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WO2013037293A1 - Composés de n-indol-1-amide et leur application en tant que médicament anticancer - Google Patents

Composés de n-indol-1-amide et leur application en tant que médicament anticancer Download PDF

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WO2013037293A1
WO2013037293A1 PCT/CN2012/081297 CN2012081297W WO2013037293A1 WO 2013037293 A1 WO2013037293 A1 WO 2013037293A1 CN 2012081297 W CN2012081297 W CN 2012081297W WO 2013037293 A1 WO2013037293 A1 WO 2013037293A1
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acid
cancer
phenyl
dihydro
group
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PCT/CN2012/081297
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English (en)
Chinese (zh)
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张世喜
宋述强
谭玉婷
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湖南有色凯铂生物药业有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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

Definitions

  • the present invention relates to N-indol-1-amide compounds which are useful as kinase inhibitors such as VEGFR-2, and their use in the preparation of a medicament for the treatment of diseases mediated by kinases such as VEGFR-2. Background technique
  • protein kinases regulate and amplify information by phosphorylating upstream proteins, downstream proteins, and themselves, controlling cell growth, differentiation, and apoptosis. It is known that Raf/MEK/ERK is a signaling pathway in all eukaryotic cells, which transmits signals from the extracellular to the nucleus through specific cascade phosphorylation of Ras, Raf, MEK and ERK, about 30%. Tumor cells have an upregulation of this pathway.
  • the signal begins with the binding of epidermal growth factor (EGF) to the epidermal growth factor receptor (EGFR) on the cell membrane, and the phosphorylation site of EGFR at the SH2 site and the adaptor protein GRB2 (growth factor) Receptor-bound protein 2 ) Binding, recruiting the guanylate exchange factor SOS protein and Ras bind to the adjacent inner cell membrane, GTP replaces the Ras binding GDP and stimulates Ras, Ras is one of the key signal transduction centers, Multiple upstream and downstream signal transductions.
  • EGF epidermal growth factor
  • EGFR epidermal growth factor receptor
  • the intensified Ras binds to the cell pad/threonine kinase Raf, Raf rephosphorylates MAPK kinase (MAPKK, also known as MEK), and MEK activates ERK1/2 (extracel lular signal regulated kinase, ERK). After activation, ERK enters the nucleus and directly activates transcription factors to initiate biological processes such as cell growth, differentiation and apoptosis. Once this pathway is overactivated, accelerated cell proliferation and prolonged cell survival can lead to tumor formation and progression (Kolch W. Biochem J, 2000, 351: 289-305; Gi shizky ML. Annu. Rep. Med. Chem. 1995, 30: 247-253).
  • the signaling proteins in the signaling pathway cascade may be activated or inhibited by different upstream proteins to form an extremely complex Network regulation structure.
  • Raf and ERK on the Raf/MEK/ERK signaling pathway can also exert their signal transduction regulation in a Ras-independent manner; Ras activity can also be increased by a decrease in GTP hydrolysis caused by mutation of the tumor suppressor gene NF1. .
  • epidermal growth factor receptor EGFR
  • PI3K phosphatidylinositol 3-kinase
  • Ras and PI3K together regulate molecular lactation
  • mTOR animal rapamycin target protein
  • S6 kinase and 4EBP1 are phosphorylated by mTOR to initiate ribosomal protein synthesis (Hay N, Sonenberg N) (2004) .
  • the protein kinase gene co-expresses more than 518 protein kinases, of which the receptor kinase has 20 subfamilies of 58 types, and the cell paddle kinase has 10 subfamilies of 32 types; among the more than 50 known oncogenes, most of them are protein kinases.
  • Gene Manning et al. Sicence, 2002, 298, 1912).
  • Cancer genes are usually in a state of inhibition, but when they are mutated or abnormally activated, such as chemical poisons, long-term ultraviolet light, or radioactive substances, oncogenes overexpress kinases, or express persistently activated kinases, resulting in Cancer cells are produced out of control by important factors such as cell growth, differentiation and apoptosis (Croce CM. Engl J Med. 2008, 358 (5): 502 - 11).
  • Raf kinase on the Raf/MEK/ERK signaling pathway is overexpressed in many cancer cells, and more than 60% of human malignant melanoma, 12% of colorectal cancer, and 14% of ovarian cancers have found B-raf activating mutations. This mutation is also present in tumors of the thyroid and lungs; on the other hand, there is abnormally high C-raf activity in 50% of kidney cancers and almost 100% of liver cancer cells, although C-raf does not have mutations.
  • the B-raf mutant kinase B-raf-V600E which is 500 times more active than wild-type kinase, forms a heterodimer with C-raf and continues to activate downstream ERK and protein kinase mTOR (Sridhar SS, Hedley) D, Siu LL. Mol. Cancer Ther.
  • RAF kinase inhibitors There are three subtypes of RAF kinase, including A-raf, B-raf and C-raf (also Raf-1), which are highly homologous and enjoy high sequence similarity, so small molecule RAF kinase inhibitors usually antagonize B-ref, C-raf and B_raf-V600E. Sorafenib, developed by Bayer, was the first RAF kinase inhibitor approved in 2005 to treat advanced kidney cancer. In 2007, it was approved as a treatment for metastatic liver cancer.
  • VHL its encoded amino acid protein
  • HIF-la hypoxia-inducible factor-la
  • HIF-loc re-stimulates the expression and synthesis of VEGF and PDGF- ⁇ and other cell growth factors, and participates in neovascularization of tumor tissues.
  • most kidney cancers have EGFR expression, and the degree of expression is related to prognosis.
  • HIF-loc promotes cell proliferation and survival by activating autocrine action by activating TGF-oc.
  • VEGF vascular endothelial growth factor
  • VAGFR receptor for vascular endothelial growth factor
  • MMPs matrix metalloproteinases
  • Fibroblast Growth Factor and the like.
  • Growth factors such as PDGF and FGF secreted by cancer cells help the formation of new blood vessels by recruiting and stimulating the growth of fibroblasts, smooth muscle cells, and adventitial cells to form new cancer cell vascular stroma.
  • this new tumor blood vessel tends to be irregular in structure, imperfect vascular matrix, and high permeability. Therefore, tumor cells can penetrate into the blood, spread and attach to other parts of the body to grow and multiply to form cancer metastasis (metastasi s ).
  • Clinical studies have shown that inhibition of this process can effectively prevent tumor growth and metastasis and prolong patient life (Folkman J. Scientific American 1996, 275 (3): 150 - 4 ).
  • VEGFR-1 Flt-1
  • VEGFR-2 KDR, or Flk-1
  • PDGF platelet-derived growth factor
  • FGF fibroblast growth factor receptor FGFR1-4
  • a structurally similar VEGFR-3 (Flt-4) receptor is mainly involved in the formation of lymphatic vessels
  • Imatinib tyrosine kinase small molecule inhibitor imatinib
  • CML chronic myeloid leukemia
  • Imatinib demonstrated for the first time the feasibility of kinase inhibitors in the treatment of cancer, while imatinib showed lower drug toxicity relative to chemotherapy and improved patient quality of life.
  • imatinib inhibits cell growth and division by antagonizing over-expressed bcr-abl kinase in leukemia cancer cells; it also antagonizes c-kit kinase activity and clinically displays its gastrointestinal tract
  • the efficacy of stromal cell tumors has been approved as a therapeutic drug for gastrointestinal stromal tumors.
  • Bristol-Myers Squibb and Novartis developed two other treatments for chronic bone marrow cancer in 2006 and 2007 - Dasha Dasatinib and Nilotinib, and both have good effects against patients with imatinib.
  • Gefitinib developed by AstraZeneca in the United Kingdom, was approved for marketing in Japan in August 2002.
  • Gefitinib a first-line treatment for non-small cell lung cancer, is particularly effective in smoking non-small cell lung cancer in Asian men.
  • Genentech and 0SI Pharmaceutical jointly developed erlotinib, which is more widely used as a first-line treatment, maintenance therapy and sequential in non-small cell lung cancer in seven or eighty countries around the world.
  • Gefitinib and erlotinib are epidermal growth factor receptor (EGFR) inhibitors that antagonize the binding of EGFR receptors to epidermal growth factor (EGF) on the cell surface transmembrane and inhibit EGFR-mediated Raf/MEK/ Signal channels such as ERK (Raymond E, Faivre S, Armand J.
  • EGFR epidermal growth factor receptor
  • erlotinib is also effective in inhibiting the growth of pancreatic tumor cells, becoming the first FDA-approved targeted drug for the treatment of pancreatic cancer.
  • Sunitinib As a small molecule inhibitor of tyrosine kinase for the treatment of renal cancer (RCC), sunitinib inhibits the growth and metastasis of cancer cells by antagonizing the vascular endothelial growth factor receptor (VGEFR) and inhibiting the formation of neovascularization of cancer cells. Sunitinib also inhibits the activity of c-kit kinase and is approved for the treatment of patients with gastrointestinal stromal tumors of imatinib. Sorafenib, developed by Bayer, simultaneously antagonizes RAF kinase, vascular endothelial growth factor receptor (VGEFR) and platelet-derived growth factor receptor
  • VGEFR vascular endothelial growth factor receptor
  • liver cancer Multiple pathways such as (PDGFR- ⁇ ) fight cancer growth and metastasis, and are approved by the FDA as treatments for advanced renal cancer and metastatic liver cancer.
  • PDGFR- ⁇ blood pressure regulation
  • sorafenib in metastatic liver cancer is a major breakthrough in the field of liver cancer treatment.
  • Liver cancer is recognized as one of the most difficult to treat, one of the most metastatic cancers.
  • rapamycin The mammalian target of rapamycin (mTOR) is a multifunctional silk/threonine kinase in the PI3K/AKT signaling pathway, which is directly related to the growth, division, survival and metastasis of cancer cells (Rubio-Viqueira). , B, Hidalgo M. Curr. Op in. Invest ig. Z? i/ ⁇ 2006, 7 : 501 - 512 ).
  • mTOR kinase in renal cell metastasis is particularly pronounced.
  • Uncontrolled mTOR causes an increase in intracellular HIF-loc concentration.
  • HIF_loc induces VGEF synthesis and promotes angiogenesis in cancer cells.
  • many renal cancer cells are due to VHL tumors.
  • a decrease in HIF-loc degradation caused by mutation or loss of the suppressor gene also increases the concentration of HIF-loc (Thomas GV. et al. Nature Medicine 2006, 12: 122-127).
  • the first clinical mTOR inhibitor was the rapamycin derivative temasirol imus developed by Wyeth Pharmaceuticals of the United States. In 2007, it was approved by the FDA as a therapeutic drug for kidney cancer.
  • Lapatinib is a dual inhibitor of small molecule tyrosine kinase that inhibits both epidermal growth factor receptor (EGFR) and ErbB2 (HER-2/neu) receptors, with approximately 30% of breast cancers. The patient develops an excess of HER-2/neu receptor due to the HER-2/neu proto-oncogene.
  • EGFR epidermal growth factor receptor
  • HER-2/neu ErbB2
  • lapatinib was approved by the FDA as a combination therapy for breast cancer, and in 2010 it was approved as a first-line drug for ER+/EGFR+/HER2+ triple-positive breast cancer patients (Wood ER et al. Cancer research 2004, 64 (18) : 6652 _ 9 ).
  • kinase inhibitors Due to the high homology and diversity of kinases, most of the small molecule anticancer drugs currently being developed are multi-kinase inhibitors. Fortunately, unlike previous concerns, lower kinase selectivity does not affect the efficacy of the drug; Preferred multiple kinase inhibitors may be more conducive to the treatment of complex, diverse forms of cancer, and may be versatile. Unlike multi-molecular kinase inhibitor multiplicities, macromolecular monoclonal antibodies are usually specific inhibitors targeting only a single target in the cell signaling pathway, and several clinical examples have demonstrated the efficacy of specific monoclonal antibodies in the treatment of cancer. . In 1998, trastuzumab
  • trastuzumab is approved by the US FDA for breast cancer treatment and is indicated for breast cancer patients overexpressing HER-2/neu (Hudi s, CA. N Engl J Med. 2007, 357 (1): 39-51). In 2004, the FDA approved Bevacizumab in combination with standard chemotherapy drugs for metastatic colorectal cancer (mCRC) and non-small cell lung cancer.
  • mCRC metastatic colorectal cancer
  • NSCLC vascular endothelial growth factor
  • panitumumab and cetuximab have also been approved for metastatic colorectal cancer. Unlike bevacizumab, panitumumab and cetuximab inhibit the growth and division of cancer cells by binding to the epidermal growth factor receptor (EGFR).
  • EGFR epidermal growth factor receptor
  • cetuximab (IgGl) and panitumumab (IgG2) belong to different subtypes of immunoglobulins, and they have subtle differences in anticancer mechanism.
  • the West produced by Squibb Topoxib can also treat head and neck cancer.
  • cancer is one of the most complicated diseases.
  • Various organs of the body may form cancers with different structures and structures through various mechanisms. Many cancers are caused by simultaneous mutation of multiple genes, and similar cancers can be formed by different cancerous causes. Wait.
  • the diversity of the genetic mechanism of cancer the diversity of its formal structure has made its treatment always full of challenges. Cancer experts have to use a variety of different combinations of drugs to fight against tumor ailments; on the other hand, cancer will also There are drugs that produce drug resistance, so it is necessary to continuously develop new targeted drugs with novel structures, different functions, and better efficacy.
  • VEGF Vascular endothelial growth factor
  • Kidney and Bladder Cancer (Brown et al. Am. J Palhol. 1993, 143L 1255), Ovarian Cancer (Ol son et al. Cancer Res. 1994, 54, 1255), cervical cancer (Guidi et al. J Nat 'l Cancer 30 Inst. 1995, 87, 12137), and angiosarcoma (Hashimoto et al. Lab. Invest. 1995) , 73, 859) and various intracranial tumors (Plate et al. Nature 1992, 359, 845; Phi ll ips et al. Int. J Oncol. 1993, 2, 913; Berkman et al. J Clin. Invest. 1993, 91 ; 153).
  • angiogenesis inhibitors such as VEGFR-2 and PDGFR- ⁇ inhibitors
  • Anticancer drugs have become a hot area and have yielded new, promising clinical trial results.
  • W0-2004007458 discloses a group of 2 amidamine nicotinamide derivatives as VEGFR, PDGFR and Kit inhibitors for the treatment of non-squamous non-small cell lung cancer in clinical phase III trials, other indications including parenchymal cancer, gastrointestinal Cancer, colorectal cancer, endocrine cancer, breast cancer and lung cancer.
  • WO-2004113304 discloses a group of carbazole, benzisoxazole and benzothiazole derivatives as CSFR-1, PDGFR, Flt3, Kit, VEGFR-K VEGFR-2, VEGFR-3 inhibitors, in a clinical phase III trial.
  • the second phase of clinical use for non-small cell lung cancer, breast cancer, colorectal cancer other indications also include kidney cancer, acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • W0-2000043366 discloses a group of quinoline-urea derivatives as Kit, PDGFR receptor, VEGFR-1, VEGFR-2, VEGFR-3 inhibitors, for the treatment of renal cancer in a clinical phase III trial, other clinical trials Including breast cancer, colorectal cancer, gastrointestinal cancer, non-small cell lung cancer and liver cancer.
  • W0-200102369 discloses a group of carbazole derivatives as CSFR-1, PDGF, VEGF-K VEGF-2 and VEGF-3 inhibitors for the treatment of renal cancer in a clinical phase III trial, phase II clinical trial including mesothelium Cancer, angiosarcoma, adrenal cortical adenocarcinoma and liver cancer.
  • W0-200232872 discloses a new class of quinoline-urea derivatives as VEGFR_2, VEGFR-3, FGFR 1-4 and RET inhibitors for the treatment of thyroid cancer in a clinical phase III trial, and phase II clinical trials including liver cancer. Endometrial cancer, melanoma, kidney cancer and glioma.
  • W0-2003082272 discloses a group of arylamine benzimidazoles as Raf, VEGFR-2, PDGFR- ⁇ and Kit inhibitors for the treatment of melanoma.
  • the present invention relates to a compound of the formula (I) and (II), or a pharmaceutically acceptable salt thereof, and a method of treating a patient, the method comprising administering to a patient an effective amount of a kinase that inhibits a kinase such as VEGFR-2 (I And a compound of (II) or a pharmaceutically acceptable salt thereof.
  • the present invention relates to an N-indol-1-amide compound which inhibits a kinase such as VEGFR-2, which is a compound of the formula (I) and (II) or a pharmaceutically acceptable salt thereof:
  • R is selected from halogen, cyano, hydroxy, trifluoromethyl, methoxy, trifluoromethoxy, substituted or unsubstituted C1-C6 straight chain, C1-C6 branched fluorenyl, C3-C7 cyclodecyl a C6-C10 aryl group, a C6-C10 heteroaryl group or a C6-C10 heterocyclic group containing one or more selected from N, S, 0 atoms;
  • the substituent is selected from the group consisting of amino, halogen, C1-C6 fluorenyl, hydroxy, C1-C6 decyloxy, nitro, cyano, fluorenyl, C1-C6 thiol, halogen-C1-C6 thiol, hetero Cyclo, heteroaryl, heterocyclyl fluorenyl, heteroaryl C1-C6 fluorenyl, C1-C6 decanoyl or carbamoyl.
  • R is further selected from the group consisting of halogen, cyano, hydroxy, substituted or unsubstituted fluorenyl, decyloxy, cyclodecyl, aryl, heteroaryl or heterocyclic;
  • R is further selected from halogen, cyano, hydroxy, substituted or unsubstituted lower fluorenyl, lower decyloxy, lower cyclodecyl, C6-C20 aryl, C6-C20 heteroaryl or C6-C20 heterocyclic;
  • R is further selected from halogen, cyano, hydroxy, substituted or unsubstituted C1-C6 straight chain, C1-C6 branched fluorenyl, C3-C7 cyclodecyl, C6-C10 aryl, C6-C10 heteroaryl or a C6-C10 heterocyclic group containing one or more selected from N, S, O atoms;
  • R is further preferably fluorine, chlorine, bromine, methyl, ethyl, cyano, hydroxy, tert-butyl, cyclopropyl or cyclobutyl, phenyl, pyridyl, pyrrolyl or piperazinyl;
  • R may also preferably be chlorine, bromine, methyl, cyano, hydroxy, trifluoromethyl, methoxy or trifluoromethoxy.
  • the substituent is selected from the group consisting of amino, halogen, C1-C6 fluorenyl, hydroxy, C1-C6 decyloxy, nitro, cyano, fluorenyl, C1-C6 thiol, halogen-C1-C6 thiol, hetero Cyclo, heteroaryl, heterocyclyl fluorenyl, heteroaryl C1-C6 fluorenyl, C1-C6 decanoyl or carbamoyl. Wherein the C1-C6 mercapto substituent may be unsubstituted or further substituted.
  • Preferred specific compounds of the invention, or pharmaceutically acceptable salts thereof, are:
  • the present invention relates to a compound of the formula (II) or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • an acid salt of a cationic organic and inorganic base selected from the group consisting of an alkali metal cation, an alkaline earth metal cation, an ammonium ion, an aliphatic substituted ammonium ion or an aromatic substituted ammonium ion.
  • the pharmaceutical composition for treating cancer of the present invention comprises a compound of the formula (11) or a pharmaceutically acceptable salt thereof, and a physiologically suitable carrier.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be used for the manufacture of a medicament for inhibiting kinase-mediated cancer cell growth and metastasis such as VEGEFR-2.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can also be used for the preparation of a medicament for treating cancer diseases.
  • the cancer of the present invention includes parenchymal cancer, renal cancer, lung cancer, breast cancer, liver cancer, ovarian cancer, pancreatic cancer, thyroid cancer, bladder cancer, leukemia, adenocarcinoma, melanoma, gastrointestinal cancer, colorectal cancer, endocrine cancer.
  • renal cancer acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), mesothelioma, angiosarcoma, adrenal cortical adenocarcinoma, endometrial cancer, and glioma.
  • Particularly effective cancers are kidney cancer, liver cancer, lung cancer, lung cancer, colorectal cancer, gastrointestinal cancer, breast cancer, gastrointestinal cancer, and angiosarcoma.
  • lower when referring to a substituent such as decyl, decyloxy, decylamine, decylthio or the like means having up to 7 and including a maximum of 7, preferably 1 to up to 6 and including a maximum of 6 a group of carbon atoms which is unbranched or branched one or more times.
  • the fluorenyl moiety in the lower fluorenyl group, the lower fluorenyloxy group and the substituent having a fluorenyl moiety is preferably a C r C 6 fluorenyl group such as n-butyl group, sec-butyl group, tert-butyl group, n-propyl group or isopropyl group. , methyl or ethyl.
  • the thiol substituent is unsubstituted or is halogen, hydroxy, nitro, cyano, lower decyloxy, C 3 -C 7 cyclodecyl, amino or mono- or di-low Substituted by mercaptoamino.
  • Halogen-lower fluorenyl, 3 ⁇ 4 gram-lower decyloxy is included in the substituted lower fluorenyl group, substituted lower decyloxy group.
  • the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably fluorine, chlorine or bromine, especially fluorine.
  • the phenyl group is generally an unsubstituted phenyl group or a phenyl group substituted by 1 to 5, preferably 1 or 2, substituents.
  • Suitable substituents include, but are not limited to, amino, mono- or di-lower fluorenyl substituted amino groups (wherein lower fluorenyl substituents may be unsubstituted or further substituted by those listed above for fluorenyl: ), halogen, lower fluorenyl, substituted lower fluorenyl, hydroxy, lower decyloxy, substituted lower decyloxy, nitro, cyano, fluorenyl, lower thiol, halogen-lower thiol, heterocycle a carbamoyl group, a heteroaryl group, a heteroaryl fluorenyl group, a heteroaryl fluorenyl group, a lower decanoyl group, a carbamoyl group, and an N-mono- or N,N
  • R which is a phenyl group is preferably an unsubstituted phenyl group or a phenyl group substituted by one or more substituents, preferably up to three, preferably one substituent.
  • substituents which are especially important for phenyl include amino, mono- or di-lower mercaptoamino (wherein the indenyl group is unsubstituted or substituted:), halogen, lower indenyl, substituted lower indenyl, hydroxy , lower decyloxy, substituted lower decyloxy, nitro, cyano, decyl, lower sulfonylthio and substituted lower sulfonylthio.
  • R which is a phenyl group is preferably an unsubstituted phenyl group or a phenyl group substituted by one or two identical or different substituents selected from halogen, preferably fluorine or chlorine; lower fluorenyl group, preferably methyl group, ethyl group Base, propyl or tert-butyl; halogen-lower fluorenyl, preferably trifluoromethyl; hydroxy; lower decyloxy, preferably methoxy or ethoxy; halogen-lower decyloxy, eg trifluoromethoxy Or 1, 1, 2, 2-tetrafluoroethoxy; more preferably a phenyl group substituted by a substituent selected from unsubstituted or substituted lower fluorenyl groups, preferably methyl, halogen-lower fluorene
  • the group is, for example, a trifluoromethyl group, an unsubstituted or substituted lower alkoxy group
  • R phenyl groups include unsubstituted phenyl and lower decyloxy substituted phenyl, preferably phenyl substituted by lower decyloxy.
  • the heteroaryl group preferably contains from 1 to 3 5- to 7-membered aromatic rings selected from hetero atoms of N, 0 and S.
  • the heteroaryl group is unsubstituted or substituted by one or more, preferably one to three, for example one identical or different substituent.
  • heteroaryl groups are those selected from Substituents: halogen, such as fluorine or chlorine; mono- or di-lower mercapto-substituted amino group, wherein the indenyl group is unsubstituted or is halogen, hydroxy, nitro, cyano, lower decyloxy, c 3 -c 7 cyclodecyl, heterocyclyl or heteroaryl substituted; lower fluorenyl, for example methyl or ethyl; halogen - lower fluorenyl, for example trifluoromethyl; lower decyl, such as methoxy or Oxyl; halogen-lower decyloxy, such as trifluoromethoxy; lower sulfonyl, such as methylthio; halogen-lower thiol, such as trifluoromethylthio; heteroaryl; heteroaryl-lower Amidino group; heterocyclic or heterocyclic-lower fluorine or chlorine
  • the heterocyclic group preferably has a 5- or 6-membered non-aromatic ring having 1 or 2 hetero atoms selected from nitrogen, oxygen and sulfur, and the heterocyclic ring may be fully or partially saturated, and is unsubstituted or substituted. Preferably, it is substituted by an unsubstituted or substituted lower fluorenyl group.
  • Heterocyclic groups include morpholino, thiomorpholino, piperidinyl, piperazinyl and the like.
  • the pharmaceutically acceptable salt is preferably a pharmaceutically acceptable acid addition salt of a compound of formula (I) (II).
  • Such salts are formed, for example, by a compound of formula (II) having a basic nitrogen atom, such as an acid addition salt, preferably an acid addition salt with an organic or inorganic acid, preferably a pharmaceutically acceptable salt.
  • Suitable inorganic acids are, for example, hydrohalic acids such as hydrochloric acid, sulfuric acid or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic acids, phosphonic acids, sulfonic acids or sulfamic acids, such as acetic acid, propionic acid, caprylic acid, capric acid, dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid, Fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactose diacid, amino acid, such as glutamic acid, day Aspartic acid, ⁇ -methylglycine, acetaminoacetic acid, ⁇ -acetyl asparagine, ⁇ -acetylcysteine, pyruvic acid, acetoacetic acid, phosphoserine, 2- or 3-glycerol phosphate, Malay Acid, hydroxymaleic acid, methyl maleic acid, cyclohex
  • the present invention relates to 3-chloro- and 3-methoxy-oxime-methyl-2-pyridine amide compound compounds useful as kinase inhibitors such as VEGER-2, and their use in the preparation of a therapeutic kinase such as VEGFR-2.
  • kinase inhibitors such as VEGER-2
  • VEGFR-2 a therapeutic kinase
  • the compounds of the invention are useful for treating cancer in a mammal, preferably human cancer, including but not limited to malignant melanoma, colorectal cancer, ovarian cancer, papillary thyroid cancer, liver cancer, lung cancer, kidney cancer, pancreatic cancer, glioblasts Tumor, spinal proliferative disease, mesothelioma, gastrointestinal cancer, breast cancer and angiosarcoma.
  • the compounds of the invention are also useful in the treatment of inflammatory diseases mediated by kinases such as VEGFR-2, including rheumatoid arthritis, retinopathy (including diabetic retinopathy and macular degeneration), cardiovascular disease and metabolic diseases.
  • the compound of the formula (II) of the present invention or a pharmaceutically acceptable salt thereof has valuable pharmacological properties as described above.
  • an acid salt of a cationic organic and inorganic base selected from the group consisting of an alkali metal cation, an alkaline earth metal cation, an ammonium ion, an aliphatic substituted ammonium ion and an aromatic substituted ammonium ion.
  • the pharmaceutically acceptable salt of the compound of the formula (I) (II) according to the invention is a pharmaceutically acceptable acid addition salt.
  • Such salts are formed, for example, by a compound of formula (II) having a basic nitrogen atom, such as an acid addition salt, preferably an acid addition salt, especially a pharmaceutically acceptable salt, with an organic or inorganic acid.
  • Suitable inorganic acids are selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like.
  • Suitable organic acids are selected from the group consisting of carboxylic acids, phosphonic acids, sulfonic acids or sulfamic acids, such as methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, Acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, propionic acid, octanoic acid, citric acid , dodecanoic acid, glycolic acid, 2-hydroxybutyric acid,
  • the compounds of the present invention may be administered alone or in combination with other anticancer drugs, such as compounds that inhibit tumor angiogenesis, such as protease inhibitors, epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, and the like; Toxic drugs, such as antimetabolites, such as anti-metabolites of purines and pyrimidine analogs; anti-mitotic drugs such as microtubule stabilizing drugs and anti-mitotic alkaloids; platinum coordination complexes; antitumor antibiotics; deuterated agents such as nitrogen mustard and Nitrosoureas; endocrines, such as adrenal corticosteroids, androgens, antiandrogens, estrogens, antiestrogens, aromatase inhibitors, gonadotropin releasing hormone agonists, and somatostatin Analogs, as well as compounds that target enzymes or receptors that are overexpressed and/or otherwise associated with specific metabolic pathways that are up-regulated in tumor cells, such as
  • the compounds of the invention may also be administered with radiation therapy, immunotherapy, surgery, or a combination thereof. It is also possible to treat a patient's condition after tumor reduction or even chemopreventive treatment (e.g., in the case of a patient at risk:).
  • the compounds of the invention are useful not only for the prophylactic and preferably therapeutic: treatment of humans, but also for the treatment of other warm-blooded animals, such as commercially useful warm-blooded animals, such as rodents such as mice, rabbits or Rat, or guinea pig.
  • the invention also includes a medicament comprising a compound of formula (II) and a physiologically acceptable carrier
  • a medicament comprising a compound of formula (II) and a physiologically acceptable carrier
  • the compounds of the invention may be administered by injection, inhalation or spraying or rectally, orally, dermally, parenterally, or in unit dosage form.
  • injectable administration includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as the application of infusion techniques.
  • Skin administration includes topical or transdermal administration.
  • One or more compounds can be co-existed with one or more pharmaceutically acceptable non-toxic carriers, as well as other active ingredients, as appropriate.
  • compositions can be prepared according to any suitable method known in the art of pharmaceutical composition manufacture.
  • the composition may contain one or more of the following agents: diluents, sweeteners, perfumes, colorants and preservatives.
  • Tablets contain the active ingredients which are in admixture with pharmaceutically acceptable non-toxic excipients suitable for tablet manufacture.
  • the excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as corn starch or alginic acid; binders such as magnesium stearate, hard Fatty acid or talcum powder.
  • the tablets may be uncoated or they may be coated by known techniques to delay their disintegration and absorption in the gastrointestinal tract, providing a long lasting effect.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • the compounds can also be formulated as solid, immediate release forms.
  • the oral preparation may also be a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsule in which the active ingredient is mixed with water or, for example, peanut oil, liquid paraffin or olive Oil and other oils are mixed.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • a soft gelatin capsule in which the active ingredient is mixed with water or, for example, peanut oil, liquid paraffin or olive Oil and other oils are mixed.
  • Aqueous suspensions containing the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions may also be employed.
  • the excipient is a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and gum arabic;
  • the dispersing or wetting agent may be a natural phospholipid, such as lecithin, or a condensation product of an epoxy oxime with a fatty acid, such as polyoxyethylene stearate, or a condensation product of an epoxy oxime with a long chain fatty alcohol, for example A condensation product of heptahexylethylene hexadecanol, or an epoxy oxime with a partial ester of a fatty acid with hexitol, such as polyoxyethylene sorbitan monooleate.
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • preservatives for example ethyl or n-propyl p-hydroxybenzoate
  • coloring agents for example, ethyl or n-propyl p-hydroxybenzoate
  • coloring agents for example, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • sweetening agents for example, sucrose or saccharin.
  • Suitable for adding water to dispersible powders or granules of aqueous suspensions, active ingredients and fractions A powder or wetting agent, a suspending agent and one or more preservatives are mixed. Suitable dispersing or wetting agents and suspending agents can be exemplified above. Other excipients such as sweeteners, perfumes and colorants may also be included.
  • the form of the compound may also be a non-aqueous liquid preparation such as an oily suspension, which can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or peanut oil or a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol.
  • a thickening agent for example, beeswax, hard paraffin or cetyl alcohol.
  • an antioxidant such as ascorbic acid.
  • the pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion.
  • the oil phase may be a vegetable oil such as olive oil or peanut oil or a mineral oil such as liquid beeswax, or a mixture thereof.
  • Suitable emulsifiers may be natural gums such as tragacanth and gum arabic, or natural phospholipids such as soy lecithin or lecithin; partial esters of fatty acids with anhydrohexitol, such as sorbitan oleate; A condensation product of a partial ester with epoxy oxime, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweeteners and flavors.
  • Sugar candies and tinctures can also be formulated with sweetening agents such as glycerin, polypropylene glycol, sorbitol or sucrose. Such preparations may also contain emollients, preservatives, and perfumes and colorants.
  • the pharmaceutical composition of the present invention is prepared by a method known per se, for example, by a conventional mixing, granulating, forming, dissolving or lyophilizing method.
  • compositions Preference is given to using solutions of the active ingredient, in addition to suspensions or dispersions, in particular isotonic solutions, dispersions or suspensions, for example, lyophilized solutions containing only active substances or containing active substances with carriers such as mannitol
  • solutions of the active ingredient in addition to suspensions or dispersions, in particular isotonic solutions, dispersions or suspensions, for example, lyophilized solutions containing only active substances or containing active substances with carriers such as mannitol
  • the pharmaceutical compositions may be sterilized and/or contain excipients such as preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers, and are known per se
  • the method is prepared, for example, by a conventional dissolution or lyophilization method.
  • the solution or suspension may contain a viscosity increasing substance such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin or a solubilizing agent such as Tween 80.
  • a viscosity increasing substance such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin or a solubilizing agent such as Tween 80.
  • Suspensions in oils contain vegetable oils, synthetic oils or semi-synthetics conventionally used for injection purposes Oil is formed as an oil component.
  • liquid fatty acid esters comprising as long as a fatty acid component having from 8 to 22, in particular from 12 to 22, carbon atoms, for example lauric acid, tridecanoic acid, myristic acid, Pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, arachidic acid, didecanoic acid or the corresponding unsaturated acid, such as oleic acid, oleic acid, erucic acid, eicosanic acid or linoleic acid
  • An antioxidant such as vitamin ⁇ , ⁇ -carotene or 3,5-di-tert-butyl-4-hydroxytoluene is optionally added.
  • the alcohol component of these fatty acid esters has up to 6 carbon atoms and is a mono- or poly-hydric alcohol such as a mono-, di- or tri-alcohol such as methanol, ethanol, propanol, butanol or pentanol or Their isomers, but especially ethylene glycol and glycerol.
  • fatty acid esters which may be mentioned are: ethyl oleate, isopropyl myristate, isopropyl palmitate, etc., but especially vegetable oils such as cottonseed oil, almond oil, olive oil, sesame oil, Soybean oil and more especially peanut oil.
  • the preparation of the injectable compositions is carried out in a conventional manner under sterile conditions, and the introduction into a container such as an ampoule or vial and a container is also carried out under aseptic conditions in a conventional manner.
  • compositions for oral administration can be obtained, for example, by mixing the active ingredient with one or more solid carriers, granulating the resulting mixture, if appropriate, processing the mixture or granules, if appropriate, adding Excipients:) into the core of a tablet or dragee.
  • Suitable carriers are, in particular, fillers, for example sugars such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate, and also binders such as starches such as corn, Wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or if necessary, a disintegrating agent, such as mentioned above Starch, carboxymethyl starch, cross-linked polyvinylpyrrolidone Ketone, alginic acid or a salt thereof, such as sodium alginate.
  • fillers for example sugars such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate, and also binders such as starches such as corn, Wheat, rice or potato starch, methyl
  • excipients are, in particular, flow regulators and lubricants, for example silicic acid, talc, stearic acid or its salts, for example magnesium stearate or calcium stearate, and/or polyethylene glycol or derivatives thereof Things.
  • flow regulators and lubricants for example silicic acid, talc, stearic acid or its salts, for example magnesium stearate or calcium stearate, and/or polyethylene glycol or derivatives thereof Things.
  • the dragee core may have a suitable coating, optionally an enteric coating, especially a concentrated sugar solution, which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide. Or using a coating solution in a suitable organic solvent or solvent mixture, or for the preparation of an enteric coating, using a solution of a suitable cellulosic product, such as cellulose acetate phthalate or hydroxypropyl methylcellulose Phthalates. Colorants or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to show different dosages of the active ingredient.
  • a suitable coating especially a concentrated sugar solution, which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide.
  • a coating solution in a suitable organic solvent or solvent mixture or for the preparation of an enteric coating, using a solution of a suitable cellulosic product, such as cellulose acetate phthalate or hydroxypropy
  • compositions for oral administration are also hard gelatin capsules and soft, sealed capsules consisting of gelatin and a plasticizer such as glycerol or sorbitol.
  • the hard gelatine capsules may contain the active ingredient in the form of granules, for example, in the form of granules mixed with fillers such as corn starch, binders and/or glidants such as talc or magnesium stearate and optionally stabilizers.
  • the active ingredient is preferably dissolved or suspended in a suitable liquid vehicle such as a fatty oil, a paraffin oil or a liquid polyethylene glycol or a fatty acid ester of ethylene glycol or propylene glycol, as well as stabilizers and Detergents, such as polyoxyethylene sorbitan fatty acid ester detergents.
  • a suitable liquid vehicle such as a fatty oil, a paraffin oil or a liquid polyethylene glycol or a fatty acid ester of ethylene glycol or propylene glycol, as well as stabilizers and Detergents, such as polyoxyethylene sorbitan fatty acid ester detergents.
  • Suitable rectal-administered pharmaceutical compositions are, for example, suppositories, which consist of a mixture of the active ingredient and a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, strepylene hydrocarbons, polyethylene glycol or higher chain sterols.
  • aqueous solutions for example aqueous solutions of the active ingredient in the form of water-soluble salts, or aqueous injection suspensions, which comprise a viscosity-increasing substance, for example Sodium carboxymethylcellulose, sorbitol and/or dextran, and if necessary, stabilizers.
  • the active ingredient optionally together with excipients, may also be in the form of a lyophilizate which may be formulated into solutions by the addition of a suitable solvent before parenteral administration.
  • Solutions for parenteral administration can also be used in the form of infusions.
  • Preferred preservatives are, for example, antioxidants such as ascorbic acid or microbicides such as sorbic acid or benzoic acid.
  • the daily oral dose is preferably from 0.01 to 200 mg/kg body weight.
  • Injections including intravenous, intramuscular, subcutaneous and parenteral injections, and application of the input technique, preferably have a daily dose of 0.01-200 mg/kg body weight.
  • the daily dose for rectal administration is preferably from 0.01 to 200 mg/kg body weight.
  • the daily dose for external use is 1 to 4 times a day, preferably 0.1-200 mg per time.
  • the daily dose for inhalation is preferably 0.01-10 mg/kg body weight.
  • the particular mode of administration will depend on a variety of factors, which are often considered in conventional administration.
  • the specific dosage of a particular patient depends on the activity of the particular compound used, the age of the patient, the patient's weight, the overall health of the patient, the patient's gender, the patient's diet, the time of administration, the route of administration, the rate of discharge, the drug A combination of factors and the severity of the current condition.
  • the optimal therapeutic regimen i.e., the therapeutic regimen within a certain number of days and the number of daily administrations of the formula ( ⁇ ) ( ⁇ ) compound or a pharmaceutically acceptable salt thereof, can be routinely treated by those skilled in the art. Test to determine.
  • the specific level of recording for a particular patient depends on a number of factors, including the activity of the particular compound used, the age of the patient, the patient's weight, the overall health of the patient, the patient's gender, the patient's diet, the time of administration, the route of administration, the rate of discharge, the drug Combination and current treatment The severity of the situation.
  • the compound of the present invention can be produced by a known compound (or a starting material which can be obtained from a known compound:), for example, by a general method as described later.
  • the activity of VEGFR-2 kinase can be determined by a usual method described later.
  • the following examples are illustrative only and not limiting.
  • the general reaction scheme described in the general method is prepared.
  • the in vitro biological activity of a compound inhibiting kinase is generally measured by the degree of phosphorylation of its antagonistic kinase to a foreign substrate (Zhou S. et al. Nature 1995, 373: 536-539).
  • VEGRF-2 in vitro inhibitory activity test (Itokawa T. et al. Mol. Cancer Ther. 2001, 1 : 295-302 )
  • VEGFR-2 is a recombinant human kinase, which is expressed and purified by SF9 cells, and the degree of reaction of a kinase or a phosphorylated substrate under compound antagonism is determined by fluorescence resonance energy transfer.
  • FRET Fluoresence resonance energy trasnfer
  • the fluorescence intensity of the microporous mixture at wavelengths of 337 nM, 620 nM, and 655 nM was measured using a ⁇ per-embleter (Envision, Perkin Elmer).
  • the activity of the kinase was directly proportional to the fluorescence intensity of 655 nm / 620 nM, expressed as a percent inhibition relative to the control sample (water), and the basal fluorescence intensity was read from the control wells without kinase.
  • Reaction IC 5 Values were obtained from 8 to 10 different concentrations of compound kinase percent inhibition curves, under the experimental conditions, the standard compound staurosporine IC 5 . It is 3.5 nM.
  • Example 3 it was obtained using 5-bromo-2,3-dihydro-1H-indole.
  • Example 3 it was obtained using 4-trifluoromethyl-2,3-dihydro-1H-indole.
  • Example 3 it was obtained using 5-chloro-2,3-dihydro-1H-indole.
  • Example 8 it was obtained using 5-bromo-2,3-dihydro-1H-indole.
  • Example 8 it was obtained using 5-chloro-2,3-dihydro-1H-indole.
  • m/e 422.86.

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Abstract

L'invention concerne des composés de N-indol-1-amide tels que représentés par la formule (I) ou (II) utilisés en tant qu'inhibiteur de VEGFR-2 kinase, et leur utilisation pour la préparation d'un médicament pour le traitement d'une maladie médiée par VEGFR-2. La définition de R est telle que présentée dans la description.
PCT/CN2012/081297 2011-09-14 2012-09-12 Composés de n-indol-1-amide et leur application en tant que médicament anticancer WO2013037293A1 (fr)

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CN106565589A (zh) * 2016-10-13 2017-04-19 云南大学 一种酰肼吲哚类药物的制备方法及用途

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CN101723894A (zh) * 2009-12-03 2010-06-09 南京大学 N-喹啉酰胺类衍生物及其制法与用途
CN102432595A (zh) * 2011-09-14 2012-05-02 湖南有色凯铂生物药业有限公司 N-吲哚-1-酰胺类化合物及作为抗癌药物的应用

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KR100976076B1 (ko) * 2003-05-22 2010-08-17 아보트 러보러터리즈 인다졸, 벤즈이속사졸 및 벤즈이소티아졸 키나제 억제제
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CN101723894A (zh) * 2009-12-03 2010-06-09 南京大学 N-喹啉酰胺类衍生物及其制法与用途
CN102432595A (zh) * 2011-09-14 2012-05-02 湖南有色凯铂生物药业有限公司 N-吲哚-1-酰胺类化合物及作为抗癌药物的应用

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