DE10335782A1 - Chromenonderivate - Google Patents

Abstract

New compounds of formula I, DOLLAR F1 wherein DOLLAR AR · 1 ·, R · 2 ·, R · 3 · and Het have the meaning given in claim 1, DOLLAR A are inhibitors of tyrosine kinases and / or Raf kinases and can be used for treatment of tumors, for neuroprotection and to protect the skin's stress proteins.

Description

The Invention was based on the task of creating new compounds with valuable Find properties, especially those that are used to manufacture of drugs can be used.

The The present invention relates to compounds in which the inhibition, Regulation and / or modulation of signal transduction of kinases, especially the tyrosine kinases and Raf kinases, pharmaceutical compositions containing these compounds included, as well as the use of the compounds for treatment of kinase-related diseases.

in the In particular, the present invention relates to compounds that Inhibit, regulate and / or signal transduction of tyrosine kinases modulate, compositions containing these compounds, as well Methods of their use in the treatment of tyrosine kinase-related Diseases and conditions such as cancer, tumor growth, arteriosclerosis, age-related macular degeneration, diabetic retinopathy, inflammatory diseases and the like in mammals. Tyrosine kinases are a class of enzymes the the transfer the terminal Phosphate of adenosine triphosphate on tyrosine residues in protein substrates catalyze. The tyrosine kinases are thought to be present in various Cell functions over substrate phosphorylation plays an essential role in signal transduction due. Although the exact mechanisms of signal transduction are still are unclear, the tyrosine kinases have been shown to be important factors in cell proliferation, carcinogenesis and cell differentiation represent.

The Tyrosine kinases can be broken down into receptor tyrosine kinases and cytosolic Classify tyrosine kinases. The receptor tyrosine kinases have one extracellular Part, a transmembrane part and an intracellular part on while the cytosolic tyrosine kinases are only present intracellularly.

The Receptor tyrosine kinases consist of a variety of transmembrane receptors with different biological effectiveness. So about 20 different ones Subfamilies of receptor tyrosine kinases identified. A tyrosine kinase subfamily, which is called the HER subfamily consists of EGFR, HER2, HER3 and HER4. The ligands of this receptor subfamily include the Epithelial growth factor, TGF-α, Amphiregulin, HB-EGF, Betacellulin and Heregulin. The insulin subfamily, which include INS-R, IGF-IR and IR-R, represents another subfamily of these receptor tyrosine kinases The PDGF subfamily includes the PDGF-α- and -β receptor, CSFIR, c-kit and FLK-II. Moreover there is the FLK family that comes from 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 (flt-1). The PDGF and FLK family are common due to the similarities between the two groups discussed together. For one for a detailed discussion of receptor tyrosine kinases, see the work of Plowman et al., DN & P 7 (6): 334-339, 1994, which is hereby incorporated by reference.

The Cytosolic tyrosine kinases also consist of a variety of subfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further in different receptors divided. For example, the Src subfamily one of the largest subfamilies It includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Src enzyme subfamily has been linked to oncogenesis brought. For 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 is made.

Either the receptor tyrosine kinases as well as the cytosolic tyrosine kinases are on signal transmission paths the cell that leads to various conditions, including cancer, psoriasis and hyperimmune responses.

It it has been suggested that various receptor tyrosine kinases as well the growth factors that bind them play a role in angiogenesis play, although some may indirectly promote angiogenesis (Mustonen and Alitalo, J. Cell Biol. 129: 895-898, 1995). One of these receptor tyrosine kinases is the fetal Liver kinase 1, also called FLK-1. The human analog of the FLK-1 is the kinase insert domain containing Receptor KDR, also called vascular endothelial cell growth factor receptor 2 or VEGFR-2 is known because it binds VEGF with high affinity. Finally was the mouse version of this receptor is also called NYK (Oelrichs et al., Oncogene 8 (1): 11-15, 1993). VEGF and KDR represent a ligand-receptor pair, the one essential role in the proliferation of vascular endothelial cells and formation and blood vessel sprout that called vasculogenesis or angiogenesis, plays.

Angiogenesis is due to excessive vascular endothelial growth factor activity (VEGF) marked. VEGF actually consists of a family of ligands (Klagsburn and D'Amore, Cytokine & Growth Factor Reviews 7: 259-270, 1996). VEGF binds the high affinity transmembrane tyrosine kinase receptor KDR and the related fms tyrosine kinase-1, also known as Flt-1 or vascular endothelial cell growth factor receptor 1 (VEGFR-1). 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 appears to modulate non-mitogenic functions, such as those related to cell adhesion. Inhibition of the KDR therefore modulates the level of mitogenic VEGF activity. In fact, it has been shown that tumor growth is affected by the antiangiogenic effects of VEGF receptor antagonists (Kim et al., Nature 362, pp. 841-844, 1993).

firm Tumors can therefore be treated with tyrosine inhibitors as these tumors are essential for the formation of for support required for their growth to depend on angiogenesis are. These solid tumors include monocyte leukemia, Brain, urogenital, lymphatic, gastric, larynx and lung carcinoma, including lung adenocarcinoma and small cell lung carcinoma. To count other examples Carcinomas with overexpression or activation of Raf activating oncogenes (e.g. K-ras, erb-B) is observed. These cancers include pancreatic and Breast carcinoma. Inhibitors of these tyrosine kinases are therefore suitable for the prevention and treatment of proliferative diseases which are caused by these enzymes.

The 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 pO ₂ levels in the mouse, which lead to neovascularization. Intraocularly injected monoclonal anti-VEGF antibodies, or VEGF receptor immunoconjugates, inhibit vascularization in the eye in both the primate and rodent models. Regardless of the reason for the induction of VEGF in diabetic retinopathy in humans, the inhibition of eye VEGF is suitable for the treatment of this disease.

The VEGF expression is also found in hypoxic regions of animal and human tumors next to necrosis zones greatly increased. The VEGF will also by expression of the oncogenes ras, raf, src and p53 mutant (all in fighting of cancer are important). Inhibit anti-VEGF monoclonal antibodies the growth of human tumors in the nude mouse. Although the same tumor cells the antibodies continue to express VEGF in culture, the antibodies decrease theirs Cell division rate not. This is how VEGF comes from tumors not as an autocrine mitogenic factor. The VEGF therefore bears contributes to tumor growth in vivo by its paracrine Vascular endothelial cell chemotactic and mitogenesis activity promotes angiogenesis. These monoclonal antibodies also inhibit the growth of typically less vascularized ones Human colon carcinomas in thymusless mice and reduce the number of tumors arising from inoculated cells.

The Expression of a VEGF-binding construct of Flk-1, Flt-1, the to remove the cytoplasmic tyrosine kinase domains, however while maintaining a membrane anchor, shortened mouse KDR receptor homolog, in viruses practically 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 are usually in the form of solid in the nude mouse Tumors grow, do not form any knock-out of both VEGF alleles detectable tumors. The role comes from this data together of the VEGF in the growth of solid tumors. The inhibition of KDR or Flt-1 is involved in pathological angiogenesis, and these receptors are useful for treating diseases, where angiogenesis is part of the total pathology, e.g. Inflammation, diabetic Retinal vascularisation as well as various forms of cancer, since it is known that tumor growth depends on angiogenesis (Weidner et al., N. Engl. J. Med., 324, pp. 1-8, 1991).

The The present invention further relates to the compounds as inhibitors by 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 propagated through a cascade of protein phosphorylation and dephosphorylation events, eg in the p21 ^ras / raf pathway.

The p21 ^ras 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. Sci., 19, 279-83).

biochemical Ras is a guanine nucleotide binding protein, and cycling between a GTP-linked activated and a GDP-linked dormant Form is from Ras endogenous GTPase activity and other regulatory proteins strictly controlled. The Ras gene product binds to guanine triphosphate (GTP) and guanine diphosphate (GDP) and hydrolyzed GTP to GDP. Ras is active in the GTP-bound state. In the Ras mutants in cancer cells is the endogenous GTPase activity attenuated and consequently the protein gives constitutive growth signals to "downstream" effectors such as for example to the enzyme Raf Kinase.

This leads to cancerous growth of the cells that carry these mutants (Magnuson et al. (1994) Semin. Cancer Biol., 5, 247-53). The Ras Proto Oncogene needed a functionally intact C-Raf-1 proto-oncogene, which is used in higher eukaryotes by receptor and non-receptor tyrosine kinases to transduce initiated growth and differentiation signals.

activated Ras is for activation of the C-Raf-1 proto-oncogene necessary, the biochemical steps, through the Ras the Raf-1 protein (Ser / Thr) kinase activated, but are now well characterized. It was demonstrated that inhibiting the effect of active Ras by inhibition the Raf kinase pathway by administering deactivators antibodies against Raf kinase or by means of co-expression of more dominant negative ones Raf kinase or dominant negative MEK (MAPKK), the substrate of the Raf kinase, which leads to the reversion of transformed cells to the normal growth phenotype, see: Daum et al. (1994) Trends Biochem. Sci., 19, 474-80; Fridman et al. (1994) J Biol. Chem., 269, 30105-8. Kolch et al. (1991) Nature, 349, 426-28) and for discussion Weinstein-Oppenheimer et al. Pharm. & Therap. (2000), 88, 229-279.

Similar ones Inhibition of Raf kinase (by antisense oligodeoxynucleotides) in vitro and in vivo with the inhibition of the growth of a number different human tumor types have been related (Monia et al., Nat. Med. 1996, 2, 668-75).

Raf serine and threonine-specific protein kinases are cytosolic enzymes, that stimulate cell growth in a number of different cell systems (Rapp, U.R., et al. (1988) in The Oncogene Handbook; T. Curran, E.P. Reddy and A. Skalka (ed.) Elsevier Science Publishers; Netherlands, Pp. 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 and Melchers (ed.), Berlin, Springer-Verlag 166: 129-139).

Three isozymes have been characterized:
C-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 cells if they are expressed in specifically modified forms. Genetic changes that lead to oncogenic activation produce a constitutively active protein kinase by removal or interference with an N-terminal negative regulatory domain of the protein (Heidecker, G., et al. (1990) Mol. Cell. Biol. 10: 2503-2512 ; Rapp, UR, et al. (1987) in Oncogenes and Cancer; SA Aaronson, J. Bishop, T. Sugimura, M. Terada, K. Toyoshima and PK: 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 expression vectors from Escherichia coli 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: 3828-3833).

consequently 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, since Raf oncogenes face the growth arrest resulting from a blockade cellular Ras activity due to a cellular Mutation (Ras revertant cells) or microinjection of anti-Ras antibodies results (Rapp, U.R., et al. (1988) in The Oncogene Handbook, T. Curran, E.P. Reddy and A. Skalka (ed.), Elsevier Science Publishers; Netherlands, S. 213-253; Smith, M.R., et al. (1986) Nature (London) 320: 540-543).

The C-Raf function is for transformation through a number of different membrane-bound oncogenes and for growth stimulation by mitogens contained in sera is required (Smith, M.R., et al. (1986) Nature (London) 320: 540-543). Raf-1 protein serine kinase activity is characterized by Mitogens over regulates phosphorylation (Morrison, D.K., et al. (1989) Cell 58: 648-657) which is also the subcellular Distribution causes (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. To Raf-1 activating growth factors include those from platelets Growth factor (PDGF) (Morrison, D.K., et al. (1988) Proc. Natl. Acad. Sci. USA 85: 8855-8859) Colony stimulating factor (Baccarini, M., et al. (1990) EMBO J. 9: 3649-3657), Insulin (Blackshear, P.J., et al. (1990) J. Biol. Chem. 265: 12115-12118), the epidermal growth factor (EGF) (Morrison, R.K., et al. (1988) Proc. Natl. Acad. Sci. USA 85: 8855-8859), Interleukin-2 (Turner, B.C., et al. (1991) Proc. Natl. Acad. Sci. USA 88: 1227) and Interleukin-3 and the granulocyte macrophage colony stimulating factor (Carroll, M.P., et al. (1990) J. Biol. Chem. 265: 19812-19817).

To the mitogen treatment of cells translocates the transiently activated Raf-1 protein serine kinase in the perinuclear area and the 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). cells, that contain activated Raf are in their gene expression pattern changed (Heidecker, G., et al. (1989) in Genes and signal transduction in multistage carcinogenesis, N. Colburn (ed.), Marcel Dekker, Inc., New York, Pp. 339–374) and Raf-oncogenes activate transcription from Ap-I / PEA3-dependent promotors in transient transfection assays (Jamal, S., et al. (1990) Science 344: 463-466; Kaibuchi, K., et al. (1989) J. Biol. Chem. 264: 20855-20858; Wasylyk, C., et al. (1989) Mol. Cell. Biol. 9: 2247-2250).

It are at least two independent Ways for Raf-1 activation by extracellular mitogens: one, the protein kinase C (KC) includes, and a second, by protein tyrosine kinases is initiated (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. Sci. USA 85: 8855-8859; Seal, J.N., et al. (1990) J. Biol. Chem. 265: 18472-18480; Turner, B.C., et al. (1991) Proc. Natl. Acad. Sci. USA 88: 1227). In any case included activation of Raf-1 protein phosphorylation. Raf-1 phosphorylation can be a consequence of a kinase cascade that is amplified by autophosphorylation, or may be complete caused by autophosphorylation by binding of a putative activation ligand to the Raf-1 regulator domain, analogously for PKC activation is initiated by diacylglycerol (Nishizuka, Y. (1986) Science 233: 305-312).

one the main mechanisms by which cell regulation is effected is through the transduction of the extracellular signals over the Membrane, which in turn modulate biochemical pathways in the cell. Protein Phosphorylation represents a process about the intracellular Signals from molecule to molecule what will eventually be propagated results in a cell response. These signal transduction cascades are highly regulated and overlap frequently, as from the presence of many protein kinases as well as phosphatases evident. Phosphorylation of proteins mainly occurs Serine, threonine or tyrosine residues, and protein kinases therefore according to their specificity the phosphorylation site, d. H. the serine / threonine kinases and tyrosine kinases classified. Because phosphorylation is so widespread Process in cells is and because cell phenotypes largely depend on the activity of these Ways are influenced, it is currently believed that a number of disease states and / or diseases on either deviating activation or functional mutations in the molecular components of kinase cascades are due. consequently has been characterizing these proteins and compounds that to modulate their activity are able paid considerable attention (review article: Weinstein-Oppenheimer et al. Pharma. &. Therap., 2000, 88, 229-279).

The protein kinase PKB (also known as AKT and RAC-PK) is a member of the AKT / PKB family of serine / threonine kinases and has been shown to be involved in a variety of signaling pathways in human malignancy ( Nicholson et al., Cell. Signal., 2002, 14, 381-395). PKB, like other Mit members of the AKT / PKB family, is localized in the cytosol of non-stimulated cells and translocates to the cell membrane after stimulation. PKB translocation can be activated by several ligands, including platelet-derived growth factor, epidermal growth factor, basic fibroblast growth factor, cell stress such as heat shock and hyperosmolarity and also insulin (Bos, Trends Biochem. Sci., 1995, 20, 441-442), and other studies have shown that this activation occurs via PI3 kinase, which is Wortmannin sensitive (Franke et al., Science, 1997, 275, 665-668). Once PKB is located on the plasma membrane, it has been shown to mediate several functions in the cell, including apoptosis, the metabolic effects of insulin, induction of differentiation and / or proliferation, protein synthesis and stress responses (Alessi and Cohen, Curr. Opin. Genet Dev., 1998, 8, 55-62; Downward, Curr. Opin. Cell Biol., 1998, 10, 262-267).

PKB was independently cloned in 1991 from three groups (Bellacosa et al., Science, 1991, 254, 274-277; Coffer and Woodgett, Eur. J. Biochem., 1991, 201, 475-481; Jones et al., Cell Regul ., 1991, 2, 1001-1009), however, their association with primary human gastric carcinoma was recognized as early as 1987 (Staal et al., Proc. Natl. Acad. Sci. USA, 1987, 84, 5034-5037). Sequencing of PKBα revealed homology to the PKA (approx. 68%) and PKC isozymes (approx. 73%) in the kinase domains (Jones et al., Proc. Natl. Acad. Sci. USA, 1991, 88, 4171 –5), a fact that led to it being renamed PKB. There are three cellular PKB isoforms and two splice variants (PKBα, β, γ, β ₁ , γ ₁ ; Brazil et al. Trends in Bio Sci, 2001, 26, 657–663). PKBα has been found to be amplified or overexpressed in gastric adenocarcinomas and a breast cancer cell line (Staal et al., Proc. Natl. Acad. Sci. USA, 1987, 84, 5034-7; Jones et al., Cell Regul., 1991, 2, 1001-9). PKBβ is found in 3% of the breast (Bellacosa et al., Int. J. Cancer, 1995 64, 280-5), 12% of the pancreas (Cheng et al., Proc. Natl. Acad. Sci. USA, 1996 , 93, 3636-41) and 15% of ovarian cancer amplified or overexpressed (Bellacosa et al., Int. J. Cancer, 1995, 64, 280-5; Cheng et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 9267-71).

PKBγ is at Estrogen receptor-deficient breast cancer and overexpressed in androgen-independent prostate cell lines (Nakatani et al., J. Biol. Chem. 1999, 274, 21528-32).

It it has been suggested that PKB is involved in the chromosomal rearrangement gene involved in chromosome band 14q32. From this locus is known to treat human T cell malignancies, such as prolymphocytic leukemia and leukaemias mixed race children are subject to reorganization (state et al., Genomics, 1988, 2, 96-98).

PKB also plays a role in preventing "programmed cell death" or apoptosis inhibitory phosphorylation of ASK-1, Bad, Caspase9 and FKHR (Overview see Nicholson et al., Cell Signaling 2001, 14, 281-395). It it was demonstrated that PKB is a survival signal (overview see Lawlor et al., J. of Cell Science 2001, 114, 2903-2910) for cells supplies to them in front of a number of agents, including UV radiation (Dudek et al., Science, 1997, 275, 661-665), withdrawal of IGF1 from neuronal cells, detachment from the extracellular Protect matrix, stress and heat shock (Alessi and Cohen, Curr. Opin. Genet. Dev., 1998, 8, 55-62).

The dual-specific phosphatase PTEN (Phosphatase and Tensin homologue deleted on Chromosome Ten [Phosphatase and Tensin homologue deleted on chromosome ten]) increases the Ptdlns (3, 4, 5) P ₃ level in the cell by dephosphorylation of Ptdlns (3, 4, 5) P ₃ . Ptdlns (3, 4, 5) P ₃ binds to the PH domain (pleckstrin homology domain) of PKB. This binding represents an essential step for membrane translocation and activation of PKB. PTEN is a tumor suppressor gene mutated in a large fraction of glioblastoma and melanoma cell lines, advanced prostate carcinomas and endometrial carcinomas. It is also deleted in> 80% of patients with inherited conditions such as Cowden syndrome, Lhermitte-Duclos syndrome and Bannayan-Zonana syndrome. Patients have several similar characteristics, including multiple benign tumors (harmatomas) and an increased susceptibility to breast and thyroid malignancies (Di Cristofano et al. Cell, 2000, 100, 387-390).

Il lines derived from heterozygous PTEN ^+/- mice (heterozygous PTEN ^{- / -} mice are not viable) have elevated Ptdlns (3, 4, 5) P ₃ levels, which are associated with increased PKB activity, with a reduced sensitivity against apoptosis (Di Christofano et al. Nat. Genet. 1998, 19, 348-355; Stambolic et al., Cell, 1998, 95, 29-39, Myers et al., Proc. Natl. Acad. Si. USA , 1998, 96 13513-13518).

PKB is also used to promote cell cycle progression through inhibition of the p21 cell cycle inhibitor (Zhou et al .; Nat. Cell Biol., 2002, 3, 245-252).

This Findings the over-experiment from PKB declare which is observed in cancer cells, the preferential survival and carcinoma proliferation by preventing normal progression for apoptosis.

to There are currently no known therapeutic agents that are effective for PKB activity inhibit. Consequently, there is still a long-felt one Need for additional Agents that act as chemotherapeutic agents for the effective inhibition of PKB function to activate proapoptotic proteins capable of all types of cancer are.

The Identification of small connections that signal transduction that specifically inhibit, regulate tyrosine kinases and / or Raf kinases and / or modulate is therefore desirable and an object of the present invention.

It it was found that the Compounds of formula I and their salts with good tolerance possess very valuable pharmacological properties.

In particular, they show inhibitory properties of tyrosine kinase. It has furthermore been found that the compounds of the formula I, which are generally described as chromenone derivatives, 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 prove to be useful when inhibiting the Raf kinase pathway, for example in the treatment of tumors and / or by Raf kinase mediated cancerous cell growth, the compounds are particularly useful in the treatment of solid carcinomas in humans and animals, for example murine cancer, since the progression of these cancers is dependent on the Ras protein signal transduction cascade and therefore on the treatment by Disruption of the cascade, ie inhibition of Raf kinase, responds accordingly the compound of formula I or a pharmaceutically acceptable salt thereof is administered for the treatment of diseases mediated by the Raf kinase route, particularly cancer, including solid ones Carcinomas, such as carcinomas (e.g. of the lungs, pancreas, thyroid, bladder or colon), myeloid diseases (e.g. myeloid leukemia) or adenomas (e.g. villous colon adenoma), pathological angiogenesis and metastatic cell migration. The compounds are also useful in the treatment of complement activation dependent chronic inflammation (Niculescu et al. (2002) Immunol. Res., 24: 191-199) and immunodeficiency induced by HIV-1 (Human Immunodeficiency Virus Type 1) (Popik et al. (1998) J Virol, 72: 6406-6413).

It has surprisingly been found that compounds according to the invention can interact with signaling pathways, in particular with the signaling pathways described herein and preferably the Raf kinase signaling pathway. Chromenon derivatives according to the invention preferably exhibit an advantageous biological activity which is easily detectable in enzyme-based assays, for example assays as described herein. In such enzyme-based assays, chromenon derivatives according to the invention preferably show and bring about an inhibitory effect which is usually documented by IC ₅₀ values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range.

How Discussed herein are these signaling pathways for various diseases relevant. Accordingly, chromenone derivatives are useful in the prophylaxis and / or treatment of diseases caused by the mentioned signaling paths through interaction with one or more of the signal paths mentioned are dependent.

object The present invention is therefore compounds according to the invention as promoters or inhibitors, preferably as inhibitors of the herein described signal paths. Preferred subject of the invention are therefore compounds according to the invention as promoters or inhibitors, preferably as inhibitors of the Raf kinase pathway. Derivatives according to the invention are therefore a more preferred subject matter of 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 a or more Raf kinases selected from the group consisting of from A-Raf, B-Raf and C-Raf-1. A particularly preferred item 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 ins special diseases which are caused and mediated by Raf kinases selected from the group consisting of A-Raf, B-Raf and C-Raf-1. 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 immunodeficiency diseases are considered non-cancerous diseases, of which arthritis, inflammation, immunological diseases, autoimmune diseases and immunodeficiency diseases are usually regarded as non-hyperproliferative diseases. 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 and all types of cancer, all of which are considered to be cancerous, all of which are cancerous and acute leukemia can be considered as 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 medicaments and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of the diseases mentioned and the use of compounds according to the invention for the production of a pharmaceutical for the treatment and / or prophylaxis of the diseases mentioned and also a method for treatment of said diseases comprising the administration of one or more compounds according to the invention to a patient in need of such an administration.

In A comparative measurement was also found that the compounds of formula I act as PKB inhibitors. This effect can Example can be demonstrated by a method by Alessi et al. EMBO L. 1996, 15, 6541-6551 is described.

It can be shown that the compounds according to the invention are antiproliferative in vivo Have effect. The compounds of the invention are administered to a patient with hyperproliferative disease, e.g. to inhibit tumor growth, to reduce the with an inflammation associated with lymphoproliferative disease, Inhibition of 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 "treat" is used as a reference both on disease prevention as well as pre-existing treatment Suffering used. The prevention of proliferation is through Administration of the compounds according to the invention before development of the evident disease, e.g. to prevent the Tumor growth, prevention of metastatic growth, reduction of with cardiovascular Surgery associated restenosis, etc. achieved. As alternative are the compounds for the treatment of ongoing diseases Stabilization or improvement of the patient's clinical symptoms used.

The The host or patient can belong to any mammalian species, e.g. a primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. animal models are for experimental studies of interest, being a model to treat a human disease.

The susceptibility facing a particular cell treatment with the compounds according to the invention can be carried out by In vitro testing can be determined. Typically a culture the cell with a compound according to the invention at different Concentrations for combined a period of time sufficient for the active funds to allow To induce cell death or to inhibit migration, usually between approximately an hour and a week. For in vitro testing, cultured Cells from a biopsy sample can be used. The after treatment remaining viable Cells are then counted.

The Dose varies depending the specific compound used, the specific disease, patient status etc. Typically therapeutic Dose sufficient to make the unwanted Significantly reduce cell population in target tissue; while the viability of the patient is maintained. Treatment is general continued until there is a significant reduction, e.g. at least Approx. 50% reduction in cell load and can be continued until essentially no unwanted Cells more in the body be detected.

Various 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 FIashPlate 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 assays use specific phospho-antibodies (phospho-AK). The phospho-AK only binds the phosphorylated substrate. This bond is through with a second peroxidase conjugated anti-sheep antibody Chemiluminescence detectable (Ross et al., 2002, Biochem. J., immediately before publication, Manuscript BJ20020786).

It are many with a deregulation of cell proliferation and Cell death (apoptosis) associated diseases. The sufferings of interest conclude the following ailments, but are not limited to them. The compounds of the invention are useful in the treatment of a number of different conditions in which proliferation and / or smooth muscle cell and / or inflammatory cell migration in the intimal layer of a vessel, resulting in restricted Blood flow to this vessel, e.g. in neointimal occlusive lesions. On occlusive graft vascular diseases count of interest Atherosclerosis, coronary artery disease after transplantation, vein graft stenosis, peri-anastomotic prosthesis restenosis, Restenosis after angioplasty or stent placement and the like.

The compounds of the invention are also suitable as food additives, for the treatment of diseases and / or Malfunctions characterized by oxidative stress conditions, as well as food additives, also in cosmetic formulations as a sunscreen.

STATE OF TECHNOLOGY

In WO 92/20642 are bis-mono- and bicyclic aryl and heteroaryl compounds described that can inhibit tyrosine kinase. Chromenone derivatives are not revealed.

Chromenone derivatives as components of photographic materials are known from patent no. JP 07191431 (Registration no. JP 0347126 ). The present compounds of the generic formula I are to be regarded as selection inventions in relation to the prior art mentioned.

Fluorine-containing heteroaryl flavonoids with fungicidal activity are known from Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (1987), 26B (5), 493-5. Chromenone derivatives are listed below, which are described in the literature but not in the context of tyrosine kinase inhibition:
CAS RN 477545-79-2
1 - [(4-oxo-4H-1-benzopyran-2-yl) carbonyl] -4-phenyl-piperazine;
CAS RN 476298-55-2
1 - [(4-oxo-4H-1-benzopyran-2-yl) carbonyl] -3,5-dimethyl-piperidine;
CAS RN 380469-63-6
10 - [(4-oxo-4H-1-benzopyran-2-yl) carbonyl] phenothiazine;
CAS RN 380328-67-6
1 - [(4-oxo-4H-1-benzopyran-2-yl) carbonyl] -4-piperidine-carboxylate;
CAS RN 361166-59-8
1 - [(4-oxo-4H-1-benzopyran-2-yl) carbonyl] -1-H-indole;
CAS RN 361166-57-6
1,2,3,4-tetrahydro-2 - [(4-oxo-4H-1-benzopyran-2-yl) carbonyl] isoquinoline;
CAS RN 361166-50-9
1,2,3,4-tetrahydro-2 - [(4-oxo-4H-1-benzopyran-2-yl) carbonyl] quinoline;
CAS RN 361166-57-6
4 - [(6-bromo-4-oxo-4H-1-benzopyran-2-yl) carbonyl] morpholine;
CAS RN 352667-41-5
4 - [(6-chloro-4-oxo-4H-1-benzopyran-2-yl) carbonyl] morpholine;
CAS RN 352667-39-1
1 - [(6-bromo-4-oxo-4H-1-benzopyran-2-yl) carbonyl] -pyrrolidine;
CAS RN 352667-38-0
1 - [(6-bromo-4-oxo-4H-1-benzopyran-2-yl) carbonyl] -piperidine;
CAS RN 113734-98-8
2 - [(8-bromo-6-fluoro-4-oxo-4H-1-benzopyran-2-yl) carbonyl] thiophene.

SUMMARY OF THE INVENTION

worin
R¹ -OH, -OA, Phenoxy, Ar, -O-CO-A, SO₃H, SO₃A, -OSO₃H, -OSO₃A, -OSO₂A, SO₂A, COOH, COOA, CONH₂, NHSO₂A, COA, CHO oder SO₂NH₂,
R² H, -OH, -OA, Phenoxy, Ar, -O-CO-A, SO₃H, SO₃A, -OSO₃H, -OSO₃A, -OSO₂A, SO₂A, Hal, COOH, COOA, CONH₂, NHSO₂A, COA, CHO oder SO₂NH₂,
R³ H, -OH, -OA, Phenoxy, Ar, -O-CO-A, SO₃H, SO₃A, -OSO₃H, -OSO₃A, -OSO₂A, SO₂A, Hal, COOH, COOA, CONH₂, NHSO₂A, COA, CHO oder SO₂NH₂,
R¹ und R² zusammen auch Methylendioxy oder Ethylendioxy,
Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-, O- und/oder S-Atomen, der unsubstituiert oder ein-, zwei- oder dreifach durch Carbonylsauerstoff, =S, =NH, Hal, A, -(CH₂)_o-Ar, -(CH₂)_o-Cycloalkyl, -(CH₂)_o-OH, -(CH₂)_o-NH₂, NO₂, CN, -(CH₂)_o-COOH, -(CH₂)_o-COOA, -(CH₂)_o-CONH₂, -(CH₂)_o-NHCOA, NHCONH₂, -(CH₂)_o-NHSO₂A, CHO, COA', SO₂NH₂ und/oder S(O)_oA substituiert sein kann,
Ar unsubstituiertes oder ein-, zwei- oder dreifach durch Hal, A, OH, OA, NH₂, NO₂, CN, COOH, COOA, CONH₂, NHCOA, NHCONH₂, NHSO₂A, CHO, COA, SO₂NH₂ oder S(O)_oA substituiertes Phenyl, Naphthyl oder Biphenyl,
A unverzweigtes oder verzweigtes Alkyl mit 1-10 C-Atomen, wobei 1-7 H-Atome durch F ersetzt sein können,
A' Alkyl mit 1 bis 6 C-Atomen oder Benzyl,
Hal F, Cl, Br oder I,
o 0, 1 oder 2,
bedeuten,
sowie ihre pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.The invention relates to compounds of the formula I.

wherein
R ¹ -OH, -OA, phenoxy, Ar, -O-CO-A, SO ₃ H, SO ₃ A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A, SO ₂ A, COOH, COOA, CONH ₂ , NHSO ₂ A, COA, CHO or SO ₂ NH ₂ ,
R ² H, -OH, -OA, phenoxy, Ar, -O-CO-A, SO ₃ H, SO ₃ A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A, SO ₂ A, Hal, COOH, COOA, CONH ₂ , NHSO ₂ A, COA, CHO or SO ₂ NH ₂ ,
R ³ H, -OH, -OA, phenoxy, Ar, -O-CO-A, SO ₃ H, SO ₃ A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A, SO ₂ A, Hal, COOH, COOA, CONH ₂ , NHSO ₂ A, COA, CHO or SO ₂ NH ₂ ,
R ¹ and R ² together also methylenedioxy or ethylenedioxy,
Het a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen, = S, = NH, Hal, A , - (CH ₂ ) _o -Ar, - (CH ₂ ) _o -cycloalkyl, - (CH ₂ ) _o -OH, - (CH ₂ ) _o -NH ₂ , NO ₂ , CN, - (CH ₂ ) _o - COOH, - (CH ₂ ) _o -COOA, - (CH ₂ ) _o -CONH ₂ , - (CH ₂ ) _o -NHCOA, NHCONH ₂ , - (CH ₂ ) _o -NHSO ₂ A, CHO, COA ', SO ₂ NH ₂ and / or S (O) _o A can be substituted,
Ar unsubstituted or single, double or triple by Hal, A, OH, OA, NH ₂ , NO ₂ , CN, COOH, COOA, CONH ₂ , NHCOA, NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ or S (O) _o A substituted phenyl, naphthyl or biphenyl,
A unbranched or branched alkyl having 1-10 C atoms, where 1-7 H atoms can be replaced by F,
A 'alkyl having 1 to 6 carbon atoms or benzyl,
Hal F, Cl, Br or I,
o 0, 1 or 2,
mean,
as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios.

object The invention relates to the compounds of the formula I and their salts and a process for the preparation of compounds of the formula I according to the claims 33-41 as well as their pharmaceutically usable derivatives, solvates and stereoisomers, characterized in that one

• a) first a compound of formula II
  
  wherein R ¹ , R ² , R ^{3 have} the meaning given in claim 33, with a compound of formula III
  
  wherein A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, to a compound of formula IV
  
  in which R ¹ , R ² , R ^{3 have} the meaning given in claim 33, and A denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,
• b) then the ester IV with a compound of formula V M-Het V wherein Het has the meaning given in claim 33, and M denotes sodium, potassium or lithium, converted to a compound of the formula I and / or
• c) a base or acid of the formula I converted into one of its salts.

object of the invention are also the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Taking solvate of the compounds will add inert solvent molecules to the Connections understood that are due to their mutual attraction form. Solvates are e.g. Mono- or dihydrates or alcoholates.

Under pharmaceutically usable derivatives are understood e.g. the salts the compounds according to the invention, as well as so-called prodrug compounds.

Under Prodrug derivatives are understood to mean e.g. Alkyl or acyl groups, Compounds of the formula modified by sugars or oligopeptides I, which in the organism quickly become the active compounds according to the invention be split.

For this belong also biodegradable polymer derivatives of the compounds according to the invention, like this e.g. in Int. J. Pharm. 115, 61-67 (1995).

object The invention also relates to mixtures of the compounds according to the invention of formula I, e.g. Mixtures of two diastereomers e.g. in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000.

Especially these are preferably mixtures of stereoisomeric compounds.

For all leftovers, that occur multiple times, e.g. A, their meanings are independent of each other are.

A means alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. A preferably means Methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, more preferably e.g. Trifluoromethyl.

A means very particularly preferably alkyl with 1, 2, 3, 4, 5 or 6 C atoms, preferably Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1,1-trifluoroethyl.

A 'preferably means Alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, preferably methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, Hexyl or benzyl.

OA means alkoxy and is preferably e.g. Methoxy, ethoxy, propoxy, Isopropoxy, butoxy, trifluoromethoxy or cyclopentoxy.

--COA (Acyl) preferably means acetyl, propionyl, and also butyryl, Pentanoyl, hexanoyl or e.g. Benzoyl.

Hal preferably denotes F, Cl or Br, but also I.

Ar means e.g. unsubstituted phenyl, naphthyl or biphenyl preferably e.g. through A, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, Ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, nitro, cyan, formyl, Acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino, Dimethylamino, diethylamino, benzyloxy, sulfonamido, methylsulfonamido, Ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, Phenylsulfonamido, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl mono-, di- or tri-substituted phenyl, naphthyl or biphenyl.

Ar means very particularly preferably phenyl.

Het means of the possible Apart from substituents, e.g. 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol- 3 or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1,4] oxazinyl, more preferred 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl, 2,1,3-benzoxadiazol-5-yl or chromenyl.

The heterocyclic radicals can also partially or completely be hydrated.

Het can e.g. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, Tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or-5-yl, Hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo [1,4] oxazinyl preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3- (2-oxo-methylenedioxy) phenyl or 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, further preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxo-furanyl.

Het means particularly preferably unsubstituted or single or double Hal and / or A substituted chromen-2-one-yl, benzothiazolyl, Thienyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl, Imidazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl or isoquinolyl.

R ¹ preferably denotes -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A or -OSO ₂ A, very particularly preferably -OH or -OA.

R ² is preferably H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal.

R ³ is preferably H.

R ¹ and R ² together preferably also mean methylenedioxy.

The Compounds of formula I can occur in various stereoisomeric forms. Formula I encompasses everyone these shapes.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Ig, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
in Ia R ¹ -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A or -OSO ₂ A
means;
in Ib R ¹ -OH or -OA
means
in Ic R ¹ -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A or -OSO ₂ A,
R ² H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal,
R ³ H,
R ¹ and R ² together also methylenedioxy or ethylenedioxy,
mean,
in Id R ¹ -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A or -OSO ₂ A,
R ² H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal,
R ³ H,
R ¹ and R ² together also methylenedioxy or ethylenedioxy,
Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal and / or A,
mean,
in Ie R ¹ -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A or -OSO ₂ A,
R ² H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal,
R ³ H,
R ¹ and R ² together also methylenedioxy or ethylenedioxy,
Het is a mono- or dinuclear aromatic heterocycle with 1 to 3 N, O and / or S atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal and / or A,
mean,
in If R ¹ -OH or -OA,
R ² H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal,
R ³ H,
R ¹ and R ² together also methylenedioxy or ethylenedioxy,
Het unsubstituted or mono- or disubstituted by Hal and / or A-substituted chromen-2-one-yl, benzothiazolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl or isoquinolyl,
A unbranched or branched alkyl having 1-6 C atoms, where 1-5 H atoms can be replaced by F,
mean,
in Ig R ¹ -OH or -OA,
R ² H, -OH, -OA or Hal,
R ³ H,
R ¹ and R ² together also methylenedioxy or ethylenedioxy,
Het unsubstituted or mono- or disubstituted by Hal and / or A benzothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl or thiazolyl,
A unbranched or branched alkyl having 1-6 C atoms, where 1-5 H atoms can be replaced by F,
mean,
as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios.

The invention particularly relates to the following compounds of the formula I.
6-hydroxy-2- (1-methyl-1H-imidazol-2-carbonyl) chromen-4-one,
5,7-dihydroxy-2- (1-methyl-1H-imidazol-2-carbonyl) chromen-4-one,
7-hydroxy-2- (1-methyl-1H-imidazol-2-carbonyl) chromen-4-one,
6- (1-methyl-1H-imidazol-2-carbonyl) - [1,3] dioxolo [4,5-g] chromen-8-one,
5,7-dihydroxy-2- (pyridin-2-carbonyl) chromen-4-one,
6-hydroxy-2- (pyridin-2-carbonyl) chromen-4-one,
6-hydroxy-2- (3,5-dichloropyrazine-2-carbonyl) chromen-4-one,
6-hydroxy-2- (benzothiazolyl-2-carbonyl) chromen-4-one,
as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios.

The Compounds of formula I and also the starting materials for their preparation will be followed by the rest known methods prepared as in the literature (e.g. in the standard works such as Houben-Weyl, methods of organic Chemie, Georg-Thieme-Verlag, Stuttgart) are described under Reaction conditions for the implementations mentioned are known and suitable. It can one also makes use of variants which are known per se and are not mentioned here in greater detail.

The Starting materials can if desired, also be formed in situ so that they can be removed from the reaction mixture not isolated, but immediately to the compounds of the formula I implemented.

The Starting compounds of the formulas II and III are generally known. If they are new, they can but can be produced by methods known per se.

links of formula I can preferably obtained by using compounds of formula II with compounds of formula III first to compounds of formula IV implements.

The Implementation takes place according to methods known to the person skilled in the art. First takes place in a suitable alcohol in the presence of a reaction Alkali or alkaline earth alcoholates, e.g. in ethanol / sodium ethanolate or methanol / potassium methanolate.

Basically, too the following inert solvents be used.

As 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 disulphide; Carboxylic acids like formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.

The Response time is between depending on the conditions used a few minutes and 14 days, the reaction temperature between about -30 ° and 140 °, normally between -10 ° and 90 °, in particular between about 0 ° and about 70 °.

The Cyclization to the compound of formula IV is acid-catalyzed, by adding suitable mineral acids, such as. Hydrochloric acid, phosphoric acid or sulfuric acid.

reaction time and temperature are preferably as indicated above.

The Esters of formula IV are after with the compounds of formula V. Standard methods in an inert solvent to the compounds Formula I implemented.

As Compound of formula V is preferably Li-Het used. inert Solvent, Reaction time and temperature are preferably as indicated above, the reaction in THF at -80 to -75 ° C. is particularly preferred.

A Base of the formula I can be converted into the associated acid addition salt using an acid, for example, by implementing equivalents Amounts of the base and acid in an inert solvent like ethanol and subsequent Evaporation. For this implementation comes in particular acids that are physiological deliver safe salts. So inorganic acids can be used e.g. Sulfuric acid, Nitric acid, Hydrogen halides like hydrochloric acid or hydrobromic acid, phosphoric like orthophosphoric acid, sulfamic, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carbon, sulfone or sulfuric acids, e.g. formic acid, Acetic acid, propionic acid, pivalic, Diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, ethanedisulfonic, 2-hydroxyethanesulfonic acid, benzenesulfonic, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, Lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates, can be used Isolation and / or purification of the compounds of formula I used become.

on the other hand can Compounds of formula I with bases (e.g. sodium or potassium hydroxide or carbonate) in the corresponding metal, especially alkali metal or alkaline earth metal, or in the corresponding ammonium salts being transformed.

Also physiologically harmless organic bases, e.g. ethanolamine can be used.

Compounds according to the invention of formula I can because of their molecular structure be and can be chiral accordingly occur in different enantiomeric forms. You can therefore present in racemic or optically active form.

There the pharmaceutical effectiveness of the racemates or the stereoisomers of the compounds of the invention can distinguish it may be desirable be to use the enantiomers. In these cases, the final product or but already the intermediates in enantiomeric compounds chemical or physical measures known to the person skilled in the art, separated or already used as such in the synthesis become.

in the In the case of racemic amines, the mixture is reacted with an optically active release agent diastereomers formed. As a release agent are e.g. optically active acids, such as the R and S forms of tartaric acid, diacetyl tartaric dibenzoyltartaric, Mandelic acid, malic acid, lactic acid, are suitable N-protected amino acids (e.g. N-benzoylproline or N-benzenesulfonylproline) or the different optically active camphorsulfonic acids. A chromatographic separation of enantiomers with is also advantageous With the help of an optically active release agent (e.g. dinitrobenzoylphenylglycine, Cellulose triacetate or other derivatives of carbohydrates or chiral derivatized methacrylate polymers fixed on silica gel). Suitable solvents for this are watery or alcoholic solvent mixtures such as. Hexane / isopropanol / acetonitrile e.g. in the ratio 82: 15: 3.

object the invention is furthermore the use of the compounds of the formula I and / or their physiologically acceptable salts for the preparation a drug (pharmaceutical preparation), in particular in a non-chemical way. You can do this together with at least a solid, liquid and / or semi-fluid Carrier- or auxiliary and optionally in combination with an or several other active ingredients brought into a suitable dosage form become.

object The invention furthermore comprises medicaments containing at least one Compound of formula I and / or their pharmaceutically usable Derivatives, solvates and stereoisomers, including their mixtures in all conditions as well as, if applicable, and / or auxiliary substances.

This Preparations can used as medicinal products in human or veterinary medicine. As excipients there are organic or inorganic substances that can be used for the enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, Benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, Carbohydrates like lactose or starch, Magnesium stearate, talc, petroleum jelly. For oral use in particular Tablets, pills, dragees, capsules, powders, granules, syrups, Juices or Drops, for rectal use suppositories, for parenteral Application solutions, preferably oily or watery Solutions, also suspensions, emulsions or implants, for topical Use ointments, creams or powder or as a nasal spray. The new connections can also lyophilized and the lyophilizates obtained e.g. for the production of injectables be used. The specified preparations can be sterilized be and / or auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic Pressure, buffer substances, color, taste and / or several more Contain active ingredients, e.g. one or more vitamins.

object The invention also includes medicaments containing at least one Compound of formula I and / or their pharmaceutically usable Derivatives, solvates and stereoisomers, including their mixtures in all conditions and at least one other drug ingredient.

• (a) einer wirksamen Menge an einer Verbindung der Formel I und/oder ihrer pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und
• (b) einer wirksamen Menge eines weiteren Arzneimittelwirkstoffs.

The invention also relates to a set (kit) consisting of separate packs of

• (a) an effective amount of a compound of formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including their mixtures in all proportions, and
• (b) an effective amount of another drug ingredient.

The Set contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules. The set can e.g. contain separate ampoules, each in an effective amount of a compound of formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including their Mixtures in all proportions, and an effective amount of another drug ingredient solved or is in lyophilized form.

USE

details

worin
R¹ H, -OH, -OA, Phenoxy, Ar, -O-CO-A, SO₃H, SO₃A, -OSO₃H, -OSO₃A, -OSO₂A, SO₂A, Hal, COOH, COOA, CONH₂, NHSO₂A, COA, CHO oder SO₂NH₂,
R² H, -OH, -OA, Phenoxy, Ar, -O-CO-A, SO₃H, SO₃A, -OSO₃H, -OSO₃A, -OSO₂A, SO₂A, Hal, COOH, COOA, CONH₂, NHSO₂A, COA, CHO oder SO₂NH₂,
R³ H, -OH, -OA, Phenoxy, Ar, -O-CO-A, SO₃H, SO₃A, -OSO₃H, -OSO₃A, -OSO₂A, SO₂A, Hal, COOH, COOA, CONH₂, NHSO₂A, COA, CHO oder SO₂NH₂,
R¹ und R² zusammen auch Methylendioxy oder Ethylendioxy,
Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-, O- und/oder S-Atomen, der unsubstituiert oder ein-, zwei- oder dreifach durch Carbonylsauerstoff, =S, =NH, Hal, A, -(CH₂)_o-Ar, -(CH₂)_o-Cycloalkyl, -(CH₂)_o-OH, -(CH₂)_o-NH₂, NO₂, CN, -(CH₂)_o-COOH, -(CH₂)_o-COOA, -(CH₂)_o-CONH₂, -(CH₂)_o-NHCOA, NHCONH₂, -(CH₂)_o-NHSO₂A, CHO, COA', SO₂NH₂ und/oder S(O)_oA substituiert sein kann,
Ar unsubstituiertes oder ein-, zwei- oder dreifach durch Hal, A, OH, OA, NH₂, NO₂, CN, COOH, COOA, CONH₂, NHCOA, NHCONH₂, NHSO₂A, CHO, COA, SO₂NH₂ oder S(O)_oA substituiertes Phenyl, Naphthyl oder Biphenyl,
A unverzweigtes oder verzweigtes Alkyl mit 1-10 C-Atomen, wobei 1-7 H-Atome durch F ersetzt sein können,
A' Alkyl mit 1 bis 6 C-Atomen oder Benzyl,
Hal F, Cl, Br oder I,
o 0, 1 oder 2,
bedeuten,
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.I. The invention also relates to the use of compounds of the formula I below according to claim 1

wherein
R ¹ H, -OH, -OA, phenoxy, Ar, -O-CO-A, SO ₃ H, SO ₃ A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A, SO ₂ A, Hal, COOH, COOA, CONH ₂ , NHSO ₂ A, COA, CHO or SO ₂ NH ₂ ,
R ² H, -OH, -OA, phenoxy, Ar, -O-CO-A, SO ₃ H, SO ₃ A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A, SO ₂ A, Hal, COOH, COOA, CONH ₂ , NHSO ₂ A, COA, CHO or SO ₂ NH ₂ ,
R ³ H, -OH, -OA, phenoxy, Ar, -O-CO-A, SO ₃ H, SO ₃ A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A, SO ₂ A, Hal, COOH, COOA, CONH ₂ , NHSO ₂ A, COA, CHO or SO ₂ NH ₂ ,
R ¹ and R ² together also methylenedioxy or ethylenedioxy,
Het a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen, = S, = NH, Hal, A , - (CH ₂ ) _o -Ar, - (CH ₂ ) _o -cycloalkyl, - (CH ₂ ) _o -OH, - (CH ₂ ) _o -NH ₂ , NO ₂ , CN, - (CH ₂ ) _o - COOH, - (CH ₂ ) _o -COOA, - (CH ₂ ) _o -CONH ₂ , - (CH ₂ ) _o -NHCOA, NHCONH ₂ , - (CH ₂ ) _o -NHSO ₂ A, CHO, COA ', SO ₂ NH ₂ and / or S (O) _o A can be substituted,
Ar unsubstituted or single, double or triple by Hal, A, OH, OA, NH ₂ , NO ₂ , CN, COOH, COOA, CONH ₂ , NHCOA, NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ or S (O) _o A substituted phenyl, naphthyl or biphenyl,
A unbranched or branched alkyl having 1-10 C atoms, where 1-7 H atoms can be replaced by F,
A 'alkyl having 1 to 6 carbon atoms or benzyl,
Hal F, Cl, Br or I,
o 0, 1 or 2,
mean,
and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions, for the manufacture of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of signal transduction of kinases plays a role.

in this connection tyrosine kinases and / or Raf kinases are preferred.

object the invention is also the use of compounds of Formula I according to claim 1 or 2, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions, for the manufacture of a medicament for the treatment of diseases, by inhibiting tyrosine kinase by the compounds Formula I influenced become.

object the invention is also the use according to claim 1 or 2 of compounds of formula I according to claim 1, and their pharmaceutical usable derivatives, solvates and stereoisomers, including their Mixtures in all proportions, for the manufacture of a medicament for the treatment of diseases, that are caused, mediated and / or propagated by Raf kinases the Raf kinase from the group consisting of A-Raf, B-Raf and Raf-1 selected becomes.

The meanings and preferred embodiments generally correspond to those as under SUMMARY OF THE INVENTION.

Accordingly, the invention relates in particular to the uses according to one or more of claims 1 to 26 of those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred uses of groups of compounds can be expressed by the following sub-formulas Ia to Ig, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
in Ia R ¹ H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal
means;
in Ib R ¹ H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal,
R ² H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal,
R ³ H,
R ¹ and R ² together also methylenedioxy or ethylenedioxy,
mean;
in Ic R ¹ -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal,
R ² H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal,
R ³ H,
R ¹ and R ² together also methylenedioxy or ethylenedioxy,
Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal and / or A;
in Id R ¹ -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A or -OSO ₂ A,
R ² H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal,
R ³ H,
R ¹ and R ² together also methylenedioxy or ethylenedioxy,
Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal and / or A,
mean;
in Ie R ¹ -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal,
R ² H, -OH, -OA, phenoxy, -O-CO-A,
R ³ H,
R ¹ and R ² together also methylenedioxy or ethylenedioxy,
Het is a mono- or dinuclear aromatic heterocycle with 1 to 3 N, O and / or S atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal and / or A,
mean;
in If R ¹ -OH or -OA,
R ² H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal,
R ³ H,
R ¹ and R ² together also methylenedioxy or ethylenedioxy,
Het is a mono- or dinuclear aromatic heterocycle with 1 to 4 N, O and / or S atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal and / or A,
mean;
in Ig R ¹ -OH or -OA,
R ² H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal,
R ³ H,
R ¹ and R ² together also methylenedioxy or ethylenedioxy,
Het unsubstituted or mono- or disubstituted by Hal and / or A-substituted chromen-2-one-yl, benzothiazolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl or isoquinolyl,
A unbranched or branched alkyl having 1-6 C atoms, where 1-5 H atoms can be replaced by F,
mean;
as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios.

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), which promotes the growth of solid tumors, neovascularization in the eye (diabetic retinopathy, age-related Macular degeneration and the like) and inflammation (psoriasis, rheumatoid arthritis and the like).

The present invention includes the use of compounds of the Formula I according to claim 1 and / or its physiologically acceptable Salts and solvates for the manufacture of a medicament for treatment or cancer prevention. Preferred carcinomas for treatment come from the group brain carcinoma, urogenital tract carcinoma, carcinoma of the lymphatic system, gastric carcinoma, larynx carcinoma and lung carcinoma. Another group of preferred forms of cancer are monocyte leukemia, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, glioblastoma and Breast carcinoma. The use of connections is also included of formula I according to claim 1 and / or its physiologically acceptable Salts and solvates for the manufacture of a medicament for treatment or prevention of a disease involving angiogenesis.

A such disease in which angiogenesis is involved is one Eye disease, such as retinal vascularization, diabetic retinopathy, age-related macular degeneration and the like.

The Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts and solvates for their production a medicine to treat or prevent inflammatory diseases, also falls within the scope of the present invention. To such inflammatory diseases counting for example rheumatoid arthritis, psoriasis, contact dermatitis, Late type of hypersensitivity reaction and the same.

Likewise includes the use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts and solvates for Manufacture of a medicinal product to treat or prevent an tyrosine kinase-related disease or a tyrosine kinase-related disease Suffering in a mammal, using this method a sick mammal, such Treatment requires a therapeutically effective amount of a compound of formula I administered. The therapeutic amount depends on the disease and can be done by a specialist without any great effort be determined.

The present invention also includes the use of compounds of formula I according to claim 1 and / or its physiologically acceptable Salts and solvates for the manufacture of a medicament for treatment or prevention of retinal vascularization.

method to treat or prevent eye diseases such as diabetic Retinopathy and age-related macular degeneration are also part of the invention. Use for treatment or Prevention of inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis and Late-types the hypersensitivity reaction, as well as the treatment or prevention of bone pathologies from the group osteosarcoma, Osteoarthritis and rickets, falls also within the scope of the present invention.

The Expression "tyrosine kinase-related Disease or suffering " affect pathological conditions, that of the activity are dependent on one or more tyrosine kinases. The tyrosine kinases are either directly or indirectly on the signal transduction pathways different cell activities, including proliferation, adhesion and migration and differentiation involved. To diseases, those with tyrosine kinase activity are associated, count the proliferation of tumor cells, the pathological formation of new vessels, which promotes the growth of solid tumors, neovascularization in the eye (diabetic retinopathy, age-related macular degeneration and the like) and inflammation (Psoriasis, rheumatoid arthritis and the like).

The compounds of the invention of formula I according to claim 1 administered to patients for the treatment of cancer. The present Compounds inhibit tumor angiogenesis and thus influence that Growth of tumors (J. Rak et al. Cancer Research, 55: 4575-4580, 1995). The angiogenesis-inhibiting properties of the present compounds of formula I according to claim 1 are also suitable for the treatment of certain Forms of blindness associated with retinal vascularization being related.

The compounds of formula I 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 useful for the treatment and prevention of conditions related to bone resorption, such as osteoporosis and Paget's disease.

The Connections can by having cerebral edema, tissue damage and ischemia-related Reduce reperfusion injuries, including reducing or Prevention of tissue damage that after cerebral ischemic Events such as brain stroke occur can be used (Drug News Perspect 11: 265-270 (1998); J. Clin. Invest. 104: 1613-1620 (1999)).

The Compounds of formula I according to claim 1 are suitable for the preparation a medicine used to treat diseases caused by Raf kinases caused, mediated and / or propagated, the Raf kinase is selected from the group consisting of A-Raf, B-Raf and Raf-1.

Prefers is the use for the treatment of diseases, preferably from the group of hyperproliferative and non-hyperproliferative Diseases.

in this connection are cancerous or non-cancerous diseases.

The non-cancerous diseases are selected from the group consisting of from psoriasis, arthritis, inflammation, Endometriosis, scarring, benign prostatic hyperplasia, immunological Diseases, autoimmune diseases and immune deficiency diseases.

The cancerous diseases are selected from the group consisting of from brain cancer, lung cancer, squamous cell cancer, bladder cancer, stomach cancer, Pancreatic cancer, liver cancer, kidney cancer, colorectal cancer, breast cancer, Head cancer, neck cancer, esophageal cancer, gynecological Cancer, thyroid cancer, Lymphoma, chronic leukemia and acute leukemia.

The compounds of the invention can to mammals, preferably humans, either alone or preferably in Combination with pharmaceutically acceptable carriers or extenders, if necessary with known excipients such as alum, in a pharmaceutical Composition administered as usual in pharmaceutical practice become. The connections can administered orally or parenterally, including on the intravenous, intramuscular, intreperitoneal, subcutaneous, rectal and topical route of administration.

at the oral use of a chemotherapeutic compound according to the invention can the chosen one Compound for example in the form of tablets or capsules or as watery solution or suspension can be administered. For oral tablets count to the usual used carriers Lactose and corn starch, and it usually becomes Lubricants such as magnesium stearate added. When administered orally count in capsule form Lactose and dried corn starch to suitable extenders. Are aqueous suspensions for oral Use required, so the active ingredient with emulsifiers and suspending agents combined. If desired, can certain sweeteners and / or flavorings are added. For intramuscular, intraperitoneal, subcutaneous and intravenous Usage becomes common sterile solutions of the active ingredient, and the pH of the solutions should be set and buffered in a suitable manner. With intravenous use the total concentration of dissolved substances should be set so be that the preparation becomes isotonic.

The exact dose for depends on the patient however, based on a number of factors, such as effectiveness the particular compounds used, age, body weight, general state of health, gender, of nutrition, of Time and route of administration, from the excretion rate, the Type of administration, the dosage form to be administered, the combination of drugs and the severity of the disease against which the therapy is used becomes. The respective therapeutically effective dose for each Patients can easily be determined through routine experimentation to Example given by the doctor on this therapeutic treatment advises or she accompanies.

The substances according to the invention are usually preferably in doses between about 1 and 500 mg, in particular between 5 and 100 mg per dosage unit administered. The daily Dosage is preferably between about 0.02 and 10 mg / kg body weight.

The compounds according to the invention can also be administered together with other well-known therapeutic agents which are selected on the basis of their suitability for the condition being treated. For example, combinations with bone antisorptive bisphos would be beneficial for bone disorders phonates such as alendronate and risedronate, integrin blockers (as defined below) such as ανβ3 antagonists, conjugated estrogens used in hormone therapy such as Prempro ^® , Premarin ^® and Endometrion ^® ; 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 ones Anticancer agents. These known anti-cancer agents include following: estrogen receptor modulators, Androgen receptor modulators, retinoid receptor modulators, cytotoxics, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other angiogenesis inhibitors. The present compounds are particularly suitable for common use Use with radiotherapy. The synergistic effects of inhibition VEGF in combination with radiotherapy are described in the professional world (see WO 00/61186).

"Estrogen receptor modulators" refers to Compounds that interfere with the binding of estrogen to the receptor or inhibit them, independently of how this happens. To the estrogen receptor modulators counting 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-dinitrophenyl hydrazone and SH646, which is not intended to be a limitation.

"Androgen receptor modulators" refers to Compounds that disrupt the binding of androgens to the receptor or inhibit them, independently of how this happens. Androgen receptor modulators include Example finasteride and other 5α-reductase inhibitors, Nilutamide, Flutamide, Bicalutamide, Liarozol and Abiraterone Acetate.

"Retinoid receptor modulators" refers to Compounds that interfere with the binding of retinoids to the receptor or inhibit them, independently of how this happens. To such retinoid receptor modulators counting 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.

"Cytotoxic" refers to Connections primarily through direct action on the Cell function lead to cell death or that inhibit or interfere with cell myosis, including alkylating agents, Tumor necrosis factors, intercalating agents, microtubulin inhibitors and topoisomerase inhibitors.

To count the cytotoxics for example tirapazimin, sertenef, cachectin, ifosfamide, tasonermin, Lonidamine, carboplatin, altretamine, prednimustine, dibromodulcite, Ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, Estramustine, improsulfan tosylate, trofosfamide, nimustine, dibrospidium chloride, Pumitepa, Lobaplatin, Satraplatin, Profiromycin, Cisplatin, Irofulven, Dexifosfamide, cis-amine dichloro (2-methylpyridine) platinum, Benzylguanine, glufosfamide, GPX100, (trans, trans, trans) -bis-mu- (hexane-1,6-diamine) -mu- [diamine-platinum (II)] to [diamine (chlorine) 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-deoxo-10-hydroxycarminomycin, Annamycin, Galarubicin, Elinafid, MEN10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyldaunorubicin (see WO 00/50032), but this is not intended to be a limitation.

To count the microtubulin inhibitors for example paclitaxel, vindesine sulfate, 3 ', 4'-dideshydro-4'-deoxy-8'-norvincaleukoblastin, Docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, Cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, Anhydrovinblastine, N, N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-prolin-t-butylamide, TDX258 and BMS188797.

Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ', 4'-O-exo-benzylidenchartreusin, 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-1H, 12H-benzo [de] pyrano [3 ', 4 ': b, 7] indolizino [1,2b] quinoline-10,13 (9H, 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] carbazole-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-one, 2,3- (methylenedioxy) -5 -methyl-7-hydroxy-8-methoxybenzo [c] phenanthridinium, 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-thioxanthene-4-ylmethyl] formamide, N- (2- (dimethylamino) ethyl) acridine-4-carboxamide, 6 - [[2- (dimethylamino) ethyl] amino] -3-hydroxy-7H-indeno [2,1-c] quinolin-7-one and Dimesna.

To the "antiproliferative Means "include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, as well as antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, Fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabin sodium hydrate, Raltitrexed, paltitrexide, emitefur, tiazofurin, decitabine, nolatrexed, Pemetrexed, nelzarabine, 2'-deoxy-2'-methylidencytidine, 2'-fluoromethylene-2'-deoxycytidine, N- [5- (2,3-dihydrobenzofuryl) sulfonyl] -N '- (3,4-dichlorophenyl) urea, N6- [4-deoxy-4- [N2- [2 (E), 4 (E) -tetradecadienoyl] glycylamino] -L-glycero-B-L-mannoheptopyranosyl] adenine, Aplidine, 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-glutamic acid, aminopterin, 5-flurouracil, 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-ylessigsäureester, Swainsonin, lometrexol, dexrazoxane, methioninase, 2'-cyan-2'-deoxy-N4-palmitoyl-1-B-D-arabinofuranosylcytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. The "antiproliferative Means " also other monoclonal antibodies against growth factors as already mentioned under the "angiogenesis inhibitors", such as trastuzumab, as well as tumor suppressor genes, such as p53, via recombinant virus-mediated gene transfer can be given (see e.g. U.S. patent No. 6,069,134).

ASSAYS

The Compounds according to the invention described in the examples were in the assays described below, and it was found that they have a kinase-inhibiting effect. Other assays are known from the literature and could easily carried out by a specialist (see e.g. Dhanabal et al., Cancer Res. 59: 189-197; Xin et al., J. Biol. Chem. 274: 9116-9121; Sheu et al., 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 achieved by incorporating radioactively labeled phosphate in 4: 1 polyglutamic acid / tyrosine substrate (pEY) determined. The phosphorylated pEY product is on a filter membrane and the incorporation of the radioactively labeled phosphate is by scintillation counting quantified.

MATERIALS

VEGF receptor kinase

The intracellular tyrosine kinase domains of human KDR (Terman, B.I. et al. Oncogene (1991) Vol. 6, S. 1677-1683.) and Flt-1 (Shibuya, M. et al. Oncogene (1990) Vol. 5, pp. 519-524) cloned as glutathione-S-transferase (GST) gene fusion proteins. This was done by cloning the cytoplasmic domain of the KDR kinase as a reading frame Fusion at the carboxy terminus of the GST gene. The soluble recombinant GST kinase domain fusion proteins Insect cells (Invitrogen) were found in Spodoptera frugiperda (Sf21) using a baculovirus expression vector (pAcG2T, Pharmingen) expressed.

lysis buffer

50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.5% Triton X-100, 10% glycerin, 10 mg / ml each of leupeptin, pepstatin and aprotinin and 1 mM phenylmethylsulfonyl fluoride (all from Sigma).

wash buffer

50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.05% Triton X-100, 10% glycerin, 10 mg / ml each of leupeptin, pepstatin and aprotinin and 1 mM phenylmethylsulfonyl fluoride.

dialysis buffer

50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM EDTA, 0.05% Triton X-100, 50% glycerin, 10 mg / ml each of leupeptin, pepstatin and aprotinin and 1 mM phenylmethylsulfonyl fluoride.

10 × reaction buffer

200 mM Tris, pH 7.4, 1.0 M NaCl, 50 mM MnCl ₂ , 10 mM DTT and 5 mg / ml bovine serum albumin [bovine serum albumin = BSA] (Sigma).

Enzyme Diluent

50 mM Tris, pH 7.4, 0.1 M NaCl, 1 mM DTT, 10% glycerin, 100 mg / ml BSA.

10 × substrate

750 μg / ml poly (glutamic acid / tyrosine; 4: 1) (Sigma).

Stop Solution

30% trichloroacetic 0.2 M sodium pyrophosphate (both from Fisher).

wash solution

15% trichloroacetic 0.2 M sodium pyrophosphate.

filter plates

Millipore #MAFC NOB, GF / C 96-well glass fiber plate.

Method A - Protein Purification

• 1. The Sf21 cells were made with the recombinant virus one m.o.i. (multiplicity infection) of 5 virus particles / cell infected and 48 hours long at 27 ° C bred.
• 2. All steps were at 4 ° C carried out. The infected cells were harvested by centrifugation at 1000 x g and 30 minutes at 4 ° C lysed with 1/10 volume of lysis buffer and then centrifuged for 1 hour at 100,000 × g. The supernatant was then over one equilibrated with lysis buffer Glutathione-Sepharose acid (Pharmacia) and with 5 volumes of the same buffer and subsequently 5 volumes of wash buffer washed. The recombinant GST-KDR protein was eluted with wash buffer / 10 mM reduced glutathione (Sigma) and dialyzed against dialysis puffers.

Method B - VEGF receptor kinase assay

• 1. 5 µl assay Put inhibitor or control in 50% DMSO.
• 2. Add 35 μl reaction mixture containing 5 μl 10 × reaction buffer, 5 μl 25 mM ATP / 10 μCi [ ³³ P] ATP (Amersham) and 5 μl 10 × substrate.
• 3. Reaction by adding 10 μl KDR (25 nM) in enzyme dilution buffer start.
• 4. Mix and incubate for 15 minutes at room temperature.
• 5. Stop the reaction by adding 50 μl stop solution.
• 6. At 4 ° C for 15 minutes incubate.
• 7. 90 µl aliquot transfer to filter plate.
• 8. Aspirate and wash 3 times with washing solution.
• 9. 30 ul Add the scintillation cocktail, close the plate and in a scintillation counter Count type Wallac Microbeta.

Mitogenesis assay on human umbilical vein endothelial cells The expression of VEGF receptors that mediate mitogenic reactions 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 treated with the constituent or the test compound 2 hours before the addition of VEGF or "basic fibroblast growth factor" (bFGF). The mitogenic response to VEGF or bFGF is measured by measuring the incorporation of [ ³ H] thymidine in the cell DNA determined.

materials

HUVECs

As Primärkulturisolate frozen HUVECs are purchased from Clonetics Corp. The cells are in the endothelial growth medium EGM; Clonetics) and in the 3rd – 7th Passage for the mitogenicity assays used.

culture plates

NUNCLON 96-well polystyrene tissue culture plates (NUNC # 167008).

Assay Medium

To Dulbecco modified Eagle medium with 1 g / ml glucose (DMEM with low glucose content; Mediatech) plus 10% (v / v) fetal bovine serum (Clonetics).

test compounds

With the working stock solutions the test compounds with 100% dimethyl sulfoxide (DMSO) as long a serial dilution carried out, until their concentrations are 400 times higher than the desired final concentration are. The last dilutions (Concentration 1 ×) are prepared with assay medium immediately prior to addition to the cells.

10 × growth factors

Solutions of the human VEGF 165 (500 ng / ml; R&D Systems) and bFGF (10 ng / ml; R&D Systems) made with assay medium.

10 × [ ³ H] thymidine

[Methyl- ³ H] -thymidine (20 Ci / mmol; Dupont-NEN) is diluted to 80 μCi / ml with DMEM medium with a low glucose content.

Cell Wash Medium

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 .

Procedure 1

HUVEC 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

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

After 2 hours of pretreatment, the cells are stimulated by adding 10 μl assay medium, 10 × VEGF solution or 10 × bFGF solution per well. The cells are then incubated at 37 ° C / 5% CO ₂ .

Procedure 4

After 24 hours in the presence of the growth factors, 10 × [ ³ H] thymidine (10 μl / well) is added.

Procedure 5

Three days after adding [ ³ H] -thymidine, the medium is suctioned off and the cells are washed twice with cell 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 are the compounds of formula I VEGF inhibitors and are suitable therefore to inhibit angiogenesis, as in the treatment of Eye diseases, e.g. diabetic retinopathy, and for treatment carcinomas, e.g. solid tumors. The present connections inhibit VEGF-stimulated mitogenesis in cultured human vascular endothelial cells with HK50 values of 0.01-5.0 μM. These compounds are compared to related tyrosine kinases (e.g. FGFR1 and Src family; on the relationship between Src kinases and VEGFR kinases, see Eliceiri et al., Molecular Cell, Vol. 4, pp. 915-924, December 1999) also selective.

II. The invention furthermore relates to the use of compounds of formula I and / or their physiologically acceptable salts and Solvate for the manufacture of a medicament for the treatment of diseases and / or malfunctions characterized by oxidative stress conditions are, in a mammal, that requires such treatment, whereby the mammal, that requires such treatment, a therapeutically effective one Amount of a compound according to claim 1 administered orally.

at the diseases and / or malfunctions are in particular about memory loss and neurodegenerative diseases.

The compounds of the invention are therefore used for neuroprotection.

The Use of isoquercetin and ascorbic acid for appropriate purposes is described in WO 00/54754.

object the invention is also the use of the compounds according to the invention and / or their physiologically acceptable salts and solvates as food additives.

object The invention is also a composition containing ascorbic acid, ascorbate or an ascorbic acid derivative and at least one compound according to the invention and / or her physiologically safe salt and solvate.

III. The compounds of the invention have antioxidative properties as flavonoid derivatives.

The Use of ectoin derivatives with antioxidants for protection of skin stress proteins in topical formulations is e.g. described in WO 01/72263.

object the invention is therefore the use of the compounds according to the invention and / or their physiologically acceptable salts and solvates in cosmetic formulations, preferably in the form of a topical Formulation.

The invention furthermore relates to the use of the compounds according to the invention and / or their physiologically acceptable salts and solvates for protecting the skin's stress proteins, preferably in the form of a topical formulation.

The Preparation of the topical composition is done by at least one of the used according to the invention Compounds, optionally with auxiliaries and / or carriers, be brought into a suitable formulation. The auxiliary and carriers come from the group of carriers, Preservatives and other common auxiliary substances.

The topical compositions based on at least one used according to the invention Connection becomes external applied to the skin or skin adnexa.

As Application form are e.g. called solutions, suspensions, emulsions, Pastes, ointments, gels, creams, lotions, powders, soaps, surfactants Cleaning preparations, oils and sprays. additionally to one or more compounds used according to the invention any conventional carriers, auxiliaries and optionally added other active ingredients.

preferred Excipients come from the group of preservatives, antioxidants, Stabilizers, solubilizers, Vitamins, colorants and odor improvers. In addition to ointments, pastes, creams and gels one or more compounds used according to the invention the usual Contain carriers, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, Cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.

powder and sprays can besides one or more compounds used according to the invention, the usual ones excipients included, e.g. Milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also contain the usual propellants, e.g. Chloro fluorocarbons, Propane / butane or dimethyl ether.

Solutions and Emulsions can in addition to one or more compounds used according to the invention the usual Carriers, like solvents, solubilizers and emulsifiers, e.g. Water, ethanol, isopropanol, ethyl carbonate, Ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol, oils, in particular cottonseed, Peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin fatty acid esters, Polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

suspensions can in addition to one or more compounds used according to the invention the usual Carriers, like liquid Diluents, e.g. Water, ethanol or propylene glycol, suspending agents e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures of these substances.

Soap can in addition to one or more compounds used according to the invention the usual carriers, like alkali salts of fatty acids, Salts of fatty acid half-esters, Fatty acid protein hydrolyzates, isothionates, Lanolin, fatty alcohol, vegetable oils, Plant extracts, glycerin, sugar or mixtures of these substances, contain.

surfactant Cleaning products can in addition to one or more compounds used according to the invention the usual Carriers, such as salts of fatty alcohol sulfates, fatty alcohol ether sulfates, sulfosuccinic acid semiesters, fatty acid protein, Isothionates, imidazolinium derivatives, methyl taurates, sarcosinates, Fettsäureamidethersulfate, Alkyl amido betaines, fatty alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable and synthetic oils, Lanolin derivatives, ethoxylated glycerol fatty acid esters or mixtures thereof Substances.

facial and body oils can alongside one or more compounds used according to the invention the usual Carriers, like synthetic oils, like fatty acid esters, Fatty alcohols, silicone oils, natural oils, such as vegetable oils and oily Plant extracts, Paraffin oils, lanolin or mixtures of these substances.

Further typical cosmetic forms of use are also lipsticks, lip care sticks, Mascara, eyeliner, eye shadow, blush, powder, emulsion and wax make-up up as well as sun protection, pre-sun and after-sun preparations.

At least one used according to the invention Compound lies in the topical composition in an amount from preferably 0.0001 to 50% by weight, particularly preferably 0.001 up to 10% by weight, particularly preferably 0.1 to 1% by weight on the composition, before.

Test for examination the radical scavenger properties or the antioxidant effect

The assay is used to screen the antioxidant or radical scavenger property of a substance or an extract. To determine this property, the substance is allowed to react with the stable radical DPPH * (2,2-diphenyl-1-picrylhydrazyl hydrate) in ethanolic solution. The reduction in DPPH * is followed by the decrease in absorbance at the characteristic wavelength of the radical. In its radical form, DPPH * absorbs at 515 nm, when reduced by an antioxidant (AOX) the absorbance decreases. Different concentrations are examined for each antioxidant (expressed as the ratio of mole of antioxidant / mole of DPPH *). The decrease in absorbance at 515 nm is determined after 1 second, 2 minutes, 10 minutes, and then every 10 minutes until the absorbance remains constant. The exact initial concentration of DPPH * is determined using the extinction coefficient. At each antioxidant concentration, the remaining DPPH * concentration is determined as a percentage of the initial concentration and plotted against the molar ratio of antioxidant with DPPH *. Antiradical activity is defined as the proportion of the antioxidant that lowers the DPPH concentration to 50 percent of the initial amount (Efficient Concentration = EC ₅₀ ). The smaller this value, the greater the activity against radicals. The reaction behavior of the individual antioxidants is very different. One can differentiate between fast, medium and slow reacting substances, the steady state can be reached between 30 seconds and 12 hours.

All 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, evaporates and purifies by chromatography on silica gel and / or by crystallization. Rf values on silica gel; Eluent:
Ethyl acetate / methanol 9: 1.
Mass spectrometry (MS): EI (electron impact ionization) M ⁺
FAB (Fast Atom Bombardment) (M + H) ⁺
ESI (Electrospray Ionization) (M + H) ⁺ (unless otherwise stated)

example 1

Preparation of 6-hydroxy-2- (1-methyl-1H-imidazol-2-carbonyl) -chromen-4-one

• 1.1 3.8 g of sodium are added in portions with stirring 300 ml of ethanol dissolved. Subsequently will be a solution of 5.0 g of 2,5-dihydroxyacetophenone and 17.8 ml of diethyl oxalate in 25 ml of ethanol dropwise. The reaction mixture is then heated to 80 ° for 3 hours. You cool to room temperature and 10 ml of 32% HCl are added dropwise. One heats up 30 minutes at 90 °, cools down, and removes the solvent. After usual Refurbishment received 5.6 g of 6-hydroxy-2-ethoxycarbonyl-chromen-4-one ("AA").
• 1.2 2.4 ml of a 1.6 M n-BuLi solution are added to a solution of 0.3 ml of 1-methyl-1H-imidazole in 5 ml of THF, cooled to -78 °, under an N ₂ atmosphere and stirred for 30 minutes to. A solution of 300 mg of "AA" in 5 ml of THF is then added and the mixture is stirred for 1 hour. The mixture is worked up in the customary manner and 303 mg of 6-hydroxy-2- (1-methyl-1H-imidazol-2-carbonyl) -chromen-4-one are obtained. ¹ H NMR (DMSO-d6) δ 4.02 (s, 3H), 7.32 (m, 3H), 7.59 (s, 1H), 7.62 (dd, J = 9.6, 2.0 Hz, 1H), 7.74 (s, 1H) , 10.21 (s, 1H). ¹³ C NMR (DMSO-d6) δ 36.1, 107.2, 115.3, 120.3, 124.2, 124.6, 129.7, 129.9, 141.1, 149.2, 155.2, 156.0, 174.8, 177.4. EI MS (m / z) 267 (M ⁺ ), 239, 211 UV-Vis ( ¹ PrOH): λ _max . (1g. Ε): Analogously, the following compounds 6-hydroxy-2- (1-methyl-1 H-imidazole-2-carbonyl) -chromene-4on, 5,7-dihydroxy-2- (1-methyl-1 H-imidazole-2-carbonyl) -chromene-4on, 7-hydroxy-2- (1-methyl-1H-imidazole-2-carbonyl) -chromene-4on, 6- (1-methyl-1H-imidazole-2 -carbonyl) - [1,3] dioxolo [4.5g] chromen-8-one, 5,7-dihydroxy-2- (pyridin-2-carbonyl) -chromen-4-one, 6-hydroxy-2- ( pyridin-2-carbonyl) -chromen-4-one, 6-hydroxy-2- (3,5-dichloropyrazine-2-carbonyl) -chromen-4-one, 6-hydroxy-2- (benzothiazolyl-2-carbonyl) chromen-4-one.

Pharmacological test results

How the measurements show that the compounds according to the invention are good tyrosine kinase inhibitors, but as in the comparative example of the serine / threonine kinase inhibitors Bad PKB inhibitors have been shown.

The The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogen phosphate is in 3 l of double distilled water with 2 N hydrochloric acid pH adjusted 6.5, sterile filtered, filled into injection glasses, under sterile conditions lyophilized and sealed sterile. each Contains injection glass 5 mg of active ingredient.

Example B: Suppositories

you melts a mixture of 20 g of an active ingredient of the formula I. 100 g soy lecithin and 1400 g cocoa butter, pour into molds and let cool. Each suppository contains 20 mg of active ingredient.

Example C: solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH ₂ PO ₄ .2H ₂ O, 28.48 g of Na ₂ HPO ₄ .12H ₂ O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water , The pH is adjusted to 6.8 , make up to 1 l and sterilize by irradiation. This solution can be used in the form of eye drops.

Example D: ointment

you mixes 500 mg of an active ingredient of formula I with 99.5 g of petroleum jelly under aseptic conditions.

Example E: tablets

On Mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate become tablets in the usual way pressed, such that each Tablet contains 10 mg of active ingredient.

Example F: coated tablets

Analogous Example E tablets are pressed, which are then in the usual Show off with a cover Sucrose, potato starch, Talc, tragacanth and dye coated become.

Example G: capsules

2 kg of active ingredient of formula I are in the usual way in hard gelatin capsules filled, so that each Capsule contains 20 mg of the active ingredient.

Example H: ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, under sterile conditions lyophilized and sealed sterile. Each ampoule contains 10 mg Active ingredient.

Claims (46)

Use of compounds of formula I.

wherein R ¹ H, -OH, -OA, phenoxy, Ar, -O-CO-A, SO ₃ H, SO ₃ A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A, SO ₂ A, Hal , COOH, COOA, CONH ₂ , NHSO ₂ A, COA, CHO or SO ₂ NH ₂ , R ² H, -OH, -OA, phenoxy, Ar, -O-CO-A, SO ₃ H, SO ₃ A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A, SO ₂ A, Hal, COOH, COOA, CONH ₂ , NHSO ₂ A, COA, CHO or SO ₂ NH ₂ , R ³ H, -OH, -OA , Phenoxy, Ar, -O-CO-A, SO ₃ H, SO ₃ A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A, SO ₂ A, Hal, COOH, COOA, CONH ₂ , NHSO ₂ A, COA, CHO or SO ₂ NH ₂ , R ¹ and R ² together also methylenedioxy or ethylenedioxy, het a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, which is unsubstituted or once, twice or three times by carbonyl oxygen, = S, = NH, Hal, A, - (CH ₂ ) _o -Ar, - (CH ₂ ) _o -cycloalkyl, - (CH ₂ ) _o -OH, - (CH ₂ ) _o -NH ₂ , NO ₂ , CN, - (CH ₂ ) _o -COOH, - (CH ₂ ) _o -COOA, - (CH ₂ ) _o -CONH ₂ , - (CH ₂ ) _o - NHCOA, NHCONH ₂ , - (CH ₂ ) _o -NHSO ₂ A, CHO, COA ', SO ₂ NH ₂ and / or S (O) _o A substituted Ar can be unsubstituted or mono-, di- or triple by Hal, A, OH, OA, NH ₂ , NO ₂ , CN, COOH, COOA, CONH ₂ , NHCOA, NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ or S (O) _o A substituted phenyl, naphthyl or biphenyl, A unbranched or branched alkyl having 1-10 C atoms, where 1-7 H atoms can be replaced by F, A 'alkyl having 1 to 6 carbon atoms or benzyl, Hal F, Cl, Br or I, o 0, 1 or 2, 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 signal transduction by kinases is a Role play. Use according to claim 1, wherein the kinases are selected from the group of tyrosine kinases and / or Raf kinases. Use according to claim 1 or 2 of compounds of formula I according to claim 1, and their pharmaceutically usable derivatives, solvates and Stereoisomers, including their mixtures in all proportions, for the manufacture of a medicament for the treatment of diseases, by inhibiting the tyrosine kinases by the compounds Formula I influenced become. Use according to claim 3, wherein the to be treated Disease is a solid tumor. Use according to claim 4, wherein the solid tumor from the group brain tumor, tumor of the urogenital tract, tumor of the lymphatic system, gastric tumor, larynx tumor and lung tumor comes. Use according to claim 5, wherein the solid tumor from the group monocyte leukemia, Pulmonary adenocarcinoma, small cell lung cancer, pancreatic cancer, Glioblastoma and breast carcinoma originated. Use according to claim 3 for the treatment of a disease, is involved in angiogenesis. Use according to claim 7, wherein it is the Disease is an eye disease. Use according to claim 3 for the treatment of retinal vascularization, diabetic retinopathy, age-related macular degeneration and / or Inflammatory diseases. Use according to claim 9, wherein the inflammatory disease from the group rheumatoid arthritis, psoriasis, contact dermatitis and late-type the hypersensitivity reaction comes. Use according to claim 3 for the treatment of bone pathologies, wherein the bone pathology from the group osteosarcoma, osteoarthritis and rickets. Use according to claim 3 of compounds of Formula I 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 inhibitors, 8) HIV protease inhibitors, 9) reverse transcriptase inhibitors and 10) other angiogenesis inhibitors becomes. Use according to claim 3 of compounds of Formula I 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 radiotherapy and a combination of the 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 inhibitors, 8) HIV protease inhibitors, 9) reverse transcriptase inhibitors and 10) other angiogenesis inhibitors is administered. Use according to claim 1 or 2 of compounds of formula I according to claim 1, and their pharmaceutically usable derivatives, solvates and Stereoisomers, including their mixtures in all proportions, for the manufacture of a medicament for the treatment of diseases, that are caused, mediated and / or propagated by Raf kinases become. Use according to claim 14, wherein the Raf kinase is selected from the group consisting of A-Raf, B-Raf and Raf-1. Use according to claim 14, wherein the diseases selected are from the group of hyperproliferative and non-hyperproliferative Diseases. Use according to claim 14 or 16, wherein the disease Is cancer. Use according to claim 14 or 16, wherein the disease is not cancerous. Use according to claim 14, 16 or 18, wherein the non-cancerous diseases are selected from the group consisting of from psoriasis, arthritis, inflammation, Endometriosis, scarring, benign prostatic hyperplasia, immunological Diseases, autoimmune diseases and immune deficiency diseases. Use according to one of claims 14, 16 or 17, wherein the Selected diseases are 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, chronic leukemia and acute leukemia. Use according to one or more of claims 1 to 20 of compounds of formula I according to claim 1 wherein R ^{1 is} H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios. Use according to one or more of claims 1 to 21 of compounds of the formula I according to claim 1 wherein R ^{1 is} H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal, R ² H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal, R ³ H, R ¹ and R ² together also mean methylenedioxy or ethylenedioxy, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios. Use according to one or more of claims 1 to 22 of compounds of the formula I according to claim 1 wherein R ^{1 is} -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal, R ² H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal, R ³ H, R ¹ and R ² together also Methylenedioxy or ethylenedioxy, Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or trisubstituted by Hal and / or A. can mean, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios. Use according to one or more of claims 1 to 23 of compounds of the formula I according to claim 1 wherein R ^{1 is} -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal, R ² H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal, R ³ H, R ¹ and R ² together also Methylenedioxy or ethylenedioxy, Het is a mono- or dinuclear aromatic heterocycle having 1 to 3 N, O and / or S atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal and / or A, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their Mi in all circumstances. Use according to one or more of claims 1 to 24 of compounds of the formula I according to claim 1 wherein R ^{1 is} -OH or -OA, R ² H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H , -OSO ₃ A, -OSO ₂ A or Hal, R ³ H, R ¹ and R ² together also methylenedioxy or ethylenedioxy, Het a mono- or dinuclear aromatic heterocycle with 1 to 4 N-, O- and / or S- Atoms, which may be unsubstituted or substituted once, twice or three times by Hal and / or A, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios. Use according to one or more of claims 1 to 25 of compounds of the formula I according to claim 1 wherein R ^{1 is} -OH or -OA, R ² H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H , -OSO ₃ A, -OSO ₂ A or Hal, R ³ H, R ¹ and R ² together also methylenedioxy or ethylenedioxy, het unsubstituted or mono- or disubstituted by Hal and / or A, chromen-2-one-yl, Benzothiazolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl or isoquinolyl, A unbranched or branched alkyl having 1-6 C atoms, where 1-5 H atoms can be replaced by F, and their pharmaceutically acceptable derivatives, solvates and stereoisomers, including their mixtures in all proportions. Compounds of formula I.

wherein R ¹ -OH, -OA, phenoxy, Ar, -O-CO-A, SO ₃ H, SO ₃ A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A, SO ₂ A, COOH, COOA , CONH ₂ , NHSO ₂ A, COA, CHO or SO ₂ NH ₂ , R ² H, -OH, -OA, phenoxy, Ar, -O-CO-A, SO ₃ H, SO ₃ A, -OSO ₃ H , -OSO ₃ A, -OSO ₂ A, SO ₂ A, Hal, COOH, COOA, CONH ₂ , NHSO ₂ A, COA, CHO or SO ₂ NH ₂ , R ³ H, -OH, -OA, phenoxy, Ar , -O-CO-A, SO ₃ H, SO ₃ A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A, SO ₂ A, Hal, COOH, COOA, CONH ₂ , NHSO ₂ A, COA, CHO or SO ₂ NH ₂ , R ¹ and R ² together also methylenedioxy or ethylenedioxy, Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, which is unsubstituted or an -, double or triple through carbonyl oxygen, = S, = NH, Hal, A, - (CH ₂ ) _o -Ar, - (CH ₂ ) _o -cycloalkyl, - (CH ₂ ) _o -OH, - (CH ₂ ) _o -NH ₂ , NO ₂ , CN, - (CH ₂ ) _o -COOH, - (CH ₂ ) _o -COOA, - (CH ₂ ) _o -CONH ₂ , - (CH ₂ ) _o -NHCOA, NHCONH ₂ , - (CH ₂ ) _o -NHSO ₂ A, CHO, COA ', SO ₂ NH ₂ and / or S (O) _o A may be substituted nn, Ar unsubstituted or single, double or triple by Hal, A, OH, OA, NH ₂ , NO ₂ , CN, COOH, COOA, CONH ₂ , NHCOA, NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ or S (O) _o A substituted phenyl, naphthyl or biphenyl, A unbranched or branched alkyl having 1-10 C atoms, where 1-7 H atoms can be replaced by F, A 'alkyl having 1 to 6 C atoms or benzyl, Hal F, Cl, Br or I, o 0, 1 or 2, mean, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions. Compounds of formula I according to claim 27, wherein R ^{1 is} -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A or -OSO ₂ A, and their pharmaceutically usable derivatives, solvates and Stereoisomers, including their mixtures in all proportions. Compounds of formula I according to claim 28, wherein R ^{1 is} -OH or -OA, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions. Compounds of formula I according to claim 27, wherein R ¹ -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A or -OSO ₂ A, R ² H, -OH, -OA , Phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal, R ³ H, R ¹ and R ² together also mean methylenedioxy or ethylenedioxy, and their pharmaceutically usable derivatives, Solvates and stereoisomers, including their mixtures in all proportions. Compounds of formula I according to claim 27, wherein R ¹ -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A or -OSO ₂ A, R ² H, -OH, -OA , Phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal, R ³ H, R ¹ and R ² together also methylenedioxy or ethylenedioxy, Het a mono- or dinuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal and / or A, and their pharmaceutically usable derivatives, solvates and Stereoisomers, including their mixtures in all proportions. Compounds of formula I according to claim 27, wherein R ¹ -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A or -OSO ₂ A, R ² H, -OH, -OA , Phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal, R ³ H, R ¹ and R ² together also methylenedioxy or ethylenedioxy, Het a mono- or dinuclear aromatic heterocycle with 1 to 3 N, O and / or S atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal and / or A, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their Mixtures in all proportions. Compounds of formula I according to claim 27, wherein R ¹ -OH or -OA, R ² H, -OH, -OA, phenoxy, -O-CO-A, -OSO ₃ H, -OSO ₃ A, -OSO ₂ A or Hal, R ³ H, R ¹ and R ² together also methylenedioxy or ethylenedioxy, Het unsubstituted or mono- or disubstituted by Hal and / or A, chromen-2-one-yl, benzothi azolyl, thienyl, pyridnyl, pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl or isoquinolyl, A unbranched or branched alkyl having 1-6 C atoms, where 1-5 H atoms through F can be replaced, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios. Compounds of formula I according to claim 27, wherein R ¹ -OH or -OA, R ² H, -OH, -OA or Hal, R ³ H, R ¹ and R ² together also methylenedioxy or ethylenedioxy, Het unsubstituted or mono- or benzothiazolyl, pyridnyl, pyrimidinyl, pyrazinyl, indisubstituted by Hal and / or A, pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl or thiazolyl, A unbranched or branched alkyl having 1-6 C atoms, 1-5 H atoms by F can be replaced, mean, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios. Compounds according to claim 27 selected from the group 6-hydroxy-2- (1-methyl-1H-imidazol-2-carbonyl) chromen-4-one, 5,7-dihydroxy-2- (1-methyl-1H-imidazol-2-carbonyl) chromen-4-one, 7-hydroxy-2- (1-methyl-1H-imidazol-2-carbonyl) chromen-4-one, 6- (1-methyl-1H-imidazol-2-carbonyl) - [1,3] dioxolo [4,5-g] chromen-8-one, 5,7-dihydroxy-2- (pyridin-2-carbonyl) chromen-4-one, 6-hydroxy-2- (pyridin-2-carbonyl) chromen-4-one, 6-hydroxy-2- (3,5-dichloropyrazine-2-carbonyl) chromen-4-one, 6-hydroxy-2- (benzothiazolyl-2-carbonyl) chromen-4-one, such as their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions. Medicament containing at least one compound of formula I according to one or more of claims 27 to 35 and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions, as well as, if applicable, and / or auxiliary substances. Medicament containing at least one compound of formula I according to one or more of the claims 27 to 35 and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions, and at least one other drug ingredient. Set consisting of separate packs of (A) an effective amount of a compound of formula I according to one or more of the claims 27 to 35 and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions, and (b) an effective amount of another drug ingredient. A process for the preparation of compounds of formula I according to claims 27-35 and their pharmaceutically usable derivatives, solvates and stereoisomers, characterized in that a) first a compound of formula II

wherein R ¹ , R ² , R ^{3 have} the meaning given in claim 33, with a compound of formula III

wherein A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, to a compound of formula IV

wherein R ¹ , R ² , R ^{3 have} the meaning given in claim 33, and A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, b) then reacting the ester IV with a compound of the formula V M-Het V wherein Het has the meaning given in claim 33, and M means sodium, potassium or lithium is converted into a compound of the formula I and / or c) converts a base or acid of the formula I into one of its salts. Use of compounds of formula I according to one or more of the claims 27-35 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment of diseases and / or malfunctions that are characterized by oxidative stress conditions. Use according to claim 40, wherein the Diseases and / or malfunctions related to memory loss and neurodegenerative Diseases. Use of compounds according to one or more of claims 27-35 and / or their physiologically acceptable salts and solvates as Food additives. Use of compounds according to one or more of claims 27-35 and / or their physiologically acceptable salts and solvates in cosmetic formulations. Use according to claim 43 for the protection of the stress proteins of the skin. Use according to claim 43 or 44 in the form of a topical composition. Use according to claim 43, 44 or 45, characterized characterized that at least a compound used in a topical composition in an amount of 0.0001 to 50% by weight, based on the composition, is present.