  • the relative cell proliferation was calculated as a percentage of the control (HUVEC without inhibitor) and the drug concentration, which inhibits cell proliferation by 50% (IC50), was derived.
  • the compounds of general formula I are suitable for the treatment of diseases in which the proliferation of cells, in particular that of endothelial cells, plays a role.
  • endothelial cells and the associated neovascularization represent a crucial step in tumor progression (Folkman J. et al., Nature 339, 58-61, (1989); Hanahan D. and Folkman J., Cell 86, 353 -365, (1996)).
  • the proliferation of endothelial cells is also important in hemangiomas, metastasis, rheumatoid arthritis, psoriasis and ocular neovascularization (Folkman J., Nature Med. 1, 27-31, (1995)).
  • the therapeutic benefit of inhibitors of endothelial cell proliferation has been described in the animal model, for example by O'Reilly et al. and Parangi et al. (O'Reilly MS et al., Cell 88, 277-285, (1997); Parangi S. et al., Proc Natl Acad Sei USA 93, 2002-2007, (1996)).
  • the compounds of the general formula I, their tautomers, their stereoisomers or their physiologically tolerable salts are thus suitable, for example, for the treatment of tumors (e.g. squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, bladder cancer, neck and neck cancer, Melanoma, ovarian carcinoma, prostate carcinoma, breast cancer, small cell lung carcinoma, glioma, colorectal carcinoma, urogenital cancer and gastrointestinal carcinoma as well as haematological cancers, such as multiple myeloma), psoriasis, arthritis (e.g.
  • tumors e.g. squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, bladder cancer, neck and neck cancer, Melanoma, ovarian carcinoma, prostate carcinoma, breast cancer, small cell lung carcinoma, glioma, colorectal carcinoma, ur
  • rheumatoid arthritis angiopathy
  • hemi-angioma hemiangioma
  • hemi-angioma hemi-angioma
  • neovascular glaucoma kidney diseases (eg glomerulonephritis), diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndromes, transplant rejection and glomerulopathy, fibrotic diseases (eg cirrhosis of the liver), mesangial cell proliferative diseases, injuries degenerative nerve tissue and to inhibit the reocclusion of vessels after balloon catheter treatment, in vascular prosthetics or after the insertion of mechanical devices to keep vessels open (e.g. Stents), or other diseases in which cell proliferation or angiogenesis play a role.
  • kidney diseases eg glomerulonephritis
  • diabetic nephropathy malignant nephrosclerosis
  • thrombic microangiopathic syndromes transplant rejection and glomerulopathy
  • the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutic agents, for example in combination with topoisomerase inhibitors (for example Etoposides), mitotic inhibitors (e.g. vinblastine, taxol), compounds interacting with nucleic acids (e.g. cis-platinum, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons ), Kinase inhibitors, antibodies, or in combination with radiation therapy etc. These combinations can be administered either simultaneously or sequentially.
  • topoisomerase inhibitors for example Etoposides
  • mitotic inhibitors e.g. vinblastine, taxol
  • compounds interacting with nucleic acids e.g. cis-platinum, cyclophosp
  • the compounds according to the invention are generally used in warm-blooded vertebrates, in particular in humans, in doses of 0.01-100 mg / kg of body weight, preferably at 0.1-20 mg / kg.
  • these are mixed with one or more conventional inert carriers and / or diluents, e.g.
  • TBTU O- (benzotriazol-1-yl) -N, N, N ', N'-bis (tetramethylene uronium hexafluorophosphate
  • HOBt 1-hydroxy-1 H-benzotriazole
  • 6-carboxylic acid methyl ester Made from 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4-amino-N, N-dimethylbenzamide.
  • Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for injections.
  • Active ingredient and mannitol are dissolved in water. After filling, freeze-drying.
  • the ready-to-use solution is dissolved with water for injections.
  • composition (1) Active ingredient 350.0 mg
  • Preparation (1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with a facet on both sides and a partial notch on one side. Tablet diameter: 12 mm.
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
  • (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 0 hard gelatin capsules on a capsule filling machine.
  • 1 suppository contains: active ingredient 100.0 mg
  • Polyethylene glycol (M.G. 1500) 600.0 mg
  • the polyethylene glycol is melted together with polyethylene sorbitan monostearate. At 40 ° C, the ground active substance is melted homogeneously dispersed. It is cooled to 38 ° C and poured into weakly pre-cooled suppository molds.

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  • Chemical & Material Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP02735201A 2001-04-06 2002-03-30 In 6-stellung substituierte indoline und ihre verwendung als kinase-inhibitoren Withdrawn EP1379501A1 (de)

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DE10117204A DE10117204A1 (de) 2001-04-06 2001-04-06 In 6-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
DE10117204 2001-04-06
PCT/EP2002/003583 WO2002081445A1 (de) 2001-04-06 2002-03-30 In 6-stellung substituierte indoline und ihre verwendung als kinase-inhibitoren

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DE10233500A1 (de) * 2002-07-24 2004-02-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg 3-Z-[1-(4-(N-((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylen]-6-methoxycarbonyl-2-indolinon-Monoethansulfonat und dessen Verwendung als Arzneimittel
US7148249B2 (en) * 2002-09-12 2006-12-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Indolinones substituted by heterocycles, the preparation thereof and their use as medicaments
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
PE20061155A1 (es) * 2004-12-24 2006-12-16 Boehringer Ingelheim Int Derivados de indolinona como agentes para el tratamiento o la prevencion de enfermedades fibroticas
PE20060777A1 (es) 2004-12-24 2006-10-06 Boehringer Ingelheim Int Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas
US20060154939A1 (en) * 2004-12-24 2006-07-13 Boehringer Ingelheim International Gmbh Medicaments for the Treatment or Prevention of Fibrotic Diseases
WO2007057397A1 (en) * 2005-11-15 2007-05-24 Boehringer Ingelheim International Gmbh Treatment of cancer
EP2212297B1 (en) 2007-10-12 2011-05-25 Ingenium Pharmaceuticals GmbH Inhibitors of protein kinases
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US20170065529A1 (en) 2015-09-09 2017-03-09 Boehringer Ingelheim International Gmbh Pharmaceutical dosage form for immediate release of an indolinone derivative
US8344018B2 (en) * 2008-07-14 2013-01-01 Gilead Sciences, Inc. Oxindolyl inhibitor compounds
UY32010A (es) * 2008-07-29 2010-02-26 Boehringer Ingelheim Int Nuevas indolinonas, composiciones conteniéndolas y aplicaciones
EP2545037A1 (en) 2010-03-10 2013-01-16 Ingenium Pharmaceuticals GmbH Inhibitors of protein kinases
CN102267934B (zh) * 2010-06-02 2013-04-17 金凯美(大连)医药科技有限公司 一种6-甲氧羰基吲哚酮的制备方法
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ECSP034776A (es) 2003-12-01
DE10117204A1 (de) 2002-10-10
BR0208900A (pt) 2004-04-20
AR035813A1 (es) 2004-07-14
CA2442695A1 (en) 2002-10-17
EA200301005A1 (ru) 2004-04-29
US20030092756A1 (en) 2003-05-15
US6858641B2 (en) 2005-02-22
JP2004525173A (ja) 2004-08-19
WO2002081445A1 (de) 2002-10-17
ZA200307306B (en) 2004-08-31
MXPA03008896A (es) 2003-12-08
PL366458A1 (en) 2005-02-07
SK12412003A3 (sk) 2004-04-06
IL158254A0 (en) 2004-05-12
CZ20032975A3 (cs) 2004-02-18
NO20034434D0 (no) 2003-10-03
HUP0303737A2 (hu) 2004-03-01
BG108220A (bg) 2004-09-30
HUP0303737A3 (en) 2004-09-28
NO20034434L (no) 2003-10-03
EE200300491A (et) 2004-02-16
CN1509270A (zh) 2004-06-30
KR20030090712A (ko) 2003-11-28

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