EP1656377A1 - Aminobenzimidazole derivatives - Google Patents

Abstract

Novel compounds of formula (I) are disclosed, where R<1>, R<1'>, L, Y, m and p have the meanings given in claim 1, which are inhibitors of tyrosine kinases, in particular, TIE-2 and Raf kinases and can be used for the treatment of tumours.

Description

 aminobenzimidazole derivatives

BACKGROUND OF THE INVENTION

The object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.

The present invention relates to compounds in which the inhibition, regulation and / or modulation of the signal transduction of kinases, in particular the tyrosine kinases and / or Raf kinases, plays a role, furthermore pharmaceutical compositions which contain these compounds and the use of the compounds for treatment of kinase-related diseases.

More particularly, the present invention relates to compounds that inhibit, regulate and / or modulate the signal transduction of tyrosine kinases, compositions containing these compounds, and methods of their use for the treatment of tyrosine kinase-related diseases and conditions such as angiogenesis, cancer, tumor growth , Arteriosclerosis, age-related macular degeneration, diabetic retinopathy, inflammatory diseases and the like in mammals.

Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues on protein substrates. It is believed that tyrosine kinases play an essential role in signal transduction in various cell functions via substrate phosphorylation. Although the exact mechanisms of signal transduction are still unclear, the tyrosine kinases have been shown to be important factors cell proliferation, carcinogenesis and cell differentiation.

The tyrosine kinases can be divided into receptor tyrosine kinases and cytosolic tyrosine kinases. The receptor tyrosine kinases have an extracellular part, a transmembrane part and an intracellular part, while the cytosolic tyrosine kinases are only present intracellularly.

The receptor tyrosine kinases consist of a large number of transmembrane receptors with different biological effectiveness. About 20 different subfamilies of receptor tyrosine kinases have been identified. A tyrosine kinase subfamily called the HER subfamily consists of EGFR, HER2, HER3 and HER4. Ligands of this receptor subfamily include epithelial growth factor, TGF-α, amphiregulin, HB-EGF, betacellulin and heregulin. The insulin subfamily, which includes INS-R, IGF-IR and IR-R, is another subfamily of these receptor tyrosine kinases. The PDGF subfamily includes the PDGF-α and β receptor, CSFIR, c- kit and FLK-II. There is also the FLK family, which consists of the kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and fms tyrosine kinase-1 (flt-1 ) consists. The PDGF and FLK families are usually discussed together due to the similarities between the two groups. For a detailed discussion of receptor tyrosine kinases, see the work of Plowman et al., D / V & P 7 (6): 334-339, 1994, which is hereby incorporated by reference. The cytosolic tyrosine kinases also consist of a large number of subfamilies, including Src, Frk, Btk, Csk, Abi, Zap70, Fes / Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further divided into different receptors. For example, the Src subfamily is one of the largest subfamilies. It contains Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr and Yrk. The Src enzyme subfamily has been linked to oncogenesis. For a more detailed discussion of the cytosolic Tyrosine kinases, see the work of Bolen Oncogene, 8: 2025-2031 (1993), which is hereby incorporated by reference. Both the receptor tyrosine kinases and the cytosolic tyrosine kinases are on signaling pathways of the cell that differ

Suffering, including cancer, psoriasis and hyper-immune reactions, are involved.

Various receptor tyrosine kinases and the growth factors that bind them have been suggested to play a role in angiogenesis, although some may promote angiogenesis indirectly (Mustonen and Alitalo, J. C0ll Biol. 129: 895-898, 1995). One of these receptor tyrosine kinases is fetal liver kinase 1, also called FLK-1. The human analogue of FLK-1 is the kinase insert domain-containing receptor KDR, which is also known as vascular endothelial cell growth factor receptor 2 or VEGFR-2, because it binds VEGF with high affinity. Finally, the mouse version of this receptor was also called NYK (Oelrichs et al., Oncogene 8 (1): 11-

15, 1993). VEGF and KDR represent a ligand-receptor pair that play an essential role in the proliferation of vascular endothelial cells and

Formation and sprouting of the blood vessels, which are called vasculogenesis or

Angiogenesis plays.

Angiogenesis is characterized by excessive vascular endothelial growth factor (VEGF) activity. VEGF actually consists of a family of ligands (Klagsbum 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 non-mitogenic functions, such as those involved in cell adhesion Connected, seems to modulate. Inhibition of the KDR therefore modulates the level of mitogenic VEGF activity. In fact, it has been shown that tumor growth is affected by the antiangiogenic effects of the VEGF receptor antagonists (Kim et al., Nature 362, pp. 841-844, 1993).

Three PTK (protein tyrosine kinase) receptors for VEGFR have been identified: VEGFR-1 (Flt-1); VEGRF-2 (Flk-1 or KDR) and VEGFR-3 (Flt-4). VEGFR-2 is of particular interest. 0

Solid tumors can therefore be treated with tyrosine kinase inhibitors, since these tumors rely on angiogenesis for the formation of the blood vessels required to support their growth. ₅ These solid tumors include monocyte leukemia, brain,

Urogenital, lymphatic, gastric, larynx and lung carcinomas, including lung adenocarcinoma and small cell lung carcinoma. Other examples include carcinomas in which overexpression or activation of Raf-activating oncogenes (eg K-ras, erb-B) 0 is observed. These cancers include pancreatic and breast cancer. Inhibitors of these tyrosine kinases are therefore suitable for the prevention and treatment of proliferative diseases which are caused by these enzymes. 5 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 Q blindness. VEGF mRNA and protein levels in the eye are increased due to conditions such as retinal venous occlusion in the primate and reduced pθ 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 human diabetic retinopathy, the inhibition of eye VEGF is suitable for the treatment of these

Illness.

VEGF expression is also greatly increased in hypoxic regions of animal and human tumors in addition to necrosis zones. VEGF is also characterized by the expression of the oncogenes ras, raf, src and p53-

Mutant (all of which are important in the fight against cancer) upregulated. Anti-VEGF monoclonal antibodies inhibit the

Nude mouse the growth of human tumors. Although the same tumor cells continue to express VEGF in culture, the antibodies do not decrease their cell division rate. VEGF, which originates from tumors, does not act as an autocrine mitogenic factor. VEGF therefore contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotaxis and mitogenesis activity. These monoclonal antibodies also inhibit the growth of typically less vascularized human colon carcinomas in thymus-less mice and reduce the number of tumors arising from inoculated cells.

The expression of a VEGF-binding construct of Flk-1, Flt-1, the shortened mouse KDR- to remove the cytoplasmic tyrosine kinase domains but while maintaining a membrane anchor

Receptor homolog in viruses virtually stops the growth of a transplantable glioblastoma in the mouse, presumably due to the dominant-negative mechanism of heterodimer formation with transmembrane endothelial cell VEGF receptors. Embryo stem cells, which usually grow in the form of solid tumors in the nude mouse, do not form any detectable knock-out of both VEGF alleles

Tumors. The role of VEGF in

Growth of solid tumors. Inhibition of KDR or Flt-1 is involved in pathological angiogenesis and these receptors are useful for the treatment of diseases in which angiogenesis is part of the total pathology, e.g. Inflammation, diabetic retinal

Vascularization, as well as various forms of cancer, represents that tumor growth is known to be angiogenic (Weidner et al., N. Engl. J. Med., 324, pp. 1-8, 1991).

With angiopoietin 1 (Ang1), a ligand for the endothelium-specific

Receptor tyrosine kinase TIE-2, it is a new angiogenic factor (Davis et al, Gell, 1996, 87: 1161-1169; Partanen et al,

Mol. Cell Biol., 12: 1698-1707 (1992); U.S. Patent No. 5,521,073; 5,879,672;

5,877,020; and 6,030,831). The acronym TIE stands for "tyrosine kinase with Ig and EGF homology domains". TIE is used to identify a class of receptor tyrosine kinases that are only expressed in vascular endothelial cells and early hemopoietic cells. TIE receptor kinases are typically present an EGF-like domain and an immunoglobulin (IG) -like domain, which consists of extracellular folding units that are stabilized by inter-chain disulfide bonds (Partanen et al Curr. Topics Microbiol. Immunol., 1999, 237: 159-172 In contrast to VEGF, which functions during the early stages of vascular development, Ang1 and its receptor TIE-2 act during the later stages of vascular development, ie during vascular remodeling (reshaping refers to the formation of a vascular lumen) and Maturation (Yancopoulos et al, Cell, 1998, 93: 661-664; Peters, KG, Circ. Res., 19 98, 83 (3): 342-3; Suri et al, Cell 87, 1171-1180 (1996)).

Accordingly, inhibition of TIE-2 would be expected to disrupt the remodeling and maturation of a new vascular system initiated by angiogenesis and thereby the angiogenesis process. Furthermore, inhibition at the kinase domain binding site of VEGFR-2 would block the phosphorylation of tyrosine residues and serve to interrupt the initiation of angiogenesis. It can therefore be assumed that the inhibition of TIE-2 and / or VEGFR-2 should prevent tumor angiogenesis and serve to slow down or eliminate growth entirely.

Accordingly, treatment for cancer and other diseases associated with inappropriate angiogenesis could be provided.

The present invention is directed to methods for regulating, modulating or inhibiting TIE-2 for the prevention and / or treatment of diseases in connection with unregulated or impaired TIE-2 activity. In particular, the compounds according to the invention can also be used in the treatment of certain forms of cancer. Furthermore, the compounds of the invention can be used to provide additive or synergistic effects in certain existing cancer chemotherapies, and / or can be used to restore the efficacy of certain existing cancer chemotherapies and radiation treatments.

The present invention is directed to methods for regulating, modulating or inhibiting VEGFR-2 for the prevention and / or treatment of diseases in connection with unregulated or impaired VEGFR-2 activity.

The compounds according to the invention are aminobenzimidazoid derivatives of TIE-2 and / or VEGFR-2 kinase activity.

The present invention further relates to the compounds as inhibitors of Raf kinases. Protein phosphorylation is a fundamental process for the regulation of cell functions. The coordinated action of both protein kinases and phosphatases controls the levels of phosphorylation and consequently the activity of specific target proteins. One of the predominant

Role of protein phosphorylation is in signal transduction when extracellular signals are amplified and by a cascade of protein Phosphorylation and dephosphorylation events, e.g. B. be propagated in the p21 ^ra raf way.

The p21 ^ras gene was identified as an oncogene of the Harvey and Kirsten rats

Sarcoma viruses (H-Ras or K-Ras) discovered. In humans, characteristic mutations in the cellular Ras gene (c-Ras) have been associated with many different types of cancer. Of these mutants

Alleles that make Ras constitutively active have been shown to transform cells, such as the murine NIH 3T3 cell line, in culture.

The p21 ^ras oncogene is an important contributing factor in the development and progression of solid human carcinomas and is mutated in 30% of all human carcinomas (Bolton et al. (1994) Ann. Rep. Med. Chem., 29, 165-74; Bos. (1989) Cancer Res., 49, 4682-9). In its normal, non-mutated form, the Ras protein is a key element of the signal transduction cascade, which is controlled by growth factor receptors in almost all tissues (Avruch et al. (1994) Trends Biochem. Sei., 19, 279-83) ,

Biochemically, Ras is a guanine nucleotide binding protein, and the cycling between a GTP-linked activated and a GDP-linked quiescent form is strictly controlled by Ras endogenous GTPase activity and other regulatory proteins. The Ras gene product binds to guanine triphosphate (GTP) and guanine diphosphate (GDP) and hydrolyzes GTP to GDP. Ras is active in the GTP-bound state. In the Ras mutants in cancer cells, endogenous GTPase activity is weakened, and consequently the protein emits constitutive growth signals to "downstream" effectors, such as the Raf kinase enzyme. This leads to the cancerous growth of the cells that produce them Mutants carry (Magnuson et al. (1994) Semin. Cancer Biol., 5, 247-53). The Ras proto-oncogene requires a functionally intact C-Raf-1 proto-oncogene in order to be able to and not- Transduce receptor tyrosine kinases initiated growth and differentiation signals.

Activated Ras is necessary for the activation of the C-Raf-1 proto-oncogene, the biochemical steps through which Ras activates the Raf-1 protein

(Ser / Thr) kinase activated, but are now well characterized. It has been shown to inhibit the effect of active Ras

Inhibition of the Raf kinase signaling pathway by administration of deactivating antibodies against Raf kinase or by means of coexpression of dominant negative Raf kinase or dominant negative MEK (MAPKK), the substrate of the Raf kinase, 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.

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

Raf-serine and threonine-specific protein kinases are cytosolic enzymes that stimulate cell growth in a number of different cell systems (Rapp, UR, et al. (1988) in The Oncogene Handbook; T. Curran, EP Reddy and A. Skalka (Ed.) Elsevier Science Publishers; Netherlands, pp. 213-253; Rapp, UR, et al. (1988) Gold Spring Harbor Sym. Quant. Biol. 53: 173-184; Rapp, UR, et al. (1990 ) Inv Curr. Top. Microbiol. Immunol. Potter and Melchers (ed.), Berlin, Springer-Verlag 166: 129-139).

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 Escherichia coli expression vectors leads to morphological transformation and stimulates DNA synthesis (Rapp, UR, et al. (1987) in Oncogenes and Cancer ; SA Aaronson, J. Bishop, T. Sugimura, M. Terada, K. Toyoshima, and PK Vogt (ed.) Japan Scientific Press, Tokyo; Smith, MR, et al. (1990) Mol. Cell. Biol. 10 : from 3828 to 3833).

Thus activated Raf-1 is an intracellular activator of cell growth. Raf-1 protein serine kinase is a candidate for the "downstream" effector of mitogen signal transduction because Raf oncogenes face growth arrest resulting from blockade of cellular Ras activity due to a cellular mutation (Ras revertant cells) or micro-injection of anti-Ras antibodies results (Rapp, UR, et al. (1988) in

The Oncogene Handbook, T. Curran, EP Reddy and A. Skalka (ed.), Elsevier Science Publishers; Netherlands, pp. 213-253; Smith, MR, et al. (1986) Nature (London) 320: 540-543).

The C-Raf function is required for transformation by a number of different membrane-bound oncogenes and for growth stimulation by mitogens contained in sera (Smith, M.R., et al. (1986)

Nature (London) 320: 540-543). Raf-1 protein serine kinase activity is regulated by mitogens via phosphorylation (Morrison, DK, et al. (1989) Cell 58: 648-657), which also effects the subcellular distribution (Olah, Z., et al. (1991) Exp. Brain Res. 84: 403; Rapp, UR, et al. (1988) Cold Spring Harbor Sym. Quant. Biol. 53: 173-184. Raf-1 activating growth factors include those from platelets growth factor (PDGF) (Morrison, DK, et al. (1988) Proc. Natl. Acad. Sci.

USA 85: 8855-8859), the colony stimulating factor (Baccarini, M., et al. (1990) EMBO J. 9: 3649-3657), insulin (Blackshear, PJ, et al. (1990) J. Biol Chem. 265: 12115-12118), epidermal growth factor (EGF) (Morrison, RK, et al. (1988) Proc. Natl. Acad. Sci. USA 85: 8855-8859), Interleukin-2 (Turner, BC , et al. (1991) Proc. Natl. Acad. Sci. USA 88: 1227) and interleukin-3 and the granulocyte-macrophage colony stimulating factor (Carroll, MP, et al. (1990) J. Biol. Chem 265: 19812-19817).

After the mitogen treatment of cells, the transiently activated Raf-1 protein serine kinase translocates into the perinuclear region and the nucleus (Olah, Z., et al. (1991) Exp. Brain Res. 84: 403; Rapp, UR, et al. (1988) Cold Spring Habor Sym. Quant. Biol. 53: 173-184). Cells containing activated Raf are changed in their gene expression pattern (Heidecker, G., et al. (1989) in Genes and Signal transduction in multistage carcinogenesis, N. Colburn (ed.), Marcel Dekker, Inc., New York, P. 339-

374) and Raf-oncogenes activate transcription from Ap-1 / PEA3-dependent promotors in transient transfection assays (Jamal, S., et al. (1990) Science 344: 463-466; Kaibuchi, K., et al. (1989) J. Biol. Chem. 264: 20855-20858; Wasylyk, C, et al. (1989) Mol. Cell. Biol. 9: 2247-2250).

There are at least two independent routes for Raf-1 activation by extracellular mitogens: one that contains protein kinase C (KC) and a second that is initiated by protein tyrosine kinases (Blackshear, PJ, et al. (1990) J. Biol. Chem. 265: 12131-12134; Kovacina, KS, et al. (1990) J. Biol. Chem. 265: 12115-12118; Morrison, D; K., Et al. (1988 ) Proc. Natl. Acad. Sci. USA 85: 8855-8859; Siegel, JN, et al. (1990) J. Bioi. Chem. 265: 18472-18480; Turner, BC, et al. (1991) Proc. Natl. Acad. Sci. USA 88: 1227). In any case, activation involves Raf-1 protein phosphorylation. Raf-1 phosphorylation may be a result of a kinase cascade that is amplified by autophosphorylation, or may be entirely caused by autophosphorylation that is initiated by binding a putative activation ligand to the Raf-1 regulator domain, analogous to PKC activation by diacylglycerol becomes

(Nishizuka, Y. (1986) Science 233: 305-312).

One of the main mechanisms by which cell regulation is effected is through the transduction of extracellular signals across the membrane, which in turn modulate biochemical pathways in the cell. Protein phosphorylation is a process by which intracellular signals are propagated from molecule to molecule, which ultimately results in a cell response. These signal transduction cascades are highly regulated and often overlap, as can be seen from the presence of many protein kinases as well as phosphatases. Phosphorylation of

Proteins occur predominantly with serine, threonine or tyrosine residues, and protein kinases were therefore classified according to their specificity of the phosphorylation site, ie the serine / threonine kinases and tyrosine kinases. Because phosphorylation is such a widespread process in cells 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 illnesses are due to either abnormal activation or functional mutations in the molecular

Components of kinase cascades are due. Consequently, the characterization of these proteins and compounds, which are used for

Modulation of their activity are capable of paying considerable attention

(For an overview see: Weinstein-Oppenheimer et al. Pharma. &.

Therap., 2000, 88, 229-279).

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

It has been found that the compounds according to the invention and their salts have very valuable pharmacological properties with good tolerability.

In particular, they show inhibitory properties of tyrosine kinase. It has furthermore been found that the compounds according to the invention are inhibitors of the enzyme Raf kinase. Since the enzyme is a "downstream" effector of p21 ^ras , the inhibitors in pharmaceutical compositions for human or veterinary use are found to be useful when inhibiting the Raf kinase pathway, for example in the treatment of tumors and / or cancer cell mediated by Raf kinase The compounds are particularly useful in the treatment of solid carcinomas in humans and animals, e.g., murine cancer, since the progression of these cancers is dependent on the Ras protein signal transduction cascade and therefore the treatment by interrupting the cascade, ie by inhibiting the Raf kinase, responds. Accordingly, the compound of the invention or a pharmaceutically acceptable salt thereof is administered for the treatment of diseases mediated by the Raf kinase route, particularly cancer, including solid carcinomas such as

Example carcinomas (e.g. the lungs, the pancreas, the thyroid, the

Bladder or colon), myeloid disorders (e.g. myeloisehe

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 with the Raf kinase signaling pathway. The compounds according to the invention preferably exhibit an advantageous biological activity which is easily detectable in enzyme-based assays, for example assays as described here. In such enzyme-based assays exhibit and cause the compounds of the invention preferably have an inhibiting effect, which is usually by IC ₅ o values in a suitable range, preferably in the micromolar range and more preferably will be documented in the nanomolar range.

As discussed herein, these signaling pathways are relevant to various diseases. Accordingly, the compounds of the invention are useful in the prophylaxis and / or treatment of diseases which are dependent on the said signaling pathways through interaction with one or more of the said signaling pathways. The present invention therefore relates to the invention

Compounds as promoters or inhibitors, preferably as inhibitors of the signaling pathways described herein. Preferred subject of the

The invention therefore relates to compounds according to the invention as promoters or inhibitors, preferably as inhibitors of the Raf kinase pathway. A preferred subject of the invention are therefore according to the invention

Compounds as promoters or inhibitors, preferably as inhibitors of Raf kinase. A more preferred subject of the invention are compounds according to the invention as promoters or inhibitors, preferably as inhibitors of one or more Raf kinases, selected from the group consisting of A-Raf, B-Raf and C-Raf-1. A particularly preferred subject of the invention are compounds according to the invention as promoters or inhibitors, preferably as inhibitors of C-Raf-1.

Another object of the present invention is the use of one or more compounds according to the invention in the treatment and / or prophylaxis of diseases, preferably the diseases described here, which are caused, mediated and / or propagated by Raf kinases and in particular diseases caused by Raf -Kinases selected from the group consisting of A-Raf, B-Raf and C-Raf-1 are caused, mediated and / or propagated. The diseases discussed here are usually divided into two groups, hyperproliferative and non-hyperproliferative diseases. In this context, psoriasis, arthritis, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and 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 acute leukemia are all considered cancerous diseases, all of which are usually considered to be hyperproliferative diseases. Especially cancerous

Cell growth, and in particular cancerous cell growth mediated by Raf kinase, is a disease that is an object of the present invention. The present invention therefore relates to compounds according to the invention as medicaments and / or 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.

It can be shown that the compounds according to the invention are antiproliferative in vivo in a xenograft tumor model

Have effect. The compounds of the invention are administered to a patient with a hyperproliferative disease, e.g. For example, to inhibit tumor growth, to reduce inflammation associated with lymphoproliferative disease, to inhibit graft rejection or neurological damage due to tissue repair, etc. The present compounds are useful for prophylactic or therapeutic purposes. As used herein, the term "treating" is used to refer to both the prevention of diseases and the treatment of pre-existing conditions. The prevention of proliferation is described by

Administration of the compounds of the invention before development of the evident disease, e.g. B. to prevent tumor growth,

Preventing metastatic growth, lowering it with cardiovascular surgery associated restenosis, etc. achieved. As

Alternatively, the connections to treatment become more permanent

Diseases through stabilization or improvement of clinical

Symptoms used by the patient.

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

The susceptibility of a particular cell to treatment with the compounds according to the invention can be determined by testing in vitro. Typically, a culture of the cell is combined with a compound of the invention at various concentrations for a period of time sufficient to enable the active agents to induce cell death or to inhibit migration, usually between about an hour and a week. Cultured cells from a biopsy sample can be used for in vitro testing. The viable cells remaining after treatment are then counted.

The dose varies depending on the specific compound used, the specific disease, the patient status, etc. Typically, a therapeutic dose is sufficient to significantly reduce the undesired cell population in the target tissue while the

Viability of the patient is maintained. Treatment generally continues until there is a substantial reduction, e.g. B. at least about 50% reduction in cell load and can be continued until essentially no more unwanted cells are detected in the body. 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 flash plate assay, the radioactive phosphorylation of a protein or peptide is considered

Substrate measured with γATP. If an inhibitory compound is present, no or a reduced radioactive signal is detectable. Homogeneous time-resolved fluorescence resonance energy transfer (HTR-FRET) and fluorescence polarization (FP) technologies are also 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 binding can be detected with a second peroxidase-conjugated anti-sheep antibody by chemiluminescence (Ross et al., 2002, Biochem. J., immediately before publication, manuscript BJ20020786).

There are many with deregulation of cell proliferation and cell death

(Apoptosis) associated diseases. The sufferings of interest include, but are not limited to, the following sufferings. The compounds of the invention are useful in the treatment of a

A number of different disorders in which proliferation and / or migration of smooth muscle cells and / or inflammatory cells into the intimal layer of a vessel is present, resulting in restricted blood flow to this vessel, e.g. B. in neointimal occlusive lesions. Occlusive graft vascular diseases of interest include atherosclerosis, coronary vascular disease after transplantation, venous graft stenosis, peri-anastomotic prosthetic restenosis and restenosis

Angioplasty or stent placement and the like. The compounds according to the invention are also suitable as p38 kinases

Inhibitors.

Other heteroaryl ureas that inhibit p38 kinase are in WO

02/85859.

STATE OF THE ART

WO 02/44156 describes benzimidazole derivatives other than TIE-2 and / or VEGFR2 inhibitors. WO 99/32436 discloses substituted phenylureas as Raf kinase inhibitors. From WO 02/062763 and WO 02/085857, quinolyl, isoquinolyl and pyridylurea derivatives are known as Raf kinase inhibitors. Heteroaryl ureas as p38 kinase inhibitors are described in WO 02/85859. WO 00/42012 describes ω-carboxyaryl-diphenylureas as Raf kinase inhibitors and WO 00/41698 as p38 kinase inhibitors. Other aryl and heteroaryl-substituted heterocyclic ureas are disclosed in WO 99/32455 as Raf kinase inhibitors and in WO 99/32110 as p38 kinase inhibitors. Other diphenyl urea derivatives are known from WO 99/32463. Substituted heterocyclic urea derivatives as p38 kinase inhibitors are disclosed in WO 99/32111.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula

wherein

R ¹ , R ¹ 'each independently of one another shark, A, OH, OA, CN, COOH,

COOA, CONH ₂ , CONHA or CONA ₂ , L CH ₂ , CH ₂ CH ₂ , 0, S, SO, S0 ₂ , NH, NA, C = 0 or CHOH,

Y is a heterocycle selected from the list

R ² shark, A, OH, OA, CN, COOH, COOA, CONH ₂ , CONHA or

CONA2, R ³ H, A, NH ₂ , COOH, COOA, CONH ₂ , CONHA, CONA ₂ or

NHCOOA, XS, O, NH, NA or CH ₂ ,

Z -CH =, CH ₂ , NH, -N = or C = 0,

Z 'S or O,

A unbranched, branched or cyclic alkyl with 1 -10 C-

Atoms in which 1-7 H atoms can also be replaced by F and / or chlorine, shark F, Cl, Br or I, m, p, q each independently represent 0, 1, 2, 3 or 4, n 1, 2 or 3, and their pharmaceutically usable derivatives, solvates, salts and

Stereoisomers, including their mixtures in all proportions.

The invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Solvates of the compounds are understood to mean the addition of inert solvent molecules to the compounds, which are formed on account of their mutual attraction. Solvates are e.g. Mono- or dihydrates or alcoholates.

Pharmaceutically usable derivatives are e.g. the salts of the compounds according to the invention and also so-called prodrug compounds.

Prodrug derivatives are understood with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly cleaved in the organism to the active compounds of the invention. This also includes biodegradable polymer derivatives of the compounds according to the invention, as described, for. B. in Int. J. Pharm. 115. 61-67 (1995).

The term "effective amount" means the amount of a drug or active pharmaceutical ingredient that elicits a biological or medical response in a tissue, system, animal or human that is sought or sought by, for example, a researcher or medical professional. Furthermore, the term "therapeutically effective amount" means an amount which, compared to a corresponding subject, means that

Has not received a lot, which results in: improved healing, healing, prevention or elimination of a

Illness, a clinical picture, a disease state, one

Suffering, a disorder or side effects or even that

Reducing the progression of a disease, condition or disorder. The term "therapeutically effective amount" also includes

Amounts that are effective in increasing normal physiological function.

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

For all radicals that occur more than once, such as R ¹ , the meanings are independent of one another.

Above and below, the radicals or parameters R ¹ , L, Y, m and p have the meanings given in formula I, unless expressly stated otherwise.

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

2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl, more preferably, for example, trifluoromethyl. A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

Atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or

1, 1, 1 trifluoroethyl. A also means cycloalkyl.

Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl,

Cyclohexyl or cycloheptyl.

R ¹ preferably denotes A or shark, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl, 1, 1, 1-trifluoroethyl, Fluorine or chlorine; trifluoromethyl, F or Br is particularly preferred.

R ¹ 'is preferably A or shark, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl, 1, 1, 1-trifluoroethyl, fluorine or bromine; very particularly preferably methyl, ethyl, propyl, fluorine or bromine.

L is preferably O, S or CH ₂ , particularly preferably O.

R s2. preferably means A, e.g. Methyl, ethyl, propyl, butyl or pentyl; COOA, such as Methoxycarbonyl, ethoxycarbonyl; or CONH.

R ³ is preferably H, NH ₂ or COOA, such as methoxycarbonyl or ethoxycarbonyl.

m is preferably 1, 2 or 3. p is preferably 0 or 1. q is preferably 0 or 1.

In the meanings for Y

the radical (s) R and the linking bond -} can occupy any position in the bi- or tricyclic ring system, and is not restricted to the ring, as indicated in the formulas.

(R ² ) _c

{

In the dotting means that either one

Single or a double bond can be present.

The compounds of formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms. Formula I encompasses all of these forms.

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 la R ¹ A or Hai, m is 1, 2 or 3;

in Ib R ^{1 is} CF ₃ , F or Br, m is 1, 2 or 3;

in Ic R ^{1 '} shark or A,

P represents 0 or 1;

in Id means LO, S or CH ₂ ;

in le R ^{2 is} A, COOA or CONH ₂ , q is 0, 1 or 2;

in If R ^{3 is} H, NH ₂ or COOA;

in ig R ¹ A or shark, m 1, 2 or 3, R ^{1 '} shark or A,

P 0 or 1,. LO, S or CH ₂ , a heterocycle selected from the list

R ^ώ A, COOA or CONH ₂ , q 0, 1 or 2,

R ° is H, NH ₂ or COOA, n is 1, 2 or 3; as well as their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all ratios.

The invention relates to the compounds of formula I and their salts and a process for the preparation of compounds of formula I according to claims 1-10 and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, characterized in that

a compound of formula II

wherein R ¹ and m have the meanings given in Claim 1,

with a compound of formula III

in which R ¹ , L, Y and p have the meanings given in claim 1,

implements,

and / or converts a base or acid of the formula I into one of its salts.

The compounds of the invention and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Veriag, Stuttgart) , namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail. If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately converted further into the compounds according to the invention.

Compounds of formula I are preferably obtained by

Reacts compounds of formula II with compounds of formula III.

The reaction is usually carried out in an inert solvent, in the presence of a coupling reagent such as e.g. N, N'-diisopropyl carbodiimide.

Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature is between about 0 ° and 150 °, normally between 20 ° and 130 °.

Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.

The starting compounds are generally known. If they are new, they can be manufactured according to methods known per se. The thioisocyanates of the formula III are preferably obtained from the corresponding aniline derivatives by reaction with, for example, 1,1'-thiocarbonyldiimidazole.

A base of the compounds according to the invention can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. So inorganic acids can be used, e.g. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. Formic acid, acetic acid, trifluoroacetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic , p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds according to the invention.

The invention further relates to the use of the compounds and / or their physiologically acceptable salts for the production of a medicament (pharmaceutical preparation), in particular in a non-chemical way. Here they can be combined with at least one solid, liquid and / or semi-liquid carrier or auxiliary and if necessary, in combination with one or more other active ingredients are brought into a suitable dosage form.

The invention further relates to medicaments containing at least one compound according to the invention and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their

Mixtures in all ratios, as well as carrier and / or

Excipients.

Pharmaceutical formulations can be presented in the form of dose units containing a predetermined amount of active ingredient per dose unit. Such a unit can contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a compound according to the invention, depending on the condition of the disease treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be presented in the form of dose units containing a predetermined amount of active ingredient per dose unit. Preferred dosage unit formulations are those which contain a daily dose or partial dose, as stated above, or a corresponding fraction thereof of an active ingredient. Furthermore, such pharmaceutical formulations can be produced using one of the methods generally known in the pharmaceutical field.

Pharmaceutical formulations can be administered by any suitable route, for example orally

(including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.

Such formulations can be prepared by any method known in the pharmaceutical art, for example by the Active ingredient is brought together with the carrier (s) or auxiliary (s).

Pharmaceutical formulations adapted for oral administration can be used as separate units, e.g. Capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam dishes; or

Oil-in-water liquid emulsions or water-in-oil liquid emulsions.

For example, in the case of oral administration in the form of a tablet or capsule, the active ingredient component can be treated with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as e.g. Ethanol, glycerin, water etc. combine. Powders are made by comminuting the compound to an appropriate fine size and with a similarly comminuted pharmaceutical carrier such as e.g. an edible carbohydrate such as starch or mannitol is mixed. A flavor, preservative, dispersant and color may also be present.

Capsules are made by making a powder mixture as described above and filling shaped gelatin shells with it. Lubricants such as e.g. finely divided silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process. A disintegrant or solubilizer, e.g. Agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medication after taking the capsule.

In addition, if desired or necessary, suitable binding lubricants and disintegrants and dyes can also be added to the mixture be incorporated. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners from corn, natural and synthetic gums such as acacia,

Tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol,

Waxes, etc. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and others. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and others. The tablets are formulated by, for example, producing a powder mixture, granulating or pressing them dry, adding a lubricant and a disintegrant and compressing the whole thing into tablets. A powder mixture is prepared by appropriately comminuting the compound with a diluent or a base as described above and optionally with a binder such as e.g. Carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a solution slower, e.g. Paraffin, a resorption accelerator, e.g. a quaternary salt and / or an absorbent such as e.g. Bentonite, kaolin or dicalcium phosphate is mixed. The powder mixture can be granulated by mixing it with a binder such as e.g. Syrup, starch paste, Acadia slime or solutions made of cellulose or polymer materials are wetted and pressed through a sieve. As an alternative to

The powder mixture can be granulated through a tabletting machine, with irregularly shaped lumps which are broken up into granules. The granules can be greased by adding stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets. The compounds according to the invention can also be combined with a free-flowing inert carrier and then pressed directly into tablets without carrying out the granulation or dry compression steps. A transparent or opaque protective layer consisting of A shellac sealant, a layer of sugar or polymeric material, and a glossy layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.

Oral liquids, e.g. Solution, syrups and elixirs can be prepared in unit dosage forms so that a given quantity contains a given amount of the compound. Syrups can be made by dissolving the compound in an aqueous solution with a suitable taste, while elixirs are made using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,

Preservatives, flavor additives, e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, etc. can also be added.

Dosage unit formulations for oral administration can optionally be enclosed in microcapsules. The formulation can also be prepared in such a way that the release is prolonged or delayed, for example by coating or embedding particulate material in polymers, wax and the like.

The compounds according to the invention and salts, solvates and physiologically functional derivatives thereof can also be in the form of

Liposome delivery systems such as administer small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.

Liposomes can be made from various phospholipids, e.g.

Cholesterol, stearylamine or phosphatidylcholines. The compounds of the invention and the salts, solvates and physiologically functional derivatives thereof can also be found under

Use of monoclonal antibodies as individual carriers to which the

Compound molecules are coupled, supplied. The

Compounds can also be targeted with soluble polymers

Drug carriers are coupled. Such polymers can be polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol,

Polyhydroxyethylaspartamide phenol or polyethylene oxide polylysine substituted with palmitoyl residues. Furthermore, the

Connections to a class of biodegradable polymers that are suitable for achieving controlled release of a drug, e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutter acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipatic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration can be administered as independent patches for prolonged, close contact with the epidermis of the recipient. For example, the active ingredient can be supplied from the patch by means of iontophoresis, as generally described in Pharmaceutical Research, 3 (6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, e.g. Mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated into an ointment, the active ingredient can be either paraffinic or water-miscible

Cream base can be used. Alternatively, the active ingredient can be a Cream can be formulated with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eye include eye drops, the active ingredient being dissolved or suspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical adapted to the topical application in the mouth

Formulations include lozenges, lozenges and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can be administered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration, in which the carrier substance is a solid, contain a coarse powder with a particle size, for example in the range of 20-500 micrometers, which is administered in the manner in which snuff is taken up, i.e. by rapid inhalation via the nasal passages from a container with the powder held close to the nose. Suitable formulations for administration as a nasal spray or nasal drops with a liquid as carrier include active ingredient solutions in water or oil.

Pharmaceutical adapted for inhalation administration

Formulations include fine particulate dusts or mists using various types of pressurized dispensers

Aerosols, nebulizers or insufflators can be generated.

Pharmaceutical formulations adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations. Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions, the antioxidants, buffers, bacteriostatics and solutes, through which the formulation is isotonic with the blood of the person to be treated

Recipient is made included; as well as aqueous and non-aqueous sterile suspensions, which can contain suspending agents and thickeners. The formulations can be in single dose or multiple dose containers, e.g. sealed ampoules and vials, presented and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections is required immediately before use. Injection solutions and suspensions prepared according to the recipe can be made from sterile powders, granules and tablets.

It is understood that the formulations may contain, in addition to the above-mentioned ingredients, other means common in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration may contain flavorings.

A therapeutically effective amount of a compound of the present invention depends on a number of factors, including, for example, the age and weight of the animal, the exact condition of the disease requiring treatment, its severity, the nature of the formulation and the route of administration, and will ultimately determined by the attending doctor or veterinarian. However, an effective amount of a compound according to the invention for the treatment of neoplastic growth, for example colon or breast carcinoma, is generally in the range from 0.1 to 100 mg / kg body weight of the recipient (mammal) per day and particularly typically in the range from 1 to 10 mg / kg body weight per day. That would be enough for a 70 kg adult mammals, the actual amount per day is usually between 70 and 700 mg, which amount can be given as a single dose per day or more usually in a series of divided doses (such as two, three, four, five or six) per day so that the total daily dose is the same. An effective amount of a salt or solvate or a physiologically functional derivative thereof can be used as a proportion of the effective

Amount of the compound of the invention can be determined perse. It is believed that similar dosages are suitable for the treatment of the other conditions mentioned above.

The invention further relates to medicaments containing at least one compound according to the invention and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and at least one further active pharmaceutical ingredient.

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

(a) an effective amount of a compound according to the invention and / or its pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all ratios, and

(b) an effective amount of another drug ingredient.

The set contains suitable containers, such as boxes or cartons, individual bottles, bags or ampoules. The set can contain, for example, separate ampoules, each containing an effective amount of a compound according to the invention and / or its pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all ratios, and an effective amount of another drug ingredient is dissolved or in lyophilized form.

USE

The present compounds are suitable as pharmaceutical active substances for mammals, in particular for humans, in the treatment of tyrosine kinase-related diseases. To this

Diseases include tumor cell proliferation, pathological neovascularization (or angiogenesis) that promotes the growth of solid tumors, neovascularization (diabetic retinopathy, age-related macular degeneration and the like) and inflammation 5 (psoriasis, rheumatoid arthritis and the like) ,

The present invention comprises the use of the compounds according to the invention according to claim 1 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of cancer. Preferred carcinomas for the treatment come from the group of brain carcinoma, urogenital tract carcinoma, carcinoma of the lymphatic system, gastric carcinoma, larynx carcinoma and lung carcinoma. Another group of preferred 5 types of cancer are monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma. The use of the compounds according to the invention and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of a disease in which angiogenesis is involved is also included. 5 One such disease in which angiogenesis is involved is an eye disorder such as retinal vascularization, diabetic retinopathy, age-related macular degeneration and the like.

The use of compounds according to the invention according to claim 1 and / or their physiologically acceptable salts and solvates for

The manufacture of a medicament for the treatment or prevention of inflammatory diseases also falls within the scope of the present invention. Such inflammatory diseases include, for example, rheumatoid arthritis, psoriasis, contact dermatitis, late-type hypersensitivity reaction and the like. Also included is the use of the compounds according to the invention as claimed in claim 1 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of a tyrosine kinase-related disease or a tyrosine kinase-related condition in a mammal, this method being a sick mammal such treatment requires a therapeutically effective amount of a compound of the invention. The therapeutic amount depends on the respective disease and can be determined by the person skilled in the art without any great effort. The present invention also includes the use of the compounds according to the invention and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of retinal vascularization. Methods for treating or preventing eye diseases such as diabetic retinopathy and age-related macular degeneration are also part of the invention. The use for the treatment or prevention of inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis and late types of the hypersensitivity reaction, as well as the treatment or prevention of bone pathologies from the group of osteosarcoma, osteoarthritis and rickets also falls within the scope of the present invention. The term "tyrosine kinase-related diseases or conditions" refers to pathological conditions that result from the activity of one or more

Tyrosine kinases are dependent. The tyrosine kinases are either directly or indirectly involved in the signal transduction pathways of various cell activities, including proliferation, adhesion and migration as well as differentiation. Diseases associated with tyrosine kinase activity include tumor cell proliferation, pathological neovascularization that promotes the growth of solid tumors, neovascularization (diabetic retinopathy, age-related macular degeneration and the like), and inflammation (psoriasis, rheumatoid arthritis and the like) ).

The compounds of claim 1 according to the invention can

Patients are given for cancer treatment. The present compounds inhibit tumor angiogenesis and thus influence the growth of tumors (J. Rak et al. Cancer Research, 55: 4575-4580, 1995). The angiogenesis-inhibiting properties of the present compounds according to claim 1 are also suitable for the treatment of certain forms of blindness which are associated with retinal vascularization. The compounds according to claim 1 are also suitable for the treatment of certain bone pathologies such as osteosarcoma, osteoarthritis and

Rachitis, 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, p. 623- 628, June 1999). Since VEGF directly promotes osteoclastic bone resorption through the KDR / Flk-1 expressed in mature osteoclasts (FEBS Let. 473: 161-164 (2000); Endocrinology, 141: 1667 (2000)), the present compounds are also suitable for treatment and prevention of conditions related to bone resorption, such as osteoporosis and Paget's disease. The compounds can be characterized by the fact that they have cerebral edema,

Reduce tissue damage and ischemic reperfusion injury, also to reduce or prevent tissue damage that occurs after cerebral ischemic events such as stroke (Drug News Perspect 11: 265-270 (1998); J. Clin.

Invest. 104: 1613-1620 (1999)).

The invention thus relates to the use of compounds according to claim 1, and their pharmaceutically usable derivatives, solvates, salts 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 plays a role.

Kinases are preferably selected from the group of tyrosine kinases and Raf kinases.

The tyrosine kinases are preferably TIE-2.

Preferred is the use of compounds according to claim 1, as well as their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all ratios, for the manufacture of a medicament for the treatment of diseases which are influenced by the compounds according to claim 1 by inhibiting the tyrosine kinases become.

Particularly preferred is the use for the manufacture of a medicament for the treatment of diseases which are influenced by inhibition of TIE-2 by the compounds according to claim 1. The use for the treatment of a disease is particularly preferred, the disease being a solid tumor. The solid tumor is preferably selected from the group consisting of brain tumor, tumor of the genitourinary tract, tumor of the lymphatic system, stomach tumor, larynx tumor and lung tumor.

The solid tumor is also preferably selected from the group consisting of monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma.

The invention further relates to the use of the compounds according to the invention for the treatment of a disease in which angiogenesis is involved.

The disease is preferably an eye disease.

The invention further relates to the use for the treatment of retinal vascularization, diabetic retinopathy, age-related macular degeneration and / or inflammatory diseases.

The inflammatory disease is preferably selected from the group rheumatoid arthritis, psoriasis, contact dermatitis and late-type hypersensitivity reaction.

The invention further relates to the use of the compounds according to the invention for the treatment of bone pathologies, the bone pathology coming from the group of osteosarcoma, osteoarthritis and rickets.

The compounds according to claim 1 are suitable for the preparation of a

Medicament for the treatment of diseases caused by Raf kinases, mediated and / or propagated, wherein the Raf kinase is selected from the group consisting of A-Raf, B-Raf and Raf-1. Preferred is the use for the treatment of diseases, preferably from the group of hyperproliferative and non-hyperproliferative diseases.

These are cancers or non-cancerous diseases.

The non-cancerous diseases are selected from the group consisting of 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 brain cancer, lung cancer, squamous cell cancer, bladder cancer, stomach cancer, pancreatic cancer, liver cancer, kidney cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophageal cancer, gynecological cancer, thyroid cancer, lymphoma and chronic leukemia, chronic leukemia.

The compounds of the invention can also be used in conjunction with other well-known therapeutic agents based on their respective

Suitability for the condition being treated can be administered. For example, in the case of bone disorders, combinations that contain antiresorptive bisphosphonates, such as alendronate and risedronate, integrin blockers (as defined below), such as αvß3 antagonists, conjugated estrogens such as Prempro®, Premarin® and Endometrion® used in hormone therapy would be beneficial; contain selective estrogen receptor modulators (SERMs) such as raloxifene, droloxifene, CP-336,156 (Pfizer) and lasofoxifene, cathepsin K inhibitors and ATP proton pump inhibitors. The present compounds are also suitable for combination with known anti-cancer agents. These known anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxics, antiproliferative Agent, prenyl protein transferase inhibitor, HMG-CoA reductase inhibitor,

HIV protease inhibitors, reverse transcriptase inhibitors and others

Angiogenesis inhibitors. The present compounds are particularly suitable for joint use with radiotherapy. The synergistic effects of inhibiting VEGF in combination with

Radiotherapy has been described in the professional world (see WO

00/61186).

"Estrogen receptor modulators" refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of how this is done. The estrogen receptor modulators include, for example, tamoxifen, raloxifene, idoxifene, LY353381, LY 117081, toremifene, fulvestrant , 4- [7- (2,2-Dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1 - piperidinyl) ethoxy] phenyl] -2H-1 - benzopyran-3-yl] phenyl -2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646, which, however, is not intended to be a limitation.

"Androgen receptor modulators" refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of how this is done. The androgen receptor modulators include, for example, finasteride and other 5α-reductase inhibitors, Nilutamide, Flutamide, Bicalutamide , Liarozole and abiraterone acetate.

"Retinoid receptor modulators" refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of how this is done. Such retinoid receptor modulators include, for example, bexarotene, tretinoin, 13-cis-retinoic acid, 9- cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl) retinamide and N-4-carboxyphenylretinamide. "Cytotoxics" refers to compounds that are primarily affected by direct action on cell function lead to cell death or which inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalating agents, microtubulin inhibitors and topoisomerase

Inhibitors.

The cytotoxics include, 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)] bis [diamine (chloro) platinum (II)] - tetrachloride, diarizidinyl spermine, arsenic trioxide, 1 - (11 -dodecylamino-10-hydroxyundecyl) -3,7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, Mitoxantrone, pirarubicin,

Pinafid, Valrubicin, Amrubicin, Antineoplaston, 3'-Desamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin, Annamycin, Galarubicin, Elinafid, MEN10755 and 4-Desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl daunorubicin (see WO 00/50032), but this should not be a limitation.

The microtubulin inhibitors include, for example, paclitaxel, vindesin sulfate, S '^' - Dideshydro ^ '- deoxy-δ'-norvincaleukoblastin, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR1097676, VinMSin Cryptophycin, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine, N, N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl -L-prolyl-L-prolin-t-butylamide, TDX258 and BMS188797. Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecan, e-ethoxypropionyl-S '^' - O-exo-benzylidene-chartreusin, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4,5 -kl] acridine-2- (δH) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1 H, 12H-benzo [de] pyrano [3 ', ^4,: b, 7] indolizino [1, 2b] quinoline-10 _J 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-thioxanthen-4-ylmethyl] formamide, N- (2- (dimethylamino) ethyl) acridine-4-carboxamide, 6 - [[2- (dimethylamino) ethyl] amino] -3-hydroxy-7H-indeno [2,1-c] quinoline-7- on and Dimesna. The "antiproliferative agents" include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, as well as antimetabolites such as enocitabine, Carmofur, Tegafur, pentostatin, doxifluridine, trimetrexate, flabinarababin, capud ocfosfat, fosteabin sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidencytidine, 2'-fluoromethylene-2'-deoxycytidine, 3- dihydrobenzofuryl) sulfonyl] -N '- (3,4-dichlorophenyl) urea, N6- [4-deoxy- 4- [N2- [2 (E), 4 (E) -tetradecadienoyl] glycylamino] -L-glycero -BL-manno- heptopyranosyljadenine, aplidine, ecteinascidine, troxacitabine, 4- [2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino [5,4-b] [1,4] thiazine -6-yl- (S) -ethyl] - 2,5-thienoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, 11-acetyl-8- (carbamoyloxymethyl) -4-formyl-6-methoxy-14- oxa-1, 11 -diaza-tetracyclo (7.4.1.0.0) -tetradeca-2,4,6-trien-9-ylacetic acid ester, Swainson in, lometrexol, dexrazoxane, methioninase, 2'-cyan-2'-deoxy-N4-palmitoyl-1-BD-arabinofuranosylcytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. The "antiproliferative agents" also contain monoclonal antibodies against growth factors other than those already mentioned under the "angiogenesis inhibitors", such as trastuzumab, and tumor suppressor genes, such as p53, which mediate via recombinant virus Gene transfer can be delivered (see, for example, US Patent No. 6,069,134).

The invention furthermore relates to the use of the compounds according to the invention for the production of a medicament for

Treatment of diseases, the disease being disturbed by

Angiogenesis is characterized. The disease is preferably cancer. The disturbed angiogenesis preferably results from an impaired VEGFR-1, VEGFR-2 and / or VEGFR-3 activity. It is therefore particularly preferred to use the compounds according to the invention for the manufacture of a medicament for inhibiting VEGFR-2 activity.

ASSAYS

The compounds of the invention described in the examples were tested in the assays described below and were found to have a kinase inhibitory effect. Further assays are known from the literature and could easily be carried out by a person skilled in the art (see, for example, Dhanabal et al., Cancer Res. 59: 189-197; Xin et al., J. Biol. Chem. 274: 9116-9121; Sheu et 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

VEGF receptor kinase activity is determined by incorporating radioactively labeled phosphate in 4: 1 polyglutamic acid / tyrosine substrate (pEY). The phosphorylated pEY product is held on a filter membrane and the incorporation of the radioactively labeled phosphate is quantified by scintillation counting. MATERIALS

VEGF receptor kinase

The intracellular tyrosine kinase domains of the human KDR

(Terman, B.I. et al. Oncogene (1991) Vol. 6, pp. 1677-1683.) And Flt-1

(Shibuya, M. et al. Oncogene (1990) Vol. 5, pp. 519-524) were considered

Glutathione-S-transferase (GST) gene fusion proteins. This was done by cloning the cytoplasmic domain of the KDR kinase as a read-frame fusion at the carboxy terminus of the GST gene. The soluble recombinant GST-kinase domain fusion proteins were found in

Spodoptera frugiperda (Sf21) insect cells (Invitrogen) under

Use of a baculovirus expression vector (pAcG2T,

Pharmingen) expressed.

lysis buffer

50mM Tris pH 7.4, 0.5M NaCl, 5mM DTT, 1mM EDTA, 0.5% Triton X-

100, 10% glycerin, each 10 mg / ml leupeptin, pepstatin and aprotinin as well

1mM phenylmethylsulfonyl fluoride (all from Sigma). wash buffer

50mM Tris pH 7.4, 0.5M NaCI, 5mM DTT, 1mM EDTA, 0.05% Triton X-

100, 10% glycerol, 10 mg / ml each of leupeptin, pepstatin and aprotinin and 1 mM phenylmethylsulfonyl fluoride.

dialysis buffer

50mM Tris pH 7.4, 0.5M NaCI, 5mM DTT, 1mM EDTA, 0.05% Triton X-

100, 50% glycerol, 10 mg / ml each of leupeptin, pepstatin and aprotinin and 1 mM phenylmethylsulfonyl fluoride.

10x 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 = BSA] (Sigma).

Enzyme Diluent

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

10x substrate 750 µg / ml poly (glutamic acid / tyrosine; 4: 1) (Sigma).

Stop Solution

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

wash solution

15% trichloroacetic acid, 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 challenged with the recombinant virus in an m.o.i. (Multiplicity of infection) of 5 virus particles / cell infected and grown for 48 hours at 27 ° C. 2. All steps were carried out at 4 ° C. The infected cells were harvested by centrifugation at 1000xg and lysed for 30 minutes at 4 ° C with 1/10 volume of lysis buffer and then centrifuged at 100,000xg for 1 hour. The supernatant was then passed over a glutathione-Sepharose acid (Pharmacia) equilibrated with lysis buffer and washed with 5 volumes of the same buffer and then 5 volumes of wash buffer. The recombinant GST-KDR protein was eluted with wash buffer / 10 mM reduced glutathione (Sigma) and dialyzed against dialysis buffer. Method B - VEGF Receptor Kinase Assay 1. Add 5 μl inhibitor or control to 50% DMSO in the assay.

2. Add 35 μl reaction mixture containing 5 μl 10x reaction buffer, 5 μl 25 mM ATP / 10 μCi [ ³³ P] ATP (Amersham) and 5 μl 10x substrate.

3. Start the reaction by adding 10 μl KDR (25 nM) in enzyme dilution buffer.

4. Mix and incubate for 15 minutes at room temperature.

5. Stop the reaction by adding 50 μl stop solution. 6. Incubate at 4 ° C for 15 minutes.

7. Transfer 90 μl aliquot to filter plate.

8. Aspirate and wash 3 times with washing solution. 9. Add 30 μl of scintillation cocktail, close the plate and count in a Wallac Microbeta scintillation counter. Mitogenesis assay on human umbilical vein endothelial cells

The expression of VEGF receptors that have mitogenic responses to the

Mediating growth factor is largely limited 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 described assay, single cell layers of HUVECs are treated with the constituent or the test compound at rest 2 hours before the addition of VEGF or "basic fibroblast growth factor" (bFGF). The mitogenic response to VEGF or bFGF is measured by measuring the incorporation of [ ³ H] thymidine determined in the cell DNA Materials

HUVECs

Frozen HUVECs as primary culture isolates are obtained from Clonetics Corp. The cells are in the endothelial growth medium (endothelial

Growth Medium = EGM; Clonetics) and used in the 3rd - 7th passage for the mitogenicity assays.

culture plates

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

Assay Medium

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

The working stock solutions of the test compounds are diluted in series with 100% dimethyl sulfoxide (DMSO) until their concentrations are 400 times higher than the desired final are concentration. The last dilutions (concentration 1x) are made with assay medium immediately before addition to the cells.

10x growth factors

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

10x [ ³ H] thymidine

[Methyl- 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 . Method 2 The growth stop medium is replaced with 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, 10x VEGF solution or 10x 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, 10x

[ ³ H] thymidine (10 μl / well) 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, the compounds of the formula I are VEGF inhibitors and are therefore suitable for inhibiting angiogenesis, such as in the treatment of eye diseases, for example diabetic retinopathy, and for the treatment of carcinomas, for example solid tumors. The present compounds inhibit VEGF-stimulated mitogenesis of cultured human vascular endothelial cells with HK50 values of 0.01-5.0 μM. These compounds are also selective in comparison to related tyrosine kinases (eg FGFR1 and Src family; for the relationship between Src kinases and VEGFR kinases see Eliceiri et al., Molecular Cell, Vol. 4, pp. 915-924, December 1999) ,

The T / E-2 tests can e.g. can be carried out analogously to the methods specified in WO 02/44156. The assay determines the inhibitory activity of those to be tested

Substances in the phosphorylation of the substrate poly (Glu, Tyr) by Tie-2-Kinase in the presence of radioactive ³³ P-ATP. The phosphorylated substrate binds to the surface of one during the incubation period

"Flash" microtitre plate. After removing the reaction mixture, it is washed several times and then the radioactivity on the

Surface of the microtiter plate measured. An inhibitory effect of the measuring substances results in a lower radioactivity compared to an undisturbed enzymatic reaction.

All temperatures above and below are given in ° C. In the examples below, "customary workup" means: if necessary, water is added, if necessary, depending on the constitution of the

End product to pH values between 2 and 10, extracted with

Ethyl acetate or dichloromethane, separated off, the organic phase dried over sodium sulfate, evaporated and purified by chromatography

Silica gel and / or by crystallization. Rf values on silica gel; Eluent:

Ethyl acetate / methanol 9: 1.

Mass spectrometry (MS): El (electron impact ionization) M ⁺ FAB (Fast Atom Bombardment) (M + H) \ ⁴ +

ESI (Electrospray lonization) (M + H) ⁺

example 1

The Preparation of [4- (Benzo [1,2,5] thiadiazol-5-yloxy) phenyl] - (4-bromo-6-trifluoromethyl-1 H -benzimidazol-2-yl) amine ("A1") takes place according to the following scheme:

1.1 Preparation of 4- (benzo [1,2,5] thiadiazol-5-yloxy) phenylamine

("A2"):

1.8 g of benzo [1, 2.5] thiadiazol-5-ol and 1.3 ml of 4-fluoronitrobenzene are dissolved in 25 ml of DMF and 3.9 g of cesium carbonate are added. The reaction mixture is stirred at 85 C overnight.

For working up, the mixture is mixed with water and extracted with ethyl acetate. The collected organic phase is dried with anhydrous sodium sulfate, filtered and evaporated. The residue is triturated with diethyl ether. 2.8 g of 5- (4-nitrophenoxy) benzo [1,2,5] thiadiazole are obtained; Rf (CH ₂ CI ₂ ) 0.65; EI-MS (M + H) ⁺ 274.

The nitro compound is hydrogenated with Raney nickel to the desired compound. After chromatography with petroleum ether / ethyl acetate, 1.3 g of "A2" are obtained; Rf (petroleum ether / ethyl acetate 1/1) 0.75, EI-MS (M + H) ⁺ 244.

1.2 400 mg of "A2" and 352 mg of 1,1'-thiocarbonyldiimidazole are dissolved in 40 ml of dichloromethane and stirred overnight at room temperature. For working up, the solvent is drawn off on a Rotavapor and the residue is triturated with methanol. The solid substance is suctioned off. 421 mg of the desired thioisocyanate (Rf CH ₂ CI ₂ 0.67) are obtained.

1.3 For further reaction, 89 mg of 1-bromo-2,3-diamino-5-trifluoromethyl-benzene are dissolved in 0.4 ml of dichloromethane. Subsequently, a solution of 100 mg of Thioisocyanates prepared in 0.4 ml of dichloromethane and a 0.05 mL of N, N ^{'-Diisoρropylcarbodiimid} in 0.3 ml of dichloromethane were added sequentially. The reaction mixture is stirred overnight with gentle warming.

For working up, the solvent is evaporated in a rotary evaporator and the residue is chromatographed (silica gel chromatography, petroleum ether / ethyl acetate

8: 2).

60 mg of "A1" are obtained; Rf (petroleum ether / ethyl acetate 1: 1) 0.51;

EI-MS (M + H) ⁺ 508.

For purification, a preparative HPLC can be used with the following

Conditions are used:

Column: RP 18 (7 μm) Lichrosorb 250x25

Eluent: A: 98 H ₂ 0, 2 CH ₃ CN, 0.1% TFA

B: 10 H ₂ 0, 90 CH ₃ CN, 0.1% TFA UV: 225NM; Flow: 10ml / min.

The following compounds are obtained analogously by reacting the aromatic diamine with the corresponding thioisocyanate:

35

35

35

35

ESI-MS

Pharmacological test results

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.

Example B: Suppositories

A mixture of 20 g of an active ingredient according to the invention is melted with 100 g soy lecithin and 1400 g cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: solution

A solution of 1 g of an active ingredient is prepared according to the invention, 9.38 g of NaH ₂ P0 ₄ ^• 2 H ₂ 0, 28.48 g Na ₂ HP0 • 12 H ₂ 0 and 0.1 g of

Benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment

500 mg of an active ingredient according to the invention are mixed with 99.5 g of petroleum jelly under aseptic conditions. Example E: tablets

A mixture of 1 kg of active ingredient, 4 kg of lactose, 1, 2 kg of potato starch,

0.2 kg talc and 0.1 kg magnesium stearate becomes 5 in the usual way

Tablets pressed in such a way that each tablet contains 10 mg of active ingredient.

Example F: coated tablets

^" 10 Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

^ 5 Example G: capsules

2 kg of active ingredient are filled into hard gelatin capsules in a conventional manner so that each capsule contains 20 mg of the active ingredient.

Example H: Ampoules 0

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

25

0

5

Claims

 claims

1. Compounds of the formula

wherein

R ¹ , R ^{1 '} each independently of one another shark, A, OH, OA, CN, COOH,

COOA, CONH ₂ , CONHA or CONA ₂ , L CH ₂ , CH ₂ CH ₂ , O, S, SO, S0 ₂ , NH, NA, C = 0 or CHOH,

Y is a heterocycle selected from the list

R ² shark, A, OH, OA, CN, COOH, COOA, CONH ₂ , CONHA or

CONA2, R ³ H, A, NH ₂ , COOH, COOA, CONH ₂ , CONHA, CONA ₂ or NHCOOA,

XS, O, NH, NA or CH ₂ ,

Z -CH =, CH ₂ , NH, -N = or C = 0, Z ¹ S or O,

A unbranched, branched or cyclic alkyl with 1 -10 C-

Atoms in which 1-7 H atoms can also be replaced by F and / or chlorine, shark F, Cl, Br or I, m, p, q each independently of one another 0, 1, 2, 3 or 4, n 1, 2 or 3, and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all

Conditions.

2. Compounds according to claim 1, wherein R ¹ A or Hai, m is 1, 2 or 3, and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all

Conditions.

Compounds according to claim 1 or 2, wherein

R ^{1 is} CF ₃ , F or Br, m is 1, 2 or 3, and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all

Conditions.

4. Compounds according to one or more of claims 1-3, wherein R is shark or A, p is 0 or 1, and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all ratios.

5. Compounds according to one or more of claims 1-4, wherein LO, S or CH ₂ , and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios.

Compounds according to one or more of claims 1-5, wherein R ² A, COOA or CONH ₂ , q is 0, 1 or 2, and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including mixtures thereof in all ratios.

7. Compounds according to one or more of claims 1-6, wherein R ^{3 is} H, NH ₂ or COOA, and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including mixtures thereof in all

Conditions. Compounds according to one or more of claims 1-7, wherein R ¹ A or shark, m 1, 2 or 3,

R ¹ shark or A, p 0 or 1,

LO, S or CH ₂ ,

Y is a heterocycle selected from the list

R ² A, COOA or CONH ₂₎ q 0, 1 or 2,

R ^{3 is} H, NH ₂ or COOA, n is 1, 2 or 3, and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all

Conditions. Compounds according to claim 1, selected from the group

[4- (benzo [1,2,5] thiadiazol-5-yloxy) phenyl] - (4-bromo-6-trifluoromethyl-1 H -benzimidazol-2-yl) amine,

[4- (benzo [1,2,5] thiadiazol-5-yloxy) phenyl] - (4-chloro-6-trifluoromethyl-1 H -benzimidazol-2-yl) amine,

[4- (benzo [1,3] dioxol-5-yloxy) phenyl] - (4-chloro-6-trifluoromethyl-1 H -benzimidazol-2-yl) amine,

[4- (Benzo [1,2,5] thiadiazol-4-yloxy) phenyl] - (4-bromo-6-trifluoromethyl-1 H -benzimidazol-2-yl) amine,

(4-bromo-6-trifluoromethyl-1 H -benzimidazol-2-yl) - [4- (imidazo [1,2-a] quinolin-9-yloxy) phenyl] amine,

(4-chloro-6-trifluoromethyl-1 H -benzimidazol-2-yl) - [4- (imidazo [1, 2-a] quinolin-9-yloxy) phenyl] amine,

(7-bromo-5-trifluoromethyl-1H-benzimidazol-2-yl) - [4- (2-butylimidazo [4,5-ό] pyridin-4-ylmethyl) phenyl] amine,

[4- (2-butylimidazo [4,5-ό] pyridin-4-ylmethyl) phenyl] - (7-chloro-5-trifluoromethyl-1H-benzimidazol-2-yl) amine,

(4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) - [4- (1H-indol-6-yloxy) phenyl] amine,

[4- (Benzo [1,2,5] thiadiazol-4-yloxy) phenyl] - (4-chloro-6-trifluoromethyl-1 / - / - benzimidazol-2-yl) amine, (4-bromo 6-trifluoromethyl-1 H-benzimidazol-2-yl) - [4- (1 H-indol-5-yloxy) phenyl] amine,

(4-chloro-6-trifluoromethyl-1 H -benzimidazol-2-yl) - [4- (1H-indol-5-yloxy) phenyl] amine, (4-bromo-6-trifluoromethyl-1H- benzimidazol-2-yl) - [4- (1 H-indol-6-yloxy) phenyl] amine,

(7-bromo-5-trifluoromethyl-1 H -benzimidazol-2-yl) - (4-imidazo [4,5-ö] pyridin-3-ylmethylphenyl) amine,

(7-chloro-5-trifluoromethyl-1 H -benzimidazol-2-yl) - (4-imidazo [4,5-b] pyridin-3-ylmethylphenyl) amine, (7-bromo-5-trifluoromethyl-1 H -benzimidazol-2-yl) - [4- (2,3,6,7-tetrahydro-1H, 5H-pyrido [3,2,1-i] quinoline- 8-yloxy) -phenyl] -amine,

(7-chloro-5-trifluoromethyl-1 H -benzimidazol-2-yI) - [4- (2,3,6,7-tetrahydro-1H, 5H-pyrido [3,2,1-ij] quinoline- 8-yloxy) -phenyl] -amine,

5- [4- (7-bromo-5-trifluoromethyl-1 H -benzimidazol-2-ylamino) phenoxy] -1 / - indole-2-carboxylic acid ethyl ester,

5- [4- (7-Chloro-5-trifluoromethyl-1H-benzimidazol-2-ylamino) phenoxy] -1 H-indole-2-carboxylic acid, ethyl ester, 7- [4- (7-bromo-5-trifluoromethyl -1 H-benzimidazol-2-ylaminq) phenoxy] benzofuran-2-carboxylic acid methyl ester

Methyl 7- [4- (7-chloro-5-trifluoromethyl-1 H -benzimidazol-2-ylamino) phenoxy] benzofuran-2-carboxylate, [4- (benzo [1,2,5] oxadiazole-5 -yloxy) -phenyl] - (4-bromo-6-trifluoromethyl-1 / - / - benzimidazol-2-yl) amine,

7- [4- (4-bromo-6-trifluoromethyl-1 H -benzimidazol-2-ylamino) phenoxy] benzofuran-2-carboxylic acid amide,

7- [4- (4-chloro-6-trifluoromethyl-1 H -benzimidazol-2-ylamino) phenoxy] benzofuran-2-carboxylic acid amide,

[4- (Benzo [1,2,5] oxadiazol-5-yloxy) phenyl] - (4-fluoro-6-trifluoromethyl-1 H -benzimidazol-2-yl) amine,

[4- (benzo [1,2,5] thiadiazol-4-yloxy) phenyl] - (4-fluoro-6-trifluoromethyl-1 H -benzimidazol-2-yl) amine,

[4- (Benzo [1, 3] dioxol-5-yloxy) phenyl] - (4-bromo-6-trifluoromethyl-1 H -benzimidazol-2-yl) amine,

(4-bromo-6-trifluoromethyl-1 H -benzimidazol-2-yl) - [4- (3-methyl-3H-imidazo [4,5-c] pyridin-4-ylsulfanyl) phenyl] amine,

6- [4- (7-chloro-5-trifluoromethyl-1 H -benzimidazol-2-ylamino) phenoxy] -4,7-dimethyl-benzothiazol-2-ylamine,

(7-chloro-5-trifluoromethyl-1 H -benzimidazol-2-yl) - [4- (imidazo [1,2-a] pyridin-8-yloxy) phenyl] amine, [4- (benzo [1,2,5] thiadiazol-5-yloxy) phenyl] - (4-fluoro-6-trifluoromethyl-1 H -benzimidazol-2-yl) amine,

[4- (benzo [1,2,5] thiadiazol-5-yloxy) phenyl] - (4,6-difluoro-1 H -benzimidazol-2-yl) amine,

(4-bromo-6-trifluoromethyl-1 H -benzimidazol-2-yl) - [2- (2,3-dihydrobenzo [1, 4] dioxin-6-yloxy) phenyl] amine,

[4- (Benzo [1,2,5] thiadiazol-5-yloxy) phenyl] - (4,5-difluoro-1 H -benzimidazol-2-yl) amine, [4- (Benzo [1,2 , 5] thiadiazol-5-yloxy) phenyl] - (5,6-difluoro-1 H -benzimidazol-2-yl) amine,

(7-chloro-5-trifluoromethyl-1 H -benzimidazol-2-yl) - [2- (2,3-dihydrobenzo [1, 4] dioxin-6-yloxy) phenyl] amine, 6- [ 4- (7-chloro-5-trifluoromethyl-1 H -benzimidazol-2-ylamino) phenoxy] benzothiazol-2-ylamine,

(6,7-difluoro-1 H -benzimidazol-2-yl) - [4- (3-methyl-3H-imidazo [4,5-c] pyridin-4-ylsulfanyl) phenyl] amine,

(4-bromo-6-trifluoromethyl-1 H -benzimidazol-2-yI) - [4- (2-methylbenzothiazol-5-yloxy) phenyl] amine,

(4-chloro-6-trifluoromethyl-1 H -benzimidazol-2-yl) - [4- (2-methylbenzothiazol-5-yloxy) phenyl] amine,

[2- (benzo [1,2,5] thiadiazol-5-yloxy) phenyl] - (4-bromo-6-trifluoromethyl-1 H -benzimidazol-2-yl) amine,

(7-bromo-5-trifluoromethyl-1 H -benzimidazol-2-yl) - [4- (imidazo [1, 2-a] pyridin-8-yloxy) phenyl] amine,

[2- (benzo [1,2,5] thiadiazol-5-yloxy) phenyl] - (7-chloro-5-trifluoromethyl-1 H -benzimidazol-2-yl) amine,

(4-bromo-6-trifluoromethyl-1 H -benzimidazol-2-yl) - [4- (2,3-dihydrobenzo [1, 4] dioxin-6-yloxy) phenyl] amine,

(7-chloro-5-trifluoromethyl-1 H -benzimidazol-2-yl) - [4- (2,3-dihydrobenzo [1, 4] dioxin-6-yloxy) phenyl] amine, [2- (benzo [1,2,5] thiadiazol-4-yloxy) phenyl] - (4-bromo-6-trifluoromethyl-1 H -benzimidazol-2-yl) amine,

[2- (benzo [1,2,5] thiadiazol-4-yloxy) phenyl] - (7-chloro-5-trifluoromethyl-1 / - -benzimidazol-2-yl) amine,

(4-bromo-6-trifluoromethyl-1 H -benzimidazol-2-yl) - [4- (1-methyl-1H-imidazo [4,5-c] pyridin-4-ylsulfanyl) phenyl] amine,

[4- (Benzo [1,2,5] thiadiazol-5-yloxy) -3-methylphenyl] - (7-bromo-5- trifluoromethyl-1 - benzimidazol-2-yl) amine, [4- (Benzo [1,2,5] thiadiazol-5-yloxy) -3-methylphenyl] - (7-chloro-5-trifluoromethyl-1 H -benzimidazol-2-yl) amine,

[4- (Benzo [1,2,5] thiadiazol-5-yloxy) -2-methylphenyl] - (7-bromo-5- trifluoromethyl-1 H -benzimidazol-2-yl) amine, [4- (Benzo [1,2,5] thiadiazol-5-yloxy) -2-methylphenyl] - (7-chloro-5-trifluoromethyl-1 H -benzimidazol-2-yl) amine,

(4-bromo-6-trifluoromethyl-1 H -benzimidazol-2-yl) - [4- (2,3-dihydrobenzo [1, 4] dioxin-5-yloxy) phenyl] amine,

(4-chloro-6-trifluoromethyl-1 H -benzimidazol-2-yl) - [4- (2,3-dihydrobenzo [1, 4] dioxin-5-yloxy) -phenylj-amine,

[4- (Benzo [1,3] dioxol-4-yloxy) phenyl] - (4-bromo-6-trifluoromethyl-1 H -benzimidazol-2-yl) amine,

[4- (Benzo [1, 3] dioxol-4-yloxy) phenyl] - (4-chloro-6-trifluoromethyl-1 H-benzimidazol-2-yl) amine,

[4- (benzo [1,3] dioxol-5-yloxy) phenyl] - (4,5-difluoro-1 H -benzimidazol-2-yl) amine,

[4- (benzo [1,3] dioxol-5-yloxy) phenyl] - (5-fluoro-1 H -benzimidazol-2-yl) amine,

[4- (benzo [1,3] dioxol-5-yloxy) phenyl] - (4,6-difluoro-1 H -benzimidazol-2-yl) amine,

[4- (Benzo [1, 2,5] thiadiazol-5-yloχy) phenyl] - (5-fluoro-1 H -benzimidazol-2-yl) amine, [4- (benzo [1,2,5] thiadiazol-5-yloxy) phenyl] - (4,5,6-trifluoro-1 H -benzimidazol-2-yl) amine,

(6-chloro-4-trifluoromethyl-1 H -benzimidazol-2-yl) - [2- (2,3-dihydrobenzo [1, 4] dioxin-6-yloxy) phenyl] amine,

[4- (benzo [1,2,5] thiadiazol-5-ylsulfanyl) phenyl] - (4-bromo-6-trifluoromethyl-1 H -benzimidazol-2-yl) amine,

[4- (Benzo [1,2,5] thiadiazol-5-ylsulfanyl) phenyl] - (4-chloro-6-trifluoromethyl-1 H -benzimidazol-2-yl) amine, (4-bromo-6- trifluoromethyl-1 H -benzimidazol-2-yl) - [4- (indan-5-yloxy) phenyl] amine,

5- [4- (6-fluoro-1 H -benzimidazol-2-ylamino) phenoxy] indan-1 -one,

[4- (benzo [1,2,5] thiadiazol-5-yloxy) -3-fluorophenyl] - (7-bromo-5- trifluoromethyl-1 H -benzimidazol-2-yl) amine,

[4- (benzo [1,2,5] thiadiazol-5-yloxy) -3-fluorophenyl] - (7-chloro-5-trifluoromethyl-1 - benzimidazol-2-yl) amine,

(6,7-difluoro-1 H -benzimidazol-2-yl) - [4- (indan-5-yloxy) phenyl] amine,

(6-fluoro-1 H -benzimidazol-2-yl) - [4- (indan-5-yloxy) phenyl] amine,

[4- (indan-5-yloxy) phenyl] - (5,6,7-trifluoro-1 H -benzimidazol-2-yl) amine,

(5,7-difluoro-1 H -benzimidazol-2-yl) - [4- (indan-5-yloxy) phenyl] amine,

Ethyl 5- [4- (4-bromo-6-trifluoromethyl-1H-benzimidazol-2-ylamino) phenoxy] benzofuran-2-carboxylate,

5- [4- (4-chloro-6-trifluoromethyl-1 H -benzimidazol-2-ylamino) phenoxy] benzofuran-2-carboxylic acid ethyl ester,

as well as their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all

Conditions.

0. A process for the preparation of compounds of formula I according to claims 1-9 and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, characterized in that

a compound of formula II

wherein R ¹ and m have the meanings given in Claim 1,

with a compound of formula III

in which R ^{1 '} , L, Y and p have the meanings given in claim 1,

implements,

and / or converts a base or acid of the formula I into one of its salts.

11. Medicament containing at least one compound according to claim

1 and / or their pharmaceutically usable derivatives, solvates,

Salts and stereoisomers, including their mixtures in all

Ratios, and optionally carrier and / or auxiliary substances.

12. Use of compounds according to claim 1, and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all

Conditions, for the manufacture of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of the ₅ signal transduction of kinases plays a role.

13. Use according to claim 12, wherein the kinases are selected from the group of

Tyrosine kinases and Raf kinases. 0

14. Use according to claim 13, wherein the tyrosine kinases are TIE-2. 5 15. Use according to claim 12 of compounds according to claim 1, and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all ratios, Q for the manufacture of a medicament for the treatment of diseases caused by the inhibition of tyrosine kinases by the compounds be influenced according to claim 1.

16. Use according to claim 15, for the manufacture of a medicament5 for the treatment of diseases which are influenced by inhibition of TIE-2 by the compounds according to claim 1.

17. Use according to claim 15 or 16, wherein the disease to be treated is a solid tumor.

18. Use according to claim 17, wherein the solid tumor comes from the group of brain tumor, tumor of the genitourinary tract, tumor of the lymphatic system, stomach tumor, larynx tumor and lung tumor.

19. Use according to claim 17, wherein the solid tumor comes from the group monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma.

20. Use according to claim 15 or 16 for the treatment of a disease in which angiogenesis is involved.

21. Use according to claim 20, wherein the disease is an eye disease.

22. Use according to claim 15 or 16 for the treatment of retinal vascularization, diabetic retinopathy, age-related macular degeneration and / or inflammatory diseases.

23. Use according to claim 22, wherein the inflammatory disease comes from the group of rheumatoid arthritis, psoriasis, contact dermatitis and late-type hypersensitivity reaction.

24. Use according to claim 15 or 16 for the treatment of

Bone pathologies, with bone pathology from the group

Osteosarcoma, osteoarthritis and rickets originated.

25. Medicament containing at least one compound according to

Claim 1 and / or their pharmaceutically usable derivatives,

Solvates, salts and stereoisomers, including their mixtures in all proportions, and at least one other

Drug ingredient.

26. Set (kit) consisting of separate packs of

(a) an effective amount of a compound according to claim 1 and / or its pharmaceutically usable derivatives,

Solvates, salts and stereoisomers, including their mixtures in all proportions, and (b) an effective amount of another

Drug ingredient.

27. Use of compounds according to claim 1 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment of solid tumors, wherein a therapeutically effective amount of a compound according to claim 1 in combination with a compound from group 1) estrogen receptor modulator , 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic, 5) antiproliferative agent, 6)

Prenyl protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8) HIV protease inhibitor, 9) reverse transcriptase inhibitor and 10) other angiogenesis inhibitor.

28. Use of compounds according to claim 1 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment of solid tumors, wherein a therapeutically effective amount of a compound according to claim 1 in combination with radiotherapy and 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

Inhibitor and 10) other angiogenesis inhibitor is administered.

29. Use according to claim 12, 13 or 14, for the manufacture of a medicament for the treatment of diseases which are based on an impaired TIE-2 activity, wherein a therapeutically effective amount of a compound according to

Claim 1 is administered in combination with a growth factor receptor inhibitor.

₅ 30. Use according to claim 12 or 13 of compounds according to claim 1, and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all proportions, for the manufacture of a medicament for the treatment of diseases 0 caused by Raf kinases , mediated and / or propagated.

Use according to claim 30, wherein the Raf kinase is selected from the group consisting of A-Raf, B-Raf and Raf-1.

32. Use according to claim 30, wherein the diseases are selected from the group of hyperproliferative and non-Q hyperproliferative diseases.

33. Use according to claim 30 or 32, wherein the disease is cancer. 5

34. Use according to claim 30 or 32, wherein the disease is not cancerous.

35. Use according to claim 30, 32 or 34, wherein the non-cancerous diseases are selected from the group consisting of psoriasis, arthritis, inflammation, endometriosis,

Scarring, benign prostatic hyperplasia, immunological

Diseases, autoimmune diseases and immune deficiency diseases.

36. Use according to any one of claims 30, 32 or 33, wherein the diseases are selected from the group consisting of brain cancer, lung cancer, squamous cell cancer, bladder cancer, stomach cancer, pancreatic cancer, liver cancer, kidney cancer, colorectal cancer, breast cancer, head cancer, neck cancer, esophageal cancer , gynecological cancer, thyroid cancer, lymphoma, chronic leukemia and acute leukemia.