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WO1999051590A1 - Indolinones substituees utilisees comme inhibiteurs de kinases - Google Patents

Indolinones substituees utilisees comme inhibiteurs de kinases Download PDF

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Publication number
WO1999051590A1
WO1999051590A1 PCT/EP1999/002186 EP9902186W WO9951590A1 WO 1999051590 A1 WO1999051590 A1 WO 1999051590A1 EP 9902186 W EP9902186 W EP 9902186W WO 9951590 A1 WO9951590 A1 WO 9951590A1
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WIPO (PCT)
Prior art keywords
indolinone
nitro
phenyl
methyl
imidazol
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PCT/EP1999/002186
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German (de)
English (en)
Inventor
Wolfgang Grell
Rainer Walter
Armin Heckel
Frank Himmelsbach
Helmut Wittneben
Jacobus C. A. Van Meel
Norbert Redemann
Robert Haigh
Original Assignee
Boehringer Ingelheim Pharma Kg
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Application filed by Boehringer Ingelheim Pharma Kg filed Critical Boehringer Ingelheim Pharma Kg
Priority to AU37034/99A priority Critical patent/AU3703499A/en
Publication of WO1999051590A1 publication Critical patent/WO1999051590A1/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
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • 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
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • p21 mainly regulates transcription. p21 transcription is induced by the tumor suppressor gene p53, a transcriptional regulator that mediates the stopping of the cell cycle after DNA damage or in case of senescence. Basal concentrations of p21 may represent a threshold that must be exceeded before complexes can become active. Transcriptional control may also be important for pisI N K 4 B, the expression of which is greatly increased when treated with the negative growth factor TGFß. An additional effect of TGFß appears to be the release of p27, which is located in a heat-labile compartment. p27 is also likely to be involved in the effects of positive growth factors. For example, interleukin-2 stimulation appears to induce a decrease in the concentration of p27 and thereby the proliferation of T cells.
  • chromosome 9p21-22 The loss of chromosome 9p21-22 is of particular interest.
  • a gene with the name CDKN2 (MTS1, multiple tumor suppressor gene 1) is localized, which encodes a pl6 protein.
  • MTS1 multiple tumor suppressor gene 1
  • the pl6 protein binds to CDK4 and CDK6 and thereby inhibits their interaction with D-cyclins. Damage or mutations in the pl6 gene may influence the relative balance of functional pl6 and cyclin D, which leads to unregulated CDK activity and abnormal cell growth.
  • Deregulated CDK activity can therefore result from: (a) mutation or excessive expression of the kinase; (b) induced expression, overexpression or slow degradation of cyclins; (c) functional inactivation of CKIs by gene "silencing", damage or mutation; or (d) a combination of these phenomena.
  • the result of these deviations is a deregulated cell cycle with deregulated cell division that causes various diseases or contributes to their progression.
  • R ] _ is a hydrogen, fluorine, chlorine, bromine or iodine atom, a nitro, amino, C ⁇ __ 4 alkanoylamino, (C; L_5-alkoxy) carbonylamino or benzyloxycarbonylamino group,
  • a C ⁇ _5-alkyl group by an amino, phthalimido, C ⁇ __5-alkylamino, C 3 _ 7 -cycloalkylamino-, C 3 _ 4 -alkenylamino-, benzylamino-, di- (C ⁇ _5-alkyl) -amino-, C2 -6-Alkylenimino-, di- (C 3 _ 4 ⁇ alkenyl) -amino-, N- (C ⁇ ._5-alkyl) -N- (C 3 _ 4 -alkenyl) -amino-, N- (C ⁇ __5-alkyl ) -N-benzylamino-, C 1 _ 4 -alkanoylamino-, (C ⁇ __5-alkoxy) carbonylamino-, benzyloxycarbonylamino-, N- (C ⁇ _ 4 -alkanoyl) - N ⁇
  • R a and R which may be the same or different, each represent a hydrogen atom or a methyl group
  • R c is a hydrogen atom, a (C; ⁇ _.5-alkoxy) carbonyl- C ⁇ _5-alkyl or benzyloxycarbonyl-C ⁇ _ 5 alkyl group and
  • R d is a hydrogen atom, a C 5 alkyl, C ⁇ . -Alkanoyl-, (C ⁇ _ 5 -alkoxy) carbonyl or benzyloxycarbonyl group, and
  • Het is a 5-membered heteroaromatic ring containing a nitrogen atom or a nitrogen atom and an oxygen, sulfur or nitrogen atom, the aforementioned ring also by a C ⁇ .. 5 alkyl, C 5 _ 7 -cycloalkyl -, Ph ⁇ nyl-, phenyl-C ⁇ __ 3 -alkyl-, amino-, C ⁇ . -Alkanoylamino, (C__5-alkoxy) carbonylamino or benzyloxycarbonylamino group and can also be substituted by a further C 1 -C 5 -alkyl group,
  • a 5-membered dihydrogenated heteroaromatic ring which contains a nitrogen atom or a nitrogen atom and an oxygen, sulfur or nitrogen atom, the ring mentioned above also being substituted by one or two C ⁇ _5-alkyl groups and can contain a carbonyl group and additionally on a ring nitrogen atom may be substituted by a (C ⁇ . 5 alkoxy) carbonyl or benzyloxycarbonyl,
  • a 5-membered tetrahydrated heteroaromatic ring which contains a nitrogen atom the ring mentioned above additionally by one or two C] __ 5-al yl groups a hydroxyl, carboxy, (C ⁇ __5-alkoxy) carbonyl or aminocarbonyl group can be substituted and can also contain one or two carbonyl groups,
  • R ⁇ _ is a hydrogen, fluorine, chlorine or bromine atom, a nitro, amino, C ⁇ __ 4 alkanoylamino, (C ⁇ __ 5 alkoxy) carbonylamino or benzyloxycarbonylamino group,
  • R2 is a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano, aminocarbonyl, nitro or amino group,
  • D and Het are defined as mentioned above and A represents a bond, a C ⁇ _ 3 alkylene, C ⁇ __ 3 alkylidene, C2 -3 alkenylene or C2_ 3 alkenylidene group, with a hydrogen atom, the rest of Het the carbon atom of the linking point is bonded, together with an ⁇ -hydrogen atom of the radical A can also be replaced by a further carbon-carbon bond,
  • R ⁇ is a hydrogen atom or a nitro group
  • R 2 is a hydrogen or chlorine atom, a methyl, trifluoromethyl, cyano, aminomethyl, aminoethyl or phthalimido group, a methyl or ethyl group, each represented by a methylamine, dimethylamino, ethylamino, diethylamino -, Pyrrolidino, piperidino, ⁇ -oxo-pyrrolidino, ⁇ -oxo-piperidino, acetylamino, methoxycarbonylamino, ethoxycarbonylamino, benzyloxycarbonylamino, N-acetyl-N-methylamino, N-methoxycarbonyl -N-methyl-amino, N-ethoxycarbonyl-N-methyl-amino, N-benzyloxycarbonyl-N-methyl-aminomethyl, 2- (N-benzyloxycarbonyl-N-methyl-amino) -ethy
  • R 3 is 1-methyl-2-oxo-2, 3-dihydro-1H-benzimidazol-5-yl-, 1,2,3, 4-tetrahydro-isoquinolin-6-yl-, 2-acetyl-1,2 , 3, 4-tetra-hydro-isoquinolin-6-yl-, 2-acetyl-l, 2, 3, 4-tetrahydro-isochi nolin-7-yl-, 2-ethyl-1,2,3, -tetrahydro-isoquinolin-6-yl-, 2-ethyl-1, 2, 3, 4 -tetrahydro-isoquinolin-7-yl-, 4- (Imidazol-2-yl) phenyl-, 4- (1-methyl-imidazol-2-yl) -phenyl-, 4- (imidazol-4-yl) -phenyl-, 4- (l-methyl-imidazole- 4-yl) phenyl-, 4- (1-methylimidazol-5
  • R 1 is a hydrogen atom or a 5-position nitro group
  • R2 represents a hydrogen atom, a methyl or trifluoromethyl group
  • R 3 is 4- (1-methyl-imidazol-2-yl) phenyl, 4- (imidazol-4-yl) phenyl, 4- (imidazol-5-yl) phenyl, 4- (l -Methyl-imidazol-4-yl) -phenyl-, 4- (1-methyl-imidazol-5-yl) -phenyl-, 4- (2-methyl-imidazol-4-yl) -phenyl-, 4 - (2-Acetylamino-imidazol-4-yl) phenyl-, 4- [(2,4-dioxo-imidazolidin-5-ylidene) methyl] phenyl-, 4- [(1-pyrrolidinyl) methyl ] -phenyl-, 4- [2- (imidazol-4-yl) ethenyl] phenyl or 1, 2, 3, 4-tetrahydro-isoquinolin-6-yl group,
  • R ⁇ _ and R2 are defined as mentioned above, R 4 is a hydrogen atom or a protective group for the nitrogen atom of the lactam group and
  • 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,
  • an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
  • a primary or secondary organic base such as 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.
  • R2 represents one of the substituted alkenyl radicals mentioned at the beginning for R2, in the presence of a suitable noble metal-containing catalyst and, if necessary, subsequent cleavage of a protective group used for the nitrogen atom of the lactam group.
  • the Heck reaction is advantageously carried out under protective gas, for example under nitrogen or argon, if appropriate in a pressure vessel and advantageously in a solvent such as acetonitrile, dimethylformamide or N-methyl-pyrrolidin-2-one at temperatures between 20 and 180 ° C., preferably at temperatures between 80 and 150 ° C, carried out.
  • protective gas for example under nitrogen or argon
  • a solvent such as acetonitrile, dimethylformamide or N-methyl-pyrrolidin-2-one
  • the subsequent splitting off of a protective group that may be required is expediently carried out either hydrolytically in an aqueous or alcoholic solvent, for example in methanol / water, ethanol / water, isopropanol / water, tetrahydrofuran / water, dioxane / water, dimethylformamide / water, methanol or ethanol in the presence an alkali base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or sodium acetate at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C,
  • a 1 represents a C 2 - 4 "alkenylene group, in the presence of a suitable noble metal-containing catalyst and, if necessary, subsequent cleavage of a protective group used for the nitrogen atom of the lactam group.
  • 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, potassium hydroxide or sodium acetate at temperatures between 0 and 100 ° C., preferably at temperatures between 10 and 50 ° C,
  • a primary or secondary organic base such as 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 see 0 and 100 ° C, preferably carried out at temperatures between 10 and 50 ° C.
  • R 2 R 4 un ⁇ ⁇ w ⁇ e mentioned at the outset A' R l is a bond or an alkylene group, and R5 C ⁇ _ 4 is an alkyl group such as methyl or ethyl, represent
  • an ethylenediamine which can be substituted on one of the nitrogen or carbon atoms or on one of the nitrogen atoms and on one of the carbon atoms by a C ⁇ _5-alkyl group and, if necessary, subsequent removal of a protective group used for the nitrogen atom of a lactam group.
  • the reaction is advantageously carried out in a solvent such as diethyl ether, methanol or ethanol, but preferably in an excess of the ethylenediamine used at a temperature of temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.
  • a solvent such as diethyl ether, methanol or ethanol
  • 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, Dirnethylforrnamid / 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,
  • an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
  • a primary or secondary organic base such as 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.
  • a compound of the general formula I in which R2 represents a cyano, cyanoalkyl or cyanoalkenyl group this can be converted into a corresponding aminomethyl or aminoalkyl compound by means of reduction, preferably by means of catalytic hydrogenation, or a compound of the general formula I in which R 2 represents a cyano, cyanoalkyl or cyanoalkenyl group, this can be converted into a corresponding aminocarbonyl, aminocarbonylalkyl or aminocarbonylalkenyl compound by means of hydration, or
  • R 3 represents a phthalimido residue which is substituted by a (C ⁇ _ 5 -alkoxy) carbonyl-C ⁇ _5-alkyl or benzyloxycarbonyl-C ⁇ _5-alkyl group
  • this can be by means of acidolysis or hydrogenolysis in a corresponding carboxy compound can be converted, or
  • Het represents one of the aforementioned groups for Het which is substituted on a ring nitrogen atom by a (C ⁇ _ 5 alkoxy) carbonyl group or benzyloxycarbonyl group, this can by acidolysis or hydrogenolysis into a corresponding NH connection.
  • the subsequent hydrazinolysis is preferably carried out in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane, but particularly advantageously in hydrazine hydrate as the solvent, at temperatures between 20 and 120 ° C., preferably at the boiling point of the solvent used.
  • a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane, but particularly advantageously in hydrazine hydrate as the solvent, at temperatures between 20 and 120 ° C., preferably at the boiling point of the solvent used.
  • the subsequent hydrogenolysis is preferably carried out by means of catalytic hydrogenation with hydrogen in the presence of a catalyst such as palladium / carbon or platinum 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 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 platinum
  • a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid
  • an acid such as hydrochloric acid
  • 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 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-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorophlorochloride, phosphorus phosphorus , N '-dicyclohexylcarbodiimide, N, N' -dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N '-dicyclohexylcarbodiimide / l-hydroxy-benzotriazole, 2- (IH-benzotriazol-l-yl) -1.1, 3, 3-tetramethyluronium tetrafluoroborate, 2- (IH-benzotriazol-l-yl) -1,1,
  • the subsequent dehalogenation is preferably carried out by means of catalytic hydrogenation with hydrogen in the presence of a catalyst such as palladium / carbon or platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dirnethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as glacial acetic acid or a base such as sodium umbicarbonate or triethylamine 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 platinum
  • a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dirnethylformamide / acetone or glacial acetic acid
  • an acid such as glacial acetic acid or a base such as sodium umbicarbonate or triethylamine at temperatures
  • 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, dirnethylformamide / 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, dirnethylformamide / acetone or glacial acetic acid
  • an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50 ° C.
  • 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 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, in particular acids and their activated derivatives or alcohols, with the racing compound and separating the mixture of diastereomeric salts or derivatives obtained in this way, for example on the basis of different solubilities, the free antipodes being obtained from the pure diastereomeric salts or derivatives by the action of suitable agents. tel can be released.
  • 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, calcium sulfonic acid, glutamic acid, N-acetyl-glutamic 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 or maleic acid.
  • the new compounds of the formula I obtained in this way 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 sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the new compounds of the general formula I have valuable pharmacological properties, in particular inhibitory effects on various kinases and cyclin / CDK complexes, on the proliferation of cultured human tumor cells and on growth after oral administration of tumors in nude mice infected with human tumor cells.
  • the biological compounds were tested for their biological properties in the following tests, for example:
  • Tnh-ib-ie-nmg of Cyr ⁇ i n / CDK enzyme Activity in vit-.rn High Five TM insect cells (BTI-TN-5B1-4) 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, PlO enhancer promoter), GST-tagged cyclins (eg Cyclin Dl or Cyclin D3) with the corresponding Hisg-tagged CDK subunit ( 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 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 multi-well mixed with 5% TCA (trichloroacetic acid) in hydrophobic PVDF Microtiter plates (Millipore) or precipitated 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 0 values for enzyme inhibition were calculated.
  • 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.
  • a kinase inhibitor was administered orally daily (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.
  • Such diseases include (without claim to completeness): viral infections (e.g. HIV and Kaposi sarcoma); Inflammation and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and / or parasitic infections; Leukemia, lymphoma and solid tumors; Skin disorders (e.g. 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.
  • proliferating cells e.g. hair, intestinal, blood and progenitor cells
  • 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 inert carriers and / or diluents, e.g.
  • TBTU 0- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyl uronium tetrafluoroborate
  • Example B The mixture obtained in Example B consisting of 66% l-acetyl-3- ⁇ l-ethoxy-l-phenylmethylidene ⁇ -2-indolinone and 34% 1-acetyl-2-indolinone is suspended in ethanol (8 ml / g), added 2 equivalents of 4N sodium hydroxide solution and stirred at room temperature for 1.5 hours. After adding water (25 ml / g), the precipitate is filtered off, washed with water and a little ether and dried at 80 ° C.
  • Example 10 Prepared analogously to Example 10 (a) from l-acetyl-5-nitro-2-indoline and 4-methyl-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hünig's base (20 ° C, overnight) and final cleaning by column chromatography on silica gel with CH2CI2 as the eluent.
  • Example 10 Prepared analogously to Example 10 (a) from l-acetyl-2-indolinone and 4-bromo-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hünig's base (20 ° C, overnight) and final purification by column chromatography on silica gel with CK2Cl 2 / MeOH
  • Example 10 Prepared analogously to Example 10 (a) from l-acetyl-5-nitro-2-indoline and 4-bromo-benzoic acid in dry DMF in the presence of TBTU, HOBT and Hünig's base (20 ° C, overnight) and evaporation in Vacuum.
  • a sample of the crude product obtained was purified by column chromatography on silica gel with CH 2 Cl2 / MeOH (20: 1) as the eluent.
  • Example 10 Prepared analogously to Example 10 (a) from l-acetyl-5-nitro-indolinone and 4- (imidazol-1-yl-methyl) benzoic acid in dry DMF in the presence of TBTU, HOBT and Hünig's base.
  • Example 11.4 Prepared analogously to Example 11.4 (b) by reacting 1-acetyl-3- (l-hydroxy-1- [4- (imidazol-1-yl-methyl) phenyl] methylidene ⁇ - 5-nitro-2-indolinone with PCI5 in toluene and then with 4- (IH-imidazol -4-yl) aniline and triethylamine in THF.Yield: 25% of theory; melting point: 230-235 ° C; C 28 H 21 N 7 0 3 (503.53)
  • Example 10 Prepared analogously to Example 10 (a) from 1-acetyl-2-indolinone and 4-phthalimidomethylbenzoic acid (melting point: 260-262 ° C) in dry DMF in the presence of TBTU, HOBT and Hünig's base (20 ° C, 4 hours) , Stir in dilute hydrochloric acid, extraction with CH2CI2, evaporation of the dried organic extract in vacuo, trituration of the evaporation residue with EtOAc and drying of the solid substance. Yield: 69% of theory; Melting point: 200-201 ° C; Enol reaction (with FeCl 3 solution in EtOH): positive.
  • Example 11 Prepared analogously to Example 11 (b) from the obtained under (a) enol with 2 equivalents of PC1 5 in toluene (100 ° C / l hour) and evaporated to incipient turbidity in vacuo, treated with petroleum ether, the precipitate formed, washing him with petroleum ether and dry it at 75 ° C in a vacuum.

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Abstract

L'invention concerne des indolinones de formule générale (I) dans laquelle R1 à R3 sont tels que définis dans la revendication 1, leurs isomères et leurs sels, en particulier leurs sels physiologiquement compatibles présentant des propriétés pharmacologiques précieuses, notamment un effet inhibiteur sur différentes kinases et différents complexes cycline/CDK, ainsi que sur la prolifération de différentes cellules tumorales. L'invention concerne en outre des médicaments renfermant ces composés, leur utilisation et leur procédé de fabrication.
PCT/EP1999/002186 1998-04-03 1999-03-30 Indolinones substituees utilisees comme inhibiteurs de kinases WO1999051590A1 (fr)

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AU37034/99A AU3703499A (en) 1998-04-03 1999-03-30 Substituted indolinones as kinase inhibitors

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DE19815020A DE19815020A1 (de) 1998-04-03 1998-04-03 Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel

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WO2000064872A1 (fr) * 1999-04-23 2000-11-02 Vertex Pharmaceuticals Incorporated Inhibiteurs des c-jun n-terminal kinases (jnk)
EP1103552A4 (fr) * 1998-08-07 2003-01-15 Takeda Chemical Industries Ltd Derives de benzothiepine, leur procede de preparation et leurs utilisations
US6818632B2 (en) 1999-03-04 2004-11-16 Smithkline Beecham Corporation 3-(anilinomethylene)oxindoles
WO2006114371A1 (fr) * 2005-04-28 2006-11-02 Boehringer Ingelheim International Gmbh Nouveaux composes destines au traitement de maladies inflammatoires
US7612065B2 (en) 2000-04-21 2009-11-03 Vertex Pharmaceuticals Incorporated Inhibitors of c-JUN N-terminal kinases (JNK)
CN111269192A (zh) * 2020-02-25 2020-06-12 成都睿智化学研究有限公司 一种5-羟甲基四氮唑及其衍生物的合成方法
CN115703758A (zh) * 2021-08-12 2023-02-17 中国医学科学院药物研究所 一类用作激酶抑制剂的化合物及其制备方法和用途

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US6624171B1 (en) 1999-03-04 2003-09-23 Smithkline Beecham Corporation Substituted aza-oxindole derivatives
JP3952369B2 (ja) * 1999-08-27 2007-08-01 ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト 新規な置換インドリノン類、その製造及びその薬剤としての使用
DE19949209A1 (de) * 1999-10-13 2001-04-19 Boehringer Ingelheim Pharma In 5-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
US6762180B1 (en) 1999-10-13 2004-07-13 Boehringer Ingelheim Pharma Kg Substituted indolines which inhibit receptor tyrosine kinases
UA75054C2 (uk) * 1999-10-13 2006-03-15 Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг Заміщені в положенні 6 індолінони, їх одержання та їх застосування як лікарського засобу
PE20060777A1 (es) 2004-12-24 2006-10-06 Boehringer Ingelheim Int Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1103552A4 (fr) * 1998-08-07 2003-01-15 Takeda Chemical Industries Ltd Derives de benzothiepine, leur procede de preparation et leurs utilisations
US6818632B2 (en) 1999-03-04 2004-11-16 Smithkline Beecham Corporation 3-(anilinomethylene)oxindoles
US7129253B2 (en) 1999-03-04 2006-10-31 Smithkline Beecham Corporation Compounds
WO2000064872A1 (fr) * 1999-04-23 2000-11-02 Vertex Pharmaceuticals Incorporated Inhibiteurs des c-jun n-terminal kinases (jnk)
US7612065B2 (en) 2000-04-21 2009-11-03 Vertex Pharmaceuticals Incorporated Inhibitors of c-JUN N-terminal kinases (JNK)
EA013239B1 (ru) * 2005-04-28 2010-04-30 Бёрингер Ингельхайм Интернациональ Гмбх Новые соединения для лечения воспалительных заболеваний
WO2006114371A1 (fr) * 2005-04-28 2006-11-02 Boehringer Ingelheim International Gmbh Nouveaux composes destines au traitement de maladies inflammatoires
US7723381B2 (en) 2005-04-28 2010-05-25 Boehringer Ingelheim International Gmbh Compounds for the treatment of inflammatory diseases
US8173699B2 (en) 2005-04-28 2012-05-08 Boehringer Ingelheim International Gmbh Compounds for the treatment of inflammatory diseases
AU2006239389B2 (en) * 2005-04-28 2012-06-28 Boehringer Ingelheim International Gmbh Novel compounds for treating inflammatory diseases
CN111269192A (zh) * 2020-02-25 2020-06-12 成都睿智化学研究有限公司 一种5-羟甲基四氮唑及其衍生物的合成方法
CN115703758A (zh) * 2021-08-12 2023-02-17 中国医学科学院药物研究所 一类用作激酶抑制剂的化合物及其制备方法和用途
CN115703758B (zh) * 2021-08-12 2024-03-26 中国医学科学院药物研究所 一类用作激酶抑制剂的化合物及其制备方法和用途

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