WO2003027109A1 - 3-(heteroarylamino)methylene-1, 3-dihydro-2h-indol-2-ones as kinase inhibitors - Google Patents

3-(heteroarylamino)methylene-1, 3-dihydro-2h-indol-2-ones as kinase inhibitors Download PDF

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WO2003027109A1
WO2003027109A1 PCT/US2002/029630 US0229630W WO03027109A1 WO 2003027109 A1 WO2003027109 A1 WO 2003027109A1 US 0229630 W US0229630 W US 0229630W WO 03027109 A1 WO03027109 A1 WO 03027109A1
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group
alkyl
compound
hydrocarbyl
integer
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French (fr)
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Steven W. Andrews
Julie A. Wurster
Iii C. Eugene Hull
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Allergan, Inc.
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    • 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
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel compounds capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction.
  • the present invention is also directed to methods of regulating, modulating or inhibiting tyrosine kinases, whether of the receptor or non-receptor class, for the prevention and/or treatment of disorders related to unregulated tyrosine kinase signal transduction, including cell growth, metabolic, and blood vessel proliferative disorders.
  • PTKs Protein tyrosine kinases
  • receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic homeostasis, and responses to the extracellular microenvironment). With respect to receptor tyrosine kinases, it has been shown also that tyrosine phosphorylation sites function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules.
  • RTKs receptor tyrosine kinases
  • Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
  • the RTKs comprise a large family of transmembrane receptors with diverse biological activities.
  • the intrinsic function of RTKs is activated upon ligand binding, which results in phophorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses.
  • RTK subfamilies At present, at least nineteen (19) distinct RTK subfamilies have been identified.
  • One RTK subfamily designated the HER subfamily, is believed to be comprised of EGFR, HER2, HER3 and HER4.
  • Ligands to the Her subfamily of receptors include epithelial growth factor (EGF), TGF- ⁇ , amphiregulin, HB-EGF, betacellulin and heregulin.
  • a second family of RTKs designated the insulin subfamily, is comprised of the INS-R, the IGF-1R and the IR-R.
  • a third family, the "PDGF" subfamily includes the PDGF ⁇ and ⁇ receptors, CSFIR, c-kit and FLK-II.
  • Another subfamily of RTKs, identified as the FLK family is believed to be comprised of the Kinase insert Domain-Receptor fetal liver kinase-1 (KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fins-like tyrosine kinase 1 (flt-1). Each of these receptors was initially believed to be receptors for hematopoietic growth factors.
  • Two other subfamilies of RTKs have been designated as the FGF receptor family (FGFRl, FGFR2, FGFR3 and FGFR4) and the Met subfamily (c-met and Ron).
  • the non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences. At present, over twenty- four individual non-receptor tyrosine kinases, comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Za ⁇ 70, Fes/Fps, Fak, Jak, Ack and LIMK) have been identified. At present, the Src subfamily of non-receptor tyrosine kinases is comprised of the largest number of PTKs and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
  • the present invention relates to organic molecules capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction.
  • Such compounds are useful for the treatment of diseases related to unregulated TKS transduction, including cell proliferative diseases such as cancer, atherosclerosis, restenosis, metabolic diseases such as diabetes, inflammatory diseases such as psoriasis and chronic obstructive pulmonary disease, vascular proliferative disorders such as diabetic retinopathy, age-related macular degeneration and retinopathy of prematurity, autoimmune diseases and transplant rejection.
  • the compounds of the present invention have the following general formula I:
  • R 1 is selected from the group consisting of halogen and Ci to C 4 alkyl
  • Y is selected from the group consisting of O and S
  • R 2 is selected from the group consisting of to C alkyl and COOR 3 wherein R 3 is selected from the group consisting of H and C ⁇ to C 4 alkyl; and b is 0 or an integer of from 1 to 2
  • a is 0 or an integer of from 1 to 2
  • R 4 is selected from the group consisting of H and Ci to C 4 alkyl
  • R 8 is selected from the group consisting of H and d to Cio alkyl, e.g, d to C 4 alkyl and the wavy line represents a cis or trans bond and pharmaceutically acceptable salts thereof.
  • R 1 is selected from the group consisting of H, i.e. b is 0; CH 3 and CI.
  • R 8 is H.
  • R 4 is H.
  • b is 0.
  • a is 1.
  • R 2 is COOR 3 .
  • Y is O.
  • Y is O.
  • R 2 is COOCH 3 .
  • Y is S.
  • R 2 is COOC 2 H 5 .
  • the compounds of the present invention are selected from the group consisting of 5-[(2-Oxo-l ,2-dihydro-indol-3-ylidenemethyl)ammo]-furan-2- carboxylic acid methyl ester and 4-Methyl-2-[(2-oxo-l ,2-dihydro-indol-3- ylidenemethyl)-amino]-thiophene-3-carboxylic acid ethyl ester. More preferably the compound of the present invention is 5-[(2-Oxo-l,2-dihydro-indol-3- ylidenemethyl) amino] -furan-2-carboxylic acid methyl ester
  • the present invention is further directed to pharmaceutical compositions comprising a pharmaceutically effective amount of the above-described compounds and a pharmaceutically acceptable carrier or excipient.
  • a composition is believed to modulate signal transduction by a tyrosine kinase, either by inhibition of catalytic activity, affinity to ATP or ability to interact with a substrate.
  • compositions of the present invention may be included in methods for treating diseases comprising proliferation, fibrotic or metabolic disorders, for example cancer, fibrosis, psoriasis, atherosclerosis, arthritis, and other disorders related to abnormal vasculogenesis and/or angiogenesis, such as diabetic retinopathy.
  • diseases comprising proliferation, fibrotic or metabolic disorders, for example cancer, fibrosis, psoriasis, atherosclerosis, arthritis, and other disorders related to abnormal vasculogenesis and/or angiogenesis, such as diabetic retinopathy.
  • Me refers to methyl
  • tBu refers to t-butyl
  • iPr refers to i-propyl
  • “Pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • “Alkyl” refers to a straight-chain, branched or cyclic saturated aliphatic hydrocarbon. Preferably, the alkyl group has 1 to 12 carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.
  • Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like.
  • Alkenyl refers to a straight-chain, branched or cyclic unsaturated hydrocarbon group containing at least one carbon-carbon double bond.
  • the alkenyl group has 1 to 12 carbons. More preferably it is a lower alkenyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.
  • Alkynyl refers to a straight-chain, branched or cyclic unsaturated hydrocarbon containing at least one carbon-carbon triple bond.
  • the alkynyl group has 1 to 12 carbons. More preferably it is a lower alkynyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.
  • "Alkoxyl” refers to an "O-alkyl” group.
  • Aryl refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups.
  • the aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO 2 , amine, thioether, cyano, alkoxy, alkyl, and amino.
  • Alkaryl refers to an alkyl that is covalently joined to an aryl group.
  • the alkyl is a lower alkyl.
  • Carbocyclic aryl refers to an aryl group wherein the ring atoms are carbon.
  • Heterocyclic aryl refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remainder of the ring atoms being carbon. Heteroatoms include oxygen, sulfur, and nitrogen. Thus, heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.
  • Hydrocarbyl refers to a hydrocarbon radical having only carbon and hydrogen atoms.
  • the hydrocarbyl radical has from 1 to 20 carbon atoms, more preferably from 1 to 12 carbon atoms and most preferably from 1 to 7 carbon atoms.
  • Substituted hydrocarbyl refers to a hydrocarbyl radical wherein one or more, but not all, of the hydrogen and/or the carbon atoms are replaced by a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radical including a halogen, nitrogen, oxygen, sulfur or phosphorus atom, e.g. fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, etc.
  • Amide refers to -C(O)-NH-R', wherein R' is alkyl, aryl, alkylaryl or hydrogen.
  • Thioamide refers to -C(S)-NH-R', wherein R' is alkyl, aryl, alkylaryl or hydrogen.
  • “Amine” refers to a -N(R")R'" group, wherein R' and R" are independently selected from the group consisting of alkyl, aryl, and alkylaryl.
  • Thioether refers to -S-R", wherein R" is alkyl, aryl, or alkylaryl.
  • alkyaryl alkyaryl, sulfonamide, NH-alkyl, NH-alkylaryl, or NH-aryl.
  • the substituent on the aniline moiety is referred to as an o, m or p substituent or a 2, 3 or 4 substituent, respectively.
  • the 5 substituent is also a m substituent and the 6 substituent is an o substituent.
  • the present invention relates to compounds capable of regulating and/or modulating tyrosine kinase signal transduction and more particularly receptor and non-receptor tyrosine kinase signal transduction.
  • Receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic effects and responses to the extracellular microenvironment).
  • tyrosine phosphorylation sites in growth factor receptors function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules.
  • SH2 serosine kinases
  • Tyrosine kinase signal transduction results in, among other responses, cell proliferation, differentiation and metabolism.
  • Abnormal cell proliferation may result in a wide array of disorders and diseases, including the development of neoplasia such as carcinoma, sarcoma, leukemia, ghoblastoma, hemangioma, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy (or other disorders related to uncontrolled angiogenesis and/or vasculogenesis. e.g. macular degeneration).
  • This invention is therefore directed to compounds which regulate, modulate and/or inhibit tyrosine kinase signal transduction by affecting the enzymatic activity of the RTKs and/or the non-receptor tyrosine kinases and interfering with the signal transduced such proteins.
  • the present invention is directed to compounds which regulate, modulate and/or inhibit the RTK and/or non-receptor tyrosine kinase mediated signal transduction pathways as a therapeutic approach to cure many kinds of solid tumors, including but not limited to carcinoma, sarcoma, leukemia, erythroblastoma, ghoblastoma, meningioma, astrocytoma, melanoma and myoblastoma.
  • Indications may include, but are not limited to brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreas cancers, colon cancers, blood cancers, lung cancers and bone cancers.
  • HUNEC human umbilical vein endothelial cells
  • Cells were seeded in 96-well fibronectin coated black- walled plates overnight @ 37°C/5%CO2. Cells were loaded with calcium indicator Fluo-4 for 45 minutes at 37°C. Cells were washed 4 times (Original Cell Wash, Labsystems) to remove extracellular dye.
  • test agents For screening, cells were pre-incubated with test agents for 30 minutes, at a single concentration (10 uM) or at concentrations ranging from 0.01 to 10.0 uM followed by VEGF stimulation (5ng/mL). Changes in fluorescence at 516 nm were measured simultaneously in all 96 wells using a cooled CCD camera. Data were generated by determining max- min fluorescence levels for unstimulated, stimulated, and drug treated samples. IC 50 values for test compounds were calculated from % inhibition of VEGF stimulated responses in the absence of inhibitor.
  • the cytoplasmic domain of the human VEGF receptor (VEGFR-2) was expressed as a Histidine-tagged fusion protein following infection of insect cells using an engineered baculovirus. His-VEGFR-2 was purified to homogeneity, as determined by SDS-PAGE, using nickel resin chromatography. Kinase assays were performed in 96 well microtiter plates that were coated overnight with 30 ⁇ g of poly-Glu-Tyr (4: 1) in lOmM Phosphate Buffered Saline (PBS), pH 7.2-7.4. The plates were incubated with 1% BSA and then washed four times with PBS prior to starting the reaction.
  • PBS lOmM Phosphate Buffered Saline
  • Reactions were carried out in 120 ⁇ L reaction volumes containing 3.6 ⁇ M ATP in kinase buffer (50mM Hepes pH 7.4, 20mM MgCl 2 , 0.1 mM MnCl 2 and 0.2 mM Na 3 NO 4 ). Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%.
  • IC 50 values for compound inhibition were calculated directly from graphs of optical density (arbitrary units) versus compound concentration following subtraction of blank values.
  • R 5 is selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and sulfonyl;
  • R is selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and sulfonyl and phosphonic acid;
  • R 6 is selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
  • R 8 is selected from the group consisting of H and Ci to Cio alkyl;
  • b is 0 or an integer from 1 to 2;
  • a is 0 or an integer of from 1 to 3; the wavy line represents a cis or trans bond and pharmaceutically acceptable salts thereof.
  • Said hydrocarbyl and/or substituted hydrocarbyl may be alkyl, alkenyl, alkynyl,

Abstract

The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.

Description

3-(HETEROARYLAMINO)METHYLENE-l, 3-DIHYDRO-2H-INDOL-2-ONES
AS KINASE INHIBITORS
BACKGROUND OF THE INVENTION
1. Field Of The Invention
The present invention relates to novel compounds capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction. The present invention is also directed to methods of regulating, modulating or inhibiting tyrosine kinases, whether of the receptor or non-receptor class, for the prevention and/or treatment of disorders related to unregulated tyrosine kinase signal transduction, including cell growth, metabolic, and blood vessel proliferative disorders.
2. Description Of The Related Art
Protein tyrosine kinases (PTKs) comprise a large and diverse class of proteins having enzymatic activity. The PTKs play an important role in the control of cell growth and differentiation.
For example, receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic homeostasis, and responses to the extracellular microenvironment). With respect to receptor tyrosine kinases, it has been shown also that tyrosine phosphorylation sites function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules. Several intracellular substrate proteins that associate with receptor tyrosine kinases (RTKs) have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such domain but serve as adapters and associate with catalytically active molecules. The specificity of the interactions between receptors or proteins and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors are consistent with the observed differences in their substrate phosphorylation profiles. These observations suggest that the function of each receptor tyrosine kinase is determined not only by its pattern of expression and ligand availability but also by the array of downstream signal transduction pathways that are activated by a particular receptor. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors.
Aberrant expression or mutations in the PTKs have been shown to lead to either uncontrolled cell proliferation (e.g. malignant tumor growth) or to defects in key developmental processes. Consequently, the biomedical community has expended significant resources to discover the specific biological role of members of the PTK family, their function in differentiation processes, their involvement in tumorigenesis and in other diseases, the biochemical mechanisms underlying their signal transduction pathways activated upon ligand stimulation and the development of novel drugs.
Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
The RTKs comprise a large family of transmembrane receptors with diverse biological activities. The intrinsic function of RTKs is activated upon ligand binding, which results in phophorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses.
At present, at least nineteen (19) distinct RTK subfamilies have been identified. One RTK subfamily, designated the HER subfamily, is believed to be comprised of EGFR, HER2, HER3 and HER4. Ligands to the Her subfamily of receptors include epithelial growth factor (EGF), TGF-α, amphiregulin, HB-EGF, betacellulin and heregulin.
A second family of RTKs, designated the insulin subfamily, is comprised of the INS-R, the IGF-1R and the IR-R. A third family, the "PDGF" subfamily includes the PDGF α and β receptors, CSFIR, c-kit and FLK-II. Another subfamily of RTKs, identified as the FLK family, is believed to be comprised of the Kinase insert Domain-Receptor fetal liver kinase-1 (KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fins-like tyrosine kinase 1 (flt-1). Each of these receptors was initially believed to be receptors for hematopoietic growth factors. Two other subfamilies of RTKs have been designated as the FGF receptor family (FGFRl, FGFR2, FGFR3 and FGFR4) and the Met subfamily (c-met and Ron).
Because of the similarities between the PDGF and FLK subfamilies, the two subfamilies are often considered together. The known RTK subfamilies are identified in Plowman et al, 1994, DN&P 7(6): 334-339, which is incorporated herein by reference.
The non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences. At present, over twenty- four individual non-receptor tyrosine kinases, comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Zaρ70, Fes/Fps, Fak, Jak, Ack and LIMK) have been identified. At present, the Src subfamily of non-receptor tyrosine kinases is comprised of the largest number of PTKs and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Src subfamily of enzymes has been linked to oncogenesis. A more detailed discussion of non-receptor tyrosine kinases is provided in Bolen, 1993, Oncogen 8: 2025-2031, which is incorporated herein by reference. Many of the tyrosine kinases, whether an RTK or non-receptor tyrosine kinase, have been found to be involved in cellular signaling pathways leading to cellular signal cascades leading to pathogenic conditions, including cancer, psoriasis and hyper immune response. Development of Compounds to Modulate the PTKs. In view of the surmised importance of PTKs to the control, regulation and modulation of cell proliferation the diseases and disorders associated with abnormal cell proliferation, many attempts have been made to identify receptor and non-receptor tyrosine kinase "inhibitors" using a variety of approaches, including the use of mutant ligands (U.S. Patent No. 4,966,849), soluble receptors and antibodies (PCT
Application No. WO 94/10202; Kendall & Thomas, 1994, Proc. Nat'l Acad. Sci 90: 10705-09; Kim, et al, 1993, Nature 362: 841-844), RNA ligands (Jellinek, et al, Biochemistry 33: 10450-56); Takano, et al, 1993, Mol. Bio. Cell 4:358A; Kinsella, et al, 1992, Exp. Cell Res. 199: 56-62; Wright, et al, 1992, J. Cellular Phys. 152: 448-57) and tyrosine kinase inhibitors (PCT Application Nos. WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808; U.S. Patent No. 5,330,992; Mariani, et al, 1994, Proc. Am. Assoc. Cancer Res. 35: 2268).
More recently, attempts have been made to identify small molecules which act as tyrosine kinase inhibitors. For example, bis monocyclic, bicyclic or heterocyclic aryl compounds (PCT Application No. WO 92/20642), vinylene- azaindole derivatives (PCT Application No. WO 94/14808) and l-cyclopropyl-4- pyridyl-quinolones (U.S. Patent No. 5,330,992) have been described generally as tyrosine kinase inhibitors. Styryl compounds (U.S. Patent No. 5,217,999), styryl- substituted pyridyl compounds (U.S. Patent No. 5,302,606), certain quinazoline derivatives (EP Application No. 0 566 266 Al), seleoindoles and selenides (PCT Application No. WO 94/03427), tricyclic polyhydroxylic compounds (PCT Application No. WO 92/21660) and benzylphosphonic acid compounds (PCT Application No. WO 91/15495) have been described as compounds for use as tyrosine kinase inhibitors for use in the treatment of cancer. The identification of effective small compounds which specifically inhibit signal transduction by modulating the activity of receptor and non-receptor tyrosine kinases to regulate and modulate abnormal or inappropriate cell proliferation is therefore desirable and one object of this invention. Finally, certain small compounds are disclosed in U.S. Patents 5,792,783;
5,834,504; 5,883,113; 5,883,116 and 5,886,020 as useful for the' treatment of diseases related to unregulated TKS transduction. These patents are hereby incorporated by reference in its entirety for the purpose of disclosing starting materials and methods for the preparation thereof, screens and assays to determine a claimed compound's ability to modulate, regulate and/or inhibit cell proliferation, indications which are treatable with said compounds, formulations and routes of administration, effective dosages, etc.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to organic molecules capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction. Such compounds are useful for the treatment of diseases related to unregulated TKS transduction, including cell proliferative diseases such as cancer, atherosclerosis, restenosis, metabolic diseases such as diabetes, inflammatory diseases such as psoriasis and chronic obstructive pulmonary disease, vascular proliferative disorders such as diabetic retinopathy, age-related macular degeneration and retinopathy of prematurity, autoimmune diseases and transplant rejection.
In one illustrative embodiment, the compounds of the present invention have the following general formula I:
Figure imgf000007_0001
wherein R1 is selected from the group consisting of halogen and Ci to C4 alkyl; Y is selected from the group consisting of O and S; R2 is selected from the group consisting of to C alkyl and COOR3 wherein R3 is selected from the group consisting of H and C\ to C4 alkyl; and b is 0 or an integer of from 1 to 2; a is 0 or an integer of from 1 to 2; R4 is selected from the group consisting of H and Ci to C4 alkyl; R8 is selected from the group consisting of H and d to Cio alkyl, e.g, d to C4 alkyl and the wavy line represents a cis or trans bond and pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention R1 is selected from the group consisting of H, i.e. b is 0; CH3 and CI. Preferably R8 is H.
Preferably R4 is H.
Preferably b is 0.
Preferably a is 1.
Preferably R2 is COOR3. Preferably Y is O.
In one aspect of the invention Y is O.
In this aspect of the invention R2 is COOCH3. In another aspect of the invention Y is S.
In this aspect of the invention R2 is COOC2H5.
In particular, the compounds of the present invention are selected from the group consisting of 5-[(2-Oxo-l ,2-dihydro-indol-3-ylidenemethyl)ammo]-furan-2- carboxylic acid methyl ester and 4-Methyl-2-[(2-oxo-l ,2-dihydro-indol-3- ylidenemethyl)-amino]-thiophene-3-carboxylic acid ethyl ester. More preferably the compound of the present invention is 5-[(2-Oxo-l,2-dihydro-indol-3- ylidenemethyl) amino] -furan-2-carboxylic acid methyl ester
The present invention is further directed to pharmaceutical compositions comprising a pharmaceutically effective amount of the above-described compounds and a pharmaceutically acceptable carrier or excipient. Such a composition is believed to modulate signal transduction by a tyrosine kinase, either by inhibition of catalytic activity, affinity to ATP or ability to interact with a substrate.
More particularly, the compositions of the present invention may be included in methods for treating diseases comprising proliferation, fibrotic or metabolic disorders, for example cancer, fibrosis, psoriasis, atherosclerosis, arthritis, and other disorders related to abnormal vasculogenesis and/or angiogenesis, such as diabetic retinopathy.
The following defined terms are used throughout this specification: "Me" refers to methyl.
"Et" refers to ethyl.
"tBu" refers to t-butyl.
"iPr" refers to i-propyl.
"Pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. "Alkyl" refers to a straight-chain, branched or cyclic saturated aliphatic hydrocarbon. Preferably, the alkyl group has 1 to 12 carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, most preferably 1 to 4 carbons. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like. The alkyl group may be optionally substituted with one or more substituents are selected from the group consisting of hydroxyl, cyano, alkoxy, =O, =S, NO2, halogen, dimethyl amino, and SH.
"Alkenyl" refers to a straight-chain, branched or cyclic unsaturated hydrocarbon group containing at least one carbon-carbon double bond. Preferably, the alkenyl group has 1 to 12 carbons. More preferably it is a lower alkenyl of from 1 to 7 carbons, most preferably 1 to 4 carbons. The alkenyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, =0, =S, NO2, halogen, dimethyl amino, and SH. " Alkynyl" refers to a straight-chain, branched or cyclic unsaturated hydrocarbon containing at least one carbon-carbon triple bond. Preferably, the alkynyl group has 1 to 12 carbons. More preferably it is a lower alkynyl of from 1 to 7 carbons, most preferably 1 to 4 carbons. The alkynyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, =O, =S, NO2, halogen, dimethyl amino, and SH. "Alkoxyl" refers to an "O-alkyl" group.
"Aryl" refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups. The aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO2, amine, thioether, cyano, alkoxy, alkyl, and amino.
"Alkaryl" refers to an alkyl that is covalently joined to an aryl group. Preferably, the alkyl is a lower alkyl.
"Carbocyclic aryl" refers to an aryl group wherein the ring atoms are carbon.
"Heterocyclic aryl" refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remainder of the ring atoms being carbon. Heteroatoms include oxygen, sulfur, and nitrogen. Thus, heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.
"Hydrocarbyl" refers to a hydrocarbon radical having only carbon and hydrogen atoms. Preferably, the hydrocarbyl radical has from 1 to 20 carbon atoms, more preferably from 1 to 12 carbon atoms and most preferably from 1 to 7 carbon atoms.
"Substituted hydrocarbyl" refers to a hydrocarbyl radical wherein one or more, but not all, of the hydrogen and/or the carbon atoms are replaced by a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radical including a halogen, nitrogen, oxygen, sulfur or phosphorus atom, e.g. fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, etc.
"Amide" refers to -C(O)-NH-R', wherein R' is alkyl, aryl, alkylaryl or hydrogen. "Thioamide" refers to -C(S)-NH-R', wherein R' is alkyl, aryl, alkylaryl or hydrogen.
"Amine" refers to a -N(R")R'" group, wherein R' and R" are independently selected from the group consisting of alkyl, aryl, and alkylaryl.
"Thioether" refers to -S-R", wherein R" is alkyl, aryl, or alkylaryl. "Sulfonyl" refers to -S(O)2-R"", where R"" is aryl, C(CN)=C-aryl,
CH2CN, alkyaryl, sulfonamide, NH-alkyl, NH-alkylaryl, or NH-aryl.
Also, alternatively the substituent on the aniline moiety is referred to as an o, m or p substituent or a 2, 3 or 4 substituent, respectively. (Obviously, the 5 substituent is also a m substituent and the 6 substituent is an o substituent.)
The present invention relates to compounds capable of regulating and/or modulating tyrosine kinase signal transduction and more particularly receptor and non-receptor tyrosine kinase signal transduction.
Receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic effects and responses to the extracellular microenvironment).
It has been shown that tyrosine phosphorylation sites in growth factor receptors function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules. Several intracellular substrate proteins that associate with receptor tyrosine kinases have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such domain but serve as adapters and associate with catalytically active molecules. The specificity of the interactions between receptors and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors are consistent with the observed differences in their substrate phosphorylation profiles. These observations suggest that the function of each receptor tyrosine kinase is determined not only by its pattern of expression and ligand availability but also by the array of downstream signal transduction pathways that are activated by a particular receptor. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors.
Tyrosine kinase signal transduction results in, among other responses, cell proliferation, differentiation and metabolism. Abnormal cell proliferation may result in a wide array of disorders and diseases, including the development of neoplasia such as carcinoma, sarcoma, leukemia, ghoblastoma, hemangioma, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy (or other disorders related to uncontrolled angiogenesis and/or vasculogenesis. e.g. macular degeneration).
This invention is therefore directed to compounds which regulate, modulate and/or inhibit tyrosine kinase signal transduction by affecting the enzymatic activity of the RTKs and/or the non-receptor tyrosine kinases and interfering with the signal transduced such proteins. More particularly, the present invention is directed to compounds which regulate, modulate and/or inhibit the RTK and/or non-receptor tyrosine kinase mediated signal transduction pathways as a therapeutic approach to cure many kinds of solid tumors, including but not limited to carcinoma, sarcoma, leukemia, erythroblastoma, ghoblastoma, meningioma, astrocytoma, melanoma and myoblastoma. Indications may include, but are not limited to brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreas cancers, colon cancers, blood cancers, lung cancers and bone cancers.
Biological data for compounds of the present invention was generated by use of the following assays.
NEGF Stimulated Ca^ Signal in vitro
Automated FLIPR (Fluorometric Imaging Plate Reader) technology was used to screen for inhibitors of VEGF induced increases in intracellular calcium levels in fluorescent dye loaded endothelial cells. HUNEC (human umbilical vein endothelial cells) (Clonetics) were seeded in 96-well fibronectin coated black- walled plates overnight @ 37°C/5%CO2. Cells were loaded with calcium indicator Fluo-4 for 45 minutes at 37°C. Cells were washed 4 times (Original Cell Wash, Labsystems) to remove extracellular dye. For screening, cells were pre-incubated with test agents for 30 minutes, at a single concentration (10 uM) or at concentrations ranging from 0.01 to 10.0 uM followed by VEGF stimulation (5ng/mL). Changes in fluorescence at 516 nm were measured simultaneously in all 96 wells using a cooled CCD camera. Data were generated by determining max- min fluorescence levels for unstimulated, stimulated, and drug treated samples. IC50 values for test compounds were calculated from % inhibition of VEGF stimulated responses in the absence of inhibitor.
Protocol for KDR Assay: The cytoplasmic domain of the human VEGF receptor (VEGFR-2) was expressed as a Histidine-tagged fusion protein following infection of insect cells using an engineered baculovirus. His-VEGFR-2 was purified to homogeneity, as determined by SDS-PAGE, using nickel resin chromatography. Kinase assays were performed in 96 well microtiter plates that were coated overnight with 30μg of poly-Glu-Tyr (4: 1) in lOmM Phosphate Buffered Saline (PBS), pH 7.2-7.4. The plates were incubated with 1% BSA and then washed four times with PBS prior to starting the reaction. Reactions were carried out in 120μL reaction volumes containing 3.6μM ATP in kinase buffer (50mM Hepes pH 7.4, 20mM MgCl2, 0.1 mM MnCl2 and 0.2 mM Na3NO4). Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%.
Reactions were initiated by the addition 0.5 ng of purified protein. Following a ten minute incubation at 25° C, the reactions were washed four times with PBS containing 0.05% Tween-20. lOOμl of a monoclonal anti-phosphotyrosine antibody-peroxidase conjugate was diluted 1:10000 in PBS-Tween-20 and added to the wells for 30 minutes. Following four washes with PBS-Tween-20, 1 OOμl of 0- Phenylenediamine Dihydrochloride in Phosphate-citrate buffer, containing urea hydrogen peroxide, was added to the wells for 7 minutes as a colorimetric substrate for the peroxidase. The reaction was terminated by the addition of lOOμl of 2.5N
H2SO4 to each well and read using a microplate ELISA reader set at 492 nm. IC50 values for compound inhibition were calculated directly from graphs of optical density (arbitrary units) versus compound concentration following subtraction of blank values.
The results of said assays are reported in Table 1, below, wherein NT means not tested.
TABLE 1
Figure imgf000014_0001
The invention is further illustrated by the following non-limiting examples.
Example 1
5-[(2-Oxo-l,2-dihydro-indol-3-ylidenemethyl)amino]-furan-2- carboxylic acid methyl ester
2.42 mL of ethylformate are combined with 1.33 gms of 1,3 dihydro-indol- 2-one in a solution of 21%,, by weight, sodium formate in ethanol (4.85 mL). The resulting solution is allowed to stand at room temperature for 30 minutes and then refluxed for 30 minutes to yield suspension. Once at room temperature the suspension was acidified to pH 1.0 with 10% HCl(aq) then 5 mL of H2O was added.
The resulting precipitate was filtered and washed with H2O (4X20 mL) to provide a mixture of E & Z-3-[(hydroxy)-methylene]-l, 3-dihydro-indol-2-one as a solid.
E & Z-3-[(hydroxy)-methylene]-l, 3-dihydro-indol-2-one (0.10 g) is reacted with 0.206 gms. of methyl 5-amino-2 furoate by refluxing in tetrahydrofuran (2.7 mL) for 48 hours to yield 0.0668 gms of the named compound as a solid following concentration in vacuo, dilution with isopropanol and filtration.
Example 2 4-Methyl-2-[(2-oxo-l,2-dihydro-indol-3-ylidenemethyl)-amino]- thiophene-3-carboxylic acid ethyl ester
The named compound is prepared by substituting ethyl 2-amino-4- methylthiophene-3-carboxylate for methyl 5-amino-2-furoate in the reaction of Example 1. The present invention is not to be limited in scope by the exemplified embodiments which are intended as illustrations of single aspects of the invention only. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. For example novel compounds of formula II, below maybe utilized in the method of treating diseases described above.
Figure imgf000015_0001
wherein R5 is selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and sulfonyl; R is selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and sulfonyl and phosphonic acid; R6 is selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl; R8 is selected from the group consisting of H and Ci to Cio alkyl; b is 0 or an integer from 1 to 2; a is 0 or an integer of from 1 to 3; the wavy line represents a cis or trans bond and pharmaceutically acceptable salts thereof. Said hydrocarbyl and/or substituted hydrocarbyl may be alkyl, alkenyl, alkynyl, aryl (including carbocylic aryl and heterocyclic aryl) and alkaryl.
Such modifications are intended to fall within the scope of the appended claims.
All references cited herein are hereby incorporated by reference in their entirety.
The foregoing description details specific methods and compositions that can be employed to practice the present invention, and represents the best mode contemplated. However, it is apparent for one of ordinary skill in the art that further compounds with the desired pharmacological properties can be prepared in an analogous manner, and that the disclosed compounds can also be obtained from different starting compounds via different chemical reactions. Similarly, different pharmaceutical compositions may be prepared and used with substantially the same result. Thus, however detailed the foregoing may appear in text, it should not be construed as limiting the overall scope hereof; rather, the ambit of the present invention is to be governed only by the lawful construction of the appended claims.

Claims

A compound represented by the general formula I
Figure imgf000017_0001
wherein R1 is selected from the group consisting of halogen and Ci to C4 alkyl; Y is selected from the group consisting of O and S; R2 is selected from the group consisting of Ci to C alkyl and COOR3, wherein R3 is selected from the group consisting of H and Ci to C4 alkyl; and b is 0 or an integer of from 1 to 2; a is 0 or an integer of from 1 to 2; R4 is selected from the group consisting of H and Ci to C4 alkyl; R is selected from the group consisting of H and Ci to o alkyl and the wavy line represents a cis or trans bond, and pharmaceutically acceptable salts thereof.
The compound of claim 1 wherein R and R are H.
The compound of claim 2 wherein b is 0.
The compound of claim 3 wherein a is 1.
The compound of claim 4 wherein Y is O.
The compound of claim 5 wherein R is COOCH .
7. The compound of claim 4 wherein Y is S.
8. The compound of claim 7 wherein R2 is COOC2H5.
9. The compound of claim 1, that is 5-[(2-Oxo-l,2-dihydro-indol-3- ylidenemethyl)amino]-furan-2-carboxylic acid methyl ester
10. The compound of claim 1, that is 4-Methyl-2-[(2-oxo-l,2-dihydro-indol-3- ylidenemethyl)-amino]-thiophene-3-carboxylic acid ethyl ester
11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound according to Claim 1.
12. The method for treating diseases related to unregulated tyrosine kinase signal transduction, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound represented by the general formula I:
Figure imgf000018_0001
wherein R1 is selected from the group consisting of halogen and Ci to C alkyl; Y is selected from the group consisting of O and S; R2 is selected from the group consisting of Ci to C4 alkyl and COOR , wherein R is selected from the group consisting of H and Ci to C4 alkyl; and b is 0 or an integer of from 1 to 2; a is 0 or an integer of from 1 to 2; R4 is selected from the group consisting of H and Ci to C4 alkyl; R8 is selected from the group consisting of H and Ci to Cio alkyl and the wavy line represents a cis or trans bond, and pharmaceutically acceptable salts thereof.
13. The method of claim 12 wherein said disease is selected from the group consisting of cancer, blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders and metabolic diseases.
14. The method of claim 12 wherein the blood vessel proliferative disorder is selected from the group consisting of diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, arthritis and restenosis.
15. The method of claim 12 wherein the fibrotic disorder is selected from the group consisting of hepatic cirrhosis and atherosclerosis.
16. The method of claim 12 wherein the mesangial cell proliferative disorder is selected from the group consisting of glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection and glomerulopathies.
17. The method of claim 12 wherein the metabolic disorder is selected from the group consisting of psoriasis, diabetes mellitus, wound healing, inflammation and neurodegenerative diseases.
18. A compound represented by the general formula II:
Figure imgf000020_0001
wherein R5 is selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and sulfonyl; R7 is selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and sulfonyl and phosphonic acid; R6 is selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl; R8 is selected from the group consisting of H and Ci to Cio alkyl, b is 0 or an integer from 1 to 2; a is 0 or an integer of from 1 to 3; the wavy line represents a cis or trans bond and pharmaceutically acceptable salts thereof.
19. A method for treating diseases related to unregulated tyrosine kinase signal transduction, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound represented by the general formula II:
Figure imgf000021_0001
wherein R5 is selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, ti ioether and sulfonyl; R7 is selected from the group consisting of halogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide, thioamide, amine, thioether and sulfonyl and phosphonic acid; R6 is selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl; R8 is selected from the group consisting of H and Ci to Cio alkyl, b is 0 or an integer from 1 to 2; a is 0 or an integer of from 1 to 3; the wavy line represents a cis or trans bond and pharmaceutically acceptable salts thereof.
20. The method of claim 19 wherein said disease is selected from the group consisting of cancer, blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders and metabolic diseases.
21. The method of claim 19 wherein the blood vessel proliferative disorder is selected from the group consisting of diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, arthritis and restenosis.
22. The method of claim 19 wherein the fibrotic disorder is selected from the group consisting of hepatic cirrhosis and atherosclerosis.
23. The method of claim 19 wherein the mesangial cell proliferative disorder is selected from the group consisting of glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection and glomerulopathies.
24. The method of claim 19 wherein the metabolic disorder is selected from the group consisting of psoriasis, diabetes mellitus, wound healing, inflammation and neurodegenerative diseases.
PCT/US2002/029630 2001-09-27 2002-09-18 3-(heteroarylamino)methylene-1, 3-dihydro-2h-indol-2-ones as kinase inhibitors WO2003027109A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005087726A1 (en) * 2004-03-12 2005-09-22 Boehringer Ingelheim International Gmbh Novel aryl-containing 5-acylindolinones, the production thereof and their use as medicaments

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994003427A1 (en) * 1992-08-06 1994-02-17 Warner-Lambert Company 2-thioindoles (selenoindoles) and related disulfides (selenides) which inhibit protein tyrosine kinases and which have antitumor properties
WO1999015500A1 (en) * 1997-09-05 1999-04-01 Glaxo Group Limited Substituted oxindole derivatives as protein tyrosine kinase and as protein serine/threonine kinase inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994003427A1 (en) * 1992-08-06 1994-02-17 Warner-Lambert Company 2-thioindoles (selenoindoles) and related disulfides (selenides) which inhibit protein tyrosine kinases and which have antitumor properties
WO1999015500A1 (en) * 1997-09-05 1999-04-01 Glaxo Group Limited Substituted oxindole derivatives as protein tyrosine kinase and as protein serine/threonine kinase inhibitors

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005087726A1 (en) * 2004-03-12 2005-09-22 Boehringer Ingelheim International Gmbh Novel aryl-containing 5-acylindolinones, the production thereof and their use as medicaments
US7176231B2 (en) 2004-03-12 2007-02-13 Boehringer Ingelheim International Gmbh Aryl-containing 5-acylindolinones, the preparation thereof and their use as medicaments

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