WO2007079820A1 - Triazolderivate - Google Patents
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- WO2007079820A1 WO2007079820A1 PCT/EP2006/011277 EP2006011277W WO2007079820A1 WO 2007079820 A1 WO2007079820 A1 WO 2007079820A1 EP 2006011277 W EP2006011277 W EP 2006011277W WO 2007079820 A1 WO2007079820 A1 WO 2007079820A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- 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
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- 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
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- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention relates to compounds and to the use of compounds in which the inhibition, regulation and / or modulation of the signal transduction of kinases, in particular the TGF-beta receptor kinases, also plays a role, pharmaceutical compositions containing these compounds, as well as the use the compounds for the treatment of kinase-related diseases.
- Transforming growth factor beta is the prototype of the TGF-beta superfamily, a family of highly conserved, pleiotrophic growth factors that play important roles during both embryonic development and in the adult organism.
- TGF-beta 1, 2 and 3 three isoforms of TGF-beta (TGF-beta 1, 2 and 3) have been identified, with TGF-beta 1 being the most abundant isoform (Kingsley (1994) Genes Dev 8: 133-146).
- TGF-beta 3 is only expressed in mesenchymal cells, whereas TGF-beta 1 is found in mesenchial and epithelial cells.
- TGF-beta is synthesized as a preproprotein and delivered in an inactive form to the extracellular matrix (Derynck (1985) Nature 316: 701-705; Bottinger (1996) PNAS 93: 5877-5882).
- LAP latency associated peptides
- one of the 4 isoforms of the latent TGF-beta binding protein (LTBP 1-4) may also be bound to TGF-beta ( Gentry (1988) Mol Cell Biol 8: 4162-4168, Munger (1997) Kindey Int 51: 1376-1382).
- the activated ligand TGF-beta mediates its biological activity via three membrane-bound TGF-beta receptors, the ubiquitously expressed type I and type II receptors and the type III receptors betaglycan and endoglin, the latter being expressed only in endothelial cells (Gougos (1990) J Biol Chem 264: 8361-8364, Loeps-Casillas (1994) J Cell Biol 124: 557-568). Both type III TGF-beta receptors lack an intracellular kinase domain that allows signal transduction into the cell.
- type III TGF-beta receptors bind all three TGF-beta isoforms with high affinity and also type II TGF-beta receptor has a higher affinity for ligands bound to type III receptor, the biological function presumably exists in the regulation of the availability of ligands for type I and type II TGF-beta receptors (Lastres (1996) J Cell Biol 133: 1109-1121; Lopes-Casillas (1993) Cell 73: 1435-1344).
- the structurally closely related type I and type II receptors have a serine / threonine kinase domain in the cytoplasmic region that is responsible for signal transduction.
- Type II TGF-beta receptor binds TGF-beta, whereupon the type I TGF-beta receptor is recruited to this signal-relaying complex.
- the serine / threonine kinase domain of the type II receptor is constitutively active and can phosphorylate seryl residues in the so-called GS domain of the type I receptor in this complex. This phosphorylation activates the kinase of the type I receptor, which in turn is able to phosphorylate intracellular signaling mediators that can phosphorylate SMAD proteins and thus initiate intracellular signal transduction (summarized in Derynck (1997)
- the proteins of the SMAD family serve as substrates for all TGF-beta
- R-SMADs receptor-associated SMADs
- SMAD1 TGF- ⁇ receptor kinases
- Co-SMADs Co-SMADs interacting with the R-Smads during the
- SMAD6, 7 which inhibit the activity of the above-mentioned SMAD proteins.
- SMAD2 and SMAD3 are the TGF-beta specific signaling mediators.
- SMAD2 / SMAD3 are phosphorylated by the type I TGF-beta receptor, allowing them to associate with SMAD4.
- SMAD2 / SMAD3 and SMAD4 can now be translocated into the cell nucleus and there initiate transcription of the TGF-beta regulated genes directly or via other proteins (summarized in Itoh (2000) Eur J Biochem 267: 6954-6967; 2003) Cell 113: 685-700).
- TGF-beta The spectrum of functions of TGF-beta is broad and depends on cell type and differentiation status (Roberts (1990)
- TGF-beta Functions that are influenced by TGF-beta include: apoptosis,
- TGF-beta plays an important role in various biological processes. During embryonic development, it is expressed at sites of morphogenesis, and particularly at sites of epithelial-mesenchymal interaction, where it induces important differentiation processes (Pelton (1991) J Cell Biol 115: 1091-1105). TGF-beta also plays a key role in self-renewal and maintenance of an undifferentiated state of stem cells (Mishra (2005) Science 310: 68-71). In addition, TGF-beta also fulfills important functions in the regulation of the immune system. It is generally immunosuppressive, as it has u.a. the proliferation of
- Lymphocytes inhibits and restricts the activity of tissue macrophages.
- TGF-beta suppresses inflammatory reactions and helps to avoid excessive immune reactions - A -
- TGF-beta Another function of TGF-beta is the regulation of cell proliferation. TGF-beta inhibits the growth of cells of endothelial, epithelial and hematopoietic origin but promotes the growth of cells of mesenchymal origin (Tucker (1984) Science 226: 705-707, Shipley (1986) Cancer Res 46: 2068-2071, Shipley (1985) PNAS 82: 4147-4151). Another important function of TGF-beta is the regulation of cellular adhesion and cell-cell interactions.
- TGF-beta promotes the construction of the extracellular matrix by the induction of extracellular matrix proteins, e.g. Fibronectin and collagen.
- TGF-beta reduces the expression of matrix-degrading metalloproteases and metalloproteinase inhibitors (Roberts (1990) Ann NY Acad 580: 225-232, Ignotz (1986) J Biol Chem 261: 4337-4345, Overall (1989) J. Biol Chem 264: 1860-1869); Edwards (1987) EMBO J 6: 1899-1904).
- TGF-beta plays an important role in many physiological conditions, such as the
- TGF-beta is one of the key growth factors in wound healing (summarized in O 'Kane (1997) Int J Biochem Cell Biol 29: 79-89). During the granulation phase, TGF-beta is released from platelets at the site of injury. TGF-beta then regulates its own production in macrophages and induces the secretion of other growth factors eg by monocytes. The most important functions during wound healing include the stimulation of inflammatory cell chemotaxis, the synthesis of extracellular matrix and the regulation of proliferation, differentiation and gene expression of all major cell types involved in the wound healing process.
- TGF-beta mediated effects, in particular the regulation of the production of extracellular matrix (ECM) for fibrosis or in the skin can lead to scars (Border (1994) N Engl J Med 331: 1286-1292).
- ECM extracellular matrix
- TGF-beta For fibrotic diseases, diabetic nephropathy and glomeronephritis, TGF-beta has been shown to promote renal cell hypertrophy and pathogenic accumulation of the extracellular matrix. The interruption of the TGF-beta signaling pathway by treatment with anti-TGF-beta antibodies prevents the
- TGF-beta also plays an important role in liver fibrosis.
- the activation of the hepatic stellate cells (hepatic stellate cell), which is essential for the development of liver fibrosis, into myofibroblasts, the main producer of the extracellular matrix in the context of the
- TGF-beta also plays a key role in carcinogenesis (reviewed in Derynck (2001) Nature Genetics: 29: 117-129, Elliott (2005) J Clin One 23: 2078-2093). In the early stages of cancer development, TGF-beta counteracts carcinogenesis. This tumor suppressing effect is mainly due to the ability of TGF-beta to inhibit the division of epithelial cells. In contrast, TGF-beta promotes cancer growth and metastasis in late-stage tumors. This can be attributed to the fact that most epithelial tumors develop a resistance to the growth-inhibiting effect of TGF-beta and TGF-beta. beta simultaneously supports the growth of cancer cells through other mechanisms. These mechanisms include the promotion of angiogenesis, the immunosuppressive effect, the tumor cells in the
- TGF-beta promotes this process through its cellular ability
- TGF-beta plays ⁇ 5 important role in the promotion of cancer growth is also demonstrated studies that show a correlation between strong TGF-beta expression and a poor prognosis. Increased TGF-beta levels have been found in patients with prostate, breast, colon and lung cancer (Wikström
- TGF-.beta activity include those conditions wherein TGF-.beta. Synthesis is stimulated such that TGF-.beta. Is present at elevated levels, or wherein the latent TGF-.beta. Protein is undesirably activated or incorporated into the active TGF- ⁇
- TGF-.beta. Receptors are upregulated or wherein the TGF-.beta. Protein has increased binding to cells or to the extracellular matrix at the site of the disease.
- impaired activity refers to any condition in which the biological activity of TGF- ⁇ is undesirably high, regardless of the cause.
- TGF-ß1 A number of diseases have been linked to the overproduction of TGF-ß1.
- Inhibitors of the intracellular TGF- ⁇ signaling pathway are suitable treatments for fibroproliferative disorders.
- Fibroproliferative disorders specifically include renal disorders associated with unregulated TGF- ⁇ activity, and severe fibrosis, including glomerulonephritis (GN), such as mesangial proliferative GN, immune GN, and crescent GN.
- Other renal conditions include diabetic nephropathy, renal interstitial fibrosis, renal fibrosis in transplant patients receiving cyclosporin, and nephropathy associated with HIV.
- Collagen vascular disorders include progressive systemic sclerosis, polymyositis, scleroderma, dermatomyositis, eosinophilic fascitis, morphea, or those associated with the incidence of Raynaud's syndrome.
- Pulmonary fibrosis caused by excessive TGF- ⁇ activity includes adult respiratory distress syndrome, idiopathic pulmonary fibrosis, and interstitial pulmonary fibrosis, often associated with autoimmune disorders such as systemic lupus erythematosus and scleroderma, chemical contact, or allergies.
- Another autoimmune disorder associated with fibroproliferative properties is rheumatoid arthritis.
- Ocular disorders associated with a fibroproliferative condition include proliferative vitreoretinopathy, which occurs during retinal reattachment surgery, cataract extraction with intraocular lens implantation, and post-glaucoma drainage surgery, and are associated with TGF- ⁇ 1 overproduction.
- Fibrosis disorders associated with TGF-ß1 overproduction can be linked to chronic conditions such as kidney, lung, and lung fibrosis
- TGF- ⁇ 1 Liver, and more acute conditions such as skin scarring and restenosis (Chamberlain, J. Cardiovascular Drug Reviews, 19 (4): 329-344).
- the synthesis and secretion of TGF- ⁇ 1 by tumor cells can also lead to immunosuppression, as observed in patients with aggressive brain or breast tumors (Arteaga, et al., (1993) J. Clin. Invest. 92: 2569-2576).
- the course of Leishmania infection in mice is drastically altered by TGF- ⁇ 1 (Barral-Netto, et al. (1992) Science 257: 545-547).
- TGF- ⁇ 1 worsened the disease, whereas TGF- ⁇ 1 antibodies halted the progression of the disease in genetically susceptible mice. Genetically resistant mice became susceptible to Leishmania infection upon administration of TGF- ⁇ 1.
- TGF- ⁇ 1 levels are elevated in diabetic glomerulosclerosis in humans (advanced neuropathy) (Yamamoto, et al., (1993) Proc Natl Acad., 90: 1814-1818).
- TGF-ß1 is an important mediator in the Genesis of renal fibrosis in a number of animal models (Phan, et al.
- TGF- ⁇ 1 may be a factor in the progressive thickening of the arterial wall, which is caused by the proliferation of smooth muscle cells and the deposition of extracellular matrix in the artery after the balloon vessel plastic.
- the diameter of the resealed artery can be reduced by 90% due to this thickening, and since the majority of the reduction in diameter is due to the extracellular matrix and not to the bodies of smooth muscle cells, these vessels can be reopened to 50% by simply removing the excess Deposition of the extracellular matrix is reduced.
- TGF- ⁇ 1 gene expression was associated with both extracellular matrix synthesis and hyperplasia (Nabel, et al., 1993). Proc Natl.
- TGF- ⁇ 1-induced hyperplasia was not as extensive as that induced with PDGF-BB, but the extracellular matrix was more pronounced with TGF- ⁇ 1 transfectants. There was no deposition of extracellular matrix in FGF-1 (a secreted form of FGF) -induced hyperplasia in this gene transfer model in pigs (Nabel (1993) Nature 362: 844-846). There are several types of cancer, and the tumor-produced TGF- ⁇ 1 can be harmful.
- TGF- ⁇ 1 has been associated with angiogenesis, metastasis, and poor prognosis in human prostate and advanced colorectal cancer (Wikstrom, P., et al., (1988) Prostate 37, 19-29; Saito, H., et al. (1999) Cancer 86: 1455-1462).
- Breast cancer is associated with a poor prognosis associated with elevated TGF- ⁇ (Dickson, et al., (1987) Proc Natl Acad. See, USA 84: 837-841; Kasid, et al. (1987) Cancer Res.
- TGF- ⁇ can cause endocrine immunosuppression.
- High plasma concentrations of TGF- ⁇ 1 show a poor prognosis for patients with advanced breast cancer (Anscher, et al. (1993) N. Engl. J. Med. 328: 1592-1598).
- TGF- ⁇ transforming growth factor ⁇
- EL4 normally lethal TGF- ⁇ overexpressing lymphoma tumor
- EL4 normally lethal TGF- ⁇ overexpressing lymphoma tumor
- TGF- ⁇ may act as a powerful tumor suppressor and may mediate the effects of some chemopreventive agents. At some point during
- TGF-ß-dependent growth inhibition To deprive tumor cells of the TGF-ß-dependent growth inhibition parallel to the appearance of biologically active TGF-ß in the microenvironment.
- the dual tumor suppression and tumor promotion roles ⁇ i n u of TGF-beta has been shown in a transgenic system most clearly, the TGF-ß in keratinocytes overexpressed.
- transgenics were more resistant to the formation of benign skin lesions, the rate of metastasis conversion in the transgenes was dramatically increased
- TGF- ⁇ 1 The production of TGF- ⁇ 1 by malignant cells in primary tumors appears to increase with progressive stages of tumor progression. Studies in many major epithelial cancers suggest that the increased production of TGF- ⁇ 0 by human cancer may be a relatively late event during the course of human cancer
- Tumor progression occurs.
- this tumor-associated TGF-ß helps the tumor cells to a selective advantage and promotes tumor progression.
- the effects of TGF- ⁇ on cell-cell and cell-stromal interactions lead to a greater propensity for invasion and metastasis.
- Tumor-associated TGF- ⁇ may allow tumor cells to escape immune surveillance as it is a potent inhibitor of clonal expansion of activated lymphocytes. It has also been shown that TGF- ⁇ inhibits the production of angiostatin. 0
- Cancer therapy modalities such as radiation therapy and chemotherapy, induce the production of activated TGF- ⁇ in the tumor, thereby selecting outgrowth of malignant cells that are resistant to TGF- ⁇ growth inhibitory effects.
- these 5 anticancer treatments increase the risk and accelerate the development of tumors with increased growth and invasiveness.
- agents that trigger TGF-ß-mediated signal transduction can be a very efficient therapeutic strategy. It has been shown that the resistance of the tumor cells to TGF-ß
- TGF- ⁇ in the stroma may even be detrimental as it makes the microenvironment more conductive to tumor progression and contributes to tissue damage leading to fibrosis.
- TGF- ⁇ signal transduction inhibitors probably have an advantage for the treatment of advanced cancer alone and in combination with other therapies.
- the compounds are useful for the treatment of cancer and other disease states influenced by TGF-ß can be by inhibiting TGF-beta in a patient in need thereof, by subjecting the compound (s) is administered to the patient or , TGF-ß is too
- T.A. McCaffrey TGF-ßs and TGF-ß
- the compounds of the present invention preferably exhibit beneficial biological activity that is useful in enzyme-based assays, e.g. Example assays as described herein are readily detectable.
- the compounds of the invention preferably exhibit and effect an inhibiting effect, usually documented by IC 50 values in a suitable range, preferably in the micromolar range, and more preferably in the nanomolar range.
- the compounds of the present invention are useful in the prophylaxis and / or treatment of diseases which are dependent on said signal pathways by interaction with one or more of said signal pathways.
- the present invention therefore relates to compounds according to the invention as promoters or inhibitors, preferably as inhibitors of the signaling pathways described herein.
- Preferred subject of the invention are therefore compounds of the invention as promoters or inhibitors, preferably as inhibitors of the TGFß signaling pathway.
- Another object of the present invention is the use of one or more compounds of the invention in the treatment and / or prophylaxis of diseases, preferably the diseases described here, which are caused, mediated and / or propagated by an increased TGFß activity.
- 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 said diseases and the use of compounds according to the invention for the preparation of a pharmaceutical for the treatment and / or prophylaxis of said
- the host or patient may be of any mammalian species, e.g. B. a 5
- mice Mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for the treatment of a human disease.
- the susceptibility of a particular cell to treatment with the compounds of the invention can be determined by testing in vitro A c .
- a culture of the cell is combined with a compound of the invention at various concentrations for a period of time sufficient to allow the active agents to induce cell death or inhibit migration, usually between about one hour and one week.
- Cultured cells from a biopsy sample can be used. The viable cells remaining after treatment are then counted.
- the dose will vary depending on the specific compound used, the specific disease used, the patient status, etc. Typically, a therapeutic dose will be sufficient to substantially reduce the undesirable cell population in the target tissue while maintaining the viability of the patient.
- the treatment will be in
- O Q generally continued until a significant reduction, for. 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 activity is well known to those skilled in the art.
- Generic test systems for the determination of kinase activity with substrates eg histone (eg Alessi et al., FEBS Lett. 1996, 399, 3, pages 333-338) or the basic myelin protein are described in the literature (eg Campos-Gonzalez, R. and Glenney, Jr, JR 1992, J.
- Non-radioactive ELISA assay methods use specific 5 phospho-antibodies (Phospho-AK).
- the phospho-AK binds only the phosphorylated substrate. This bond is linked to a second peroxidase chemiluminescence conjugated anti-sheep antibodies (Ross et al., 2002, Biochem J., just before publication, manuscript BJ20020786).
- the compounds B2, B3, B4, B5, B8, B9, B10, B12, B14, B16 11 , B17, B19, "B20” are described in DE 2 409 308 as active pharmaceutical ingredients with analgesic and / or antiinflammatory effect
- the compounds "B1", “B6", “B7”, “B11”, “B13”, “B15”, “B18”, “B21”, “B22” are described by E. Szarvasi et al., Eur. J. Med., 1978, 13, 113-119, as analgesic and / or anti-inflammatory drugs.
- TGF-beta inhibitors are disclosed as TGF-beta inhibitors in WO 03/042211 A1. Again, other triazole derivatives are known as TGF-beta inhibitors
- Biyclic pyrrole derivatives are described as TGF-beta inhibitors in WO 02/094833. SUMMARY OF THE INVENTION
- the invention relates to compounds selected from the group
- the invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.
- solvates of the compounds are deposits of inert solvent molecules understood by the connections that are due to their mutual
- Solvates are e.g. Mono- or dihydrate or
- an effective amount means that amount of a drug or pharmaceutical agent which elicits a biological or medical response in a tissue, system, animal or human, e.g. sought or desired by a researcher or physician.
- the term "therapeutically effective amount” means an amount which, compared to a corresponding subject who has not received this amount, results in: improved curative treatment, cure, prevention or elimination of a disease, a disease, a disease state, complaint, disorder or side effects or also the reduction in Q of the progress of a disease, complaint or disorder.
- the term "therapeutically effective amount” also includes the amounts effective to increase normal physiological function. 5
- the invention also provides the use of mixtures of the compounds according to the invention, for example mixtures of two diastereomers, for example in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000th These are particularly preferably mixtures of stereoisomeric compounds.
- the compounds according to the invention can preferably be obtained by reacting tetrahydrobenzo [d] [1,4] diazepine-2-thione derivatives with 0
- the reaction is usually carried out in an inert solvent.
- the reaction time is between 5 minutes and 14 days depending on the conditions used, the reaction temperature between about
- 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, 5
- 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-propan
- Tetrahydrofuran (THF) or dioxane 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 dimethylsulfoxide (DMSO); Carbon disulphide;
- Carboxylic acids such as formic acid or acetic acid
- Nitro compounds such as 5
- Nitromethane or nitrobenzene are Nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of said solvents. Particularly preferred is 1-butanol.
- suitable salts form by reacting the compound with a suitable base to the corresponding base addition salt.
- bases include, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal
- OQ hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, eg potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine and N-methylglutamine.
- Alkali metal alcoholates eg potassium ethanolate and sodium propanolate
- organic bases such as piperidine, diethanolamine and N-methylglutamine.
- the aluminum salts of the compounds of the invention are also included.
- Compounds can acid addition salts form in that one of these compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts such as acetate, trifluoroacetate , Tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like.
- organic and inorganic acids for example hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as
- pharmaceutically acceptable acid addition salts of the compounds of the invention include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate , Cyclopentane propionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate,
- Fumarate Galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-
- Methyl benzoate monohydrogen phosphate, 2-naphthalene sulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenyl acetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not limiting.
- the base salts of the compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium -
- Sodium and zinc salts but this is not intended to be limiting.
- Preferred among the above salts are ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts
- Compounds derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and salts tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, eg arginine, betaine, caffeine, chloroprocaine, choline,
- Triethylamine trimethylamine, tripropylamine and tris (hydroxymethyl) - methylamine (tromethamine), but this is not intended to be limiting.
- Groups can be, with agents such as (CrC 4 ) alkyl halides, for example, methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide;
- Ci 8 alkyl halides, eg decyl, dodecyl, lauryl, myristyl and
- AryKCrC-Oalkyl halides e.g. Benzyl chloride and phenethyl bromide quaternize.
- Preferred pharmaceutical salts include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate,
- Meglumine nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, but this is not intended to be limiting.
- the free base form is contacted with a sufficient amount of the desired acid to form the salt in a conventional manner.
- the free base can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner.
- the free base forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; however, in the context of the invention, the salts otherwise correspond to their respective free base forms.
- the pharmaceutically acceptable base addition salts of the compounds of the invention are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines.
- metals are sodium, potassium, magnesium and calcium.
- Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
- the base addition salts of acidic compounds of the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner.
- the free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
- the free acid forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; However, in the context of the invention, the salts otherwise correspond to their respective free acid forms.
- Invention also multiple salts.
- Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, Diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.
- pharmaceutically acceptable salt as used herein means an active ingredient containing a compound of the invention in the form of one of its salts, especially when that salt form is the active ingredient compared to the free form of the active ingredient or any other salt form of the active ingredient previously used, imparts improved pharmacokinetic properties.
- the pharmaceutically acceptable salt form of the active substance may also first impart a desired pharmacokinetic property to this active ingredient which it has not previously possessed, and may even positively influence the pharmacodynamics of this active ingredient in terms of its therapeutic activity in the body.
- the invention furthermore relates to medicaments comprising at least one compound according to the invention and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.
- compositions may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
- a moiety may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the invention, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be used in
- Preferred unit dosage formulations are those containing a daily or partial dose, as indicated above, or a corresponding fraction thereof of an active ingredient. Furthermore, such pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art. 5
- compositions may be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal,
- compositions including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes.
- vaginal or parenteral including subcutaneous, intramuscular, intravenous or intradermal routes.
- parenteral including subcutaneous, intramuscular, intravenous or intradermal routes.
- ⁇ 5 known methods be prepared by or to the excipient (s) or excipient (s) is brought together, for example, the active ingredient with the.
- compositions adapted for oral administration are provided.
- Capsules or tablets may 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 foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
- the active ingredient component in the form of a tablet or capsule, can be combined with an oral, non - toxic and pharmaceutically acceptable inert carrier, such as, for example, ethanol, glycerol, water and the like.
- an oral, non - toxic and pharmaceutically acceptable inert carrier such as, for example, ethanol, glycerol, water and the like.
- Powders are prepared by comminuting the compound to a suitable fine size and using a similarly comminuted pharmaceutical grade
- Carrier such as e.g. an edible carbohydrate such as
- Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith.
- Lubricants such as e.g. highly dispersed silicic acid, talc, 5
- Magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process.
- a disintegrants or solubilizers e.g. Agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.
- suitable binding, lubricating and disintegrants as well as dyes may also be incorporated into the mixture c .
- suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol,
- the mittein include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- the disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
- the tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing, adding a lubricant and a disintegrating agent, and pressing the whole into tablets.
- a powder mixture is prepared by mixing the appropriately comminuted compound with
- a diluent or a base as described above, and optionally with a binder such as carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a Wegsverlangsamer, such as paraffin, a absorption accelerator, such as a quaternary salt and / or an absorbent , such as bentonite,
- a binder such as carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a Wegsverlangsamer, such as paraffin, a absorption accelerator, such as a quaternary salt and / or an absorbent , such as bentonite,
- the powder mixture can be granulated by mixing it with a binder, such as syrup, starch paste, Acadia slime or solutions of cellulose or polymer materials wetted and pressed through a sieve.
- a binder such as syrup, starch paste, Acadia slime or solutions of cellulose or polymer materials wetted and pressed through a sieve.
- the powder mixture can be run through a tabletting machine to produce non-uniformly shaped lumps which are formed in
- Granules are broken up.
- the granules may be greased by the addition 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 pressed directly into tablets without carrying out the granulation or dry-pressing 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 differentiate between different dosage units.
- Oral fluids e.g. Solution, syrups and elixirs may be prepared in unit dosage form such that a given quantity contains a predetermined amount of the compound.
- Syrups can be prepared by dissolving the compound in an appropriate taste aqueous solution while preparing elixirs 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, flavoring additives such as e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, i.a. can also be added.
- the unit dosage formulations for oral administration may optionally be encapsulated in microcapsules.
- the formulation can also be prepared so that the release is prolonged or retarded, such as by coating or embedding of particulate material in polymers, wax, etc.
- the compounds of the invention can also be administered in the form of liposome delivery systems, e.g. small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
- liposomes can be prepared from various phospholipids, such as e.g.
- Cholesterol, stearylamine or phosphatidylcholines Cholesterol, stearylamine or phosphatidylcholines.
- Drug carriers are coupled.
- Such polymers may include polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol,
- Polyhydroxyethylaspartamidphenol or polyethylene oxide polylysine substituted with Palmitoylresten include.
- the compounds can be attached to a class of biodegradable polymers suitable for the controlled release of a drug, e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyano-acrylates, and cross-linked or amphipathic block copolymers of hydrogels.
- compositions adapted for transdermal administration may be used as stand-alone patches for longer, narrower patches
- Pharmaceutical compounds 5 adapted for topical administration may be used as ointments, creams, suspensions, lotions, powders, solutions,
- the formulations are preferably applied as a topical ointment or cream.
- the active ingredient can be used with either a paraffinic or water miscible cream base.
- the active ingredient may be a ⁇ c cream with an oil-in-water cream base or a water-in-oil base to be formulated.
- eye drops wherein the active ingredient is in
- a suitable carrier in particular an aqueous solvent, dissolved or suspended.
- compositions adapted for topical application in the mouth include lozenges, lozenges and mouthwashes.
- compositions adapted for rectal administration may be presented in the form of suppositories or enemas.
- compositions adapted for nasal administration in which the vehicle is a solid contain a coarse powder having a particle size, for example, in the range of 20-500
- Microns which is administered in the manner in which snuff is absorbed, ie by rapid inhalation via the nasal passages from a container held close to the nose with the powder.
- Suitable formulations for administration as a nasal spray or nasal drops with a liquid as a carrier substance include solutions of active substance in water or oil.
- Formulations include fine particulate dusts or mists that can be generated by various types of pressurized dosing dispensers with aerosols, nebulizers or insufflators.
- compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
- Formulations include aqueous and non-aqueous sterile injection solutions containing the antioxidants, buffers, bacteriostats and solutes, by which the formulation is isotonic with the blood of the treatment
- Recipient is included; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners.
- the formulations may be administered in single or multiple dose containers, e.g. sealed vials and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections, needed immediately before use.
- sterile carrier liquid e.g. Water for injections
- formulations may include other means conventional in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration
- a therapeutically effective amount of a compound of the invention will depend on a number of factors including, but not limited to, the age and weight of the animal, the exact disease state requiring treatment, as well as its severity, nature of the formulation and route of administration doctor or veterinarian. However, an effective amount of a compound of the invention is for the treatment of neoplastic materials.
- ⁇ C actual amount per day normally mg between 70 and 700, this amount may be given in a single dose per day or usually in a series of part-doses (such as two, three, four, five or six) per day, so that the Total daily dose is the same.
- Derivatives thereof can be determined as the proportion of the effective amount of the compound according to the invention per se. It can be assumed that similar dosages are suitable for the treatment of the other, above-mentioned disease states.
- the invention furthermore relates to medicaments comprising at least one compound according to the invention and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including their derivatives
- the invention is also a set (kit), consisting of separate
- the kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
- the set may e.g. containing separate ampoules, in each of which an effective amount of a compound of the invention and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and an effective amount of another drug substance dissolved or in lyophilized form.
- Illness where the disease is a solid tumor.
- the solid tumor is preferably selected from the group of
- the solid tumor is further preferably selected from the group
- 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 lymphoblastic leukemia
- the present compounds are also useful for combination with known anticancer agents.
- known anticancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, antiproliferative agents, antiproliferative agents, antiproliferative agents, antiproliferative agents, antiproliferative agents, antiproliferative agents, antiproliferative agents, antiproliferative, anticancer agents.
- known anticancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative
- prenyl-proteintransferase inhibitors prenyl-proteintransferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other angiogenesis inhibitors.
- present compounds are particularly suitable for co-administration with radiotherapy.
- Estrogen receptor modulators refers to compounds that have the
- Estrogen receptor modulators include, for example, tamoxifen, raloxifene, idoxifen, LY353381, LY 117081, toremifene, fulvestrant, 4- [7- (2,2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (4-methyl) 1-piperidinyl) ethoxy] phenyl] -2H-1 -
- Androgen receptor modulators include, for example, finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
- Retinoid receptor modulators refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of how this occurs
- retinoid receptor modulators include, for example, bexarotene, tretinoin, 13-cis-retinoic acid, Q 9- cis -retinoic acid, ⁇ -difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl) -retinamide and N-4-carboxyphenylretinamide.
- Cytotoxic agents refers to compounds that are primarily active by direct action on cell function lead to cell death or inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors and topoisomerase
- the cytotoxic agents include, for example, tirapazimine, Sertenef, cachectin, ifosfamide, tasonermine, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcite, ranimustine, fotemustine, nedaplatin, oxaliplatin,
- Temozolomide Temozolomide, heptaplatin, estramustine, improvisulfan-tosylate, trofosfamide,
- MEN 10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-daunorubicin see WO 00/50032, but this is not intended to be limiting.
- microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, 3 ⁇ 4'-didehydro-4'-deoxy-8'-norvincaleukoblastin, docetaxol,
- Rhizoxin Rhizoxin, Dolastatin, Mivobulin Isethionate, Auristatin, Cemadotin,
- Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecane, 6-ethoxypropionyl-3 ', 4'-O-exo-benzylidene-chartreusine, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4; 5-kl] acridine-2
- BNP1350 BNP1350, BNPH 100, BN80915, BN80942, etoposide-phosphate, teniposide,
- Antiproliferative agents include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and
- ⁇ c INX3001 as well as antimetabolites such as enocitabine, carmofur, tegafur,
- Pentostatin doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabic sodium hydrate, raltitrexed, paltitrexide, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-
- antiproliferative agents also include other monoclonal antibodies against growth factors than those already mentioned under the “angiogenesis inhibitors”, such as trastuzumab, as well as
- Tumor suppressor genes such as p53, recombinantly mediated by virus
- Gene transfer can be delivered (see, e.g., U.S. Pat.
- the ability of the inhibitors to abrogate TGF-beta mediated growth inhibition is tested.
- Cells of the lung epithelial cell line MvILu are seeded in defined cell density in a 96-well microtiter plate and cultured overnight under standard conditions. On the following day, the medium is replaced with medium containing 0.5% FCS and 1 ng / ml TGF-beta, and the test substances in defined concentrations, usually in the form of dilution series with 5-fold steps added. The concentration of the solvent DMSO is constant at 0.5%. After two more days, crystal violet staining of the cells occurs. After extracting the crystal violet from the fixed cells, absorbance at 550 nm is measured spectrophotometrically. It can be used as a quantitative measure of the existing adherent cells and thus of cell proliferation during culture.
- the kinase assay is performed as a 384-well flashplate assay.
- 31.2 nM GST-ALK5, 439 nM GST-SMAD2 and 3 mM ATP (with 0.3 ⁇ Ci 33 P 0 ATP / well) are, in a total volume of 35 ⁇ l (20 mM HEPES, 10 mM MgCl, 5 mM MnCl, 1 mM DTT 0.1% BSA, pH 7.4) with or without test substance (5-10 concentrations) for 45 min at 30 0 C.
- the reaction is stopped with 25 ⁇ l of 200 mM EDTA solution, after 30 min at
- “usual workup” means adding water if necessary, adjusting to pH values between 2 and 10, if necessary, depending on the constitution of the final product, extracting with ethyl acetate or dichloromethane, separating, drying the organic phase over sodium sulfate, evaporated and purified by chromatography on 5
- APCI-MS atmospheric pressure chemical ionization - mass spectrometry
- Example A Injection glasses
- a solution of 100 g of an active compound of the formula I and 5 g disodium hydrogen phosphate is adjusted to pH 6.5 in 3 l bidistilled water with 2 N hydrochloric acid, sterile filtered, filled into injection jars, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
- each suppository contains 20 mg of active ingredient.
- a solution is prepared from 1 g of an active ingredient of the formula I 1 9.38 g of NaH 2 PO 4 • 2H 2 O, 28.48 g of Na 2 HPO 4 • 12H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. This solution can be used in the form of eye drops.
- a mixture of 1 kg of active ingredient of the formula I 1 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is in the usual
- Tablets are pressed analogously to Example E, which are then coated in the usual way with a coating of sucrose, potato starch, talc, tragacanth and dye.
- a solution of 1 kg of active compound of the formula I in 60 l of bidistilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each vial contains 10 mg of active ingredient.
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Abstract
Description
Claims
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
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CA2634553A CA2634553C (en) | 2005-12-23 | 2006-11-24 | Triazole derivatives |
ES06818796T ES2400728T3 (es) | 2005-12-23 | 2006-11-24 | Derivados de triazol |
US12/158,344 US8093240B2 (en) | 2005-12-23 | 2006-11-24 | Triazole derivatives |
JP2008546162A JP5236490B2 (ja) | 2005-12-23 | 2006-11-24 | トリアゾール誘導体 |
BRPI0620241-1A BRPI0620241A2 (pt) | 2005-12-23 | 2006-11-24 | derivados de triazol |
EA200801430A EA015254B1 (ru) | 2005-12-23 | 2006-11-24 | Производные триазола |
EP06818796A EP1966211B1 (de) | 2005-12-23 | 2006-11-24 | Triazolderivate |
AU2006334899A AU2006334899B2 (en) | 2005-12-23 | 2006-11-24 | Triazole derivatives |
CN2006800487919A CN101346383B (zh) | 2005-12-23 | 2006-11-24 | 三唑衍生物 |
IL192286A IL192286A (en) | 2005-12-23 | 2008-06-18 | Triazole derivatives and drugs containing them |
HK09105550.2A HK1128022A1 (en) | 2005-12-23 | 2009-06-19 | Triazole derivatives |
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DE102005061840.5 | 2005-12-23 | ||
DE102005061840A DE102005061840A1 (de) | 2005-12-23 | 2005-12-23 | Triazolderivate |
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US (1) | US8093240B2 (de) |
EP (2) | EP1966211B1 (de) |
JP (1) | JP5236490B2 (de) |
KR (1) | KR20080090458A (de) |
CN (1) | CN101346383B (de) |
AR (1) | AR056860A1 (de) |
AU (1) | AU2006334899B2 (de) |
BR (1) | BRPI0620241A2 (de) |
CA (1) | CA2634553C (de) |
DE (1) | DE102005061840A1 (de) |
EA (1) | EA015254B1 (de) |
ES (1) | ES2400728T3 (de) |
HK (1) | HK1128022A1 (de) |
IL (1) | IL192286A (de) |
WO (1) | WO2007079820A1 (de) |
ZA (1) | ZA200806358B (de) |
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US9249161B2 (en) | 2010-12-02 | 2016-02-02 | Constellation Pharmaceuticals, Inc. | Bromodomain inhibitors and uses thereof |
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US9624244B2 (en) | 2012-06-06 | 2017-04-18 | Constellation Pharmaceuticals, Inc. | Benzo [B] isoxazoloazepine bromodomain inhibitors and uses thereof |
US9969747B2 (en) | 2014-06-20 | 2018-05-15 | Constellation Pharmaceuticals, Inc. | Crystalline forms of 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[C]isoxazolo[4,5-e]azepin-4-yl)acetamide |
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CN110172068A (zh) * | 2019-06-05 | 2019-08-27 | 河南龙湖生物技术有限公司 | 具有抗肿瘤活性的苯并噻唑类化合物及其制备方法和应用 |
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2006
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- 2006-11-24 EP EP10014370A patent/EP2322527A1/de not_active Withdrawn
- 2006-11-24 KR KR1020087018192A patent/KR20080090458A/ko not_active Application Discontinuation
- 2006-11-24 CN CN2006800487919A patent/CN101346383B/zh not_active Expired - Fee Related
- 2006-11-24 JP JP2008546162A patent/JP5236490B2/ja not_active Expired - Fee Related
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- 2006-11-24 AU AU2006334899A patent/AU2006334899B2/en not_active Ceased
- 2006-11-24 WO PCT/EP2006/011277 patent/WO2007079820A1/de active Application Filing
- 2006-11-24 ES ES06818796T patent/ES2400728T3/es active Active
- 2006-11-24 EA EA200801430A patent/EA015254B1/ru not_active IP Right Cessation
- 2006-12-20 AR ARP060105637A patent/AR056860A1/es unknown
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- 2008-07-22 ZA ZA200806358A patent/ZA200806358B/xx unknown
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Also Published As
Publication number | Publication date |
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KR20080090458A (ko) | 2008-10-08 |
EP1966211A1 (de) | 2008-09-10 |
HK1128022A1 (en) | 2009-10-16 |
IL192286A0 (en) | 2008-12-29 |
CA2634553C (en) | 2014-04-08 |
CA2634553A1 (en) | 2007-07-19 |
ES2400728T3 (es) | 2013-04-11 |
US8093240B2 (en) | 2012-01-10 |
AR056860A1 (es) | 2007-10-31 |
EP1966211B1 (de) | 2012-12-26 |
AU2006334899B2 (en) | 2012-06-07 |
CN101346383B (zh) | 2011-11-30 |
IL192286A (en) | 2012-10-31 |
DE102005061840A1 (de) | 2007-06-28 |
EP2322527A1 (de) | 2011-05-18 |
ZA200806358B (en) | 2009-12-30 |
EA200801430A1 (ru) | 2008-12-30 |
EA015254B1 (ru) | 2011-06-30 |
US20080306042A1 (en) | 2008-12-11 |
CN101346383A (zh) | 2009-01-14 |
BRPI0620241A2 (pt) | 2011-11-08 |
JP2009520706A (ja) | 2009-05-28 |
JP5236490B2 (ja) | 2013-07-17 |
AU2006334899A1 (en) | 2007-07-19 |
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