EP1856116A1 - Derives de tetrahydro-pyrrolo-quinoleine substitues servant de modulateurs de kinase, plus specialement de tyrosine kinases et de raf-kinases - Google Patents

Derives de tetrahydro-pyrrolo-quinoleine substitues servant de modulateurs de kinase, plus specialement de tyrosine kinases et de raf-kinases

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Publication number
EP1856116A1
EP1856116A1 EP06706893A EP06706893A EP1856116A1 EP 1856116 A1 EP1856116 A1 EP 1856116A1 EP 06706893 A EP06706893 A EP 06706893A EP 06706893 A EP06706893 A EP 06706893A EP 1856116 A1 EP1856116 A1 EP 1856116A1
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Prior art keywords
compounds
salts
cancer
solvates
stereoisomers
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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.)
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EP06706893A
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German (de)
English (en)
Inventor
Wolfgang Staehle
Timo Heinrich
Maria Kordowicz
Andree Blaukat
Lars Thore Burgdorf
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Merck Patent GmbH
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Merck Patent GmbH
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Publication of EP1856116A1 publication Critical patent/EP1856116A1/fr
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P35/00—Antineoplastic agents
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention had the object of finding new compounds with valuable properties, in particular those that can be used for the production of medicaments.
  • the present invention relates to compounds and the use of
  • the present invention relates to compounds of the formula I which inhibit, regulate and / or modulate the signal transduction of tyrosine kinases, compositions containing these compounds, and methods for their use in the treatment of tyrosine kinase-related diseases and conditions, such as angiogenesis, cancer,
  • Tumor development, growth and spread arteriosclerosis, eye diseases such as age-related macular degeneration, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, thrombosis, fibrosis, glomerulonephritis, neurodegenera- tion, psoriasis, restenosis, wound healing, transpi- mitate rejection, metabolic and Immune system disorders, including autoimmune diseases, cirrhosis, diabetes and blood vessel diseases, as well as instability and permeability (permeability) and the like in mammals.
  • eye diseases such as age-related macular degeneration, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, thrombosis, fibrosis, glomerulonephritis, neurodegenera- tion, psoriasis, restenosis, wound healing, transpi- mitate rejection, metabolic and Immune system disorders, including autoimmune diseases, cirrhosis, diabetes and blood vessel diseases, as well
  • Tyrosine kinases are a class of enzymes with at least 400 members that catalyze the transfer of the terminal phosphate of adenosine triphosphate (gamma-phosphate) to tyrosine residues on protein substrates. It is assumed that tyrosine kinases play an important role in signal transduction in different cell functions via substrate phosphorylation. Although the exact mechanisms of signal transduction are still unclear, it has been shown that the tyrosine kinases are important factors in the
  • the tyrosine kinases can be classified into receptor tyrosine kinases and cytosolic tyrosine kinases.
  • the receptor tyrosine kinases have an extracellular part, a transmembrane part and an intracellular
  • the receptor tyrosine kinases consist of a multiplicity of transmembrane receptors with different biological activity. So
  • a tyrosine kinase subfamily named HER subfamily consists of EGFR, HER2, HER3 and HER4.
  • the ligands of this receptor subfamily include the epithelial wax
  • TGF- ⁇ amphiregulin
  • HB-EGF betacellulin
  • IR-R insulin receptor tyrosine kinases
  • the PDGF subfamily includes the PDGF- ⁇ and -ß receptor, CSFIR, c- kit and
  • FLK-II O 0 FLK-II.
  • FLK-1 kinase single domain receptor
  • FLK-2 fetal liver kinase-1
  • FLK-4 fetal liver kinase-4
  • flt-1 fms-tyrosine kinase-1
  • the RTKs also include TIE2 and its
  • TIE1 is known as a homologue of TIE2.
  • the TIE RTKs are selectively expressed on endothelial cells and find their function in processes of angiogenesis and maturation of the
  • Examples of kinase inhibitors already tested in cancer therapy may be L.K. Shawyer et al. Cancer Cell 1, 117-123 (2002) and D. Fabbro & C. Garcia-Echeverria Current Opin. Drug Discovery &
  • the cytosolic tyrosine kinases also consist of a plurality of subfamilies, including Src, Frk, Btk, Csk, AbI, Zap70, Fes / Fps, Fak,
  • the Src subfamily is one of the largest subfamilies. It includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, - A -
  • Both the receptor tyrosine kinases and the cytosolic tyrosine kinases are involved in cell signaling pathways leading to various conditions of suffering, including cancer, psoriasis, and hyperimmune reactions.
  • a c of these receptor tyrosine kinases is the fetal liver kinase 1, also called FLK-1.
  • FLK-1 The human analog of FLK-1 is the kinase-insert domain-containing receptor KDR, also known as vascular endothelial cell growth factor receptor 2 or VEGFR-2, because it binds VEGF with high affinity.
  • VEGFR-2 vascular endothelial cell growth factor receptor 2
  • VEGF and KDR constitute a ligand-receptor pair that play an essential role in the proliferation of vascular endothelial cells and the formation and budding of the blood vessels, which are called vasculogenesis or
  • Angiogenesis is characterized by an excessively high activity of vascular endothelial growth factor (VEGF).
  • VEGF vascular endothelial growth factor
  • the VEGF actually consists of a family of ligands (Klagsburn and D'Amore,
  • the VEGF binds the high-affinity transmembrane tyrosine kinase receptor KDR and the related fms tyrosine kinase-1, also known as Flt-1 or vascular endothelial cell growth factor receptor 1 (VEGFR-1).
  • Receptor contributes to different aspects of angiogenesis.
  • KDR induces the mitogenic function of VEGF
  • FIM appears to modulate non-mitogenic functions, such as those associated with cell adhesion.
  • Inhibition of KDR therefore modulates the level of mitogenic VEGF activity.
  • tumor growth is affected by the antiangiogenic effect of the VEGF receptor antagonists (Kim et al., Nature 362, pp. 841-844, 1993).
  • VEGFR-1 Flt-1
  • VEGRF-2 Flk-1 or KDR
  • VEGFR-3 FIt-4
  • Solid tumors can therefore be treated with tyrosine kinase inhibitors 15 , as these tumors are responsible for the formation of the support
  • These solid tumors include monocytic leukemia, brain, urogenital, lymphatic, gastric, laryngeal and lung carcinomas, including lung adenocarcinoma and small cell lung carcinoma.
  • Another 20 examples include cancers in which overexpression or activation of Raf activating oncogenes (e.g., K-ras, erb-B) is observed. These carcinomas include pancreatic and breast carcinoma. Inhibitors of these tyrosine kinases are therefore suitable for
  • the angiogenic activity of VEGF is not limited to tumors.
  • the VEGF is for those with diabetic retinopathy in or near the
  • O0 retina produced angiogenic activity responsible. This vascular growth in the retina leads to weakened eyesight and eventually blindness. Eye VEGF mRNA and protein levels are increased by conditions such as retinal vein occlusion in primates and reduced murine pO 2 levels leading to neovascularization.
  • Receptor-immunoconjugates inhibit both in primate and in the Rodent model the neovascularization in the eye. Regardless of the reason for induction of VEGF in human diabetic retinopathy, inhibition of ocular VEGF is useful in treating this
  • VEGF expression is also greatly increased in hypoxic regions of animal and human tumors adjacent to necrosis zones.
  • the VEGF is further enhanced by the expression of the oncogenes ras, raf, src and p53 mutant (all of which are important in the fight against cancer)
  • a c VEGF not as an autocrine mitogenic factor.
  • the VEGF therefore, contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotaxis and mitogenesis activity.
  • These monoclonal antibodies also inhibit the growth of typically less highly vascularized human colon carcinomas
  • Embryo stem cells which usually grow in the nude mouse in the form of solid tumors, do not form detectable tumors upon knock-out of both VEGF-AIIeIe. From these data together the role of VEGF goes down
  • angiogenesis is a part total pathology, eg, inflammation, diabetic retinal vascularization, as well as various forms of cancer, since it is known that tumor growth is angiogenesis-dependent (Weidner et al., N.B.
  • Angiopoietin 1 (Ang1), a ligand for the endothelium-specific receptor tyrosine kinase TIE-2, is a novel angiogenic factor (Davis et al, Cell, 1996, 87: 1161-1169, Partanen et al, Mol.
  • TIE tyrosine kinase with Ig and EGF homology domains. TIE is used to identify a class of receptor tyrosine kinases that are exclusively expressed in
  • TIE receptor kinases are typically characterized by the presence of an EGF-like domain and an immunoglobulin (IG) -like domain, which consists of extracellular folding units linked by disulfide bonds between the chains
  • Ang1 and its receptor TIE-2 act during later stages in vascular development, i.e., 25%. during vessel remodeling (remodeling refers to the formation of a vessel lumen) and maturation (Yancopoulos et al, Cell, 1998, 93: 661-664; Peters, KG, Circ.Res., 1998, 83 (3): 342-3; Suri et al, Cell 87, 1171-1180 (1996)).
  • VEGFR-2 block the phosphorylation of tyrosine residues and serve to interrupt the initiation of angiogenesis. Therefore one may suppose that inhibition of TIE-2 and / or VEGFR-2 should prevent tumor angiogenesis and serve to slow or completely eliminate tumor growth. Accordingly, one could treat cancer and others with inappropriate 5
  • the present invention is directed to methods for the regulation, modulation or inhibition of TIE-2 for the prevention and / or treatment of
  • the compounds of the formula I can also be used in the treatment of certain forms of cancer. Furthermore, the compounds of the formula I can be used to
  • TIE-2 Examination of the activity or expression of TIE-2 can be used. In addition, they are particularly suitable for use in diagnostic procedures for diseases associated with unregulated or impaired TIE-2 activity.
  • the present invention is further directed to methods for the regulation, modulation or inhibition of VEGFR-2 for the prevention of OQ and / or treatment of disorders associated with unregulated or impaired VEGFR-2 activity.
  • the present invention furthermore relates to the compounds of the formula I as inhibitors of Raf kinases.
  • Protein phosphorylation is a fundamental process for the regulation of cellular functions. The coordinated action of both protein kinases as well as phosphatases controls the levels of phosphorylation and consequently the activity of specific target proteins.
  • One of the predominant roles of protein phosphorylation is in signal transduction when extracellular signals are amplified and encoded by a cascade of protein 5
  • Phosphorylation and dephosphorylation events e.g. B, be propagated in the p21 ras / raf way.
  • the p21 ras gene was discovered as an oncogene of the Harvey and Kirsten rat 10 sarcoma viruses (H-ras and K-ras, respectively).
  • H-ras and K-ras characteristic mutations in the cellular Ras gene (c-Ras) have been implicated in many different types of cancer.
  • c-Ras characteristic mutations in the cellular Ras gene
  • These mutant alleles that make Ras constitutively active have been shown to cells ⁇ 5 such as the murine cell line NIH 3T3, transformed into culture.
  • the p21 ras oncogene is an important contributory factor in the development and progression of human solid carcinomas and is mutated in 30% of all human carcinomas (Bolton et al (1994) Ann. Rep. Med. Chem.
  • Ras protein is a key element of the signal transduction cascade, which is controlled by growth factor receptors in almost all tissues (Avruch et al., (1994) Trends Biochem., Pp. 25, 19, 279-83 ).
  • Ras is a guanine nucleotide binding protein, and cycling between a GTP-bound activated and a GDP-2Q-linked quiescent form is strictly controlled by Ras-endogenous GTPase activity and other regulatory proteins.
  • the Ras gene product binds to guanine triphosphate (GTP) and guanine diphosphate (GDP) and hydrolyzes GTP to GDP. Ras is active in the GTP-bound state. In the Ras mutants in cancer cells, endogenous GTPase activity is abolished.
  • Ras proto-oncogene requires a functionally intact C-RaM proto-oncogene to be expressed in higher eukaryotes by receptor and non-5
  • Ras Activated Ras is necessary for the activation of the C-Raf-1 proto-oncogene, and the biochemical steps by which Ras activates the Raf-1 protein
  • Raf kinase by antisense oligodeoxynucleotides
  • inhibition of Raf kinase in vitro and in vivo has been correlated with the inhibition of growth of a variety of human tumor types (Monia et al., Nat. Med. 1996, 2, 668 -75).
  • Raf serine and threonine-specific protein kinases are cytosolic enzymes that stimulate cell growth in a variety of cell systems (Rapp, UR, et al., (1988) The Oncogene Handbook; T. Curran, EP Reddy and A Skalka (ed.) Elsevier Science Publishers, The Netherlands, pp. 213-253; Rapp, UR, et al. (1988) CoId Spring Harbor Sym. Quant. Biol. 53: 173-184; Rapp, UR, et al. (1990) Inv Curr. Top. Microbiol. Immunol. Potter and Melchers (ed.), Berlin, Springer-Verlag 166: 129-139).
  • Raf genes are proto-oncogenes: they can initiate malignant transformation of cells when expressed in specifically altered forms. Genetic alterations leading to oncogenic activation produce a constitutively active protein kinase by removal or interference with an N-terminal negative regulatory domain of the protein (Heidecker, G., et al. (1990) Mol. Cell. Biol. 10: 2503-2512 Rapp, UR, et al., (1987), Oncogenes and Cancer; SA Aaronson, J. Bishop, T. Sugimura, M. Terada, K. Toyoshima, and PK Vogt (ed.) Japan
  • Raf-1 protein serine kinase is a candidate for "downstream" Mitogen signal transduction effector, as Raf oncogenes counteract the growth arrest resulting from blockage of cellular Ras activity due to cellular mutation (Ras revertant cells) or microinjection of anti-Ras antibodies (Rapp, UR, et al (1988) in The Oncogene Handbook, T. Curran, EP Reddy and A. Skalka (eds), Elsevier Science Publishers, The Netherlands, pp. 213-253; Smith, MR, et al. (1986) Nature (London). 320: 540-543).
  • Growth factors include thrombocyte-derived growth
  • PDGF Tumor Factor
  • the transiently activated Raf-1 protein serine kinase translocates into the perinuclear area and the
  • Raf-oncogenes activate transcription from Ap-1 / PEA3-dependent promoters in transient transfection assays (Jamal, S., et al. (1990) Science 344: 463-466; Kaibuchi, K., et al. (1989) J. Biol. Chem. 264 : 20855-20858; Wasylyk, C, et al. (1989) Mol. Cell. Biol. 9: 2247-2250).
  • Raf-1 protein phosphorylation may be a consequence of a kinase
  • the compounds according to the invention are inhibitors of the enzyme Raf kinase. Since the enzyme is a "downstream" effector of p21 ras , the inhibitors in pharmaceutical compositions prove useful for human or veterinary use when inhibiting the Raf kinase pathway, eg, in the treatment of tumors and / or by
  • Compounds are particularly useful in the treatment of solid Carcinomas in humans and animals, eg. As murine cancer, since the progression of these cancers is dependent on the Ras protein signal transduction cascade and therefore responds to the treatment by interrupting the cascade, ie by inhibiting the Raf kinase. Accordingly, the compound of the invention or a pharmaceutically acceptable salt thereof is administered for the treatment of diseases mediated by the Raf kinase pathway, especially cancer, including solid carcinomas such as, for example
  • Carcinomas eg, the lungs, pancreas, thyroid, urinary bladder, or colon
  • myeloid diseases eg, myeloid leukemia
  • adenomas eg, villous colon adenoma
  • the compounds of the invention interact with signaling pathways, particularly the signaling pathways described herein, and preferably the Raf kinase signaling pathway
  • the compounds of the invention preferably exhibit beneficial biological activity which is readily detectable in enzyme-based assays, for example assays as described herein. In such enzyme-based assays, and show the
  • 3 Q compounds of the invention preferably has an inhibiting effect, which usually carried ICso values in a suitable range, preferably in the micromolar range and more preferably will be documented in the nanomolar range.
  • the invention Compounds useful in the prophylaxis and / or treatment of diseases which are dependent on said signaling pathways by interaction with one or more of said signaling pathways.
  • preferred subject of the invention are therefore compounds of the invention as promoters or inhibitors, preferably as inhibitors of Raf kinase.
  • a more preferred object of the invention are compounds according to the invention as promoters or inhibitors,
  • a c is preferred as inhibitors of one or more Raf kinases selected from the group consisting of A-Raf, B-Raf and C-Raf-1.
  • a particularly preferred subject matter of the invention are compounds according to the invention as promoters or inhibitors, preferably as inhibitors of C-Raf-1. 20
  • Another object of the present invention is the use of one or more compounds of the invention in the treatment and / or prophylaxis of diseases, preferably the described here
  • Raf kinases 25 include diseases caused, mediated and / or propagated by Raf kinases, and in particular mediated diseases caused by Raf kinases selected from the group consisting of A-Raf, B-Raf and C-Raf-1, and / or propagated.
  • mediated diseases caused by Raf kinases selected from the group consisting of A-Raf, B-Raf and C-Raf-1, and / or propagated.
  • Cancer-like diseases of which arthritis, inflammation, immunological diseases, autoimmune diseases and immune Weaknesses are usually regarded as non-hyperproliferative disorders.
  • pancreatic cancer liver cancer, kidney cancer, colorectal cancer, breast cancer,
  • cancerous diseases all of which are commonly considered to be hyperproliferative disorders.
  • cancerous diseases all of which are commonly considered to be hyperproliferative disorders.
  • Cell growth, and in particular Raf kinase-mediated, cancerous cell growth is a disease that is an object of the present invention.
  • the present invention therefore relates to compounds according to the invention as medicaments and / or medicaments.
  • the compounds of the invention are administered to a patient with a hyperproliferative disorder, e.g. To inhibit tumor growth, to reduce inflammation associated with a 3Q lymphoproliferative disease
  • the graft rejection or neurological.ee. Damage due to tissue repair, etc.
  • the present compounds are useful for prophylactic or therapeutic purposes.
  • the term "treating" is used as reference to both
  • Prevention of proliferation is by Administration of the compounds of the invention prior to the development of the obvious disease, e.g. To prevent tumor growth, prevent metastatic growth, reduce cardiovascular surgery-related restenosis, etc.
  • the compounds are used to treat persistent diseases by stabilizing or ameliorating the clinical symptoms of the patient.
  • the host or patient may be of any mammalian species, e.g. A primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for the treatment of human disease.
  • the susceptibility of a particular cell to treatment with the compounds of the invention can be determined by testing in vitro.
  • a culture of the cell is combined with a compound of the invention at various concentrations for a period of time sufficient to allow the active agents to induce cell death or inhibit migration, usually between about one hour and one week.
  • cultured cells from a biopsy sample can be used. The viable cells remaining after treatment are then counted.
  • the dose will vary depending on the specific compound used, the specific disease, the patient status, etc.
  • a therapeutic dose will be sufficient to substantially reduce the undesired cell population in the target tissue, while the
  • Viability of the patient is maintained. Treatment is generally continued until there is a significant reduction, e.g. B. at least about 50% reduction in cell load and can continue until substantially no more unwanted cells are detected in the body.
  • Interactions between different signal transduction pathways have been developed by various scientists as appropriate models or model systems, e.g. Cell culture models (e.g., Khwaja et al., EMBO, 1997, 16, 2783-93) and models of transgenic animals (e.g., White et al., Oncogene, 2001, 20, 7064-7072).
  • interacting compounds can be used to modulate the signal (e.g., Stephens et al., Biochemical J., 2000, 351, 95-105).
  • the compounds according to the invention can also be used as reagents for testing kinase-dependent signal transduction pathways in animals and / or cell culture models or in the clinical diseases mentioned in this application.
  • HTR-FRET Homogeneous Time-resolved Fluorescence Resonance Energy transfer
  • FP fluorescence polarization
  • Non-radioactive ELISA assay methods use specific phospho-antibodies (Phospho-AK).
  • Phospho-AK binds only the phosphorylated substrate. This binding is detectable by chemiluminescence with a second peroxidase-conjugated anti-sheep antibody (Ross et al., 2002, Biochem J., just prior to publication, manuscript BJ20020786).
  • the ailments of interest include, but are not limited to, the following conditions.
  • the compounds of the present invention are useful in the treatment of a variety of conditions in which proliferation and / or migration of smooth muscle cells and / or inflammatory cells into the intimal layer of a vessel results in limited blood flow to that vessel, e.g. In neointimal occlusive lesions.
  • Occlusive transplant vascular diseases of interest include atherosclerosis, coronary vascular disease after transplantation, vein graft stenosis, peri-anastomotic prosthetic restenosis, restenosis after angioplasty or stent placement, and the like.
  • the compounds according to the invention are also suitable as p38 kinase inhibitors.
  • Heteroaryl ureas which inhibit p38 kinase are described in WO 02/85859, WO 02/85857 W ⁇ 99 / 32111. STATE OF THE ART
  • the invention relates to compounds of the formula I.
  • X is CH or N, with the proviso that at most one X is N,
  • R 1 R Hal, CN, NO 2 , NHR, NRR 1 , NHCOR, NHSO 2 R, OR, COR,
  • R 2 Ar, Het, OR, NHR, NRR 1 , NR 5 CHO or NR 5 COA,
  • R, R ' are each, independently of one another, H, A, Ar, (CH 2 ) n Het or -Y-Ar, R 4 is Hal, OH, CN, NO 2 , A, OA or SA,
  • Y is an alkylene chain having 1-8 C atoms, which may be monosubstituted, disubstituted or trisubstituted by R 4 , and in which also one, two or three CH 2 groups may be replaced by O,
  • A, A ' are each independently of one another straight or branched alkyl having 1-10 C atoms, in which one, two or three
  • CH 2 groups by O 1 S, SO 1 SO 2 , NH and / or by CH CH groups and / or 1-5 H atoms by F and / or
  • Chlorine can be replaced
  • NCOOR 5 can be replaced, Alk alkenyl with 2-6 C atoms,
  • Ar is unsubstituted or mono-, di- or trisubstituted by Hal, A,
  • Phenyl, naphthyl or biphenyl, Z is Het a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N-, O- and / or S-
  • Carbonyl oxygen may be substituted
  • R 5 is H or A
  • Ar ' is unsubstituted or mono-, di- or trisubstituted by A, OA,
  • Hal is F, Cl, Br or I 1 , and their pharmaceutically usable derivatives, solvates, salts, tautomers and stereoisomers, including mixtures thereof in all ratios.
  • the invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.
  • Solvates of the compounds are understood to mean additions of inert solvent molecules to the compounds which form due to their mutual attraction. Solvates are e.g. Mono or dihydrate or alcoholates.
  • Pharmaceutically usable derivatives are understood, for example, as the salts of the compounds according to the invention as well as so-called prodrug compounds.
  • biodegradable polymer derivatives of the compounds of the invention include biodegradable polymer derivatives of the compounds of the invention, as z. In Int. J. Pharm. 115, 61-67 (1995).
  • the term "effective amount” means the amount of a drug or pharmaceutical agent which elicits a biological or medical response in a tissue, system, animal or human, e.g. sought or desired by a researcher or physician.
  • terapéuticaally effective amount means an amount that, compared to a corresponding subject, this
  • Quantity has not resulted in: improved treatment, cure, prevention or elimination of a
  • Illness a disease picture, a disease state, one Suffering, a disorder or side effects or even the reduction of the progression of a disease, a disease or a disorder.
  • terapéuticaally effective amount also includes the
  • the invention also provides the use of mixtures of the compounds of formula I, e.g. Mixtures of two diastereomers, e.g. in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereoisomeric compounds.
  • the invention relates to the compounds of the formula I and their
  • R 2 -CH CH 2 IM, wherein R 2 has the meaning given in claim 1,
  • R 3 has the meaning given in claim 1,
  • radicals R 1 , R 2 , R 3 and X are those in the
  • A is alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4,
  • A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-,
  • A also denotes cycloalkyl.
  • Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl,
  • Alkylene is preferably unbranched and is preferably methylene, ethylene, propylene, butylene or pentylene.
  • R 1 is preferably Hal.
  • R 2 is preferably Het, NR 5 CHO or NR 5 COA.
  • R 2 particularly preferably 2-oxo-pyrrolidin-1-yl.
  • R 3 is preferably 2,3-dichlorophenyl, 3-bromophenyl, 2-fluoro-4-chloro-phenyl, 4-ethylphenyl, 3-chlorophenyl, 3-trifluoromethylphenyl, 4-tert-butylphenyl, 4-isopropylphenyl, 3 Methylphenyl, 4-propylphenyl, 2-bromophenyl, 3,5-di- (trifluoromethyl) -phenyl, 4-chloro-3-nitrophenyl, 2-fluorophenyl, 2-chlorophenyl, 4-methylphenyl, 2-fluoro-4- bromophenyl, A-
  • R 3 particularly preferably represents mono-, di- or trisubstituted by Hal, 30 nitro, OA and / or A-substituted phenyl.
  • R 5 is preferably H or methyl, more preferably H.
  • Ar means e.g. Phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-,
  • Ar is preferably, for example, unsubstituted or mono-, di- or trisubstituted by Hal, A, OR 5 , N (R 5 ) 2 , NO 2 , (CH 3) n Ar ', O (CH 2 ) n Ar - [C ( R 5) 2] n-COOR 5 and / or -O [C (R 5) 2] 0 -COOR 5 substituted phenyl, particularly preferably unsubstituted or mono-, di- or trisubstituted by
  • Ar ' is preferably unsubstituted or mono-, di- or trisubstituted by Hal, A, OH, OA, NO 2 and / or noxzyl substituted phenyl.
  • Het means e.g. 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, A- or 5-imidazolyl, 1-, 3-, A- or 5-pyrazolyl, 2 -, A- or 5-oxazolyl, 3-, 4- or 5-lsoxazolyl, 2-, A- or 5-Thiazoiyl, 3-, A- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2 -, A-, 5- or 6-pyrimidinyl, further preferably 1,2,3-TriazoM-, -A- or -5-yl, 1, 2,4-triazole-1, -3- or 5-yl , 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4 or -5-yl, 1, 2,4-oxadiazol-3 or -5-yl, 1, 3,4-thiadiazol-2 or -5-yl, 1, 2,4-thiadiazol-3 or -5-
  • Benzo [1,4] oxazinyl more preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4 or -5-yl or 2,1, 3-Benzoxadiazol-5-yl.
  • the heterocyclic radicals may also be partially or completely hydrogenated.
  • B. also mean 2,3-dihydro-2-, -3-, -A- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2 - or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1-, 2-, -3-, -4- or -5- pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -A- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2 - or 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -A- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1, 4 Dihydro
  • the mono- or binuclear saturated, unsaturated or aromatic heterocycle particularly preferably denotes piperidinyl, pyrrolidinyl,
  • Hal preferably denotes F, Cl or Br, but also I 1 particularly preferably F or Cl.
  • Alkenyl has 2, 3, 4, 5 or 6 carbon atoms and is preferably vinyl, 1-O- Q or 2-propenyl, 1-butenyl, isobutenyl, sec-butenyl, furthermore preferred is 1-pentenyl, iso-pentenyl or 1-hexenyl.
  • the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings given above.
  • Some preferred groups of compounds may be through the following
  • R 1 is H or Hal
  • Atoms in which 1-5 H atoms may be replaced by F and / or chlorine means 25;
  • Hal, A, OR 5, N (R 5) 2, NO 2, (CH 2) ⁇ Ar ⁇ 0 (CHz) n Ar 1, - [C (R 5) 2] n -COOR 5 and / or -O [C (R 5) 2] 0 -COOR 5 substituted phenyl, naphthyl or biphenyl, or a mono- or bicyclic unsaturated or aromatic heterocycle having 1 to 3 N and / or O atoms, which mono-, di- or trisubstituted by A, Hal, (CH 2 ) n Ar 'and / or O (carbonyl oxygen) may be substituted;
  • R 1 is H or Hal
  • R 2 is a monocyclic saturated heterocycle having 1 to 2
  • Carbonyl oxygen may be substituted
  • R 3 is unsubstituted or monosubstituted, disubstituted or trisubstituted
  • Ar 1 is unsubstituted or mono-, di- or trisubstituted by A,
  • R 5 is H or A
  • Hal is F, Cl, Br or I; 10 in Il R 2 represents 2-oxopyrrolidin-1-yl or 2-oxo-piperidin-1-yl;
  • the position is prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart) under reaction conditions which are suitable for the 25 known reactions are known and suitable.
  • compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of formula III and IV are reacted.
  • the reaction is preferably carried out as a one-pot reaction.
  • the compounds of formula II, III and IV are known in the rule. 35
  • the reaction is generally carried out in an inert solvent, if appropriate in the presence of an inorganic or organic acid.
  • the reaction time depending on the conditions used, between a few minutes and 14 days, the reaction temperature between about -15 ° and 150 °, normally between -5 ° and 60 °, particularly preferably between 0 and 2O 0 C.
  • Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DM
  • Carboxylic acids such as formic acid or acetic acid; Nitro compounds like
  • the abovementioned compounds according to the invention can be used in their final non-salt form.
  • the present invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases according to procedures known in the art.
  • Pharmaceutically acceptable salt forms of the compounds of formula I are for the most part prepared conventionally. If the compound of formula I is a carbonyl
  • Acid group one of its suitable salts can be formed by reacting the compound with a suitable base.
  • reacting base addition salt Such bases include, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, eg, potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine and N-methylglutamine.
  • alkali metal hydroxides including potassium hydroxide, sodium hydroxide and lithium hydroxide
  • Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide
  • Alkali metal alcoholates eg, potassium ethanolate and sodium propanolate
  • various organic bases such as piperidine, diethanolamine and N-methylglutamine.
  • the aluminum salts of the compounds of formula I are also included.
  • acid addition salts can be formed by adding these
  • J 5 and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like. Accordingly, pharmaceutically acceptable acid addition
  • the base salts of the compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium -
  • Salts of compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, eg arginine, betaine, Caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine 5 (benzathine), dicyclohexylamine, diethariolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine , Hydrabamine, iso-propylamine, lidocaine, lysine,
  • Compounds of the present invention containing basic nitrogen-containing groups can be formulated with agents such as (C 1 -C 4 ) alkyl halides, eg, methyl, ethyl, isopropyl, and tert-butyl chloride, bromide, and iodide; Di (C 1 -C 4 ) alkyl sulfates, eg dimethyl, diethyl and diamylsulfate; (C 10 - Q Ci 8 ) alkyl halides, for example decyl, dodecyl, lauryl, myristyl and
  • Preferred pharmaceutical salts include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate,
  • the acid addition salts of basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner.
  • the free base can be achieved by contacting the salt form with a base and isolating the free base in a conventional manner regenerate ⁇ K.
  • the free base forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; however, in the context of the invention, the salts otherwise correspond to their respective free base forms.
  • the pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines.
  • metals or amines such as alkali metals and alkaline earth metals or organic amines.
  • Preferred metals are sodium, potassium, magnesium and calcium.
  • Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
  • the base addition salts of acidic compounds according to the invention are prepared by bringing the free acid form with a sufficient amount of the desired base, causing the formation of the salt in the conventional manner.
  • the free acid can be passed through
  • a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the invention also encompasses multiple salts.
  • Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.
  • the pharmaceutically acceptable salt form of the active ingredient may also first impart a desired pharmacokinetic property to this active ingredient, which it has not previously possessed, and may even have pharmacodynamics
  • the invention furthermore relates to medicaments comprising at least O0 a compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.
  • compositions may take the form of dosage units containing
  • Such a unit may, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound according to the invention, depending on the treated disease state, the route of administration and the age, weight and
  • Condition of the patient, or pharmaceutical formulations may be in 5
  • dosage units containing a predetermined amount of active ingredient per dosage unit.
  • Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof of a 10% active ingredient. Furthermore, such pharmaceutical
  • compositions can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous,
  • Such formulations may be prepared by any method known in the pharmaceutical art, such as by bringing the active ingredient together with the carrier (s) or excipient (s) 25.
  • compositions adapted for oral administration may be presented as separate entities, such as capsules or tablets; Powders 30 or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • Tablet or capsule containing the active substance component with an oral, non- toxic and pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc. combine.
  • Powders are prepared by comminuting the compound to a suitable fine size and using a similarly comminuted pharmaceutical grade
  • Carrier such as e.g. an edible carbohydrate such as starch or mannitol.
  • a flavor, preservative, dispersant and dye may also be present.
  • Capsules are made by preparing a powder mixture as described above and filling shaped geiatin shells therewith.
  • Lubricants such as e.g. fumed silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process.
  • Disintegrants or solubilizers e.g. Agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.
  • Lubricants and disintegrants as well as dyes are also incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars, e.g. Glucose or beta-lactose, sweet corn sweeteners, natural and synthetic gums, e.g. acacia,
  • the lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc.
  • the disintegrating agents include, but are not limited to, starch, methylcellulose, agar, Bentonite, xanthan gum, etc.
  • the tablets are formulated by, for example, preparing a powder mix, granulating or dry-pressing, adding a lubricant and a disintegrant, and pressing the whole into tablets.
  • a powder mixture is prepared by mixing the appropriately comminuted compound with a diluent or a base, as described above, and optionally with a binder, such as carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a Wegsverlangsamer, such as paraffin, a absorption accelerator, such as a quaternary salt and / or an absorbent, such as bentonite, kaolin or dicalcium phosphate, is mixed.
  • the powder mixture can be granulated by wetting it with a binder such as syrup, starch paste, Acadia slime or solutions of cellulose or polymer materials and pressing it through a sieve.
  • a binder such as carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a Wegsverlangsamer, such as paraffin, a absorption accelerator, such as a quaternary salt and / or an absorbent, such as bentonite, ka
  • Granulation can run the powder mixture through a tableting machine, resulting in irregularly shaped lumps, which are broken up into granules.
  • the granules may be greased by adding stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets.
  • the compounds of the invention can also be used with a free-flowing inert
  • a transparent or opaque protective layer consisting of a shellac sealant, a layer of sugar or polymeric material, and a glossy layer of wax may be present. Dyes can be added to these coatings in order to differentiate between different dosage units.
  • Oral fluids e.g. Solution, syrups and elixirs
  • Oral fluids e.g. Solution, syrups and elixirs
  • Syrups can be prepared by dissolving the compound in an appropriate taste aqueous solution while preparing elixirs using a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, among others may also be added. 5
  • the unit dosage formulations for oral administration may optionally be encapsulated in microcapsules.
  • the formulation may also be prepared to prolong or retard the release, such as by coating or embedding particulate material in polymers, wax, and the like.
  • Liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles administered.
  • Liposomes can be made of different phospholipids, such as
  • the compounds of formula I as well as the salts, solvates and physiologically functional derivatives thereof may also be prepared using monoclonal antibodies as individual carriers to which the compound molecules
  • the compounds can also be coupled with soluble polymers as targeted drug carriers.
  • Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol
  • O is Q or polyethylene oxide polylysine substituted with palmitoyl radicals.
  • the compounds can be attached to a class of biodegradable polymers which are suitable for the controlled release of a drug, eg polylactic acid, polyepsulfon-caprolactone,
  • Polyhydroxybutyric acid Polyorthoesters, polyacetals, polydihydroxy
  • compositions adapted for transdermal administration may be presented as discrete patches for prolonged, intimate contact with the epidermis of the recipient.
  • the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
  • Pharmaceutical compounds adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient may be either paraffinic or water-miscible
  • Cream base can be used.
  • the active ingredient may become 0
  • Cream can be formulated with an oil-in-water cream base or a water-in-oil base.
  • the pharmaceutical formulations adapted for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, in particular an aqueous solvent.
  • Formulations include lozenges, lozenges and mouthwashes.
  • compositions adapted for rectal administration may be presented in the form of suppositories or enemas.
  • Pharmaceutical formulations adapted for nasal administration in which the vehicle is a solid contain a coarse powder having a particle size, for example in the range of 20-500 microns, which is administered in the manner in which snuff is received, ie by rapid inhalation via the nasal passages from a container held close to the nose with the powder.
  • Suitable formulations for administration as a nasal spray or nasal drops with a fluid carrier comprise 10 drug solutions in water or oil.
  • adapted pharmaceutical formulations encompass finely particulate dusts or mists
  • the various means of ⁇ 5 types of pressurized dispensers with aerosols, nebulisers or insufflators can be generated.
  • Formulations can be used as pessaries, tampons, creams, gels, pastes,
  • Foams or spray formulations are presented.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection
  • formulations may be presented in single or multi-dose containers, eg, sealed vials and vials, and stored in the freeze-dried (lyophilized) state such that only the addition of the sterile carrier liquid, eg water for
  • Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets. It will be understood that in addition to the above particularly mentioned ingredients, the formulations may include other means conventional in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration may contain flavorings.
  • a therapeutically effective amount of a compound of formula I depends on a number of factors, including e.g. the age and
  • an effective amount of a compound of the invention is useful for the treatment of neoplastic growth, e.g. Colon or breast carcinoma, generally in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day and more typically in the range of 1 to 10 mg / kg body weight per
  • the actual amount per day would usually be between 70 and 700 mg, this amount being given as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same.
  • An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a proportion of the effective amount of the compound of the invention per se. It can be assumed that similar dosages are suitable for the treatment of the other, above-mentioned disease states.
  • the invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable compounds thereof
  • the invention is also a set (kit), consisting of separate packages of
  • the kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
  • suitable containers such as boxes or boxes, individual bottles, bags or ampoules.
  • the set may, for example, comprise separate ampoules each containing an effective amount of a 15 compound of the formula I and / or pharmaceutically usable
  • the present compounds are suitable as pharmaceutical active he, fabrics for mammals, especially for humans, in the treatment of tyrosine kinase-25 diseases.
  • diseases include the proliferation of tumor cells, pathological neovascularization (or angiogenesis) that promotes the growth of solid tumors, neovascularization in the eye (diabetic retinopathy, age-related macular degeneration)
  • the present invention includes the use of the compounds of formula I and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of Cancer.
  • Preferred carcinomas for the treatment are from the group of brain carcinoma, genitourinary tract carcinoma, carcinoma of the lymphatic system, gastric carcinoma, laryngeal carcinoma and lung carcinoma.
  • Another group of preferred forms of cancer are monocytic leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma.
  • J 5 eye disease such as retinal vascularisation, diabetic retinopathy, age-related macular degeneration and the like.
  • Such inflammatory diseases include, for example, rheumatoid arthritis, psoriasis, contact dermatitis, late-type hypersensitivity reaction, and the like.
  • 3Q suffering in a mammal said method administering to a diseased mammal in need of such treatment a therapeutically effective amount of a compound of the invention.
  • the therapeutic amount depends on the particular disease and can be determined by the skilled person without great effort.
  • the present invention also encompasses the use of compounds of the formula I and / or their physiologically acceptable salts and Solvates for the manufacture of a medicament for the treatment or
  • Methods for the treatment or prevention of ocular diseases such as diabetic retinopathy and age-related macular degeneration are also part of the invention.
  • ocular diseases such as diabetic retinopathy and age-related macular degeneration
  • the use for treating or preventing inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis and late-type hypersensitivity reactions, as well as the treatment or prevention of bone pathologies from the group of osteosarcoma, osteoarthritis and rickets, is also within the scope of the present invention.
  • tyrosine kinase-related diseases or conditions refers to pathological conditions that are dependent on the activity of one or more tyrosine kinases.
  • the tyrosine kinases are involved either directly or indirectly in the signal transduction pathways of various cellular activities, including proliferation, adhesion and migration as well as differentiation
  • Diseases associated with tyrosine kinase activity include the proliferation of tumor cells, the pathological vascular regeneration that promotes the growth of solid tumors, neovascularization in the tumor
  • Eye diabetic retinopathy, age-related macular degeneration and the like
  • inflammation psoriasis, rheumatoid arthritis and the like.
  • the compounds of formula I can be administered to patients for the treatment of cancer.
  • the present compounds inhibit tumor angiogenesis and thus affect the growth of tumors (Rak, Rak et al., Cancer Research, 55: 4575-4580, 1995).
  • the angiogenesis-inhibiting properties of the present compounds of formula I are also useful in the treatment of certain forms of blindness associated with retinal neovascularization.
  • the compounds of the formula I are also suitable for the treatment of certain bone pathologies such as osteosarcoma, osteoarthritis and
  • Rickets also known as oncogenic osteomalacia (Hasegawa et al., Skeletal Radiol., 28: 41-45, 1999; Gerber et al., Nature Medicine, Vol. 5, No. 6, p. 623-628, June 1999).
  • VEGF directly promotes osteoclastic bone resorption by KDR / Flk-1 expressed in mature osteoclasts (FEBS Let. 473: 161-164 (2000); Endocrinology, 141: 1667 (2000))
  • the present compounds are also useful in the treatment and prevention of conditions associated with bone resorption, such as osteoporosis and Paget's disease.
  • the compounds may be damaged by causing cerebral edema,
  • the invention thus relates to the use of compounds of the formula I, and their pharmaceutically usable derivatives, solvates and stereoisomers, including mixtures thereof in all
  • Conditions for the manufacture of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of signal transduction of kinases plays a role in which the inhibition, regulation and / or modulation of signal transduction of kinases plays a role.
  • kinases selected from the group of tyrosine kinases and Raf kinases are preferred here.
  • the tyrosine kinases are TIE-2, VEGFR 1 PDGFR, FGFR and / or FLT / KDR.
  • the compounds of the formula I inhibit or regulate the
  • IR insulin receptor
  • IRR insulin-like growth factor-1
  • ROS ROS
  • ALK ALK
  • LTK LTK
  • TIE-1 TIE-2
  • Particularly preferred is the use for the manufacture of a medicament for the treatment of diseases which are affected by the inhibition of TIE-2, VEGFR, PDGFR, FGFR and / or FLT / KDR by the compounds of claim 1.
  • a disease wherein the disease is a solid tumor.
  • the solid tumor is preferably selected from the group of
  • the solid tumor is furthermore preferably selected from the group of lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma, colon carcinoma and breast carcinoma.
  • a tumor of the blood and immune system preferably for the treatment of a tumor selected from the group of acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia and / or chronic lymphocytic leukemia.
  • the invention furthermore relates to the use of the compounds of the formula I for the treatment of a disease in which angiogenesis is involved.
  • the disease is an eye disease.
  • the invention furthermore relates to the use for the treatment of retinal vascularization, diabetic retinopathy, age-related macular degeneration and / or inflammatory diseases.
  • the inflammatory disease is preferably selected from the group rheumatoid arthritis, psoriasis, contact dermatitis and late-type,. 5 of the hypersensitivity reaction comes.
  • the invention further relates to the use of the compounds according to the invention for the treatment of bone pathologies, wherein the bone pathology from the group osteosarcoma, osteoarthritis and
  • the compounds of the formula I are suitable for the preparation of a
  • Raf kinases 25 Drug for the treatment of diseases caused, mediated and / or propagated by Raf kinases 25, wherein the Raf kinase is selected from the group consisting of A-Raf, B-Raf and Raf-1.
  • the use for the treatment of diseases preferably from the group of hyperproliferative and non- 3Q hyperproliferative diseases.
  • the non-cancerous diseases are selected from the group consisting of psoriasis, arthritis, inflammation, endometriosis,
  • the cancerous diseases are selected from the group consisting of brain cancer, lung cancer, squamous cell cancer, bladder cancer,
  • Stomach cancer pancreatic cancer, liver cancer, kidney cancer, colorectal cancer,
  • Cancer thyroid cancer, lymphoma, chronic leukemia and acute leukemia.
  • the compounds of formula I may also be coadministered with other well-known therapeutics selected for their particular suitability for the condition being treated.
  • the antiresorptive bisphosphonates such as alendronate and risedronate, integrin blockers (as defined below) such as ⁇ v ⁇ 3 antagonists, conjugated estrogens used in hormone therapy such as Prempro®, Premarin® and Endometrion®; selective estrogen receptor modulators
  • SERMs such as raloxifene, droloxifene, CP-336,156 (Pfizer) and lasofoxifene
  • Cathepsin K inhibitors and ATP proton pump inhibitors are included.
  • the present compounds are also useful for combination with known anticancer agents.
  • known anticancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other angiogenesis inhibitors.
  • the present compounds are particularly suitable for co-administration with radiotherapy. The synergistic effects of inhibiting VEGF in combination with radiotherapy have been described in the art (see WO 00/61186).
  • Estrogen receptor modulators refers to compounds that have the
  • estrogen receptor modulators include, for example, tamoxifen, raloxifene, idoxifen, LY353381, LY 117081, toremifene, fulvestrant, 4- [7- (2,2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1 - piperidinyl) ethoxy] phenyl] -2H-1-benzopyran-3-yl] phenyl 2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646, but this is not intended to be limiting.
  • “Androgen receptor modulators” refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of how this occurs
  • Androgen receptor modulators include, for example, finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
  • Retinoid receptor modulators refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of how this occurs.
  • uch retinoid receptor modulators include, for example, bexarotene, tretinoin, 13-cis-retinoic acid.
  • Cytotoxic agents refers to compounds that cause cell death, primarily by direct action on cell function, or that inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors.
  • the cytotoxic agents include, for example, tirapazimine, Sertenef, cachectin, ifosfarnide, tasonermine, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcite, ranimustine, fotemustine, nedaplatin, oxaliplatin,
  • Temozolomide Heptaplatin, Estramustine, Improsulfan-tosylate, Trofosfamide, Nimustin, Dibrospidium chloride, Pumitepa, Lobaplatin, Satraplatin, Profiromycin, Cisplatin, Irofulvene, Dexifosfamide, cis-Amine dichloro (2-methylpyridine) platinum, Benzylguanine, Glufosfamide, GPX100,
  • microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, 3 ', 4'-didehydro-4'-deoxy-8'-norvincaleukoblastin, docetaxol, rhizoxin, dolastatin, mivobulinisethionate, auristatin, cemadotin, RPR109881, BMS184476, Vinflunine, Cryptophycin, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine, N 1 N-dimethyl-L-valyl-L-valyl! -N-methyl- L-valy
  • Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecane, 6-ethoxypropionyl-3 ', 4'-O-exo-benzylidene-chartreusine, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4; 5-kl] acridine-2
  • Antiproliferative agents include antisense RNA and DNA
  • Oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and
  • antiproliferative agents also include other monoclonal antibodies to growth factors than those already listed under the “angiogenesis inhibitors”, such as trastuzumab, as well as tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see, eg, US Patent No. 6,069,134 ).
  • the invention further relates to the use of the compounds of formula I for the manufacture of a medicament for the treatment of diseases, wherein the disease is characterized by impaired angiogenesis.
  • the disease is preferably
  • the disturbed angiogenesis preferably results from a disturbed
  • VEGFR-1, VEGFR-2 and / or VEGFR-3 activity are particularly preferred.
  • VEGF receptor kinase activity is determined by incorporation of radiolabelled phosphate into 4: 1 polyglutamic acid / tyrosine substrate (pEY).
  • the phosphorylated pEY product is captured on a filter membrane and the incorporation of radiolabelled phosphate is quantitated by scintillation counting.
  • the intracellular tyrosine kinase domains of human KDR (Terman, BI et al Oncogene (1991) Vol. 6, pp. 1677-1683) and Flt-1 (Shibuya, M. et al., Oncogene (1990) Vol , Pp. 519-524) were cloned as glutathione-S-transferase (GST) gene fusion proteins. This was accomplished by cloning the cytoplasmic domain of KDR kinase as a read-fit merger at the carboxy-terminus of the GST gene.
  • GST glutathione-S-transferase
  • the soluble recombinant GST kinase domain fusion proteins were engrafted into Spodoptera frugiperda (Sf21) insect cells (Invitrogen) Use of a baculovirus expression vector (pAcG2T,
  • Tris pH 7.4 50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.5% Triton X-5
  • BSA Bovine Serum Albumin
  • Substrate 25 750 ⁇ g / ml poly (glutamic acid / tyrosine 4: 1) (Sigma).
  • Millipore #MAFC NOB GF / C 96-well fiberglass board.
  • the Sf21 cells were infected with the recombinant virus at a m.o.i.
  • HUVECs at rest 2 hours before the addition of VEGF or bFGF The mitogenic response to VEGF or bFGF is determined by measuring the incorporation of [ 3 H] thymidine into the cell DNA
  • Frozen HUVECs as primary culture isolates are purchased from Clonetics Corp. 1 n .
  • the cells are obtained in the endothelial growth medium (EGM; Clonetics) and used in the 3rd to 7th passage for the mitogenicity assays.
  • EMM endothelial growth medium
  • NUNCLON 96-Well Polystyrene Tissue Culture Plates (NUNC # 167008).
  • test compounds Dulbecco's modified Eagle's medium with 1 g / ml glucose (low glucose DMEM; Mediatech) plus 10% (v / v) fetal bovine serum (Clonetics). 20 test compounds
  • HUVEC monolayers maintained in EGM are harvested by trypsin treatment and incubated at a density of 4000 cells per 100 ⁇ l assay.
  • the growth stop medium is replaced with 100 ⁇ l of assay medium containing either the constituent (0.25% [v / v] DMSO) or the desired final concentration of the test compound. All provisions will be
  • the cells are then incubated at 37 ° C / 5% CO 2 .
  • OQ washed (400 ul / well, then 200 ul / well).
  • the washed, adherent cells are then solubilized by adding cell lysis solution (100 ⁇ l / well) and heating at 37 ° C for 30 minutes.
  • the cell lysates are transferred to 7 ml glass scintillation vials containing 150 ⁇ l of water. It is mixed with the scintillation cocktail (5
  • the compounds of the formula I are VEGF inhibitors and are therefore suitable for the inhibition of angiogenesis, as in the treatment of ocular diseases, eg diabetic retinopathy, and for the treatment of carcinomas, eg solid tumors.
  • the present compounds inhibit VEGF-stimulated mitogenesis of cultured human vascular endothelial cells with HK50 values of 0.01-5.0 ⁇ M.
  • the r / E-2 tests can, for example, analogous to the ⁇ indicated in WO 02/44156 five methods are carried out.
  • the assay determines the inhibitory activity of the substances to be tested in the phosphorylation of the substrate poly (Glu, Tyr) by Tie-2 kinase in the presence of radioactive 33 P-ATP.
  • the phosphorylated substrate poly Glu, Tyr
  • Substrate binds to the surface during incubation
  • Flash microtitre plate After removal of the reaction mixture is washed several times and then measured the radioactivity on the surface of the microtiter plate. An inhibitory effect of the substances to be measured results in a lower radioactivity compared to an undisturbed enzymatic reaction.
  • “usual work-up” means: add water if necessary, adjust to pH values between 2 and 10, if necessary, depending on the constitution of the final product, extract with ethyl acetate or dichloromethane, separate, dry the organic phase over sodium sulfate, evaporated and purified by chromatography
  • APCI-MS atmospheric pressure chemical ionization - mass spectrometry (M + H) + .
  • PerkinElmer Proximity Homogeneous Assay
  • the AlphaScreen test is based on traditional kinase testing with the
  • the binding of molecules captured on the beads results in energy transfer from one bead to the other, eventually leading to a luminescence / fluorescence signal.
  • the kinase phosphorylates the biotinylated polypeptide (polyGlu, Tyr, 4: 1) on tyrosine.
  • the phosphorylated biotinylated peptide binds to streptavidin donor "beads" (biotin-streptavidin linkage).
  • streptavidin donor "beads” biotin-streptavidin linkage.
  • the donorbeads When light of 680 nm wavelength is irradiated, the donorbeads produce singlet oxygen, which, with sufficient proximity of the acceptor beads (only when the complex is formed) emits them for emission. j 5 at 520/620 nm.
  • Test procedure The test is carried out in 384-well OptiPlate TM - 384 Art .: 6007290 from Perkin Elmer
  • test substance or standard sample 3.0 ⁇ l
  • Acceptor / donor beads are previously placed in AlphaScreen 5 Detection / Stop buffer (25 mM HEPES buffer with 100 mM NaCl,
  • a solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 l of bidistilled water with 2N hydrochloric acid, filtered sterile, filled into injection jars, lyophilized under sterile conditions and sealed under sterile conditions , Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution is prepared from 1 g of an active ingredient of the formula I 1 9.38 g of NaH 2 PO 4 • 2H 2 O, 28.48 g of Na 2 HPO 4 • 12H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. This solution can be used in the form of eye drops.
  • a mixture of 1 kg of active ingredient of the formula I 1 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is in the usual
  • Tablets are pressed analogously to Example E, which are then coated in the usual way with a coating of sucrose, potato starch, talc, tragacanth and dye.
  • a solution of 1 kg of active compound of the formula I in 60 l of bidistilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each vial contains 10 mg of active ingredient.

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Abstract

La présente invention concerne des composés de formule (I) dans laquelle X, R<SUP>1</SUP>, R<SUP>2</SUP> et R<SUP>3</SUP> ont les significations énoncées dans la revendication 1. Ces composés sont des inhibiteurs des tyrosine kinases, en particulier des TIE-2, et des Raf-kinases et peuvent être utilisées entre autres pour traiter des tumeurs.
EP06706893A 2005-03-10 2006-02-13 Derives de tetrahydro-pyrrolo-quinoleine substitues servant de modulateurs de kinase, plus specialement de tyrosine kinases et de raf-kinases Withdrawn EP1856116A1 (fr)

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DE102005011058A DE102005011058A1 (de) 2005-03-10 2005-03-10 Substituierte Tetrahydro-pyrrolo-chinolinderivate
PCT/EP2006/001281 WO2006094600A1 (fr) 2005-03-10 2006-02-13 Derives de tetrahydro-pyrrolo-quinoleine substitues servant de modulateurs de kinase, plus specialement de tyrosine kinases et de raf-kinases

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WO2010099139A2 (fr) 2009-02-25 2010-09-02 Osi Pharmaceuticals, Inc. Thérapie anti-cancer combinée
EP2401614A1 (fr) 2009-02-27 2012-01-04 OSI Pharmaceuticals, LLC Méthodes d'identification d'agents qui inhibent les cellules cancéreuses mésenchymateuses ou leur formation
JP2012519282A (ja) 2009-02-27 2012-08-23 オーエスアイ・ファーマシューティカルズ，エルエルシー 間葉様腫瘍細胞またはその生成を阻害する薬剤を同定するための方法
WO2010099138A2 (fr) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Procédés pour l'identification d'agents qui inhibent les cellules tumorales de type mésenchymateuses ou leur formation
WO2010146059A2 (fr) 2009-06-16 2010-12-23 F. Hoffmann-La Roche Ag Biomarqueurs pour une thérapie par inhibiteur d'igf-1r
EP2702173A1 (fr) 2011-04-25 2014-03-05 OSI Pharmaceuticals, LLC Utilisation de signatures de gènes de tem dans la découverte de médicaments contre le cancer, diagnostics et traitement du cancer
WO2013152252A1 (fr) 2012-04-06 2013-10-10 OSI Pharmaceuticals, LLC Polythérapie antinéoplasique
MX366703B (es) * 2013-03-15 2019-07-22 Incyte Holdings Corp Heterociclos tricíclicos como inhibidores de la proteína bet.
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US9399640B2 (en) 2013-11-26 2016-07-26 Incyte Corporation Substituted pyrrolo[2,3-c]pyridines and pyrazolo[3,4-c]pyridines as BET protein inhibitors
WO2015081189A1 (fr) 2013-11-26 2015-06-04 Incyte Corporation Hétérocycles bicycliques servant d'inhibiteurs des protéines bet
WO2015095492A1 (fr) 2013-12-19 2015-06-25 Incyte Corporation Hétérocycles tricycliques en tant qu'inhibiteurs des protéines bet
EA034972B1 (ru) 2014-04-23 2020-04-13 Инсайт Корпорейшн 1h-пирроло[2,3-c]пиридин-7(6h)-оны в качестве ингибиторов белков bet
US9527864B2 (en) 2014-09-15 2016-12-27 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
TW201722966A (zh) 2015-10-29 2017-07-01 英塞特公司 Bet蛋白質抑制劑之非晶固體形式
KR102643344B1 (ko) 2016-06-20 2024-03-07 인사이트 코포레이션 Bet 저해제의 결정질 고체 형태
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AU675645B2 (en) * 1992-04-27 1997-02-13 Mochida Pharmaceutical Co., Ltd. Tricyclic compound having antiallergic effect
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