EP1651626A1 - Urea derivatives and their use as tyrosinkinase inhibitors - Google Patents

Urea derivatives and their use as tyrosinkinase inhibitors

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Publication number
EP1651626A1
EP1651626A1 EP04763077A EP04763077A EP1651626A1 EP 1651626 A1 EP1651626 A1 EP 1651626A1 EP 04763077 A EP04763077 A EP 04763077A EP 04763077 A EP04763077 A EP 04763077A EP 1651626 A1 EP1651626 A1 EP 1651626A1
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EP
European Patent Office
Prior art keywords
phenyl
urea
yloxy
fluoro
cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04763077A
Other languages
German (de)
French (fr)
Inventor
Günter Hölzemann
Karl-August Ackermann
Wolfgang Stähle
Alfred Jonczyk
Wilfried Rautenberg
Francesc Mitjans
Elisabet Rosell-Vives
Jaume Adan
Marta Soler
Helene Crassier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1651626A1 publication Critical patent/EP1651626A1/en
Withdrawn legal-status Critical Current

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    • 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
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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 in which the inhibition, regulation and / or modulation of the signal transduction of kinases, in particular the tyrosine kinases and / or Raf kinases, plays a role, furthermore pharmaceutical compositions which contain these compounds and the use of the compounds for treatment of kinase-related diseases.
  • the present invention relates to compounds that inhibit, regulate and / or modulate the signal transduction of tyrosine kinases, compositions containing these compounds, and methods for their use in the treatment of tyrosine kinase-related diseases and conditions such as angiogenesis, cancer, tumor growth, arteriosclerosis , age-related macular degeneration, diabetic retinopathy, inflammatory diseases and the like in mammals.
  • tyrosine kinase-related diseases and conditions such as angiogenesis, 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 on protein substrates. It is believed that tyrosine kinases play an essential role in signal transduction in various cell functions via substrate phosphorylation. Although the exact mechanisms of signal transduction are still unclear, the tyrosine kinases have been shown to be important factors 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 the HER subfamily consists of EGFR, HER2, HER3 and HER4. Ligands of this receptor subfamily include 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 ⁇ receptor, CSFIR, c- kit and FLK-II.
  • 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 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 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.
  • 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. Cell Biol. 129: 895-898, 1995).
  • One of these receptor tyrosine kinases is the fetal liver kiriase " 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 is because it binds VEGF with high affinity.
  • VEGF and KDR represent a ligand-receptor pair , which plays an essential role in the proliferation of vascular endothelial cells and the formation and sprout of blood vessels, which are referred to as vasculogenesis or angiogenesis, which is characterized by an excessive activity of the vascular endothelial growth factor (VEGF) .
  • VEGF actually exists from a family of ligands (Klagsbum and D'Amore, Cytokine &.
  • VEGF vascular endothelial cell growth factor receptor 1
  • Solid tumors can therefore be treated with tyrosine kinase inhibitors, since these tumors rely 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 carcinomas including lung adenocarcinoma and small cell lung carcinoma.
  • Other examples include carcinomas in which overexpression or activation of Raf-activating oncogenes (e.g. K-ras, erb-B) is observed.
  • Raf-activating oncogenes e.g. 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 proliferative 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 p0 2 levels in the mouse, which lead to neovascularization.
  • VEGF expression is also greatly increased in hypoxic regions of animal and human tumors in addition to necrosis zones.
  • the VEGF is also upregulated by the expression of the oncogenes ras, raf, src and p53 mutant (all of which are important in the fight against cancer).
  • Anti-VEGF monoclonal antibodies inhibit the
  • VEGF tumor growth factor
  • VEGF which originates from tumors, does not act 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.
  • These 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.
  • Embryo stem cells which usually grow in the form of solid tumors in the nude mouse, do not form any detectable knock-out of both VEGF alleles
  • Ang1 angiopoietin 1
  • Receptor tyrosine kinase TIE-2 it is a new angiogenic factor (Davis et al, Cell, 1996, 87: 1161-1169; Partanen et al,
  • TIE Teyrosine Kinase
  • TIE is used to identify a cell
  • TIE receptor kinases are typically characterized by the presence of an EGF-like domain and an immunoglobulin (IG) -like domain consisting of extracellular folding units that 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 of vascular development, i.e.
  • TIE-2 would be expected to disrupt the remodeling and maturation of a new vascular system initiated by angiogenesis and thereby the angiogenesis process. Furthermore, 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 inhibition of TIE-2 and / or VEGFR-2 should prevent tumor angiogenesis and serve to slow down or completely eliminate tumor growth. Accordingly, one could treat cancer and others provide diseases associated with inappropriate angiogenesis.
  • the present invention is directed to methods for regulation
  • TIE-2 Modulation or inhibition of TIE-2 for prevention and / or
  • the compounds of the invention can be used to provide additive or synergistic effects in certain existing cancer chemotherapies, and / or can be used to restore the efficacy of certain existing cancer chemotherapies 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 levels of phosphorylation and consequently the activity of specific target proteins.
  • One of the predominant roles of protein phosphorylation is in signal transduction when extracellular signals are amplified and by a cascade of protein phosphorylation and dephosphorylation events, e.g. B. are propagated in the p21 ras / raf way.
  • the p21 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.
  • endogenous GTPase activity is weakened, and consequently the protein emits constitutive growth signals to "downstream" effectors, such as the Raf kinase enzyme. This leads to the cancerous growth of the cells that produce them Mutants carry (Magnuson et al. (1994) Semin. Cancer Biol., 5, 247-53).
  • the Ras proto-oncogene requires a functionally intact C-Raf-1 proto-oncogene in order to be able to and not-
  • Transduce receptor tyrosine kinases initiated growth and differentiation signals.
  • 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 by antisense oligodeoxynucleotides
  • the 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, UR, et al. (1988) in The Oncogene Handbook; T. Curran, EP Reddy and A. Skalka (Ed.) Elsevier Science Publishers; Netherlands, pp. 213-253; Rapp, UR, et al. (1988) Cold Spring Harbor Sym. Quant. Biol. 53: 173-184; Rapp, UR, et al. (1990 ) Inv Curr. Top. Microbiol. Immunol. Potter and Melchers (ed.), Berlin, Springer-Verlag 166: 129-139).
  • Raf-1 is expressed in all organs and in all cell lines that have been examined, and A- and B-Raf are expressed in urogenital and brain tissues, respectively (Storm, SM (1990) Oncogene 5: 345-351).
  • Raf genes are proto-oncogenes: they can initiate the malignant transformation of lines 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 regulator domain of the protein
  • 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 microinjection 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).
  • 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.
  • PDGF platelet growth factor
  • the transiently activated Raf-1 protein serine kinase translocates into the perinuclear area and the
  • Raf-oncogenes activate transcription from Ap-1 / PEA3-dependent promotors in transient transfection assays (Jamal, S, et al. (1990) Science
  • Raf-1 protein phosphorylation may be a result of a kinase cascade that is amplified by autophosphorylation, or may be caused entirely by autophosphorylation that is initiated by binding a putative activation ligand to the Raf-1 regulator domain, analogous to PKC activation by diacylglycerol (Nishizuka, Y. (1986) Science 233: 305-312).
  • 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 can be seen from the presence of many protein kinases as well as phosphatases. Phosphorylation of proteins occurs predominantly with serine, threonine or tyrosine residues, and protein kinases were therefore classified according to their specificity for the location of the phosphoryl. H. of serine / threonine kinases and tyrosine kinases.
  • 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 cancer cell mediated by Raf kinase.
  • the compounds are particularly useful in the treatment of solid carcinomas in humans and animals, e.g., murine cancer, since the progression of these cancers is dependent on the Ras protein signal transduction cascade and therefore responsive to cascade disruption treatment, ie inhibition of 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 Cancer, including solid cancers, such as
  • carcinomas e.g. the lungs, pancreas, thyroid, bladder or colon
  • myeloid diseases e.g. myeloid leukemia
  • adenomas e.g. villous colon adenoma
  • pathological angiogenesis e.g. 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 HIV-1 (Human Immunodeficiency Virus Type 1) induced immune deficiency (Popik et al. (1998) J Virol, 72: 6406-6413).
  • the compounds according to the invention preferably exhibit an advantageous biological activity which is easily detectable in enzyme-based assays, for example assays as described here. In such enzyme-based assays exhibit and cause the compounds of the invention preferably have an inhibiting effect, which is usually by IC 5 o values in a suitable range, preferably in the micromolar range and more preferably will be documented in the nanomolar range.
  • the compounds of 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.
  • the present invention therefore relates to compounds according to the invention as promoters or inhibitors, preferably as inhibitors of the signaling pathways described herein.
  • 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 special one preferred subject matter of the invention are compounds according to the invention as promoters or inhibitors, preferably as inhibitors of C-Raf-1.
  • Another object of the present invention is 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 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. In this
  • Context, psoriasis, arthritis, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and immune deficiency diseases are regarded as non-cancerous diseases, of which arthritis, inflammation, immunological diseases, autoimmune diseases and immune deficiency diseases are usually regarded as non-hyperproliferative diseases.
  • 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, all types of cancer and acute leukemia are usually considered hyperproliferative diseases.
  • cancerous cell growth and in particular cancerous cell growth mediated by Raf kinase is a disease which is an object of the present invention.
  • the present invention therefore relates to compounds according to the invention as pharmaceuticals and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of the diseases mentioned and the use of inventive Compounds for the manufacture of a pharmaceutical for the treatment and / or prophylaxis of said diseases as well as a method for the treatment of said diseases comprising the administration of one or more compounds according to the invention to one
  • 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 a patient with a hyperproliferative disease, 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.
  • a hyperproliferative disease 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 "treating" 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 apparent disease, e.g., to prevent tumor growth Prevention of metastatic growth, reduction of restenoses 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.
  • 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 viable cells remaining after treatment are then counted.
  • 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 cell load and can be continued until essentially no more unwanted cells are detected in the body.
  • Phospho-AK Phospho-Antibodies
  • 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 02/44156 describes benzimidazole derivatives other than TIE-2 and / or VEGFR2 inhibitors.
  • WO 99/32436 discloses substituted phenyl ureas as Raf kinase inhibitors. From WO 02/062763 and WO 02/085857 one knows quinolyl, Isoquinolyl and pyridyl urea derivatives as Raf kinase inhibitors. Heteroaryl ureas as p38 kinase inhibitors are described in WO 02/85859.
  • WO 00/42012 are ⁇ -carboxyaryl-diphenylureas as Raf kinase inhibitors and in WO 00/41698 as p38 kinase
  • aryl and heteroaryl-substituted heterocyclic ureas are disclosed in WO 99/32455 as Raf kinase inhibitors and in WO 99/32110 as p38 kinase inhibitors.
  • Other diphenyl urea derivatives are known from WO 99/32463.
  • Substituted heterocyclic urea derivatives as p38 kinase inhibitors are disclosed in WO 99/32111.
  • the invention relates to urea derivatives selected from the group
  • the invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.
  • Solvates of the compounds are understood to mean the addition of inert solvent molecules to the compounds, which are formed on account of their mutual attraction. Solvates are e.g. Mono- or dihydrates or alcoholates.
  • Salts of the compounds according to the invention as well as so-called prodrug compounds are salts of the compounds according to the invention as well as so-called prodrug compounds.
  • Prodrug derivatives are understood with z. B. alkyl or acyl groups,
  • 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, one Suffering, a disorder or side effects, or even reducing the progression of an illness, suffering or disorder.
  • terapéuticaally 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 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 according to the invention.
  • the starting compounds are generally known. If they are new, they can be manufactured according to methods known per se.
  • the implementation takes place according to methods which are known to the person skilled in the art.
  • the reaction is first carried out in a suitable solvent, optionally in the presence of an organic base, e.g.
  • Triethylamine or an inorganic base such as e.g. an alkali or
  • Alkaline earth metal carbonate Alkaline earth metal carbonate.
  • 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);
  • Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitrover- bonds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.
  • Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide
  • Carboxylic acids such as formic acid or acetic acid
  • Nitrover- bonds such as nitromethane or nitrobenzene
  • Esters such as ethyl acetate or mixtures of the solvents mentioned.
  • reaction time is between a few minutes and 14 days, the reaction temperature between about
  • a base of the compounds according to the invention 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 subsequent evaporation.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • So inorganic acids can be used, e.g. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, aicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g.
  • Formic acid acetic acid, trifluoroacetic acid, propionic acid, pivalic acid, diethylacetic 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, ethanodisulfonic acid, methanoic acid sulfonic acid, methane sulfonic acid, methane acid , Benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds according to the invention.
  • Salts with physiologically unacceptable acids e.g. Picrates can be used for the isolation and / or purification of the compounds according to the invention.
  • the invention further relates to the use of the compounds and / or their physiologically acceptable salts for the preparation of a Medicament (pharmaceutical preparation), in particular by non-chemical means. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
  • the invention further relates to pharmaceutical compositions containing at least one compound according to the invention and / or their pharmaceutically usable derivatives, salts, solvates and stereoisomers, including their mixtures in all ratios, and, if appropriate, carriers and / or auxiliaries.
  • compositions can be presented in the form of dose units containing a predetermined amount of active ingredient per dose unit.
  • 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 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 which contain a daily dose or partial dose, as stated above, or a corresponding fraction thereof of an active ingredient.
  • 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 oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • oral including buccal or sublingual
  • rectal including buccal or sublingual
  • nasal including buccal, sublingual or transdermal
  • vaginal or parenteral including subcutaneous, intramuscular, intravenous or intradermal
  • parenteral including subcutaneous, intramuscular, intravenous or intradermal
  • 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 or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam dishes; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • Tablet or capsule the active ingredient with an oral, non-toxic and pharmaceutically acceptable inert carrier such as e.g. Ethanol, glycerin, water etc. combine.
  • Powders are made by comminuting the compound to an appropriate fine size and with a similarly comminuted pharmaceutical carrier such as e.g. an edible carbohydrate such as starch or mannitol is mixed.
  • 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.
  • a disintegrant or solubilizer such as agar, calcium carbonate or sodium carbonate, can also be added to improve the availability of the medication after taking the capsule.
  • suitable binding agents, lubricants and disintegrants, and also dyes 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.
  • the lubricants used in these dosage forms include sodium oleate, sodium stearate , Magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and others.
  • the disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and others.
  • the tablets are formulated by, for example, preparing a powder mixture, granulating or compressing it dry, a lubricant and a disintegrant are added and the whole is compressed 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
  • the powder mixture can be granulated by wetting it with a binder, such as syrup, starch paste, Acadia mucilage or solutions made of cellulose or polymer materials, and pressing it through a sieve.
  • a binder such as syrup, starch paste, Acadia mucilage or solutions made of 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 of the invention can also be used with a free-flowing inert Carrier combined and then pressed directly into tablets without performing the granulation or dry pressing steps.
  • a transparent or opaque protective layer consisting of a shellac seal, a layer of sugar or polymer material and a glossy layer of wax may be present.
  • Dyes can be added to coatings to distinguish between different dosage units.
  • Oral liquids e.g. Solution, syrups and elixirs can be prepared in unit dosage forms 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 e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, etc. can also be added.
  • Dosage unit formulations for oral administration can optionally be enclosed in microcapsules.
  • the formulation can also be prepared in such a way that the release is prolonged or delayed, for example by coating or embedding particulate material in polymers, wax and the like.
  • Liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds can also be coupled with soluble polymers as targeted drug carriers.
  • Such polymers can include polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl aspartamide 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, polyhydroxybutter acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipatic block copolymers of hydrogels.
  • compositions adapted for transdermal administration can be administered 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).
  • 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 used as a topical ointment or cream applied.
  • the active ingredient can be either paraffinic or water-miscible
  • Cream base can be used.
  • the active ingredient can be a
  • Cream can be formulated 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.
  • compositions adapted for topical application in the mouth include lozenges, lozenges and mouthwashes.
  • compositions adapted for rectal administration can be administered in the form of suppositories or enemas.
  • Formulations in which the vehicle 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, i.e. by quick inhalation over the
  • Powder Suitable formulations for administration as a nasal spray or
  • compositions 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.
  • Pharmaceutical formulations adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • Formulations include aqueous and non-aqueous sterile solutions for injection containing antioxidants, buffers, bacteriostatics and solutes by which the formulation is rendered isotonic with the blood of the recipient to be treated; as well as aqueous and non-aqueous sterile suspensions, which can 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
  • Injection solutions and suspensions prepared according to the recipe can be made from sterile powders, granules and tablets.
  • formulations may contain, in addition to the above-mentioned ingredients, other means common in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration may contain flavorings.
  • a therapeutically effective amount of a compound of the present invention 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, its severity, the nature of the formulation and the route of administration, and is ultimately determined by the treating doctor or veterinarian.
  • an effective amount of a compound according to the invention for the treatment of neoplastic growth, for example colon or breast carcinoma generally in the range of 0.1 to 100 mg / kg 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 used as a proportion of the effective
  • Amount of the compound of the invention can be determined perse. 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 according to the invention and / or their pharmaceutically usable derivatives, salts, solvates and stereoisomers, including their mixtures in all ratios, and at least one further active pharmaceutical ingredient.
  • 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 pharmaceutically usable derivatives, salts, solvates and stereoisomers, including their mixtures in all ratios, 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 contain, for example, separate ampoules, each containing an effective amount of a compound according to the invention and / or its pharmaceutical 05/019192 - 33 -
  • 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 comprises the use of the compounds according to the invention according to claim 1 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of cancer.
  • Preferred carcinomas for the treatment come from the group of brain carcinoma, urogenital tract carcinoma, carcinoma of the lymphatic system, gastric carcinoma,
  • Larynx and lung cancer are Larynx and lung cancer.
  • Another group of preferred forms of cancer are monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma.
  • Eye disease such as retinal vascularization, diabetic retinopathy, age-related macular degeneration and the like.
  • a medicament for the treatment or prevention of inflammatory diseases also falls within the scope of the present invention.
  • inflammatory diseases include, for example, rheumatoid arthritis, psoriasis, contact dermatitis, late-type hypersensitivity reaction and the like.
  • compounds according to the invention as claimed in claim 1 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of a tyrosine kinase-related disease or a tyrosine kinase-related condition in a mammal, this method being 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 includes 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 retinal vascularization.
  • Methods for treating or preventing eye diseases such as diabetic retinopathy and age-related macular degeneration are also part of the invention.
  • the use for the treatment or prevention of inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis and late types of the hypersensitivity reaction, as well as the treatment or prevention of bone pathologies from the group of osteosarcoma, osteoarthritis and rickets also falls within the scope of the present invention.
  • the term "tyrosine kinase-related diseases or conditions” refers to pathological conditions that result from the activity of one or more
  • Tyrosine kinases are dependent.
  • the tyrosine kinases are either directly or indirectly involved in the signal transduction pathways of various cell 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 (diabetic retinopathy, age-related macular degeneration and the like), and inflammation (psoriasis, rheumatoid arthritis and the like) ).
  • 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 according to claim 1 are also suitable for the treatment of certain forms of blindness which are associated with retinal vascularization.
  • the compounds according to claim 1 are also suitable for the treatment of certain bone pathologies such as osteosarcoma, osteoarthritis and
  • Rickets which is also known as oncogenic osteomalacia (Hasegawa et al, Skeletal Radiol. 28, pp. 41-45, 1999; Gerber et al, Nature Medicine, Vol. 5, No. 6, pp. 623-628, June 1999). Since VEGF directly promotes osteoclastic bone resorption through the KDR / Flk-1 expressed in mature osteoclasts (FEBS Let. 473: 161-164 (2000); Endocrinology, 141: 1667 (2000)), the present compounds are also suitable for treatment and prevention of conditions related to bone resorption, such as osteoporosis and Paget's disease. The compounds can be characterized by the fact that they have cerebral edema,
  • the invention thus relates to the use of compounds according to claim 1, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, for the manufacture of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of the Signal transduction of kinases plays a role.
  • Kinases are preferably selected from the group of tyrosine kinases and Raf kinases.
  • the tyrosine kinases are preferably TIE-2.
  • the use for the treatment of a disease is particularly preferred, the disease being a solid tumor.
  • the solid tumor is preferably selected from the group consisting of brain tumor, tumor of the genitourinary tract, tumor of the lymphatic system, stomach tumor, larynx tumor and lung tumor.
  • the solid tumor is also preferably selected from the group consisting of monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma.
  • the invention further relates to the use of the compounds according to the invention for the treatment of a disease in which angiogenesis is involved.
  • the disease is preferably an eye disease.
  • the invention further relates to the use for the treatment of retinal vascularization, diabetic retinopathy, age-related macular degeneration and / or inflammatory diseases.
  • the inflammatory disease is preferably selected from the group rheumatoid arthritis, psoriasis, contact dermatitis and late-type 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 according to claim 1 are suitable for the preparation of a
  • the use for the treatment of diseases preferably from the group of hyperproliferative and non-hyperproliferative diseases.
  • the non-cancerous diseases are selected from the group consisting of psoriasis, arthritis, inflammation, endometriosis,
  • the cancerous diseases are selected from the group consisting of brain cancer, lung cancer, squamous cell cancer, bladder cancer, stomach cancer, pancreatic cancer, liver cancer, kidney cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophageal cancer, gynecological cancer, thyroid cancer, lymphoma and chronic leukemia, chronic leukemia.
  • the compounds of the invention can also be used in conjunction with other well-known therapeutic agents based on their respective
  • Suitability for the condition being treated can be administered.
  • combinations that contain antiresorptive bisphosphonates, such as alendronate and risedronate, integrin blockers (as defined below), such as ⁇ vß3 antagonists, conjugated estrogens such as Prempro®, Premarin® and Endometrion® used in hormone therapy would be beneficial; 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.
  • anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxics, antiproliferative Agent, prenyl protein transferase inhibitor, HMG-CoA reductase inhibitor,
  • HIV protease inhibitors HIV protease inhibitors, reverse transcriptase inhibitors and others
  • Angiogenesis inhibitors are particularly suitable for joint use with radiotherapy.
  • Estrogen receptor modulators refers to compounds that 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-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 that interfere with or inhibit the binding of androgens to the receptor, regardless of how this is done.
  • the 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.
  • 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 direct action on cell function lead to cell death or which inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalating agents, microtubulin inhibitors and topoisomerase
  • the cytotoxics include, for example, tirapazimin, sertenef, cachectin,
  • Dibromodulcite ranimustine, fotemustine, nedaplatin, oxaliplatin,
  • Temozolomide Temozolomide, heptaplatin, estramustine, improsulfan tosylate, trofosfamide,
  • microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, 3 ', 4'-dideshydro-4'-deoxy-8'-norvincaleukoblastin, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR1094476, BMS 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
  • Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ', 4'-0-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-1 H, 12H-benzo [de] pyrano [ 3 ', 4': b, 7] indolizino [1, 2b] quinoline-10, 13 (91-1.15H) - dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl] - (20S) camptothecin , BNP1350, BNPI1100, BN80915, BN80942, e
  • antiproliferative agents include antisense RNA and DNA oligonucleotides such as G3139, 0DN698, RVASKRAS, GEM231 and INX3001, as well as antimetabolites such as enocitabine, Carmofur, Tegafur, pentostatin, doxifluridine, trimetrexate, flabinarababin, capud ocfosfate, fosteabin sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidencytidine, 2'-fluoromethylene-2'-deoxycytidine, N- [5- 3- dihydrobenzofuryl) sulfonyl] -N '- (3,4-dichlorophenyl) urea, N6- [4-deoxy- 4- [
  • antiproliferative agents also contain 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 mediate via recombinant virus Gene transfer can be delivered (see, for example, US Patent No. 6,069,134).
  • VEGF receptor kinase assay The 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.
  • 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.
  • GST glutathione-S-transferase
  • the soluble recombinant GST-kinase domain fusion proteins were found in Spodoptera frugiperda (Sf21) insect cells (Invitrogen) Use of a baculovirus expression vector (pAcG2T, Pharmingen).
  • Tris pH 7.4 50mM Tris pH 7.4, 0.5M NaCl, 5mM DTT, 1mM EDTA, 0.5% Triton X-
  • Tris pH 7.4 50 mM Tris pH 7.4, 0.5 M NaCI, 5 mM DTT, 1 mM EDTA, 0.05% Triton X-100, 10% glycerol, 10 mg / ml each of leupeptin, pepstatin and aprotinin and 1 mM phenylmethylsulfonyl fluoride.
  • Bovine serum albumin BSA] (Sigma).
  • Millipore #MAFC NOB GF / C 96-well glass fiber plate.
  • the Sf21 cells were with the recombinant virus in an m.o.i.
  • volume lysis buffer lysed and then centrifuged for 1 hour at 100,000xg. The supernatant was then passed through a glutathione-Sepharose acid (Pharmacia) equilibrated with lysis buffer and with 5
  • 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 to quantify the effects of KDR kinase inhibitors on VEGF stimulation.
  • VEGF vascular endothelial growth factor
  • bFGF Basic fibroblast growth factor
  • 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).
  • Dulbecco modified Eagle medium with 1 g / ml glucose (DMEM with low glucose content; Mediatech) plus 10% (v / v) fetal
  • [Methyl- 3 H] -thymidine (20 Ci / mmol; Dupont-NEN) is diluted to 80 ⁇ Ci / ml with DMEM medium with a low glucose content.
  • Hank's balanced salt solution Mediatech
  • 1 mg / ml bovine serum albumin Boehringer-Mannheim
  • Cell lysis solution 1N NaOH, 2% (w / v) Na 2 CO 3 .
  • HUVEC single cell layers kept in EGM are harvested by trypsin treatment and inoculated in a density of 4000 cells per 100 ⁇ l 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 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. Procedure 3
  • 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. According to these assays, the compounds of the formula I VEGF-
  • Inhibitors are therefore suitable for inhibiting angiogenesis, such as in the treatment of eye diseases, e.g. diabetic retinopathy, and for the treatment of carcinomas, e.g. solid tumors.
  • the present compounds inhibit VEGF-stimulated mitogenesis of cultured human vascular endothelial cells with HK50 values of
  • Tyrosine kinases e.g. FGFR1 and Src family; for the relationship between Src kinases and VEGFR kinases see Eliceiri et al, Molecular Cell, Vol.
  • the T7E-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 poly Glu, Tyr
  • Substrate binds to the surface of one during the incubation period
  • 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, evaporated and purified by chromatography
  • the mixture is mixed with water and extracted with ethyl acetate.
  • the collected organic phases are dried with anhydrous sodium sulfate, filtered and evaporated.
  • the residue is triturated with diethyl ether. 2.8 g of 5- (4-nitrophenoxy) benzo [1,2,5] thiadiazole are obtained; Rf (CH2Cl2) 0.65; EI-MS (M + H) + 274.
  • the nitro compound is hydrogenated with Raney nickel to the desired compound.
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogenphosphate 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 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 of 1 g of an active ingredient is prepared according to the invention, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g Na 2 HP0 4 • 12 H 2 0 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.
  • Example D ointment
  • Example E tablets
  • 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 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

The invention relates to novel urea derivatives which inhibit tyrosinkinases, especially TIE-2, and Raf kinases and which are used in the treatment of tumors.

Description

HARNSTOFFDERIVATE UND DEREN VERWENDUNG ALS INHIBITOREN DER TYROSINKINASENH AR NUMBER DERIVATIVES AND THEIR USE AS INHIBITORS OF TYROSINKINASES
HINTERGRUND DER ERFINDUNGBACKGROUND OF THE INVENTION
Der Erfindung lag die Aufgabe zugrunde, neue Verbindungen mit wertvollen Eigenschaften aufzufinden, insbesondere solche, die zur Herstellung von Arzneimitteln verwendet werden können.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.
Die vorliegende Erfindung betrifft Verbindungen, bei denen die Hemmung, Regulierung und/oder Modulation der Signaltransduktion von Kinasen, insbesondere der Tyrosinkinasen und/oder Raf-Kinasen eine Rolle spielt, ferner pharmazeutische Zusammensetzungen, die diese Verbindungen enthalten, sowie die Verwendung der Verbindungen zur Behandlung von kinasebedingter Krankheiten.The present invention relates to compounds in which the inhibition, regulation and / or modulation of the signal transduction of kinases, in particular the tyrosine kinases and / or Raf kinases, plays a role, furthermore pharmaceutical compositions which contain these compounds and the use of the compounds for treatment of kinase-related diseases.
Im einzelnen betrifft die vorliegende Erfindung Verbindungen, die die Signaltransduktion der Tyrosinkinasen hemmen, regulieren und/oder modulieren, Zusammensetzungen, die diese Verbindungen enthalten, sowie Verfahren zu ihrer Verwendung zur Behandlung von tyrosinkinase- bedingten Krankheiten und Leiden wie Angiogenese, Krebs, Tumorwachstum, Arteriosklerose, altersbedingte Makula-Degeneration, diabetische Retinopathie, Entzündungserkrankungen und dergleichen bei Säugetieren.More specifically, the present invention relates to compounds that inhibit, regulate and / or modulate the signal transduction of tyrosine kinases, compositions containing these compounds, and methods for their use in the treatment of tyrosine kinase-related diseases and conditions such as angiogenesis, cancer, tumor growth, arteriosclerosis , age-related macular degeneration, diabetic retinopathy, inflammatory diseases and the like in mammals.
Bei den Tyrosinkinasen handelt es sich um eine Klasse von Enyzmen, die die Übertragung des endständigen Phosphats des Adenosintriphosphats auf Tyrosinreste bei Proteinsubstraten katalysieren. Man nimmt an, dass den Tyrosinkinasen bei verschiedenen Zellfunktionen über die Substrat- phosphorylierung eine wesentliche Rolle bei der Signaltransduktion zukommt. Obwohl die genaue Mechanismen der Signaltransduktion noch unklar sind, wurde gezeigt, dass die Tyrosinkinasen wichtige Faktoren bei der Zellproliferation, der Karzinogenese und der Zelldifferenzierung darstellen.Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues on protein substrates. It is believed that tyrosine kinases play an essential role in signal transduction in various cell functions via substrate phosphorylation. Although the exact mechanisms of signal transduction are still unclear, the tyrosine kinases have been shown to be important factors cell proliferation, carcinogenesis and cell differentiation.
Die Tyrosinkinasen lassen sich in Rezeptor-Tyrosinkinasen und zytosolische Tyrosinkinasen einteilen. Die Rezeptor-Tyrosinkinasen weisen einen extrazellulären Teil, einen Transmembranteil und einen intrazellulären Teil auf, während die zytosolischen Tyrosinkinasen ausschließlich intrazellulär vorliegen.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.
Die Rezeptor-Tyrosinkinasen bestehen aus einer Vielzahl von Trans- membranrezeptoren mit unterschiedlicher biologischer Wirksamkeit. So wurden ungefähr 20 verschiedene Unterfamilien von Rezeptor-Tyrosinkinasen identifiziert. Eine Tyrosinkinase-Unterfamilie, die die Bezeichnung HER-Unterfamilie trägt, besteht aus EGFR, HER2, HER3 und HER4. Zu den Liganden dieser Rezeptor-Unterfamilie zählen der Epithel-Wachstumsfaktor, TGF-α, Amphiregulin, HB-EGF, Betacellulin und Heregulin. Die Insulin-Unterfamilie, zu der INS-R, IGF-IR und IR-R zählen, stellt eine weitere Unterfamilie dieser Rezeptor-Tyrosinkinasen dar. Die PDGF- Unterfamilie beinhaltet den PDGF-α- and -ß-Rezeptor, CSFIR, c-kit und FLK-II. Außerdem gibt es die FLK-Familie, die aus dem Kinaseinsert- domänenrezeptor (KDR), der fötalen Leberkinase-1 (FLK-1), der fötalen Leberkinase-4 (FLK-4) und der fms-Tyrosinkinase-1 (fit- 1 ) besteht. Die PDGF- und FLK-Familie werden üblicherweise aufgrund der zwischen den beiden Gruppen bestehenden Ähnlichkeiten gemeinsam diskutiert. Für eine genaue Diskussion der Rezeptor-Tyrosinkinasen siehe die Arbeit von Plowman et al., DN & F 7(6):334-339, 1994, die hiermit durch Bezugnahme aufgenommen wird. Die zytosolischen Tyrosinkinasen bestehen ebenfalls aus einer Vielzahl von Unterfamilien, darunter Src, Frk, Btk, Csk, Abi, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK. Jede dieser Unterfamilien ist weiter in verschiedene Rezeptoren unterteilt. So stellt zum Beispiel die Src-Unterfamilie eine der größten Unterfamilien dar. Sie beinhaltet Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr und Yrk. Die Src-Enzymunterfamilie wurde mit der Onkogenese in Verbindung gebracht. Für eine genauere Diskussion der zytosolischen Tyrosinkinasen, siehe die Arbeit von Bolen Oncogene, 8:2025-2031 (1993), die hiermit durch Bezugnahme aufgenommen wird. Sowohl die Rezeptor-Tyrosinkinasen als auch die zytosolischen Tyrosinkinasen sind an Signalübertragungswegen der Zelle, die zu verschiedenenThe 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 the HER subfamily consists of EGFR, HER2, HER3 and HER4. Ligands of this receptor subfamily include epithelial growth factor, TGF-α, 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-α and β receptor, CSFIR, c- kit and 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. The PDGF and FLK families are usually discussed together due to the similarities between the two groups. For a detailed discussion of receptor tyrosine kinases, see the work of Plowman et al., DN & F 7 (6): 334-339, 1994, which is hereby incorporated by reference. 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 receptors. For example, 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. For a more detailed discussion of the cytosolic 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 on signaling pathways of the cell that differ
Leidenszuständen führen, darunter Krebs, Schuppenflechte und Hyper- immunreaktionen, beteiligt.Suffering, including cancer, psoriasis and hyper-immune reactions, are involved.
Es wurde vorgeschlagen, dass verschiedene Rezeptor-Tyrosinkinasen sowie die an sie bindenden Wachstumsfaktoren eine Rolle bei den Angiogenese spielen, obwohl einige die Angiogenese indirekt fördern könnten (Mustonen und Alitalo, J. Cell Biol. 129:895-898, 1995). Eine dieser Rezeptor-Tyrosinkinasen ist die fötale Leberkiriase "1 , auch FLK-1 genannt. Das menschliche Analog der FLK-1 ist der kinase-insert- domänenhaltige Rezeptor KDR, der auch unter der Bezeichnung Gefäß- endothelzellenwachstumsfaktorrezeptor 2 bzw. VEGFR-2 bekannt ist, da er VEGF hochaffin bindet. Schließlich wurde die Maus-Version dieses Rezeptors auch ebenfalls NYK genannt (Oelrichs et al., Oncogene 8(1):11- 15, 1993). VEGF und KDR stellen ein Ligand-Rezeptor-Paar dar, das eine wesentliche Rolle bei der Proliferation der Gefäßendothelzellen und der Bildung und Sprossung der Blutgefäße, die als Vaskulogenese bzw. Angiogenese bezeichnet werden, spielt. Die Angiogenese ist durch eine übermäßig starke Aktivität des Gefäß- endothelwachstumsfaktors (VEGF) gekennzeichnet. Der VEGF besteht eigentlich aus einer Familie von Liganden (Klagsbum und D'Amore, Cytokine &. Growth Factor Reviews 7:259-270, 1996). Der VEGF bindet den hochaffinen transmembranösen Tyrosinkinaserezepzor KDR und die verwandte fms-Tyrosinkinase-1 , auch unter der Bezeichnung Flt-1 oder Gefäßendothelzellenwachstumsfaktorrezeptor 1 (VEGFR-1) bekannt. Aus Zellkultur- und Gen- Knockout-Versuchen geht hervor, dass jeder Rezeptor zu unterschiedlichen Aspekten der Angiogenese beiträgt. Der KDR führt die mitogene Funktion des VEGF herbei, während Flt-1 nichtmitogene Funktionen, wie diejenigen, die mit der Zelladhäsion in Zusammenhang stehen, zu modulieren scheint. Eine Hemmung des KDR moduliert daher das Niveau der mitogenen VEGF-Aktivität. Tatsächlich wurde gezeigt, dass das Tumorwachstum von der antiangiogenen Wirkung der VEGF-Rezeptor-Antagonisten beeinflusst wird (Kim et al., Nature 362, S. 841- 844, 1993).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. Cell Biol. 129: 895-898, 1995). One of these receptor tyrosine kinases is the fetal liver kiriase " 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 is because it binds VEGF with high affinity. Finally, the mouse version of this receptor was also called NYK (Oelrichs et al., Oncogene 8 (1): 11-15, 1993). VEGF and KDR represent a ligand-receptor pair , which plays an essential role in the proliferation of vascular endothelial cells and the formation and sprout of blood vessels, which are referred to as vasculogenesis or angiogenesis, which is characterized by an excessive activity of the vascular endothelial growth factor (VEGF) .VEGF actually exists from a family of ligands (Klagsbum and D'Amore, Cytokine &. Growth Factor Reviews 7: 259-270, 1996) .VEGF binds to the high-affinity transmembrane tyrosine kinaser ezepzor KDR and the related fms tyrosine kinase-1, also known as Flt-1 or vascular endothelial cell growth factor receptor 1 (VEGFR-1). Cell culture and gene knockout experiments show that each receptor contributes to different aspects of angiogenesis. The KDR induces the mitogenic function of VEGF, while Flt-1 non-mitogenic functions, such as those involved in cell adhesion Connected, seems to modulate. Inhibition of the KDR therefore modulates the level of mitogenic VEGF activity. In fact, it has been shown that tumor growth is affected by the antiangiogenic effects of the VEGF receptor antagonists (Kim et al., Nature 362, pp. 841-844, 1993).
Feste Tumore können daher mit Tyrosinkinasehemmern behandelt werden, da diese Tumore für die Bildung der zur Unterstützung ihres Wachstums erforderlichen Blutgefäße auf Angiogenese angewiesen sind. Zu diesen festen Tumoren zählen die Monozytenleukämie, Hirn-,Solid tumors can therefore be treated with tyrosine kinase inhibitors, since these tumors rely on angiogenesis for the formation of the blood vessels required to support their growth. These solid tumors include monocyte leukemia, brain,
Urogenital-, Lymphsystem-, Magen-, Kehlkopf- und Lungenkarzinom, darunter Lungenadenokarzinom und kleinzelliges Lungenkarzinom. Zu weiteren Beispielen zählen Karzinome, bei denen eine Überexpression oder Aktivierung von Raf-aktivierenden Onkogenen (z.B. K-ras, erb-B) beobachtet wird. Zu diesen Karzinomen zählen Bauchspeicheldrüsen- und Brustkarzinom. Hemmstoffe dieser Tyrosinkinasen eignen sich daher zur Vorbeugung und Behandlung von proliferativen Krankheiten, die durch diese Enzyme bedingt sind.Urogenital, lymphatic, gastric, larynx and lung carcinomas, including lung adenocarcinoma and small cell lung carcinoma. Other examples include carcinomas in which overexpression or activation of Raf-activating oncogenes (e.g. K-ras, erb-B) is observed. These cancers include pancreatic and breast cancer. Inhibitors of these tyrosine kinases are therefore suitable for the prevention and treatment of proliferative diseases which are caused by these enzymes.
Die angiogene Aktivität des VEGF ist nicht auf Tumore beschränkt. Der VEGF ist für die bei diabetischer Retinopathie in bzw. in der Nähe der Retina produzierte angiogene Aktivität verantwortlich. Dieses Gefäßwachstum in der Retina führt zu geschwächter Sehkraft und schließlich Erblindung. Die VEGF-mRNA- und -protein-Spiegel im Auge werden durch Leiden wie Netzhautvenenokklusion beim Primaten sowie verringertem p02-Spiegel bei der Maus, die zu Gefäßneubildung führen, erhöht. Intraokular injizierte monoklonale Anti-VEGF-Antikörper, oder VEGF- Rezeptor-Immunkonjugate, hemmen sowohl im Primaten- als auch imThe angiogenic activity of VEGF is not limited to tumors. VEGF is responsible for the angiogenic activity produced in or near the retina in diabetic retinopathy. This vascular growth in the retina leads to weakened eyesight and eventually blindness. VEGF mRNA and protein levels in the eye are increased due to conditions such as retinal venous occlusion in the primate and reduced p0 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
Nagetiermodell die Gefäßneubildung im Auge. Unabhängig vom Grund derRodent model eye formation. Regardless of the reason of the
Induktion des VEGF bei der diabetischen Retinopathie des Menschen, eignet sich die Hemmung des Augen-VEGF zur Behandlung dieserInduction of VEGF in diabetic retinopathy in humans, the inhibition of eye VEGF is suitable for the treatment of this
Krankheit.Illness.
Die VEGF-Expression ist auch in hypoxischen Regionen von tierischen und menschlichen Tumoren neben Nekrosezonen stark erhöht. Der VEGF wird außerdem durch die Expression der Onkogene ras, raf, src und p53- Mutante (die alle bei der Bekämpfung von Krebs von Bedeutung sind) hinaufreguliert. Monoklonale Anti-VEGF-Antikörper hemmen bei derVEGF expression is also greatly increased in hypoxic regions of animal and human tumors in addition to necrosis zones. The VEGF is also upregulated by the expression of the oncogenes ras, raf, src and p53 mutant (all of which are important in the fight against cancer). Anti-VEGF monoclonal antibodies inhibit the
Nacktmaus das Wachstum menschlicher Tumore. Obwohl die gleichenNude mouse the growth of human tumors. Although the same
Tumorzellen in Kultur weiterhin VEGF exprimieren, verringern die Antikörper ihre Zellteilungsrate nicht. So wirkt der aus Tumoren stammende VEGF nicht als autokriner mitogener Faktor. Der VEGF trägt daher in vivo dadurch zum Tumorwachstum bei, dass er durch seine parakrine Gefäß- endothelzellen-Chemotaxis- und -Mitogeneseaktivität die Angiogenese fördert. Diese monokionalen Antikörper hemmen auch das Wachstum von typischerweise weniger stark vaskularisierten Human-Kolonkarzinomen bei thymuslosen Mäusen und verringern die Anzahl der aus inokulierten Zellen entstehenden Tumore.Tumor cells in culture continue to express VEGF, the antibodies do not decrease their cell division rate. VEGF, which originates from tumors, does not act 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. These 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.
Die Expression eines VEGF-bindenden Konstrukts von Flk-1 , Flt-1 , dem zur Entfernung der zytoplasmatischen Tyrosinkinasedomänen, jedoch unter Beibehaltung eines Membranankers, verkürzten Maus-KDR- Rezeptorhomologs, in Viren stoppt praktisch das Wachstum eines transplantierbaren Glioblastoms bei der Maus, vermutlich aufgrund des dominant-negativen Mechanismus der Heterodimerbildung mit trans- membranösen Endothelzellen-VEGF-Rezeptoren. Embryostammzellen, die in der Nacktmaus üblicherweise in Form von festen Tumoren wachsen, bilden bei Knock-out aller beider VEGF-Allele keine nachweisbarenThe expression of a VEGF-binding construct of Flk-1, Flt-1, the shortened mouse KDR receptor homolog to remove the cytoplasmic tyrosine kinase domains, but 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 transmembrane 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 knock-out of both VEGF alleles
Tumore. Aus diesen Daten gemeinsam geht die Rolle des VEGF beim Wachstum fester Tumore hervor. Die Hemmung von von KDR bzw. Flt-1 ist an der pathologischen Angiogenese beteiligt, und diese Rezeptoren eignen sich zur Behandlung von Krankheiten, bei denen Angiogenese einen Teil der Gesamtpathologie, z.B. Entzündung, diabetische Retina-Tumors. 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 these receptors are useful for the treatment of diseases in which angiogenesis is part of the total pathology, e.g. Inflammation, diabetic retinal
Vaskularisierung sowie verschiedene Formen von Krebs, darstellt, da bekannt ist, dass das Tumorwachstum angiogeneseabhängig ist (Weidner et al, N. Engl. J. Med, 324, S. 1-8, 1991).' Bei Angiopoietin 1 (Ang1), einem Liganden für die endothelspezifischeVascularization, as well as various forms of cancer, since it is known that tumor growth is angiogenic (Weidner et al, N. Engl. J. Med, 324, pp. 1-8, 1991). ' With angiopoietin 1 (Ang1), a ligand for the endothelium-specific
Rezeptor-Tyrosinkinase TIE-2, handelt es sich um einen neuen angiogenen Faktor (Davis et al, Cell, 1996, 87:1161-1169; Partanen et al,Receptor tyrosine kinase TIE-2, it is a new angiogenic factor (Davis et al, Cell, 1996, 87: 1161-1169; Partanen et al,
Mol. Cell Biol., 12:1698-1707 (1992); US-Patent Nr. 5,521 ,073; 5,879,672;Mol. Cell Biol., 12: 1698-1707 (1992); U.S. Patent No. 5,521,073; 5,879,672;
5,877,020; und 6,030,831). Das Akronym TIE steht für „Tyrosinkinase mit5,877,020; and 6,030,831). The acronym TIE stands for “Tyrosine Kinase with
Ig- und EGF-Homologiedomänen". TIE wird zur Identifizierung einerIg and EGF homology domains ". TIE is used to identify a
Klasse von Rezeptor-Tyrosinkinasen verwendet, die ausschließlich inClass of receptor tyrosine kinases used exclusively in
Gefäßendothelzellen und frühen hämopoietischen Zellen exprimiert werden. TIE-Rezeptorkinasen sind typischerweise durch das Vorhandensein einer EGF-ähnlichen Domäne und einer Immunglobulin (IG)- ähnlichen Domäne charakterisiert, die aus extrazellulären Faltungseinheiten, die durch Disulfidbrückenbindungen zwischen den Ketten stabilisiert sind, besteht (Partanen et al Curr. Topics Microbiol. Immunol., 1999, 237:159-172). Im Gegensatz zu VEGF, der seine Funktion während der frühen Stadien in der Gefäßentwicklung ausübt, wirken Ang1 und sein Rezeptor TIE-2 während der späteren Stadien in der Gefäßentwicklung, d.h. während der Gefäßumbildung (Umbildung bezieht sich auf die Bildung eines Gefäßlumens) und Reifung (Yancopoulos et al, Cell, 1998, 93:661- 664; Peters, K.G, Circ. Res, 1998, 83(3):342-3; Suri et al, Cell 87, 1171- 1180 (1996)).Vascular endothelial cells and early hemopoietic cells are expressed. TIE receptor kinases are typically characterized by the presence of an EGF-like domain and an immunoglobulin (IG) -like domain consisting of extracellular folding units that are stabilized by inter-chain disulfide bonds (Partanen et al Curr. Topics Microbiol. Immunol. , 1999, 237: 159-172). Unlike VEGF, which functions during the early stages of vascular development, Ang1 and its receptor TIE-2 act during the later stages of vascular development, i.e. during vascular remodeling (remodeling refers to vascular lumen formation) 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)).
Demzufolge würde man erwarten, daß eine Hemmung von TIE-2 die Umbildung und Reifung eines durch Angiogenese initiierten neuen Gefäßsystems und dadurch den Angiogeneseprozeß unterbrechen sollte. Weiterhin würde eine Hemmung an der Kinasedomäne-Bindungsstelle von VEGFR-2 die Phosphorylierung von Tyrosinresten blockieren und dazu dienen, die Initiation der Angiogenese zu unterbrechen. Daher darf man annehmen, daß die Hemmung von TIE-2 und/oder VEGFR-2 die Tumorangiogenese verhindern und dazu dienen sollte, das Tumorwachstum zu verlangsamen oder vollständig zu beseitigen. Dementsprechend könnte man eine Behandlung von Krebs und anderen mit unangemessener Angiogenese einhergehenden Erkrankungen bereitstellen.Accordingly, inhibition of TIE-2 would be expected to disrupt the remodeling and maturation of a new vascular system initiated by angiogenesis and thereby the angiogenesis process. Furthermore, 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 inhibition of TIE-2 and / or VEGFR-2 should prevent tumor angiogenesis and serve to slow down or completely eliminate tumor growth. Accordingly, one could treat cancer and others provide diseases associated with inappropriate angiogenesis.
Die vorliegende Erfindung richtet sich auf Verfahren zur Regulation,The present invention is directed to methods for regulation,
Modulation oder Hemmung der TIE-2 zur Vorbeugung und/oderModulation or inhibition of TIE-2 for prevention and / or
Behandlung von Erkrankungen im Zusammenhang mit unregulierter oder gestörter TIE-2-Aktivität. Insbesondere lassen sich die erfindungsgemäßenTreatment of diseases related to unregulated or impaired TIE-2 activity. In particular, the inventive
Verbindungen auch bei der Behandlung gewisser Krebsformen einsetzen. Weiterhin können die erfindungsgemäßen Verbindungen verwendet werden, um bei gewissen existierenden Krebschemotherapien additive oder synergistische Effekte bereitzustellen, und/oder können dazu verwendet werden, um die Wirksamkeit gewisser existierender Krebschemotherapien und -bestrahlungen wiederherzustellen.Use compounds also in the treatment of certain forms of cancer. Furthermore, the compounds of the invention can be used to provide additive or synergistic effects in certain existing cancer chemotherapies, and / or can be used to restore the efficacy of certain existing cancer chemotherapies and radiation treatments.
Die vorliegende Erfindung betrifft weiterhin die Verbindungen als Inhibitoren von Raf-Kinasen.The present invention further relates to the compounds as inhibitors of Raf kinases.
Protein-Phosphorylierung ist ein fundamentaler Prozess für die Regulation von Zellfunktionen. Die koordinierte Wirkung von sowohl Proteinkinasen als auch Phosphatasen kontrolliert die Phosphorylierungsgrade und folglich die Aktivität spezifischer Zielproteine. Eine der vorherrschenden Rollen der Protein-Phosphorylierung ist bei der Signaltransduktion, wenn extrazelluläre Signale amplifiziert und durch eine Kaskade von Protein- Phosphorylierungs- und Dephosphorylierungsereignissen, z. B. im p21 ras/raf-Weg propagiert werden.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. One of the predominant roles 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.
Das p21 -Gen wurde als ein Onkogen der Harvey- und Kirsten-Ratten- Sarkom-Viren (H-Ras bzw. K-Ras) entdeckt. Beim Menschen wurden charakteristische Mutationen im zellulären Ras-Gen (c-Ras) mit vielen verschiedenen Krebstypen in Verbindung gebracht. Von diesen mutanten Allelen, die Ras konstitutiv aktiv machen, wurde gezeigt, dass sie Zellen, wie zum Beispiel die murine Zelllinie NIH 3T3, in Kultur transformieren. Das p21ras-Onkogen ist ein wichtiger beitragender Faktor bei der Entwicklung und Progression humaner solider Karzinome und ist bei 30 % aller humaner Karzinome mutiert (Bolton et al. (1994) Ann. Rep. Med. Chem., 29, 165-74; Bos. (1989) Cancer Res., 49, 4682-9). In seiner normalen, nicht mutierten Form ist das Ras-Protein ein Schlüsselelement der Signal- transduktionskaskade, die durch Wachstumsfaktor-Rezeptoren in fast allen Geweben gesteuert wird (Avruch et al. (1994) Trends Biochem. Sei., 19, 279-83).The p21 gene was discovered as an oncogene of the Harvey and Kirsten rat sarcoma viruses (H-Ras and K-Ras, respectively). In humans, characteristic mutations in the cellular Ras gene (c-Ras) have been associated with many different types of cancer. 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). In its normal, non-mutated form, 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) ,
Biochemisch ist Ras ein Guanin-Nukleotid-bindendes Protein, und das Zyklieren zwischen einer GTP-gebundenen aktivierten und einer GDP- gebundenen ruhenden Form wird von Ras-endogener GTPase-Aktivität und anderen Regulatorproteinen strikt kontrolliert. Das Ras-Genprodukt bindet an Guanintriphosphat (GTP) und Guanindiphosphat (GDP) und hydrolysiert GTP zu GDP. Ras ist im GTP-gebundenen Zustand aktiv. In den Ras-Mutanten in Krebszellen ist die endogene GTPase-Aktivität abgeschwächt, und folglich gibt das Protein konstitutive Wachstumssignale an „Downstream"-Effektoren, wie zum Beispiel an das Enzym Raf-Kinase ab. Dies führt zum krebsartigen Wachstum der Zellen, die diese Mutanten tragen (Magnuson et al. (1994) Semin. Cancer Biol., 5, 247-53). Das Ras-Proto-Onkogen benötigt ein funktioneil intaktes C-Raf-1-Proto- Onkogen, um in höheren Eukaryoten durch Rezeptor- und Nicht-Biochemically, 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. In the Ras mutants in cancer cells, endogenous GTPase activity is weakened, and consequently the protein emits constitutive growth signals to "downstream" effectors, such as the Raf kinase enzyme. This leads to the cancerous growth of the cells that produce them Mutants carry (Magnuson et al. (1994) Semin. Cancer Biol., 5, 247-53). The Ras proto-oncogene requires a functionally intact C-Raf-1 proto-oncogene in order to be able to and not-
Rezeptor-Tyrosin-Kinasen initiierte Wachstums- und Differenzierungssignale zu transduzieren.Transduce receptor tyrosine kinases initiated growth and differentiation signals.
Aktiviertes Ras ist für die Aktivierung des C-Raf-1 -Proto-Onkogens notwendig, die biochemischen Schritte, durch die Ras die Raf-1-Protein- (Ser/Thr)-Kinase aktiviert, sind jedoch inzwischen gut charakterisiert. Es wurde gezeigt, dass das Inhibieren des Effekts von aktivem Ras durchActivated 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
Inhibition des Raf-Kinase-Signalwegs mittels Verabreichung von deaktivie- renden Antikörpern gegen Raf-Kinase oder mittels Koexpression dominanter negativer Raf-Kinase oder dominanter negativer MEK (MAPKK), dem Substrat der Raf-Kinase, zur Reversion transformierter Zellen zum normalen Wachstumsphänotyp führt, siehe: Daum et al. (1994) TrendsInhibition of the Raf kinase signaling pathway by administration of deactivating antibodies against Raf kinase or by means of coexpression of dominant negative Raf kinase or dominant negative MEK (MAPKK), the substrate of the Raf kinase, for the reversion of transformed cells to the normal growth phenotype, see: Daum et al. (1994) Trends
Biochem. Sei., 19, 474-80; Fridman et al. (1994) J Biol. Chem, 269,Biochem. Sci., 19, 474-80; Fridman et al. (1994) J Biol. Chem, 269,
30105-8. Kolch et al. (1991) Nature, 349, 426-28) und zur Besprechung30105-8. Kolch et al. (1991) Nature, 349, 426-28) and for discussion
Weinstein-Oppenheimer et al. Pharm. & Therap. (2000), 88, 229-279.Weinstein-Oppenheimer et al. Pharm. & Therap. (2000), 88, 229-279.
Auf ähnliche Weise wurde die Inhibition von Raf-Kinase (durch Antisense- Oligodesoxynukleotide) in vitro und in vivo mit der Inhibition des Wachs- tums einer Reihe verschiedener humaner Tumortypen in Beziehung gebracht (Monia et al., Nat. Med. 1996, 2, 668-75).Similarly, the inhibition of Raf kinase (by antisense oligodeoxynucleotides) 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-Serin- und Threonin-spezifische Protein-Kinasen sind cytosolische Enzyme, die das Zellwachstum in einer Reihe verschiedener Zellsysteme stimulieren (Rapp, U.R., et al. (1988) in The Oncogene Handbook; T. Curran, E.P. Reddy und A. Skalka (Hrsg.) Elsevier Science Publishers; Niederlande, S. 213-253; Rapp, U.R., et al. (1988) Cold Spring Harbor Sym. Quant. Biol. 53:173-184; Rapp, U.R., et al. (1990) Inv Curr. Top. Microbiol. Immunol. Potter und Melchers (Hrsg.), Berlin, Springer-Verlag 166:129-139).Raf-serine and threonine-specific protein kinases are cytosolic enzymes that stimulate cell growth in a number of different cell systems (Rapp, UR, et al. (1988) in The Oncogene Handbook; T. Curran, EP Reddy and A. Skalka (Ed.) Elsevier Science Publishers; Netherlands, pp. 213-253; Rapp, UR, et al. (1988) Cold Spring Harbor Sym. Quant. Biol. 53: 173-184; Rapp, UR, et al. (1990 ) Inv Curr. Top. Microbiol. Immunol. Potter and Melchers (ed.), Berlin, Springer-Verlag 166: 129-139).
Drei Isozyme wurden charakterisiert:Three isozymes have been characterized:
C-Raf (Raf-1) (Bonner, T.I., et al. (1986) Nucleic Acids Res. 14:1009- 1015). A-Raf (Beck, T.W., et al. (1987) Nucleic Acids Res. 15:595-609), und B-Raf (Qkawa, S., et al. (1998) Mol. Cell. Biol. 8:2651-2654; Sithanandam, G. et al. (1990) Oncogene:1775). Diese Enzyme unterscheiden sich durch ihre Expression in verschiedenen Geweben. Raf-1 wird in allen Organen und in allen Zelllinien, die untersucht wurden, exprimiert, und A- und B-Raf werden in Urogenital- bzw. Hirngeweben exprimiert (Storm, S.M. (1990) Oncogene 5:345-351). Raf-Gene sind Proto-Onkogene: Sie können die maligne Transformation von Zeilen initiieren, wenn sie in spezifisch veränderten Formen exprimiert werden. Genetische Veränderungen, die zu onkogener Aktivierung führen, erzeugen eine konstitutiv aktive Proteinkinase durch Entfernung oder Inter- ferenz mit einer N-terminalen negativen Regulatordomäne des ProteinsC-Raf (Raf-1) (Bonner, TI, et al. (1986) Nucleic Acids Res. 14: 1009-1015). A-Raf (Beck, TW, et al. (1987) Nucleic Acids Res. 15: 595-609), and B-Raf (Qkawa, S., et al. (1998) Mol. Cell. Biol. 8: 2651 -2654; Sithanandam, G. et al. (1990) Oncogene: 1775). These enzymes differ in their expression in different tissues. Raf-1 is expressed in all organs and in all cell lines that have been examined, and A- and B-Raf are expressed in urogenital and brain tissues, respectively (Storm, SM (1990) Oncogene 5: 345-351). Raf genes are proto-oncogenes: they can initiate the malignant transformation of lines 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 regulator domain of the protein
(Heidecker, G., et al. (1990) Mol. Cell. Biol. 10:2503-2512; Rapp, U.R., et al. (1987) in Oncogenes and Cancer; S. A. Aaronson, J. Bishop, T.(Heidecker, G., et al. (1990) Mol. Cell. Biol. 10: 2503-2512; Rapp, U.R., et al. (1987) in Oncogenes and Cancer; S. A. Aaronson, J. Bishop, T.
Sugimura, M. Terada, K. Toyoshima und P. K. Vogt (Hrsg.) Japan Scientific Press, Tokyo). Mikroinjektion in NIH 3T3-Zellen von onkogen aktivierten, aber nicht Wildtyp-Versionen des mit Expressionsvektoren von Escherichia coli präparierten Raf-Proteins führt zu morphologischer Transformation und stimuliert die DNA-Synthese (Rapp, U.R., et al. (1987) in Oncogenes and Cancer; S. A. Aaronson, J. Bishop, T. Sugimura, M. Terada, K. Toyoshima, und P. K. Vogt (Hrsg.) Japan Scientific Press, Tokyo; Smith, M. R., et al. (1990) Mol. Cell. Biol. 10:3828-3833).Sugimura, M. Terada, K. Toyoshima and P. K. Vogt (ed.) Japan Scientific Press, Tokyo). Microinjection into NIH 3T3 cells of oncogenically activated but not wild-type versions of the Raf protein prepared with Escherichia coli expression vectors leads to morphological transformation and stimulates DNA synthesis (Rapp, UR, et al. (1987) in Oncogenes and Cancer ; SA Aaronson, J. Bishop, T. Sugimura, M. Terada, K. Toyoshima, and PK Vogt (ed.) Japan Scientific Press, Tokyo; Smith, MR, et al. (1990) Mol. Cell. Biol. 10 : from 3828 to 3833).
Folglich ist aktiviertes Raf-1 ein intrazellulärer Aktivator des Zellwachstums. Raf-1-Protein-Serin-Kinase ist ein Kandidat für den „Downstream"- Effektor der Mitogen-Signaltransduktion, da Raf-Onkogene dem Wachstumsarrest begegnen, der aus einer Blockade zellulärer Ras-Aktivität aufgrund einer zellulären Mutation (Ras-revertante Zellen) oder Mikro- injektion von Anti-Ras-Antikörpem resultiert (Rapp, U.R., et al. (1988) in The Oncogene Handbook, T. Curran, E.P. Reddy und A. Skalka (Hrsg.), Elsevier Science Publishers; Niederlande, S. 213-253; Smith, M.R., et al. (1986) Nature (London) 320:540-543).Thus activated 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 microinjection 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).
Die C-Raf-Funktion ist für die Transformation durch eine Reihe verschiedener Membran-gebundener Onkogene und für die Wachstumsstimulation durch in Sera enthaltene Mitogene erforderlich (Smith, M.R., et al. (1986) Nature (London) 320:540-543). Raf-1 -Protein-Serin-Kinase-Aktivität wird durch Mitogene über die Phosphorylierung reguliert (Morrison, D.K., et al. (1989) Cell 58:648-657), welche auch die subzelluläre Verteilung bewirkt (Olah, Z., et al. (1991) Exp. Brain Res. 84:403; Rapp, U.R., et al. (1988) Cold Spring Harbor Sym. Quant. Biol. 53:173-184. Zu Raf-1 -aktivierenden Wachstumsfaktoren zählen der aus Thrombozyten stammende Wachstumsfaktor (PDGF) (Morrison, D.K., et al. (1988) Proc. Natl. Acad. Sei.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, 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 Spring Harbor Sym. Quant. Biol. 53: 173-184. On Raf-1 activating growth factors include platelet growth factor (PDGF) (Morrison, DK, et al. (1988) Proc. Natl. Acad.
USA 85:8855-8859), der Kolonien-stimulierende Faktor (Baccarini, M, et al. (1990) EMBO J. 9:3649-3657), Insulin (Blackshear, P.J., et al. (1990) J. Biol. Chem. 265:12115-12118), der epidermale Wachstumsfaktor (EGF) (Morrison, R.K., et al. (1988) Proc. Natl. Acad. Sei. USA 85:8855-8859), lnterleukϊn-2 (Turner, B.C., et al. (1991) Proc. Natl. Acad. Sei. USAUSA 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), Interleukϊn-2 (Turner, BC, et al. (1991) Proc. Natl. Acad. Sci. USA
88:1227) und lnterleukin-3 und der Granulozyten-Makrophagen-Kolonien- stimulierende Faktor (Carroll, M.P., et al. (1990) J. Biol. Chem. 265:19812- 19817).88: 1227) and interleukin-3 and the granulocyte-macrophage colony stimulating factor (Carroll, M.P., et al. (1990) J. Biol. Chem. 265: 19812-19817).
Nach der Mitogen-Behandlung von Zellen transloziert die transient aktivierte Raf-1 -Protein-Serin-Kinase in den perinukleären Bereich und denAfter the mitogen treatment of cells, the transiently activated Raf-1 protein serine kinase translocates into the perinuclear area and the
Nukleus (Olah, Z., et al. (1991) Exp. Brain Res. 84:403; Rapp, U.R., et al.Nucleus (Olah, Z., et al. (1991) Exp. Brain Res. 84: 403; Rapp, U.R., et al.
(1988) Cold Spring Habor Sym. Quant. Biol. 53:173-184). Zellen, die aktiviertes Raf enthalten, sind in ihrem Genexpressionsmuster verändert(1988) Cold Spring Habor Sym. Quant. Biol. 53: 173-184). Cells that contain activated Raf are changed in their gene expression pattern
(Heidecker, G, et al. (1989) in Genes and Signal transduction in multistage carcinogenesis, N. Colburn (Hrsg.), Marcel Dekker, Inc., New York, S. 339-(Heidecker, G, et al. (1989) in Genes and Signal transduction in multistage carcinogenesis, N. Colburn (ed.), Marcel Dekker, Inc., New York, pp. 339-
374) und Raf-oncogenes activate transcription from Ap-l/PEA3-dependent promotors in transient transfection assays (Jamal, S, et al. (1990) Science374) and 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;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).Wasylyk, C, et al. (1989) Mol. Cell. Biol. 9: 2247-2250).
Es gibt mindestens zwei unabhängige Wege für die Raf-1 -Aktivierung durch extrazelluläre Mitogene: Einen, der Proteinkinase C (KC) beinhaltet, und einen zweiten, der durch Protein-Tyrosin-Kinasen initiiert wird (Blackshear, P.J., et al. (1990) J. Biol. Chem. 265:12131-12134; Kovacina, K.S., et al. (1990) J. Biol. Chem. 265:12115-12118; Morrison, D.K., et al. (1988) Proc. Natl. Acad. Sei. USA 85:8855-8859; Siegel, J.N., et al. (1990) J. Biol. Chem. 265:18472-18480; Turner, B.C., et al. (1991) Proc. Natl. Acad. Sei. USA 88:1227). In jedem Fall beinhaltet die Aktivierung Raf-1 -Protein- Phosphorylierung. Raf-1 -Phosphorylierung kann eine Folge einer Kinase- Kaskade sein, die durch Autophosphorylierung amplifiziert wird, oder kann vollkommen durch Autophosphorylierung hervorgerufen werden, die durch Bindung eines vermutlichen Aktivierungsliganden an die Raf-1 -Regulatordomäne, analog zur PKC-Aktivierung durch Diacylglycerol initiiert wird (Nishizuka, Y. (1986) Science 233:305-312).There are at least two independent routes for Raf-1 activation by extracellular mitogens: one that contains protein kinase C (KC) and a second that is initiated by protein tyrosine kinases (Blackshear, PJ, et al. (1990 ) J. Biol. Chem. 265: 12131-12134; Kovacina, KS, et al. (1990) J. Biol. Chem. 265: 12115-12118; Morrison, DK, et al. (1988) Proc. Natl. Acad USA 85: 8855-8859; Siegel, JN, et al. (1990) J. Biol. Chem. 265: 18472-18480; Turner, BC, et al. (1991) Proc. Natl. Acad. USA 88: 1227). In any case, activation involves Raf-1 protein phosphorylation. Raf-1 phosphorylation may be a result of a kinase cascade that is amplified by autophosphorylation, or may be caused entirely by autophosphorylation that is initiated by binding a putative activation ligand to the Raf-1 regulator domain, analogous to PKC activation by diacylglycerol (Nishizuka, Y. (1986) Science 233: 305-312).
Einer der Hauptmechanismen, durch den die Zellregulation bewirkt wird, ist durch die Transduktion der extrazellulären Signale über die Membran, die wiederum biochemische Wege in der Zelle modulieren. Protein- Phosphorylierung stellt einen Ablauf dar, über den intrazelluläre Signale von Molekül zu Molekül propagiert werden, was schließlich in einer Zellantwort resultiert. Diese Signaltransduktionskaskaden sind hoch reguliert und überlappen häufig, wie aus dem Vorliegen vieler Protein- kinasen wie auch Phosphatasen hervorgeht. Phosphorylierung von Proteinen tritt vorwiegend bei Serin-, Threonin- oder Tyrosinresten auf, und Proteinkinasen wurden deshalb nach ihrer Spezifität des Phosporylie- rungsortes, d. h. der Serin-/ Threonin-Kinasen und Tyrosin-Kinasen klassifiziert. Da Phosphorylierung ein derartig weit verbreiteter Prozess in Zellen ist und da Zellphänotypen größtenteils von der Aktivität dieser Wege beeinflusst werden, wird zur Zeit angenommen, dass eine Anzahl von Krankheitszuständen und/oder Erkrankungen auf entweder abweichende Aktivierung oder funktionelle Mutationen in den molekularen Komponenten von Kinasekaskaden zurückzuführen sind. Folglich wurde der Charakterisierung dieser Proteine und Verbindungen, die zurOne of the main mechanisms by which cell regulation is effected is through the transduction of extracellular signals across the membrane, which in turn modulate biochemical pathways in the cell. 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 can be seen from the presence of many protein kinases as well as phosphatases. Phosphorylation of proteins occurs predominantly with serine, threonine or tyrosine residues, and protein kinases were therefore classified according to their specificity for the location of the phosphoryl. H. of serine / threonine kinases and tyrosine kinases. Because phosphorylation is such a widespread process in cells and because cell phenotypes are largely influenced by the activity of these pathways, it is currently believed that a number of disease states and / or illnesses are due to either abnormal activation or functional mutations in the molecular components of kinase cascades are. Consequently, the characterization of these proteins and compounds, which are used for
Modulation ihrer Aktivität fähig sind, erhebliche Aufmerksamkeit geschenkt (Übersichtsartikel siehe: Weinstein-Oppenheimer et al. Pharma. &. Therap, 2000, 88, 229-279). Die Identifikation von kleinen Verbindungen, die die Signaltransduktion der Tyrosinkinasen und/oder Raf-Kinasen spezifisch hemmen, regulieren und/oder modulieren, ist daher wünschenswert und ein Ziel der vorliegenden Erfindung.Modulation of their activity are capable of paying considerable attention (review article see: Weinstein-Oppenheimer et al. Pharma. &. Therap, 2000, 88, 229-279). The identification of small compounds that specifically inhibit, regulate and / or modulate the signal transduction of the tyrosine kinases and / or Raf kinases is therefore desirable and an object of the present invention.
Es wurde gefunden, daß die erfindungsgemäßen Verbindungen und ihre Salze bei guter Verträglichkeit sehr wertvolle pharmakologische Eigenschaften besitzen.It has been found that the compounds according to the invention and their salts have very valuable pharmacological properties with good tolerability.
Insbesondere zeigen sie inhibierende Eigenschaften der Tyrosinkinase. Es wurde weiterhin gefunden, daß die erfindungsgemäße Verbindungen Inhibitoren des Enzyms Raf-Kinase sind. Da das Enzym ein „Downstream"- Effektor von p21 ras ist, erweisen sich die Inhibitoren in pharmazeutischen Zusammensetzungen für die human- oder veterinärmedizinische Anwendung als nützlich, wenn Inhibition des Raf-Kinase-Weges, z. B. bei der Behandlung von Tumoren und/oder durch Raf-Kinase vermitteltem krebsartigen Zellwachstum, angezeigt ist. Die Verbindungen sind insbesondere nützlich bei der Behandlung solider Karzinome bei Mensch und Tier, z. B. von murinem Krebs, da die Progression dieser Krebse abhängig ist von der Ras-Protein- Signaltransduktionskaskade und deshalb auf die Behandlung durch Unterbrechung der Kaskade, d. h. durch Inhibition der Raf-Kinase, anspricht. Dementsprechend wird die erfindungsgemäßen Verbindung oder ein pharmazeutisch unbedenkliches Salz davon für die Behandlung von Krankheiten verabreicht, die durch den Raf-Kinase-Weg vermittelt werden, besonders Krebs, einschließlich solider Karzinome, wie zumIn particular, they show inhibitory properties of tyrosine kinase. It has furthermore been found that 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 cancer cell mediated by Raf kinase The compounds are particularly useful in the treatment of solid carcinomas in humans and animals, e.g., murine cancer, since the progression of these cancers is dependent on the Ras protein signal transduction cascade and therefore responsive to cascade disruption treatment, ie inhibition of Raf kinase. Accordingly, the compound of the invention or a pharmaceutically acceptable salt thereof is administered for the treatment of diseases mediated by the Raf kinase route Cancer, including solid cancers, such as
Beispiel Karzinome (z. B. der Lungen, des Pankreas, der Schilddrüse, der Harnblase oder des Kolons), myeloische Erkrankungen (z. B. myeloische Leukämie) oder Adenome (z. B. villöses Kolonadenom), pathologische Angiogenese und metastatische Zellmigration. Die Verbindungen sind ferner nützlich bei der Behandlung der Komplementaktivierungs- abhängigen chronischen Entzündung (Niculescu et al. (2002) Immunol. Res, 24:191-199) und durch HIV-1 (Human Immunodeficiency Virus Typ 1) induzierte Immunschwäche (Popik et al. (1998) J Virol, 72: 6406- 6413).Examples include 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 HIV-1 (Human Immunodeficiency Virus Type 1) induced immune deficiency (Popik et al. (1998) J Virol, 72: 6406-6413).
Es wurde überraschend gefunden, dass erfindungsgemäßenIt has surprisingly been found that the invention
Verbindungen mit Signalwegen, besonders mit den hierin beschriebenenConnections with signaling pathways, particularly those described herein
Signalwegen und bevorzugt dem Raf-Kinase-Signalweg interagieren können. Die erfindungsgemäßen Verbindungen zeigen bevorzugt eine vorteilhafte biologische Aktivität, die in auf Enzymen basierenden Assays, zum Beispiel Assays wie hierin beschrieben, leicht nachweisbar ist. In derartigen auf Enzymen basierenden Assays zeigen und bewirken die erfindungsgemäßen Verbindungen bevorzugt einen inhibierenden Effekt, der gewöhnlich durch IC5o-Werte in einem geeigneten Bereich, bevorzugt im mikromolaren Bereich und bevorzugter im nanomolaren Bereich dokumentiert wird.Signal paths and preferably the Raf kinase signal path can interact. The compounds according to the invention preferably exhibit an advantageous biological activity which is easily detectable in enzyme-based assays, for example assays as described here. In such enzyme-based assays exhibit and cause the compounds of the invention preferably have an inhibiting effect, which is usually by IC 5 o values in a suitable range, preferably in the micromolar range and more preferably will be documented in the nanomolar range.
Wie hierin besprochen, sind diese Signalwege für verschiedene Erkrankungen relevant. Dementsprechend sind die erfindungsgemäßen Verbindungen nützlich bei der Prophylaxe und/oder Behandlung von Erkrankungen, die von den genannten Signalwegen durch Interaktion mit einem oder mehreren der genannten Signalwege abhängig sind. Gegenstand der vorliegenden Erfindung sind deshalb erfindungsgemäße Verbindungen als Promotoren oder Inhibitoren, bevorzugt als Inhibitoren der hierin beschriebenen Signalwege. Bevorzugter Gegenstand der Erfindung sind deshalb erfindungsgemäße Verbindungen als Promotoren oder Inhibitoren, bevorzugt als Inhibitoren des Raf-Kinase-Weges. Ein bevorzugter Gegenstand der Erfindung sind deshalb erfindungsgemäße Verbindungen als Promotoren oder Inhibitoren, bevorzugt als Inhibitoren der Raf-Kinase. Ein noch bevorzugterer Gegenstand der Erfindung sind erfindungsgemäße Verbindungen als Promotoren oder Inhibitoren, bevorzugt als Inhibitoren einer oder mehrerer Raf-Kinasen, ausgewählt aus der Gruppe bestehend aus A-Raf, B-Raf und C-Raf-1. Ein besonders bevorzugter Gegenstand der Erfindung sind erfindungsgemäße Verbindungen als Promotoren oder Inhibitoren, bevorzugt als Inhibitoren von C-Raf-1.As discussed herein, these signaling pathways are relevant to various diseases. Accordingly, the compounds of 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. The present invention therefore relates to compounds according to the invention as promoters or inhibitors, preferably as inhibitors of the signaling pathways described herein. 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 special one preferred subject matter of the invention are compounds according to the invention as promoters or inhibitors, preferably as inhibitors of C-Raf-1.
Ein weiterer Gegenstand der vorliegenden Erfindung ist die Verwendung einer oder mehrerer erfindungsgemäßer Verbindungen bei der Behandlung und/oder Prophylaxe von Erkrankungen, bevorzugt den hier beschriebenen Erkrankungen, die durch Raf-Kinasen veruracht, vermittelt und/oder propagiert werden und insbesondere Erkrankungen, die durchAnother object of the present invention is 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 caused by
Raf-Kinasen ausgewählt aus der Gruppe, bestehend aus A-Raf, B-Raf and C-Raf-1 verursacht, vermittelt und/oder propagiert werden. Gewöhnlich werden die hier besprochenen Erkrankungen in zwei Gruppen eingeteilt, in hyperproliferative und nicht hyperproliferative Erkrankungen. In diesemRaf 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. In this
Zusammenhang werden Psoriasis, Arthritis, Entzündungen, Endometriose, Vernarbung, gutartige Prostatahyperplasie, immunologische Krankheiten, Autoimmunkrankheiten und Immunschwächekrankheiten als nicht krebsartige Krankheiten angesehen, von denen Arthritis, Entzündung, immunologische Krankheiten, Autoimmunkrankheiten und Immunschwächekrankheiten gewöhnlich als nicht hyperproliferative Erkrankungen angesehen werden. In diesem Zusammenhang sind Hirnkrebs, Lungenkrebs, Plattenepithelkrebs, Blasenkrebs, Magenkrebs, Pankreaskrebs, Leberkrebs, Nierenkrebs, Kolorektalkrebs, Brustkrebs, Kopfkrebs, Halskrebs, Ösophaguskrebs, -gynäkologischer Krebs, Schilddrüsenkrebs, Lymphome, chronische Leukämie und akute Leukämie als krebsartige Erkrankungen anzusehen, die alle gewöhnlich als hyper- proliferative Erkrankungen angesehen werden. Insbesondere krebsartiges Zellwachstum und insbesondere durch Raf-Kinase vermitteltes krebsartiges Zellwachstum ist eine Erkrankung, die ein Ziel der vorliegenden Erfindung darstellt. Gegenstand der vorliegenden Erfindung sind deshalb erfindungsgemäße Verbindungen als Arzneimittel und/oder Arzneimittelwirkstoffe bei der Behandlung und/oder Prophylaxe der genannten Erkrankungen und die Verwendung von erfindungsgemäßen Verbindungen zur Herstellung eines Pharmazeutikums für die Behandlung und/oder Prophylaxe der genannten Erkrankungen wie auch ein Verfahren zur Behandlung der genannten Erkrankungen umfassend die Verabreichung eines oder mehrerer erfindungsgemäßer Verbindungen an einenContext, psoriasis, arthritis, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and immune deficiency diseases are regarded as non-cancerous diseases, of which arthritis, inflammation, immunological diseases, autoimmune diseases and immune deficiency diseases are usually regarded as non-hyperproliferative diseases. In this context, 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, all types of cancer and acute leukemia are usually considered hyperproliferative diseases. In particular cancerous cell growth and in particular cancerous cell growth mediated by Raf kinase is a disease which is an object of the present invention. The present invention therefore relates to compounds according to the invention as pharmaceuticals and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of the diseases mentioned and the use of inventive Compounds for the manufacture of a pharmaceutical for the treatment and / or prophylaxis of said diseases as well as a method for the treatment of said diseases comprising the administration of one or more compounds according to the invention to one
Patienten mit Bedarf an einer derartigen Verabreichung.Patients in need of such administration.
Es kann gezeigt werden, dass die erfindungsgemäßen Verbindungen in einem Xenotransplantat-Tumor-Modell eine in vivo antiproliferative Wirkung aufweisen. Die erfindungsgemäßen Verbindungen werden an einen Patienten mit einer hyperproliferativen Erkrankung verabreicht, z. B. zur Inhibition des Tumorwachstums, zur Verminderung der mit einer lymphoproliferativen Erkrankung einhergehenden Entzündung, zur Inhibition der Transplantatabstoßung oder neurologischer Schädigung aufgrund von Gewebereparatur usw. Die vorliegenden Verbindungen sind nützlich für prophylaktische oder therapeutische Zwecke. Wie hierin verwendet, wird der Begriff „Behandeln" als Bezugnahme sowohl auf die Verhinderung von Krankheiten als auch die Behandlung vorbestehender Leiden verwendet. Die Verhinderung von Proliferation wird durch Verabreichung der erfindungsgemäßen Verbindungen vor Entwicklung der evidenten Krankheit, z. B. zur Verhinderung des Tumorwachstums, Verhinderung metastatischen Wachstums, der Herabsetzung von mit kardiovaskulärer Chirurgie einhergehenden Restenosen usw. erreicht. Als Alternative werden die Verbindungen zur Behandlung andauernder Krankheiten durch Stabilisation oder Verbesserung der klinischen Symptome des Patienten verwendet.It can be shown that 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 a patient with a hyperproliferative disease, 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. As used herein, the term "treating" 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 apparent disease, e.g., to prevent tumor growth Prevention of metastatic growth, reduction of restenoses associated with cardiovascular surgery, etc. Alternatively, the compounds are used to treat persistent diseases by stabilizing or improving the clinical symptoms of the patient.
Der Wirt oder Patient kann jeglicher Säugerspezies angehören, z. B. einer Primatenspezies, besonders Menschen; Nagetieren, einschließlich Mäusen, Ratten und Hamstern; Kaninchen; Pferden, Rindern, Hunden, Katzen usw. Tiermodelle sind für experimentelle Untersuchungen von Interesse, wobei sie ein Modell zur Behandlung einer Krankheit des Menschen zur Verfügung stellen. Die Suszeptibilität einer bestimmten Zelle gegenüber der Behandlung mit den erfindungsgemäßen Verbindungen kann durch Testen in vitro bestimmt werden. Typischerweise wird eine Kultur der Zelle mit einer erfindungsgemäßen Verbindung bei verschiedenen Konzentrationen für eine Zeitdauer kombiniert, die ausreicht, um den aktiven Mitteln zu ermöglichen, Zelltod zu induzieren oder Migration zu inhibieren, gewöhnlich zwischen ungefähr einer Stunde und einer Woche. Zum Testen in vitro können kultivierte Zellen aus einer Biopsieprobe verwendet werden. Die nach der Behandlung zurückbleibenden lebensfähigen Zellen werden dann gezählt. Die Dosis variiert abhängig von der verwendeten spezifischen Verbindung, der spezifischen Erkrankung, dem Patientenstatus usw.. Typischerweise ist eine therapeutische Dosis ausreichend, um die unerwünschte Zellpopulation im Zielgewebe erheblich zu vermindern, während die Lebensfähigkeit des Patienten aufrechterhalten wird. Die Behandlung wird im Allgemeinen fortgesetzt, bis eine erhebliche Reduktion vorliegt, z. B. mindestens ca. 50 % Verminderung der Zelllast und kann fortgesetzt werden, bis im Wesentlichen keine unerwünschten Zellen mehr im Körper nachgewiesen werden.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. 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 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 cell load and can be continued until essentially no more unwanted cells are detected in the body.
Zur Identifikation von Kinase-Inhibitoren stehen verschiedene Assay- Systeme zur Verfügung. Beim Scintillation-Proximity-Assay (Sorg et al., J. of. Biomolecular Screening, 2002, 7, 11-19) und dem Flash Plate-Assay wird die radioaktive Phosphorylierung eines Proteins oder Peptids als Substrat mit γATP gemessen. Bei Vorliegen einer inhibitorischen Verbindung ist kein oder ein vermindertes radioaktives Signal nachweisbar. Ferner sind die Homogeneous Time-resolved Fluorescence Resonance Energy Transfer- (HTR-FRET-) und Fluoreszenzpolarisations- (FP-) Technologien als Assay-Verfahren nützlich (Sills et al., J. of Biomolecular Screening, 2002, 191-214). Andere nicht radioaktive ELISA-Assay-Verfahren verwenden spezifischeVarious assay systems are available for the identification of kinase inhibitors. In the scintillation proximity assay (Sorg et al., J. of. Biomolecular Screening, 2002, 7, 11-19) and the flash plate assay, the radioactive phosphorylation of a protein or peptide as a substrate with γATP is measured. If an inhibitory compound is present, no or a reduced radioactive signal is detectable. Furthermore, 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). Other non-radioactive ELISA assay procedures use specific ones
Phospho-Antikörper (Phospho-AK). Der Phospho-AK bindet nur das phosphorylierte Substrat. Diese Bindung ist mit einem zweiten Peroxidase- konjugierten Anti-Schaf-Antikörper durch Chemilumineszenz nachweisbarPhospho-Antibodies (Phospho-AK). The phospho-AK only binds the phosphorylated substrate. This binding can be detected with chemiluminescence using a second peroxidase-conjugated anti-sheep antibody
(Ross et al, 2002, Biochem. J, unmittelbar vor der Veröffentlichung,(Ross et al, 2002, Biochem. J, immediately before publication,
Manuskript BJ20020786).Manuscript BJ20020786).
Es gibt viele mit einer Deregulation der Zeilproliferation und des Zelltods (Apoptose) einhergehende Erkrankungen. Die Leiden von Interesse schließen die folgenden Leiden ein, sind aber nicht darauf beschränkt. Die erfindungsgemäßen Verbindungen sind nützlich bei der Behandlung einer Reihe verschiedener Leiden, bei denen Proliferation und/oder Migration glatter Muskelzellen und/oder Entzündungszellen in die Intimaschicht eines Gefäßes vorliegt, resultierend in eingeschränkter Durchblutung dieses Gefäßes, z. B. bei neointimalen okklusiven Läsionen. Zu okklusiven Transplantat-Gefäßerkrankungen von Interesse zählen Atherosklerose, koronare Gefäßerkrankung nach Transplantation, Venentransplantat- stenose, peri-anastomotische Prothesenrestenose, Restenose nach Angioplastie oder Stent-Platzierung und dergleichen.There are many diseases associated with deregulation of cell proliferation and cell death (apoptosis). 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.
Die erfindungsgemäßen Verbindungen eignen sich auch als p38 Kinase- Inhibitoren.The compounds according to the invention are also suitable as p38 kinase inhibitors.
Andere Heteroarylhamstoffe, die p38 Kinase inhibieren sind in der WO 02/85859 beschrieben.Other heteroaryl ureas that inhibit p38 kinase are described in WO 02/85859.
STAND DER TECHNIKSTATE OF THE ART
In der WO 02/44156 sind andere Benzimidazol-Derivate als TIE-2 und/oder VEGFR2-lnhibitoren beschrieben. In der WO 99/32436 sind substituierte Phenylhamstoffe als Raf-Kinase-Inhibitoren offenbart. Aus der WO 02/062763 und der WO 02/085857 kennt man Chinolyl- , Isochinolyl- und Pyridylharnstoffderivate als Raf-Kinase-Inhibitoren. Heteroarylharnstoffe als p38-Kinase-lnhibitoren sind in der WO 02/85859 beschrieben. In der WO 00/42012 sind ω-Carboxyaryl-diphenyl-hamstoffe als Raf-Kinase-Inhibitoren und in der WO 00/41698 als p38-Kinase-WO 02/44156 describes benzimidazole derivatives other than TIE-2 and / or VEGFR2 inhibitors. WO 99/32436 discloses substituted phenyl ureas as Raf kinase inhibitors. From WO 02/062763 and WO 02/085857 one knows quinolyl, Isoquinolyl and pyridyl urea derivatives as Raf kinase inhibitors. Heteroaryl ureas as p38 kinase inhibitors are described in WO 02/85859. In WO 00/42012 are ω-carboxyaryl-diphenylureas as Raf kinase inhibitors and in WO 00/41698 as p38 kinase
Inhibitoren beschrieben. Andere Aryl- und Heteroaryl-substituierte heterocyclische Harnstoffe sind in WO 99/32455 als Raf-Kinase- Inhibitoren und in WO 99/32110 als p38-Kinase-lnhibitoren offenbart. Andere Diphenylhamstoffderivate kennt man aus der WO 99/32463. Substituierte heterocyclische Harnstoffderivate als p38-Kinase-lnhibitoren sind in der WO 99/32111 offenbart.Inhibitors described. Other aryl and heteroaryl-substituted heterocyclic ureas are disclosed in WO 99/32455 as Raf kinase inhibitors and in WO 99/32110 as p38 kinase inhibitors. Other diphenyl urea derivatives are known from WO 99/32463. Substituted heterocyclic urea derivatives as p38 kinase inhibitors are disclosed in WO 99/32111.
ZUSAMMENFASSUNG DER ERFINDUNGSUMMARY OF THE INVENTION
Die Erfindung betrifft Harnstoffderivate ausgewählt aus der GruppeThe invention relates to urea derivatives selected from the group
4-{4-[3-(Fluor-trifluormethyl-phenyl)-ureido]-phenoxy}-pyridin-2- carbonsäure-Λ/-methylamid, 1 -[4-(Benzo[1 ,2,5]thiadiazol-5-yloxy)-phenyl]-3-(2-fluor-5- trifluormethyl-phenyl)-hamstoff, 1-(2-Fluor-5-trifluormethyl-phenyl)-3-[4-(pyridin-4-ylsulfanyl)-phenyl]- harnstoff, 1 -[4-(2,3-Dihydro-benzo[1 ,4]dioxin-6-yloxy)-phenyl]-3-(2-fluor-5- trifluormethyl-phenyl)-hamstoff, 7-{4-[3-(2-Fluor-5-trifluormethyl-phenyl)-ureido]-phenoxy}-benzofuran- 2-carbonsäure-amid, 1 -[4-(Benzo[1 ,3]dioxol-5-yloxy)-phenyl]-3-(2-fluor-5-trifluormethyl- phenyl)-harnstoff, 1-(2-Fluor-5-trifluormethyl-phenyl)-3-[4-(6-methoxy-pyridin-3-yloxy)- phenylj-hamstoff, (5-{4-[3-(4-Fluor-3-trifluormethyl-phenyl)-ureido]-phenoxy}-1 H- benzimidazol-2-yl)-carbaminsäure-methylester, 1 -[4-(Benzo[1 ,2,5]thiadiazol-5-yloxy)-phenyl]-3-(4-chlor-3- trifluormethyl-phenyl)-harnstoff, 1-(2-Fluor-5-trifluormethyl-phenyI)-3-[4-(imidazo[1 ,2-a]pyridin-8- yloxy)-phenyl]-harnstoff, 1-(2-Fluor-5-trifluormethyl-phenyl)-3-[4-(2-methyl-benzothiazol-5- yloxy)-phenyl]-harnstoff, 1-(2-Fluor-5-trifluormethyl-phenyl)-3-[4-(1 H-indol-6-yloxy)-phenyl]- harnstoff, 1 -(4-Chlor-3-trifluormethyl-phenyl)-3-[4-(imidazo[1 ,2-a]chinolin-9- yloxy)-phenyl]-harnstoff, 1-(2-Fluor-5-trifluormethyl-phenyl)-3-[4-(imidazo[1 ,2-a]chinolin-9- yloxy)-phenyl]-harnstoff, 1 -(2-Fluor-5-trifluormethyl-phenyl)-3-[4-(1 H-indol-5-yloxy)-phenyl]- hamstoff, 7-{4-[3-(2-Fluor-5-trifluormethyl-phenyl)-ureido]-phenoxy}-benzofuran-4- {4- [3- (fluoro-trifluoromethyl-phenyl) -ureido] -phenoxy} -pyridine-2-carboxylic acid Λ / -methylamide, 1 - [4- (Benzo [1, 2.5] thiadiazole-5 -yloxy) phenyl] -3- (2-fluoro-5-trifluoromethyl-phenyl) urea, 1- (2-fluoro-5-trifluoromethyl-phenyl) -3- [4- (pyridin-4-ylsulfanyl) - phenyl] urea, 1 - [4- (2,3-dihydro-benzo [1,4] dioxin-6-yloxy) phenyl] -3- (2-fluoro-5-trifluoromethylphenyl) urea, 7 - {4- [3- (2-Fluoro-5-trifluoromethyl-phenyl) -ureido] -phenoxy} -benzofuran-2-carboxylic acid amide, 1 - [4- (Benzo [1, 3] dioxol-5-yloxy ) phenyl] -3- (2-fluoro-5-trifluoromethylphenyl) urea, 1- (2-fluoro-5-trifluoromethylphenyl) -3- [4- (6-methoxy-pyridin-3-yloxy ) - phenylj-urea, (5- {4- [3- (4-fluoro-3-trifluoromethyl-phenyl) -ureido] -phenoxy} -1 H -benzimidazol-2-yl) -carbamic acid methyl ester, 1 - [4- (Benzo [1,2,5] thiadiazol-5-yloxy) phenyl] -3- (4-chloro-3-trifluoromethylphenyl) urea, 1- (2-fluoro-5-trifluoromethyl -phenyI) -3- [4- (imidazo [1, 2-a] pyridin-8-yloxy) phenyl] urea, 1- (2-fluoro-5-trifluoromethylphenyl) -3- [4- ( 2-methyl-benzothiazol-5-yloxy) phenyl] urea, 1- (2-fluoro-5-trifluoromethylphenyl) -3- [4- (1 H-indol-6-yloxy) phenyl] urea , 1 - (4-Chloro-3-trifluoromethylphenyl) -3- [4- (imidazo [1, 2-a] quinolin-9-yloxy) phenyl] urea, 1- (2-fluoro-5- trifluoromethyl-phenyl) -3- [4- (imidazo [1, 2-a] quinolin-9-yloxy) phenyl] urea, 1 - (2-fluoro-5-trifluoromethyl-phenyl) -3- [4- (1 H-indol-5-yloxy) phenyl] urea, 7- {4- [3- (2-fluoro-5-trifluoromethylphenyl) urido] phenoxy} benzofuran
2-carbonsäure-methylester, 1-[4-(Benzo[1 ,3]dioxol-5-yloxy)-phenyl]-3-(4-chlor-3-trifluormethyI- phenyl)-harnstoff, 1 -[4-(Benzo[1 ,2,5]thiadiazol-4-yloxy)-phenyl]-3-(2-fluor-5- trifluormethyl-phenyl)-harnstoff, 1-(4-Chlor-3-trifluormethyl-phenyl)-3-[4-(6-methoxy-pyridin-3-yloxy)- phenylj-harnstoff, 1-[4-(lmidazo[1 ,2-a]chinolin-9-yloxy)-phenyl]-3-(4-trifluormethoxy- phenyl)-harnstoff, 1-[4-(Benzo[1 ,2,5]thiadiazol-5-yloxy)-3-methyl-phenyl]-3-(2-fluor-5- trifluormethyl-phenyl)-hamstoff, 1-[4-(Benzo[1 ,2,5]thiadiazol-5-yloxy)-3-methyl-phenyl]-3-(4-chlor-3- trifluormethyl-phenyl)-hamstoff, 1 -[4-(Benzo[1 ,2,5]thiadiazol-5-yloxy)-2-methyl-phenyl]-3-(2-fluor-5- trifluormethyl-phenyl)-hamstoff, 1-[4-(Benzo[1 ,2,5]thiadiazol-5-yloxy)-2-methyl-phenyl]-3-(4-chlor-3- trifluormethyl-phenyl)-hamstoff, 1-[4-(Benzo[1 ,2,5]thiadiazol-5-yloxy)-3-fluor-phenyl]-3-(2-fluor-5- trifluormethyl-phenyl)-hamstoff, 1-[4-(2-Amino-benzothiadiazol-6-yloxy)-phenyl]-3-(2-fIuor-5- trifiuormethyl-phenyl)-harnstoff, 1-[4-(2-Amino-4,7-dimethyl-benzothiadiazol-6-yloxy)-phenyl]-3-(2- fluor-5-trifluormethyl-phenyl)-harnstoff, 4-{4-[3-(2-Fluor-4-trifluormethyl-phenyl)-ureido]-phenylsulfanyl}- pyridin-2-carbonsäure-methylamid, sowie ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.2-carboxylic acid methyl ester, 1- [4- (benzo [1, 3] dioxol-5-yloxy) phenyl] -3- (4-chloro-3-trifluoromethylphenyl) urea, 1 - [4- ( Benzo [1, 2,5] thiadiazol-4-yloxy) phenyl] -3- (2-fluoro-5-trifluoromethylphenyl) urea, 1- (4-chloro-3-trifluoromethylphenyl) -3- [4- (6-methoxypyridin-3-yloxy) phenylj-urea, 1- [4- (imidazo [1,2-a] quinolin-9-yloxy) phenyl] -3- (4-trifluoromethoxy- phenyl) urea, 1- [4- (benzo [1,2,5] thiadiazol-5-yloxy) -3-methylphenyl] -3- (2-fluoro-5-trifluoromethylphenyl) urea, 1 - [4- (Benzo [1, 2.5] thiadiazol-5-yloxy) -3-methylphenyl] -3- (4-chloro-3-trifluoromethylphenyl) urea, 1 - [4- (benzo [1,2,5] thiadiazol-5-yloxy) -2-methylphenyl] -3- (2-fluoro-5-trifluoromethylphenyl) urea, 1- [4- (Benzo [1, 2,5] thiadiazol-5-yloxy) -2-methylphenyl] -3- (4-chloro-3-trifluoromethylphenyl) urea, 1- [4- ( Benzo [1, 2,5] thiadiazol-5-yloxy) -3-fluorophenyl] -3- (2-fluoro-5-trifluoromethylphenyl) urea, 1- [4- (2-amino-benzothiadiazole- 6-yloxy) phenyl] -3- (2-fluorine-5-trifluoromethylphenyl) urea, 1- [4- (2-amino-4,7-dimethyl-benzothiadiazol-6-yloxy) phenyl] - 3- (2-fluoro-5-trifluoromethyl-phenyl) urea, 4- {4- [3- (2-fluoro-4-trifluoromethyl-phenyl) -ureido] phenylsulfanyl} - pyridine-2-carboxylic acid methylamide, as well as their pharmaceutically usable derivatives, salts, solvates and stereoisomers, including their mixtures in all ratios.
Gegenstand der Erfindung sind auch die optisch aktiven Formen (Stereoisomeren), die Enantiomeren, die Racemate, die Diastereomeren sowie die Hydrate und Solvate dieser Verbindungen. Unter Solvate der Verbindungen werden Anlagerungen von inerten Lösungsmittelmolekülen an die Verbindungen verstanden, die sich aufgrund ihrer gegenseitigen Anziehungskraft ausbilden. Solvate sind z.B. Mono- oder Dihydrate oder Alkoholate.The invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Solvates of the compounds are understood to mean the addition of inert solvent molecules to the compounds, which are formed on account of their mutual attraction. Solvates are e.g. Mono- or dihydrates or alcoholates.
Unter pharmazeutisch verwendbaren Derivaten versteht man z.B. diePharmaceutically usable derivatives are e.g. the
Salze der erfindungsgemäßen Verbindungen als auch sogenannte Prodrug-Verbindungen.Salts of the compounds according to the invention as well as so-called prodrug compounds.
Unter Prodrug-Derivaten versteht man mit z. B. Alkyl- oder Acylgruppen,Prodrug derivatives are understood with z. B. alkyl or acyl groups,
Zuckern oder Oligopeptiden abgewandelte Verbindungen der Formel I, die im Organismus rasch zu den wirksamen erfindungsgemäßenSugars or oligopeptides modified compounds of formula I, which in the organism quickly to the effective invention
Verbindungen gespalten werden. Hierzu gehören auch bioabbaubare Polymerderivate der erfindungsgemäßen Verbindungen, wie dies z. B. in Int. J. Pharm. 115, 61-67 (1995) beschrieben ist.Connections are split. 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).
Der Ausdruck "wirksame Menge" bedeutet die Menge eines Arzneimittels oder eines pharmazeutischen Wirkstoffes, die eine biologische oder medizinische Antwort in einem Gewebe, System, Tier oder Menschen hervorruft, die z.B. von einem Forscher oder Mediziner gesucht oder erstrebt wird.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.
Darüberhinaus bedeutet der Ausdruck "therapeutisch wirksame Menge" eine Menge, die, verglichen zu einem entsprechenden Subjekt, das diese Menge nicht erhalten hat, folgendes zur Folge hat: verbesserte Heilbehandlung, Heilung, Prävention oder Beseitigung einer Krankheit, eines Krankheitsbildes, eines Krankheitszustandes, eines Leidens, einer Störung oder von Nebenwirkungen oder auch die Verminderung des Fortschreitens einer Krankheit, eines Leidens oder einer Störung.Furthermore, the term "therapeutically 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, one Suffering, a disorder or side effects, or even reducing the progression of an illness, suffering or disorder.
Die Bezeichnung "therapeutisch wirksame Menge" umfaßt auch die Mengen, die wirkungsvoll sind, die normale physiologische Funktion zu erhöhen.The term "therapeutically effective amount" also includes the amounts that are effective in increasing normal physiological function.
Gegenstand der Erfindung sind auch Mischungen der erfindungsgemäßen Verbindungen der Formel I, z.B. Gemische zweier Diastereomerer z.B. im Verhältnis 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :10, 1 :100 oder 1 :1000. Besonders bevorzugt handelt es sich dabei um Mischungen stereo- isomerer Verbindungen.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.
Die erfindungsgemäßen Verbindungen und auch die Ausgangsstoffe zu ihrer Herstellung werden im übrigen nach an sich bekannten Methoden hergestellt, wie sie in der Literatur (z.B. in den Standardwerken wieThe compounds of the invention and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (e.g. in the standard works such as
Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag,Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag,
Stuttgart) beschrieben sind, und zwar unter Reaktionsbedingungen, die für die genannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten Varianten Gebrauch machen.Stuttgart) are described, namely under reaction conditions that for the implementations mentioned are known and suitable. Use can also be made of variants which are known per se and are not mentioned here in detail.
Die Ausgangsstoffe können, falls erwünscht, auch in situ gebildet werden, so daß man sie aus dem Reaktionsgemisch nicht isoliert, sondern sofort weiter zu den erfindungsgemäßen Verbindungen umsetzt.If desired, 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 according to the invention.
Die Ausgangsverbindungen sind in der Regel bekannt. Sind sie neu, so I können sie aber nach an sich bekannten Methoden hergestellt werden.The starting compounds are generally known. If they are new, they can be manufactured according to methods known per se.
Verbindungen der Formel I können vorzugsweise erhalten werden, indem man Anilinderivate mit Isocyanaten umsetzt.Compounds of the formula I can preferably be obtained by reacting aniline derivatives with isocyanates.
Die Umsetzung erfolgt nach Methoden, die dem Fachmann bekannt sind. Zunächst erfolgt Reaktion in einem geeigneten Lösungsmittel, gegebenenfalls in Gegenwart einer organischen Base, wie z.B.The implementation takes place according to methods which are known to the person skilled in the art. The reaction is first carried out in a suitable solvent, optionally in the presence of an organic base, e.g.
Triethylamin oder einer anorganischen Base, wie z.B. eines Alkali- oderTriethylamine or an inorganic base such as e.g. an alkali or
Erdalkalicarbonats.Alkaline earth metal carbonate.
Als inerte Lösungsmittel eignen sich z.B. Kohlenwasserstoffe wie Hexan, Petrolether, Benzol, Toluol oder Xylol; chlorierte Kohlenwasserstoffe wie Trichlorethylen, 1 ,2-Dichlorethan,Tetrachlorkohlenstoff, Chloroform oder Dichlormethan; Alkohole wie Methanol, Ethanol, Isopropanol, n-Propanol, n-Butanol oder tert.-Butanol; Ether wie Diethylether, Diisopropylether, Tetrahydrofuran (THF) oder Dioxan; Glykolether wie Ethylenglykol- monomethyl- oder -monoethylether (Methylglykol oder Ethylglykol), Ethylenglykoldimethylether (Diglyme); Ketone wie Aceton oder Butanon; Amide wie Acetamid, Dimethylacetamid oder Dimethylformamid (DMF);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);
Nitrile wie Acetonitril; Sulfoxide wie Dimethylsulfoxid (DMSO); Schwefel- kohlenstoff; Carbonsäuren wie Ameisensäure oder Essigsäure; Nitrover- bindungen wie Nitromethan oder Nitrobenzol; Ester wie Ethylacetat oder Gemische der genannten Lösungsmittel.Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitrover- bonds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.
Die Reaktionszeit liegt je nach den angewendeten Bedingungen zwischen einigen Minuten und 14 Tagen, die Reaktionstemperatur zwischen etwaDepending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature between about
-30° und 140°, normalerweise zwischen -10° und 90°, insbesondere zwischen etwa 0° und etwa 70°.-30 ° and 140 °, usually between -10 ° and 90 °, especially between about 0 ° and about 70 °.
Eine Base der erfindungsgemäßen Verbindungen kann mit einer Säure in das zugehörige Säureadditionssalz übergeführt werden, beispielsweise durch Umsetzung äquivalenter Mengen der Base und der Säure in einem inerten Lösungsmittel wie Ethanol und anschließendes Eindampfen. Für diese Umsetzung kommen insbesondere Säuren in Frage, die physiologisch unbedenkliche Salze liefern. So können anorganische Säuren verwendet werden, z.B. Schwefelsäure, Salpetersäure, Halogenwasserstoffsäuren wie Chlorwasserstoffsäure oder Bromwasserstoffsäure, Phosphorsäuren wie Orthophosphorsäure, Sulfaminsäure, ferner organische Säuren, insbesondere aliphatische, aiicyclische, araliphatische, aromatische oder heterocyclische ein- oder mehrbasige Carbon-, Sulfon- oder Schwefelsäuren, z.B. Ameisensäure, Essigsäure, Trifluoressigsäure, Propionsäure, Pivalinsäure, Diethylessigsäure, Malonsäure, Bemstein- säure, Pimelinsäure, Fumarsäure, Maleinsäure, Milchsäure, Weinsäure, Äpfelsäure, Citronensäure, Gluconsäure, Ascorbinsäure, Nicotinsäure, Isonicotinsäure, Methan- oder Ethansulfonsäure, Ethandisulfonsäure, 2- Hydroxyethansulfonsäure, Benzolsulfonsäure, p-Toluolsulfonsäure, Naphthalin-mono- und -disulfonsäuren, Laurylschwefelsäure. Salze mit physiologisch nicht unbedenklichen Säuren, z.B. Pikrate, können zur Isolierung und /oder Aufreinigung der erfindungsgemäßen Verbindungen verwendet werden.A base of the compounds according to the invention 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 subsequent evaporation. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. So inorganic acids can be used, e.g. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, aicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. Formic acid, acetic acid, trifluoroacetic acid, propionic acid, pivalic acid, diethylacetic 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, ethanodisulfonic acid, methanoic acid sulfonic acid, methane sulfonic acid, methane acid , Benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds according to the invention.
Gegenstand der Erfindung ist ferner die Verwendung der Verbindungen und/oder ihrer physiologisch unbedenklichen Salze zur Herstellung eines Arzneimittels (pharmazeutische Zubereitung), insbesondere auf nichtchemischem Wege. Hierbei können sie zusammen mit mindestens einem festen, flüssigen und/oder halbflüssigen Träger- oder Hilfsstoff und gegebenenfalls in Kombination mit einem oder mehreren weiteren Wirkstoffen in eine geeignete Dosierungsform gebracht werden.The invention further relates to the use of the compounds and / or their physiologically acceptable salts for the preparation of a Medicament (pharmaceutical preparation), in particular by non-chemical means. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
Gegenstand der Erfindung sind ferner Arzneimittel, enthaltend mindestens eine erfindungsgemäße Verbindung und/oder ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, sowie gegebenenfalls Trägerund/oder Hilfsstoffe.The invention further relates to pharmaceutical compositions containing at least one compound according to the invention and / or their pharmaceutically usable derivatives, salts, solvates and stereoisomers, including their mixtures in all ratios, and, if appropriate, carriers and / or auxiliaries.
Pharmazeutische Formulierungen können in Form von Dosiseinheiten, die eine vorbestimmte Menge an Wirkstoff pro Dosiseinheit enthalten, dargereicht werden. Eine solche Einheit kann beispielsweise 0,5 mg bis 1 g, vorzugsweise 1 mg bis 700 mg, besonders bevorzugt 5 mg bis 100 mg einer erfindungsgemäßen Verbindung enthalten, je nach dem behandelten Krankheitszustand, dem Verabreichungsweg und dem Alter, Gewicht und Zustand des Patienten, oder pharmazeutische Formulierungen können in Form von Dosiseinheiten, die eine vorbestimmte Menge an Wirkstoff pro Dosiseinheit enthalten, dargereicht werden. Bevorzugte Dosierungs- einheitsformulierungen sind solche, die eine Tagesdosis oder Teildosis, wie oben angegeben, oder einen entsprechenden Bruchteil davon eines Wirkstoffs enthalten. Weiterhin lassen sich solche pharmazeutischen Formulierungen mit einem der im pharmazeutischen Fachgebiet allgemein bekannten Verfahren herstellen.Pharmaceutical formulations can be presented 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, 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 which contain a daily dose or partial dose, as stated above, or a corresponding fraction thereof of an active ingredient. Furthermore, such pharmaceutical formulations can be produced using one of the methods generally known in the pharmaceutical field.
Pharmazeutische Formulierungen lassen sich zur Verabreichung über einen beliebigen geeigneten Weg, beispielsweise auf oralem (einschließlich buccalem bzw. sublingualem), rektalem, nasalem, topischem (einschließlich buccalem, sublingualem oder transdermalem), vaginalem oder parenteralem (einschließlich subkutanem, intramuskulärem, intravenösem oder intradermalem) Wege, anpassen. Solche Formulierungen können mit allen im pharmazeutischen Fachgebiet bekannten Verfahren hergestellt werden, indem beispielsweise derPharmaceutical formulations can be administered for administration by any suitable route, for example oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations can be prepared by any method known in the pharmaceutical art, for example by the
Wirkstoff mit dem bzw. den Trägerstoff(en) oder Hilfsstoff(en) zusammengebracht wird.Active ingredient is brought together with the carrier (s) or auxiliary (s).
An die orale Verabreichung angepaßte pharmazeutische Formulierungen können als separate Einheiten, wie z.B. Kapseln oder Tabletten; Pulver oder Granulate; Lösungen oder Suspensionen in wäßrigen oder nichtwäßrigen Flüssigkeiten; eßbare Schäume oder Schaumspeisen; oder ÖI-in-Wasser-Flüssigemulsionen oder Wasser-in-ÖI-Flüssigemulsionen dargereicht werden.Pharmaceutical formulations adapted for oral administration can be used as separate units, e.g. Capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam dishes; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
So läßt sich beispielsweise bei der oralen Verabreichung in Form einerFor example, in the case of oral administration in the form of a
Tablette oder Kapsel die Wirkstoffkomponente mit einem oralen, nichttoxischen und pharmazeutisch unbedenklichen inerten Trägerstoff, wie z.B. Ethanol, Glyzerin, Wasser u.a. kombinieren. Pulver werden hergestellt, indem die Verbindung auf eine geeignete feine Größe zerkleinert und mit einem in ähnlicher Weise zerkleinerten pharmazeutischen Trägerstoff, wie z.B. einem eßbaren Kohlenhydrat wie beispielsweise Stärke oder Mannit vermischt wird. Ein Geschmacksstoff, Konservierungs- mittel, Dispersionsmittel und Farbstoff können ebenfalls vorhanden sein.Tablet or capsule the active ingredient with an oral, non-toxic and pharmaceutically acceptable inert carrier such as e.g. Ethanol, glycerin, water etc. combine. Powders are made by comminuting the compound to an appropriate fine size and with a similarly comminuted pharmaceutical carrier such as e.g. an edible carbohydrate such as starch or mannitol is mixed. A flavor, preservative, dispersant and color may also be present.
Kapseln werden hergestellt, indem ein Pulvergemisch wie oben beschrieben hergestellt und geformte Gelatinehüllen damit gefüllt werden. Gleit- und Schmiermittel wie z.B. hochdisperse Kieselsäure, Talkum, Magnesiumstearat, Kalziumstearat oder Polyethylenglykol in Festform können dem Pulvergemisch vor dem Füllvorgang zugesetzt werden. Ein Sprengmittel oder Lösungsvermittler, wie z.B. Agar-Agar, Kalziumcarbonat oder Natriumcarbonat, kann ebenfalls zugesetzt werden, um die Verfügbarkeit des Medikaments nach Einnahme der Kapsel zu verbessern. Außerdem können, falls gewünscht oder notwendig, geeignete Bindungs-, Schmier- und Sprengmittel sowie Farbstoffe ebenfalls in das Gemisch eingearbeitet werden. Zu den geeigneten Bindemitteln gehören Stärke,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. A disintegrant or solubilizer, such as agar, calcium carbonate or sodium carbonate, can also be added to improve the availability of the medication after taking the capsule. In addition, if desired or necessary, suitable binding agents, lubricants and disintegrants, and also dyes, can also be incorporated into the mixture. Suitable binders include starch,
Gelatine, natürliche Zucker, wie z.B. Glukose oder Beta-Lactose, Süßstoffe aus Mais, natürliche und synthetische Gummi, wie z.B. Akazia, Traganth oder Natriumalginat, Carboxymethylzellulose, Polyethylenglykol, Wachse, u.a. Zu den in diesen Dosierungsformen verwendeten Schmier- mittein gehören Natriumoleat, Natriumstearat, Magnesiumstearat, Natrium- benzoat, Natriumacetat, Natriumchlorid u.a. Zu den Sprengmitteln gehören, ohne darauf beschränkt zu sein, Stärke, Methylzellulose, Agar, Bentonit, Xanthangummi u.a. Die Tabletten werden formuliert, indem beispielsweise ein Pulvergemisch hergestellt, granuliert oder trocken- verpreßt wird, ein Schmiermittel und ein Sprengmittel zugegeben werden und das Ganze zu Tabletten verpreßt wird. Ein Pulvergemisch wird hergestellt, indem die in geeigneter Weise zerkleinerte Verbindung mit einem Verdünnungsmittel oder einer Base, wie oben beschrieben, und gegebenenfalls mit einem Bindemittel, wie z.B. Carboxymethylzellulose, einem Alginat, Gelatine oder Polyvinylpyrrolidon, einem Lösungsverlang- samer, wie z.B. Paraffin, einem Resorptionsbeschleuniger, wie z.B. einem quaternären Salz und/oder einem Absorptionsmittel, wie z.B. Bentonit, Kaolin oder Dikalziumphosphat, vermischt wird. Das Pulvergemisch läßt sich granulieren, indem es mit einem Bindemittel, wie z.B. Sirup, Stärkepaste, Acadia-Schleim oder Lösungen aus Zellulose- oder Polymer- materialen benetzt und durch ein Sieb gepreßt wird. Als Alternative zur Granulierung kann man das Pulvergemisch durch eine Tablettiermaschine laufen lassen, wobei ungleichmäßig geformte Klumpen entstehen, die in Granulate aufgebrochen werden. Die Granulate können mittels Zugabe von Stearinsäure, einem Stearatsalz, Talkum oder Mineralöl gefettet werden, um ein Kleben an den Tablettengußformen zu verhindern. Das gefettete Gemisch wird dann zu Tabletten verpreßt. Die erfindungsgemäßen Verbindungen können auch mit einem freifließenden inerten Trägerstoff kombiniert und dann ohne Durchführung der Granulierungs- oder Trockenverpressungsschritte direkt zu Tabletten verpreßt werden.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. The lubricants used in these dosage forms include sodium oleate, sodium stearate , Magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and others. The disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and others. The tablets are formulated by, for example, preparing a powder mixture, granulating or compressing it dry, a lubricant and a disintegrant are added and the whole is compressed 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. The powder mixture can be granulated by wetting it with a binder, such as syrup, starch paste, Acadia mucilage or solutions made of cellulose or polymer materials, and pressing it through a sieve. As an alternative to granulation, 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 of the invention can also be used with a free-flowing inert Carrier combined and then pressed directly into tablets without performing the granulation or dry pressing steps.
Eine durchsichtige oder undurchsichtige Schutzschicht, bestehend aus einer Versiegelung aus Schellack, einer Schicht aus Zucker oder Polymer- material und einer Glanzschicht aus Wachs, kann vorhanden sein. DiesenA transparent or opaque protective layer consisting of a shellac seal, a layer of sugar or polymer material and a glossy layer of wax may be present. this
Beschichtungen können Farbstoffe zugesetzt werden, um zwischen unterschiedlichen Dosierungseinheiten unterscheiden zu können.Dyes can be added to coatings to distinguish between different dosage units.
Orale Flüssigkeiten, wie z.B. Lösung, Sirupe und Elixiere, können in Form von Dosierungseinheiten hergestellt werden, so daß eine gegebene Quantität eine vorgegebene Menge der Verbindung enthält. Sirupe lassen sich herstellen, indem die Verbindung in einer wäßrigen Lösung mit geeignetem Geschmack gelöst wird, während Elixiere unter Verwendung eines nichttoxischen alkoholischen Vehikels hergestellt werden. Suspensionen können durch Dispersion der Verbindung in einem nichttoxischen Vehikel formuliert werden. Lösungsvermittler und Emulgiermittel, wie z.B. ethoxylierte Isostearylalkohole und Polyoxyethylensorbitolether, Konservierungsmittel, Geschmackszusätze, wie z.B. Pfefferminzöl oder natürliche Süßstoffe oder Saccharin oder andere künstliche Süßstoffe, u.ä. können ebenfalls zugegeben werden.Oral liquids, e.g. Solution, syrups and elixirs can be prepared in unit dosage forms 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, e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, etc. can also be added.
Die Dosierungseinheitsformulierungen für die orale Verabreichung können gegebenenfalls in Mikrokapseln eingeschlossen werden. Die Formulierung läßt sich auch so herstellen, daß die Freisetzung verlängert oder retardiert wird, wie beispielsweise durch Beschichtung oder Einbettung von partikulärem Material in Polymere, Wachs u.ä.Dosage unit formulations for oral administration can optionally be enclosed in microcapsules. The formulation can also be prepared in such a way that the release is prolonged or delayed, for example by coating or embedding particulate material in polymers, wax and the like.
Die erfindungsgemäßen Verbindungen sowie Salze, Solvate und physiologisch funktioneile Derivate davon lassen sich auch in Form vonThe compounds according to the invention and salts, solvates and physiologically functional derivatives thereof can also be in the form of
Liposomenzuführsystemen, wie z.B. kleinen unilamellaren Vesikeln, großen unilamellaren Vesikeln und multilamellaren Vesikeln, verabreichen. Liposomen können aus verschiedenen Phospholipiden, wie z.B. Cholesterin, Stearylamin oder Phosphatidylcholinen, gebildet werden.Administer liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Die erfindungsgemäßen Verbindungen sowie die Salze, Solvate und physiologisch funktionellen Derivate davon können auch unterThe compounds of the invention and the salts, solvates and physiologically functional derivatives thereof can also be found under
Verwendung monoklonaler Antikörper als individuelle Träger, an die dieUse of monoclonal antibodies as individual carriers to which the
Verbindungsmoleküle gekoppelt werden, zugeführt werden. DieCompound molecules are coupled, supplied. The
Verbindungen können auch mit löslichen Polymeren als zielgerichtete Arzneistoffträger gekoppelt werden. Solche Polymere können Polyvinyl- pyrrolidon, Pyran-Copolymer, Polyhydroxypropylmethacrylamidphenol, Polyhydroxyethylaspartamidphenol oder Polyethylenoxidpolylysin, substituiert mit Palmitoylresten, umfassen. Weiterhin können die Verbindungen an eine Klasse von biologisch abbaubaren Polymeren, die zur Erzielung einer kontrollierten Freisetzung eines Arzneistoffs geeignet sind, z.B. Polymilchsäure, Polyepsilon-Caprolacton, Polyhydroxybutter- säure, Polyorthoester, Polyacetale, Polydihydroxypyrane, Polycyano- acrylate und quervernetzte oder amphipatische Blockcopolymere von Hydrogelen, gekoppelt sein.Compounds can also be coupled with soluble polymers as targeted drug carriers. Such polymers can include polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl aspartamide phenol or polyethylene oxide polylysine substituted with palmitoyl residues. Furthermore, 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, polyhydroxybutter acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipatic block copolymers of hydrogels.
An die transdermale Verabreichung angepaßte pharmazeutische Formulierungen können als eigenständige Pflaster für längeren, engen Kontakt mit der Epidermis des Empfängers dargereicht werden. So kann beispielsweise der Wirkstoff aus dem Pflaster mittels lontophorese zugeführt werden, wie in Pharmaceutical Research, 3(6), 318 (1986) allgemein beschrieben.Pharmaceutical formulations adapted for transdermal administration can be administered as independent patches for prolonged, close contact with the epidermis of the recipient. For example, the active ingredient can be supplied from the patch by means of iontophoresis, as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
An die topische Verabreichung angepaßte pharmazeutische Verbindungen können als Salben, Cremes, Suspensionen, Lotionen, Pulver, Lösungen, Pasten, Gele, Sprays, Aerosole oder Öle formuliert sein.Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
Für Behandlungen des Auges oder anderer äußerer Gewebe, z.B. Mund und Haut, werden die Formulierungen vorzugsweise als topische Salbe oder Creme appliziert. Bei Formulierung zu einer Salbe kann der Wirkstoff entweder mit einer paraffinischen oder einer mit Wasser mischbarenFor treatments of the eye or other external tissues, such as the mouth and skin, the formulations are preferably used as a topical ointment or cream applied. When formulated into an ointment, the active ingredient can be either paraffinic or water-miscible
Cremebasis eingesetzt werden. Alternativ kann der Wirkstoff zu einerCream base can be used. Alternatively, the active ingredient can be a
Creme mit einer Öl-in-Wasser-Cremebasis oder einer Wasser-in-ÖI-Basis formuliert werden.Cream can be formulated with an oil-in-water cream base or a water-in-oil base.
Zu den an die topische Applikation am Auge angepaßten pharmazeutischen Formulierungen gehören Augentropfen, wobei der Wirkstoff in einem geeigneten Träger, insbesondere einem wäßrigen Lösungsmittel, gelöst oder suspendiert ist. iPharmaceutical formulations 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. i
An die topische Applikation im Mund angepaßte pharmazeutische Formulierungen umfassen Lutschtabletten, Pastillen und Mundspülmittel.Pharmaceutical formulations adapted for topical application in the mouth include lozenges, lozenges and mouthwashes.
An die rektale Verabreichung angepaßte pharmazeutische Formulierungen können in Form von Zäpfchen oder Einlaufen dargereicht werden.Pharmaceutical formulations adapted for rectal administration can be administered in the form of suppositories or enemas.
An die nasale Verabreichung angepaßte pharmazeutischePharmaceutical adapted for nasal administration
Formulierungen, in denen die Trägersubstanz ein Feststoff ist, enthalten ein grobes Pulver mit einer Teilchengröße beispielsweise im Bereich von 20-500 Mikrometern, das in der Art und Weise, wie Schnupftabak aufgenommen wird, verabreicht wird, d.h. durch Schnellinhalation über dieFormulations in which the vehicle 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, i.e. by quick inhalation over the
Nasenwege aus einem dicht an die Nase gehaltenen Behälter mit demNasal passages from a container held close to the nose with the
Pulver. Geeignete Formulierungen zur Verabreichung als Nasenspray oderPowder. Suitable formulations for administration as a nasal spray or
Nasentropfen mit einer Flüssigkeit als Trägersubstanz umfassenInclude nasal drops with a liquid as a vehicle
Wirkstofflösungen in Wasser oder Öl.Active ingredient solutions in water or oil.
An die Verabreichung durch Inhalation angepaßte pharmazeutische Formulierungen umfassen feinpartikuläre Stäube oder Nebel, die mittels verschiedener Arten von unter Druck stehenden Dosierspendern mit Aerosolen, Verneblern oder Insufflatoren erzeugt werden können. An die vaginale Verabreichung angepaßte pharmazeutische Formulierungen können als Pessare, Tampons, Cremes, Gele, Pasten, Schäume oder Sprayformulierungen dargereicht werden.Pharmaceutical formulations 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. Pharmaceutical formulations adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Zu den an die parenterale Verabreichung angepaßten pharmazeutischenFor pharmaceuticals adapted for parenteral administration
Formulierungen gehören wäßrige und nichtwäßrige sterile Injektionslösungen, die Antioxidantien, Puffer, Bakteriostatika und Solute, durch die die Formulierung isotonisch mit dem Blut des zu behandelnden Empfängers gemacht wird, enthalten; sowie wäßrige und nichtwäßrige sterile Suspensionen, die Suspensionsmittel und Verdicker enthalten können. Die Formulierungen können in Einzeldosis- oder Mehrfachdosisbehältern, z.B. versiegelten Ampullen und Fläschchen, dargereicht und in gefriergetrocknetem (lyophilisiertem) Zustand gelagert werden, so daß nur die Zugabe der sterilen Trägerflüssigkeit, z.B. Wasser fürFormulations include aqueous and non-aqueous sterile solutions for injection containing antioxidants, buffers, bacteriostatics and solutes by which the formulation is rendered isotonic with the blood of the recipient to be treated; as well as aqueous and non-aqueous sterile suspensions, which can 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
Injektionszwecke, unmittelbar vor Gebrauch erforderlich ist.Injection is required immediately before use.
Rezepturmäßig hergestellte Injektionslösungen und Suspensionen können aus sterilen Pulvern, Granulaten und Tabletten hergestellt werden.Injection solutions and suspensions prepared according to the recipe can be made from sterile powders, granules and tablets.
Es versteht sich, daß die Formulierungen neben den obigen besonders erwähnten Bestandteilen andere im Fachgebiet übliche Mittel mit Bezug auf die jeweilige Art der Formulierung enthalten können; so können beispielsweise für die orale Verabreichung geeignete Formulierungen Geschmacksstoffe enthalten.It is understood that the formulations may contain, in addition to the above-mentioned ingredients, other means common in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration may contain flavorings.
Eine therapeutisch wirksame Menge einer Verbindung der vorliegenden Erfindung hängt von einer Reihe von Faktoren ab, einschließlich z.B.. dem Alter und Gewicht des Tiers, dem exakten Krankheitszustand, der der Behandlung bedarf, sowie seines Schweregrads, der Beschaffenheit der Formulierung sowie dem Verabreichungsweg, und wird letztendlich von dem behandelnden Arzt bzw. Tierarzt festgelegt. Jedoch liegt eine wirk- same Menge einer erfindungsgemäßen Verbindung für die Behandlung von neoplastischem Wachstum, z.B. Dickdarm- oder Brustkarzinom, im allgemeinen im Bereich von 0,1 bis 100 mg/kg Körpergewicht des Empfängers (Säugers) pro Tag und besonders typisch im Bereich von 1 bis 10 mg/kg Körpergewicht pro Tag. Somit läge für einen 70 kg schweren erwachsenen Säuger die tatsächliche Menge pro Tag für gewöhnlich zwischen 70 und 700 mg, wobei diese Menge als Einzeldosis pro Tag oder üblicher in einer Reihe von Teildosen (wie z.B. zwei, drei, vier, fünf oder sechs) pro Tag gegeben werden kann, so daß die Gesamttagesdosis die gleiche ist. Eine wirksame Menge eines Salzes oder Solvats oder eines physiologisch funktioneilen Derivats davon kann als Anteil der wirksamenA 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 animal, the exact condition of the disease that requires treatment, its severity, the nature of the formulation and the route of administration, and is ultimately determined by the treating doctor or veterinarian. However, there is an effective amount of a compound according to the invention for the treatment of neoplastic growth, for example colon or breast carcinoma generally in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day and particularly typically in the range of 1 to 10 mg / kg body weight per day. Thus, for a 70 kg adult mammal, 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 used as a proportion of the effective
Menge der erfindungsgemäßen Verbindung perse bestimmt werden. Es läßt sich annehmen, daß ähnliche Dosierungen für die Behandlung der anderen, obenerwähnten Krankheitszustände geeignet sind.Amount of the compound of the invention can be determined perse. It is believed that similar dosages are suitable for the treatment of the other conditions mentioned above.
Gegenstand der Erfindung sind ferner Arzneimittel enthaltend mindestens eine erfindungsgemäße Verbindung und/oder ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und mindestens einen weiteren Arzneimittelwirkstoff.The invention further relates to medicaments containing at least one compound according to the invention and / or their pharmaceutically usable derivatives, salts, solvates and stereoisomers, including their mixtures in all ratios, and at least one further active pharmaceutical ingredient.
Gegenstand der Erfindung ist auch ein Set (Kit), bestehend aus getrennten Packungen von (a) einer wirksamen Menge an einer erfindungsgemäßen Verbindung und/oder ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und (b) einer wirksamen Menge eines weiteren Arzneimittelwirkstoffs.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 pharmaceutically usable derivatives, salts, solvates and stereoisomers, including their mixtures in all ratios, and (b ) an effective amount of another drug ingredient.
Das Set enthält geeignete Behälter, wie Schachteln oder Kartons, individuelle Flaschen, Beutel oder Ampullen. Das Set kann z.B. separate Ampullen enthalten, in denen jeweils eine wirksame Menge an einer erfindungsgemäßen Verbindung und/oder ihrer pharmazeutisch 05/019192 - 33 -The set contains suitable containers, such as boxes or cartons, individual bottles, bags or ampoules. The set can contain, for example, separate ampoules, each containing an effective amount of a compound according to the invention and / or its pharmaceutical 05/019192 - 33 -
verwendbaren Derivate, Salze, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und einer wirksamen Menge eines weiteren Arzneimittelwirkstoffs gelöst oder in lyophylisierter Form vorliegt.usable derivatives, salts, solvates and stereoisomers, including their mixtures in all proportions, and an effective amount of another active pharmaceutical ingredient dissolved or in lyophilized form.
VERWENDUNGUSE
Die vorliegenden Verbindungen eignen sich als pharmazeutische Wirkstoffe für Säugetiere, insbesondere für den Menschen, bei der Behandlung von tyrosinkinasebedingten Krankheiten. Zu diesen Krankheiten zählen die Proliferation von Tumorzellen, die pathologische Gefäßneubildung (oder Angiogenese), die das Wachstum fester Tumoren fördert, die Gefäßneubildung im Auge (diabetische Retinopathie, altersbedingte Makula-Degeneration und dergleichen) sowie Entzündung (Schuppenflechte, rheumatoide Arthritis und dergleichen).The present compounds are suitable as pharmaceutical active substances for mammals, in particular for humans, in the treatment of tyrosine kinase-related diseases. These 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).
Die vorliegende Erfindung umfasst die Verwendung der erfindungsgemäßen Verbindungen nach Anspruch 1 und/oder ihre physiologisch unbedenklichen Salze und Solvate zur Herstellung eines Arzneimittels zur Behandlung oder Vorbeugung von Krebs. Bevorzugte Karzinome für die Behandlung stammen aus der Gruppe Hirnkarzinom, Urogenital- traktkarzinom, Karzinom des lymphatischen Systems, Magenkarzinom,The present invention comprises the use of the compounds according to the invention according to claim 1 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of cancer. Preferred carcinomas for the treatment come from the group of brain carcinoma, urogenital tract carcinoma, carcinoma of the lymphatic system, gastric carcinoma,
Kehlkopfkarzinom und Lungenkarzinom. Eine weitere Gruppe bevorzugter Krebsformen sind Monozytenleukämie, Lungenadenokarzinom, kleinzellige Lungenkarzinome, Bauchspeicheldrüsenkrebs, Glioblastome und Brust- karzinom.Larynx and lung cancer. Another group of preferred forms of cancer are monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma.
Ebensfalls umfasst ist die Verwendung der erfindungsgemäßen Verbindungen nach Anspruch 1 und/oder ihre physiologisch unbedenklichen Salze und Solvate zur Herstellung eines Arzneimittels zur Behandlung oder Vorbeugung einer Krankheit, an der Angiogenese beteiligt ist. Eine derartige Krankheit, an der Angiogenese beteiligt ist, ist eineThe 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 is involved is also included. Such a disease, in which angiogenesis is involved, is one
Augenkrankheit, wie Retina-Vaskularisierung, diabetische Retinopathie, altersbedingte Makula-Degeneration und dergleichen. Die Verwendung von erfindungsgemäßen Verbindungen nach Anspruch 1 und/oder ihre physiologisch unbedenklichen Salze und Solvate zurEye disease such as retinal vascularization, diabetic retinopathy, age-related macular degeneration and the like. The use of compounds according to the invention according to claim 1 and / or their physiologically acceptable salts and solvates for
Herstellung eines Arzneimittels zur Behandlung oder Vorbeugung von Entzündungskrankheiten, fällt ebenfalls unter den Umfang der vorliegenden Erfindung. Zu solchen Entzündungskrankheiten zählen zum Beispiel rheumatoide Arthritis, Schuppenflechte, Kontaktdermatitis, Spät-Typ der Überempfindlichkeitsreaktion und dergleichen. Ebenfalls umfasst ist die Verwendung derverfindungsgemäßen Verbindungen nach Anspruch 1 und/oder ihre physiologisch unbedenk- liehen Salze und Solvate zur Herstellung eines Arzneimittels zur Behandlung oder Vorbeugung einer tyrosinkinasebedingten Krankheit bzw. eines tyrosinkinasebedingten Leidens bei einem Säugetier, wobei man diesem Verfahren einem kranken Säugetier, das einer derartigen Behandlung bedarf, eine therapeutisch wirksame Menge einer erfindungsgemäßen Verbindung verabreicht. Die therapeutische Menge hängt von der jeweiligen Krankheit ab und kann vom Fachmann ohne allen großen Aufwand bestimmt werden. Die vorliegende Erfindung umfasst auch die Verwendung der erfindungs- gemäßen Verbindungen nach Anspruch 1 und/oder ihre physiologisch unbedenklichen Salze und Solvate zur Herstellung eines Arzneimittels zur Behandlung oder Vorbeugung von Retina-Vaskularisierung. Verfahren zur Behandlung oder Vorbeugung von Augenkrankheiten wie diabetischer Retinopathie und altersbedingter Makula-Degeneration sind ebenfalls ein Bestandteil der Erfindung. Die Verwendung zur Behandlung oder Vorbeugung von Entzündungskrankheiten wie rheumatoider Arthritis, Schuppenflechte, Kontaktdermatitis und Spät-Typen der Überempfindlichkeitsreaktion, sowie die Behandlung oder Vorbeugung von Knochen- Pathologien aus der Gruppe Osteosarkom, Osteoarthritis und Rachitis, fällt ebenfalls unter den Umfang der vorliegenden Erfindung. Der Ausdruck „tyrosinkinasebedingte Krankheiten oder Leiden" bezieht sich auf pathologische Zustände, die von der Aktivität einer oder mehrererThe manufacture of a medicament for the treatment or prevention of inflammatory diseases also falls within the scope of the present invention. Such inflammatory diseases include, for example, rheumatoid arthritis, psoriasis, contact dermatitis, late-type hypersensitivity reaction and the like. Also included is the use of the compounds according to the invention as claimed in claim 1 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of a tyrosine kinase-related disease or a tyrosine kinase-related condition in a mammal, this method being 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 includes 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 retinal vascularization. Methods for treating or preventing eye diseases such as diabetic retinopathy and age-related macular degeneration are also part of the invention. The use for the treatment or prevention of inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis and late types of the hypersensitivity reaction, as well as the treatment or prevention of bone pathologies from the group of osteosarcoma, osteoarthritis and rickets also falls within the scope of the present invention. The term "tyrosine kinase-related diseases or conditions" refers to pathological conditions that result from the activity of one or more
Tyrosinkinasen abhängig sind. Die Tyrosinkinasen sind entweder direkt oder indirekt an den Signaltransduktionswegen verschiedener Zellaktivi- täten, darunter Proliferation, Adhäsion und Migration sowie Differenzierung beteiligt. Zu den Krankheiten, die mit Tyrosinkinaseaktivität assoziiert sind, zählen die Proliferation von Tumorzellen, die pathologische Gefäßneubildung, die das Wachstum fester Tumore fördert, Gefäßneubildung im Auge (diabetische Retinopathie, altersbedingte Makula-Degeneration und dergleichen) sowie Entzündung (Schuppenflechte, rheumatoide Arthritis und dergleichen).Tyrosine kinases are dependent. The tyrosine kinases are either directly or indirectly involved in the signal transduction pathways of various cell 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 (diabetic retinopathy, age-related macular degeneration and the like), and inflammation (psoriasis, rheumatoid arthritis and the like) ).
Die erfindungsgemäßen Verbindungen nach Anspruch 1 können anThe compounds of claim 1 according to the invention can
Patienten zur Behandlung von Krebs verabreicht werden. Die vorliegenden Verbindungen hemmen die Tumorangiogenese und beeinflussen so das Wachstum von Tumoren (J. Rak et al. Cancer Research, 55:4575-4580, 1995). Die angiogenesehemmenden Eigenschaften der vorliegenden Verbindungen nach Anspruch 1 eignen sich auch zur Behandlung bestimmter Formen von Blindheit, die mit Retina-Gefäßneubildung in Zusammenhang stehen. Die Verbindungen nach Anspruch 1 eignen sich auch zur Behandlung bestimmter Knochen-Pathologien wie Osteosarkom, Osteoarthritis undPatients are given for cancer treatment. 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 according to claim 1 are also suitable for the treatment of certain forms of blindness which are associated with retinal vascularization. The compounds according to claim 1 are also suitable for the treatment of certain bone pathologies such as osteosarcoma, osteoarthritis and
Rachitis, die auch unter der Bezeichnung onkogene Osteomalazie bekannt ist (Hasegawa et al, Skeletal Radiol. 28, S.41-45, 1999; Gerber et al, Nature Medicine, Bd. 5, Nr. 6, S.623-628, Juni 1999). Da der VEGF durch den in reifen Osteoklasten exprimierten KDR/Flk-1 direkt die osteoklastische Knochenresorption fördert (FEBS Let. 473:161-164 (2000); Endocrinology, 141 :1667 (2000)), eignen sich die vorliegenden Verbindungen auch zur Behandlung und Vorbeugung von Leiden, die mit Knochenresorption in Zusammenhang stehen, wie Osteoporose und Morbus Paget. Die Verbindungen können dadurch, dass sie zerebrale Ödeme,Rickets, which is also known as oncogenic osteomalacia (Hasegawa et al, Skeletal Radiol. 28, pp. 41-45, 1999; Gerber et al, Nature Medicine, Vol. 5, No. 6, pp. 623-628, June 1999). Since VEGF directly promotes osteoclastic bone resorption through the KDR / Flk-1 expressed in mature osteoclasts (FEBS Let. 473: 161-164 (2000); Endocrinology, 141: 1667 (2000)), the present compounds are also suitable for treatment and prevention of conditions related to bone resorption, such as osteoporosis and Paget's disease. The compounds can be characterized by the fact that they have cerebral edema,
Gewebeschädigung und ischämiebedingte Reperfusionsverletzungen reduzieren, auch zur Verringerung oder Vorbeugung von Gewebeschäden, die nach zerebralen ischämischen Ereignissen wie Gehirnschlag auftreten, verwendet werden (Drug News Perspect 11 :265-270 (1998); J. Clin.Reduce tissue damage and ischemic reperfusion injury, also 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)).Invest. 104: 1613-1620 (1999)).
Gegenstand der Erfindung ist somit die Verwendung von Verbindungen nach Anspruch 1 , sowie ihrer pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, bei denen die Hemmung, Regulierung und/oder Modulation der Signaltransduktion von Kinasen eine Rolle spielt.The invention thus relates to the use of compounds according to claim 1, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, for the manufacture of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of the Signal transduction of kinases plays a role.
Bevorzugt sind hierbei Kinasen ausgewählt aus der Gruppe der Tyrosinkinasen und Raf-Kinasen.Kinases are preferably selected from the group of tyrosine kinases and Raf kinases.
Vorzugsweise handelt es sich bei den Tyrosinkinasen um TIE-2.The tyrosine kinases are preferably TIE-2.
Bevorzugt ist die Verwendung von Verbindungen gemäß Anspruch 1 , sowie ihrer pharmazeutisch verwendbaren Derivate, Solvate und Stereo- isomere, einschließlich deren Mischungen in allen Verhältnissen, zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, die durch Inhibierung der Tyrosinkinasen durch die Verbindungen nach Anspruch 1 beeinflußt werden.Preferred is the use of compounds according to claim 1, as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, for the manufacture of a medicament for the treatment of diseases which are influenced by the compounds according to claim 1 by inhibiting the tyrosine kinases become.
Besonders bevorzugt ist die Verwendung zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, die durch Inhibierung von TIE-2 durch die Verbindungen nach Anspruch 1 beeinflußt werden. Insbesondere bevorzugt ist die Verwendung zur Behandlung einer Krankheit, wobei die Krankheit ein fester Tumor ist. Der feste Tumor ist vorzugsweise ausgewählt aus der Gruppe Gehirntumor, Tumor des Urogenitaltrakts, Tumor des lymphatischen Systems, Magentumor, Kehlkopftumor und Lungentumor.Particularly preferred is the use for the manufacture of a medicament for the treatment of diseases which are influenced by inhibition of TIE-2 by the compounds according to claim 1. The use for the treatment of a disease is particularly preferred, the disease being a solid tumor. The solid tumor is preferably selected from the group consisting of brain tumor, tumor of the genitourinary tract, tumor of the lymphatic system, stomach tumor, larynx tumor and lung tumor.
Der feste Tumor ist weiterhin vorzugsweise ausgewählt aus der Gruppe Monozytenleukämie, Lungenadenokarzinom, kleinzellige Lungenkarzinome, Bauchspeicheldrüsenkrebs, Glioblastome und Brustkarzinom.The solid tumor is also preferably selected from the group consisting of monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma.
Gegenstand der Erfindung ist weiterhin die Verwendung der erfindungsgemäßen Verbindungen zur Behandlung einer Krankheit, an der Angiogenese beteiligt ist.The invention further relates to the use of the compounds according to the invention for the treatment of a disease in which angiogenesis is involved.
Vorzugsweise handelt es sich bei der Krankheit um eine Augenkrankheit.The disease is preferably an eye disease.
Gegenstand der Erfindung ist weiterhin die Verwendung zur Behandlung von Retina-Vaskularisierung, diabetischer Retinopathie, altersbedingter Makula-Degeneration und/oder Entzündungskrankheiten.The invention further relates to the use for the treatment of retinal vascularization, diabetic retinopathy, age-related macular degeneration and / or inflammatory diseases.
Die Entzündungskrankheit ist vorzugsweise ausgewählt aus der Gruppe rheumatoide Arthritis, Schuppenflechte, Kontaktdermatitis und Spät-Typ der Überempfindlichkeitsreaktion stammt.The inflammatory disease is preferably selected from the group rheumatoid arthritis, psoriasis, contact dermatitis and late-type hypersensitivity reaction.
Gegenstand der Erfindung ist weiterhin die Verwendung der erfindungsgemäßen Verbindungen zur Behandlung von Knochen-Pathologien, wobei die Knochenpathologie aus der Gruppe Osteosarkom, Osteoarthritis und Rachitis stammt.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.
Die Verbindungen nach Anspruch 1 eignen sich zur Herstellung einesThe compounds according to claim 1 are suitable for the preparation of a
Arzneimittels zur Behandlung von Krankheiten, die durch Raf-Kinasen verursacht, vermittelt und/oder propagiert werden, wobei die Raf-Kinase aus der Gruppe bestehend aus A-Raf, B-Raf und Raf-1 ausgewählt wird. Bevorzugt ist die Verwendung zur Behandlung von Erkrankungen, vorzugsweise aus der Gruppe der hyperproliferativen und nicht hyperproliferativen Erkrankungen.Medicament for the treatment of diseases caused by Raf kinases, mediated and / or propagated, wherein the Raf kinase 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.
Hierbei handelt es sich um Krebserkrankungen oder nicht krebsartigeThese are cancerous or non-cancerous
Erkrankungen.Diseases.
Die nicht krebsartigen Erkrankungen sind ausgewählt aus der Gruppe bestehend aus Psoriasis, Arthritis, Entzündungen, Endometriose,The non-cancerous diseases are selected from the group consisting of psoriasis, arthritis, inflammation, endometriosis,
Vernarbung, gutartiger Prostatahyperplasie, immunologischer Krankheiten, Autoimmunkrankheiten und Immunschwächekrankheiten.Scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and immune deficiency diseases.
Die krebsartigen Erkrankungen sind ausgewählt aus der Gruppe bestehend aus Hirnkrebs, Lungenkrebs, Plattenepithelkrebs, Blasenkrebs, Magenkrebs, Pankreaskrebs, Leberkrebs, Nierenkrebs, Kolorektalkrebs, Brustkrebs, Kopfkrebs, Halskrebs, Ösophaguskrebs, gynäkologischem Krebs, Schilddrüsenkrebs, Lymphom, chronischer Leukämie und akuter Leukämie.The cancerous diseases are selected from the group consisting of brain cancer, lung cancer, squamous cell cancer, bladder cancer, stomach cancer, pancreatic cancer, liver cancer, kidney cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophageal cancer, gynecological cancer, thyroid cancer, lymphoma and chronic leukemia, chronic leukemia.
Die erfindungsgemäßen Verbindungen können auch gemeinsam mit anderen gut bekannten Therapeutika, die aufgrund ihrer jeweiligenThe compounds of the invention can also be used in conjunction with other well-known therapeutic agents based on their respective
Eignung für das behandelte Leiden ausgewählt werden, verabreicht werden. So wären zum Beispiel bei Knochenleiden Kombinationen günstig, die antiresorptiv wirkende Bisphosphonate, wie Alendronat und Risedronat, Integrinblocker (wie sie weiter unten definiert werden), wie αvß3-Antagonisten, bei der Hormontherapie verwendetete konjugierte Östrogene wie Prempro®, Premarin® und Endometrion®; selektive Östrogenrezeptormodulatoren (SERMs) wie Raloxifen, Droloxifen, CP- 336,156 (Pfizer) und Lasofoxifen, Kathepsin-K-Hemmer und ATP- Protonenpumpenhemmer enthalten. Die vorliegenden Verbindungen eignen sich auch zur Kombination mit bekannten Antikrebsmitteln. Zu diesen bekannten Antikrebsmitteln zählen die folgenden: Östrogenrezeptormodulatoren, Androgenrezeptor- modulatoren, Retinoidrezeptormodulatoren, Zytotoxika, antiproliferative Mittel, Prenyl-Proteintransferasehemmer, HMG-CoA-Reduktase-Hemmer,Suitability for the condition being treated can be administered. For example, in the case of bone disorders, combinations that contain antiresorptive bisphosphonates, such as alendronate and risedronate, integrin blockers (as defined below), such as αvß3 antagonists, conjugated estrogens such as Prempro®, Premarin® and Endometrion® used in hormone therapy would be beneficial; contain selective estrogen receptor modulators (SERMs) such as raloxifene, droloxifene, CP-336,156 (Pfizer) and lasofoxifene, cathepsin K inhibitors and ATP proton pump inhibitors. The present compounds are also suitable for combination with known anti-cancer agents. These known anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxics, antiproliferative Agent, prenyl protein transferase inhibitor, HMG-CoA reductase inhibitor,
HIV-Protease-Hemmer, Reverse-Transkriptase-Hemmer sowie weitereHIV protease inhibitors, reverse transcriptase inhibitors and others
Angiogenesehemmer. Die vorliegenden Verbindungen eignen sich insbesondere zur gemeinsamen Anwendung mit Radiotherapie. Die synergistischen Wirkungen der Hemmung des VEGF in Kombination mitAngiogenesis inhibitors. The present compounds are particularly suitable for joint use with radiotherapy. The synergistic effects of inhibiting VEGF in combination with
Radiotherapie sind in der Fachwelt beschrieben worden (siehe WORadiotherapy has been described in the professional world (see WO
00/61186).00/61186).
„Östrogenrezeptormodulatoren" bezieht sich auf Verbindungen, die die Bindung von Östrogen an den Rezeptor stören oder diese hemmen, und zwar unabhängig davon, wie dies geschieht. Zu den Östrogenrezeptormodulatoren zählen zum Beispiel Tamoxifen, Raloxifen, Idoxifen, LY353381 , LY 117081 , Toremifen, 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-dimethylpropanoat, 4,4'- Dihydroxybenzophenon-2,4-dinitrophenylhydrazon und SH646, was jedoch keine Einschränkung darstellen soll."Estrogen receptor modulators" refers to compounds that 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-benzopyran-3-yl] phenyl -2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646, which, however, is not intended to be a limitation.
„Androgenrezeptormodulatoren" bezieht sich auf Verbindungen, die die Bindung von Androgenen an den Rezeptor stören oder diese hemmen, und zwar unabhängig davon, wie dies geschieht. Zu den Androgenrezeptormodulatoren zählen zum Beispiel Finasterid und andere 5α-Reduktase-Hemmer, Nilutamid, Flutamid, Bicalutamid, Liarozol und Abirateron-acetat."Androgen receptor modulators" refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of how this is done. The androgen receptor modulators include, for example, finasteride and other 5α-reductase inhibitors, Nilutamide, Flutamide, Bicalutamide , Liarozole and abiraterone acetate.
„Retinoidrezeptormodulatoren" bezieht sich auf Verbindungen, die die Bindung von Retinoiden an den Rezeptor stören oder diese hemmen, und zwar unabhängig davon, wie dies geschieht. Zu solchen Retinoidrezeptor- modulatoren zählen zum Beispiel Bexaroten, Tretinoin, 13-cis-Retinsäure, 9-cis-Retinsäure, α-Difluormethylornithin, ILX23-7553, trans-N-(4'-Hydroxy- phenyl)retinamid und N-4-Carboxyphenylretinamid. „Zytotoxika" bezieht sich auf Verbindungen, die in erster Linie durch direkte Einwirkung auf die Zellfunktion zum Zelltod führen oder die die Zellmyose hemmen oder diese stören, darunter Alkylierungsmittel, Tumomekrose- faktoren, interkaliernde Mittel, Mikrotubulin-Hemmer und Topoisomerase-"Retinoid receptor modulators" refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of how this is done. Such retinoid receptor modulators include, for example, bexarotene, tretinoin, 13-cis-retinoic acid, 9- cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl) retinamide and N-4-carboxyphenylretinamide. "Cytotoxics" refers to compounds that are primarily affected by direct action on cell function lead to cell death or which inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalating agents, microtubulin inhibitors and topoisomerase
Hemmer.Inhibitors.
Zu den Zytotoxika zählen zum Beispiel Tirapazimin, Sertenef, Cachectin,The cytotoxics include, for example, tirapazimin, sertenef, cachectin,
Ifosfamid, Tasonermin, Lonidamin, Carboplatin, Altretamin, Prednimustin,Ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine,
Dibromdulcit, Ranimustin, Fotemustin, Nedaplatin, Oxaliplatin,Dibromodulcite, ranimustine, fotemustine, nedaplatin, oxaliplatin,
Temozolomid, Heptaplatin, Estramustin, Improsulfan-tosylat, Trofosfamid,Temozolomide, heptaplatin, estramustine, improsulfan tosylate, trofosfamide,
Nimustin, Dibrospidium-chlorid, Pumitepa, Lobaplatin, Satraplatin,Nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin,
Profiromycin, Cisplatin, Irofulven, Dexifosfamid, cis-Amindichlor(2- methylpyridin)platin, Benzylguanin, Glufosfamid, GPX100, (trans,trans,trans)-bis-mu-(hexan-1 ,6-diamin)-mu-[diamin- platin(ll)]bis[diamin(chlor)platin(ll)]-tetrachlorid, Diarizidinylspermin, Arsentrioxid, 1 -(11 -Dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthin, Zorubicin, Idarubicin, Daunorubicin, Bisantren, Mitoxantron, Pirarubicin,Profiromycin, cisplatin, irofulven, dexifosfamide, cis-amine dichloro (2-methylpyridine) platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans) -bis-mu- (hexane-1, 6-diamine) -mu- [diamine - platinum (II)] bis [diamine (chloro) platinum (II)] - tetrachloride, diarizidinyl spermine, arsenic trioxide, 1 - (11 -dodecylamino-10-hydroxyundecyl) -3,7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, Mitoxantrone, pirarubicin,
Pinafid, Valrubicin, Amrubicin, Antineoplaston, 3'-Desamino-3'-morpholino- 13-desoxo-10-hydroxycarminomycin, Annamycin, Galarubicin, Elinafid, MEN10755 und 4-Desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl- daunorubicin (siehe WO 00/50032), was jedoch keine Einschränkung darstellen soll.Pinafid, Valrubicin, Amrubicin, Antineoplaston, 3'-Desamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin, Annamycin, Galarubicin, Elinafid, MEN10755 and 4-Desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl daunorubicin (see WO 00/50032), but this should not be a limitation.
Zu den Mikrotubulin-Hemmem zählen zum Beispiel Paclitaxel, Vindesin- sulfat, 3',4'-Dideshydro-4'-desoxy-8'-norvincaleukoblastin, Docetaxol, Rhizoxin, Dolastatin, Mivobulin-isethionat, Auristatin, Cemadotin, RPR109881 , BMS184476, Vinflunin, Cryptophycin, 2,3,4,5,6-pentafluor-N- (3-fluor-4-methoxyphenyl)benzolsulfonamid, Anhydrovinblastin, N,N- dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-prolin-t-butylamid, TDX258 und BMS188797. Topoisomerase-Hemmer sind zum Beispiel Topotecan, Hycaptamin, Irinotecan, Rubitecan, 6-Ethoxypropionyl-3',4'-0-exo-benzyliden- chartreusin, 9-Methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridin-2- (6H)propanamin, 1-Amino-9-ethyl-5-fluor-2,3-dihydro-9-hydroxy-4-methyl- 1 H, 12H-benzo[de]pyrano[3',4':b,7]indolizino[1 ,2b]chinolin-10, 13(91-1,15H)- dion, Lurtotecan, 7-[2-(N-lsopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100, BN80915, BN80942, Etoposid-phosphat, Teniposid, Sobuzoxan, 2'-Dimethylamino-2'-desoxy-etoposid, GL331, N-[2- (Dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazol-1- carboxamid, Asulacrin, (5a,5aB,8aa,9b)-9-[2-[N-[2-(Dimethylamino)ethyl]-The microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, 3 ', 4'-dideshydro-4'-deoxy-8'-norvincaleukoblastin, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR1094476, BMS 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. Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ', 4'-0-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-1 H, 12H-benzo [de] pyrano [ 3 ', 4': b, 7] indolizino [1, 2b] quinoline-10, 13 (91-1.15H) - dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl] - (20S) camptothecin , BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, Sobuzoxane, 2'-dimethylamino-2'-deoxy-etoposide, GL331, N- [2- (dimethylamino) ethyl] -9-hydroxy-5,6-dimethyl-6H-pyrido [4,3-b] carbazol-1 - carboxamide, asulacrine, (5a, 5aB, 8aa, 9b) -9- [2- [N- [2- (dimethylamino) ethyl] -
N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9- hexohydrofuro(3',4':6,7)naphtho(2,3-d)-1 ,3-dioxol-6-on, 2,3-N-methylamino] ethyl] -5- [4-hydroxy-3,5-dimethoxyphenyl] -5,5a, 6,8,8a, 9-hexohydrofuro (3 ', 4': 6,7) naphtho (2,3 -d) -1, 3-dioxol-6-one, 2,3-
(Methylendioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phenanthridinium,(Methylenedioxy) -5-methyl-7-hydroxy-8-methoxybenzo [c] phenanthridinium,
6,9-Bis[(2-aminoethyl)amino]benzo[g]isochinolin-5, 10-dion, 5-(3-Amino- propylamino)-7, 10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H- pyrazolo[4,5, 1 -de]acridin-6-on, N-[1 -[2(Diethylamino)ethylamino]-7- methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamid, N-(2-(Dimethyl- amino)-ethyl)acridin-4-carboxamid, 6-[[2-(Dimethylamino)-ethyl]amino]-3- hydroxy-7H-indeno[2,1-c]chinolin-7-on und Dimesna. Zu den „antiproliferativen Mitteln" zählen Antisense-RNA- und -DNA- Oligonucleotide wie G3139, 0DN698, RVASKRAS, GEM231 und INX3001 , sowie Antimetaboliten wie Enocitabin, Carmofur, Tegafur, Pentostatin, Doxifluridin, Trimetrexat, Fludarabin, Capecitabin, Galocitabin, Cytarabin-ocfosfat, Fosteabin-Natriumhydrat, Raltitrexed, Paltitrexid, Emitefur, Tiazofurin, Decitabin, Nolatrexed, Pemetrexed, Nelzarabin, 2'- Desoxy-2'-methylidencytidin, 2'-Fluormethylen-2'-desoxycytidin, N-[5-(2,3- Dihydrobenzofuryl)sulfonyl]-N'-(3,4-dichlorphenyl)harnstoff, N6-[4-Desoxy- 4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno- heptopyranosyljadenin, Aplidin, Ecteinascidin, Troxacitabine, 4-[2-Amino- 4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]- 2,5-thienoyl-L-glutaminsäure, Aminopterin, 5-Flurouracil, Alanosin, 11- Acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1 , 11 -diaza- tetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylessigsäureester, Swainsonin, Lometrexol, Dexrazoxan, Methioninase, 2'-cyan-2'-desoxy-N4-palmitoyl-1- B-D-Arabinofuranosylcytosin und 3-Aminopyridin-2-carboxaldehyd- thiosemicarbazon. Die „antiproliferativen Mittel" beinhalten auch andere monoklonale Antikörper gegen Wachstumsfaktoren als bereits unter den „Angiogenese-Hemmem" angeführt wurden, wie Trastuzumab, sowie Tumorsuppressorgene, wie p53, die über rekombinanten virusvermittelten Gentransfer abgegeben werden können (siehe z.B. US-Patent Nr. 6,069,134).6,9-bis [(2-aminoethyl) amino] benzo [g] isoquinoline-5, 10-dione, 5- (3-aminopropylamino) -7, 10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H pyrazolo [4,5, 1 -de] acridin-6-one, N- [1 - [2 (diethylamino) ethylamino] -7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl] formamide, N- (2- (dimethylamino) ethyl) acridine-4-carboxamide, 6 - [[2- (dimethylamino) ethyl] amino] -3-hydroxy-7H-indeno [2,1-c] quinoline-7- on and Dimesna. The "antiproliferative agents" include antisense RNA and DNA oligonucleotides such as G3139, 0DN698, RVASKRAS, GEM231 and INX3001, as well as antimetabolites such as enocitabine, Carmofur, Tegafur, pentostatin, doxifluridine, trimetrexate, flabinarababin, capud ocfosfate, fosteabin sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidencytidine, 2'-fluoromethylene-2'-deoxycytidine, N- [5- 3- dihydrobenzofuryl) sulfonyl] -N '- (3,4-dichlorophenyl) urea, N6- [4-deoxy- 4- [N2- [2 (E), 4 (E) -tetradecadienoyl] glycylamino] -L-glycero -BL-mannoheptopyranosyljadenine, aplidine, ecteinascidine, troxacitabine, 4- [2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino [5,4-b] [1,4] thiazine -6-yl- (S) -ethyl] - 2,5-thienoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, 11-acetyl-8- (carbamoyloxymethyl) -4-formyl-6-methoxy-14- oxa-1, 11 -diaza-tetracyclo (7.4.1.0.0) -tetradeca-2,4,6-trien-9-ylacetic acid ester, Swainson in, lometrexol, dexrazoxane, methioninase, 2'-cyan-2'-deoxy-N4-palmitoyl-1-BD-arabinofuranosylcytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. The "antiproliferative agents" also contain 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 mediate via recombinant virus Gene transfer can be delivered (see, for example, US Patent No. 6,069,134).
ASSAYSASSAYS
Die in den Beispielen beschriebenen erfindungsgemäßen Verbindungen wurden in den unten beschriebenen Assays geprüft, und es wurde gefunden, dass sie eine kinasehemmende Wirkung aufweisen. Weitere Assays sind aus der Literatur bekannt und könnten vom Fachmann leicht durchgeführt werden (siehe z.B. Dhanabal et al, Cancer Res. 59:189-197; Xin et al, J. Biol. Chem. 274:9116-9121 ; Sheu et a , Anticancer Res. 18:4435-4441 ; Ausprunk et al, Dev. Biol. 38:237-248; Gimbrone et al, J. Natl. Cancer Inst. 52:413-427; Nicosia et al. In Vitro 18:538- 549). VEGF-Rezeptorkinase-Assay Die VEGF-Rezeptorkinaseaktivität wird durch Einbau von radioaktiv markiertem Phosphat in 4:1 Polyglutaminsäure/Tyrosin-Substrat (pEY) bestimmt. Das phosphorylierte pEY-Produkt wird auf einer Filtermembran festgehalten, und der Einbau des radioaktiv markierten Phosphats wird durch Szintillationszählung quantitativ bestimmt.The compounds of the invention described in the examples were tested in the assays described below and were found to have a kinase inhibitory effect. Further assays are known from the literature and could easily be carried out by a person skilled in the art (see, for example, Dhanabal et al, Cancer Res. 59: 189-197; Xin et al, J. Biol. Chem. 274: 9116-9121; Sheu et a. Anticancer Res. 18: 4435-4441; Ausprunk et al, Dev. Biol. 38: 237-248; Gimbrone et al, J. Natl. Cancer Inst. 52: 413-427; Nicosia et al. In Vitro 18: 538- 549). VEGF receptor kinase assay The 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.
MATERIALIENMATERIALS
VEGF-RezeptorkinaseVEGF receptor kinase
Die intrazelluläre-Tyrosinkinase-Domänen des menschlichen KDR (Terman, B. I. et al. Oncogene (1991) Bd. 6, S. 1677-1683.) und Flt-1 (Shibuya, M. et al. Oncogene (1990) Bd. 5, S. 519-524) wurden als Glutathion-S-transferase (GST)-Genfusionsproteine Moniert. Dies geschah durch Klonieren der Zytoplasma-Domäne der KDR-Kinase als leserastergerechte Fusion am Carboxy-Terminus des GST-Gens. Die löslichen rekombinanten GST-Kinasedomäne-Fusionsproteine wurden in Spodoptera frugiperda (Sf21) Insektenzellen (Invitrogen) unter Verwendung eines Baculovirus-Expressionsvektors (pAcG2T, Pharmingen) exprimiert.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) Use of a baculovirus expression vector (pAcG2T, Pharmingen).
Lysepufferlysis buffer
50 mM Tris pH 7,4, 0,5 M NaCI, 5 mM DTT, 1 mM EDTA, 0,5% Triton X-50mM Tris pH 7.4, 0.5M NaCl, 5mM DTT, 1mM EDTA, 0.5% Triton X-
100, 10% Glycerin, je 10 mg/ml Leupeptin, Pepstatin und Aprotinin sowie100, 10% glycerin, each 10 mg / ml leupeptin, pepstatin and aprotinin as well
1 mM Phenylmethylsulfonylfluorid (alle von Sigma).1mM phenylmethylsulfonyl fluoride (all from Sigma).
Waschpufferwash buffer
50 mM Tris pH 7,4, 0,5 M NaCI, 5 mM DTT, 1 mM EDTA, 0.05% Triton X- 100, 10% Glycerin, je 10 mg/ml Leupeptin, Pepstatin und Aprotinin sowie 1 mM Phenylmethylsulfonylfluorid. ,50 mM Tris pH 7.4, 0.5 M NaCI, 5 mM DTT, 1 mM EDTA, 0.05% Triton X-100, 10% glycerol, 10 mg / ml each of leupeptin, pepstatin and aprotinin and 1 mM phenylmethylsulfonyl fluoride. .
Dialysepufferdialysis buffer
50 mM Tris pH 7,4, 0,5 M NaCI, 5 mM DTT, 1 mM EDTA, 0.05% Triton X- 100, 50% Glycerin, je 10 mg/ml Leupeptin, Pepstatin und Aprotinin sowie 1 mM Phenylmethylsulfonylfluorid.50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.05% Triton X-100, 50% glycerol, 10 mg / ml each of leupeptin, pepstatin and aprotinin and 1 mM phenylmethylsulfonyl fluoride.
10x Reaktionspuffer10x reaction buffer
200 mM Tris, pH 7,4, 1 ,0 M NaCI, 50 mM MnCI2, 10 mM DTT und 5 mg/ml200 mM Tris, pH 7.4, 1.0 M NaCl, 50 mM MnCl 2 , 10 mM DTT and 5 mg / ml
Rinderserumalbumin [bovine serum albumin = BSA] (Sigma).Bovine serum albumin = BSA] (Sigma).
EnzymverdünnungspufferEnzyme Diluent
50 mM Tris, pH 7,4, 0,1 M NaCI, 1 mM DTT, 10% Glycerin, 100 mg/ml50mM Tris, pH 7.4, 0.1M NaCl, 1mM DTT, 10% glycerol, 100mg / ml
BSA.BSA.
10x Substrat 750 μg/ml Poly(glutaminsäure/Tyrosin; 4:1) (Sigma).10x substrate 750 μg / ml poly (glutamic acid / tyrosine; 4: 1) (Sigma).
Stopp-LösungStop Solution
30% Trichloressigsäure, 0,2 M Natriumpyrophosphat (beide von Fisher).30% trichloroacetic acid, 0.2 M sodium pyrophosphate (both from Fisher).
Waschlösung 15% Trichloressigsäure, 0,2 M Natriumpyrophosphat.Wash solution 15% trichloroacetic acid, 0.2 M sodium pyrophosphate.
Filterplattenfilter plates
Millipore #MAFC NOB, GF/C 96-Well-Glasfaserplatte.Millipore #MAFC NOB, GF / C 96-well glass fiber plate.
Verfahren A - ProteinaufreinigungMethod A - Protein Purification
1. Die Sf21 -Zellen wurden mit dem rekombinanten Virus bei einer m.o.i.1. The Sf21 cells were with the recombinant virus in an m.o.i.
(Multiplizität der Infektion) von 5 Viruspartikeln/Zelle infiziert und 48(Multiplicity of infection) of 5 virus particles / cell infected and 48
Stunden lang bei 27°C gezüchtet. 2. Alle Schritte wurden bei 4°C durchgeführt. Die infizierten Zellen wurden durch Zentrifugieren bei 1000xg geerntet und 30 Minuten bei 4°C mit 1/10Bred at 27 ° C for hours. 2. All steps were carried out at 4 ° C. The infected cells were harvested by centrifugation at 1000xg and 30 minutes at 4 ° C at 1/10
Volumen Lysepuffer lysiert und anschließend 1 Stunde lang bei 100.000xg zentrifugiert. Der Überstand wurde dann über eine mit Lysepuffer äquilibrierte Glutathion-Sepharose-Säure (Pharmacia) gegeben und mit 5Volume lysis buffer lysed and then centrifuged for 1 hour at 100,000xg. The supernatant was then passed through a glutathione-Sepharose acid (Pharmacia) equilibrated with lysis buffer and with 5
Volumina des gleichen Puffers und anschließend 5 Volumina Waschpuffer gewaschen. Das rekombinante GST-KDR-Protein wurde mitVolumes of the same buffer and then washed 5 volumes of wash buffer. The recombinant GST-KDR protein was with
Waschpuffer/10 mM reduziertem Glutathion (Sigma) eluiert und gegen Dialysepuffer dialysiert.Wash buffer / 10 mM reduced glutathione (Sigma) eluted and dialyzed against dialysis buffer.
Verfahren B - VEGF-Rezeptorkinase-AssayMethod B - VEGF receptor kinase assay
1. Assay mit 5 μl Hemmstoff oder Kontrolle in 50% DMSO versetzen.1. Add 5 μl inhibitor or control in 50% DMSO to the assay.
2. Mit 35 μl Reaktionsmischung, die 5 μl 10x Reaktionspuffer, 5 μl 25 mM ATP/10 μCi[33 P]ATP (Amersham) und 5 μl 10x Substrat enthält, versetzen.2. Add 35 μl reaction mixture containing 5 μl 10x reaction buffer, 5 μl 25 mM ATP / 10 μCi [ 33 P] ATP (Amersham) and 5 μl 10x substrate.
3. Reaktion durch Zugabe von 10 μl KDR (25 nM) in Enzymverdünnungspuffer starten.3. Start the reaction by adding 10 μl KDR (25 nM) in enzyme dilution buffer.
4. Mischen und 15 Minuten lang bei Raumtemperatur inkubieren.4. Mix and incubate for 15 minutes at room temperature.
5. Reaktion durch Zugabe von 50 μl Stopp-Lösung stoppen.5. Stop the reaction by adding 50 μl stop solution.
6. 15 Minuten lang bei 4°C inkubieren.6. Incubate at 4 ° C for 15 minutes.
7. 90-μl-Aliquot auf Filterplatte überführen.7. Transfer 90 μl aliquot to filter plate.
8. Absaugen und 3 Mal mit Waschlösung waschen. 9. 30 μl Szintillations-Cocktail zugeben, Platte verschließen und in einem Szintillations-Zähler Typ Wallac Microbeta zählen. Mitogenese-Assay an menschlichen Nabelschnurvenenendothelzellen Die Expression von VEGF-Rezeptoren, die mitogene Reaktionen auf den Wachstumsfaktor vermitteln, ist größtenteils auf Gefäßendothelzellen beschränkt. Kultivierte menschliche Nabelschnurvenenendothelzellen (HUVECs) proliferieren als Reaktion auf Behandlung mit VEGF und können als Assaysystem zur quantitativen Bestimmung der Auswirkungen von KDR-Kinasehemmem auf die Stimulation des VEGF verwendet werden. In dem beschriebenen Assay werden Einzelzellschichten von HUVECs im Ruhezustand 2 Stunden vor der Zugabe von VEGF oder „basic fibroblast growth factor" (bFGF) mit dem Konstituens oder der Testverbindung behandelt. Die mitogene Reaktion auf VEGF oder bFGF wird durch Messung des Einbaus von [3H]Thymidin in die Zeil-DNA bestimmt. Materialien8. Aspirate and wash 3 times with washing solution. 9. Add 30 μl of scintillation cocktail, close the plate and count in a Wallac Microbeta scintillation counter. Mitogenesis Assay on Human Umbilical Vein Endothelial Cells The expression of VEGF receptors that mediate mitogenic responses to the growth factor is largely restricted to vascular endothelial cells. Cultivated human umbilical vein endothelial cells (HUVECs) proliferate in response to treatment with VEGF and can be used as an assay system to quantify the effects of KDR kinase inhibitors on VEGF stimulation. In the assay described, single cell layers of HUVECs are at rest 2 hours before the addition of VEGF or "Basic fibroblast growth factor" (bFGF) treated with the constituent or the test compound. The mitogenic response to VEGF or bFGF is determined by measuring the incorporation of [ 3 H] thymidine in the cell DNA. Materials
HUVECsHUVECs
Als Primärkulturisolate tiefgefrorene HUVECs werden von Clonetics Corp bezogen. Die Zellen werden im Endothel-Wachstumsmedium (EndothelialFrozen HUVECs as primary culture isolates are obtained from Clonetics Corp. The cells are in the endothelial growth medium (endothelial
Growth Medium = EGM; Clonetics) erhalten und in der 3. - 7. Passage für die Mitogenitätsassays verwendet. ' /Growth Medium = EGM; Clonetics) and used in the 3rd - 7th passage for the mitogenicity assays. '/
Kulturplattenculture plates
NUNCLON 96-Well-Polystyrol-Gewebekulturplattten (NUNC #167008).NUNCLON 96-well polystyrene tissue culture plates (NUNC # 167008).
Assay-MediumAssay Medium
Nach Dulbecco modifiziertes Eagle-Medium mit 1 g/ml Glucose (DMEM mit niedrigem Glucosegehalt; Mediatech) plus 10% (v/v) fötalesDulbecco modified Eagle medium with 1 g / ml glucose (DMEM with low glucose content; Mediatech) plus 10% (v / v) fetal
Rinderserum (Clonetics). TestverbindungenBovine serum (Clonetics). test compounds
Mit den Arbeitsstammlösungen der Testverbindungen wird mit 100% Dimethylsulfoxid (DMSO) solange eine Reihenverdünnung durchgeführt, bis ihre Konzentrationen um das 400-fache höher als die gewünschte End- konzentration sind. Die letzten Verdünnungen (Konzentration 1x) werden unmittelbar vor Zugabe zu den Zellen mit Assay-Medium hergestellt. 10x WachstumsfaktorenWith 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 (concentration 1x) are made with assay medium immediately before addition to the cells. 10x growth factors
Lösungen des menschlichen VEGF 165 (500 ng/ml; R&D Systems) und bFGF (10 ng/ml; R&D Systems) werden mit Assay-Medium hergestellt. 10x [3H]-ThymidinSolutions of the human VEGF 165 (500 ng / ml; R&D Systems) and bFGF (10 ng / ml; R&D Systems) are prepared with assay medium. 10x [ 3 H] thymidine
[Methyl-3H]-Thymidin (20 Ci/mmol; Dupont-NEN) wird mit DMEM-Medium mit niedrigem Glucosegehalt auf 80 μCi/ml verdünnt. Zeilwaschmedium Hank's balanced salt solution (Mediatech) mit 1 mg/ml Rinderserumalbumin (Boehringer-Mannheim). Zell-Lyse-Lösung 1 N NaOH, 2% (w/v) Na2C03.[Methyl- 3 H] -thymidine (20 Ci / mmol; Dupont-NEN) is diluted to 80 μCi / ml with DMEM medium with a low glucose content. Hank's balanced salt solution (Mediatech) with 1 mg / ml bovine serum albumin (Boehringer-Mannheim). Cell lysis solution 1N NaOH, 2% (w / v) Na 2 CO 3 .
Verfahren 1Procedure 1
In EGM gehaltene HUVEC-Einzelzellschichten werden durch Trypsinbe- handlung geerntet und in einer Dichte von 4000 Zellen pro 100 μl Assay- Medium pro Näpfchen in 96-Well-Platten überimpft. Das Wachstum der Zellen wird 24 Stunden bei 37°C in einer 5% C02 enthaltenden feuchten Atmosphäre gestoppt. Verfahren 2HUVEC single cell layers kept in EGM are harvested by trypsin treatment and inoculated in a density of 4000 cells per 100 μl 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
Das Wachstumsstoppmedium wird durch 100 μl Assay-Medium ersetzt, das entweder das Konstituens (0,25% [v/v] DMSO) oder die erwünschte Endkonzentration der Testverbindung enthält. Alle Bestimmungen werden in dreifacher Wiederholung durchgeführt. Die Zellen werden dann 2 Stunden bei 37°C/5% C02 inkubiert, so dass die Testverbindungen in die Zellen eindringen können. Verfahren 3The 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. Procedure 3
Nach 2-stündiger Vorbehandlung werden die Zellen durch Zugabe von 10 μl Assay-Medium, 10x VEGF-Lösung oder 10x bFGF-Lösung pro Näpfchen stimuliert. Die Zellen werden dann bei 37°C/5% C02 inkubiert. , Verfahren 4 Nach 24 Stunden in Anwesenheit der Wachstumsfaktoren wird mit 10x [3H]-Thymidin (10 μl/well) versetzt. Verfahren 5After 2 hours of pretreatment, the cells are stimulated by adding 10 μl assay medium, 10x VEGF solution or 10x bFGF solution per well. The cells are then incubated at 37 ° C / 5% CO 2 . Method 4 After 24 hours in the presence of the growth factors, 10x [ 3 H] thymidine (10 μl / well) are added. Procedure 5
Drei Tage nach dem Versetzen mit [3H]-Thymidin wird das Medium abgesaugt und die Zellen werden zweimal mit Zeilwaschmedium gewaschen (400 μl/well, anschließend 200 μl/well). Die gewaschenen, adhärenten Zellen werden dann durch Zugabe von Zell-Lyse-Lösung (100 μl/well) und 30-minutiges Erwärmen auf 37°C solubilisiert. Die Zell-Lysate werden in 7-ml-Szintillationsrährchen aus Glas, die 150 μl Wasser enthalten, überführt. Man versetzt mit dem Szintillations-Cocktail (5 ml/Röhrchen), und die mit den Zellen assoziierte Radioaktivität wird flüssigkeitsszintillationsspektroskopisch bestimmt. Gemäß diesen Assays stellen die Verbindungen der Formel I VEGF-Three days after adding [ 3 H] -thymidine, the medium is suctioned off and the cells are washed twice with washing medium (400 μl / well, then 200 μl / well). The washed, adherent cells are then solubilized by adding cell lysis solution (100 μl / 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. According to these assays, the compounds of the formula I VEGF-
Hemmer dar und eignen sich daher zur Hemmung der Angiogenese, wie bei der Behandlung von Augenkrankheiten, z.B. diabetischer Retinopathie, und zur Behandlung von Karzinomen, z.B. festen Tumoren. Die vorliegenden Verbindungen hemmen die VEGF-stimulierte Mitogenese von kultivierten menschlichen Gefäßendothelzellen mit HK50-Werten vonInhibitors and are therefore suitable for inhibiting angiogenesis, such as in the treatment of eye diseases, e.g. diabetic retinopathy, and for the treatment of carcinomas, e.g. solid tumors. The present compounds inhibit VEGF-stimulated mitogenesis of cultured human vascular endothelial cells with HK50 values of
0,01-5,0 μM. Diese Verbindungen sind im Vergleich zu verwandten0.01-5.0 µM. These compounds are compared to relatives
Tyrosinkinasen (z.B. FGFR1 sowie Src-Familie; zur Beziehung zwischen Src-Kinasen und VEGFR-Kinasen siehe Eliceiri et al, Molecular Cell, Bd.Tyrosine kinases (e.g. FGFR1 and Src family; for the relationship between Src kinases and VEGFR kinases see Eliceiri et al, Molecular Cell, Vol.
4, S.915-924, Dezember 1999) auch selektiv. I ' ;4, p.915-924, December 1999) also selectively. I ';
Die T7E-2-Tests können z.B. analog der in WO 02/44156 angegebenen Methoden durchgeführt werden.The T7E-2 tests can e.g. can be carried out analogously to the methods specified in WO 02/44156.
Der Assay bestimmt die inhibierende Aktivität der zu testenden Substanzen bei der Phosphorylierung des Substrats Poly(Glu, Tyr) durch Tie-2-Kinase in Gegenwart von radioaktivem 33P-ATP. Das phosphorylierteThe 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
Substrat bindet während der Inkubationszeit an die Oberfläche einerSubstrate binds to the surface of one during the incubation period
"flashplate"-Mikrotiterplatte. Nach Entfernen der Reaktionsmischung wird mehrmals gewaschen und anschließend die Radioaktivität an der"Flash" microtitre plate. After removing the reaction mixture, it is washed several times and then the radioactivity on the
Oberfläche der Mikrotiterplatte gemessen. Ein inhibierender Effekt der zu messenden Substanzen hat eine geringere Radioaktivität, verglichen mit einer ungestörten enzymatischen Reaktion, zur Folge.Surface of the microtiter plate measured. An inhibitory effect of the substances to be measured results in a lower radioactivity compared to an undisturbed enzymatic reaction.
Vor- und nachstehend sind alle Temperaturen in °C angegeben. In den nachfolgenden Beispielen bedeutet "übliche Aufarbeitung": Man gibt, falls erforderlich, Wasser hinzu, stellt, falls erforderlich, je nach Konstitution des Endprodukts auf pH-Werte zwischen 2 und 10 ein, extrahiert mit Ethylacetat oder Dichlormethan, trennt ab, trocknet die organische Phase über Natriumsulfat, dampft ein und reinigt durch Chromatographie anAll temperatures above and below are given in ° C. In the examples below, "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, evaporated and purified by chromatography
Kieselgel und /oder durch Kristallisation. Rf-Werte an Kieselgel; Laufmittel:Silica gel and / or by crystallization. Rf values on silica gel; Eluent:
Ethylacetat/Methanol 9:1. Massenspektrometrie (MS): El (Elektronenstoß-Ionisation) M+ FAB (Fast Atom Bombardment) (M+H)+ ESI (Electrospray lonization) (M+H)+ (wenn nichts anderes angegeben)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)
Beispiel 1example 1
1-[4-(Benzo[1,2,5]thiadiazol-5-yloxy)-phenyl]-3-(2-fluor-5-t fluormethyl- phenyl)-harnstoff ("A 1 ")1- [4- (Benzo [1,2,5] thiadiazol-5-yloxy) phenyl] -3- (2-fluoro-5-t fluoromethylphenyl) urea ("A 1")
Die Herstellung erfolgt analog nachstehendem SchemaThe production is carried out according to the following scheme
1.1 Herstellung von 4-(Benzo[1 ,2,5]thiadiazol-5-yioxy)-phenylamin ("A2"):1.1 Preparation of 4- (Benzo [1,2,5] thiadiazol-5-yioxy) phenylamine ("A2"):
1.8 g Benzo[1 ,2,5]thiadiazol-5-ol und 1.3 ml 4-Fluomitrobenzol werden in 25 ml DMF gelöst und 3.9 g Cäsiumcarbonat hinzugegeben. Das Reaktionsgemisch wird über Nacht bei 85° gerührt.1.8 g of benzo [1, 2.5] thiadiazol-5-ol and 1.3 ml of 4-fluomitrobenzene are dissolved in 25 ml of DMF and 3.9 g of cesium carbonate are added. The reaction mixture is stirred at 85 ° overnight.
Zur Aufarbeitung wird das Gemisch mit Wasser versetzt und mit Essigester extrahiert. Die gesammelten organischen Phasen werden mit wasserfreiem Natriumsulfat getrocknet, filtriert und einrotiert. Der Rückstand wird mit Diethylether verrieben. Man erhält 2.8 g von 5-(4-Nitro- phenoxy)-benzo[1 ,2,5]thiadiazol; Rf (CH2CI2) 0.65; EI-MS (M+H)+ 274. Die Nitro- Verbindung wird mit Raney-Nickel zur gewünschten Verbindung hydriert. Nach Chromatographie mit Petrolether/Essigester erhält man 1.3 g einer gelben Festsubstanz ("A2"); Rf (Petrolether/Essigester 1/1) 0,75, EI-MS (M+H)+ 244.For working up, the mixture is mixed with water and extracted with ethyl acetate. The collected organic phases are dried with anhydrous sodium sulfate, filtered and evaporated. The residue is triturated with diethyl ether. 2.8 g of 5- (4-nitrophenoxy) benzo [1,2,5] thiadiazole are obtained; Rf (CH2Cl2) 0.65; EI-MS (M + H) + 274. The nitro compound is hydrogenated with Raney nickel to the desired compound. After chromatography with petroleum ether / ethyl acetate, 1.3 g of a yellow solid ("A2") are obtained; Rf (petroleum ether / ethyl acetate 1/1) 0.75, EI-MS (M + H) + 244.
1.2 100 mg "A2" und 0.1 ml 2-Fluor-5-(trifluormethyl)phenyl isocyanat werden in 5 ml Dichlormethan gelöst und 0.12 ml Triethylamin hinzugegeben. Die Mischung wird über Nacht bei Raumtemperatur gerührt. Zur Aufarbeitung wird das Lösungsmittel am Rotavapor abgezogen und der Rückstand mit Hilfe der präparative HPLC gereinigt.1.2 100 mg of "A2" and 0.1 ml of 2-fluoro-5- (trifluoromethyl) phenyl isocyanate are dissolved in 5 ml of dichloromethane and 0.12 ml of triethylamine are added. The mixture is stirred at room temperature overnight. For working up, the solvent is drawn off on a Rotavapor and the residue is purified using preparative HPLC.
Säule: RP 18 (7 μm) Lichrosorb 250x25 Fließmittel: A: 98H20, 2CH3CN, 0, 1 %TFA B: 10H2O, 90CH3CN, 0,1%TFA UV: 225NM Fluß: 10ml/min Man erhält 69 mg einer weißen Festsubstanz ("A1 ,Trifluoracetat"); Rf (Petrolether/Essigester 1/1) 0,63; EI-MS (M+H)+ 449.Column: RP 18 (7 microns) Lichrosorb 250x25 eluent: A: 98H 2 0, 2CH 3 CN, 0, 1% TFA B: 10H 2 O, 90CH 3 CN, 0.1% TFA UV: 225 nm Flow rate: 10ml / min 69 mg of a white solid substance are obtained ("A1, trifluoroacetate"); Rf (petroleum ether / ethyl acetate 1/1) 0.63; EI-MS (M + H) + 449.
Analog erhält man nachstehende VerbindungenThe following connections are obtained analogously
HPLC-APCI-MSn HPLC-APCI-MSn
Pharmakologische TestergebnissePharmacological test results
Die nachfolgenden Beispiele betreffen pharmazeutische Zubereitungen:The following examples relate to pharmaceutical preparations:
Beispiel A: InjektionsgläserExample A: Injection glasses
Eine Lösung von 100 g eines erfindungsgemäßen Wirkstoffes und 5 g Dinatriumhydrogenphosphat wird in 3 I zweifach destilliertem Wasser mit 2 n Salzsäure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jedes Injektionsglas enthält 5 mg Wirkstoff.A solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogenphosphate 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.
Beispiel B: SuppositorienExample B: Suppositories
Man schmilzt ein Gemisch von 20 g eines erfindungsgemäßen Wirkstoffes mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und läßt erkalten. Jedes Suppositorium enthält 20 mg Wirkstoff.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.
Beispiel C: LösungExample C: solution
Man bereitet eine Lösung aus 1 g eines erfindungsgemäßen Wirkstoffes, 9,38 g NaH2P04 • 2 H20, 28,48 g Na2HP04 • 12 H20 und 0,1 gA solution of 1 g of an active ingredient is prepared according to the invention, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g Na 2 HP0 4 • 12 H 2 0 and 0.1 g of
Benzalkoniumchlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 ein, füllt auf 1 I auf und sterilisiert durch Bestrahlung. Diese Lösung kann in Form von Augentropfen verwendet werden.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.
Beispiel D: SalbeExample D: ointment
Man mischt 500 mg eines erfindungsgemäßen Wirkstoffes mit 99,5 g Vaseline unter aseptischen Bedingungen. Beispiei E: Tabletten500 mg of an active ingredient according to the invention are mixed with 99.5 g of petroleum jelly under aseptic conditions. Example E: tablets
Ein Gemisch von 1 kg Wirkstoff, 4 kg Lactose, 1 ,2 kg Kartoffelstärke,A mixture of 1 kg of active ingredient, 4 kg of lactose, 1, 2 kg of potato starch,
0,2 kg Talk und 0,1 kg Magnesiumstearat wird in üblicher Weise zu0.2 kg talc and 0.1 kg magnesium stearate is added in the usual way
Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält.Tablets pressed in such a way that each tablet contains 10 mg of active ingredient.
Beispiel F: DrageesExample F: coated tablets
Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.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 dye.
Beispiel G: KapselnExample G: capsules
2 kg Wirkstoff werden in üblicher Weise in Hartgelatinekapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.2 kg of active ingredient are filled into hard gelatin capsules in a conventional manner so that each capsule contains 20 mg of the active ingredient.
Beispiel H: AmpullenExample H: ampoules
Eine Lösung von 1 kg eines erfindungsgemäßen Wirkstoffes in 60 I zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff. 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.

Claims

Patentansprüche claims
1. Harnstoffderivate ausgewählt aus der Gruppe1. urea derivatives selected from the group
4-{4-[3-(Fluor-trifluormethyl-phenyl)-ureido]-phenoxy}-pyridin-2- carbonsäure-Λ-methylamid, 1 -[4-(Benzo[1 ,2,5]thiadiazol-5-yloxy)-phenyl]-3-(2-fluor-5- trifluormethyl-phenyl)-hamstoff , 1-(2-Fluor-5-trifluormethyl-phenyl)-3-[4-(pyridin-4-ylsulfanyl)- phenylj-hamstoff, 1-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yloxy)-phenyl]-3-(2-fluor-5- trifluormethyl-phenyl)-harnstoff, 7-{4-[3-(2-Fluor-5-trifluormethyl-phenyl)-ureido]-phenoxy}- benzofuran-2-carbonsäure-amid, 1 -[4-(Benzo[1 ,3]dioxol-5-yloxy)-phenyl]-3-(2-fluor-5- trifluormethyl-phenyl)-harnstoff, 1-(2-Fluor-5-trifluormethyl-phenyl)-3-[4-(6-methoxy-pyridin-3- yloxy)-phenyl]-hamstoff, (5-{4-[3-(4-Fluor-3-trifluormethyl-phenyl)-ureido]-phenoxy}-1H- benzimidazol-2-yl)-carbaminsäure-methylester, 1 -[4-(Benzo[1 ,2,5]thiadiazol-5-yloxy)-phenyl]-3-(4-chlor-3- trifluormethyl-phenyl)-harnstoff, 1-(2-Fluor-5-trifluormethyl-phenyl)-3-[4-(imidazo[1,2-a]pyridin-8- yloxy)-phenyl]-hamstoff, 1-(2-Fluor-5-trifluormethyl-phenyl)-3-[4-(2-methyl-benzothiazol- 5-yloxy)-phenyl]-harnstoff, 1 -(2-Fluor-5-trifluormethyl-phenyl)-3-[4-(1 H-indol-6-yloxy)- phenylj-hamstoff, 1-(4-Chlor-3-trifluormethyl-phenyl)-3-[4-(imidazo[1 ,2-a]chinolin- 9-yloxy)-phenyl]-harnstoff, 1-(2-Fluor-5-trifluormethyl-phenyl)-3-[4-(imidazo[1 ,2-a]chinolin-4- {4- [3- (fluoro-trifluoromethyl-phenyl) -ureido] -phenoxy} -pyridine-2-carboxylic acid-methyl-methylamide, 1 - [4- (Benzo [1, 2.5] thiadiazole-5- yloxy) phenyl] -3- (2-fluoro-5-trifluoromethylphenyl) urea, 1- (2-fluoro-5-trifluoromethylphenyl) -3- [4- (pyridin-4-ylsulfanyl) phenylj urea, 1- [4- (2,3-dihydro-benzo [1,4] dioxin-6-yloxy) phenyl] -3- (2-fluoro-5-trifluoromethylphenyl) urea, 7- { 4- [3- (2-Fluoro-5-trifluoromethyl-phenyl) -ureido] phenoxy} - benzofuran-2-carboxylic acid amide, 1 - [4- (Benzo [1, 3] dioxol-5-yloxy) - phenyl] -3- (2-fluoro-5-trifluoromethylphenyl) urea, 1- (2-fluoro-5-trifluoromethylphenyl) -3- [4- (6-methoxy-pyridin-3-yloxy) - phenyl] urea, (5- {4- [3- (4-fluoro-3-trifluoromethyl-phenyl) -ureido] phenoxy} -1H-benzimidazol-2-yl) carbamic acid methyl ester, 1 - [4- (Benzo [1,2,5] thiadiazol-5-yloxy) phenyl] -3- (4-chloro-3-trifluoromethylphenyl) urea, 1- (2-fluoro-5-trifluoromethylphenyl) -3 - [4- (imidazo [1,2-a] pyridin-8-yloxy) phenyl] urea, 1- (2-fluoro-5-trifluoromethylphenyl) -3- [4- (2-methylbenzoth iazol- 5-yloxy) phenyl] urea, 1 - (2-fluoro-5-trifluoromethylphenyl) -3- [4- (1 H-indol-6-yloxy) phenylj-urea, 1- (4th Chloro-3-trifluoromethyl-phenyl) -3- [4- (imidazo [1, 2-a] quinolin-9-yloxy) phenyl] urea, 1- (2-fluoro-5-trifluoromethyl-phenyl) -3- [4- (imidazo [1, 2-a] quinoline-
9-yloxy)-phenyl]-harnstoff, 1 -(2-Fluor-5-trifluormethyl-phenyl)-3-[4-(1 H-indol-5-yloxy)- phenylj-hamstoff, 7-{4-[3-(2-Fluor-5-trifluormethyl-phenyl)-ureido]-phenoxy}- benzofuran-2-carbonsäure-methylester, 1 -[4-(Benzo[1 ,3]dioxol-5-yloxy)-phenyl]-3-(4-chlor-3- trifluormethyl-phenyl)-hamstoff, 1 -[4-(Benzo[1 ,2,5]thiadiazol-4-yloxy)-phenyl]-3-(2-fluor-5- trifluormethyl-phenyl)-hamstoff, 1-(4-Chlor-3-trifluormethyl-phenyl)-3-[4-(6-methoxy-pyridin-3- yloxy)-phenyl]-hamstoff, 1-[4-(lmidazo[1 ,2-a]chinolin-9-yloxy)-phenyl]-3-(4- trifluormethoxy-phenyl)-hamstoff, 1-[4-(Benzo[1 ,2,5]thiadiazol-5-yloxy)-3-methyl-phenyl]-3-(2-fluor- 5-trifluormethyl-phenyl)-hamstoff, 1 -[4-(Benzo[1 ,2,5]thiadiazol-5-yloxy)-3-methyl-phenyl]-3-(4- chlor-3-trifluormethyl-phenyl)-harnstoff, 1-[4-(Benzo[1 ,2,5]thiadiazol-5-yloxy)-2-methyl-phenyl]-3-(2-fluor- 5-trifluormethyl-phenyl)-hamstoff, 1 -[4-(Benzo[1 ,2,5]thiadiazol-5-yloxy)-2-methyl-phenyl]-3-(4- chlor-3-trifluormethyl-phenyl)-harnstoff, 1-[4-(Benzo[1,2,5]thiadiazol-5-yloxy)-3-fluor-phenyl]-3-(2-fluor-5- trifluormethyl-phenyl)-harnstoff, 1-[4-(2-Amino-benzothiadiazol-6-yloxy)-phenyi]-3-(2-fluor-5- trifluormethyl-ρhenyl)-hamstoff, 1-[4-(2-Amino-4,7-dimethyl-benzothiadiazol-6-yloxy)-phenyl]-3- (2-fluor-5-trifluormethyl-phenyl)-harnstoff, 4-{4-[3-(2-Fluor-4-trifluormethyl-phenyl)-ureido]-phenyIsulfanyl}- pyridin-2-carbonsäure-methylamid, sowie ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.9-yloxy) phenyl] urea, 1 - (2-fluoro-5-trifluoromethylphenyl) -3- [4- (1 H-indol-5-yloxy) phenylj urea, 7- {4- [ 3- (2-fluoro-5-trifluoromethyl-phenyl) -ureido] -phenoxy} - benzofuran-2-carboxylic acid methyl ester, 1 - [4- (benzo [1, 3] dioxol-5-yloxy) -phenyl] - 3- (4-chloro-3-trifluoromethylphenyl) urea, 1 - [4- (benzo [1, 2.5] thiadiazol-4-yloxy) phenyl] -3- (2-fluoro-5-trifluoromethyl -phenyl) urea, 1- (4-chloro-3-trifluoromethylphenyl) -3- [4- (6-methoxy-pyridin-3-yloxy) phenyl] urea, 1- [4- (imidazo [ 1,2-a] quinolin-9-yloxy) phenyl] -3- (4-trifluoromethoxy-phenyl) urea, 1- [4- (benzo [1,2,5] thiadiazol-5-yloxy) -3 -methyl-phenyl] -3- (2-fluoro-5-trifluoromethyl-phenyl) urea, 1 - [4- (benzo [1,2,5] thiadiazol-5-yloxy) -3-methyl-phenyl] - 3- (4-chloro-3-trifluoromethyl-phenyl) urea, 1- [4- (Benzo [1, 2,5] thiadiazol-5-yloxy) -2-methylphenyl] -3- (2-fluor - 5-trifluoromethyl-phenyl) urea, 1 - [4- (benzo [1,2,5] thiadiazol-5-yloxy) -2-methyl-phenyl] -3- (4-chloro-3-trifluoromethyl-phenyl ) urea, 1- [4- (benzo [1,2,5 ] thiadiazol-5-yloxy) -3-fluorophenyl] -3- (2-fluoro-5-trifluoromethylphenyl) urea, 1- [4- (2-amino-benzothiadiazol-6-yloxy) phenyi] -3- (2-fluoro-5-trifluoromethyl-ρhenyl) urea, 1- [4- (2-amino-4,7-dimethyl-benzothiadiazol-6-yloxy) phenyl] -3- (2-fluoro- 5-trifluoromethyl-phenyl) urea, 4- {4- [3- (2-fluoro-4-trifluoromethyl-phenyl) -ureido] -phenyIsulfanyl} - pyridine-2-carboxylic acid methylamide, as well as their pharmaceutically usable derivatives, salts, solvates and stereoisomers, including their mixtures in all ratios.
2. Arzneimittel, enthaltend mindestens eine Verbindung nach Anspruch 1 und/oder ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, sowie gegebenenfalls Träger- und/oder Hilfsstoffe.2. Medicament containing at least one compound according to claim 1 and / or its pharmaceutically usable derivatives, salts, solvates and stereoisomers, including their mixtures in all ratios, and, if appropriate, carriers and / or auxiliaries.
3. Verwendung von Verbindungen nach Anspruch 1 , sowie ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, bei denen die Hemmung, Regulierung und/oder Modulation der Signaltransduktion von Kinasen eine Rolle spielt.3. Use of compounds according to claim 1, and their pharmaceutically usable derivatives, salts, solvates and stereoisomers, including their mixtures in all ratios, for the manufacture of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of the signal transduction of Kinases plays a role.
4. Verwendung nach Anspruch 3, wobei die Kinasen ausgewählt sind aus der Gruppe der Tyrosinkinasen und Raf-Kinasen.4. Use according to claim 3, wherein the kinases are selected from the group of tyrosine kinases and Raf kinases.
5. Verwendung nach Anspruch 1 , wobei es sich bei den Tyrosinkinasen um TIE-2 handelt.5. Use according to claim 1, wherein the tyrosine kinases are TIE-2.
6. Verwendung nach Anspruch 4 von Verbindungen gemäß Anspruch 1 , sowie ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, die durch Inhibierung der Tyrosinkinasen durch die Verbindungen nach Anspruch 1 beeinflußt werden. 6. Use according to claim 4 of compounds according to claim 1, and their pharmaceutically acceptable derivatives, salts, solvates and stereoisomers, including their mixtures in all proportions, for the manufacture of a medicament for the treatment of diseases caused by the inhibition of tyrosine kinases by the compounds according to claim 1 can be influenced.
7. Verwendung nach Anspruch 6, zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, die durch Inhibierung von TIE-2 durch die Verbindungen nach Anspruch 1 beeinflußt werden.7. Use according to claim 6, for the manufacture of a medicament for the treatment of diseases which are influenced by inhibition of TIE-2 by the compounds according to claim 1.
8. Verwendung nach Anspruch 6 oder 7, wobei die zu behandelnde Krankheit ein fester Tumor ist.8. Use according to claim 6 or 7, wherein the disease to be treated is a solid tumor.
9. Verwendung nach Anspruch 8, wobei der feste Tumor aus der Gruppe Gehirntumor, Tumor des Urogenitaltrakts, Tumor des lymphatischen Systems, Magentumor, Kehlkopftumor und Lungentumor stammt.9. Use according to claim 8, wherein the solid tumor comes from the group of brain tumor, tumor of the genitourinary tract, tumor of the lymphatic system, stomach tumor, larynx tumor and lung tumor.
10. Verwendung nach Anspruch 8, wobei der feste Tumor aus der Gruppe Monozytenleukämie, Lungenadenokarzinom, kleinzellige Lungenkarzinome, Bauchspeicheldrüsenkrebs, Glioblastome und Brustkarzinom stammt.10. Use according to claim 8, wherein the solid tumor comes from the group monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma.
11. Verwendung nach Anspruch 6 oder 7 zur Behandlung einer Krankheit, an der Angiogenese beteiligt ist.11. Use according to claim 6 or 7 for the treatment of a disease in which angiogenesis is involved.
12. Verwendung nach Anspruch 11 , wobei es sich bei der Krankheit um eine Augenkrankheit handelt.12. Use according to claim 11, wherein the disease is an eye disease.
13. Verwendung nach Anspruch 6 oder 7 zur Behandlung von Retina- Vaskularisierung, diabetischer Retinopathie, altersbedingter Makula- Degeneration und/oder Entzündungskrankheiten.13. Use according to claim 6 or 7 for the treatment of retinal vascularization, diabetic retinopathy, age-related macular degeneration and / or inflammatory diseases.
14. Verwendung nach Anspruch 13, wobei die Entzündungskrankheit aus der Gruppe rheumatoide Arthritis, Schuppenflechte, Kontaktdermatitis und Spät-Typ der Überempfindlichkeitsreaktion stammt. 14. Use according to claim 13, wherein the inflammatory disease comes from the group rheumatoid arthritis, psoriasis, contact dermatitis and late-type of hypersensitivity reaction.
15. Verwendung nach Anspruch 6 oder 7 zur Behandlung von Knochen- Pathologien, wobei die Knochenpathologie aus der Gruppe Osteosarkom, Osteoarthritis und Rachitis stammt.15. Use according to claim 6 or 7 for the treatment of bone pathologies, wherein the bone pathology comes from the group osteosarcoma, osteoarthritis and rickets.
16. Arzneimittel enthaltend mindestens eine Verbindung gemäß Anspruch 1 und/oder ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und mindestens einen weiteren Arzneimittelwirkstoff.16. Medicament containing at least one compound according to claim 1 and / or its pharmaceutically usable derivatives, salts, solvates and stereoisomers, including their mixtures in all ratios, and at least one further active pharmaceutical ingredient.
17. Set (Kit), bestehend aus getrennten Packungen von (a) einer wirksamen Menge an einer Verbindung gemäß Anspruch 1 und/oder ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und (b) einer wirksamen Menge eines weiteren Arzneimittelswirkstoffs.17. Set (kit) consisting of separate packs of (a) an effective amount of a compound according to claim 1 and / or its pharmaceutically acceptable derivatives, salts, solvates and stereoisomers, including their mixtures in all ratios, and (b) one effective amount of another drug ingredient.
18. Verwendung von Verbindungen gemäß Anspruch 1 und/oder ihrer physiologisch unbedenklichen Salze und Solvate zur Herstellung eines Arzneimittels zur Behandlung von festen Tumoren, wobei eine therapeutisch wirksame Menge einer Verbindung nach Anspruch 1 in Kombination mit einer Verbindung aus der Gruppe 1) Östrogen- rezeptormodulator, 2) Androgenrezeptormodulator, 3) Retinoid- rezeptormodulator, 4) Zytotoxikum, 5) antiproliferatives Mittel, 6) Prenyl-Proteintransferasehemmer, 7) HMG-CoA-Reduktase- Hemmer, 8) HIV-Protease-Hemmer, 9) Reverse-Transkriptase- Hemmer sowie 10) weiterer Angiogenese-Hemmer verabreicht wird.18. Use of compounds according to claim 1 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment of solid tumors, wherein a therapeutically effective amount of a compound according to claim 1 in combination with a compound from group 1) estrogen receptor modulator , 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic, 5) antiproliferative agent, 6) prenyl protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8) HIV protease inhibitor, 9) reverse transcriptase inhibitor Inhibitor and 10) other angiogenesis inhibitor is administered.
19. Verwendung von Verbindungen nach Anspruch 1 und/oder ihrer physiologisch unbedenklichen Salze und Solvate zur Herstellung eines Arzneimittels zur Behandlung von festen Tumoren wobei eine therapeutisch wirksame Menge einer Verbindung nach Anspruch 1 in Kombination mit Radiotherapie und einer Verbindung aus der Gruppe 1) Östrogenrezeptormodulator, 2) Androgenrezeptormodulator, 3) Retinoidrezeptormodulator, 4) Zytotoxikum, 5) antiproliferatives Mittel, 6) Prenyl-Proteintransferasehemmer, 7) HMG-CoA-Reduktase- Hemmer, 8) HIV-Protease-Hemmer, 9) Reverse-Transkriptase- Hemmer sowie 10) weiterer Angiogenese-Hemmer verabreicht wird.19. Use of compounds according to claim 1 and / or their physiologically acceptable salts and solvates for the preparation of a medicament for the treatment of solid tumors, wherein a therapeutically effective amount of a compound according to claim 1 in combination with radiotherapy and a compound from the group 1) estrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5) antiproliferative agent, 6) Prenyl protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8) HIV protease inhibitor, 9) reverse transcriptase inhibitor and 10) other angiogenesis inhibitor.
20. Verwendung nach Anspruch 3, 4 oder 5, zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, die auf einer gestörten TIE-2-Aktivität beruhen, wobei eine therapeutisch wirksame Menge einer Verbindung nach Anspruch 1 in Kombination mit einem Wachstumsfaktorrezeptor- Hemmer verabreicht wird.20. Use according to claim 3, 4 or 5 for the manufacture of a medicament for the treatment of diseases which are based on impaired TIE-2 activity, a therapeutically effective amount of a compound according to claim 1 being administered in combination with a growth factor receptor inhibitor ,
21. Verwendung nach Anspruch 3 oder 4 von Verbindungen gemäß Anspruch 1 , sowie ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, die durch Raf-Kinasen verursacht, vermittelt und/oder propagiert werden.21. Use according to claim 3 or 4 of compounds according to claim 1, and their pharmaceutically usable derivatives, salts, solvates and stereoisomers, including their mixtures in all proportions, for the manufacture of a medicament for the treatment of diseases caused by Raf kinases mediated and / or propagated.
22. Verwendung nach Anspruch 21 , wobei die Raf-Kinase aus der Gruppe bestehend aus A-Raf, B-Raf und Raf-1 ausgewählt wird.22. Use according to claim 21, wherein the Raf kinase is selected from the group consisting of A-Raf, B-Raf and Raf-1.
23. Verwendung nach Anspruch 21 , wobei die Erkrankungen ausgewählt sind aus der Gruppe der hyperproliferativen und nicht hyperproliferativen Erkrankungen. 23. Use according to claim 21, wherein the diseases are selected from the group of hyperproliferative and non-hyperproliferative diseases.
24. Verwendung nach Anspruch 21 oder 23, wobei die Erkrankung Krebs ist.24. Use according to claim 21 or 23, wherein the disease is cancer.
25. Verwendung nach Anspruch 21 oder 23, wobei die Erkrankung nicht krebsartig ist.25. Use according to claim 21 or 23, wherein the disease is not cancerous.
26. Verwendung nach Anspruch 21 , 23 oder 25, wobei die nicht krebsartigen Erkrankungen ausgewählt sind aus der Gruppe bestehend aus Psoriasis, Arthritis, Entzündungen, Endometriose, Vernarbung, gutartiger Prostatahyperplasie, immunologischer Krankheiten, Autoimmunkrankheiten und Immunschwächekrankheiten.26. Use according to claim 21, 23 or 25, wherein the non-cancerous diseases are selected from the group consisting of psoriasis, arthritis, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and immunodeficiency diseases.
27. Verwendung nach einem der Ansprüche 21 , 23 oder 24, wobei die Erkrankungen ausgewählt sind aus der Gruppe bestehend aus Hirnkrebs, Lungenkrebs, Plattenepithelkrebs, Blasenkrebs, Magenkrebs, Pankreaskrebs, Leberkrebs, Nierenkrebs, Kolo- rektalkrebs, Brustkrebs, Kopfkrebs, Halskrebs, Ösophaguskrebs, gynäkologischem Krebs, Schilddrüsenkrebs, Lymphom, chronischer Leukämie und akuter Leukämie. 27. Use according to any one of claims 21, 23 or 24, wherein the diseases are selected from the group consisting of brain cancer, lung cancer, squamous cell cancer, bladder cancer, stomach cancer, pancreatic cancer, liver cancer, kidney cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophagus cancer , gynecological cancer, thyroid cancer, lymphoma, chronic leukemia and acute leukemia.
EP04763077A 2003-07-30 2004-07-02 Urea derivatives and their use as tyrosinkinase inhibitors Withdrawn EP1651626A1 (en)

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