EP1718614A1 - Derives pyridinamide servant d'inhibiteurs de kinase - Google Patents

Derives pyridinamide servant d'inhibiteurs de kinase

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Publication number
EP1718614A1
EP1718614A1 EP05700886A EP05700886A EP1718614A1 EP 1718614 A1 EP1718614 A1 EP 1718614A1 EP 05700886 A EP05700886 A EP 05700886A EP 05700886 A EP05700886 A EP 05700886A EP 1718614 A1 EP1718614 A1 EP 1718614A1
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Prior art keywords
phenoxy
pyridine
carboxylic acid
solvates
derivatives
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EP05700886A
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German (de)
English (en)
Inventor
Lars Thore Burgdorf
Hans-Peter Buchstaller
Frank Stieber
Christiane Amendt
Hartmut Greiner
Matthias Grell
Christian Sirrenberg
Frank Zenke
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Merck Patent GmbH
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Merck Patent GmbH
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Publication of EP1718614A1 publication Critical patent/EP1718614A1/fr
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
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    • 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
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    • A—HUMAN NECESSITIES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
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    • A61P35/00—Antineoplastic agents
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    • A61P37/00—Drugs for immunological or allergic disorders
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to substituted arylamide derivatives of the formula I, compounds of the formula I,
  • Ar 1 , Ar 2 , Ar 3 each independently of one another unsubstituted or one, two or more times substituted by R 1 aromatic or Het,
  • R 1 in each case independently H, A, aryl, OR 4 , SR 4 , OAryl, SAryl, N (R 4 ) 2 , NHAryl, Hai, N0 2 , CN, (CH 2 ) m COOR 4 , (CH 2 ) m COOAryl, (CH 2 ) m CON (R 4 ) 2 , (CH 2 ) m CONHAryl, COR 4 , COAryl, S (0) m A, S (0) mAryl, NHCOA, NHCOAryl, NHS0 2 A, NHSO 2 aryl or S0 2 N (R 4) 2, 0 (CH 2) n N (R 4) 2) 0 (CH 2) n NHR 3, O (CH 2) n NH 2, 0 (CH 2) n -morpholin , 0 (CH 2 ) n piperazine, 0 (CH 2 ) n -pyrrolidine, 0 (CH 2 ) n -piperidine, O-piperidine, O (CH
  • R 2 , R 3 , R 4 each independently of one another are H, A or alkylene aryl,
  • a unbranched or branched alkyl with 1-10 C atoms, wherein one or two CH 2 groups by O or S atoms and / or by -CH CH groups and / or 1-7 H atoms by shark can be replaced
  • G 1 , G 2 each independently of one another CR 1 R 1 or E,
  • n 0, 1, 2, 3, 4 or 5
  • the invention further relates to the production of substituted arylamide derivatives according to the invention and their use for the manufacture of a medicament for the treatment of diseases, in particular tumors and / or diseases which are caused, mediated and / or propagated by angiogenesis.
  • Compounds of formula I are effective inhibitors of tyrosine kinases, in particular TIE-2 and VEGFR, and of Raf kinases.
  • the compounds of the formula I can inhibit, regulate and / or modulate the signal transduction which is mediated by kinases, in particular by tyrosine kinases and / or Raf kinases.
  • kinases in particular by tyrosine kinases and / or Raf kinases.
  • inventive ones are particularly suitable
  • Medicaments and pharmaceutical compositions according to the invention can thus be used effectively for the treatment of diseases which are caused, mediated and / or propagated by kinases and / or by kinase-mediated signal transduction or by angiogenesis.
  • the compounds according to the invention are therefore suitable for the treatment and prophylaxis of cancer, tumor growth, arteriosclerosis, age-related macular degeneration, diabetic retinopathy, inflammatory diseases and the like in mammals.
  • Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues in protein substrates. It is believed that the tyrosine 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 was shown that the tyrosine kinases are important factors in cell proliferation, carcinogenesis and cell differentiation.
  • 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 intracellular part, while the cytosolic tyrosine kinases are only present intracellularly.
  • the receptor tyrosine kinases consist of a large number of transmembrane receptors with different biological effectiveness. About 20 different subfamilies of receptor tyrosine kinases have been identified.
  • a tyrosine kinase subfamily called EGFR or HER subfamily consists of EGFR, HER2, HER3 and HER4.
  • Ligands of this receptor subfamily include the epithelial growth factor (EGF), the tissue growth factor (TGF- ⁇ ), amphi-regulin, 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 ⁇ receptor, CSFIR, c- kit and FLK-II.
  • FLK family which consists of the kinase insert domain receptor (KDR) or VEGFR-2, the fetal liver kinase-1 (FLK-1), the fetal liver kinase-4 (FLK-4) and the fms tyrosine kinase-1 (flt -1) or VEGFR- 1 exists.
  • the PDGF and FLK families are typically grouped together in the splitkinase domain receptor tyrosine kinase group due to the similarities between the two groups (Laird, A.D. and J.M.
  • 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 different subgroups.
  • the Src subfamily is one of the largest subfamilies. It includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
  • the Src enzyme subfamily has been linked to oncogenesis.
  • Tyrosine kinases see the work of Bolen, Oncogene, 8: 2025-2031 (1993), which is hereby incorporated by reference.
  • Both the receptor tyrosine kinases and the cytosolic tyrosine kinases are involved in the cell's signaling pathways
  • Cancer is a disease whose causes can be seen in impaired signal transduction. Deregulated in particular
  • Tyrosine kinases and especially receptor tyrosine kinases and the growth factors binding to them can thus be involved in deregulated apoptosis, tissue invasion, metastasis and in general in signal transduction mechanisms which lead to cancer.
  • Receptor tyrosine kinases especially play a role in angiogenesis, another important mechanism in the growth and spread of cancer (Mustonen and Alitalo, J. Cell Biol. 129: 895-898, 1995).
  • One of these receptor tyrosine kinases is fetal liver kinase 1, also called FLK-1.
  • FLK-1 fetal liver kinase 1
  • the human analog 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.
  • the mouse version of this receptor was named NYK (Oelrichs et al., Oncogene 8 (1): 11-15, 1993).
  • VEGF and KDR represent a ligand-receptor pair that plays an essential role in the proliferation of vascular endothelial cells and the formation and sprouting of the blood vessels, which are referred to as vasculogenesis or angiogenesis.
  • Angiogenesis is characterized by excessive vascular endothelial growth factor (VEGF) activity.
  • VEGF actually consists of a family of ligands (Klagsburn and D'Amore, Cytokine & Growth Factor Reviews 7: 259-270, 1996).
  • VEGF vascular endothelial cell growth factor receptor 1
  • VEGF expression is also greatly increased in hypoxic regions of animal and human tumors in addition to necrosis zones.
  • VEGF is also upregulated by the expression of the ras, raf, src and p53 mutant oncogenes (all of which are important in the fight against cancer).
  • Monoclonal anti-VEGF antibodies inhibit the growth of human tumors in the nude mouse. The same tumor cells continue to express VEGF in culture, but here the antibodies do not decrease the cell division rate, ie the tumor-derived VEGF does not act as an autocrine mitogenic factor. Instead, VEGF contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotaxis and mitogenesis activity.
  • the anti-VEGF monoclonal antibodies also inhibit the growth of typically less vascularized human colon carcinomas in thymus-less mice and reduce the number of tumors arising from inoculated cells.
  • Solid tumors can be treated with tyrosine kinase inhibitors because these tumors rely on angiogenesis to form the blood vessels needed to support their growth.
  • These solid tumors include monocyte leukemia, brain, urogenital, lymphatic, gastric, larynx and lung carcinoma, including lung adenocarcinoma and small cell lung carcinoma.
  • solid tumors include carcinomas in which overexpression or activation of Raf-activating oncogenes (e.g. Kras, erb-B) is observed.
  • Raf-activating oncogenes e.g. Kras, erb-B
  • These cancers include pancreatic and breast cancer. Inhibitors of these tyrosine kinases and / or Raf kinases are therefore suitable for the prevention and treatment of proliferative diseases which are caused by these enzymes.
  • VEGF vascular endothelial growth factor
  • VEGF mRNA and protein levels in the eye which lead to the formation of new vessels, are further increased by conditions such as retinal venous occlusion in the primate and reduced p0 2 level in the mouse.
  • Intraocularly injected monoclonal anti-VEGF antibodies or VEGF receptor immunoconjugates inhibit vascularization in the eye in both the primate and rodent models.
  • 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. These data together show the role of VEGF in the growth of solid tumors. Inhibition of KDR or Flt-1 is involved in pathological angiogenesis, and inhibitors of these receptors are useful for the treatment of diseases in which angiogenesis is part of the total pathology, e.g. Inflammation, diabetic retinal vascularization, as well as 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).
  • the present invention is directed to compounds that can regulate, modulate or inhibit VEGFR and their use for the prevention and / or treatment of diseases related to unregulated or impaired VEGFR activity.
  • the compounds according to the invention can therefore be used in the treatment of certain types of cancer and in diseases caused by pathological angiogenesis, such as diabetic retinopathy or inflammation.
  • compounds according to the invention can be used to isolate and to study the activity or expression of VEGFR. They are also particularly suitable for use in diagnostic procedures for diseases related to unregulated or impaired VEGFR activity.
  • Angiopoieten 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. Cell Biol ., 12: 1698-1707 (1992); U.S. Patent Nos. 5,521,073; 5,879,672; 5,877,020; and 6,030,831).
  • TIE stands for "Tyrosine Kinase with Ig and EGF
  • TIE Homology domains ". TIE is used to identify a class of receptor tyrosine kinases that are only expressed in vascular endothelial cells and early hemopoietic cells. 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 which are stabilized by inter-chain disulfide bonds (Partanen et al., Curr. Topics Microbiol. Immunol., 1999, 237: 159-172).
  • IG immunoglobulin
  • Ang1 and its receptor TIE-2 act during the later stages in vascular development, ie during vascular remodeling (remodeling refers to the formation of a vascular 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)).
  • TIE-2 would be expected to disrupt the remodeling and maturation of a new vascular system initiated by angiogenesis, and thereby the angiogenesis process.
  • inhibition at the kinase domain binding site of VEGFR-2 would block the phosphorylation of tyrosine residues and 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, inhibitors of TIE-2 and / or VEGFR-2 could be used to provide treatment for cancer and other diseases associated with inappropriate angiogenesis.
  • the present invention is also directed to compounds that can regulate, modulate or inhibit TIE-2 and their use for the prevention and / or treatment of diseases related to unregulated or impaired TIE-2 activity.
  • the compounds according to the invention can therefore be used in the treatment of certain types of cancer and in diseases caused by pathological angiogenesis, such as diabetic retinopathy or inflammation.
  • compounds according to the invention can be used to isolate and to study the activity or expression of TIE-2. They are also particularly suitable for use in diagnostic procedures for diseases in connection with unregulated or impaired TIE-2 activity.
  • the compounds according to the invention can be used to provide additive or synergistic effects in certain existing cancer chemotherapy and radiation treatments, and / or can be used to restore the effectiveness of certain existing cancer chemotherapy treatments and radiation treatments.
  • the present invention further relates to the compounds 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
  • the p21 ras oncogene is an important 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 cycle 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
  • GTP Guanine triphosphate
  • GDP guanine diphosphate
  • Ras is active in the GTP-bound state. Endogenous GTPase activity is weakened in the Ras mutants in cancer cells, and consequently the protein emits constitutive growth signals to “DownstreanV” effectors, such as the enzyme Raf kinase.
  • Ras proto-oncogene requires a functionally intact C-Raf-1 proto-oncogene in order to transduce growth and differentiation signals initiated in higher eukaryotes by receptor and non-receptor tyrosine kinases.
  • 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.
  • Raf kinase by antisense oligodeoxynucleotides
  • inhibition of Raf kinase in vitro and in vivo has been associated 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 genes are proto-oncogenes: they can transform the malignant
  • Raf-1 protein serine kinase is a candidate for the "downstream" effect of mitogen signal transduction because Raf oncogenes counter apoptosis resulting from a blockade of cellular Ras activity due to a cellular mutation (Ras revertant cells) or microinjection of
  • Anti-Ras antibodies result (Rapp, UR, et al. (1988) in The Oncogene Handbook, T. Curran, EP Reddy and A. Skalka (ed.), Elsevier Science Publishers; Netherlands, pp. 213-253; Smith , MR, et al. (1986) Nature (London) 320: 540-543).
  • the C-Raf function is for transformation through a number of different membrane-bound oncogenes and for growth stimulation required by mitogens contained in sera (Smith, MR, 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
  • Raf-1 activating growth factors include platelet growth factor (PDGF) (Morrison, DK, et al. (1988) Proc. Natl. Acad. Sci. USA 85: 8855-8859), 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), the epidermal growth factor (EGF ) (Morrison, RK, et al. (1988) Proc. Natl. Acad. Sci.
  • PDGF platelet growth factor
  • 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
  • EGF epidermal growth factor
  • 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 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 activation includes a Raf-1 protein
  • Raf-1 phosphorylation can be a consequence of a kinase cascade amplified by autophosphorylation, or it can be entirely induced by autophosphorylation by binding a potential activation ligand to the Raf-1 regulator domain, analogous to PKC activation is initiated by diacylglycerol (Nishizuka, Y. (1986) Science 233: 305-312).
  • the present invention is directed to compounds that can regulate, modulate or inhibit Raf kinases and their use in the prevention and / or treatment of diseases related to unregulated or impaired activity of Raf kinases.
  • the compounds according to the invention can therefore be used in the treatment of certain forms of cancer.
  • the compounds of the invention can be used to provide additive or synergistic effects in certain existing cancer chemotherapy and radiation treatments, and / or can be used to restore the efficacy of certain existing cancer chemotherapy treatments and radiation treatments.
  • compounds according to the invention can be used to isolate and to study the activity or expression of Raf kinases. They are also particularly suitable for use in diagnostic procedures for diseases related to unregulated or disturbed Raf kinase activity.
  • Protein phosphorylation is a process by which intracellular signals are propagated from molecule to molecule, which ultimately results in a cell response.
  • These signal transduction cascades are highly regulated and often overlap, as is evident from the presence of many protein kinases as well as phosphatases. Phosphorylation of proteins mainly occurs in serine, threonine or tyrosine residues, and protein kinases were therefore classified according to the specificity of the phosphorylation site, ie the serine / threonine kinases and tyrosine kinases.
  • tyrosine kinases in particular are promising targets.
  • Iressa ® or Gleevec ® there are still numerous problems to be solved, such as side effects, dosage, tumor resistance, tumor specificity and patient selection.
  • WO 02/44156 describes benzimidazole derivatives as TIE-2 and / or VEGFR2 inhibitors.
  • WO 99/32436, WO 02/062763, WO 99/32455, WO 00/42012 and WO 02/085857 disclose urea derivatives as Raf kinase inhibitors.
  • WO 98/22103 A1 discloses arylamide derivatives as Raf kinase inhibitors. 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 compounds according to the invention are surprisingly effective kinase inhibitors. So they show a tyrosine kinase inhibiting effect, in particular they show a TIE-2 and / or VEGFR inhibiting effect. Furthermore, effective inhibitors of Raf kinases according to the invention are.
  • the invention relates to compounds of the formula I given above.
  • Het means an aromatic heterocycle with 1, 2, 3 or 4 N, O and / or S atoms, such as, for example, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, isoazolyl, oxazoyl, thiazolyl, pyridinyl, pyrimidinyl, pyranyl, pyrazinyl , Pyrrolyl, pyrazidinyl, purinyl, pteridinyl, azepinyl, diazepinyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, phenazinyl. Het is particularly preferably pyridinyl
  • Aromatic means an aromatic C 6 -C 0 -carbocycle, such as phenyl or naphthyl or biphenyl.
  • Aromatic particularly preferably means phenyl.
  • A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further 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-, 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, more preferably for example trifluoromethyl.
  • Aryl preferably means unsubstituted or one, two or more times by A, phenyl, OA, SA, OPhenyl, NH 2 , NA 2 , shark, N0 2 , CN, (CH 2 ) m COOR 4 , (CH 2 ) mCON ( R 4) 2, COR 4, CHO, COAryl, S (0) m A, NHCOA or NHS0 2 A substituted phenyl .. Hai means F, Cl, Br or I.
  • substituted preferably refers to the substitution with the above-mentioned substituents, several different degrees of substitution being possible, unless stated otherwise.
  • the compounds of formula I can have one or more chiral centers. Accordingly, they can occur in various enantiomeric forms and be present in racemic or optically active form.
  • the invention therefore also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and hydrates and solvates of these compounds.
  • the pharmaceutical activity of the racemates or the stereoisomers of the compounds according to the invention can differ, it may be desirable to use the enantiomers.
  • the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art, or can already be used as such in the synthesis.
  • diastereomers are formed from the mixture by reaction with an optically active release agent.
  • optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoytartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (eg N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids.
  • a chromatographic is also advantageous
  • Enantiomer separation using an optically active release agent e.g. dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chiral derivatized methacrylate polymers fixed on silica gel.
  • Aqueous or alcoholic solvent mixtures such as e.g. Hexane / isopropanol / acetonitrile e.g. in the ratio 82: 15: 3.
  • R 1 independently denotes H, A, aryl, OR 4 , SR 4 , OAryl, SAryl, N (R 4 ) 2 , NHAryl, Hai, N0 2 , CN, (CH 2 ) m COOR 4 , (CH 2 ) m COOAryl, (CH 2 ) m CON (R 4 ) 2) (CH 2 ) m CONHAryl, COR 4 , COAryl, S (0) m A, S (0) m aryl,
  • R 1 is particularly preferably in each individual case independently H, A, shark, OH, OA, CF 3 and / or CONHA.
  • Ar 1 is preferably an aromatic, more preferably Ar 1 is a mono- or disubstituted by R 1 is phenyl.
  • R 1 here preferably denotes OH or OA, shark, CF 3 , A, such as, for example, methyl or isopropyl.
  • Ar 2 is preferably an aromatic, particularly preferably unsubstituted phenyl.
  • Ar 3 preferably denotes an aromatic heterocycle, particularly preferably Ar 3 denotes a pyridinyl substituted by R 1 .
  • R 1 here preferably denotes CONHA or CONH 2 , particularly preferably CONHCH 3 .
  • Y is preferably O or S, particularly preferably O.
  • Z preferably denotes O or CR 1 R 1 .
  • R 2 preferably denotes H or A, particularly preferably H.
  • R 1 is in each case independently H, A, shark, OH, OA, CF 3 and / or CONHA, and their pharmaceutically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all ratios.
  • R a in each case independently A, Hai, OH, OA or CF 3 ,
  • compositions are understood to mean e.g. Salts of the compounds according to the invention, as well as so-called prodrug compounds. Such derivatives are known to the person skilled in the art. Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: Principles and Practice provides an overview of physiologically tolerable ones.
  • Prodrug connections mean e.g. Alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly split or released in the organism to the active compounds of the invention. This also includes biodegradable polymer derivatives of the compounds according to the invention, such as e.g. in Int. J. Pharm. 115 (1995), 61-67.
  • Suitable acid addition salts are inorganic or organic salts of all physiologically or pharmacologically acceptable acids, for example halides, in particular hydrochlorides or hydrobromides, lactates, sulfates, citrates, tartrates, maleates, fumarates, oxalates, acetates, phosphates, methylsulfonates or p-toluenesulfonates.
  • halides in particular hydrochlorides or hydrobromides, lactates, sulfates, citrates, tartrates, maleates, fumarates, oxalates, acetates, phosphates, methylsulfonates or p-toluenesulfonates.
  • Solvates of the compounds of the formula I are understood to mean the addition of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual attraction.
  • Solvates are, for example, hydrates, such as monohydrates or Dihydrates or alcoholates, ie addition compounds with alcohols such as with methanol or ethanol.
  • the term "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, e.g. is sought or sought by a researcher or medical professional.
  • terapéuticaally effective amount means an amount which, compared to a corresponding subject who has not received this amount, has the following consequences: improved treatment, healing, prevention or elimination of a disease, a clinical picture, a disease state, a condition, disorder, or prevention of side effects, or a reduction in the progression of an illness, condition, or disorder.
  • therapeutically effective amount also includes the amounts that are effective in increasing normal physiological function.
  • the invention also relates to mixtures of the compounds of the formula I according to the invention, 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 invention also relates to processes for the preparation of compounds of the formula I and their physiologically acceptable salts, derivatives, solvates and stereoisomers, characterized in that a compound of the formula II is
  • L denotes Cl, Br, I or a free or reactive, functionally modified OH group
  • the starting compounds are generally known. If they are new, they can be manufactured according to methods known per se.
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately converted further into the compounds of the formula I.
  • the starting materials can be combined (fused) in a sealed reaction vessel or in an autoclave. However, it is also possible to react the starting materials in the presence of an inert solvent.
  • the compounds of the formula 11 and III are reacted by methods which are known to the person skilled in the art. The reaction is first carried out in a suitable solvent, in particular in an inert solvent.
  • Suitable inert solvents are e.g. Heptane, hexane, petroleum ether, benzene, toluene, xylene, trichlorethylene, 1,2-dichloroethane tetrachloromethane, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether (preferred for the substitution on
  • 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, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); Nitriles such as acetonitrile; Esters such as ethyl acetate, carboxylic acids or acid anhydrides, such as. B. such as acetic acid or acetic anhydride, nitro compounds such as nitromethane or nitrobenzene, optionally also mixtures of the solvents mentioned with one another or mixtures with water. Dimethylformamide is particularly preferred.
  • the reaction can also be carried out in a heterogeneous phase, an aqueous phase and a benzene or toluene phase being preferably used.
  • a phase transfer catalyst such as tetrabutylammonium iodide and optionally an acylation catalyst such as dimethylaminopyridine are used.
  • the amount of solvent is not critical, preferably 10 g to 500 g of solvent can be added per g of the compound of formula II to be reacted.
  • Suitable reaction temperatures are from 10 to 180 ° C., preferably from 15 to 150 ° C. and very particularly preferably from 20 to 120 ° C.
  • the pressure is preferably from 1 to 200 bar, particularly preferably at normal pressure.
  • a pH of 4 to 10 is preferred.
  • the duration of the reaction depends on the reaction conditions chosen. As a rule, the reaction time is 10 minutes to 10 days, preferably 20 minutes to 24 hours.
  • An acid of the formula I can be converted into the associated addition salt with a base, for example by reaction equivalent amounts of the acid and base in an inert solvent such as ethanol and including evaporation.
  • Bases that provide physiologically acceptable salts are particularly suitable for this implementation.
  • the acid of formula I can be converted with a base (for example sodium or potassium hydroxide or carbonate) into the corresponding metal, in particular alkali or alkaline earth metal or into the corresponding ammonium salt.
  • Organic bases which provide physiologically acceptable salts, such as ethanolamine, are also suitable for this reaction.
  • a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and then evaporating them.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic, mono- or polybasic carboxylic, sulfonic or sulfuric acids , for example formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or hydroxysulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid
  • Salts with physiologically unacceptable acids can be used for the isolation and / or purification of the compounds of the formula I.
  • the invention further relates to medicaments containing at least one compound according to the invention and / or its physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all ratios.
  • a pharmaceutical preparation according to the invention can contain further carriers and / or auxiliaries and optionally one or more further active pharmaceutical ingredients.
  • the invention further relates to a process for the preparation of a medicament, characterized in that a compound according to the invention and / or one of its physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all ratios, together with a solid, liquid or semi-liquid carrier - or brings excipient into a suitable dosage form.
  • the invention also relates to a set consisting of separate packs of a) an effective amount of a compound according to the invention and / or its physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios and b) an effective amount of one another drug ingredient.
  • the set contains suitable containers, such as boxes or cartons, individual bottles, bags or ampoules.
  • the set can contain, for example, separate ampoules, in each of which an effective amount of a compound according to the invention and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and an effective amount of a further active pharmaceutical ingredient are dissolved or in iyophylated form ,
  • Medicaments can be administered in the form of dose units which contain 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, of a compound according to the invention, depending on the condition treated, the
  • Preferred dosage unit formulations are those which contain a daily dose or partial dose, as stated above, or a corresponding fraction thereof of an active ingredient. Furthermore, such pharmaceuticals can be produced using one of the methods generally known in the pharmaceutical field.
  • Medicines 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 , to adjust.
  • Such pharmaceuticals can be produced using all methods known in the pharmaceutical field, for example by bringing the active ingredient together with the carrier (s) or auxiliary (s).
  • Drugs adapted for oral administration can be administered as separate units, e.g. Capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous
  • Liquids Liquids; edible foams or foam dishes; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active ingredient component in the case of oral administration in the form of a tablet or capsule, can be treated with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as, for example Combine ethanol, glycerin, water etc. 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, for example Combine ethanol, glycerin, water etc.
  • 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 such as e.g. finely divided silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process.
  • a disintegrant or solubilizer e.g. Agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medication after taking the capsule.
  • 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 and others.
  • the explosives include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and others.
  • the tablets are formulated by, for example, making a powder mixture, granulating or dry pressing , a lubricant and a disintegrant are added and the whole is compressed into tablets.
  • a powder mixture is prepared by appropriately comminuting the compound with a diluent or base, as described above, and optionally with a Binder, such as carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a solution retarder such as paraffin, a resorption accelerator such as a quaternary salt and / or an absorbent such as bentonite, kaolin or dicalcium phosphate is mixed.
  • a Binder such as carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a solution retarder such as paraffin, a resorption 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 made from cellulose or polymer materials, and pressing it through a sieve.
  • a binder such as syrup, starch paste, Acadia slime or solutions made from cellulose or polymer materials
  • 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 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 according to the invention can also be combined with a free-flowing inert carrier and then without carrying out the
  • Granulation or dry pressing steps can be pressed directly into tablets.
  • a transparent or opaque protective layer consisting of a shellac seal, a layer of sugar or polymer 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 ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives, such as peppermint oil or Natural sweeteners or saccharin or other artificial sweeteners, among others, can also be added.
  • Dosage unit formulations for oral administration can optionally be enclosed in microcapsules.
  • the formulation can also be prepared by prolonging or retarding the release, such as by coating or embedding particulate material in polymers, wax, etc.
  • the compounds according to the invention and salts, solvates and physiologically functional derivatives thereof can also be in the form of liposome delivery systems, such as e.g. 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 according to the invention and the salts, solvates and physiologically functional derivatives thereof can also be supplied using monoclonal antibodies as individual carriers to which the connecting molecules are coupled.
  • Compounds can also be coupled with soluble polymers as targeted drug carriers.
  • Such polymers may include polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl aspartamide phenol, or polyethylene oxide polylysine substituted with palmitoyl residues.
  • Drugs adapted for transdermal administration can be given as independent patches for prolonged, close contact with the epidermis of the recipient.
  • the active ingredient can be supplied from the patch by means of iontophoresis, as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
  • Medicaments 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 used either with a paraffinic or with a water-miscible cream base.
  • the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.
  • Medicaments 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.
  • Medicines adapted for topical application in the mouth include lozenges, lozenges and mouthwash.
  • Drugs adapted for rectal administration can be given in the form of suppositories or enemas.
  • Drugs adapted for nasal administration in which the carrier substance is a solid, contain a coarse 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 rapid 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 nasal drops with a liquid as carrier include active ingredient solutions in water or oil.
  • Medicaments adapted for administration by inhalation include fine particulate dusts or mists, which can be generated by means of various types of pressurized metering dispensers with aerosols, nebulizers or insufflators.
  • Medicines adapted for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • Drugs adapted for parenteral administration include aqueous and non-aqueous sterile solutions for injection containing antioxidants, buffers, bacteriostatics and solutes which render the formulation 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 in single dose or multiple dose containers, e.g. sealed ampoules and vials, presented and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. 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.
  • the medicinal products according to the invention may contain, in addition to the above-mentioned constituents, other agents customary in the art with reference to the particular type of pharmaceutical formulation; for example, pharmaceuticals suitable for oral administration may contain flavorings.
  • a therapeutically effective amount of a compound of the present invention depends on a number of factors, including, for example, the age and weight of the human or animal, the exact condition of the disease requiring treatment, its severity, the nature of the formulation and the route of administration, and is ultimately determined by the attending doctor or veterinarian.
  • an effective amount of a compound according to the invention for the treatment of neoplastic growth is generally in the range from 0.1 to 100 mg / kg of body weight of the recipient (mammal) per day and particularly typically in the range of 1 to 10 mg / kg body weight per day.
  • the actual amount per day would usually be between 70 and 700 mg, which amount 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 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 perse as a proportion of the effective amount of the compound of the invention.
  • the compounds according to the invention preferably exhibit an advantageous biological activity which can be easily detected in enzyme assays, as described in the examples.
  • 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.
  • the present invention relates to the invention
  • Compounds as activators or inhibitors preferably as inhibitors of the signaling pathways described herein.
  • Particularly preferred subject of The invention therefore relates to compounds according to the invention as activators and inhibitors of kinases, particularly preferably as inhibitors of tyrosine kinases, in particular TIE-2 and / or VEGFR, and / or as inhibitors of Raf kinases, in particular A-Raf, B-Raf and Raf-1 (C-Raf).
  • the signaling pathways influenced by the compounds according to the invention are relevant for various diseases. Accordingly, the compounds according to the invention are useful in the prophylaxis and / or treatment of diseases which are dependent on the said signaling pathways through interaction with one or more of the said signaling pathways.
  • Another object of the present invention is therefore the use of compounds according to the invention and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all proportions for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular such diseases, which are caused, mediated and / or propagated by kinases and / or by kinase-mediated signal transduction.
  • Kinases selected from the group of tyrosine kinases are preferred.
  • the tyrosine kinases are particularly preferably TlE-2 or VEGFR.
  • the kinases selected from the group of Raf kinases are also preferred.
  • the Raf kinases are particularly preferably A-Raf, B-Raf or Raf-1.
  • 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 cancerous cell growth mediated by Raf kinase, the compounds are particularly useful in the treatment of solid carcinomas in humans and animals, e.g. B. from murine cancer, since the progression of these types of tumor depends on the Ras protein signal transduction cascade and therefore responds to the treatment by interrupting the cascade, ie by inhibiting the Raf kinase.
  • the compound of the invention or a pharmaceutically acceptable salt thereof is administered for the treatment of diseases mediated by the Raf kinase route, particularly cancer, including solid carcinomas such as carcinomas (e.g. the lungs, pancreas) , thyroid, bladder or colon), myeloid diseases (e.g. myeloid 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 Type 1) (Popik et al. (1998) J Virol, 72: 6406-6413).
  • tyrosine kinase-related diseases refers to pathological conditions which are dependent on the activity of one or more tyrosine kinases.
  • the tyrosine kinases are either directly or indirectly involved in the signal transduction pathways of various cell activities, including proliferation, adhesion and migration and differentiation and differentiation
  • Diseases associated with tyrosine kinase activity include tumor cell proliferation, pathological neovascularization 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 diseases discussed here are divided into two groups, hyperproliferative and non-hyperproliferative diseases.
  • psoriasis, arthritis, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and immunodeficiency diseases are considered non-cancerous diseases, of which arthritis, inflammation, immunological diseases, autoimmune diseases and immunodeficiency diseases are usually regarded as non-hyperproliferative diseases ,
  • cancerous cell growth and in particular cancerous cell growth mediated directly or indirectly by TIE-2, VEGFR and Raf kinase is a disease which is an object of the present invention.
  • the present invention therefore relates to the use of compounds according to the invention for the manufacture of a medicament for the treatment and / or prophylaxis of the diseases mentioned, and also to a method for the treatment of the diseases mentioned, comprising the administration of one or more compounds according to the invention to a patient in need of a such administration.
  • the compounds according to the invention have an in vivo antiproliferative effect in a xenograft tumor model.
  • the compounds of the invention are in one Patients with hyperproliferative disease administered, e.g. For example, to inhibit tumor growth, to reduce inflammation associated with lymphoproliferative disease, to inhibit graft rejection or neurological damage due to tissue repair, etc.
  • the present compounds are useful for prophylactic or therapeutic purposes.
  • the term "treat" is used to refer to both the prevention of diseases and the treatment of pre-existing conditions.
  • the prevention of proliferation is accomplished by administering the compounds of the invention prior to the development of the evident disease, e.g., for prevention tumor growth, prevention of metastatic growth, reduction of restenosis associated with cardiovascular surgery, etc.
  • the compounds are used to treat persistent diseases by stabilizing or improving the clinical symptoms of the patient.
  • the host or patient can belong to any mammalian species, e.g. B. 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 treating a human disease.
  • mammalian species e.g. B. 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 treating a human disease.
  • the susceptibility of a particular cell to treatment with the compounds according to the invention can be determined by in vitro tests. Typically, a culture of the cell is incubated with a compound of the invention at various concentrations for a period of time sufficient to enable the active ingredients 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 tests. The viable cells remaining after treatment 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. Treatment generally continues until there is a substantial reduction, e.g. B. at least about 50% reduction in the specific cell number and can be continued until essentially no unwanted cells are detected in the body.
  • a substantial reduction e.g. B. at least about 50% reduction in the specific cell number and can be continued until essentially no unwanted cells are detected in the body.
  • kinase inhibitors Various assay systems are available for the identification of kinase inhibitors.
  • the radioactive phosphorylation of a protein or peptide as a substrate with ⁇ ATP is measured in the scintillation proximity assay (Sorg et al., J. of. Biomolecular Screening, 2002, 7, 11-19) and the flash plate assay. If an inhibitory compound is present, no or a reduced radioactive signal is detectable.
  • the homogeneous time-resolved fluorescence resonance energy transfer (HTR-FRET) and fluorescence polarization (FP) technologies are useful as assay methods (Sills et al., J. of Biomolecular Screening, 2002, 191-214).
  • 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).
  • Compounds that can be treated, prevented, or alleviated include the following diseases and conditions but not limited to this.
  • the compounds of the invention are useful in the treatment and / or prophylaxis of a number of different diseases and conditions in which proliferation and / or smooth muscle cell and / or inflammatory cell migration into the intimal layer of a vessel occurs, resulting in restricted
  • Occlusive graft vascular diseases of interest include atherosclerosis, coronary artery disease after transplantation, venous graft stenosis, peri-anastomotic prosthetic restenosis, restenosis after angioplasty or stent placement, and the like.
  • the present invention comprises the use of the compounds according to the invention for the treatment or prevention of cancer.
  • the invention relates in particular to the use of compounds according to the invention and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all proportions for the manufacture of a medicament for the treatment and / or prophylaxis of solid tumors, the solid tumor being particularly preferred from the group consisting of brain tumor, tumor of the genitourinary tract, tumor of the lymphatic system, stomach tumor,
  • Larynx tumor, lung tumor is selected.
  • Solid tumors selected from the group consisting of monocyte leukemia, lung adenocarcinoma, small cell lung carcinomas, pancreatic cancer, glioblastomas and breast carcinoma can also preferably be treated with compounds containing compounds according to the invention.
  • the compounds of the invention 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 inventive Bindings are also useful for treating certain forms of blindness associated with retinal vascularization.
  • the invention therefore also relates to the use of compounds according to the invention and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures, in all proportions for the manufacture of a medicament for the treatment and or prophylaxis of diseases caused by angiogenesis, mediated and / or be propagated.
  • the invention therefore also relates to the use of the compounds according to the invention for the manufacture of a medicament for the treatment and / or prophylaxis of the above diseases.
  • Medicaments for the treatment and / or prophylaxis of inflammatory diseases also fall within the scope of the present invention.
  • inflammatory diseases include, for example, rheumatoid arthritis, psoriasis, contact dermatitis, late-type hypersensitivity reaction and the like.
  • the compounds according to the invention are also suitable for the treatment of certain bone pathologies such as osteosarcoma, osteoarthritis and rickets, which is also known under the name oncogenic osteomalacia (Hasegawa et al., Skeletal Radiol. 28, pp. 41-45, 1999; Gerber et al .,
  • the present compounds are also suitable for the treatment and prevention of conditions associated with bone resorption, such as osteoporosis and Paget's disease
  • the invention therefore furthermore relates to the use of compounds according to the invention and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all proportions for the manufacture of a medicament for the treatment of bone pathologies, selected from the group consisting of osteosarcoma, Osteoarthritis and rickets.
  • 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 compounds according to the invention are also suitable for the preparation of a medicament for the treatment and prophylaxis of diseases which are caused, mediated and / or propagated by Raf kinases, the Raf kinase from the group consisting of A-Raf, B-Raf and Raf -1 is selected.
  • the invention also relates to the use of compounds according to the invention and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all proportions for the manufacture of a medicament for the treatment of diseases, selected from the group of non-cancerous ones
  • Another object of the invention is the use of compounds according to the invention and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their mixtures in all proportions for the manufacture of a medicament for the treatment of diseases, selected from the group of cancerous diseases consisting of brain cancer Lung cancer
  • Squamous cell cancer bladder cancer, stomach cancer, pancreatic cancer, liver cancer, kidney cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophageal cancer, gynecological cancer, thyroid cancer, lymphoma, chronic leukemia and acute leukemia.
  • the compounds according to the invention can also be administered together with other well-known therapeutic agents which are selected on the basis of their suitability for the condition being treated.
  • 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 agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors.
  • Inhibitors HIV protease inhibitors, reverse transcriptase inhibitors, growth factor inhibitors and angiogenesis inhibitors.
  • the present compounds are particularly suitable for joint use with radiotherapy.
  • the synergistic effects of inhibiting VEGF in combination with radiotherapy have been described in the specialist field (see WO 00/61186).
  • Estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of how this is done
  • 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-benzopyran-3-yl] phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646, but this is not intended to be a limitation.
  • “Androgen receptor modulators” refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of how this is done
  • 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 is done. Examples include 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 primarily cause cell death by direct action on cell function or that inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalating agents, microtubulin inhibitors and topoisomerase inhibitors.
  • the cytotoxics include, for example, tirapazimin, sertenef, cachectin, ifosfamid, tasonermin, lonidamin, carboplatin, altretamin, prednimustin, dibromdulcit, ranimustin, fotemustin, nedaplatin, oxaliplatin, temozolomid, heptaplsin, ditamamidosintramofinosin, trestramustin-trinofinusin-trinofinusin-trinofinusin-trinofinusin-trinofinusin-trinofinusin-trinofinusin-trinofinusin-trinofinusin-trinofinusin-trinofinus-trinofin-trinofin-trinofin-trinofin-trinofin-trinofin-trinofin-trinofin-trinofin-trin
  • microtubulin inhibitors include, for example, paclitaxel, vindesin sulfate, S ' ⁇ ' - Dideshydro ⁇ '- deoxy- ⁇ '-norvincaleukoblastin, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR1098876, VinMSin 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.
  • Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecan, ⁇ -ethoxypropionyl-S ' ⁇ ' - O-exo-benzylidene-chartreusin, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4,5 -kl] acridine-2- (6H) propanamine,
  • antiproliferative agents include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, and antimetabolites such as enocitabine, Carmofur, Tegafur, pentostatin,
  • Doxifluridine trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabin sodium hydrate, raltitrexed, paltitrexide, emitefur, tiazo-furin, decitabine, nolatrexed, pemetrexed, 2'-desarodine-2'-methyl-desaridine-2 !
  • the "antiproliferative agents” also include monoclonal antibodies to 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 ).
  • customary work-up means: if necessary, water is added, and if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is dried and dried organic phase over sodium sulfate, evaporates and purifies by chromatography on 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) + ESI (Electrospray ionization) (M + H) + (unless otherwise stated)
  • a) 750 ml of thionyl chloride are heated to 45 ° C. under an N 2 atmosphere and 23 ml of DMF are added dropwise.
  • 250 g (2031 mol) of pyridine-2-carboxylic acid are then added in portions, and the reaction mixture is stirred at 45 ° C. for 15 min and at 80 ° C. for 24 h.
  • the yellow suspension is evaporated and the residue is towed several times with toluene.
  • the oily residue is dissolved in 180 ml of toluene, cooled to 0 ° C. and 110 ml of methanol are added dropwise.
  • Compound 4b 4- (2-methylcarbamoyl-pyridin-4-yloxy) benzoic acid; 5.7 g (100%), contaminated with NaCl, compound is further used in the following reaction.
  • HPLC method 1 1 min 99% A / 1% B, in 2.5 min to 100% B and 1 min 100% B; A: water (0.1% TFA), B: acetonitrile (0.1% TFA); Detection at 254 nm
  • HPLC method 2 0.5 min 99% A / 1% B, in 2.5 min to 100% B and 1 min 100% B; A: water (0.1% TFA), B: acetonitrile (0.1% TFA); Detection at 254 nm
  • VEGF receptor kinase activity is determined by incorporating radioactively labeled phosphate in 4: 1 polyglutamic acid / tyrosine substrate (pEY). The phosphorylated pEY product is held on a filter membrane and the incorporation of the radioactively labeled phosphate is quantified by scintillation counting.
  • VEGF receptor kinase 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) 5, pp.
  • GST glutathione-S-transferase
  • Liquid buffer 50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.5%
  • Triton X-100 10% glycerin, 10 mg / ml each of leupeptin, pepstatin and aprotinin and 1 mM phenylmethylsulfonyl fluoride (all from Sigma).
  • Wash buffer 50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA,
  • Triton X-100 0.05% Triton X-100, 10% glycerin, 10 mg / ml each of leupeptin, pepstatin and
  • Dialysis buffer 50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA,
  • Triton X-100 50% glycerin, 10 mg / ml each of leupeptin, pepstatin and aprotinin and 1 mM phenylmethylsulfonyl fluoride.
  • Enzvmver Plantnun ⁇ spuffer 50 mM Tris, pH 7.4, 0.1 M NaCI, 1 mM DTT, 10% glycerol, 100 mg / ml BSA.
  • Stop solution 30% trichloroacetic acid, 0.2 M sodium pyrophosphate (both from Fisher).
  • Method A - Protein Purification 1.
  • the Sf21 cells are infected with the recombinant virus at a moi (multiplicity of infection) of 5 virus particles / cell and grown for 48 hours at 27 ° C. 2. All steps are carried out at 4 ° C.
  • the infected cells are harvested by centrifugation at 1000 ⁇ g and lysed for 30 minutes at 4 ° C with 1/10 volume of lysis buffer and then centrifuged at 100,000 ⁇ g for 1 hour.
  • the supernatant is then passed through a glutathione-Sepharose acid (Pharmacia) equilibrated with lysis buffer and washed with 5 volumes of the same buffer and then 5 volumes of washing buffer.
  • the recombinant GST-KDR protein is eluted with washing buffer / 10 mM reduced glutathione (Sigma) and dialyzed against dialysis buffer.
  • Procedure B - VEGF Receptor Kinase Assav 1. Add 5 ⁇ l inhibitor or control in 50% DMSO to the assay.
  • VEGF receptors that mediate mitogenic responses to the growth factor is largely restricted to vascular endothelial cells.
  • Cultivated human umbilical vein endothelial cells proliferate in response to treatment with VEGF and can be used as an assay system for the quantitative determination of the effects of KDR kinase inhibitors on the stimulation of VEGF.
  • single cell layers of HUVECs are treated with the constituent or the test compound at rest 2 hours before the addition of VEGF or "basic fibroblast growth factor" (bFGF).
  • bFGF basic fibroblast growth factor
  • the mitogenic response to VEGF or bFGF is measured by measuring the incorporation of [ 3 H] thymidine determined in the cell DNA.
  • HUVECs Frozen HUVECs as primary culture isolates are obtained from Clonetics Corp. The cells are in the endothelial growth medium (endothelial
  • NUNCLON 96-well polystyrene tissue culture plates (NUNC # 167008).
  • Assav medium Eagle medium modified according to Dulbecco at 1 g / ml
  • Glucose (DMEM with low glucose content; Mediatech) plus 10% (v / v) fetal bovine serum (Clonetics).
  • Test compounds With the working stock solutions of the test compounds, a serial dilution is carried out with 100% dimethyl sulfoxide (DMSO) until their concentrations are 400 times higher than the desired final concentration. The last dilutions
  • Diluted DMEM medium with low glucose content to 80 ⁇ Ci / ml.
  • Cell washing medium Hank's balanced salt solution (Mediatech) with 1 mg / ml
  • Bovine serum albumin (Boehringer-Mannheim). Cell Lvse solution: 1N NaOH, 2% (w / v) Na 2 CO 3 .
  • HUVEC single-cell layers kept in EGM are harvested by trypsin treatment and at a density of 4000 cells per 100 ⁇ l assay
  • the growth stop medium is replaced by 100 ul assay medium containing either the constituent (0.25% [v / v] DMSO) or the desired final concentration of the test compound. All determinations are carried out in triplicate. The cells are then incubated for 2 hours at 37 ° C / 5% CO 2 so that the test compounds can penetrate the cells.
  • the cells are stimulated by adding 10 ⁇ l assay medium, 10 ⁇ VEGF solution or 10 ⁇ bFGF solution per well. The cells are then incubated at 37 ° C / 5% CO 2 .
  • NNaacchh 2244 SSttui nden in the presence of the growth factors is mixed with 10 ⁇ [ 3 H] - thymidine (10 ul / well).
  • the medium is suctioned off and the cells are washed twice with cell 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 in 7 ml Glass scintillation tubes containing 150 ul water transferred.
  • the scintillation cocktail (5 ml / tube) is added and the radioactivity associated with the cells is determined by liquid scintillation spectroscopy. According to these assays, the compounds of the formula I VEGF-
  • the present compounds inhibit VEGF-stimulated mitogenesis of cultured human vascular endothelial cells with HK50 values of 0.01-5.0 ⁇ M.
  • the TIE-2 tests can e.g. can be carried out analogously to the methods specified 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 inhibitory effect of the substances to be measured results in a lower radioactivity compared to an undisturbed enzymatic reaction.
  • a solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogen phosphate is dissolved in 3 l of double-distilled water with 2N Hydrochloric acid adjusted to pH 6.5, 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 according to the invention is melted with 100 g soy lecithin and 1400 g 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 according to the invention, 9.38 g of NaH2P04 • 2 H2O, 28.48 g of Na2HP04 • 12 H2O and 0.1 g of benzalkonium chloride in 940 ml of 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.
  • 500 mg of an active ingredient according to the invention are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • a mixture of 1 kg of active ingredient, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a customary manner such that each tablet contains 10 mg of active ingredient.
  • Example 10 Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example 10 Capsules
  • a solution of 1 kg of an active ingredient according to the invention 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.

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Abstract

L'invention concerne des dérivés arylamide substitués représentés par la formule (I), leur fabrication et leur utilisation dans la fabrication d'un médicament destiné au traitement de maladies, notamment de tumeurs et/ou de maladies provoquées, transmises et/ou propagées par l'angiogenèse. Les composés représentés par la formule (I) sont des inhibiteurs efficaces des tyrosine kinases, notamment de TIE-2 et de VEGFR, et des Raf-kinases.
EP05700886A 2004-02-26 2005-01-13 Derives pyridinamide servant d'inhibiteurs de kinase Withdrawn EP1718614A1 (fr)

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DE102004009238A DE102004009238A1 (de) 2004-02-26 2004-02-26 Arylamid-Derivate
PCT/EP2005/000273 WO2005085202A1 (fr) 2004-02-26 2005-01-13 Derives pyridinamide servant d'inhibiteurs de kinase

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