EP2260044A2 - Thiénopyrimidines - Google Patents

Thiénopyrimidines

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Publication number
EP2260044A2
EP2260044A2 EP09731280A EP09731280A EP2260044A2 EP 2260044 A2 EP2260044 A2 EP 2260044A2 EP 09731280 A EP09731280 A EP 09731280A EP 09731280 A EP09731280 A EP 09731280A EP 2260044 A2 EP2260044 A2 EP 2260044A2
Authority
EP
European Patent Office
Prior art keywords
pyrimidine
amino
thieno
carboxylic acid
acid amide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09731280A
Other languages
German (de)
English (en)
Inventor
Guenter Hoelzemann
Hartmut Greiner
Christiane Amendt
Frank Zenke
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP2260044A2 publication Critical patent/EP2260044A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • 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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

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 of the 5 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 embryonic development as well as in the adult organism. In mammals, 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)
  • TGF-beta 3 is e.g. only in mesenchymal * 5
  • 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) PNAS0 93: 5877-5882).
  • one of the 4 isoforms of the latent TGF-beta binding protein may also be bound to TGF-beta ( Gentry (1988) Mol Cell Biol 8: 4162-4168, Munger (1997) Kindey Int 51: 1376-1382).
  • TGF-beta a latent TGF-beta binding protein
  • TGF- beta necessary activation of the inactive complex is not yet fully understood.
  • proteolytic processing eg by plasmin, plasma transglutaminase or thrombospondin, is certainly necessary (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
  • 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.
  • SMAD proteins serve as substrates for all TGF-beta family receptor kinases.
  • R-SMADs receptor-associated SMADs
  • SMAD1 receptor-associated SMADs
  • SMAD2 and SMAD3 are the TGF-beta specific signaling mediators.
  • TGF-beta receptor-associated SMADs
  • TGF-beta The spectrum of functions of TGF-beta is broad and depends on cell type and differentiation status (Roberts (1990)
  • 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.
  • TGF-beta thus suppresses inflammatory reactions and thus helps to avoid excessive immune reactions (Bogdan (1993) Ann NY Acad Sci 685: 713-739, summarized in Letterio (1998) Annu Rev Immunol 16: 137-161).
  • 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 such as fibronectin and collagen.
  • TGF-beta reduces the expression of matrix-degrading metalloproteases and inhibitors of metalloproteases (Roberts (1990) Ann
  • TGF-beta plays an important role in many physiological conditions such as wound healing and in pathological processes such as cancer and fibrosis.
  • 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 bound to the
  • TGF-beta then regulates its own production in macrophages and induces the secretion of other growth factors, e.g. through monocytes.
  • the most important functions during wound healing include the
  • 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 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 development of liver cirrhosis is stimulated by TGF-beta. Again, disruption of the TGF-beta signaling pathway has been shown to reduce fibrosis in experimental models (Yata (2002) Hepatology 35: 1022-1030, Arias (2003) BMC Gastroenterol 3:29) Q TGF-beta also plays a key role on carcinogenesis (reviewed in Derynck (2001) Nature Genetics: 29: 117-129; Elliott (2005) J Clin One 23: 2078-2093). In early stages of cancer development, TGF-beta counteracts carcinogenesis. This tumor suppressive effect is mainly due to the ability
  • TGF-beta inhibit the division of epithelial cells. in the In contrast, TGF-beta promotes cancer growth and metastasis in late tumor stages. This can be attributed to the fact that most epithelial tumors develop resistance to the growth-inhibiting effect of TGF-beta and TGF-beta simultaneously supports the growth of cancer cells via other mechanisms. These mechanisms include the promotion of angiogenesis, the immunosuppressive effect that assists tumor cells in circumventing the control function of the immune system (immuno-surveillance) and the promotion of invasiveness and
  • Conditions "characterized by increased TGF- ⁇ activity” include such conditions where TGF- ⁇ synthesis is so stimulated
  • TGF- ⁇ is present at elevated levels, or wherein the latent TGF- ⁇ protein is undesirably activated or converted to the active TGF- ⁇ protein, or wherein the TGF- ⁇ receptors are upregulated, or wherein the TGF-ß protein increased binding to cells
  • enhanced activity refers to any condition in which the biological activity of TGF- ⁇ is undesirably high, regardless of the cause.
  • 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.
  • GN glomerulonephritis
  • Other kidney conditions include diabetic nephropathy, renal interstitial fibrosis, renal fibrosis
  • Transplant patients receiving cyclosporine and HIV-associated nephropathy include progressive systemic sclerosis, polymyositis, scleroderma, dermatomyositis, eosinophilic fascitis, morphea, or those associated with the occurrence of Raynaud's syndrome.
  • Pulmonary fibrosis, the 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 associated with a
  • Retinal repair surgery cataract extraction with intraocular lens implantation, and post-glaucoma drainage surgery, and is associated with TGF- ⁇ 1 overproduction.
  • Fibrosis disorders associated with TGF- ⁇ 1 overproduction can be subdivided into chronic conditions such as kidney, lung and liver fibrosis 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-ß1 is an important mediator in the
  • TGF-ß1 leads to the formation of skin scar tissue.
  • 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 most of the reduction in diameter is on the extracellular matrix and not on the
  • TGF- ⁇ 1 gene expression was associated with both extracellular matrix synthesis and hyperplasia (Nabel, et al., 1993). Proc Natl. Acad., USA 90: 10759-10763). 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 induced hyperplasia in this gene transfer model in pigs (Nabel (1993) Nature 362: 844-846).
  • TGF-ß1 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.
  • TGF- ⁇ 1 transforming growth factor ⁇
  • TGF- ⁇ transforming growth factor ⁇
  • TGF- ⁇ signaling pathway Leukocyte subpopulation with disrupted TGF- ⁇ signaling pathway in the tumor-bearing host provides a powerful tool for immunotherapy of cancer.
  • a transgenic animal model with an interrupted TGF- ⁇ signaling pathway in T cells can eradicate a normally lethal TGF- ⁇ overexpressing lymphoma tumor, EL4 (Gorelik and Flavell, (2001) Nature Medicine 7 (10): 1118-1122 ).
  • EL4 normally lethal TGF- ⁇ overexpressing lymphoma tumor
  • EL4 normally lethal TGF- ⁇ overexpressing lymphoma tumor, EL4 (Gorelik and Flavell, (2001) Nature Medicine 7 (10): 1118-1122 ).
  • Down-regulation of TGF- ⁇ secretion in tumor cells results in the restoration of immunogenicity in the host, whereas T-cell insensitivity to TGF- ⁇ results in accelerated differentiation and autoimmunity, the elements of which may be required to express the self-antigen Tumors in a tolerant host.
  • TGF-ß neutralizing
  • Antibody could reverse the effect in culture, indicating that TGF- ⁇ signaling pathway inhibitors may be useful in reversing the immunosuppression present in this proportion of HIV patients.
  • TGF- ⁇ 1 may act as a powerful tumor suppressor and may mediate the effects of some chemopreventive agents.
  • tumor cells appear to be dependent on TGF- ⁇ -dependent growth inhibition parallel to the appearance of biologically active TGF- ⁇ in the microenvironment revoke.
  • the dual tumor suppressor role of TGF- ⁇ was most clearly demonstrated in a transgenic system overexpressing TGF- ⁇ in keratinocytes. Although transgenics were more resistant to the formation of benign skin lesions, the rate of metastasis conversion in the transgenes was dramatically increased (Cui, et al. (1996) Cell 86 (4): 531-42).
  • 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 increased production of TGF- ⁇ by human cancer occurs as a relatively late event during tumor progression. In addition, this tumor-associated TGF- ⁇ helps the tumor cells to a selective advantage and promotes tumor progression.
  • TGF-ß The effects of TGF-ß on cell-cell and cell stroma
  • 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. Cancer therapy modalities, such as radiation therapy and chemotherapy, induce the production of activated TGF- ⁇ in the tumor, causing the tumor
  • TGF-ß growth-inhibitory effects
  • these anti-cancer treatments increase the risk and accelerate the development of tumors with increased growth and invasiveness.
  • agents that target TGF-ß-mediated signal transduction may be a very efficient therapeutic strategy. It has been shown that the resistance of tumor cells to TGF-ß renders much of the cytotoxic effects of radiation therapy and chemotherapy ineffective, and the treatment-dependent activation of TGF- ⁇ in the stroma may even be detrimental, as it causes the Makes microenvironment more conductive to tumor progression and contributes to tissue damage leading to fibrosis.
  • the development of TGF- ⁇ signal transduction inhibitors probably has an advantage for the treatment of advanced cancer alone and in combination with other therapies.
  • TGF- ⁇ is also useful against atherosclerosis (TA McCaffrey: TGF- ⁇ s and TGF- ⁇ Receptors in Atherosclerosis: Cytokines and Growth Factor Reviews 2000, 11, 103-114) and Alzheimer's Disease (Masliah, E., Ho, G . Wyss-
  • T . Functional Route of TGF- ⁇ in Alzheimer's Disease Microvascular Injury: Lessons from Transgenic Mice: Neurochemistry International 2001, 39, 393-400).
  • Salts with good compatibility have very valuable pharmacological properties.
  • the compounds of the invention preferably exhibit beneficial biological activity which is readily detectable in enzyme-based assays, for example assays as described herein.
  • 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.
  • IC 50 values usually documented by IC 50 values in a suitable range, preferably in the micromolar range, and more preferably in the nanomolar range.
  • these signaling pathways are relevant to various diseases. Accordingly, the invention
  • the present invention therefore relates to compounds according to the invention as promoters or inhibitors, preferably as inhibitors of the signaling pathways described herein.
  • the preferred subject matter of the invention are therefore compounds according to the invention as promoters or inhibitors, preferably as inhibitors of the TGF- ⁇ signaling pathway.
  • a further 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 herein caused by an increased TGF-beta activity, mediated and / or propagated.
  • 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
  • the host or patient may be of any mammalian species, e.g. B. one
  • 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 human disease.
  • the susceptibility of a particular cell to treatment with the compounds of 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 allow the active agents to induce cell death or inhibit migration, usually between about one hour and one week. For testing in vitro, 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, the patient status, etc. Typically, one therapeutic dose will be sufficient to eliminate the unwanted cell.
  • Treatment is generally continued until there is a significant 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.
  • suitable models or model systems have been developed by various scientists, eg, cell culture models (eg, Khwaja et al., EMBO, 1997, 16, 2783-93) and models of transgenic animals (eg, White et al , Oncogene, 2001, 20, 7064-7072).
  • cell culture models eg, Khwaja et al., EMBO, 1997, 16, 2783-93
  • models of transgenic animals eg, White et al , Oncogene, 2001, 20, 7064-7072.
  • interactive connections can be made can be used to modulate the signal (eg, Stephens et al., Biochemical J., 2000, 351, 95-105).
  • the compounds according to the invention can also be used as reagents for testing kinase-dependent signal transduction pathways in animals and / or cell culture models or in the clinical diseases mentioned in this application.
  • kinase activity is a technique well known to those skilled in the art.
  • Generic Assay Systems for Determining Kinase Activity with Substrates e.g. Histone (eg Alessi et al., FEBS Lett. 1996, 399, 3, pages 333-338) or the myelin basic protein are described in the literature (eg Campos-Gonzalez, R. and Glenney, Jr., JR 1992, J. Biol. Chem. 267, page 14535).
  • Phospho-AK phospho-antibodies
  • the phospho-AK binds only the phosphorylated substrate. This binding is detectable by chemiluminescence with a second peroxidase-conjugated anti-sheep antibody (Ross et al., 2002, Biochem J., just prior to publication, manuscript BJ20020786).
  • WO2007 / 084560 describes other thienopyrimidines for the inhibition of TNF-alpha, PDE4 and B-RAF.
  • the invention relates to compounds of the formula I.
  • R 1 unsubstituted or on. two or dr
  • Hal is substituted benzofuranyl, benzothiazolyl, benzothiophenyl, imidazo [1, 2a] pyridine, quinolinyl, isoquinolinyl or furanyl, or mono-, di- or trisubstituted by A and / or Hal, pyridinyl, R 2 is H, Alk, Het 1 , Cyc, AlkNH 2 , AlkNHA, AlkNAA 1 , AlkOH, AlkOA,
  • X is a simple bond, NH, S or SO 2 ,
  • Alk alkylene having 1 to 6 C atoms, in which 1 to 4 H atoms may be replaced by F, Cl and / or Br, Cyc cycloalkyl having 3 to 7 C atoms, wherein 1 to 4 H atoms represented by A,
  • HaI, OH and / or OA can be replaced,
  • Het 1 is a mono- or binuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms which is mono-, di- or trisubstituted by A, OH, OA, Hal,
  • Ar phenyl which is unsubstituted or mono-, di- or trihydric
  • A, A ' are each independently of one another straight or branched alkyl having 1-10 C atoms, in which one, two or three
  • the invention also relates to the optically active forms
  • Solvates of the compounds are understood to mean additions of inert solvent molecules to the compounds which form due to their mutual attraction. Solvates are e.g. Mono or dihydrate or alcoholates.
  • compositions are understood, for example, as the salts of the compounds according to the invention as well as so-called prodrug compounds.
  • the term "effective amount” means the amount of a drug or pharmaceutical agent that 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, a disease Suffering, a disorder or side effects or even the reduction of the progression of a disease, a disease or a disorder.
  • terapéuticaally effective amount also includes the
  • the invention also provides mixtures of the compounds according to the invention, e.g. Mixtures of two diastereomers, e.g. 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 invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to claims 1 to 7 and their pharmaceutically usable Derivatives, solvates, salts, tautomers and stereoisomers, characterized in that
  • R 1 has the meaning given in formula I, with a
  • Z is an OH group, the OH group optionally converted into a reactive OH group or exchanged for a halogen, and the compound of formula VI with a compound of formula VII
  • R 1 , R 2 and X are those given in formula I.
  • a base or acid of formula I is converted into one of its salts.
  • X is a single bond.
  • X is NH.
  • X is S.
  • X is SO 2 .
  • A is particularly preferred
  • Cyc is, independently of other substitutions, cycloalkyl and is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Particularly preferred is cyclopropyl.
  • Alk is C1-C1 0 alkylene, preferably methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene or decylene, isopropylene, isobutylene, sec. Butylene, 1-, 2- or 3-methylbutylene, 1, 1-, 1, 2- or 2,2-dimethylpropylene, 1-ethylpropylene, 1-, 2-, 3- or 4-
  • Methylpentylene 1,1,1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-1-methylpropylene, 1- Ethyl 2-methylpropylene, 1, 1, 2 or 1, 2,2-trimethylpropylene.
  • C 1 -C 6 alkylene more preferably methylene, ethylene, propylene, butylene, pentylene or
  • CrC 6 is aklinyl, such as methinyl, ethynyl,
  • a preferred alkynyl is the propynyl.
  • Ar means e.g. Phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p- tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-sulfonamidophenyl, o-, m- or p- (N-methyl-sulfon
  • Chloro-6-methoxyphenyl or 2,5-dimethyl-4-chlorophenyl Chloro-6-methoxyphenyl or 2,5-dimethyl-4-chlorophenyl.
  • Ar is preferably unsubstituted or mono-, di- or trisubstituted by A, OH, OA, Hal, SO 2 NH 2 , SO 2 NA and / or SO 2 NAA 'substituted phenyl. Particularly preferred as Ar is unsubstituted or monosubstituted by SO 2 NH 2 , SO 2 NA or SO 2 NAA 'phenyl.
  • R 1 represents , for example, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl or isoquinolinyl, 2-, 4-, 5-, 6- or 7- Benzothiazolyl, benzofuran-2-, 3-, 4-, 5-, 6- or 7-yl, benzothiophene-2-, 3-, 4-, 5-, 6- or 7-yl, 2-, 3- or 4-yl Furanyl, imidazo [1,2-a] pyridine-2-, 3-, 4-, 5-, 6- or 7-yl or pyridine-2-, 3-, 4- or 5-yl, is particularly preferred Quinolin-6-yl, benzothiazol-2-yl, benzofuran-2-yl, benzothiophen-2-yl, imidazo [1, 2a] pyridin-2-yl and furan-2-yl. Especially preferred is 6-methyl
  • Het 1 preferably denotes a monocyclic saturated or aromatic heterocycle having 1 to 2 N and / or O atoms which may be monosubstituted or disubstituted by A, OH, OA, Hal, SO 2 A and / or OO (carbonyl oxygen) can.
  • the compounds of formula I may possess one or more chiral centers ⁇ r- and therefore occur in different stereoisomeric forms.
  • Formula I encompasses all these forms.
  • the invention relates in particular to those compounds of the formula I in which at least one of the abovementioned
  • Benzothiazolyl benzothiophenyl, O 0 imidazo [1, 2a] pyridine, quinolinyl, or furanyl, or mono- or di-substituted by A and / or Hal, substituted pyridinyl;
  • Heterocycle having 1 to 2 N and / or O atoms, which may be mono- or disubstituted by A and / or 0 (carbonyl oxygen); 25 in Ig Het 1 pyridinyl, pyrazolyl, morpholinyl, which may be unsubstituted or monosubstituted or disubstituted by A, or 4-ethanesulfonylpiperazinyl;
  • Atoms in which one or two CH 2 groups are CH CH and / or -C ⁇ C groups may be replaced and / or 1-5 H atoms may be replaced by F and / or Cl,
  • R 2 H Alk, Het 1 , Cyc, AlkNH 2 , AlkNHA, AlkNAA ', AlkOH, AlkOA, AlkHet 1 , AlkOAlkOH, AlkO (CH 2 ) m NAA',
  • Ar is phenyl which is unsubstituted or simply substituted
  • Hal is F, Cl, Br or I, m is 1, 2, or 3
  • the starting materials can, if desired, also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of the invention.
  • the starting compounds are generally known. If they are new, they can be produced by methods known per se.
  • the compounds of formula II, III, V and VII are known in the rule. If they are not known, they can be prepared by methods known per se.
  • Z is preferably Cl, Br, I or a reactively modified OH group, such as alkylsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferably phenyl or p-butyl). tolylsulphonyloxy).
  • Z is more preferably Cl.
  • reaction is carried out by methods known to the person skilled in the art.
  • Suitable bases are preferably metal oxides, e.g. Alumina, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and
  • Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone;
  • Hydrocarbons such as hexane, petroleum ether, benzene
  • Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF);
  • Nitriles such as acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); Sulfur- carbon; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of said solvents.
  • Sulfoxides such as dimethylsulfoxide (DMSO); Sulfur- carbon
  • Carboxylic acids such as formic acid or acetic acid
  • Nitro compounds such as nitromethane or nitrobenzene
  • Esters such as ethyl acetate or mixtures of said solvents.
  • solvent particularly preferred is e.g. Water and / or tetrahydrofuran.
  • a compound of formula VIII is first formed, which then cyclized to the compound of formula I.
  • the compound of formula VIII can be isolated as an intermediate and used, for example, as starting compound for the preparation of compounds of formula I.
  • the reaction time is between a few minutes and 14 days, the reaction temperature between about -30 ° and 140 °, normally between -10 ° and 130 °, in particular between about 30 ° and about 125 °.
  • reaction is preferably carried out in inert solvents as described above, particular preference is given to acetone, acetonitrile and / or ethanol.
  • the reaction time is between a few minutes and 14 days, the reaction temperature between about -30 ° and 140 °, normally between -10 ° and 130 °, in particular between about 30 ° and about 125 °.
  • the abovementioned compounds according to the invention can be used in their final non-salt form.
  • the present invention also relates to the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases according to procedures known in the art.
  • Pharmaceutically acceptable salts which can be derived from various organic and inorganic acids and bases according to procedures known in the art.
  • Salt forms of the compounds of formula I are mostly prepared conventionally. If the compound of the formula I contains a carboxylic acid group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base addition salt.
  • bases include, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine and
  • N-methyl-glutamine N-methyl-glutamine.
  • the aluminum salts of the compounds of formula I are also included.
  • acid addition salts can be formed by reacting these compounds with pharmaceutically acceptable organic and inorganic acids
  • Acids e.g. 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.
  • 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
  • alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenes
  • pharmaceutically acceptable acid addition salts of the compounds of formula I 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,
  • 2-naphthalenesulfonate nicotinate, nitrate, oxalate, oleate, pamoate, pectinate,
  • the base salts of the invention include
  • Bevorzugt 5 Preferred among the above-mentioned salts are ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts calcium and magnesium.
  • Derive bases include salts of primary, secondary and tertiary amines,
  • Amines, cyclic amines, and basic ion exchange resins e.g. Arginine, betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethyl-
  • Groups can be treated with agents such as (Ci-C 4 ) alkyl halides, for example, methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di (C 1 -C 4 ) alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (Ci 0 - C- ⁇ 8 ) alkyl halides, such as decyl, dodecyl, lauryl, myristyl and
  • 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, which is not intended to be limiting.
  • the amount of the desired acid brings into contact, whereby one on usual
  • 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 differ in some sense from their corresponding salt forms with respect to 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 formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines.
  • Preferred metals are sodium, potassium, magnesium and calcium.
  • Suitable 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 obtained by contacting the salt form with an acid and isolating the free
  • bitartrate diacetate, difumarate, dimeglumine
  • pharmaceutically acceptable salt means an active ingredient containing a compound of formula I in the form of one of its salts, particularly when in its salt form
  • the pharmaceutically acceptable salt form of the active ingredient may also be this
  • Molecular structure can be chiral and therefore can occur in different enantiomeric forms. They may therefore be in racemic or optically active form.
  • the pharmaceutical activity of the racemates or stereoisomers of the compounds of formula I may differ, it may be desirable to use the enantiomers.
  • the end product or else the intermediates may already be separated into enantiomeric compounds, chemical or physical measures known to those skilled in the art, or already be used as such in the synthesis.
  • Suitable release agents are e.g. optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids.
  • optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids.
  • chromatographic enantiomer separation using an optically active resolving agent e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or silica gel-fixed chirally derivatized methacrylate polymers.
  • optically active resolving agent e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or silica gel-fixed chirally derivatized methacrylate polymers.
  • Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures such. Hexane / isopropanol / acetonitrile e.g. in the ratio 82: 15: 3.
  • the invention further relates to the use of the compounds and / or their physiologically acceptable salts for the preparation of a Pharmaceutical (pharmaceutical preparation), in particular non-chemical way.
  • a Pharmaceutical pharmaceutical preparation
  • they can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or excipient and optionally in combination with one or more further active ingredients.
  • the invention furthermore relates to medicaments comprising at least one compound of the formula I 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 unit may contain, for example, 0.1 mg to 3 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the invention, depending on the treatment
  • Condition of the patient, or pharmaceutical formulations may be in
  • dosage units containing a predetermined amount of active ingredient per dosage unit are those containing a daily or partial dose as indicated above or a corresponding fraction of an active ingredient.
  • pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art.
  • compositions may be administered by any suitable route, for example oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intravenous). muscular, intravenous or intradermal) routes.
  • Such formulations can be prepared by any method known in the pharmaceutical art, for example, by bringing the active ingredient together with the carrier (s) or excipient (s).
  • compositions adapted for oral administration may be administered 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.
  • Tablet or capsule the active component with an oral, non-toxic and pharmaceutically acceptable inert carrier, such. Ethanol, glycerin, water and the like. combine. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical excipient, e.g. an edible carbohydrate such as starch or mannitol. A flavor, preservative, dispersant and dye may also be present.
  • an oral, non-toxic and pharmaceutically acceptable inert carrier such as Ethanol, glycerin, water and the like.
  • a similarly comminuted pharmaceutical excipient e.g. an edible carbohydrate such as starch or mannitol.
  • a flavor, preservative, dispersant and dye may also be present.
  • Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith.
  • Lubricants and lubricants such as finely divided silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process.
  • a disintegrants or solubilizers such as 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 can also be incorporated into the mixture.
  • Suitable binders include starch, 5
  • Gelatin natural sugars, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. Acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like.
  • natural sugars e.g. Glucose or beta-lactose
  • corn sweeteners e.g. Glucose or beta-lactose
  • natural and synthetic gums e.g. Acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like.
  • 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
  • ⁇ C made, for example, a powder mixture, granulating or dry-pressing a lubricant and a disintegrant, are added and the whole is compressed into tablets.
  • a powder mixture is prepared by treating the appropriately comminuted compound with a diluent or base as described above, and
  • a binder e.g. Carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone
  • a dissolution reducer such as e.g. Paraffin
  • a resorption accelerator such as a quaternary salt and / or an absorbent, e.g. bentonite
  • an absorbent e.g. bentonite
  • the powder mixture can be granulated by mixing it with a binder, e.g. Syrup, starch paste, Acadia slime or solutions of cellulosic or polymer materials is wetted and pressed through a sieve.
  • a binder e.g. Syrup, starch paste, Acadia slime or solutions of cellulosic or polymer materials is wetted and pressed through a sieve.
  • OQ granulation can run the powder mixture through a tabletting machine, resulting in irregularly shaped lumps, which are broken up into granules.
  • 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.
  • 35 greased mixture is then compressed into tablets.
  • 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,
  • flavoring additives 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 may also be prepared to prolong or retard release, such as 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 in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from various phospholipids such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of formula I as well as the salts, solvates and physiologically functional derivatives thereof can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the connections can also be with
  • Such polymers are coupled as targeted drug carrier.
  • Such polymers may be polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals,
  • ⁇ c include. Furthermore, the compounds can be attached to a class of biodegradable polymers which are suitable for the controlled release of a drug, for example polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters,
  • compositions adapted for transdermal administration may be presented as discrete patches for prolonged, close contact with the epidermis of the recipient.
  • the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
  • Pharmaceutical compounds adapted for topical administration may 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 may be either paraffinic or water-miscible
  • Cream base can be used.
  • the active ingredient can become a
  • Cream can be formulated with an oil-in-water cream base or a water-in-oil base.
  • the pharmaceutical formulations adapted for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • Formulations 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 received, i. 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 carrier include drug solutions in water or oil.
  • Formulations include fine particulate dusts or mists, which by means of various types of pressurized dispensers with aerosols, nebulizers or insufflators can be produced.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and nonaqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; and may include aqueous and non-aqueous ⁇ c sterile suspensions, suspending agents and thickeners.
  • the formulations may be presented in single or multi-dose containers, eg, sealed vials and vials, and stored in the freeze-dried (lyophilized) state such that only the addition of the sterile carrier liquid, eg water for
  • Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.
  • formulations may contain other conventional means 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 formula I depends on a number of factors, including e.g. the age and
  • an effective amount of a compound of the invention is for the
  • Treatment generally in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day and more typically in the
  • Range of 1 to 10 mg / kg of body weight per day Range of 1 to 10 mg / kg of body weight per day.
  • the actual amount per day would usually be between 70 and 700 mg, which is a single dose
  • ⁇ C proportion of the effective amount of the compound of the formula I can be determined per se. It can be assumed that similar dosages are suitable for the treatment of the other, above-mentioned disease states.
  • the invention relates to medicaments containing at least one
  • the invention further provides the use of compounds of formula I and their pharmaceutically acceptable derivatives, salts, O0 solvates, tautomers and stereoisomers, including their
  • chemotherapeutic agents are preferred, in particular those which inhibit angiogenesis and thereby inhibit the growth and spread of tumor cells; preferred are VEGF receptor inhibitors, including robozymes and antisense, which are directed to VEGF receptors, as well as angiostatin and endostatin.
  • antineoplastic agents that can be used in combination with the compounds of the invention generally include alkylating agents, antimetabolites; Epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; Mitoxantrone or platinum coordination complexes.
  • Antineoplastic agents are preferably selected from the following classes:
  • Anthracyclines vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, epothilones, discodermolides, pteridines, diynes and podophyllotoxins.
  • Particularly preferred in the mentioned classes are e.g. Carminorhicin, daunorubicin, aminopterin, methotrexate, methopterine, dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 5-fluorodeoxyuridine
  • Vindesine, Leurosine, Docetaxel and Paclitaxel are selected from the group
  • antibiotics are preferred.
  • Preferred antibiotics are selected from the group dactinomycin, daunorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, plicamycin, mitomycin.
  • enzyme inhibitors are preferred.
  • Preferred enzyme inhibitors are selected from the group of histone deacetylation inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA]) and tyrosine kinase inhibitors (e.g., ZD 1839 [Iressa]).
  • SAHA suberoylanilide hydroxamic acid
  • tyrosine kinase inhibitors e.g., ZD 1839 [Iressa]
  • nuclear export inhibitors are preferred.
  • Nuclear export inhibitors prevent the removal of biopolymers (e.g., RNA) from the nucleus.
  • Preferred nuclear export inhibitors are selected from the group Callystatin, Leptomycin B, Ratjadone.
  • nuclear export inhibitors are preferred. Nuclear export inhibitors prevent the discharge of
  • Biopolymers eg RNA from the cell nucleus.
  • Preferred nuclear export Inhibitors are selected from the group Callystatin, Leptomycin B, Ratjadone.
  • immunosuppressants are preferred.
  • Preferred immunosuppressants are selected from the group consisting of:
  • the invention is also a set (kit), consisting of separate packages of
  • the kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
  • suitable containers such as boxes or boxes, individual bottles, bags or ampoules.
  • the set may e.g. separate
  • the compounds according to the invention and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, are suitable as pharmaceutical active ingredients for mammals, in particular for the
  • the invention therefore provides the use of compounds of the formula I and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment and / or control of cancer, tumor growth, metastasis growth, Fibrosis, restenosis, HIV infection, Alzheimer's, atherosclerosis, and / or to promote wound healing.
  • a disease wherein the disease is a solid tumor.
  • the solid tumor is preferably selected from the group of squamous cell tumors, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, Urogenital tract, lymphatic system, stomach, larynx and / or lungs.
  • the invention also provides the use of compounds according to claim 1 and / or their physiologically acceptable salts and solvates for the preparation of a medicament for the treatment of solid tumors, wherein a therapeutically effective amount of a compound of formula I in combination with a compound from group 1 ) Estrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5) antiproliferative agent, 6) prenyl protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8) HIV protease inhibitor, 9) reverse Transcriptase inhibitors and 10) other angiogenesis inhibitors is administered
  • the solid tumor is furthermore 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 lymphocytic leukemia 10 and / or chronic lymphocytic leukemia.
  • the present compounds are also useful for combination with known anticancer agents.
  • known anticancer agents ⁇ c the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-Proteintransferasehemmer, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and further
  • Angiogenesis inhibitors are suitable.
  • the invention therefore also relates to the use of compounds according to claim 1 and / or their physiologically acceptable salts and solvates for the preparation of a medicament for
  • Cytotoxic agent 5) antiproliferative agent, 6) prenyl-protein transferase
  • Estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of how this occurs: Estrogen receptor modulators include, for example, tamoxifen, raloxifene, idoxifen, LY353381, LY 117081, toremifene, fulvestrant , 4- [7- (2,2-dimethyl-1-)
  • Androgen receptor modulators refers to compounds that interfere with the binding of androgens to the receptor or inhibit, regardless of how this happens. Androgen receptor modulators include, for example, finasteride and other compounds that interfere with the binding of androgens to the receptor or inhibit, regardless of how this happens. Androgen receptor modulators include, for example, finasteride and other compounds that interfere with the binding of androgens to the receptor or inhibit, regardless of how this happens. Androgen receptor modulators include, for example, finasteride and other
  • Retinoid receptor modulators refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of how this occurs.
  • 25 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.
  • Cytotoxic agents refers to compounds that are primarily derived from direct
  • Cell function or that inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors.
  • the cytotoxic agents include, for example, tirapazimine, sertenef, cachectin,
  • microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, S''-didehydro-desoxy- ⁇ '-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- (6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl- I H.
  • Antiproliferative agents include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine.
  • ocfosfate Fosteabin Sodium Hydrate, Raltitrexed, Paltitrexide, Emitefur, Tiazofurin, Decitabine, Nolatrexed, Pemetrexed, Nelzarabine, T-Deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N- [5- (2,3 -
  • antiproliferative agents also include other monoclonal antibodies to growth factors than those already listed under the “angiogenesis inhibitors”, such as trastuzumab, as well as tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see, eg, US Patent No. 6,069,134 ).
  • angiogenesis inhibitors such as trastuzumab
  • tumor suppressor genes such as p53
  • the ability of the inhibitors to abrogate TGF-beta mediated growth inhibition is tested.
  • Cells of the lung epithelial cell line MvI Lu are seeded in a defined cell density in a 96-well microtiter plate and cultured for 16 hours under standard conditions. Subsequently, the medium with 10 medium containing 0.5% FCS and 1 ng / ml TGF-beta, replaced and added the test substances in defined concentrations, usually in the form of dilution series with 5-fold steps. The concentration of the solvent DMSO is constant at 0.5%.
  • Crystal violet staining of the cells takes place for 48 hours. After extraction 15 of 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. 20
  • 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-ATP / well) are mixed 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) without or with 30 test substance (5-10 concentrations) for 45 min at 30 0 C incubated.
  • the reaction is stopped with 25 ⁇ l of 200 mM EDTA solution, filtered off with suction at room temperature after 30 minutes, and the wells are washed 3 times with 100 ⁇ l of 0.9% NaCl solution. Radioactivity is measured in the topcount.
  • the IC 50 values are calculated with RS1.
  • “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 organic phase over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization. Rf values on silica gel; Eluent: ethyl acetate / methanol 9: 1. Mass spectrometry (MS): El (electron impact ionization) M +
  • Ion source electrospray (positive mode); Scan: 100-1000 m / z;
  • Fragmentation voltage 60 V; Gas temperature: 300 0 C, DAD: 220 nm.
  • Solvent LiChrosolv grade from Merck KGaA Solvent A: H2O (0.01% TFA) Solvent B: ACN (0.008% TFA)
  • the aluminum oxide is filtered off with suction. It's going to be fine
  • Phosphoryl chloride was added and heated to 120 0 C and stirred for 2h. The resulting black-brown solution is added 5 mL phosphoryl chloride and stirred for a further hour in the heat.
  • the batch is cooled to RT, with 20 ml
  • the batch is cooled to room temperature, with
  • the batch is mixed with ice and the fine precipitated product is filtered off with suction. You get 88mg of the desired
  • a standard method is the oxidation with meta-chloroperbenzoic acid in tetrahydrofuran stirred at room temperature for 1h.
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 2 l of twice-distilled water with 2N hydrochloric acid, filtered sterile, and dispensed into injection jars. filled, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient according to the invention is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution of 1 g of an active ingredient according to the invention 9.38 g of NaH 2 PO 4 ⁇ 2 H 2 O is prepared, 28.48 g Na 2 HPO 4 • 12 H 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.
  • 500 mg of an active ingredient according to the invention are mixed with 99.5 g of Vaseline under aseptic conditions.
  • a mixture of 1 kg of active ingredient, 4 kg of lactose, 1, 2 kg of potato starch, o, 2 kg of talc and 0.1 kg of magnesium stearate is compressed in the usual way to tablets, such that each tablet contains 10 mg of active ingredient.
  • Example F Dragees 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 dyestuff.
  • Example G Capsules 2 kg of active ingredient are filled in the usual way in hard gelatin capsules, so that each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of an active ingredient according to the invention in 60 l of 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

L'invention concerne de nouvelles thiénopyrimidines de formule (I), dans laquelle R1, R2 et X ont les significations indiquées dans la revendication 1, lesdites thiénopyrimidines étant des inhibiteurs de la kinase du récepteur du TGF bêta et pouvant être utilisées notamment dans le traitement de tumeurs.
EP09731280A 2008-04-09 2009-03-23 Thiénopyrimidines Withdrawn EP2260044A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102008017853A DE102008017853A1 (de) 2008-04-09 2008-04-09 Thienopyrimidine
PCT/EP2009/002112 WO2009124653A2 (fr) 2008-04-09 2009-03-23 Thiénopyrimidines

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EP2260044A2 true EP2260044A2 (fr) 2010-12-15

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US (1) US20110028472A1 (fr)
EP (1) EP2260044A2 (fr)
JP (1) JP2011518132A (fr)
KR (1) KR20110010721A (fr)
CN (1) CN102015724A (fr)
AR (1) AR071586A1 (fr)
AU (1) AU2009235729A1 (fr)
BR (1) BRPI0911364A2 (fr)
CA (1) CA2720878A1 (fr)
DE (1) DE102008017853A1 (fr)
EA (1) EA201001576A1 (fr)
IL (1) IL208066A0 (fr)
MX (1) MX2010011015A (fr)
WO (1) WO2009124653A2 (fr)
ZA (1) ZA201007979B (fr)

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Publication number Priority date Publication date Assignee Title
WO2010149257A1 (fr) * 2009-06-22 2010-12-29 Merck Patent Gmbh Alcoxythiénopyrimidines comme modulateurs de récepteurs kinases de tgf-bêta
MX2012004990A (es) 2009-10-30 2012-06-12 Janssen Pharmaceutica Nv Deribados de imidazo [1,2-b] pirimideazina y su uso como inhibidores de la enzima fosfodiesterasa 10.
AU2010344973B2 (en) 2010-02-05 2016-06-16 Merck Patent Gmbh Hetaryl-[1,8]naphthyridine derivatives
BR112012019561A2 (pt) 2010-02-22 2019-09-24 Merck Patent Gmbh hetarilamino naftiridinas
AR080754A1 (es) 2010-03-09 2012-05-09 Janssen Pharmaceutica Nv Derivados de imidazo (1,2-a) pirazina y su uso como inhibidores de pde10
WO2013000924A1 (fr) 2011-06-27 2013-01-03 Janssen Pharmaceutica Nv Dérivés de 1-aryl-4-méthyl-[1,2,4]triazolo[4,3-a]quinoxaline
FR2988722B1 (fr) 2012-04-03 2014-05-09 Sanofi Sa Nouveaux derives de thienopyrimidines, leurs procedes de preparation et leurs utilisations therapeutiques
US9669035B2 (en) 2012-06-26 2017-06-06 Janssen Pharmaceutica Nv Combinations comprising PDE 2 inhibitors such as 1-aryl-4-methyl-[1,2,4]triazolo-[4,3-A]]quinoxaline compounds and PDE 10 inhibitors for use in the treatment of neurological of metabolic disorders
RU2667058C2 (ru) 2012-07-09 2018-09-14 Янссен Фармацевтика Нв Ингибиторы фермента фосфодиэстеразы 10

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US5747469A (en) 1991-03-06 1998-05-05 Board Of Regents, The University Of Texas System Methods and compositions comprising DNA damaging agents and p53
GB9904387D0 (en) 1999-02-25 1999-04-21 Pharmacia & Upjohn Spa Antitumour synergistic composition
WO2000061186A1 (fr) 1999-04-08 2000-10-19 Arch Development Corporation Utilisation d'anticorps anti-vegf pour accentuer le rayonnement lors d'une therapie anticancereuse
EP1724268A4 (fr) * 2004-02-20 2010-04-21 Kirin Pharma Kk Compose ayant une activite d'inhibition du tgf-beta et composition pharmaceutique contenant celui-ci
WO2006090094A1 (fr) * 2005-02-28 2006-08-31 Vernalis R & D Ltd Composes de pyrimidothiophene pour une utilisation en tant qu’inhibiteurs de l’hsp90
DE102005013621A1 (de) * 2005-03-24 2006-09-28 Curacyte Discovery Gmbh Substituierte 2-Aryl(Hetaryl)-5-aminothieno[2,3-d]pyrimidin-6-carbonsäureamide, Verfahren zu ihrer Herstellung und Verwendung als Pharmazeutika
CA2637245A1 (fr) 2006-01-17 2007-07-26 Signal Pharmaceuticals, Llc Inhibiteurs de tnf.alpha., de pde4 et de b-raf, compositions comprenant ces inhibiteurs et methodes d'utilisation associees
JPWO2008020622A1 (ja) * 2006-08-17 2010-01-07 杏林製薬株式会社 新規なチエノ［２，３−ｄ］ピリミジン化合物

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Publication number Publication date
ZA201007979B (en) 2011-07-27
EA201001576A1 (ru) 2011-04-29
WO2009124653A3 (fr) 2009-12-03
KR20110010721A (ko) 2011-02-07
IL208066A0 (en) 2010-12-30
WO2009124653A2 (fr) 2009-10-15
AU2009235729A1 (en) 2009-10-15
MX2010011015A (es) 2010-11-22
BRPI0911364A2 (pt) 2015-12-29
AR071586A1 (es) 2010-06-30
CA2720878A1 (fr) 2009-10-15
CN102015724A (zh) 2011-04-13
DE102008017853A1 (de) 2009-10-15
JP2011518132A (ja) 2011-06-23
US20110028472A1 (en) 2011-02-03

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