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WO2013037292A1 - Composé d'urée aromatique substitué et son utilisation en tant que médicament anticancer - Google Patents

Composé d'urée aromatique substitué et son utilisation en tant que médicament anticancer Download PDF

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Publication number
WO2013037292A1
WO2013037292A1 PCT/CN2012/081296 CN2012081296W WO2013037292A1 WO 2013037292 A1 WO2013037292 A1 WO 2013037292A1 CN 2012081296 W CN2012081296 W CN 2012081296W WO 2013037292 A1 WO2013037292 A1 WO 2013037292A1
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Prior art keywords
acid
cancer
group
pharmaceutically acceptable
fluorenyl
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PCT/CN2012/081296
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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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Publication of WO2013037292A1 publication Critical patent/WO2013037292A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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

Definitions

  • the present invention relates to substituted aromatic urea compounds useful as kinase inhibitors such as VEGFR-2, and their use in the manufacture of a medicament for the treatment of diseases mediated by kinases such as VEGFR-2.
  • the signal begins with the binding of epidermal growth factor (EGF) to the epidermal growth factor receptor (EGFR) on the cell membrane, and the EGFR at its phosphorylated site SH2 and the adaptor protein GRB2 (growth factor) Receptor-bound protein 2 ) Binding, recruitment of guanylate exchange factor SOS protein and Ras bind to adjacent inner cell membrane, GTP replaces Ras combined with Ras 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 cytoplasmic/threonine kinase Raf, Raf rephosphorylates MAPK kinase (MAPKK, also known as MEK), and MEK activates ERK1/2 (extracellular signal regulated kinase, ERK) ).
  • MAPK MAPK kinase
  • MEK activates ERK1/2 (extracellular signal regulated kinase, ERK) ).
  • ERK extracellular signal regulated kinase
  • the signaling proteins in the signaling pathway cascade may be activated or inhibited by different upstream proteins to form an extremely complex network regulatory 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
  • mTOR animal rapamycin target protein
  • S6 kinase S6K
  • 4EBP1 S6 kinase
  • the protein kinase gene co-expresses more than 518 protein kinases, of which the receptor kinase has 20 subfamilies of 58 types, and the cytoplasmic 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. V Engl J Med. 2008, 358 (5): 502 - 11 ).
  • Raf kinase on the Raf/MEK/ERK signaling pathway is overexpressed in many cancer cells, over 60% of human malignant melanoma, 12% of colorectal cancer, and 14% of ovarian cancer Both have found activating mutations in B-raf, which are 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 there is no mutation in C-raf (Brose, MS et al. Cancer Res. 2000, 63: 6997-7000; Davies, H. Nature, 2002, 417: 949-954; Yuen, ST et al. Cancer Res.
  • B-raf mutant kinase B-raf-V600E which is 500 times more active than wild-type kinase, forms a heterodimer with C-raf and continuously activates downstream ERK and Protein kinase mTOR
  • 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. Further research has led Bayer's scientists to believe that sorafenib actually antagonizes multiple kinases by simultaneously antagonizing RAF kinase and several angiogenic growth factor receptors.
  • Renal cancer and liver cancer are highly metastatic cancers.
  • the main pathological type of renal cancer is clear cel l carcinoma, and its pathogenesis is related to mutation of VHL tumor suppressor gene.
  • 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
  • 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 proliferate to form metastasis. .
  • 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 VEGFR-2
  • KDR platelet-derived growth factor
  • FGF fibroblast growth factor
  • a structurally similar VEGFR-3 (Flt-4) receptor is mainly involved in the formation of lymphatic vessels (Lymphangiogenesis), in cancer through lymphoid It plays an important role in the process of systemic transfer, and these receptors can be used as targets for the growth and metastasis of solid tumors.
  • 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, Dasatinib and Nilotinib, in 2006 and 2007, respectively. Patients who are fighting imatinib also have good results.
  • Gefitinib developed by AstraZeneca in the UK, was approved for marketing in Japan in August 2002 as a first-line treatment for non-small cell lung cancer, gefitinib. It is very effective for smoking non-small cell lung cancer in Asian men.
  • Genentech and 0SI Pharmaceutical jointly developed erlotinib, which is more widely used and is used as first-line treatment, maintenance therapy and sequential in non-small cell lung cancer in seven or eighty countries around the world. Therapeutic drugs.
  • Both 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. Drugs 2000, 60 Suppl 1: 15-23; discussion 41 -2).
  • 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. On the other hand, many renal cancer cells are inhibited by VHL tumors. Mutation or loss of the gene causing a decrease in HIF-loc decomposition 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 ).
  • kinases 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. .
  • trastuzumab was approved by the US FDA for breast cancer treatment for breast cancer patients overexpressing HER-2/neu (Hudi s, CA. N Engl J Med. 2007, 357 ( 1) : 39 - 51 ).
  • Bevacizumab specifically binds to vascular endothelial growth factor (VGEF), inhibits the formation of cancerous blood vessels, and promotes the penetration of chemotherapeutic drugs into cancer tissues (Los M et al. The Oncologist 2007, 12 (4) : 443 - 50).
  • VGEF vascular endothelial growth factor
  • panitumumab and cetuximab were also approved for metastatic colorectal cancer.
  • 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. The above clinical examples fully demonstrate the feasibility of using kinase inhibitors to antagonize the uncontrolled signaling pathways of cancer cells to treat different cancers.
  • 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 mechanisms of cancer the diversity of its formal structure has made its treatments always full of challenges, and cancer experts have to make widespread use of different combinations of multiple drugs.
  • cancer can also become resistant to existing drugs, so it is necessary to continuously develop new targeted drugs with novel structures, different functions, and better efficacy, according to signaling pathways and tumor genetics. Information is used to optimize the combination of drugs to improve the efficacy of cancer treatment.
  • VEGF Vascular endothelial growth factor
  • W0-2004007458 discloses a group of 2-guanamine 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.
  • W0-2004113304 discloses a group of carbazole, benzisoxazole and benzothiazole derivatives as CSFR-PDGFR, Flt3, Kit, VEGFR-1, VEGFR-2, VEGFR-3 inhibitors, used in clinical phase III trials.
  • the second phase is used for non-small cell lung cancer, breast cancer, colorectal cancer, and other indications 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 clinical phase III trials, 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.
  • Chinese patents CN101475513A, CN101260106A and CN101735215A also disclose the use of three raf kinase inhibitor bisaryl urea compounds for the treatment of cancer. Brief description of the invention
  • the present invention relates to a compound of the formula ( ⁇ ) ( ⁇ ) or a pharmaceutically acceptable salt thereof, and a method of treating a patient, which comprises administering to a patient an inhibitory amount of a kinase such as VEGFR-2, which is an effective amount of ( ⁇ ) ( ⁇ ) A compound or a pharmaceutically acceptable salt thereof.
  • a kinase such as VEGFR-2
  • the present invention relates to an aromatic urea compound which inhibits the substitution of a kinase such as VEGFR-2, which is a compound of the formula ( ⁇ ) ( ⁇ ) or a pharmaceutically acceptable salt thereof:
  • R 3 may be bonded to the benzene ring alone or simultaneously to form a substituent, a substituted or trisubstituted product
  • Ri and further each selected from halogen, cyano, hydroxy, substituted or unsubstituted fluorenyl, decyloxy, cyclodecyl, aryl, heteroaryl or heterocyclic;
  • Ri and further respectively selected from halogen, cyano, hydroxy, substituted or unsubstituted lower fluorenyl, lower decyloxy, lower cyclodecyl, C6-C20 aryl, C6-C20 heteroaryl or C6-C20 Ring base
  • Ri and further respectively selected from halogen, cyano, hydroxy, substituted or unsubstituted C1-C6 linear, C1-C6 branched fluorenyl, C3-C7 cyclodecyl, C6-C10 aryl, C6-C10 An aryl group or a C6-C10 heterocyclic group containing one or more selected from N, S, O atoms; and R 3 are further preferably fluorine, chlorine, methyl, ethyl, cyano, hydroxy, t-butyl, Cyclopropyl or cyclobutyl, phenyl, pyridyl, pyrrolyl or piperazinyl;
  • Ri, and R 3 may also preferably be cyano, hydroxy, trifluoromethyl, methoxy or trifluoromethoxy.
  • the halogen is selected from the group consisting of fluorine, chlorine, bromine or iodine, preferably fluorine or iodine.
  • 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 alkyl substituent may be unsubstituted or further substituted.
  • Preferred specific compounds of the invention, or pharmaceutically acceptable salts thereof, are:
  • the present invention relates to formula ( ⁇ )( ⁇ ) a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of: a) a basic salt of an organic acid and an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1 -naphthalenesulfonic acid, 2-naphthalenesul
  • the present invention is a medicament for treating cancer.
  • a composition comprising a compound of the formula ( ⁇ ) ( ⁇ ) 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.
  • the fluorenyl moiety in the lower fluorenyl group, the lower fluorenyloxy group and the substituent having a fluorenyl moiety is preferably a fluorenyl group such as n-butyl group, sec-butyl group, tert-butyl group, n-propyl group, isopropyl group, Methyl or ethyl.
  • the embankment substituent is unsubstituted or substituted with halo, hydroxy, nitro, cyano, lower alkoxy embankment, 3 ⁇ 4- 7 ring embankment, amino or mono - or di - lower alkyl with Substituted by an amino group.
  • Halogen-lower fluorenyl, 3 ⁇ 4-lower methoxy, 3 ⁇ 4-lower thiol and the like mean a substituent having a fluorenyl moiety in which a fluorenyl moiety is monosubstituted to completely substituted by a halogen.
  • Halogen-lower fluorenyl, 3 ⁇ 4 gram-lower decyloxy is included in the substituted lower fluorenyl group, substituted lower methoxy 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 with 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 substituents as listed above for fluorenyl) , halogen, lower fluorenyl, substituted lower fluorenyl, hydroxy, lower decyloxy, substituted lower decyloxy, nitro, cyano, fluorenyl, lower thiol, halogen-lower thiol, heterocyclic 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-di-
  • R1, R2 and R3 which are phenyl are preferably unsubstituted phenyl or phenyl substituted by one or more substituents, preferably up to three, preferably one substituent.
  • Substituents particularly important for R1, R2 and R3 phenyl include amino, mono- or di-lower decylamino (wherein the fluorenyl group is unsubstituted or substituted), halogen, lower fluorenyl, substituted lower Mercapto, hydroxy, lower decyloxy, substituted lower decyloxy, nitro, cyano, decyl, lower sulfonylthio and substituted lower sulfonylthio.
  • R 3 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 A Base, ethyl, propyl or tert-butyl; halogen-lower fluorenyl, preferably trifluoromethyl; hydroxy; lower decyloxy, preferably methoxy or ethoxy; halogen-lower decyloxy, eg trifluoro Methoxy or 1, 1, 2, 2-tetrafluoroethoxy; more preferably phenyl substituted by one substituent selected from unsubstituted or substituted lower fluorenyl groups, preferably methyl, halogen a lower sulfhydryl group, such as a trifluoromethyl group, an unsubstituted or substituted lower alkoxy group, preferably a methoxy
  • R1, R2 and R3 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 group is those selected from the group consisting of halogens such as fluorine or chlorine; mono- or di-lower mercapto-substituted amino groups, wherein the indenyl group is unsubstituted or substituted by a phenol, a hydroxyl group, or a nitrate a cyano group, a cyano group, a lower decyloxy group, a C 3 -C 7 cyclodecyl group, a heterocyclic group or a heteroaryl group; a lower fluorenyl group such as a methyl group or an ethyl group; Lower sulfhydryl group, such as trifluoromethyl; lower decyloxy, such as methoxy or ethoxy; halogen-lower decyloxy, such as trifluoromethoxy; lower sulfonyl, such as methylthio; Lower sulfonylthio, for example
  • 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 the formula ( ⁇ ).
  • Such salts are formed, for example, by a compound of the formula ( ⁇ ) 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 substituted aromatic urea compound compounds useful as kinase inhibitors such as VEGER-2, and their use for the preparation of a medicament for treating a disease mediated by a kinase such as VEGFR-2.
  • the patient is a mammal, typically a human.
  • 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 ( ⁇ ) ( ⁇ ) 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 alkali metal cations, alkaline earth metal cations, ammonium ions, aliphatic substituted ammonium ions and aromatic substituted ammonium salts
  • the pharmaceutically acceptable salt of the compound of the formula ( ⁇ ) ( ⁇ ) according to the invention is a pharmaceutically acceptable acid addition salt.
  • Such salts are formed, for example, by a compound of the formula ( ⁇ ) ( ⁇ ) 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, examples 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 nitroso Urea; endocrine, such as adrenal corticosteroids, androgens, antiandrogens, estrogens, antiestrogens, aromatase inhibitors, gonadotropin releasing hormone agonists, and somatostatin analogues And 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. Treatment for maintaining the state of a patient after tumor reduction or even chemopreventive treatment (e.g., in the case of a patient at risk) is also possible.
  • 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 large. Rat, or guinea pig.
  • the invention also includes a medicament comprising a compound of the formula ( ⁇ ) ( ⁇ ) and a physiologically acceptable carrier
  • a medicament comprising a compound of the formula ( ⁇ ) ( ⁇ ) 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 can be a natural phospholipid, such as lecithin, or a ring a condensation product of oxyethyl hydrazine with a fatty acid, such as polyoxyethylene stearate, or a condensation product of an epoxy oxime with a long chain fatty alcohol, such as heptahexyl hexadecanol, or an epoxy oxime and a fatty acid.
  • a condensation product of a partial ester of 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. For example, sucrose or saccharin.
  • the active ingredient is mixed with a dispersion or wetting agent, a suspending agent and one or more preservatives.
  • a dispersion or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium sulfate
  • 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.
  • Sweeteners such as glycerin, polypropylene glycol, sorbitol or sucrose may also be used to formulate syrups and Tincture. 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, polyvin
  • Suspensions in oils include vegetable oils, synthetic oils or semi-synthetic oils conventionally used for injection purposes as oily components. Mention may be made, in particular, of 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.
  • 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
  • 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, as well as carboxymethyl starch, crosslinked polyvinylpyrrolidone, 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. Coloring agents or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to show different dosages of the active ingredients.
  • 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 in admixture 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 a water-soluble salt, or aqueous injection suspensions containing a viscosity increasing substance such as sodium carboxymethylcellulose, sorbitol and/or Or dextran, and if necessary, stabilizers.
  • the active ingredient optionally together with excipients, may also be in the form of a lyophilizate which can be brought into solution 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.
  • a daily oral dose is preferably from 0.01 to 200 mg/kg of body weight.
  • Injections including intravenous, intramuscular, subcutaneous and parenteral injections and application of the input technique, are preferably administered at a daily dose of from 0.01 to 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.
  • Daily dose for inhalation is 0.01-10mg/kg The weight is better.
  • 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 expulsion, 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 The combination and severity of the current condition.
  • 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) by, for example, a general method described later.
  • the activity of each compound to inhibit VEGFR-2 kinase can be determined by a usual method described later.
  • the following examples are illustrative only and not limiting.
  • the compounds of the present invention are prepared according to the general reaction schemes as described below using methods known to those of ordinary skill in the art.
  • 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. (Fluoresence resonance energy trasnfer, FRET) measurement. The experiment was performed on a 384-micro-L plate with a total volume of 10 ul. Mix the sample compound, standard compound, or water (control) with VEGFR-2 kinase in Hepes/Tris (pH7.4), EGTA/Tris. , MgCl 2 , DTT, and Tween 20 buffer solutions. Phosphorylation reaction is added to the substrate
  • 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.
  • the reaction IC 5Q value was obtained from 8 to 10 different concentrations of the compound kinase percent inhibition rate curve, and under the experimental conditions, the standard compound staurosporine 1 ( 5. was 3.5 nM.
  • Exemplary compounds have IC 5Q of 47 nM and 94 nM, respectively. detailed description

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Abstract

La présente invention concerne des composés d'urée aromatiques substitués de formule (I) ou (II) en tant qu'inhibiteurs de VEGFR-2 kinase, et leur utilisation pour la préparation d'un médicament pour le traitement de maladies médiées par VEGFR-2. R1, R2 et R3 sont choisis parmi halogène, cyano, hydroxyle, trifluorométhyle, méthoxy, trifluorométhoxy, alkyle en C1-C6 linéaire ou en C1-C6 ramifié substitué ou non substitué, cycloalkyle en C3-C7, aryle en C6-C10, hétéroaryle en C6-C10 ou un ou plusieurs groupes hétérocycliques en C6-C10 choisis parmi les atomes N, S, O ; le groupe substituant est choisi parmi amino, halogène, alkyle en C1-C6, hydroxyle, alkyloxy en C1-C6, nitro, cyano, sulfhydryle, alkylthio en C1-C6, halogéno-alkylthio en C1-C6, groupe hétérocyclique, hétéroaryle, alkyle hétérocyclique, hétéroaryl-alkyle en C1-C6, alcanoyle en C1-C6 ou carbamoyle.
PCT/CN2012/081296 2011-09-14 2012-09-12 Composé d'urée aromatique substitué et son utilisation en tant que médicament anticancer WO2013037292A1 (fr)

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CN102408426B (zh) * 2011-09-14 2013-07-10 湖南有色凯铂生物药业有限公司 取代的芳香脲类化合物及其作为抗癌药物的应用
CN110028444B (zh) * 2019-05-28 2022-02-11 沈阳药科大学 1-芳基-3-[4-(吡啶-2-基甲氧基)苯基]脲类化合物及应用

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CN1705645A (zh) * 2002-10-24 2005-12-07 默克专利有限公司 作为raf－激酶抑制剂的亚甲基脲衍生物
CN1972925A (zh) * 2004-01-30 2007-05-30 默克专利有限公司 双芳基脲类衍生物
CN102066372A (zh) * 2009-08-24 2011-05-18 苏州爱斯鹏药物研发有限责任公司 含脲基的5，6元杂芳双环化合物作为激酶抑制剂
CN102408426A (zh) * 2011-09-14 2012-04-11 湖南有色凯铂生物药业有限公司 取代的芳香脲类化合物及其作为抗癌药物的应用

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BRPI0516093A (pt) * 2004-10-12 2008-08-19 Astrazeneca Ab derivado de quinazolina, processo para a preparação do mesmo, composição farmacêutica, uso de um derivado de quinazolina, e, método para tratamento de distúrbios proliferativos celulares em um animal de sanque quente
EP1881981A1 (fr) * 2005-05-18 2008-01-30 Wyeth Inhibiteurs de 4, 6-diamino-[1,7] naphthyridine-3-carbonitrile de la tpl2 kinase et procedes de fabrication et d'utilisation de ceux-ci
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CN1705645A (zh) * 2002-10-24 2005-12-07 默克专利有限公司 作为raf－激酶抑制剂的亚甲基脲衍生物
CN1972925A (zh) * 2004-01-30 2007-05-30 默克专利有限公司 双芳基脲类衍生物
CN102066372A (zh) * 2009-08-24 2011-05-18 苏州爱斯鹏药物研发有限责任公司 含脲基的5，6元杂芳双环化合物作为激酶抑制剂
CN102408426A (zh) * 2011-09-14 2012-04-11 湖南有色凯铂生物药业有限公司 取代的芳香脲类化合物及其作为抗癌药物的应用

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