EP1685136A1 - Utilisation de thienopyrimidines - Google Patents

Utilisation de thienopyrimidines

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Publication number
EP1685136A1
EP1685136A1 EP04765963A EP04765963A EP1685136A1 EP 1685136 A1 EP1685136 A1 EP 1685136A1 EP 04765963 A EP04765963 A EP 04765963A EP 04765963 A EP04765963 A EP 04765963A EP 1685136 A1 EP1685136 A1 EP 1685136A1
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EP
European Patent Office
Prior art keywords
pyrimidine
chloro
thieno
pyridin
methylthieno
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
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EP04765963A
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German (de)
English (en)
Inventor
Hans-Michael Eggenweiler
Alfred Jonczyk
Gerhard Barnickel
Wilfried Rautenberg
Helga Drosdat
Arne Sutter
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Merck Patent GmbH
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Merck Patent GmbH
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Publication date
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Publication of EP1685136A1 publication Critical patent/EP1685136A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
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    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the object of the invention was to find new compounds and / or new uses of compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the present invention relates to compounds and the use of compounds in which the inhibition, regulation and / or modulation of the signal transduction of kinases, in particular the tyrosine kinases
  • the present invention concerns compounds and the use of compounds that inhibit the signal transduction of tyrosine kinases to regulate and / or modulate cooperation "p. Settlements containing these compounds and methods for their use
  • tyrosine kinase-related diseases and conditions such as angiogenesis, cancer, tumor formation, growth and spread, arteriosclerosis, eye diseases, such as age-related
  • Retinopathy inflammatory diseases, arthritis, thrombosis, fibrosis,
  • Glomerulonephritis neurodegeneration, psoriasis, restenosis,
  • the tyrosine kinases are a class of enzymes with at least 400 members that are responsible for the transmission of the terminal
  • tyrosine 5 kinases play an important role in signal transduction in various cell functions via substrate phosphorylation.
  • 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 one
  • the receptor tyrosine kinases consist of a large number of transmembrane receptors with different biological effectiveness. Around 20 different subfamilies of receptor tyrosine kinases have been identified.
  • a tyrosine kinase subfamily called the HER subfamily consists of EGFR, HER2, HER3 and HER4.
  • the ligands of this receptor subfamily include the epithelial growth factor, TGF- ⁇ , amphiregulin, HB-EGF, betacellulin and heregulin.
  • the insulin subfamily which includes INS-R, IGF-IR and IR-R, is another subfamily of these receptor tyrosine kinases.
  • the PDGF subfamily includes the PDGF- ⁇ and - ⁇ - receptor, CSFIR, c- kit and Q 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.
  • KDR kinase insert domain receptor
  • FLK-1 fetal liver kinase-1
  • FLK-4 fetal liver kinase-4
  • flt-1 fms tyrosine kinase-1
  • RTKs receptor tyrosine kinases
  • TIE2 receptor tyrosine kinases
  • TIE1 is known as a homologue of TIE2.
  • the TIE RTKs are selectively expressed on endothelial cells and are used in processes of angiogenesis and maturation of the blood vessels. As a result, they can be a valuable target, particularly in the case of diseases of the vascular system and pathologies in which vessels are used or even remodeled. In addition to preventing new vascularization and maturation, stimulating new vascularization can also be a valuable target for drugs.
  • angiogenesis, tumor development and kinase signaling by G. Breier Placenta (2000) 21, Suppl A, Trophoblasr Res 14, S11-S15
  • the cytosolic tyrosine kinases also consist of a large number of subfamilies, including Src, Frk, Btk, Csk, Abi, Zap70, Fes / Fps, Fak,
  • the Src subfamily is one of the largest subfamilies. It includes Src, Yes, Fyn, Lyn, Lck, BIk, Hck, Fgr and Yrk.
  • the Src enzyme subfamily has been linked to ontogenesis. For a more detailed discussion of cytosolic tyrosine kinases, see the work of Bolen Oncogene, 8: 2025-2031
  • Both the receptor tyrosine kinases and the cytosolic tyrosine kinases are involved in cell signaling pathways that lead to various conditions, including cancer, psoriasis and hyper-immune reactions.
  • Various receptor tyrosine kinases and the growth factors that bind them have been suggested to play a role in angiogenesis, although some may promote angiogenesis indirectly (Mustonen and Alitalo, J. Cell 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.
  • VEGFR-2 vascular endothelial cell growth factor receptor 2
  • VEGF and KDR represent a ligand-receptor pair that play an essential role in the proliferation of vascular endothelial cells and
  • vasculogenesis Formation and sprouting of the blood vessels, which are called vasculogenesis or angiogenesis, plays.
  • VEGF vascular endothelial growth factor
  • KDR transmembrane tyrosine kinase receptor
  • Flt-1 vascular endothelial cell growth factor receptor 1
  • PTK protein tyrosine kinase
  • VEGFR-1 (Flt-1); VEGRF-2 (Flk-1 or KDR) and VEGFR-3 (Flt-1)
  • VEGFR-2 is of particular interest.
  • Solid tumors can therefore be treated with tyrosine kinase inhibitors ⁇ 5 , since these tumors are used to support their formation
  • Blood vessels required for growth are dependent on angiogenesis.
  • These solid tumors include monocyte leukemia, brain, urogenital, lymphatic, gastric, larynx, and lung cancer, including lung adenocarcinoma and small cell lung cancer.
  • lung cancer including lung adenocarcinoma and small cell lung cancer.
  • These cancers include pancreatic and breast cancer. Inhibitors of these tyrosine kinases are therefore suitable for the prevention and treatment of proliferative diseases which are caused by these enzymes.
  • VEGF vascular endothelial growth factor
  • VEGF mRNA and protein levels in the eye are increased due to conditions such as retinal venous occlusion in the primate and reduced p0 2 levels in the mouse, which lead to neovascularization.
  • VEGF expression is also greatly increased in hypoxic regions of animal and human tumors in addition to necrosis zones.
  • VEGF is also characterized by the expression of the oncogenes ras, raf, src and p53-
  • Anti-VEGF monoclonal antibodies inhibit the
  • VEGF not as an autocrine mitogenic factor. VEGF therefore contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotaxis and mitogenesis activity.
  • monoclonal antibodies also inhibit the growth of typically less vascularized human colon carcinomas in 0 thymus-less mice and reduce the number of tumors arising from inoculated cells.
  • VEGF-binding construct of Flk-1, Flt-1 the mouse KDR receptor homolog shortened to remove the cytoplasmic tyrosine kinase domains, but 5 while maintaining a membrane anchor, virtually stops the growth of a transplantable glioblastoma in the mouse, presumably due to the dominant-negative mechanism of heterodimer formation with trans-Q membranous endothelial cell VEGF receptors.
  • Embryo stem cells which usually grow in the form of solid tumors in the nude mouse, do not form any detectable tumors when all VEGF alleles are knocked out. These data together show the role of VEGF in the growth of solid tumors.
  • the inhibition of KDR or Flt-1 5 is involved in pathological angiogenesis, and these receptors are suitable for the treatment of diseases in which angiogenesis part of the total pathology, e.g. inflammation, diabetic retinal
  • Vascularization as well as various forms of cancer, since it is known that tumor growth is dependent on angiogenesis (Weidner et al., N. Engl. J. Med., 324, pp. 1-8, 1991).
  • Angiopoietin 1 (Ang1), a ligand for the endothelium-specific receptor tyrosine kinase TIE-2, is a new angiogenic factor (Davis et al, Cell, 1996, 87: 1161-1169; Partanen et al, Mol. Cell Biol ., 12: 1698-1707 (1992); U.S. Patent Nos. 5,521,073; 5,879,672; 5,877,020; and 6,030,831).
  • TIE stands for "Tyrosine Kinase with Ig and EGF Homology Domains".
  • TIE is used to identify a class of receptor tyrosine kinases that are only expressed in vascular endothelial cells and early hemopoietic cells.
  • TIE receptor kinases are typically characterized by the presence of an EGF- similar domain and an immunoglobulin (IG) -like domain, which consists of extracellular folding units which are stabilized by inter-chain disulfide bonds (Partanen et al. Curr. Topics Microbiol. Immunol., 1999, 237: 159-172)
  • IG immunoglobulin
  • Ang1 and its receptor TIE-2 act during the later stages of vascular development, i.e.
  • TIE-2 would be expected to disrupt the remodeling and maturation of a new vascular system initiated by angiogenesis and thereby the angiogenesis process. Furthermore, inhibition at the kinase domain binding site of VEGFR-2 would block the phosphorylation of tyrosine residues and more serve to interrupt the initiation of angiogenesis. It can therefore be assumed that inhibition of TIE-2 and / or VEGFR-2 should prevent tumor angiogenesis and serve to slow down or completely eliminate tumor growth.
  • the present invention is directed to methods for regulation
  • TIE-2 Modulation or inhibition of TIE-2 for the prevention and / or treatment of diseases related to unregulated or impaired TIE-2 activity.
  • the compounds of the formula I can also be used in the treatment of certain forms of cancer.
  • the compounds of formula I can be used to provide additive or synergistic effects in certain existing cancer chemotherapy regimens and / or can be used to restore the effectiveness of certain existing cancer chemotherapy regimens and radiation treatments.
  • the compounds of the formula I can be used to isolate and to study the activity or expression of TIE-2. They are also particularly suitable for use in diagnostic procedures for diseases in connection with unregulated or impaired TIE-2 activity.
  • 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 present invention further relates to the compounds of the formula as inhibitors of Raf kinases.
  • Protein phosphorylation is a fundamental process for the regulation of cell functions. The coordinated action of both protein kinases and phosphatases controls the levels of phosphorylation and consequently the activity of specific target proteins.
  • Role of protein phosphorylation is in signal transduction when extracellular signals are amplified and by a cascade of protein
  • Phosphorylation and dephosphorylation events e.g. B. are propagated in the p21 ras / raf way.
  • the p21 ras gene was discovered as an oncogene of the Harvey and Kirsten rat sarcoma viruses (H-Ras and K-Ras, respectively).
  • H-Ras and K-Ras characteristic mutations in the cellular Ras gene (c-Ras) have been associated with many different types of cancer.
  • c-Ras characteristic mutations in the cellular Ras gene
  • These mutant alleles that make Ras constitutively active have been shown to transform cells, such as the murine cell line NIH 3T3, in culture.
  • the p21 ras oncogene is an important contributing factor in the development and progression of solid human carcinomas and is mutated in 30% of all human carcinomas (Bolton et al. (1994) Ann. Rep. Med. Chem., 29, 165-74; Bos. (1989) Cancer Res., 49, 4682-9).
  • the Ras protein is a key element of the signal transduction cascade, which is controlled by growth factor receptors in almost all tissues (Avruch et al. (1994) Trends Biochem. Sei., 19, 279-83) ,
  • Ras is a guanine nucleotide binding protein, and the cycling between a GTP-linked activated and a GDP-linked quiescent form is strictly controlled by Ras endogenous GTPase activity and other regulatory proteins.
  • the Ras gene product binds to guanine triphosphate (GTP) and guanine diphosphate (GDP) and hydrolyzes GTP to GDP. Ras is active in the GTP-bound state.
  • the endogenous GTPase activity is reduced in the Ras mutants in cancer cells. weakens, and consequently the protein indicates constitutive growth signals
  • Downstream RT effectors such as the enzyme Raf Kinase.
  • Ras proto oncogene requires a functionally intact C-Raf-1 proto-
  • Oncogene to transduce growth and differentiation signals initiated in higher eukaryotes by receptor and non-receptor tyrosine kinases.
  • Ras Activated Ras is necessary for the activation of the C-Raf-1 proto-oncogene, but the biochemical steps by which Ras activates the Raf-1 protein (Ser / Thr) kinase have now been well characterized. It has been shown to inhibit the effect of active Ras
  • Raf kinase signaling pathway Inhibition of the Raf kinase signaling pathway by administration of deactivating antibodies against Raf kinase or by co-expression of dominant negative Raf kinase or dominant negative MEK (MAPKK), the substrate of Raf kinase, leads to the reversion of transformed cells to the normal growth phenotype, see: Daum et al. (1994) Trends
  • Raf kinase by antisense oligodeoxynucleotides
  • inhibition of Raf kinase in vitro and in vivo has been associated with the inhibition of growth in a number of different human tumor types (Monia et al., Nat. Med. 1996, 2, 668- 75).
  • Raf-serine and threonine-specific protein kinases are cytosolic enzymes that stimulate cell growth in a number of different cell systems (Rapp, U.R., et al. (1988) in The Oncogene Handbook; T.
  • Raf-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, S.M. (1990) Oncogene 5: 345-351).
  • Raf genes are proto-oncogenes: they can initiate the malignant transformation of cells if they are expressed in specifically modified forms. Genetic changes that lead to oncogenic activation produce a constitutively active protein kinase by removal or interference with an N-terminal negative regulatory domain of the protein (Heidecker, G., et al. (1990) Mol. Cell. Biol. 10: 2503-2512 ; Rapp, UR, et al. (1987) in Oncogenes and Cancer; SA Aaronson, J. Bishop, T. Sugimura, M. Terada, K. Toyoshima and PK Vogt (ed.) Japan Scientific Press, Tokyo).
  • Raf-1 protein serine kinase is a candidate for the "downstream" effector of mitogen signal transduction because Raf oncogenes face growth arrest resulting from blockade of cellular Ras activity due to a cellular mutation (Ras revertant cells) or microinjection of anti-Ras antibodies results (Rapp, UR, et al. (1988) in The Oncogene Handbook, T. Curran, EP Reddy and A. Skalka (ed.), Elsevier Science Publishers; Netherlands, S. 213-253; Smith, MR, et al. (1986) Nature (London) 320: 540-543).
  • 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.
  • PDGF platelets growth factor
  • 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
  • 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 that contain activated Raf are changed in their gene expression pattern
  • Raf-oncogenes activate transcription from Ap-1 / PEA3-dependent promotors in transient transfection assays (Jamal, S., et al. (1990) Science
  • Raf-1 protein phosphorylation may be a consequence of a kinase cascade that is amplified by autophosphorylation, or may be entirely caused by autophosphorylation that is by binding a putative activation ligand to the Raf-1 regulator domain, analogous to PKC activation Diacylglycerol is initiated (Nishizuka, Y. (1986) Science 233: 305-312).
  • Proteins occur predominantly with serine, threonine or tyrosine residues, and protein kinases were therefore selected according to their specificity for the location of the phosphoryl. H. of serine / threonine kinases and tyrosine kinases. Because phosphorylation is such a common process in
  • the compounds according to the invention are inhibitors of the enzyme Raf kinase. Since the enzyme is a "downstream" effector of p21 ras , the inhibitors in pharmaceutical compositions for human or veterinary use are found to be useful when inhibiting the Raf kinase pathway, for example in the treatment of tumors and / or by Raf kinase mediated cancerous cell growth is indicated.
  • Carcinomas in humans and animals e.g. B. of murine cancer, since the
  • the compound of the invention or a pharmaceutically acceptable salt thereof is administered for the treatment of diseases mediated by the Raf kinase route, particularly cancer, including solid carcinomas such as carcinomas (e.g. the lungs, pancreas) , thyroid, bladder or colon), myeloid diseases (e.g. myeloid leukemia) or adenomas (e.g. villous colon adenoma), pathological angiogenesis and metastatic cell migration.
  • the compounds are also useful in the treatment of complement activation dependent chronic inflammation (Niculescu et al. (2002) Immunol. Res., 24: 191-199) and immunodeficiency induced by HIV-1 (Human Immunodeficiency Virus Type 1) (Popik et al. (1998) J Virol, 72: 6406-6413).
  • 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.
  • the compounds according to the invention preferably show and bring about an inhibitory effect which is usually documented by IC 50 values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range. As discussed herein, these signaling pathways are different
  • the present invention therefore relates to the invention
  • Preferred objects of the invention are therefore compounds according to the invention as promoters or inhibitors, preferably as inhibitors of the Raf kinase pathway.
  • a preferred subject of the invention is therefore compounds according to the invention as promoters or inhibitors, preferably as inhibitors of Raf kinase.
  • a more preferred subject of the invention are compounds according to the invention as promoters or inhibitors, preferably as inhibitors of one or more Raf kinases, selected from the group consisting of A-Raf, B-Raf and C-Raf-1.
  • a particularly preferred subject of the invention are compounds according to the invention as promoters or inhibitors, preferably as inhibitors of C-Raf-1.
  • the present invention furthermore relates to the use of one or more compounds according to the invention in the treatment and / or prophylaxis of diseases, preferably the diseases described here, which are caused, mediated and / or propagated by Raf kinases and in particular diseases which are caused by Raf -Kinases selected from the group consisting of A-Raf, B-Raf and C-Raf-1 are caused, mediated and / or propagated.
  • the diseases discussed here are usually divided into two groups, hyperproliferative and non-hyperproliferative diseases.
  • psoriasis, arthritis, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and immune deficiency diseases are not considered cancerous diseases, of which arthritis, inflammation, immunological diseases, autoimmune diseases and immunodeficiency diseases are usually considered non-hyperproliferative
  • 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 commonly regarded as hyperproliferative diseases.
  • cancerous cell growth and in particular cancerous cell growth mediated by Raf kinase is a disease which is an object of the present invention.
  • the present invention therefore relates to compounds according to the invention as 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.
  • the compounds according to the invention have an in vivo antiproliferative effect in a xenograft tumor model.
  • the compounds of the invention are administered to a patient with a hyperproliferative disease, e.g. For example, to inhibit tumor growth, to reduce inflammation associated with lymphoproliferative disease, to inhibit graft rejection or neurological damage due to tissue repair, etc.
  • a hyperproliferative disease e.g. For example, to inhibit tumor growth, to reduce inflammation associated with lymphoproliferative disease, to inhibit graft rejection or neurological damage due to tissue repair, etc.
  • the present compounds are useful for prophylactic or therapeutic purposes.
  • the term "treat" is used to refer to both the Disease prevention as well as pre-existing treatment
  • the host or patient can belong to any mammalian species, e.g. B. a primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for treating a human disease.
  • mammalian species e.g. B. a primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for treating a human disease.
  • the susceptibility of a particular cell to treatment with the compounds according to the invention can be determined by 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 avoid the undesirable
  • Viability of the patient is maintained.
  • the treatment will generally continue until there is a substantial reduction, e.g. B. at least about 50% reduction in cell load and can be continued until essentially no more unwanted cells are detected in the body.
  • kinase inhibitors Various assay systems are available for the identification of kinase inhibitors.
  • the radioactive phosphorylation of a protein or peptide as a substrate with ⁇ ATP is measured in the scintillation proximity assay (Sorg et al., J. of. Biomolecular Screening, 2002, 7, 11-19) and the FlashPlate assay. If an inhibitory compound is present, no or a reduced radioactive signal is detectable.
  • HTR-FRET homogeneous time-resolved fluorescence resonance energy transfer
  • FP fluorescence polarization
  • phospho-AK specific phospho-antibodies
  • the phospho-AK only binds the phosphorylated substrate. This binding can be detected with a second peroxidase-conjugated anti-sheep antibody by chemiluminescence (Ross et al., 2002, Biochem. J., immediately before publication, manuscript BJ20020786).
  • the sufferings of interest include, but are not limited to, the following sufferings.
  • the compounds of the invention are useful in the treatment of a number of different conditions in which proliferation and / or migration of smooth muscle cells and / or inflammatory cells is present in the intimal layer of a vessel, resulting in reduced blood flow to this vessel, e.g. B. in neointimal occlusive lesions.
  • Occlusive graft vascular diseases of interest include atherosclerosis, coronary vascular disease after transplantation, vein graft stenosis, peri-anastomotic prosthesis restenosis, restenosis after angioplasty or stent placement and the like.
  • the compounds according to the invention are also suitable as p38 kinases
  • the invention relates to the use of compounds of the formula I.
  • R ⁇ 1, ⁇ R2 each independently of one another H, A, OA, alkenyl, alkynyl,
  • Stereoisomers including their mixtures in all proportions, for the manufacture of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation of the
  • the invention also relates to the use of 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.
  • compositions are taken to mean, for example, 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 in the organism quickly to the effective invention
  • the term "effective amount” means the amount of a drug or active pharmaceutical ingredient that elicits a biological or medical response in a tissue, system, animal or human, e.g. is sought or sought by a researcher or medical professional.
  • terapéuticaally effective amount means an amount which, compared to a corresponding subject who has not received this amount, has the following consequences: improved treatment, healing, prevention or elimination of a disease, a clinical picture, a disease state, one Suffering, a disorder or side effects, or even reducing the progression of an illness, suffering or disorder.
  • therapeutically effective amount also includes
  • the invention also relates to the use of mixtures of the compounds of the formula I, for example mixtures of two diastereomers, for example in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereoisomeric compounds.
  • the radicals R 1 , R 2 , R 3 , R 4 , X, L and n have the meanings given in the formula I, unless expressly stated otherwise.
  • a and A ' are preferably each independently alkyl
  • alkyl is preferably unbranched and has 1, 2, 3, 4, 5 or 6 carbon atoms, preferably 1, 2, 3, 4 or 5 carbon atoms and is preferably methyl, ethyl or propyl, more preferably iso - Propyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl or isopentyl.
  • Alkyl also means e.g. Trifluoromethyl.
  • Alkylene is preferably unbranched and preferably means propylene, butylene or pentylene.
  • R 1 and R 2 are preferably H, while the other is preferably propyl or butyl, but particularly preferably ethyl or methyl. Furthermore, R 1 and R 2 together preferably also mean propylene, butylene or pentylene.
  • Shark is preferably F, Cl or Br, but also I, particularly preferably F or CI.
  • Alkenyl is preferably vinyl, 1- or 2-propenyl, 1-butenyl, isobutenyl, sec-butenyl, further preferred is 1-pentenyl, isopentyl or 1-hexenyl.
  • Alkynyl preferably represents ethynyl, propin-1-yl, furthermore butyn-1-,
  • R 3 and R 4 can be the same or different and are preferably in the 3- or 4-position of the phenyl ring. They each mean, for example, independently of one another H, alkyl, alkoxy, hydroxy,
  • R 3 , R 4 are particularly preferably H, F, methoxy, hydroxy or together 3,4-methylenedioxy.
  • the radical X is preferably unsubstituted or mono-, di- or trisubstituted by alkyl, shark or CF 3- substituted 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2nd -, 4- or 5-imidazolyl, 2-methyl-1-imidazol-1-yl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1 , 2,3-triazol-1-, -4- or -5- yl, 1, 2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1, 2,3 -Oxadiazol-4- or -5-yl, 1, 2,4-oxadiazol-3
  • X particularly preferably denotes 1-, 2-, 4- or 5-imidazolyl, 2-methyl-1-imidazol-1-yl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4- Pyridyl, 2-, 4-, 5- or 6-pyhmidinyl, further preferably 1, 2,3-triazol-1-, -4- or -5-yl, 1, 2,4-triazol-1-, -3 - or 5-yl, 3- or 4-pyridazinyl or pyrazinyl.
  • X also means morpholinyl, 4-Y-piperidin-1-yl or 4-Y-piperazin-1-yl, where Y is H, A, OH, -CH 2 OH or -CH 2 CH 2 OH.
  • the invention relates in particular to the use of those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Ih, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
  • la X represents morpholinyl, imidazolyl or pyridinyl
  • R 1 , R 2 each independently of one another H, A, OA,
  • R 3 and R 4 together -0-CH 2 -CH 2 -, -0-CH 2 -0- or
  • X is morpholinyl, imidazolyl or pyridinyl and n is 1;
  • R 1 , R 2 each independently of one another H, A, OA,
  • R 3 , R 4 each independently of one another H, A, OA, Hai, N0 2 ,
  • X is morpholinyl, imidazolyl or pyridinyl and n is 1;
  • R 3 and R 4 together -0-CH 2 -CH 2 -, -0-CH 2 -0- or -0-CH 2 -CH 2 -0,
  • X is morpholinyl, imidazolyl or pyridinyl and n is 1;
  • R 3 , R 4 each independently of one another H, A, OA, Hai, N0 2 ,
  • X is morpholinyl, imidazolyl or pyridinyl and n 1;
  • R 1 and R 2 together alkylene with 3-5 C atoms, R 3 , R 4 each independently of one another H, OA, OH or shark,
  • R 3 and R 4 together -0-CH 2 -CH 2 -, -O-CH 2 -O- or
  • R 1 and R 2 together alkylene with 3-5 C atoms, R 3 , R 4 each independently of one another H, OA, OH or shark,
  • R 3 and R 4 together -0-CH 2 -CH 2 -, -0-CH 2 -0- or -0-CH 2 -CH 2 -0,
  • compositions can be presented in the form of dose units containing a predetermined amount of active ingredient per dose unit.
  • a unit can contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a compound according to the invention, depending on the condition of the disease treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be presented in the form of dose units containing a predetermined amount of active ingredient per dose unit.
  • Preferred dosage unit formulations are those which contain a daily dose or partial dose, as stated above, or a corresponding fraction thereof of an active ingredient.
  • such pharmaceutical formulations can be produced using one of the methods generally known in the pharmaceutical field.
  • compositions can be administered by any suitable route, for example orally
  • 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).
  • compositions 5 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
  • the active drug component can be, for example, in oral administration in the form of a tablet or capsule with an oral, non • l 5-toxic and pharmaceutically acceptable inert excipient, such combined, such as ethanol, glycerol, water.
  • an oral, non • l 5-toxic and pharmaceutically acceptable inert excipient such combined, such as ethanol, glycerol, water.
  • Powders are made by crushing the compound to an appropriate fine size and with a similarly crushed pharmaceutical carrier, such as an edible carbohydrate such as, for example
  • starch or mannitol is mixed.
  • a flavor, preservative, dispersant and color may also be present.
  • Capsules are made by making a powder mixture as described above and filling shaped gelatin shells with it.
  • Lubricants and lubricants such as highly disperse silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process.
  • a 30 disintegrating agent or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament after the capsule.
  • suitable binding agents include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners from corn, natural and synthetic gums such as acacia,
  • 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,
  • 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 made
  • a binder such as carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a solution slower, such as paraffin, a resorption accelerator , such as a quaternary salt and / or an absorbent such as bentonite, kaolin or dicalcium phosphate, is mixed.
  • the powder mixture can be granulated by wetting it with a binder, such as syrup, starch paste, Acadia slime or solutions made of cellulose or polymer materials, and pressing it through a sieve.
  • a binder such as syrup, starch paste, Acadia slime or solutions made of cellulose or polymer materials
  • 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 Q of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds.
  • the greased mixture is then compressed into tablets.
  • the compounds according to the invention can also be combined with a free-flowing inert carrier and then without carrying out the granulation
  • 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,
  • 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 of the formula I and salts, solvates and physiologically functional derivatives thereof can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of the formula I and the salts, solvates and physiologically functional derivatives thereof can also be supplied using monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds can also be coupled with 5 soluble polymers as targeted drug carriers.
  • Such polymers can be polyvinyl pyrrolidone, pyran copolymer,
  • the compounds can be linked to a class of biodegradable polymers suitable for achieving controlled release of a drug, e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters,
  • polyacetals polydihydroxypyrans, polycyanoacrylates and cross-linked or amphipatic block copolymers of hydrogels.
  • compositions adapted for transdermal administration can be used as independent patches for longer, narrow ones
  • the active ingredient can be supplied from the patch by means of iontophoresis, as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
  • Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient can be used either with a paraffinic or with a water-miscible cream base.
  • the active ingredient can be a Cream can be formulated with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical application to the eye include eye drops, the active ingredient being dissolved or suspended in a suitable carrier, in particular an aqueous solvent.
  • Formulations include lozenges, lozenges and mouthwashes.
  • compositions adapted for rectal administration can be administered in the form of suppositories or enemas.
  • compositions adapted for nasal administration in which the carrier substance is a solid, contain a coarse 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.
  • compositions adapted for administration by inhalation include fine particulate dusts or mists which can be generated by means of various types of pressurized metering dispensers with aerosols, nebulizers or insufflators.
  • Pharmaceutical formulations adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • Formulations include aqueous and non-aqueous sterile solutions for injection containing antioxidants, buffers, bacteriostatics and solutes by which the formulation is rendered isotonic with the blood of the recipient to be treated; as well as aqueous and non-aqueous sterile suspensions, which can contain suspending agents and thickeners.
  • the formulations can be in single dose or multiple dose containers, e.g. sealed ampoules and vials, presented and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for
  • Injection solutions and suspensions prepared according to the recipe can be made from sterile powders, granules and tablets.
  • formulations may contain, in addition to the above-mentioned ingredients, other means common in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration may contain flavorings.
  • a therapeutically effective amount of a compound of Formula I depends on a number of factors, including e.g. the age and
  • Weight of the animal the exact disease state that requires treatment, its severity, the nature of the formulation and the route of administration, and is ultimately determined by the treating doctor or veterinarian. However, an effective one
  • Amount of a compound according to the invention for the treatment of neoplastic growth, such as colon or breast cancer, generally in the range of 0.1 to 100 mg / kg body weight of the
  • Recipient per day and particularly typically in the range of 1 to 10 mg / kg body weight per day.
  • the actual amount per day would usually be between 70 and 700 mg, which amount as a single dose per day or more usually in a series of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same.
  • An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined perse as a proportion of the effective amount of the compound of the invention. It is believed that similar dosages are suitable for the treatment of the other conditions mentioned above.
  • the present compounds are suitable as pharmaceutical active substances for mammals, in particular for humans, in the treatment of tyrosine kinase-related diseases.
  • diseases include tumor cell proliferation, pathological neovascularization (or angiogenesis) that promotes the growth of solid tumors, neovascularization (diabetic retinopathy, age-related macular degeneration and the like), and inflammation (psoriasis, rheumatoid arthritis and the like).
  • the present invention includes the use of the compounds of formula I 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 cancer Another group of preferred forms of cancer are Monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma. Also included is the use of the invention
  • angiogenesis is an eye disorder such as retinal vascularization, diabetic retinopathy, age-related macular degeneration and the like.
  • eye disorder such as retinal vascularization, diabetic retinopathy, age-related macular degeneration and the like.
  • the use of compounds of formula I 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.
  • the present invention also encompasses the use of compounds of the formula I and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment or prevention of retinal vascularization.
  • Procedures to treat or prevent eye diseases such as diabetic retinopathy and age-related macular degeneration are also part of the invention.
  • Use to treat or prevent inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis and late types of hypersensitivity reaction, as well as the treatment or prevention of bone
  • tyrosine kinase-related diseases or ailments refers to pathological conditions that are dependent on the activity of one or more tyrosine kinases.
  • the tyrosine kinases are either directly or indirectly involved in the signal transduction pathways of various cell activities, including proliferation, adhesion and migration and differentiation and differentiation
  • Diseases associated with tyrosine kinase activity include tumor cell proliferation, pathological vascularization that promotes the growth of solid tumors, vascularization in the eye (diabetic retinopathy, age-related macular degeneration, and the like), and inflammation (psoriasis, rheumatoid arthritis, and the like).
  • the compounds of formula I can be administered to patients for the treatment of cancer.
  • the present compounds inhibit tumor angiogenesis and thus influence the growth of tumors (J. Rak et al. Cancer Research, 55: 4575-4580, 1995).
  • the angiogenesis-inhibiting properties of the present compounds of formula I are also suitable for the treatment of certain forms of blindness which are associated with retinal vascularization.
  • the compounds of the formula I are also suitable for the treatment of certain bone pathologies such as osteosarcoma, osteoarthritis and rickets, which is also known under the name of oncogenic osteomalacia (Hasegawa et al., Skeletal Radiol. 28, pp. 41-45, 1999; Gerber et al., Nature Medicine, Vol. 5, No.
  • VEGF directly promotes osteoclastic bone resorption through the KDR / Flk-1 expressed in mature osteoclasts (FEBS Let. 473: 161-164 (2000); Endocrinology, 141: 1667 (2000)), the present compounds are also useful for the treatment and prevention of conditions related to bone resorption, such as osteoporosis and
  • the compounds can be characterized by the fact that they have cerebral edema
  • the invention thus relates to the use of compounds of the formula I and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all
  • Kinases are preferably selected from the group of tyrosine kinases and Raf kinases.
  • the tyrosine kinases are preferably TIE-2, VEGFR, PDGFR, FGFR and / or FLT / KDR.
  • Claim 1 are influenced.
  • the use for producing a is particularly preferred
  • TIE-2 VEGFR, PDGFR, FGFR and / or FLT / KDR through the
  • the disease is a solid tumor.
  • the solid tumor is preferably selected from the group of tumors of the squamous epithelium, the blisters, the stomach, the kidneys, the head and neck, the esophagus, the cervix, the thyroid, the intestine, the liver, the brain, the prostate, the Urogenital tract, lymphatic system, stomach, larynx and / or lungs.
  • the solid tumor is also preferably selected from the group of lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma, colon carcinoma and breast carcinoma.
  • a tumor of the blood and immune system preferably for the treatment of a tumor selected from the group of acute myelotic leukemia, chronic myelotic leukemia, acute lymphatic leukemia and / or chronic lymphatic leukemia.
  • the invention furthermore relates to the use of the compounds of the formula I 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. 5
  • the invention furthermore relates to the use of the compounds according to the invention for the treatment of bone pathologies, the bone pathology coming from the group osteosarcoma, osteoarthritis and rickets.
  • the compounds of formula I are suitable for the preparation of a
  • Raf kinase for the treatment of diseases caused by Raf kinases ⁇ 5 , mediated and / or propagated, the Raf kinase being 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 hyperprol iterative and non-hyperproliferative diseases.
  • the non-cancerous diseases are selected from the group consisting of psoriasis, arthritis, inflammation, endometriosis, 5 scarring, benign prostatic hyperplasia, immunological diseases,
  • the cancerous diseases are selected from group 0 consisting of brain cancer, lung cancer, squamous cell cancer, bladder cancer,
  • Stomach cancer pancreatic cancer, liver cancer, kidney cancer, colorectal cancer,
  • the compounds of formula I can also be administered together with other well known therapeutic agents which are selected on the basis of their suitability for the condition being treated. So would be
  • the antiresorptive bisphosphonates such as alendronate and risedronate, integrin blockers
  • Hormone therapy used conjugated estrogens like Prempro®,
  • Premarin® and Endometrion® contain selective estrogen receptor modulators (SERMs) such as raloxifene, droloxifene, CP-336,156 (Pfizer) and lasofoxifene, cathepsin K inhibitors and ATP proton pump inhibitors.
  • SERMs selective estrogen receptor modulators
  • the present compounds are also suitable for combination with known anti-cancer agents.
  • known anti-cancer agents include the following: estrogen receptor modulators, and protagen receptor modulators, retinoid receptor modulators, cytotoxics, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other transcriptiogen inhibitors.
  • the present compounds are particularly suitable for joint use with radiotherapy.
  • the synergistic effects of inhibiting VEGF in combination with radiotherapy have been described in the specialist field (see WO 00/61186).
  • Estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of how this is done.
  • 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 happens. Androgen receptor modulators include, for example, finasteride and other 5 ⁇ reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole and
  • Retinoid receptor modulators refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of how this is done.
  • retinoid receptor modulators include, for example, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis Retinoic acid, ⁇ -difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl) retinamide and N-4-carboxyphenylretinamide.
  • Cytotoxics refers to compounds that are primarily affected by cell function leading to cell death or inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalating agents, microtubulin inhibitors and topoisomerase inhibitors.
  • Cytotoxic agents include, for example tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, Dibromdulcit, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosylate, trofosfamide, nimustine, Dibrospidium- chloride, Pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-amine dichloro (2-methylpyridine) platinum, benzylguanine, glufosfamide, GPX100,
  • microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, S ' ⁇ ' - Dideshydro ⁇ '- deoxy- ⁇ '-norvincaleukoblastin, docetaxol,
  • Rhizoxin Rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,
  • Topoisomerase inhibitors are, for example, topotecan, hycaptamine,
  • 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 -ocfosfate, fosteabin sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'- Deoxy-2'-methylidencytidine, 2'-fluoromethylene-2'-deoxycytidine, N- [5- (2,3-
  • 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, that can be delivered via recombinant virus-mediated gene transfer (see, e.g., U.S. Patent No. 6,069,134).
  • the invention further relates to the use of the compounds of the formula I for the manufacture of a medicament for the treatment of
  • the disease being characterized by disturbed angiogenesis.
  • the disease is preferably cancer.
  • the disturbed angiogenesis preferably results from a disturbed one
  • VEGFR-1, VEGFR-2 and / or VEGFR-3 activity activity.
  • the invention further relates to compounds of the formula I.
  • R 1 , R 2 each independently of one another H, A, OA, alkenyl, alkynyl,
  • R 1 and R 2 together also alkylene with 3-5 C atoms, R 3 , R 4 each independently of one another H, A, OA, OH, shark, N0 2 ,
  • X morpholinyl 4-Y-piperidin-1-yl or 4-Y-piperazin-1-yl, YH, A, OH, -CH 2 OH or -CH 2 CH 2 OH,
  • the invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.
  • the radicals R 1 , R 2 , R 3 , R 4 , X, L and n have the meanings given in the formula I, unless expressly stated otherwise.
  • a and A ' are preferably each independently alkyl
  • alkyl is preferably unbranched and has 1, 2, 3, 4, 5 or 6 carbon atoms, preferably 1, 2, 3, 4 or 5 carbon atoms and is preferably methyl, ethyl or propyl, more preferably iso - Propyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl or isopentyl.
  • Alkyl also means e.g. Trifluoromethyl.
  • Alkylene is preferably unbranched and preferably means propylene, butylene or pentylene.
  • R 1 and R 2 are preferably H, while the other is preferably propyl or butyl, but particularly preferably ethyl or methyl. Furthermore, R 1 and R 2 together preferably also mean propylene, butylene or pentylene.
  • R 1 , R 2 are particularly preferably, in each case independently of one another, H or A, or together alkylene with 3-5 C atoms.
  • Shark is preferably F, Cl or Br, but also I, particularly preferably F or Cl.
  • Alkenyl is preferably vinyl, 1- or 2-propenyl, 1-butenyl,
  • Isobutenyl, sec-butenyl, further preferred is 1-pentenyl, iso-pentenyl or
  • Alkynyl preferably represents ethynyl, propin-1-yl, furthermore butyn-1-,
  • R 3 and R can be the same or different and are preferably in the 3- or 4-position of the phenyl ring. They each mean, for example, independently of one another H, alkyl, alkoxy, hydroxy, nitro, amino, alkylamino such as methylamino, dialkylamino such as dimethylamino, F, Cl, Br or I or together ethyleneoxy, methylenedioxy or ethylenedioxy. They are also preferably each alkoxy, such as methoxy, ethoxy or propoxy. 0
  • R 3 , R 4 are particularly preferably H, F, Cl, methoxy, hydroxy or together 3,4-methylenedioxy.
  • the radical X is preferably 4-morpholinyl, 4-methyl-piperazin-1-yl, 4- (2-hydroxyethyl) -piperazin-1 -yl or 4-hydroxy-piperidin-1-yl.
  • the compounds of formula I can have one or more chiral centers and therefore exist in different stereoisomeric forms.5 Formula I encompasses all of these forms.
  • the invention relates in particular to
  • Sub-formulas laa to lae are expressed, which correspond to formula I and in which the radicals not specified have the meaning given for formula I, but in which b in laa R 1 , R 2 each independently of one another H, A, OA,
  • X represents morpholinyl and n 1;
  • R 1 , R 2 each independently of one another H, A, OA,
  • R 3 , R 4 each independently of one another H, A, OA, Hai, N0 2 ,
  • R 3 and R 4 together -0-CH 2 -CH 2 -, -0-CH 2 -0- or -0-CH 2 -CH 2 -0,
  • R 3 , R 4 each independently of one another H, A, OA, Hai, N0 2 ,
  • X is morpholinyl and n is 1;
  • R 1 , R 2 each independently of one another are H, shark or A,
  • R 1 and R 2 together alkylene with 3-5 C atoms, R 3 , R 4 each independently of one another H, OA, OH or shark,
  • R 3 and R 4 together -0-CH 2 -CH 2 -, -0-CH 2 -0- or
  • the compounds of the formula I can preferably be obtained
  • R 1 , R 2 , R 3 , R 4 and n have the meanings given,
  • L denotes Cl, Br, OH, SCH 3 or a reactive esterified OH group, reacts with the N-containing heterocycles.
  • L is a reactive esterified OH group, this is preferably alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy, further also 2- naphthalenesulfonyloxy).
  • Precursors of the compounds of formula II can e.g. by cyclization and halogenation analogously to J. Med. Chem. 24, 374 (1981). Subsequent reaction with arylalkylamines gives the compounds of the formula II.
  • the compounds of the formula II are reacted with the N-containing heterocycles in the presence or, in the absence of an inert solvent, at temperatures between about -20 and about 150 °, preferably between 20 and 100 °.
  • an acid-binding agent for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or a 0. other salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium or calcium, or the addition of an organic base such as triethylamine, dimethylamine, pyridine or quinoline or an excess of the amine component may be beneficial.
  • an acid-binding agent for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or a 0. other salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium or calcium, or the addition of an organic base such as triethylamine, dimethylamine, pyridine or quinoline or an excess of the amine component may be beneficial.
  • Suitable inert solvents are, for example, 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); Ni
  • a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polycarbonate, sulfonic or Sulfuric acids, e.g.
  • Ascorbic acid nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid.
  • Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.
  • the free bases of formula I can be liberated from their salts with bases (e.g. sodium or potassium hydroxide or carbonate).
  • the compounds of the formula I and their physiologically acceptable salts can also be used as PDE V inhibitors in combating diseases in which an increase in the cGMP (cyclo-guanosine monophosphate) level leads to anti-inflammation or -Prevention and muscle relaxation leads to be used.
  • the compounds according to the invention can also find particular use in the treatment of diseases of the cardiovascular system and for the therapy of erectile dysfunction.
  • the invention further relates to pharmaceutical compositions containing at least one compound of the formula I and / or their pharmaceutically usable
  • Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin , Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly.
  • Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used in particular for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use Ointments, creams or powder or as a nasal spray.
  • the new compounds can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injectables.
  • the specified preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, for example one or more vitamins.
  • auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, for example one or more vitamins.
  • VEGF receptor kinase activity is determined by incorporating radioactively labeled phosphate in 4: 1 polyglutamic acid / tyrosine substrate (pEY).
  • pEY polyglutamic acid / tyrosine substrate
  • the phosphorylated pEY product is held on a filter membrane and the incorporation of the radioactively labeled phosphate is quantified by scintillation counting.
  • the intracellular tyrosine kinase domains of human KDR (Terman, BI et al. Oncogene (1991) Vol. 6, pp. 1677-1683.) And Flt-1 (Shibuya, M. et al. Oncogene (1990) Vol. 5 , Pp. 519-524) were cloned as glutathione-S-transferase (GST) gene fusion proteins. This was done by cloning the cytoplasmic domain of the KDR kinase as a read-frame fusion at the carboxy terminus of the GST gene.
  • GST glutathione-S-transferase
  • the soluble recombinant GST-kinase domain fusion proteins were expressed in Spodoptera frugiperda (Sf21) insect cells (Invitrogen) using a baculovirus expression vector (pAcG2T, Pharmingen).
  • lysis buffer 50mM Tris pH 7.4, 0.5M NaCl, 5mM DTT, 1mM EDTA, 0.5% Triton X-
  • Dialysis buffer 50 mM Tris pH 7.4, 0.5 M NaCI, 5 mM DTT, 1 mM EDTA, 0.05% Triton X-
  • 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).
  • the Sf21 cells were with the recombinant virus in a m.o.i. (Multiplicity of infection) of 5 virus particles / cell infected and grown for 48 hours at 27 ° C.
  • 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 reaction to VEGF or bFGF is determined by measuring the incorporation of [HjThymidin in the cell DNA.
  • Frozen HUVECs as primary culture isolates are obtained from Clonetics Corp. The cells are obtained in the endothelial growth medium (EGM; Clonetics) and used in the 3rd to 7th passages 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
  • VEGF 165 500 ng / ml; R&D Systems
  • bFGF 10 ng / ml; R&D Systems
  • HUVEC single cell layers kept in EGM are harvested by trypsin treatment and inoculated in a density of 4000 cells per 100 ⁇ l assay medium per well in 96-well plates. The growth of the cells is stopped for 24 hours at 37 ° C. in a humid atmosphere containing 5% CO 2 . Procedure 2
  • the growth stop medium is replaced 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% CO2 so that the test compounds can penetrate the cells. Procedure 3
  • the medium is suctioned off and the cells are washed twice with cell washing medium (400 ⁇ l / well, then 200 ⁇ l / well).
  • the washed, adherent cells are then solubilized by adding cell lysis solution (100 ⁇ l / well) and heating to 37 ° C. for 30 minutes.
  • the cell lysates are transferred to 7 ml glass scintillation tubes containing 150 ul water.
  • the scintillation cocktail (5 ml / tube) is added and the radioactivity associated with the cells is determined by liquid scintillation spectroscopy. According to these assays, the compounds of the formula I VEGF-
  • Inhibitors are therefore suitable for inhibiting angiogenesis, such as in the treatment of eye diseases, e.g. diabetic retinopathy, and for the treatment of carcinomas, e.g. solid tumors.
  • the present compounds inhibit VEGF-stimulated mitogenesis of cultured human vascular endothelial cells with HK50 values of
  • Tyrosine kinases e.g. FGFR1 and Src family; for the relationship between Src kinases and VEGFR kinases see Eliceiri et al., Molecular Cell, Vol.
  • the r / 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 the substances to be tested in the phosphorylation of the substrate poly (Glu, Tyr) by Tie-2-kinase in the presence of radioactive 33 P-ATP.
  • the phosphorylated substrate poly Glu, Tyr
  • Substrate binds to the surface of a "flashplate" microtiter plate during the incubation period. After removing the reaction mixture, it is washed several times and then the radioactivity is measured on the surface of the microtiter plate. An inhibitory effect of the substances to be measured results in a lower radioactivity compared to an undisturbed enzymatic reaction.
  • customary work-up means: if necessary, water is added, and if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is dried and dried organic phase over sodium sulfate, evaporated and purified by chromatography
  • the thienopyrimidine derivatives can be prepared analogously to the examples listed below.
  • Example 1 obtained 2-chloro-thieno [2,3-d] pyrimidine derivatives, which in 4-
  • Arylalkylamino are substituted, the following compounds
  • the keto group is replaced by Cl to form the aromatic

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Abstract

L'invention concerne les composés représentés par la formule (I) dans laquelle R1, R2, R3, R4, X et n ont les significations données dans la revendication (1). Lesdits composés sont des inhibiteurs de tyrosine-kinases, notamment de TIE-2, et de Raf-kinases, et peuvent par exemple être employés dans le traitement de tumeurs.
EP04765963A 2003-11-04 2004-10-14 Utilisation de thienopyrimidines Withdrawn EP1685136A1 (fr)

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DE10351436A DE10351436A1 (de) 2003-11-04 2003-11-04 Verwendung von Thienopyrimidinen
PCT/EP2004/011551 WO2005047292A1 (fr) 2003-11-04 2004-10-14 Utilisation de thienopyrimidines

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WO2007027855A2 (fr) * 2005-09-01 2007-03-08 Array Biopharma Inc. Composes inhibiteurs de la raf kinase et procedes d'utilisation de ceux-ci
US7816351B2 (en) 2005-09-23 2010-10-19 Equispharm Co., Ltd 5,6-dimethylthieno[2,3-di] pyrimidine derivatives, the preparation method thereof and the pharmaceutical composition comprising the same for anti-virus
US20080255184A1 (en) * 2005-11-04 2008-10-16 Smithkline Beecham Corporation Thienopyridine B-Raf Kinase Inhibitors
WO2007063934A1 (fr) * 2005-12-02 2007-06-07 Mitsubishi Tanabe Pharma Corporation Compose heterocyclique alicyclique
RU2448111C2 (ru) * 2006-08-21 2012-04-20 Дженентек, Инк. Соединения азабензофуранила и способ их применения
ES2528797T3 (es) 2006-08-21 2015-02-12 Genentech, Inc. Compuestos de aza-benzotiofenilo y métodos de uso
AU2007286808B2 (en) * 2006-08-21 2012-12-06 Genentech, Inc. Aza-benzofuranyl compounds and methods of use
WO2008028141A2 (fr) * 2006-08-31 2008-03-06 Array Biopharma Inc. Composés inhibiteurs de la kinase raf et procédés d'utilisation de ceux-ci
US7982035B2 (en) * 2007-08-27 2011-07-19 Duquesne University Of The Holy Spirit Tricyclic compounds having antimitotic and/or antitumor activity and methods of use thereof
EP2307456B1 (fr) 2008-06-27 2014-10-15 Amgen Inc. Inhibition de l ang-2 pour traiter la sclérose en plaques
US8815828B2 (en) * 2008-07-02 2014-08-26 University Of Florida Research Foundation, Inc. Therapeutic combinations for use in neoplasia
MX2012009851A (es) * 2010-02-26 2012-09-12 Boehringer Ingelheim Int Tienopirimidinas que contienen un grupo alquilo sustituido para composiciones farmaceuticas.
UY33241A (es) * 2010-02-26 2011-09-30 Boehringer Ingelheim Int ?Tienopirimidinas que contienen heterocicloalquilo para composiciones farmacéuticas?.
AR088218A1 (es) 2011-07-19 2014-05-21 Infinity Pharmaceuticals Inc Compuestos heterociclicos utiles como inhibidores de pi3k
KR101655649B1 (ko) * 2015-02-02 2016-09-22 한국원자력의학원 p53 유전자의 발현을 활성화하는 피리도싸이에노피리미딘 유도체 및 그를 함유하는 암 예방 및 치료용 약학 조성물
SG11201804901WA (en) 2015-12-22 2018-07-30 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
EA201992780A1 (ru) * 2017-06-21 2020-06-02 ШАЙ ТЕРАПЬЮТИКС ЭлЭлСи Соединения, которые взаимодействуют с суперсемейством ras, для лечения рака, воспалительных заболеваний, ras-опатий и фиброзного заболевания
US12391705B2 (en) 2018-12-19 2025-08-19 Shy Therapeutics, Llc Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
CN112043711A (zh) * 2020-09-29 2020-12-08 牡丹江医学院 一种用于治疗甲状腺炎的药物组合物及其制备方法和用途
CN116178374B (zh) * 2023-01-13 2024-10-08 河北医科大学 小电导钙激活钾离子通道激动剂及其合成和应用

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US20080045529A1 (en) 2008-02-21
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