EP1761503A2 - Derives d'imidazol comme inhibiteur de la tyrosine kinase - Google Patents

Derives d'imidazol comme inhibiteur de la tyrosine kinase

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Publication number
EP1761503A2
EP1761503A2 EP05716076A EP05716076A EP1761503A2 EP 1761503 A2 EP1761503 A2 EP 1761503A2 EP 05716076 A EP05716076 A EP 05716076A EP 05716076 A EP05716076 A EP 05716076A EP 1761503 A2 EP1761503 A2 EP 1761503A2
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European Patent Office
Prior art keywords
formula
compounds
phenyl
cancer
amino
Prior art date
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EP05716076A
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German (de)
English (en)
Inventor
Günter Hölzemann
Helene Crassier
Alfred Jonczyk
Wolfgang Stähle
Arne Sutter
Wilfried Rautenberg
Francesc Mitjans
Elisabet Rosell-Vives
Jaume Adan
Marta Soler Riera
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Merck Patent GmbH
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Merck Patent GmbH
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Publication of EP1761503A2 publication Critical patent/EP1761503A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin

Definitions

  • the object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the present invention relates to compounds and the use of compounds in which the inhibition, regulation and / or modulation of the signal transduction of kinases, in particular the tyrosine kinases and / or serine / threonine kinases plays a role, furthermore pharmaceutical compositions which contain these compounds, and the use of the compounds for the treatment of kinase-related diseases.
  • the present invention relates to compounds of the formula I which inhibit, regulate and / or modulate the signal transduction of the tyrosine kinases, compositions which contain these compounds and methods for their use for the treatment of tyrosine kinase-related diseases and conditions such as angiogenesis, cancer, tumorigenesis, Growth and spread, arteriosclerosis, eye diseases, such as age-related macular degeneration, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, thrombosis, fibrosis, glomerulonephritis, neurodegeneration, psoriasis, restenosis, wound healing of the immune system, transplantation and metabolic disorders , also autoimmune diseases, cirrhosis, diabetes and diseases of the blood vessels, including instability and permeability (permeability) and the like in mammals.
  • diseases and conditions such as angiogenesis, cancer, tumorigenesis, Growth and spread, arteriosclerosis, eye diseases, such as age-related macular degeneration, choroidal ne
  • 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 believed that the tyrosine 5 kinases play an important role in signal transduction in various cell functions via substrate phosphorylation. Although the exact mechanisms of signal transduction are still unclear, it has been shown that tyrosine kinases are important factors in the
  • the tyrosine kinases can be divided into receptor tyrosine kinases and cytosolic tyrosine kinases.
  • the receptor tyrosine kinases have an extracellular part, a transmembrane part and an intra-
  • the receptor tyrosine kinases consist of a large number of transmembrane receptors with different biological effectiveness. Around 20 different subfamilies of receptor tyrosine kinases have been identified.
  • a tyrosine kinase subfamily called the HER subfamily consists of EGFR, HER2, HER3 and HER4.
  • the ligands of this receptor subfamily include the epithelial growth factor, TGF- ⁇ , amphiregulin, HB-EGF, betacellulin and heregulin.
  • the insulin subfamily which includes INS-R, IGF-IR and IR-R, is another subfamily of these receptor tyrosine kinases.
  • the PDGF subfamily includes the PDGF- ⁇ and -R receptor, CSFIR, c- kit and Q FLK-II.
  • There is also the FLK family which consists of the kinase insert domain receptor (KDR), the fetal liver kinase-1 (FLK-1), the fetal liver kinase-4 (FLK-4) and the fms tyrosine kinase-1 (fit-1 ) consists.
  • KDR kinase insert domain receptor
  • FLK-1 the fetal liver kinase-1
  • FLK-4 fetal liver kinase-4
  • fit-1 fms tyrosine kinase-1
  • the RTKs (receptor tyrosine kinases) also include TIE2 and its ligands angiopoietin 1 and 2. More and more 5 homologs of these ligands have now been found, the effect of which has not yet been clearly demonstrated.
  • TIE1 is known as a homologue of TIE2.
  • the TIE RTKs are selectively expressed on endothelial cells and are used in processes of angiogenesis and maturation
  • ⁇ c Vascularization can be a valuable target for active ingredients.
  • the cytosolic tyrosine kinases also consist of a large number of subfamilies, including Src, Frk, Btk, Csk, Abi, Zap70, Fes / Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further divided into 5 different receptors.
  • the Src subfamily is one of the largest subfamilies. It includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr and Yrk.
  • the Src enzyme subfamily has been linked to oncogenesis.
  • Both the receptor tyrosine kinases and the cytosolic tyrosine kinases are involved in cell signaling pathways that lead to various conditions, including cancer, psoriasis and hyper-immune reactions.
  • Various receptor tyrosine kinases and the growth factors that bind them have been suggested to play a role in angiogenesis, although some may promote angiogenesis indirectly (Mustonen and Alitalo, J. CellBiol. 129: 895-898, 1995).
  • One of these receptor tyrosine kinases is fetal liver kinase 1, also called FLK-1.
  • the human analogue of FLK-1 is the kinase insert domain-containing receptor KDR, which is 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 represent a ligand-receptor pair that play an essential role in the proliferation of vascular endothelial cells and
  • vasculogenesis Formation and sprouting of the blood vessels, which are called vasculogenesis or angiogenesis, plays.
  • VEGF vascular endothelial growth factor
  • the KDR induces the mitogenic function of VEGF, while Flt-1 appears to modulate non-mitogenic functions, such as those related to cell adhesion. Inhibition of the KDR therefore modulates the level of mitogenic VEGF activity.
  • VEGF receptor antagonists Two PTK (protein tyrosine kinase) receptors for VEGFR have been identified
  • VEGFR-1 (Flt-1); VEGRF-2 (Flk-1 or KDR) and VEGFR-3 (Flt-4). VEGFR-2 is of particular interest.
  • Solid tumors can therefore be treated with tyrosine kinase inhibitors ⁇ 5 , since these tumors depend on angiogenesis for the formation of the blood vessels required to support their growth.
  • These solid tumors include monocyte leukemia, brain, urogenital, lymphatic, gastric, larynx, and lung cancer, including lung adenocarcinoma and small cell lung cancer.
  • lung cancer including lung adenocarcinoma and small cell lung cancer.
  • carcinomas in which overexpression or activation of Raf-activating oncogenes eg K-ras, erb-B
  • These cancers include pancreatic and breast cancer. Inhibitors of these tyrosine kinases are therefore suitable for the prevention and treatment of prol iterative diseases which are caused by these enzymes.
  • VEGF vascular endothelial growth factor
  • VEGF mRNA and protein levels in the eye are increased due to conditions such as retinal venous occlusion in the primate and reduced pO 2 levels in the mouse, which lead to neovascularization.
  • Intraocularly injected monoclonal anti-VEGF antibodies, or VEGF receptor immunoconjugates inhibit both in primate and in Rodent model the neovascularization in the eye.
  • VEGF vascular endothelial growth factor
  • Anti-VEGF monoclonal antibodies inhibit the growth of human tumors in the nude mouse. Although the same tumor cells continue to express VEGF in culture, the antibodies do not decrease their cell division rate. This is how it comes from tumors
  • VEGF not as an autocrine mitogenic factor. VEGF therefore contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotaxis and mitogenesis activity.
  • monoclonal antibodies also inhibit the growth of typically less vascularized human colon carcinomas in 0 thymus-less mice and reduce the number of tumors arising from inoculated cells.
  • VEGF-binding construct of Flk-1, Flt-1 the mouse KDR receptor homolog shortened to remove the cytoplasmic tyrosine kinase domains, but 5 while maintaining a membrane anchor, virtually stops the growth of a transplantable glioblastoma in the mouse, presumably due to the dominant-negative mechanism of heterodimer formation with trans-Q membranous endothelial cell VEGF receptors.
  • Embryo stem cells which usually grow in the form of solid tumors in the nude mouse, do not form any detectable tumors when all VEGF alleles are knocked out.
  • KDR or Flt-1 are involved in 5 pathological angiogenesis, and these receptors are useful for the treatment of diseases in which angiogenesis is a part overall pathology, e.g. inflammation, diabetic retinal vascularization and various forms of cancer, since it is known that tumor growth is dependent on angiogenesis (Weidner et al., N. Engl. J. Med., 324, pp. 1- 8, 1991). 5
  • Angiopoietin 1 (Ang1), a ligand for the endothelium-specific receptor tyrosine kinase TIE-2, is a new 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 unique to
  • 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 that are stabilized by disulfide bridges between the chains 0 (Partanen et al Curr. Topics Microbiol. Immunol ., 1999, 237: 159-172).
  • IG immunoglobulin
  • Ang1 and its receptor TIE-2 act during the later stages of vascular development, 5 i.e.
  • VEGFR-2 block the phosphorylation of tyrosine residues and so on serve to interrupt the initiation of angiogenesis. It can therefore be assumed that the inhibition of TIE-2 and / or VEGFR-2 should prevent tumor angiogenesis and serve to slow down or completely eliminate tumor growth. Accordingly, treatment for cancer and other diseases associated with inappropriate angiogenesis could be provided.
  • the present invention is directed to methods for regulating, modulating or inhibiting TIE-2 for the prevention and / or treatment of diseases in connection with unregulated or impaired TIE-2 activity.
  • the compounds of the formula I can also be used in the treatment of certain forms of cancer.
  • the compounds of formula I may be used to provide additive or synergistic effects in certain existing cancer chemotherapies, and / or can be used to restore effectiveness of certain of the existing cancer chemotherapies and radiotherapies.
  • the compounds of the formula I can be used to isolate and to study the activity or expression of TIE-2. They are also particularly suitable for use in 5 diagnostic procedures for diseases in connection with unregulated or impaired TIE-2 activity.
  • the present invention is further directed to methods for 0 the regulation, modulation or inhibition of VEGFR-2 for the prevention / or treatment of diseases and in connection with unregulated or disturbed VEGFR-2 activity.
  • the present invention further relates to the compounds of formula 5 as inhibitors of Raf kinases.
  • Protein phosphorylation is a fundamental process for the regulation of cell functions. The coordinated action of both protein kinases and phosphatases controls the levels of phosphorylation and consequently the activity of specific target proteins.
  • Role of protein phosphorylation is in signal transduction when extracellular signals are amplified and by a cascade of protein
  • Phosphorylation and dephosphorylation events e.g. B. are propagated in the p21 ras / raf way.
  • the p21 ras gene was discovered as an oncogene of the Harvey and Kirsten rat sarcoma viruses (H-Ras and K-Ras, respectively).
  • H-Ras and K-Ras characteristic mutations in the cellular Ras gene (c-Ras) have been associated with 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 transform cells, such as the murine cell line NIH 3T3, in culture.
  • the p21 ras oncogene is an important contributing factor in the development and progression of solid human carcinomas and is mutated in 30% of all human carcinomas (Bolton et al. (1994) Ann. Rep. Med. Chem., 29, 165-74; Bos. (1989) Cancer Res., 49, 4682-9).
  • the 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. Sei., 19, 279-83) ,
  • Ras is a guanine nucleotide binding protein, and the cycling between a GTP-linked activated and a GDP-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.
  • the endogenous GTPase activity is reduced in the Ras mutants in cancer cells. weakens, and consequently the protein emits constitutive growth signals to "downstream" effectors such as the Raf kinase enzyme. This leads to cancerous growth of the cells carrying these mutants (Magnuson et al.
  • the Ras proto-oncogene requires a functionally intact C-Raf-1 proto-oncogene in order to generate growth and differentiation signals in higher eukaryotes by receptor and non-receptor tyrosine kinases to transduce.
  • Ras Activated Ras is necessary for the activation of the C-Raf-1 proto-oncogene, but the biochemical steps by which Ras activates the Raf-1 protein (Ser / Thr) kinase have now been well characterized. It has been shown to inhibit the effect of active Ras
  • Raf kinase signaling pathway Inhibition of the Raf kinase signaling pathway by administration of deactivating antibodies against Raf kinase or by co-expression of dominant negative Raf kinase or dominant negative MEK (MAPKK), the substrate of Raf kinase, leads to the reversion of transformed cells to the normal growth phenotype, see: Daum et al. (1994) Trends Biochem. Sci., 19, 474-80; Fridman et al. (1994) J Biol. Chem., 269, 30105-8. Kolch et al. (1991) Nature, 349, 426-28) and for discussion Weinstein-Oppenheimer et al. Pharm. & Therap. (2000), 88, 229-279.
  • Raf kinase by Antisense-Oligodesoxynucleot.de
  • inhibition of Raf kinase has been associated in vitro and in vivo with the inhibition of growth in a number of different 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 number of different cell systems (Rapp, U.R., et al. (1988) in The Oncogene Handbook; T.
  • Raf-1 is found in all organs and in all cell lines that have been examined
  • ⁇ p- and A- and B-Raf are expressed in urogenital and brain tissues, respectively (Storm, S.M. (1990) Oncogene 5: 345-351).
  • Raf genes are proto-oncogenes: they can initiate the malignant transformation of cells if they are expressed in specifically modified forms. Genetic changes that lead 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 5 al. (1987) in Oncogenes and Cancer; SA Aaronson, J. Bishop, T. Sugimura, M. Terada, K. Toyoshima and PK Vogt (ed.) Japan Scientific Press, Tokyo).
  • Raf-1 is an intracellular activator of cell growth.
  • Raf-1 protein serine kinase is a candidate for the "downstream" effector of mitogen signal transduction because Raf oncogenes face growth arrest resulting from blockade of cellular Ras activity due to a cellular mutation (Ras revertant cells) or micro-injection of anti-Ras antibodies results (Rapp, UR, et al. (1988) in The Oncogene Handbook, T. Curran, EP Reddy and A. Skalka (ed.), Elsevier Science Publishers; Netherlands, S. 213-253; Smith, MR, et al. (1986) Nature (London) 320: 540-543).
  • the C-Raf function is required for transformation by a number of different membrane-bound oncogenes and for growth stimulation by mitogens contained in sera (Smith, M.R., et al. (1986) Nature (London) 320: 540-543).
  • Raf-1 protein serine kinase activity is regulated by mitogens via phosphorylation (Morrison, DK, et al. (1989) Cell 58: 648-657), which also effects the subcellular distribution (Olah, Z., et al. (1991) Exp. Brain Res. 84: 403; Rapp, UR, et al. (1988) Cold Spring Harbor Sym. Quant. Biol. 53: 173-184.
  • Raf-1 activating growth factors include those from platelets growth factor (PDGF) (Morrison, DK, et al. (1988) Proc. Natl. Acad. Sci. USA 85: 8855-8859), the colony-stimulating factor (Baccarini, M “et al. (1990) EMBO J 9: 3649-3657), insulin (Blackshear, PJ, et al. (1990) J. Biol. Chem. 265: 12115-12118), epidermal growth factor (EGF) (Morrison, RK, et al. (1988) Proc. Natl. Acad. Sci. USA 85: 8855-8859), Inter! Eukin-2 (Turner, BC, et al.
  • Raf-1 protein serine kinase translocates into the perinuclear region and the nucleus (Olah, Z., et al. (1991) Exp. Brain Res. 84: 403; Rapp, UR, et al. (1988) Cold Spring Habor Sym. Quant. Biol. 53: 173-184).
  • Cells containing activated Raf are changed in their gene expression pattern (Heidecker, G., et al. (1989) in Genes and signal transduction in multistage carcinogenesis, N. Colburn (ed.), Marcel Dekker, Inc., New York, Pp.
  • Raf-oncogenes activate transcription from Ap-1 / PEA3-dependent promotors in transient transfeetion 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 cascade that is amplified by autophosphorylation, or may be entirely caused by autophosphorylation that is by binding a putative activation ligand to the Raf-1 regulator domain, analogous to PKC activation Diacylglycerol is initiated (Nishizuka, Y. (1986) Science 233: 305-312).
  • Proteins occur predominantly with serine, threonine or tyrosine residues, and protein kinases were therefore selected according to their specificity for the location of the phosphoryl. H. of serine / threonine kinases and tyrosine kinases. Because phosphorylation is such a common process in
  • 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 for human or veterinary use are found to be useful when inhibiting the Raf kinase pathway, for example in the treatment of tumors and / or by Raf kinase mediated cancerous cell growth is indicated.
  • the compounds are particularly useful in the treatment of solid carcinomas in humans and animals, e.g. B. Murine cancer, since the progression of these cancers is dependent on the Ras protein signal
  • the compound of the invention or a pharmaceutically acceptable salt thereof is used for the treatment of
  • cancer including solid cancers, such as cancers (e.g., the lungs, pancreas, thyroid, bladder, or colon), myeloid disorders (e.g. myeloid
  • Ap-leukemia or adenomas (e.g. villous colon adenoma), pathological angiogenesis and metastatic cell migration.
  • the compounds are also useful in the treatment of complement activation-dependent chronic inflammation (Niculescu et al. (2002) Immunol. Res., 24: 191-199) and immunodeficiency induced by HIV-1 (Human Immunodeficiency Virus 0 type 1) (Popik et al. (1998) J Virol, 72: 6406-6413).
  • the 5 compounds according to the invention can interact with signaling pathways, in particular with the signaling pathways described herein and preferably the Raf kinase signaling pathway.
  • the compounds according to the invention preferably exhibit an advantageous biological activity in enzyme-based assays, for example assays Q as described herein, is readily detectable.
  • the compounds according to the invention preferably show and bring about an inhibitory effect which is usually documented by IC 50 values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range 5. As discussed herein, these signaling pathways are different
  • the present invention therefore relates to the invention
  • Preferred objects of the invention are therefore compounds according to the invention as promoters or inhibitors, preferably as inhibitors of the Raf kinase pathway.
  • a preferred subject of the invention is therefore compounds according to the invention as promoters or inhibitors, preferably as inhibitors of Raf kinase.
  • a more preferred subject of the invention are compounds according to the invention as promoters or inhibitors, preferably 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 of the invention are compounds according to the invention as promoters or inhibitors, preferably as inhibitors of C-Raf-1.
  • the present invention furthermore relates to the use of one or more compounds according to the invention in the treatment and / or prophylaxis of diseases, preferably the diseases described here, which are caused, mediated and / or propagated by Raf kinases and in particular diseases which are caused by Raf - Kinases selected from the group consisting of A-Raf, B-Raf and C-Raf-1 are caused, mediated and / or propagated.
  • the diseases discussed here are usually divided into two groups, hyperproliferative and non-hyperproliferative diseases.
  • psoriasis, arthritis, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and immune deficiency diseases are not considered cancerous diseases, of which arthritis, inflammation, immunological diseases, autoimmune diseases and immunodeficiency diseases are usually considered non-hyperproliferative diseases.
  • cancerous diseases to consider all of which are commonly considered hyperproliferative diseases.
  • cancerous cell growth and in particular cancerous cell growth mediated by Raf kinase, is a disease that is a goal of the present
  • a c represents invention.
  • the present invention therefore relates to compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of the diseases mentioned and the use of compounds according to the invention for the preparation of a pharmaceutical for the treatment and / or prophylaxis of the diseases mentioned and also a process for Treatment of said diseases comprising the administration of one or more compounds according to the invention to a patient in need of such an administration. 5
  • the compounds according to the invention have an in vivo antiproliferative effect in a xenograft tumor model.
  • the compounds of the invention are administered to Q a patient with a hyperproliferative disease, e.g.
  • the present compounds are useful for prophylactic or therapeutic purposes.
  • the term "treat” is used to refer to both the Disease prevention as well as the treatment of pre-existing ailments are used.
  • the prevention of proliferation is achieved by administration of the compounds according to the invention before the development of the evident disease, e.g. B. for the prevention of tumor growth, 5 prevention of metastatic growth, the reduction of restenoses associated with cardiovascular surgery, etc. achieved.
  • the compounds are used to treat persistent diseases by stabilizing or improving clinical
  • the host or patient can belong to any mammalian species, e.g. B. a primate species, especially humans; Rodents, including AC mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for treating a human disease.
  • the susceptibility of a particular cell to treatment with the compounds according to the invention can be determined by testing in vitro. Typically, a culture of the cell is combined with a compound of the invention at various concentrations for a period of time sufficient to enable the active agents to induce cell death or to inhibit migration, usually between about an hour and a week. Cultured cells from a biopsy sample can be used for in vitro testing. The 0 remaining after the treatment viable cells are then counted.
  • the dose varies depending on the specific compound used, the specific disease, patient status, etc. Typically, a therapeutic dose is sufficient to significantly reduce the unwanted cell population in the target tissue while maintaining the patient's viability.
  • the treatment will generally continue until there is a substantial reduction, e.g. B. at least about 50% reduction in cell load and can be continued until essentially no more unwanted cells are detected in the body.
  • Suitable models or model systems have been developed by various scientists to identify a signal transmission path and to demonstrate interactions between different signal transmission paths, e.g. Cell culture models (e.g. Khwaja et al.,
  • EMBO, 1997, 16, 2783-93 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 transmission paths in animals and / or cell culture models or in the clinical diseases mentioned in this application.
  • Measuring kinase activity is a technique well known to those skilled in the art.
  • Generic test systems for determining kinase activity with substrates e.g. Histone (e.g. Alessi et al., FEBS Lett. 1996, 399, 3, pages 333-338) or the basic myelin protein are described in the literature (e.g. Campos-Gonzalez, R. and Glenney, Jr., JR 1992, J. Biol. Chem. 267, page 14535).
  • phospho-AK specific phospho-antibodies
  • the phospho-AK only binds the phosphorylated substrate. This binding can be detected with a second peroxidase-conjugated anti-sheep antibody by chemiluminescence (Ross et al., 2002, Biochem. J., immediately before publication, manuscript BJ20020786).
  • the sufferings of interest include, but are not limited to, the following sufferings.
  • the compounds of the invention are useful in the treatment of a number of different conditions in which proliferation and / or migration of smooth muscle cells and / or inflammatory cells is present in the intimal layer of a vessel, resulting in reduced blood flow to this vessel, e.g. B. in neointimal occlusive lesions.
  • Occlusive graft vascular diseases of interest include atherosclerosis, coronary vascular disease after transplantation, venous 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.
  • WO 200104115 is known for aryl- and heteroaryl-substituted ureas, which act as cytokinin inhibitors for the treatment of inflammatory and
  • aryl- and heteroaryl-substituted ureas which can be used as cytokinin inhibitors for the treatment of osteoarthritis or ulcerative colitis are described in WO 200055139.
  • Heterocyclic-substituted ureas for the treatment of inflammatory diseases are described in WO 00/43384.
  • EP 0 286 979 discloses aryl- and heteroaryl-substituted ureas which can be used as antiarrhythmics.
  • WO 200006550 describes phenyl-substituted ureas as lipid peroxidase inhibitors. Madsen et al.
  • substituted aryl and heteroaryl compounds for the treatment, inter alia, in WO 03/000245.
  • allergic rhinitis, atherosclerosis, asthma or cancer Aryl- and heteroaryl-substituted urea derivatives are described in WO 00/76515 as IL-8 receptor antagonists.
  • the invention relates to compounds of the formula I.
  • R 4 , R 5 each independently of one another H, A, OH, OA, alkenyl, alkynyl, NO 2 , NH 2) NHA, NA 2) shark, CN, COOH, COOA, -OHet, -O-alkylene-Het, - O-alkylene-NR 10 R 11 or CONR 10 R 11 , two adjacent radicals selected from R 1 , R 2 , R 3 , R 4 , R 5 together also -O-CH 2 -CH 2 -, -O-CH 2 -O- or -O-CH 2 -CH 2 -O-,
  • R 6 , R 7 each independently of one another H, A, shark, OH, OA or CN, R 8 CN, COOH, COOA, CONH2, CONHA or CONA 2 , R 9 H or A,
  • a alkyl having 1 to 10 C atoms, where 1-7 H atoms can also be replaced by F and / or chlorine,
  • Hai F. CI. Br or l mean as well as their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all ratios.
  • the invention also relates to the optically active forms 5 (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.
  • Solvates of the compounds are understood to mean the addition of inert solvent molecules to the compounds, which are mutually exclusive due to their mutual nature
  • Solvates are e.g. Mono- or dihydrates or alcoholates.
  • compositions are understood to mean, for example, the 5 salts of the compounds according to the invention and so-called prodrug compounds.
  • Prodrug derivatives are understood with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly cleaved in the organism to the active 0 compounds of the invention.
  • This also includes biodegradable polymer derivatives of the compounds according to the invention, as described, for. B. in Int. J. Pharm. 115, 61-67 (1995).
  • an effective amount means the amount of a drug or active pharmaceutical ingredient that elicits a biological or medical response in a tissue, system, animal or human that is sought or sought by, for example, a researcher or medical professional .
  • therapeutically effective amount means an amount which, compared to a subject who has not received this amount, does the following:
  • terapéuticaally effective amount also includes
  • the invention also relates to the use of mixtures of the compounds of the formula I, e.g. Mixtures of two diastereomers e.g. in a ratio of 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 compounds of the invention can also exist in various polymorphic forms, e.g. as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention belong to the scope of the invention and are a further aspect of the invention.
  • the invention relates to the compounds of formula I and their salts and a process for the preparation of compounds of formula I according to claims 1-10 and their pharmaceutically usable derivatives, salts, solvates and stereoisomers, characterized in that
  • R 6 , R 7 , R 8 , R 9 , R 10 and R 11 have the meanings given in claim 1,
  • R 1 , R 2 , R 3 , R 4 and R 5 have the meanings given in claim 1, are reacted with a chloroformate derivative to give an intermediate carbamate derivative which is then reacted with a compound of the formula II,
  • R - 8 8 CN COOA, CONH 2 , CONHA or CONA 2 ,
  • R 10 , R 11 H mean a compound of formula V.
  • R 8 is CN, COOA, CONH 2 , CONHA or CONA 2 ,
  • R has the meaning given in claim 1 and A 'denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,
  • R 1 , R 2 , R 3 , R 4 and R 5 have the meanings given in claim 1, and L is Cl, Br, I or a free or reactively modified OH group, implements,
  • 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-M ethyl pentyl, 1,1-, 1, 2-, 1,3-, 2,2-, 2,3 - or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, further preferred eg Trifluoromethyl.
  • A also means cycloalkyl. Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • a ' is preferably methyl, ethyl, propyl or butyl.
  • Alkylene is preferably unbranched and preferably means methylene,
  • Ethylene, propylene, butylene or pentylene Ethylene, propylene, butylene or pentylene.
  • R 1 , R 2 , R 3 , R 4 , R 5 each independently of one another, denote H, A, OH, OA, NO 2 , NH 2) NHA, NA 2 , shark, CN,
  • R 1 , R 2 , R 3 , R 4 , R 5 each independently of one another, denote H, A, OH, OA, shark, O-alkylene-het or -O-alkylene-NR 10 R 11 .
  • R 1 , R 2 , R 3 , R 4 , R 5 each independently, preferably, for example, H; A, such as methyl or ethyl; OH, OA, such as
  • R ⁇ and R 7 are preferably H.
  • R 8 is preferably CONH 2 or CN.
  • R 10 and R 11 are preferably H.
  • Het means, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4 - or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3rd - or 4-pyridyl, 2-, 4-, 5- or 6- 5 pyrimidinyl, further preferably 1, 2,3-triazol-1-, -4- or -5-yl, 1, 2,4-triazol- 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-yl, 1, 2,4-
  • heterocyclic radicals can also be partially or completely hydrogenated.
  • Het can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 5 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-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, - 2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-,
  • Dihydro-2H-1,5-benzodioxepin-6- or -7-yl further preferably 2,3-dihydro-benzofuranyl or 2,3-dihydro-2-oxo-furanyl.
  • Het means a mononuclear saturated heterocycle with 1 to 3 N-, O- and / or S-
  • the mononuclear saturated heterocycle here means particularly preferably piperidinyl, pyrrolidinyl, morpholinyl or piperazinyl.
  • Het very particularly preferably denotes 1-, 2-, 3- or 4-piperidinyl or 2-, 3- or 4-morpholinyl, it being possible for Het to be substituted by COOA.
  • Shark is preferably F, Cl or Br, but also I, particularly preferably F or Cl.
  • Alkenyl is preferably vinyl, 1- or 2-propenyl, 1-butenyl, isobutenyl, sec-butenyl, further preferred is 1-pentenyl, isopentyl or 1-hexenyl.
  • Alkynyl is preferably ethynyl, propyn-1-yl, furthermore butyn-1, butyn-2-yl, pentyn-1, pentyn-2 or pentyn-3-yl.
  • 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 indicated above.
  • Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Ih, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
  • R 1 , R 2 , R 3 , R 4 , R 5 each independently of one another H, A, OH, OA, NO 2 , NH 2 , NHA, NA 2 , shark, CN, -OHet, -O-alkylene- Het or -O-alkylene-NR 8 ° oR9 mean;
  • Ic Het denotes a mononuclear saturated heterocycle having 1 to 3 N, O and / or S atoms, which is unsubstituted or can simply be substituted by COOA;
  • NH, R 1 , R 2 , R 3 , R 4 , R 5 each independently NH 2 , NHA, NA 2 , shark, CN, -OHet, -O-alkylene-het or - O-alkylene-NR 1'0 u rR .1'1 ', R 6 , R 7 H, R 8 CONH 2 or CN, Het unsubstituted.es or piperidinyl, pyrrolidinyl, morpholinyl or piperazinyl substituted by COOA;
  • R 1 , R 2 , R 3 , R 4 , R 5 each independently of one another H, A, OH, OA, shark, O-alkylene-het or -O-alkylene -NR 10 R 11 , R 6 , R 7 H, R 8 CONH 2 or CN, R 9 H or A, R 10 , R 11 each independently of one another H or A, Het unsubstituted or simply substituted by COOA, piperidinyl, pyrrolidinyl, morpholinyl or piperazinyl, 5 A alkyl having 1 to 10 C atoms, 1-7 H atoms also being represented by F and / or can be replaced by chlorine, mean shark F, Cl, Br or I,
  • the starting materials can also be formed in situ, 5 so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.
  • the compounds of the formula II and those of the formula III are generally known. 5
  • the reaction is usually carried out in an inert solvent, in the presence of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline.
  • an organic base such as triethylamine, dimethylaniline, pyridine or quinoline.
  • the reaction time is between a few minutes and 14 days, the reaction temperature is between about 0 ° and 150 °, normally between 15 ° and 90 °, particularly preferably between 15 and 30 ° 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, A g 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 (
  • reaction is usually carried out in an inert solvent, in the presence of an acid-binding agent, preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or one
  • an acid-binding agent preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or one
  • 35 other salt of a weak acid of the alkali or alkaline earth metals preferably potassium, sodium, calcium or cesium.
  • an organic base such as triethylamine, dimethylaniline, N, N'-
  • the reaction time is between a few minutes and 14 days
  • the reaction temperature is between about 0 ° and 150 °, normally between 20 ° and 130 °, particularly preferably between 60 and 90 °.
  • 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 (DMF);
  • the starting compounds of the formula IV are generally known.
  • R 8 CN, COOA, CONH 2 , CONHA or CONA 2 ,
  • R 10 , R 11 H can further preferably be obtained by combining compounds of the formula V with compounds of the formula VI and compounds of the
  • the reaction is usually carried out in an inert solvent as indicated above.
  • the response time depends on the one used Conditions between a few minutes and 14 days, the reaction temperature between about 0 ° and 150 °, normally between 20 ° and 130 °, particularly preferably between 60 and 90 °.
  • X is absent and X 'is NH, can further preferably be obtained by reacting compounds of the formula II with compounds of the formula VIII.
  • the compounds of the formula VIII are generally known.
  • L is preferably Cl, Br, I or a free or a reactively modified OH group such as e.g. an activated ester, an imidazolide or alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).
  • an activated ester an imidazolide or alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).
  • the reaction is usually carried out in an inert solvent
  • an acid-binding agent preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline or an excess of the carboxy component of the formula VIII.
  • alkali or alkaline earth metal hydroxide carbonate or bicarbonate or another salt of a weak acid Alkali or alkaline earth metals, preferably potassium, sodium,
  • reaction time is between a few minutes and 14 days, the reaction temperature between about
  • the compounds according to the invention mentioned 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 by methods known in the art.
  • Most of the pharmaceutically acceptable salt forms of the compounds of formula I are prepared conventionally. If the compound of the formula I contains a carboxylic acid group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base addition salt.
  • Such bases are, 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, for example potassium ethanolate and sodium propanolate; as well as 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 for example potassium ethanolate and sodium propanolate
  • various organic bases such as piperidine, diethanolamine and N-methylglutamine.
  • acid addition salts can be formed by Compounds with pharmaceutically acceptable organic and inorganic acids, e.g.
  • hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like 5 as well as 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 salts of the compounds of formula I include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphor sulfonate, caprylate, chloride,
  • the base salts of the 0 compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), Potassium, sodium and zinc salts, but this is not intended to be a limitation.
  • Preferred among the salts mentioned above are ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts
  • Amines, cyclic amines and basic ion exchange resins e.g.
  • Hydrabamine isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procain, purines,
  • Contain groups can be with agents such as (C 1 -C 4 ) alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide;
  • Di (-C 4 ) alkyl sulfates such as dimethyl, diethyl and diamyl sulfate; (C 10 -
  • Ci 8 alkyl halides, for example decyl, dodecyl, lauryl, myristyl and
  • the above-mentioned pharmaceutical salts which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, Sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, but this is not intended to be a limitation.
  • the acid addition salts of basic compounds of formula I are prepared in that the free base form with a sufficient Contact the amount of the desired acid, whereby the salt is prepared in the usual way.
  • the free base can be regenerated in a conventional manner by contacting the salt form with a base and isolating the free base.
  • the free base forms differ in a sense from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; in the context of the invention, however, the salts otherwise correspond to their respective free base forms.
  • the pharmaceutically acceptable base addition salts of the compounds of the formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines.
  • 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 contacting the free acid form with a sufficient amount of the desired base, whereby the salt is prepared in the usual way.
  • the free acid can be regenerated in a conventional manner by contacting the salt form with an acid and isolating the free acid.
  • the free acid forms differ in a sense from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; in the context of the invention, however, the salts otherwise correspond to their respective free acid forms.
  • a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, this includes
  • Invention also multiple salts.
  • Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, Diphosphate, disodium and trihydrochloride, but this is not intended to be a limitation.
  • the expression 5 “pharmaceutically acceptable salt” in the present context is to be understood as an active substance which contains a compound of the formula I in the form of one of its salts, in particular when this salt form is the active substance compared to the free form of the active substance or
  • the pharmaceutically acceptable salt form of the active ingredient can only give this active ingredient a desired pharmacokinetic property
  • the invention further relates to medicaments containing at least 0 a compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and, if appropriate, carriers and / or auxiliaries.
  • Pharmaceutical formulations can be administered in the form of dose units containing a predetermined amount of active ingredient per dose unit.
  • Such a unit can contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg Q of a compound according to the invention, depending on the condition of the disease treated, the route of administration and the age, weight and condition of the patient , or pharmaceutical formulations can be presented in the form of dose units containing a predetermined amount of active ingredient per dose unit.
  • Preferred dosage unit formulations are those that have a daily dose or partial dose as indicated above, or a corresponding fraction thereof Active ingredient included.
  • such pharmaceutical formulations can be produced using one of the methods generally known in the pharmaceutical field.
  • compositions can be administered for administration by any suitable route, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal),
  • vaginal or parenteral including subcutaneous, intramuscular, intravenous, or intradermal) routes.
  • Such formulations can be prepared by any method known in the pharmaceutical art, for example by the
  • ⁇ g of active ingredient is brought together with the carrier (s) or auxiliary (s).
  • compositions adapted for oral administration can be used as separate units, e.g. Capsules or tablets; powder
  • the active ingredient component can be combined with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as Q, for example ethanol, glycerol, water and others. Powders are made by crushing the compound to an appropriate fine size and mixing it with a similarly crushed pharmaceutical carrier such as an edible carbohydrate such as starch or mannitol. A flavor, preservative, dispersant and color may also be present.
  • an oral, non-toxic and pharmaceutically acceptable inert carrier such as Q, for example ethanol, glycerol, water and others.
  • Powders are made by crushing the compound to an appropriate fine size and mixing it with a similarly crushed pharmaceutical carrier such as an edible carbohydrate such as starch or mannitol.
  • a flavor, preservative, dispersant and color may also be present.
  • Capsules are made by making a powder mixture as described above and filling shaped gelatin shells with it.
  • Lubricants and lubricants such as highly disperse silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process.
  • suitable binding agents can also be incorporated into the mixture.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners from corn, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc.
  • Lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc.
  • Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the tablets are formulated by, for example, producing a powder mixture, granulating or pressing them dry, adding a lubricant and a disintegrant and compressing the whole thing into tablets.
  • a powder mixture is produced by the compound, which has been comminuted in a suitable manner, with a diluent or a base, as described above, and optionally with a binder, such as, for example, carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a solution-reducing agent, such as, for example, paraffin Absorption accelerator, such as a quaternary salt and / or an absorbent, such as bentonite, kaolin or dicalcium phosphate, is mixed.
  • a binder such as, for example, carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone
  • a solution-reducing agent such as, for example, paraffin Absorption accelerator, such as a quaternary salt and / or an absorb
  • the powder mixture can be granulated by mixing it with a binder such as syrup, starch paste, Acadia mucilage or solutions made from cellulose or polymer. materials are wetted and pressed through a sieve.
  • a binder such as syrup, starch paste, Acadia mucilage or solutions made from cellulose or polymer. materials are wetted and pressed through a sieve.
  • the powder mixture can be run through a tabletting machine, resulting in irregularly shaped lumps which are broken up into granules.
  • the granules can be greased by adding 5 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 clear or opaque protective layer consisting of a shellac seal, a layer of sugar or polymer
  • a 5 material and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.
  • Oral liquids such as solution, syrups and elixirs, can be prepared in the form of dosage units so that a given quantity contains a given amount of the compound.
  • Syrups can be made by dissolving the compound in an aqueous solution with a suitable taste, while elixirs are made using a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, Q preservatives, flavor additives, such as, for example, peppermint oil or natural sweeteners or saccharin or other artificial sweeteners and the like. can also be added.
  • Dosage unit formulations for oral administration can be any suitable dosage unit formulations for oral administration.
  • the formulation can also be prepared so that the release is prolonged or delayed is, such as by coating or embedding particulate material in polymers, wax, etc.
  • the compounds of the formula I and salts, solvates and physiologically functional derivatives thereof can also be in the form of liposome delivery systems, such as administer small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be made from various phospholipids, e.g. Cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of the formula I and the salts, solvates and physiologically functional derivatives thereof can also be supplied using monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds can also be coupled with soluble polymers as targeted drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxyethylaspartamide phenol or polyethylene oxide polylysine substituted with palmitoyl residues.
  • the compounds can be linked to a class of biodegradable polymers suitable for achieving controlled release of a drug, e.g.
  • Polylactic acid Polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxy-pyrans, polycyanoacrylates and cross-linked or amphipatic block copolymers of hydrogels.
  • Formulations can be given as stand-alone patches for prolonged, close contact with the recipient's epidermis.
  • the active ingredient can be supplied from the patch by means of iontophoresis, as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
  • Pharmaceutical compounds adapted for topical administration can 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 can be either paraffinic or water-miscible
  • cream base can be used.
  • the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical application to the eye include eye drops, the active ingredient being dissolved or suspended in a suitable carrier, in particular an aqueous solvent.
  • suitable carrier in particular an aqueous solvent.
  • Pharmaceutical formulations adapted for topical application in the mouth include lozenges, lozenges and mouthwashes.
  • compositions 5 adapted for rectal administration can be administered in the form of suppositories or enemas.
  • compositions adapted for nasal administration in which the carrier substance is a solid, contain a coarse Q powder with a particle size, for example in the range of 20-500 micrometers, which is administered in the manner in which snuff is taken up, ie by Quick inhalation via the nasal passages from a container with the powder held close to the nose.
  • Suitable formulations for administration as a nasal spray or 5 Nasal drops with a liquid as a carrier substance comprise active ingredient solutions in water or oil.
  • compositions adapted for administration by inhalation comprise fine particulate dusts or mists which can be generated by means of various types of pressurized metering dispensers with aerosols, nebulizers or insufflators.
  • compositions adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • a [- Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which contain antioxidants, buffers, bacteriostatics and solutes, by which the formulation is rendered isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickeners.
  • the formulations can be presented in single-dose or multi-dose containers, for example sealed ampoules and vials, and stored in a freeze-dried (lyophilized) state, so that only the addition of the sterile carrier liquid, for example water for injections, is required immediately before use.
  • Injection solutions and suspensions prepared according to the recipe can be made from sterile powders, granules and tablets. It is understood that the formulations may contain, in addition to the above-mentioned components, other means customary in the art with regard to the respective type of formulation; for example, formulations suitable for oral administration may contain 5 flavorings.
  • a therapeutically effective amount of a compound of formula I depends on a number of factors, including, for example, the age and weight of the animal, the exact condition of the disease that requires treatment, and its severity, the nature of the formulation
  • neoplastic growth e.g. Colon or breast cancer
  • the actual daily amount would usually be between 70 and 700 mg
  • a r- this amount can be given as a single dose per day or more usually in a series of divided doses (such as two, three, four, five or six) per day 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 according to the invention. It is believed that similar dosages are suitable for the treatment of the other conditions mentioned above.
  • the invention further relates to medicaments containing at least one compound of the formula I and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and at least one further active pharmaceutical ingredient.
  • the invention also relates to a set (kit) consisting of separate packs of (a) an effective amount of a compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereo ⁇
  • 35 isomers, including their mixtures in all proportions, and (b) an effective amount of another drug ingredient.
  • the set contains suitable containers, such as boxes or cartons, individual bottles, bags or ampoules.
  • suitable containers such as boxes or cartons, individual bottles, bags or ampoules.
  • the set can e.g. separate
  • Derivatives, solvates and stereoisomers, including their mixtures in all proportions, and an effective amount of another active pharmaceutical ingredient are dissolved or in lyophilized form.
  • the present compounds are suitable as pharmaceutical active substances for mammals, in particular for humans, in the treatment of tyrosine kinase-related diseases.
  • diseases include tumor cell proliferation, pathological neovascularization (or angiogenesis) that promotes the growth of solid tumors, neovascularization (diabetic retinopathy, age-related macular degeneration and the like) and inflammation (psoriasis, rheumatoid arthritis and the like).
  • the present invention encompasses the use of the compounds of
  • Preferred carcinomas for the treatment come from the group of brain carcinoma, urogenital tract carcinoma, carcinoma of the lymphatic system, gastric carcinoma, larynx carcinoma and lung carcinoma.
  • Another group of preferred forms of cancer are monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma.
  • the use of the compounds according to the invention and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of a disease in which angiogenesis 5 is involved is also included.
  • One such disease in which angiogenesis is involved is an eye disorder such as retinal vascularization, 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.
  • the compounds of the formula I and / or their physiologically acceptable salts and solvates for the preparation of a medicament for the treatment or prevention of a tyrosine kinase-related disease or a tyrosine kinase-related illness in a mammal, whereby this method involves a sick mammal such treatment requires a therapeutically effective amount of a compound of the invention.
  • the therapeutic amount depends on the respective disease and can be determined by the person skilled in the art without any great effort.
  • the present invention also encompasses the use of compounds 0 of the formula I and / or their physiologically acceptable salts and solvates for the production of a medicament for the treatment or prevention of retinal vascularization.
  • Methods for the treatment or prevention of eye diseases such as diabetic retinopathy and age-related macular degeneration are also part of the invention.
  • tyrosine kinase-related diseases or conditions refers to pathological conditions which are dependent on the activity of one or more tyrosine kinases.
  • the tyrosine kinases are either directly or indirectly on the signal transduction pathways of various cell activ
  • tyrosine kinase activity 10 activities, including proliferation, adhesion and migration as well as differentiation.
  • Diseases associated with tyrosine kinase activity include tumor cell proliferation, pathological neovascularization that promotes the growth of solid tumors, neovascularization in the
  • a ⁇ 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 influence the growth of tumors (J. Rak et al. Cancer Research, 55: 4575-4580, 1995).
  • the angiogenesis-inhibiting properties of the present compounds of the formula I 5 are also suitable for the treatment of certain forms of blindness which are associated with retinal vascularization.
  • the compounds of the formula I are also suitable for the treatment of certain bone pathologies such as osteosarcoma, osteoarthritis and Q rickets, which is also known under the name of oncogenic osteomalacia (Hasegawa et al., Skeletal Radiol. 28, pp. 41-45, 1999; Gerber et al., Nature Medicine, Vol.
  • the present compounds are also suitable for treatment and prevention of suffering associated with Bone resorption is related, such as osteoporosis and Paget's disease.
  • the compounds can also be used to reduce or prevent tissue damage that occurs after cerebral ischemic events such as stroke (Drug News Perspect 11: 265-270 (1998); J. Clin. Invest. 104: 1613-1620 (1999)).
  • the invention thus relates to the use of compounds of the formula I and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all A c ratios, for the manufacture of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of signal transduction by kinases plays a role.
  • Kinases are preferably selected from the group of 0 tyrosine kinases and Raf kinases.
  • the tyrosine kinases are preferably TIE-2, VEGFR, PDGFR, FGFR and / or FLT / KDR. 5 Preferred is the use of compounds of formula I, as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, Q for the preparation of a medicament for the treatment of diseases which are influenced by the compounds according to claim 1 by inhibiting the tyrosine kinases become.
  • the disease is a solid tumor.
  • the solid tumor is preferably selected from the group of tumors of the squamous epithelium, the blisters, the stomach, the kidneys, the head and neck, the esophagus, the cervix, the thyroid, the intestine, the liver, the brain, the prostate, the Urogenital tract, lymphatic system, stomach, larynx and / or lungs.
  • the solid tumor is also 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 myelotic leukemia, chronic myelotic leukemia, acute lymphatic leukemia and / or chronic lymphatic leukemia.
  • the invention further relates to the use of
  • the disease is preferably an eye disease.
  • the invention further relates to the use for the treatment of retinal vascularization, diabetic retinopathy, and age-related
  • the inflammatory disease is preferably selected from the group rheumatoid arthritis, psoriasis, contact dermatitis and late-type hypersensitivity reaction.
  • the invention further relates to the use of the compounds according to the invention for the treatment of bone pathologies, the bone pathology coming from the group of osteosarcoma, osteoarthritis and rickets.
  • the compounds of formula I are suitable for the manufacture of a medicament for the treatment of diseases which are caused, mediated and / or propagated by Raf kinases, the Raf kinase
  • a j - is selected from the group consisting of A-Raf, B-Raf and Raf-1.
  • Preferred is the use for the treatment of diseases, preferably from the group of hyperproliferative and non-hyperproliferative diseases. These are cancerous or non-cancerous 0 diseases.
  • the non-cancerous diseases are selected from the group consisting of psoriasis, arthritis, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, 5 autoimmune diseases and immunodeficiency diseases.
  • the cancerous diseases are selected from the group consisting of brain cancer, lung cancer, squamous cell, bladder, 0 gastric cancer, pancreatic cancer, liver cancer, renal cancer, colorectal cancer, breast cancer, head cancer, neck cancer, oesophageal cancer, gynecological cancer, thyroid cancer, lymphoma, chronic leukemia and acute leukemia. 5
  • the compounds of the formula I can also be used together with other well-known therapeutic agents which, owing to their particular suitability for the Treated ailments are selected to be administered.
  • combinations that contain antiresorptive bisphosphonates, such as alendronate and risedronate, integrin blockers (as defined below), such as ⁇ v? 3 antagonists would be beneficial
  • Conjugated estrogens such as Prempro®, Premarin® and Endometrion® used in hormone therapy; contain selective estrogen receptor modulators (SERMs) such as raloxifene, droloxifene, CP-336,156 (Pfizer) and lasofoxifene, cathepsin K inhibitors and ATP proton pump inhibitors.
  • SERMs selective estrogen receptor modulators
  • the present compounds are also suitable for combination with known anti-cancer agents.
  • known anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxics, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiproliferative, antiprolife
  • AC 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 joint use with radiotherapy.
  • the synergistic effects of inhibiting VEGF in combination with 0 radiotherapy have been described in the specialist field (see WO 00/61186).
  • Estrogen receptor modulators refers to compounds which interfere with or inhibit the binding of estrogen to the receptor, regardless of how this is done.
  • the estrogen receptor modulators include, for example, tamoxifen, raloxifene, idoxifene, LY353381, LY 117081, toremifene, fulvestrant, 4- [7- (2,2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1 - piperidinyl) ethoxy] phenyl] -2H-1-0 benzopyran-3-yl ] phenyl-2,2-dimethylpropanoate, 4,4-dihydroxybenzophenone-2,4-dinitrophenylhydrazone, and SH646, which, however, is not intended to be a limitation.
  • “Androgen receptor modulators” refers to compounds which interfere with the binding of androgens to the receptor or inhibit them,
  • Androgen receptor modulators include, for example, finasteride and others 5 ⁇ -reductase inhibitor, 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 is done.
  • retinoid receptor modulators include, for example, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis Retinoic acid, ⁇ -difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl) retinamide and N-4-carboxyphenylretinamide.
  • Cytotoxics refers to compounds that are primarily affected by cell function leading to cell death or inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalating agents, microtubulin inhibitors and topoisomerase inhibitors.
  • Cytotoxic agents include, for example tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, Dibromdulcit, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosylate, trofosfamide, nimustine, Dibrospidium- chloride, Pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-amine dichloro (2-methylpyridine) platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans) -bis-mu- (hexane-1, 6 -diamine) -mu-
  • MEN 10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-daunorubicin see WO 00/50032, which, however, is not intended to be a restriction.
  • microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, S ' ⁇ ' - Dideshydro ⁇ '- deoxy- ⁇ '-norvincaleukoblastin, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine, N, N-dimethyl-L-valyl-L-valyl-N -methyl-L-valyl-L-prolyl-L-prolin-t-butylamide, TDX258 and BMS188797.
  • paclitaxel vindesine sulfate
  • 5 topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ', 4'-O-exo-benzylidene-chartreusin, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4 , 5-kl] acridin-2- (6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-
  • antiproliferative agents include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and 0 INX3001, as well as antimetabolites such as enocitabine, Carmofur, Tegafur, pentostatin, doxifluridine, trimetrexate, flitarabinabin, fludarabin, and fludarabin -ocfosfate, fosteabin sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2-deoxy-2'-methylididine, 2'-fluoromethylene-2 , -deoxycytidine, N- [5- ( 3- 5 dihydrobenzofuryl) sulfonyl] -N '- (3,4-dichlorophenyl) urea
  • antiproliferative agents also include monoclonal antibodies against growth factors other than those already mentioned under the “angiogenesis inhibitors”, such as trastuzumab, and tumor suppressor genes, such as p53, which can be released via recombinant virus-mediated gene transfer (see, for example, US Pat. No. 6,069,134 ).
  • the invention further relates to the use of the compounds of the formula I for the manufacture of a medicament for the treatment of diseases, the disease being characterized by disturbed angiogenesis.
  • the disease is preferably cancer.
  • the disturbed angiogenesis preferably results from an impaired VEGFR-1, VEGFR-2 and / or VEGFR-3 activity. It is therefore particularly preferred to use the compounds according to the invention for the manufacture of a medicament for inhibiting VEGFR-2 activity.
  • VEGF receptor kinase activity is determined by incorporating radioactively labeled phosphate in 4: 1 polyglutamic acid / tyrosine substrate (pEY).
  • pEY polyglutamic acid / tyrosine substrate
  • the phosphorylated pEY product is held on a filter membrane and the incorporation of the radioactively labeled phosphate is quantified 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. 5 , Pp. 519-524) were cloned as glutathione-S-transferase (GST) gene fusion proteins. This was done by cloning the cytoplasmic domain of the KDR kinase as a read-frame fusion at the carboxy terminus of the GST gene. The soluble recombinant GST-kinase domain fusion proteins were found in Spodoptera frugiperda (Sf21) insect cells (Invitrogen)
  • Enzyme dilution buffer 10 50 mM Tris, pH 7.4, 0.1 M NaCl, 1 mM DTT, 10% glycerin, 100 mg / ml BSA.
  • the supernatant was then passed through a glutathione-Sepharose acid (Pharmacia) equilibrated with lysis buffer 0 and washed with 5 volumes of the same buffer and then 5 volumes of washing buffer.
  • the recombinant GST-KDR protein was eluted with wash buffer / 10 mM reduced glutathione (Sigma) and counteracted
  • Method B VEGF receptor kinase assay 1. Add 5 ⁇ ⁇ inhibitor or control in 50% DMSO to the assay. 2. Add 35 ⁇ l reaction mixture containing 5 // I 10 * reaction buffer, 5 l 25 mM ATP / 10 Ci [ 33 P] ATP (Amersham) and 5 ⁇ ⁇ 10 * substrate. 5 3. Start the reaction by adding 10 ⁇ ⁇ KDR (25 nM) in enzyme dilution buffer. 4. Mix and incubate for 15 minutes at room temperature. 5. Stop the reaction by adding 50 ⁇ ⁇ stop solution. Incubate at 6.degree. C. for 15 minutes. 7. Transfer 90 ⁇ l aliquot to filter plate. 8.
  • VEGF vascular endothelial growth factor
  • bFGF basic fibroblast growth factor
  • endothelial Growth Medium EGM; Clonetics
  • NUNCLON 96-well polystyrene tissue culture plates (NUNC # 167008).
  • Dulbecco modified Eagle medium with 1 g / ml glucose (DMEM with low glucose content; Mediatech) plus 10% (v / v) fetal
  • VEGF 165 500 ng / ml; R&D Systems
  • bFGF 10 ng / ml; R&D Systems
  • HUVEC single cell layers kept in EGM are harvested by trypsin treatment and inoculated in a density of 4000 cells per 100 ⁇ ⁇ assay medium per well in 96-well plates.
  • the growth of the cells is stopped for 24 hours at 37 ° C. in a humid atmosphere containing 5% CO 2 .
  • Procedure 2 The growth stop medium is replaced with 100 ⁇ ⁇ assay medium, which is either the constituent (0.25% [v / v] DMSO) or the desired one
  • the cells are added by adding 10 ⁇ l assay medium, 10 * VEGF solution or 10 * bFGF solution
  • the cells are then incubated at 37 ° C / 5% CO 2 .
  • the medium is suctioned off and the cells are washed twice with washing medium (400 ⁇ l / well, then 200 ⁇ l / well).
  • the washed, adherent cells are then solubilized by adding cell lysis solution (100 ⁇ l / well) and heating to 37 ° C. for 30 minutes.
  • the cell lysates are transferred to 7 ml glass scintillation tubes containing 150 ul water.
  • the scintillation cocktail (5 ml / tube) is added and the radioactivity associated with the cells is determined by liquid scintillation spectroscopy.
  • the compounds of the formula I are VEGF inhibitors and are therefore suitable for inhibiting angiogenesis, such as in the treatment of eye diseases, for example diabetic retinopathy, and for the treatment of carcinomas, for example solid tumors.
  • the present compounds inhibit VEGF-stimulated mitogenesis of cultured human vascular endothelial cells with HK50 values of 0.01-5.0 ⁇ M.
  • These compounds are compared to related tyrosine kinases (e.g. FGFR1 and Src family; the relationship between Src kinases and VEGFR kinases see also Eliceiri et al., Molecular Cell, Vol. 4, pp. 915-924, December 1999) also selectively.
  • the 77 £ -2 tests can be carried out, for example, analogously to the methods given in WO 02/44156.
  • 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 binds to the surface of a "flashplate" microtiter plate during the incubation period. After removing the reaction mixture, it is washed several times and then the radioactivity is measured on the surface of the microtiter plate. An inhibiting effect of the substances to be measured results in a lower radioactivity compared to an undisturbed enzymatic reaction.
  • customary work-up means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is between 2 and 10, , extracted with ethyl acetate or dichloromethane, separated, the organic phase dried over sodium sulfate, evaporated and purified by chromatography on 5 silica gel and / or by crystallization. Rf values on silica gel; Mobile solvent: ethyl acetate / methanol 9: 1.
  • Mass spectrometry (MS): El (electron impact ionization) M + FAB (Fast Atom Bombardment) (M + H) + Q ESI (Electrospray ionization) (M + H) + APCI-MS (atmospheric pressure chemical ionization - mass spectrometry) ( M + H) + .
  • Chlorine-1-methyl-pyridinium iodide combined and heated at 50 ° C for 2 h.
  • the desired fractions are pooled, concentrated and freeze-dried.
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy 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, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO. 12H 2 O and 0.1 g of benzalkonium chloride in 940 ml double distilled water. It is adjusted to pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • Example E tablets
  • a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is more common
  • each tablet contains 10 mg of active ingredient.
  • Example F coated tablets
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.
  • Example G capsules
  • each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Abstract

L'invention concerne des composés de la formule (I) où R1, R2, R3, R4, R5, R6, R7, R8 R9, R10, R11, X et X' ont la définition donnée dans la revendication 1. Ces composés sont des inhibiteurs de la tyrosine-kinase, notamment TIE-2, et de la Raf-kinase et permettent notamment de traiter des tumeurs.
EP05716076A 2004-03-29 2005-03-15 Derives d'imidazol comme inhibiteur de la tyrosine kinase Withdrawn EP1761503A2 (fr)

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DE102004015099A DE102004015099A1 (de) 2004-03-29 2004-03-29 Imidazolderivate
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US7777040B2 (en) 2005-05-03 2010-08-17 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
EP2004631A1 (fr) * 2006-04-12 2008-12-24 Merck Patent GmbH N-oxydes de bisarylurées à substitution hétérocyclique utilisés dans le traitement de maladies induites par une kinase
AU2009262199B2 (en) 2008-06-27 2012-08-09 Amgen Inc. Ang-2 inhibition to treat multiple sclerosis
JP2011057661A (ja) * 2009-08-14 2011-03-24 Bayer Cropscience Ag 殺虫性カルボキサミド類
CN103910714A (zh) * 2013-01-09 2014-07-09 天津泰瑞倍药研科技有限公司 氟代环丁烷基咪唑类化合物

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ZA200608998B (en) 2008-07-30
RU2006138150A (ru) 2008-05-10
AU2005231907A1 (en) 2005-10-20
CN1938282A (zh) 2007-03-28
KR20060132965A (ko) 2006-12-22
DE102004015099A1 (de) 2005-10-20
CA2561585A1 (fr) 2005-10-20
WO2005097755A3 (fr) 2006-03-09
AR048327A1 (es) 2006-04-19

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