CN102775385A - N-substituted phenyl-N'-substituted heterocyclic urea compounds and application of same as anti-cancer drugs - Google Patents
N-substituted phenyl-N'-substituted heterocyclic urea compounds and application of same as anti-cancer drugs Download PDFInfo
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- 0 CNC(c1nccc(Oc2cc(Br)c(NC(Nc(cc3)cc(C(F)(F)F)c3Cl)=O)[s]2)c1)=* Chemical compound CNC(c1nccc(Oc2cc(Br)c(NC(Nc(cc3)cc(C(F)(F)F)c3Cl)=O)[s]2)c1)=* 0.000 description 1
- SJXWHBQWFBHASX-UHFFFAOYSA-N [O-][N+](c(cc1)cnc1I)=O Chemical compound [O-][N+](c(cc1)cnc1I)=O SJXWHBQWFBHASX-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to N-substituted phenyl-N'-substituted heterocyclic urea compounds and application of the same as anti-cancer drugs and especially discloses N-substituted phenyl-N'-substituted heterocyclic urea compounds which are used as a VEGFR-2 kinase inhibitor and represented by formula (I) and application of the compounds in preparation of drugs used for treating diseases mediated by VEGFR-2. In the formula (I) as described in the specification, R1, R2 and R3 are selected from the group consisting of halogen, cyano-groups, hydroxyl groups, and substituted or unsubstituted C1-C6 straight chains, C1-C6 branched chain alkyl groups, C3-C7 cycloalkyl groups, C6-C10 aryl groups and C6-C10 heteroaryl groups or C6-C10 heterocyclic radicals containing one or more selected from the group consisting of N, S and O atoms, wherein substituent groups are selected from the group consisting of amino groups, halogen, C1-C6 alkyl groups, hydroxyl groups, C1-C6 alkyloxy groups, nitro groups, cyano-groups, mercapto groups, C1-C6 alkylthio groups, halogen-C1-C6 alkylthio groups, heterocyclic radical, heteroaryl groups, heterocyclic alkyl groups, heteroaryl C1-C6 alkyl groups, C1-C6 alkanoyl groups and carbamoyl groups; and ring A is substituted or unsubstituted pyrimidinyl groups, pyrazinyl groups, pyridyl groups, thienyl groups or thiazolyl groups, wherein substituent groups are selected from the group consisting of halogen, cyano-groups and hydroxyl groups.
Description
Invention field
The present invention relates to N-substituted-phenyl-N '-substituted heterocycle carbamide compounds as SU11752 such as VEGFR-2, and they be used for preparing kinases such as treatment VEGFR-2 the purposes of disease mediated medicine.
Background technology
Along with further investigation, become the important component part of antineoplaston through the targeted therapy method that multiple carcinogenic protein kinases is suppressed, and in all kinds of tumor treatment, obtained major progress oncomolecularbiology.In cell, protein kinase is through passing on and amplification message growth, differentiation and the apoptosis of control cell to the phosphorylation of upper reaches albumen, downstream egg bletilla self.Known at present; All there is this signal path of Raf/MEK/ERK in all eukaryotic cells; Its specificity cascade phosphorylation through Ras, Raf, MEK and ERK is imported signal in the nucleus into by the extracellular, and there is the rise of this path in about 30% tumour cell.In the Raf/MEK/ERK signal path; Signal originates in combining of Urogastron (EGF) and cytolemma upper epidermis growth factor receptors (EGFR); EGFR combines with adapter protein GRB2 (growth factor receptor-bound protein 2) at SH2 position, the position of its phosphorylation; Recruiting guanylic acid exchange factor SOS albumen and Ras is combined on the adjacent inner cell film; GTP substitutes with Ras bonded GDP and intensifies Ras, and Ras is one of crucial signal transduction center, participates in the signal transduction of a plurality of upstream and downstreams.In the path of studying at most, the Ras after intensifying combines with cytoplasm serine/threonine kinases Raf, and Raf is phosphorylation mapk kinase (MAPKK claims MEK again) again, and MEK activation ERK1/2 (extracellular signal regulated kinase, ERK).After ERK is activated, get in the nucleus and direct activating transcription factor, start the biological procedureses such as growth, differentiation and apoptosis of cell.In case this path generation over-drastic activates, the acceleration of cell proliferation and the prolongation of cells survival phase can cause formation and development (Kolch W.Biochem J, 2000, the 351:289-305 of tumour; Gishizky ML.Annu.Rep.Med.Chem.1995,30:247-253).
It is pointed out that the difference with environmental factors, the signal protein in the signal path cascade reaction all possibly activated or suppresses and form an extremely complicated network regulation structure by different upper reaches albumen.For example, Raf on the Raf/MEK/ERK signal path and ERK also can bring into play its signal transduction regulating effect through the mode that does not rely on Ras; The activity of Ras can cause that also the minimizing of GTP hydrolysis improves through the sudden change of tumor suppressor gene NF1.Except the keying action on the Raf/MEK/ERK signal path; EGF-R ELISA (EGFR) also activates the phosphatidyl-inositol 3-kinase (PI3K) on the PI3K/AKT passage, and Ras and PI3K be the effect of regulatory molecule Mammals rapamycin target protein (mTOR) together again.MTOR is another multi-functional cytoplasm serine/threonine kinases of control cell physiological effect; Substrate as downstream; S6 kinase (S6K) and 4EBP1 start synthetic (Hay N, Sonenberg N (2004) the .Genes Dev 18 (16): 1926-45) of ribosomal protein after by the mTOR phosphorylation.
More than 518 protein kinase of protein kinase gene coexpression, wherein receptor kinase has 20 subfamilies to divide 58 types, and the cytoplasm kinases has 10 subfamilies to divide 32 types; In known more than 50 kinds of oncogene, major part is protein kinase gene (Manning et al.Sicence, 2002,298,1912).The cancer gene is in repressed state usually; But after they undergo mutation perhaps by abnormal activation; For example under the effect of chemical toxicant, long-term ultraviolet lighting or radioactive substance, oncogene can excessively be expressed kinases, or expresses the kinases of continuous activation; Cause the out of control of important steps such as cell growth, differentiation and apoptosis and produce cancer cells (Croce CM.N Engl J Med.2008,358 (5): 502-11).To kinases out of control on the cell signal path or growth factor etc. as drug target; Research and development small molecules or macromole suppressor factor; The antagonism growth of cancer cells has become important directions (the Novel anticancer agents that current cancer therapy drug is researched and developed with transfer; Academic Press, 2006, editors:Alex A.Adijel; John K.Buolamwini).
Raf kinases on the Raf/MEK/ERK signal path in many cancer cell by overexpression; Surpass the activated mutant of all finding B-raf in human malignant's melanoma of 60%, 12% large bowel cancer, 14% the ovarian cancer, this sudden change also is present in the tumour of Tiroidina and lung; On the other hand, though the kidney 50% and almost exist unusual high C-raf active in 100% the liver cancer cell is do not undergo mutation (Brose, M.S.et al.Cancer Res.2000,63:6997-7000 of C-raf wherein; Davies, H.Nature, 2002,417:949-954; Yuen, S.T.et al.Cancer Res.2002,62:6451-6455).Kinase b-raf-V600E after the B-raf sudden change, its activity is 500 times of wild type kinase, it can form heterodimer with C-raf; The ERK in sustained activation downstream and protein kinase mTOR (Sridhar SS; Hedley D, Siu LL.Mol.Cancer Ther.2005,4 (4): 677-85).There are three kinds of hypotypes in the RAF kinases, comprises A-raf, B-raf and C-raf (also claiming Raf-1), and their height homologies are enjoyed very high sequence similarity, so small molecules RAF SU11752 antagonism B-ref, C-raf and B-raf-V600E simultaneously usually.Xarelto (Sorafenib) by Bayer research and development is in the RAF SU11752 of the first treatment kidney in late period of approval in 2005, is approved for the medicine of secondary liver cancer in 2007 again.Further research is thought the scientists of Bayer; Xarelto in fact can the multiple kinases of antagonism; It comes the growth and transfer (the Keating GM of anticancer through while antagonism RAF kinases and several kinds of vasculogenesis growth factor acceptors (for example VEGFR, PDGFR etc.); Santoro A.Drugs 2009,69 (2): 223-240).Kidney and liver cancer all are the extremely strong cancers of transitivity, and the main histological type of its carcinoma mesonephric is clear cell carcinoma (clear cell carcinoma), and its pathogenesis is relevant with the sudden change of VHL cancer suppressor gene.In case vhl gene is undergone mutation, even if under normal non-anoxic physiological status, its amino acids coding albumen (pVHL) also can cause the abnormal activation of HIF-1 α (hypoxia-induc ible factor-1 α, HIF-1 α); HIF-1 α stimulates the expression of ESCs such as VEGF and PDGF-β synthetic again, and the new vessel of participating in tumor tissues generates.In addition, most kidney tool EGFR expresses, and the expression degree is relevant with prognosis, and HIF-1 α combines with EGFR through activating the effect of TGF-α generation autocrine, thereby promotes cell proliferation and existence.Combining of which kind of growth factor and its acceptor no matter, all need usually through the Raf/MEK/ERK path play a role (Gunaratnam L, et al.J Biol Chem.2003,278:44966-44974).
As far back as 1971, Judah Folkman promptly proposed growth and the transfer (metastasis) that vasculogenesis theory (Angiogenesis) is explained tumour.Their experiment shows the vascular endothelial growth factor suppressor factor, and Endostatin (endostatin) can suppress the growth that mouse goes up tumour with human angiostatin (angiostatin).He thinks that tumour cell is after autotomy is bred to a certain degree (1-2 cubic millimeter); Must provide nutrient and oxygen to help it by new life's tumor vessel further increases and diffusion (Folkman J; Klagsbrun M.Science 1987,235 (4787): 442-7).In the vascularization process, the acceptor (VEGFR) on cancer cells is secreted vascular endothelial growth factor (VEGF) and cell is touched combines, and stimulates growth, division, the breeding of vascular endothelial cell; Simultaneously cell discharges matrix around proteolytic ferment (proteolytic enzymes) and matrix metalloproteinase (MMP) degraded, and cell is able to reach, increase, form canalization vascular circle and new basilar membrane, finally forms new vessel.Document shows that further multiple different growth factor is participated in newborn tumor vascular formation simultaneously; Except that VEGF, also have Thr6 PDGF BB (Platelet-derived growth factor, PDGF) and fibroblast growth factor (Fibroblast Growth Factor, FGF) etc.Growth factors such as cancer cells excretory PDGF and FGF help the formation of new vessel through recruiting and stimulating the growth of fibrocyte, smooth muscle cell, adventitial cell to form new cancer cells blood vessel matrix.Different with normal blood vessels; This newborn tumor vessel is the structure irregularity often, the vascular stroma imperfection, and perviousness is high; So tumour cell is able to be penetrated in the blood, diffusion also forms cancer metastasis (metastasis) attached to growth and breeding on other position of health.Clinical study proves, suppresses growth and transfer that this process can stop tumour effectively, prolongs patient's life-span (Folkman J.Scientific American 1996,275 (3): 150-4).The growth factor receptors that known participation cancer cells new vessel forms has VEGFR-1 (Flt-1); VEGFR-2 (KDR; Or Flk-1), Thr6 PDGF BB (PDGF) acceptor PDGFR-α and PDGFR-β, and fibroblast growth factor (FGF) acceptor FGFR1-4 etc.; On the other hand; The VEGFR-3 of structural similitude (Flt-4) acceptor is mainly participated in newborn vasculolymphatic formation (Lymphangiogenesis); In the process that cancer shifts through lymphsystem, play the part of important role; These acceptors can as the antagonism parenchymal tumor increase with the target spot that shifts (Steven A.Stacker.Lymphangiogenesis in Cancer Metastasis, Springer.2009pp.27-).
In sum; Recent two decades comes people that generation, growth, the survival of cancer and the understanding that shifts on the molecule aspect have been obtained outstanding progress; The more important thing is that a plurality of clinical study instances have all proved with small molecules or macromolecular drug and suppressed the curative effect that kinases or growth factor are treated cancer; The unremitting effort of research vasculogenesis (Angiogenesis) has also proved the clinical efficacy that suppresses vascular endothelial growth factor or acceptor finally, and the angle that forms from impedance cancer cells surrounding blood vessel delays the growth and the diffusion of cancer, prolongs patient's life-span.
May calendar year 2001; Drugs approved by FDA first Tyrosylprotein kinase micromolecular inhibitor imatinib (Imatinib) be chronic myelocytic leukemia (chronic marrow leukemia; CML) (Gambacorti-Passerini C.Lancet Oncology 2008,9 (600): 600), imatinib has proved the feasibility of kinase inhibitor for treating cancer first in medicine for treatment; Imatinib has shown the drug toxicity lower with respect to chemotherapy simultaneously, has improved patient's quality of the life.In the molecule aspect, imatinib suppresses the growth and the division of cell through the bcr-abl kinases of over-expresses in the antagonism leukaemia cancer cell; Its while is the kinase whose activity of antagonism c-kit also, and shows its curative effect to the gi tract Leydig's cell tumor clinically, is approved for the medicine for treatment of gi tract Leydig's cell tumor.After several years; 100 o'clock Mei-Shi Guibao and Novartis be again respectively at developing two other chronic marrow leukemia medicine for treatment-Dasatinib (Dasatinib) and nilotinib (Nilotinib) in 2006 and 2007, and both also have good curative effect to the sufferer of imatinib resistant.
ZD1939 (Gefitinib) by the research and development of Britain Astrazeneca AB is ratified the listing in Japan in August, 2002, and is especially very effective to Asia smoking male sex nonsmall-cell lung cancer patient as nonsmall-cell lung cancer first-line treatment medicine ZD1939.2004, Tarceva (erlotinib) was developed jointly in Genentech and 0SI pharmacy, and its scope of application is more extensive, was used as the nonsmall-cell lung cancer first-line treatment in the whole world in seven, 80 countries, kept the medicine of treatment and sequential therapy.ZD1939 and Tarceva are EGF-R ELISA (EGFR) suppressor factor; The antagonism cell surface is striden EGFR acceptor on the film suppresses the EGFR transduction with combining of Urogastron (EGF) signalling channels such as Raf/MEK/ERK (Raymond E; Faivre S; Armand J.Drugs 2000,60Suppl 1:15-23; Discussion 41-2).Same principle, Tarceva also can suppress the growth of pancreatic tumor cell effectively, become the targeted drug of first treatment carcinoma of the pancreas of FDA approval.
2006, Pfizer and Sugene developed Sutent (Sunitinib) jointly.As the Tyrosylprotein kinase micromolecular inhibitor of treatment kidney (RCC), Sutent is through antagonizing vessel endothelium cell growth factor acceptor (VGEFR), and the formation of anticancer new vessel delays the growth and the transfer of cancer cells.Sutent also can suppress the kinase whose activity of c-kit simultaneously, is approved for imatinib resistant gi tract Leydig's cell tumor patient's medicine for treatment.
Xarelto (Sorafenib) by the Bayer research and development passes through the growth and the transfer of multiple approach antagonism cancers such as antagonism RAF kinases, vascular endothelial growth factor receptor (VGEFR) and platelet derived growth factor receptor (PDGFR-β) simultaneously, by the medicine of FDA approval for late period kidney and secondary liver cancer.Xarelto is the important breakthrough in liver cancer treatment field to the curative effect of secondary liver cancer, and liver cancer is to generally acknowledge that refractory treats one of cancer that transitivity is the strongest (Escudier B, et al. (January 2007) .N.Engl.J.Med.356 (2): 125-34; Keating GM, Santoro A.Drugs 2009,69 (2): 223-240).
Mammals rapamycin target protein (mTOR) is multi-functional serine/threonine kinases in the PI3K/AKT signalling channel; With growth, division, survival and the transfer of cancer cells direct related (Rubio-Viqueira is arranged all; B, Hidalgo M.Curr.Opin.Investig.Drugs2006.7:501-512).The effect of mTOR kinases in kidney shifts is especially obvious, and mTOR out of control causes the raising of HIF-1 α concentration in the cell, and HIF-1 α brings out the synthetic of VGEF again, promotes the cancer cells vascularization; On the other hand, many kidney cancer cells since the sudden change of VHL tumor suppressor gene or lose cause minimizing that HIF-1 α decomposes also improve the concentration of HIF-1 α (Thomas GV.et al.Nature Medicine 2006,12:122-127).First clinical rapamycin derivative sirolimus (Temsirolimus) that uses the mTOR suppressor factor as U.S. Hui Shi pharmaceutical development was the medicine for treatment of kidney by FDA approval in 2007.
Lapatinibditosylate (Lapatinib) is a small molecules Tyrosylprotein kinase double inhibitor; It can suppress EGF-R ELISA (EGFR) and ErbB2 (HER-2/neu) acceptor, the HER-2/neu acceptor that nearly about 30% mammary cancer sufferer is excessive owing to the HER-2/neu proto-oncogene produces simultaneously.2007, lapatinibditosylate was the medication of mammary cancer combination treatment by the FDA approval, was approved for the triple positive patient with breast cancers' of ER+/EGFR+/HER2+ a line medication (Wood ER et al.Cancer research 2004,64 (18): 6652-9) in 2010 again.
Because kinase whose high homology and variety, the small molecules cancer therapy drug of research and development is multiple SU11752 mostly at present, different with former worry fortunately, and lower kinases selectivity does not influence the curative effect of medicine; On the contrary, preferred multiple SU11752 possibly be more conducive to resist complex genesis, various informative cancer, and can use by a medicine more.
Different with small molecules SU11752 multiplicity is that normally only to the special suppressor factor of single target spot in the cell signal passage, a plurality of clinical instances have also proved the curative effect of monoclonal antibody specific treatment cancer to the macromole monoclonal antibody.1998, it was the breast cancer treatment medication that Herceptin (Trastuzumab) obtains drugs approved by FDA, is applicable to mammary cancer sufferer (Hudis, CA.N Engl J Med.2007,357 (1): 39-51) of overexpression HER-2/neu.2004, FDA ratified rhuMAb-VEGF (Bevacizumab) and standard chemotherapeutics combined treatment Metastatic Colorectal Cancer (mCRC) and nonsmall-cell lung cancer (NSCLC).RhuMAb-VEGF is combining with vascular endothelial cell growth factor (VGEF) specifically, suppresses the formation of cancer new vessel, and can promote infiltration (the Los M et al.The Oncologist 2007,12 (4): 443-50) of chemotherapeutics to cancerous tissue.Continue after, handkerchief Buddhist nun monoclonal antibody (Panitumumab) and Cetuximab (cetuximab) also are approved for the Metastatic Colorectal Cancer medication.Different with rhuMAb-VEGF, handkerchief Buddhist nun monoclonal antibody and Cetuximab through with EGF-R ELISA (EGFR) combine to come anticancer growth splitted signalling channel.Cetuximab (IgG1) and handkerchief Buddhist nun monoclonal antibody (IgG2) belong to the different subtype of Tegeline, and there is hairline in they on anticancer mechanism, and except that the curative effect to large bowel cancer, the Cetuximab that Shi Guibao company produces also can be treated head and neck cancer.
Above-mentioned clinical instance full proof with SU11752 antagonism cancer cells signalling channel out of control, the treatment various cancers feasibility.Yet cancer is one of the most complicated disease, and each organ of health all possibly form the different cancer of structure organizations through various mechanism, and much cancers are that simultaneous mutation by a plurality of genes causes, and similar cancer also can be formed by different canceration reasons etc.The diversity of cancer origin cause of formation mechanism, the variety of form structure make the various abrim all the time challenges of its treatment, and cancer expert has to generally utilize the various combination of multiple medicine to come antitumor persistent ailment; On the other hand; Cancer also can develop immunity to drugs to existing medicine; So be necessary that constantly development structure is novel, different, the better novel targeted medicine of drug effect of function, carry out the preferably combination of medicine, the curative effect of raising cancer therapy according to signal path and cancer genetics information.
VEGF (VEGF) is a most important Porcine HGF in the tumor vessel generative process, and tumor vessel is extremely sensitive to VEGF, and VEGF mRNA concentration is higher than normal cell significantly in a lot of tumour cells, and these tumours comprise lung cancer (Mattern et al.Br.J Cancer 1996; 73,93,1); Thyroid cancer (Viglietto et al.Oncogene 1995,11,1569); Breast cancer (Brown et al.Human Pathol.1995,26,86); Human primary gastrointestinal cancers (Brown et al.Cancer Res.1993,53,4727; Suzuki et al.Cancer Res.1996,56,3004), kidney and carcinoma of urinary bladder (Brown et al.Am.JPalhol.1993; 143L 1255), oophoroma (0lson et al.Cancer Res.1994,54,1255); Cervical carcinoma (Guidi et al.J Nat ' l Cancer30 Inst.1995,87,12137) and angiosarcoma (Hashimoto et al.Lab.Invest.1995,73; 859) and multiple ICT (Plate et al.Nature 1992,359,845; Phillips et al.Int.J Oncol.1993,2,913; Berkman et al.J Clin.Invest., 1993,91; 153).So continue rhuMAb-VEGF, Sutent, Xarelto as angiogenesis inhibitor successfully be applied to clinical since; The research and development novel vascular forms suppressor factor (like VEGFR-2 and PDGFR-beta inhibitor etc.) and has become very popular field as broad-spectrum anti-cancer drug, and has obtained new, promising clinical test results.
W0-2004007458 discloses one group of 2-alkanamine nicotinamide derivates as VEGFR, PDGFR and Kit inhibitor, in clinical three phases test, is used for the treatment of non-squamous non-small cell lung cancer, and other indication comprises the essence cancer; Human primary gastrointestinal cancers; Colorectal cancer, endocrine cancer, breast cancer and lung cancer.
W0-2004113304 discloses one group of indazole, benzisoxa azoles and benzothiazole derivant as CSFR-1, PDGFR, Flt3, Kit, VEGFR-1, VEGFR-2, VEGFR-3 suppressor factor; In clinical three phases test, be used to treat liver cancer; The clinical nonsmall-cell lung cancer that is used for of second phase, mammary cancer, colorectal carcinoma; Other indication also comprises kidney, acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
WO-2000043366 discloses one group of quinoline-urea derivative as Kit, PDGFR section acceptor, VEGFR-1, VEGFR-2, VEGFR-3 inhibitor; In clinical three phases test, be used to treat kidney; Other clinical trial comprises breast cancer; Colorectal cancer, human primary gastrointestinal cancers, non-small cell lung cancer and liver cancer etc.
W0-200102369 discloses one group of indazole derivative as CSFR-1, PDGF, VEGF-1, VEGF-2 and VEGF-3 inhibitor; In clinical three phases test, be used to treat kidney; The second phase clinical trial comprises carcinoma mesothelial, angiosarcoma, adrenal cortical adenocarcinoma and liver cancer etc.
WO-200232872 discloses one group of novel quinoline-urea derivatives as VEGFR-2, VEGFR-3, FGFR 1-4 and RET suppressor factor; In clinical three phases test, be used for the treatment of thyroid carcinoma, the second stage of clinical experiment comprises liver cancer, carcinoma of endometrium; Melanoma, kidney and neurospongioma.
WO-2003082272 discloses one group of arylamine benzimidazoles compound as Raf, VEGFR-2, and PDGFR-β and Kit suppressor factor are used to treat melanoma.
Chinese patent CN101475513A, CN101260106A and CN101735215A also disclose the purposes of three kinds of raf SU11752 substituted bisarylurea compounds on the treatment cancer.
Summary of the invention
The present invention relates to general formula (I) compound or its pharmacy acceptable salt, and treatment patient's method, this method comprises to the patient uses general formula (I) compound or its pharmacy acceptable salt that suppresses VEGFR-2 kinases significant quantity.
The present invention relates to a kind of N-substituted-phenyl-N '-substituted heterocycle carbamide compounds of VEGFR-2 SU11752, it is the described compound of general formula (I) or its pharmacy acceptable salt:
Wherein:
R
1, R
2And R
3Be selected from halogen; Cyanic acid; Hydroxyl; Replace or unsubstituted C1-C6 straight chain; The C1-C6 branched-chain alkyl; The C3-C7 naphthenic base; The C6-C10 aryl; Contain one or more N of being selected from; S; The C6-C10 heteroaryl of O atom or C6-C10 heterocyclic radical; Wherein substituting group is selected from amino; Halogen; The C1-C6 alkyl; Hydroxyl; The C1-C6 alkoxyl group; Nitro; Cyanic acid; Sulfydryl; The C1-C6 alkylthio; Halogen-C1-C6 alkylthio; Heterocyclic radical; Heteroaryl; The heterocyclic radical alkyl; Heteroaryl C1-C6 alkyl; C1-C6 alkyloyl or formamyl
The A ring is for replacing or non-substituted pyrimidyl, pyrazinyl, pyridyl, thienyl or thiazolyl, and substituting group is selected from halogen, cyanic acid or hydroxyl.
Preferably, said halogen can be selected from fluorine, chlorine, bromine or iodine.
R
1, R
2And R
3Further be selected from halogen, cyanic acid, hydroxyl, replacement or unsubstituted C1-C6 straight chain, C1-C6 branched-chain alkyl, C3-C7 naphthenic base, C6-C10 aryl, C6-C10 heteroaryl respectively or contain the C3-C10 heterocyclic radical of one or more N of being selected from, S, O atom;
R
1, R
2And R
3Further be preferably fluorine, chlorine, methyl, ethyl, cyanic acid, hydroxyl, the tertiary butyl, cyclopropyl or cyclobutyl, phenyl, pyridyl, pyrryl or piperazinyl;
R
1, R
2And R
3Can also be preferably chlorine, cyanic acid, hydroxyl, trifluoromethyl, methoxyl group or trifluoromethoxy.
Described halogen is selected from fluorine, chlorine, bromine or iodine, preferred fluorine or iodine.
Said substituting group is selected from amino, halogen, C1-C6 alkyl, hydroxyl, C1-C6 alkoxyl group, nitro, cyanic acid, sulfydryl, C1-C6 alkylthio, halogen-C1-C6 alkylthio, heterocyclic radical, heteroaryl, heterocyclic radical alkyl, heteroaryl C1-C6 alkyl, C1-C6 alkyloyl or formamyl.Wherein the C1-C6 alkyl substituent can be unsubstituted or further replaced.
The preferred particular compound of the present invention or its pharmacy acceptable salt have:
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 4-(2-methylamino formyl radical pyridine-4-) oxygen) pyrimidine-2-);
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 6-(2-methylamino formyl radical pyridine-4-) oxygen) pyrimidine-4-);
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 2-(2-methylamino formyl radical pyridine-4-) oxygen) pyrimidine-5-);
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 5-(2-methylamino formyl radical pyridine-4-) oxygen) pyrazine-2-);
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 5-(2-methylamino formyl radical pyridine-4-) oxygen) thiophene-2-);
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 3-bromo-5-(2-methylamino formyl radical pyridine-4-) oxygen) thiophene-2-);
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 3-cyanic acid-5-(2-methylamino formyl radical pyridine-4-) oxygen) thiophene-2-);
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 5-(2-methylamino formyl radical pyridine-4-) oxygen) thiazole-2-).
The present invention relates to formula (I) compound pharmacy acceptable salt, these salt are selected from:
A) subsalt of organic acid and mineral acid; Said organic acid and mineral acid are selected from hydrochloric acid, Hydrogen bromide, sulfuric acid; Phosphoric acid, methylsulfonic acid, three fluosulfonic acid, Phenylsulfonic acid, tosic acid, 1-naphthalene sulfonic aicd, 2-naphthene sulfonic acid, acetate; Trifluoroacetic acid, oxysuccinic acid, tartrate, Hydrocerol A, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, phenylacetic acid or tussol; With
B) hydrogen salt of the organic and mineral alkali of cation, said positively charged ion are selected from alkali metal cation, alkaline earth metal cation, ammonium ion, aliphatic substituted ammonium ion or the substituted ammonium ion of aromatics.
The invention still further relates to the pharmaceutical composition that is used to treat cancer, said pharmaceutical composition comprises suitable carriers on formula (I) compound or its pharmacy acceptable salt and the physiology.
Compound of the present invention or its pharmacy acceptable salt can be used for making the purposes of the medicine that suppresses the kinase mediated cancerous cells growth of VEGFR-2.
Compound of the present invention or its pharmacy acceptable salt can also be used in the purposes on the preparation treatment Cancerous disease medicine.
Cancer of the present invention, including real cancer, renal cancer, lung cancer, breast cancer, liver cancer, ovarian cancer, pancreatic cancer, thyroid cancer, bladder cancer, leukemia, adenocarcinoma, melanoma, gastrointestinal cancer, colon cancer, carcinoma of , kidney cancer, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), mesothelial cancer, angiosarcoma, adrenal cortical carcinoma, endometrial cancer and glioma and so on.In particular, kidney cancer, liver cancer, lung cancer, lung cancer, colorectal cancer, gastrointestinal cancer, breast cancer, gastrointestinal cancer, and effective in the treatment of vascular sarcoma.
In the context of content of the present invention, unless otherwise indicated, otherwise the generic term that is used to describe general formula (I) compound among this paper has following implication.
When mentioning that substituting group is for example when alkyl, alkoxyl group, alkylamine, alkylthio etc.; Term " rudimentary " expression has at the most 7 and comprise 7 of peaks, preferred 1 to 6 and comprise the group of 6 carbon atoms of peak at the most, and said group is unbranched or by the branching one or many.
Low alkyl group, lower alkoxy and have the preferred C of moieties in the substituting group of moieties
1-C
6Alkyl, for example normal-butyl, sec.-butyl, the tertiary butyl, n-propyl, sec.-propyl, methyl or ethyl.Except as otherwise noted, otherwise described alkyl substituent is unsubstituted or by halogen, hydroxyl, nitro, cyanic acid, lower alkoxy, C
3-C
7Naphthenic base, amino or single-or two-low-grade alkyl amino replace.
Halogen-low alkyl group, halogen-lower alkoxy, halogen-lower alkylthio etc. be meant have moieties, wherein moieties is replaced to complete substituted substituting group by the halogen list.Halogen-low alkyl group, halogen-lower alkoxy are included within substituted low alkyl group, the substituted lower alkoxy.
The preferred fluorine of halogen, chlorine, bromine or iodine, more preferably fluorine, chlorine or bromine, particularly fluorine.
Phenyl generally is unsubstituted phenyl or, preferred 1 or 2 substituting group substituted phenyl individual by 1-5.Suitable substituting group include but not limited to amino, list-or the substituted amino of two-low alkyl group (wherein low-grade alkyl substituent can be unsubstituted or further as above those listed substituting groups of alkyl replaced), halogen, low alkyl group, substituted low alkyl group, hydroxyl, lower alkoxy, substituted lower alkoxy, nitro, cyanic acid, sulfydryl, lower alkylthio, halogen-lower alkylthio, heterocyclic radical, heteroaryl, heterocyclic radical alkyl, heteroarylalkyl, low-grade alkane acidyl, formamyl and N-single-or N; The substituted formamyl of N-two-low alkyl group, wherein low-grade alkyl substituent can be unsubstituted or further replaced.
For the preferred unsubstituted phenyl of R1, R2 and the R3 of phenyl or by one or more substituting groups, preferably three, a preferred substituted phenyl of substituting group at the most.The substituting group that R1, R2 and R3 phenyl are even more important comprises amino, list-or two-low-grade alkyl amino (wherein alkyl is unsubstituted or substituted), halogen, low alkyl group, substituted low alkyl group, hydroxyl, lower alkoxy, substituted lower alkoxy, nitro, cyanic acid, sulfydryl, lower alkylthio and substituted lower alkylthio.
R for phenyl
1, R
2And R
3Preferred unsubstituted phenyl or by the substituted phenyl of one or two identical or different substituting group, said substituting group is selected from halogen, preferred fluorine or chlorine; Low alkyl group, preferable methyl, ethyl, propyl group or the tertiary butyl; Halogen-low alkyl group, preferred trifluoromethyl; Hydroxyl; Lower alkoxy, preferred methoxy or ethoxy; Halogen-lower alkoxy, trifluoromethoxy or 1,1,2 for example, 2-tetrafluoro oxyethyl group; More preferably by a substituted phenyl of substituting group; Said substituting group is selected from unsubstituted or substituted low alkyl group, preferable methyl, halogen-low alkyl group, for example trifluoromethyl, unsubstituted or substituted lower alkoxy; Preferred methoxyl group and halogen-lower alkoxy, preferred trifluoromethoxy.
Important R1, R2 and R3 phenyl comprise unsubstituted phenyl and the substituted phenyl of lower alkoxy, preferably the substituted phenyl of lower alkoxy wherein.
Heteroaryl preferably comprises 1 to 3 heteroatomic 5 to 7 yuan of aromatic ring that are selected from N, O and S.Heteroaryl be unsubstituted or by one or more, preferred one to three, for example an identical or different substituting group replaces.Important substituting group on the heteroaryl is that those are selected from following substituting group: halogen, for example fluorine or chlorine; Single-or the substituted amino of two-low alkyl group, wherein alkyl is unsubstituted or by halogen, hydroxyl, nitro, cyanic acid, lower alkoxy, C
3-C
7Naphthenic base, heterocyclic radical or heteroaryl replace; Low alkyl group, for example methyl or ethyl; Halogen-low alkyl group, for example trifluoromethyl; Lower alkoxy, for example methoxy or ethoxy; Halogen-lower alkoxy, for example trifluoromethoxy; Lower alkylthio, for example methylthio group; Halogen-lower alkylthio, for example trifluoromethylthio; Heteroaryl; Heteroaryl-low-grade alkylidene; Heterocyclic radical or heterocyclic radical-low-grade alkylidene.
Heterocyclic radical preferably has 1 or 2 heteroatomic five yuan or the hexa-atomic non-aromatic ring that are selected from nitrogen, oxygen and sulphur, and this heterocycle can be saturated wholly or in part, and is unsubstituted or substituted, is preferably replaced by unsubstituted or substituted low alkyl group.Heterocyclic radical comprises morpholino, parathiazan generation, piperidyl, piperazinyl etc.
The pharmaceutically useful acid salt of pharmacy acceptable salt preferred formula (I) compound.This type salt is formula (I) compound formation through having basic nitrogen atom for example, acid salt for example, the acid salt that preferably forms with organic or inorganic acid, preferred pharmacologically acceptable salt.Suitable mineral acid has for example haloid acid example hydrochloric acid, sulfuric acid or phosphoric acid.Appropriate organic has for example carboxylic acid, phosphonic acids, sulfonic acid or thionamic acid; For example acetate, propionic acid, sad, capric acid, dodecylic acid, oxyacetic acid, lactic acid, 2-hydroxybutyric acid, glyconic acid, fumaric acid, Succinic Acid, hexanodioic acid, pimelic acid, suberic acid, nonane diacid, oxysuccinic acid, tartrate, Hydrocerol A, saccharic acid, tetrahydroxyadipic acid, amino acid; For example L-glutamic acid, aspartic acid, sarcosine, ethanoylaminoethanoic acid, N-ethanoyl l-asparagine, N-acetylcysteine, pyruvic acid, etheric acid, Serine O-phosphate, 2-or 3-Phosphoric acid glycerol esters, toxilic acid, hydroxymaleic acid, methyl-maleic acid, naphthenic acid, phenylformic acid, Whitfield's ointment, 1-or 3-hydroxyl naphthalene-2-formic acid, 3; 4; 5-trimethoxybenzoic acid, 2-phenoxy benzoic acid, 2-acetoxy-benzoic acid, 4-aminosallcylic acid, phthalic acid, phenylacetic acid, glucuronic acid, galacturonic acid, methane-or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1; 2-disulfonic acid, Phenylsulfonic acid, 2-naphthene sulfonic acid, 1; 5-naphthalene disulfonic acid, N-cyclohexyl thionamic acid, N-methyl-, N-ethyl-or N-propyl group-thionamic acid; Or other organic protonic acid, for example xitix.
The present invention relates to N-substituted-phenyl-N '-substituted heterocycle carbamide compounds as the VEGFR-2 SU11752, and they be used for preparing treatment VEGFR-2 kinases the purposes of disease mediated medicine.
Said patient is a Mammals, generally is the people.
The compounds of the present invention is useful for treating cancer in a mammal, preferably human cancers, including but not limited to, solid cancers, kidney cancer, lung cancer, breast cancer, liver cancer, ovarian cancer, pancreatic cancer, thyroid cancer, bladder cancer, leukemia, adenocarcinoma, black melanoma, gastrointestinal cancer, colorectal cancer, endocrine cancer, kidney cancer, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), mesothelial cancer, angiosarcoma, adrenal cortical carcinoma, endometrial cancer and glioma.Compound of the present invention also can be used for treating inflammatory diseases, comprises rheumatoid arthritis, retinopathy (comprising diabetic retina neural disease and degeneration of macula), cardiovascular disorder and metabolic trouble.
General formula of the present invention (I) compound or its pharmacy acceptable salt have aforesaid valuable pharmacological character.
The subsalt of organic acid and mineral acid, said organic acid and mineral acid are selected from hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid; Three fluosulfonic acid, Phenylsulfonic acid, tosic acid, 1-naphthalene sulfonic aicd, 2-naphthene sulfonic acid, acetate; Trifluoroacetic acid, oxysuccinic acid, tartrate, Hydrocerol A, lactic acid, oxalic acid; Succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, phenylacetic acid and tussol; With
B) hydrogen salt of the organic and mineral alkali of cation, said positively charged ion is selected from alkali metal cation, alkaline earth metal cation, ammonium ion, aliphatic substituted ammonium ion and the substituted ammonium ion of aromatics.
General formula of the present invention (I) compound pharmacy acceptable salt is pharmaceutically useful acid salt.This type salt is formula (I) compound formation through having basic nitrogen atom for example, acid salt for example, the acid salt, the especially pharmacologically acceptable salt that preferably form with organic or inorganic acid.Suitable mineral acid is selected from hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid etc.Appropriate organic is selected from carboxylic acid, phosphonic acids, sulfonic acid or thionamic acid; For example methylsulfonic acid, three fluosulfonic acid, Phenylsulfonic acid, tosic acid, 1-naphthalene sulfonic aicd, 2-naphthene sulfonic acid, acetate, trifluoroacetic acid, oxysuccinic acid, tartrate, Hydrocerol A, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid; Phenylformic acid, Whitfield's ointment, phenylacetic acid, tussol, propionic acid, sad, capric acid, dodecylic acid, oxyacetic acid, 2-hydroxybutyric acid, glyconic acid, Succinic Acid, hexanodioic acid, pimelic acid, suberic acid, nonane diacid, saccharic acid, tetrahydroxyadipic acid; Perhaps amino acid; For example L-glutamic acid, aspartic acid, sarcosine, ethanoylaminoethanoic acid, N-ethanoyl l-asparagine, N-acetylcysteine, pyruvic acid, etheric acid, Serine O-phosphate, 2-or 3-Phosphoric acid glycerol esters, hydroxymaleic acid, methyl-maleic acid, naphthenic acid, 1-or 3-hydroxyl naphthalene-2-formic acid, 3; 4; 5-trimethoxybenzoic acid, 2-phenoxy benzoic acid, 2-acetoxy-benzoic acid, 4-aminosallcylic acid, phthalic acid, phenylacetic acid, glucuronic acid, galacturonic acid, methane-or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1; 2-disulfonic acid, 1; 5-naphthalene disulfonic acid, N-cyclohexyl thionamic acid, N-methyl-, N-ethyl-or N-propyl group-thionamic acid, or other organic protonic acid, for example xitix.
Compound of the present invention can use separately or with other anticarcinogen combined administration, for example suppress the compound of tumor-blood-vessel growth, for example proteinase inhibitor, epidermal growth factor receptor kinase inhibitor, vascular endothelial growth factor receptor SU11752 etc.; Cytotoxic drug, metabolic antagonist for example is like purine and pyrimidine analogue metabolic antagonist; Antimitotic drug such as microtubule are stablized medicine and antimitotic vegeto-alkali; The platinum coordination complex; Antitumor antibiotics; Alkylating agent, for example mustargen and nitrosourea; Increta; For example AC class, androgens, anti-androgens, estrogens, anti-estrogens, aromatase inhibitor, GuRH-A and somatostatin analogs; And target is in by the relevant enzyme of overexpression and/or the specific metabolic pathway that in others and tumour cell, raised or the compound of acceptor; For example ATP and GTP phosphodiesterase inhibitor, kinases inhibitor; For example Serine, Threonine and tyrosine kinase inhibitor; For example Abelson protein tyrosine kinase and various growth factor, their acceptor and its SU11752, for example epidermal growth factor receptor kinase inhibitor, vascular endothelial growth factor receptor SU11752, fibroblast growth factor inhibitor, IGF-1 suppressor factor and platelet derived growth factor receptor kinase inhibitor etc.; Methionine(Met) aminopeptidase inhibitor, proteasome inhibitor, cyclooxygenase inhibitors, for example cyclo-oxygenase-1 or-2 suppressor factor, and histone deacetylase inhibitors.
Compound of the present invention can also combine with radiotherapy, immunotherapy, operative treatment or its and use.Be used for tumour alleviate or even chemoprophylaxis treatment after keep patient's states treatment (patient's who for example is at stake situation) also be possible.
Compound of the present invention not only is used for (prophylactically with preferred therapeutic property ground) treatment people, and is used to treat other warm-blooded animal, for example commercial useful warm-blooded animal, and rodent for example, like mouse, rabbit or rat, or cavy.
The present invention also comprises the pharmaceutical composition that comprises the carrier of approving on general formula (I) compound and the physiology.
The compounds of this invention can be through injection, suction or sprinkling or rectum, and per os, skin, parenteral give, or gives with the unit formulation formulation." injection gives " comprises vein, intramuscular, subcutaneous and parenteral injection, and uses infusion techn.Percutaneous drug delivery comprises external application or transdermal administration.One or more compounds can with one or more non-toxic carriers of pharmaceutically approving, and other activeconstituentss that depend on the needs coexistence.
Oral composition can be made the known appropriate method preparation in field according to any pharmaceutical composition.In order to improve the preparation mouthfeel, said compsn can contain one or more following reagent: thinner, sweeting agent, spices, tinting material and sanitas.Tablet contains activeconstituents, and they mix with the non-toxic excipients of pharmaceutically approving, be fit to tablet manufacturing.Said vehicle is inert diluent for example, lime carbonate for example, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example W-Gum or alginic acid; Tamanori, for example Magnesium Stearate, Triple Pressed Stearic Acid or talcum powder.Tablet can not have dressing, can wrap up with known technology yet, to postpone its disintegration and absorption in gi tract, secular continuous action is provided.For example, can adopt time-delay material such as glyceryl monostearate or distearin.Said compound also can be processed solid, releases form soon.
Oral prepns can also be a hard gelatin capsule; Activeconstituents wherein mixes with for example inert solid diluent such as lime carbonate, calcium phosphate or kaolin mutually; Or soft gelatin capsule, activeconstituents wherein is with water or for example peanut oil, whiteruss or olive wet goods oil mix.
Also can use and contain active substance and the suitable waterborne suspension of making the mixed with excipients of waterborne suspension.Said vehicle is a suspension agent, Xylo-Mucine for example, methylcellulose gum, hydroxypropyl-methylcellulose gum, sodiun alginate, PVP K120, tragakanta and Sudan Gum-arabic; Dispersion agent or wetting agent can be natural phospholipids; The condensation product of for example Yelkin TTS, or oxyethane and lipid acid, for example polyoxyethylene stearic acid ester; Or the condensation product of oxyethane and long chain aliphatic alcohol; For example 17 oxygen ethene cetyl alcohols, or oxyethane and the condensation product of lipid acid with partial ester that hexitol becomes, for example single oleic acid polyoxyethylene sorbitan ester.Waterborne suspension also can contain one or more sanitass, for example ethylparaben or n-propyl, one or more tinting materials, one or more spices and one or more sweeting agents, for example sucrose or asccharin.
Become in the dispersed powders or particle of waterborne suspension but be fit to add water, activeconstituents and dispersion agent or wetting agent, suspension agent mixes with one or more sanitass.Suitable dispersion agent or wetting agent and suspension agent can mentioned abovely be example.Can also contain other vehicle, for example sweeting agent, spices and tinting material.
The form of compound can also be non-aqueous liquid preparation, oily suspensions for example, and this can be through being suspended in activeconstituents peanut oil, sweet oil, til or peanut wet goods vegetables oil or such as preparing in the MO such as whiteruss.This oily suspensions can contain thickening material, for example beeswax, paraffinum durum or Tego Alkanol 16.In order to improve mouthfeel, can add above-mentioned sweeting agent and spices.Said compsn can be guaranteed the quality such as inhibitors such as xitix through adding.
The form of pharmaceutical composition of the present invention can also be an O/w emulsion.Oil phase can be such as sweet oil or peanut wet goods vegetables oil or MO such as liquid beeswax for example, or their mixture.Suitable emulsifying agent can be natural gums such as tragakanta and Sudan Gum-arabic, or natural phospholipid, for example soybean lecithin or Yelkin TTS; The partial ester that lipid acid and dewatering hexitol form, for example but the oleic acid SPAN; The condensation product of said partial ester and oxyethane, for example single oleic acid Sorbitan ethoxylate.Said emulsion also can contain sweeting agent and spices.
Sweeting agent obtain syrup and elixirs such as also available for example glycerine, W 166, sorbyl alcohol or sucrose.This type preparation also can contain demulcen, sanitas and spices and tinting material.
Pharmaceutical composition of the present invention is with known method preparation itself, for example through conventional mixing, granulation, moulding, dissolving or freeze drying process preparation.
The preferred solution that uses activeconstituents; Also can use suspension or dispersion-s in addition; Especially wait the aqueous solution, dispersion-s or the suspension opened; For example only containing active substance or containing active substance and carrier for example under the situation of the lyophilised compsns of N.F,USP MANNITOL, these formulations can prepare before use.Pharmaceutical composition can and/or comprise vehicle by sterilization; The for example salt and/or the buffer reagent of sanitas, stablizer, wetting agent and/or emulsifying agent, solubilizing agent, adjusting osmotic pressure; And with known method preparation itself, for example through conventional dissolving or freeze drying process preparation.Described solution or suspension can comprise for example Xylo-Mucine, CMC 99.5, VISOSE, Vinylpyrrolidone polymer or gelatin or solubilizing agent Tween 80 for example of tackify material.
Suspension in oil comprises vegetables oil, synthetic oil or semi-synthetic oil that routine is used to inject purpose as oily components.Can mention like liquid aliphatic acid esters especially; It comprises have 8 to 22, especially the longer chain fatty acid of 12 to 22 carbon atoms is as acid constituents; For example LAURIC ACID 99 MIN, tridecanoic acid, tetradecanoic acid, pentadecylic acid, palmitinic acid, margaric acid, Triple Pressed Stearic Acid, eicosanoic acid, docosoic acid or corresponding unsaturated acid; For example oleic acid, elaidic acid, erucic acid, brassidic acid or linolic acid; Randomly add inhibitor, for example vitamin E, β-Hu Luobusu or 3,5-two-tertiary butyl-4-hydroxy toluene.The alkoxide component of these fatty esters has maximum 6 carbon atoms, is single-or many-unit's alcohol, for example single-, two-or three-unit alcohol, for example methyl alcohol, ethanol, propyl alcohol, butanols or amylalcohol or their isomer, still especially terepthaloyl moietie and glycerine.Therefore, the example of the fatty ester that can mention has: OE, Isopropyl myristate, Wickenol 111 etc., but vegetables oil especially, for example oleum gossypii seminis, Prunus amygdalus oil, sweet oil, til, soya-bean oil and more particularly peanut oil.
Being prepared under the aseptic condition of injectable composition carried out with ordinary method, is introduced in ampoule for example or the bottle also under aseptic condition, to carry out with ordinary method with the sealing of container.
Being used for Orally administered pharmaceutical composition can for example obtain through following method: activeconstituents is mixed with one or more solid carriers; With the granulating mixture that obtains; If it is suitable; Core with mixture or particle processing (if desired, taking the circumstances into consideration to add other vehicle) one-tenth tablet or drageeing.
Suitable carriers is weighting agent especially; For example sugar is like lactose, sucrose, N.F,USP MANNITOL or Sorbitol Powder, cellulosis and/or calcium phosphate for example tricalcium phosphate or secondary calcium phosphate; Also have tackiness agent, for example starch such as corn, wheat, rice or yam starch, methylcellulose gum, Vltra tears, Xylo-Mucine and/or Vinylpyrrolidone polymer, and/or if desired; Disintegrating agent; The starch of mentioning for example also has CMS, cross-linked polyvinylpyrrolidone, Lalgine or its salt, for example sodiun alginate.Other vehicle is fluidity regulator and lubricant especially, for example silicic acid, talcum powder, Triple Pressed Stearic Acid or its salt, for example Magnesium Stearate or calcium stearate, and/or polyoxyethylene glycol or derivatives thereof.
The drageeing core can have suitable dressing; Optional enteric coating especially uses priming, and said priming can contain gum arabic, talcum powder, Vinylpyrrolidone polymer, polyoxyethylene glycol and/or titanium oxide; Or the dressing solution of use in suitable organic solvent or solvent mixture; Perhaps, use the solution of suitable cellulosis, for example cellulose acetate phthalate or hydroxypropylmethylcellulose phthalate for the preparation of enteric coating.Can in tablet or drageeing dressing, add tinting material or pigment, for example in order to differentiate purpose or in order to show the various dose of activeconstituents.
Be used for that Orally administered pharmaceutical composition also has hard gelatin capsule and by gelatin and the softening agent soft seal capsule formed of glycerine or sorbyl alcohol for example.Hard gelatin capsule can contain the activeconstituents of particle form, for example is mixed with weighting agent such as W-Gum, tackiness agent and/or glidant such as talcum powder or Magnesium Stearate and the activeconstituents of the particle form of stablizer randomly.In soft capsule; Activeconstituents preferred dissolution or be suspended in the suitable liquid excipient; The fatty ester of wax, Yellow Protopet 2A or liquid macrogol or terepthaloyl moietie or Ucar 35 for example; Can add stablizer and sanitising agent equally, for example the sanitising agent of Vykamol Sorbitol 8B class.
But the pharmaceutical composition of suitable rectal administration has for example suppository, and its mixture by activeconstituents and suppository base is formed.Suitable suppository base has for example natural or synthetic triglyceride level, paraffinic hydrocarbons, polyoxyethylene glycol or higher alkanols.
Use for parenteral, what especially be fit to is the aqueous solution of the activeconstituents of water-soluble form, for example water-soluble salt form, or the water-based injection suspension; It comprises tackify material; For example Xylo-Mucine, sorbyl alcohol and/or VISOSE, and if desired, also contain stablizer.Randomly the activeconstituents with vehicle also can be the form of lyophilized products, and it can be made into solution through adding suitable solvent before parenteral is used.
Being used for the solution that parenteral for example uses also can be used with the transfusion form.Preferred sanitas has for example inhibitor such as xitix or microbiocide such as Sorbic Acid or phenylformic acid.
All use in the regimen of general formula (I) compound in this article, and every day, oral dosage was good with the 0.01-200mg/kg body weight.Injection comprises vein, intramuscular, subcutaneous and parenteral injection and uses input technology, dosage every day be good with the 0.01-200mg/kg body weight.The per daily dose of rectal administration is good with the 0.01-200mg/kg body weight.External application every day dosage with every day 1 to 4 time, it is good not having each 0.1-200mg.Dosage every day that sucks is good with the 0.01-10mg/kg body weight.
Those skilled in the art will find out that concrete administering mode depends on multiple factor, and these are all considered in conventional administration often.Yet; It can also be seen that the concrete dosage of particular patient depends on the multiple factors such as severity of the activity, patient age, weight in patients, patient's general health, patient's sex, patient's diet, administration time, route of administration, the velocity of discharge, drug regimen and the current feelings of curing the disease that comprise used particular compound.Those skilled in the art also will find, the optimal treatment formula, and the therapeutic modality in promptly certain fate and the day administration number of times of general formula (I) compound or its salt of pharmaceutically approving, those skilled in the art can confirm with the conventional treatment test.
Obviously; Concrete patient's physical record level depends on multiple factor, comprises the severity of activity, patient age, weight in patients, patient's general health, patient's sex, patient's diet, administration time, route of administration, the velocity of discharge, drug regimen and the current feelings of curing the disease of used particular compound.
The compounds of this invention can be prepared through the for example civilian described general method in back by known compound (or with the raw material that can be made by known compound as initiator).Can civilian later on described domestic method measure the kinase whose activity of the known VEGFR-2 of each compound.Following examples for illustrative purposes only, and are and non-limiting.
General method
Compound of the present invention is to utilize the known method of those of ordinary skills to prepare according to the general reacting flow chart that is described below.
Scheme 1
Scheme 2
Part pharmacological testing method is following
Compound suppress kinase whose external biological activity usually by its antagonism kinases to external source substrate phosphorylation degree measure (Zhou S.et al.Nature 1995,373:536-539).
VEGRF-2 vitro inhibition active testing (Itokawa T.et al.Mol.Cancer Ther.2001,1:295-302)
VEGFR-2 be obtain behind SF9 cell expressing and the purifying the human recombinant kinases; Kinases or under the compound antagonism level of response of phosphorylated substrate (Fluoresence resonance energy trasnfer FRET) measures by the FRET method.Experiment is carried out on the 384-microwell plate, and TV is 10ul, is blended in sample compound, n-compound or water (contrast) and VEGFR-2 kinases earlier to contain Hepes/Tris (pH7.4), EGTA/Tris, MgCl
2, DTT and Tween 20 buffered soln.Phosphorylation reaction (begins behind Ulight-CAGAGAlETDKEYYTVKD (JAK1) and the ATP, carries out under the room temperature interrupting reaction with EDTA after 60 minutes at the adding substrate.After 5 minutes, add Eu-labelled-anti-phospho-PT66 in the micropore, measure microporous mixture respectively in wavelength 337nM, 620nM, and the fluorescence intensity of 655nM with ELIASA (Envision, Perkin Elmer) after 60 minutes.Kinase whose activity is directly proportional with the 655nm/620nM fluorescence intensity, be expressed as the percent inhibition with respect to control sample (water), and the substrate fluorescence intensity never adds kinase whose control wells and reads.Reaction IC
50Value is obtained by the compound kinases percent inhibition curve of 8 to 10 different concns, under this experiment condition, and the IC of n-compound staurosporine
50Be 3.5nM.
The IC of compound all gives an example
50All between 15nM to 1 μ M.N-(4-chloro-3-trifluoromethyl) phenyl-N '-((IC of urea of 4-(2-methylamino formyl radical pyridine-4-) oxygen) pyrimidine-2-) for example
50Be 15nM.
Embodiment
Below further explain or explanation content of the present invention, but embodiment should not be understood that the restriction to protection domain of the present invention through embodiment.
Embodiment 1
The preparation of 2-amino-5-(2-methylamino formyl radical pyridine-4-oxygen) pyrimidine
(341mg is 2mmol) with 2-amino-5-hydroxy pyrimidine (2mmol) and CsCO with N-methyl-4-chloropyridine-2-methane amide
3(6mmol) add among the DMSO (5mL), 80 ℃ were reacted 5 hours.Concentrating under reduced pressure, silicagel column purifying (eluent CHCl
3/ MeOH=100/8), get 2-amino-5-(2-methylamino formyl radical pyridine-4-oxygen) pyrimidine (white solid, 407mg, 83.0%)
Embodiment 2
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 4-(2-methylamino formyl radical pyridine-4-) oxygen) pyrimidine-2-)
(300mg 1.22mmol) is dissolved in dry DMF (5mL) to 2-amino-5-(2-methylamino formyl radical pyridine-4-oxygen) pyrimidine, and (184mg 6.12mmol), stirred 15 minutes 0 ℃ of adding 80%NaH.(406mg, 1.83mmol), 0 ℃ was stirred 1 hour to add 4-chloro-3-trifluoromethylbenzene based isocyanate then.Add water and chloroform, stirred 15 minutes, standing demix, organic layer is used water washing, MgSO
4Drying, concentrating under reduced pressure.Product is with silicagel column purifying (eluent CHCl
3/ MeOH=100/5), N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea (74mg, 13%) of 4-(2-methylamino formyl radical pyridine-4-) oxygen) pyrimidine-2-).1HNMR(DMSO-d6)：δ＝2.78(d，3H)，δ＝7.28(m，1H)，δ＝7.52(d，1H)，δ＝7.68(d，1H)，δ＝7.85(m，1H)，δ＝8.18(d，1H)，δ＝8.53(d，1H)，δ＝8.73(s，2H)，δ＝8.78(d，1H)，δ＝10.57(s，1H)，δ＝11.45(s，1H)。m/e＝466.80。
Embodiment 3
The preparation of 6-amino-4-(2-methylamino formyl radical pyridine-4-oxygen) pyrimidine
(300mg 2.31mmol) is dissolved in DMI to 4-chloro-6-aminopyrimidine, adds 4-hydroxy-n-picoline-2-methane amide (1.1eq), Pd
2(dba)
3(0.1eq) and x-phos (0.1eq) and potassium tert.-butoxide (3.0eq), 160 ℃, stirred 5 hours.Add water washing, product is used the silicagel column purifying, gets 6-amino-4-(2-methylamino formyl radical pyridine-4-oxygen) pyrimidine (white solid, 100mg, 18%).
Embodiment 4
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((6-(2-methylamino formyl radical pyridine-4-) oxygen) pyrimidine-4-) preparation of urea
With reference to embodiment 2, make by 6-amino-4-(2-methylamino formyl radical pyridine-4-oxygen) pyrimidine.1HNMR(DMSO-d6)：δ＝2.81(d，3H)，δ＝7.36(m，1H)，δ＝7.48(m，1H)，δ＝7.65(m，2H)，δ＝7.79(d，1H)，δ＝8.07(s，1H)，δ＝8.53(s，1H)，δ＝8.65(d，1H)，δ＝8.81(d，1H)，δ＝9.99(d，2H)。m/e＝466.80。
Embodiment 5
The preparation of 2-iodo-5-nitro-pyrimidine
2-chloro-5-nitro-pyrimidine (1.6g 10.0mmol) is dissolved in DCM (60mL), the ice bath cooling, and (47%, 16.5g 50mmol), stirred 1 hour under the room temperature, added K to add hydroiodic acid HI
2CO
3Solution, layering, water layer is used the DCM extracted twice.Organic phase merges, anhydrous MgSO
4Drying, concentrating under reduced pressure gets brown solid (1.3g, 51.8%).
Embodiment 6
The preparation of 5-nitro-2-((2-(methylamino formyl radical) pyridine-4-) oxygen) pyrimidine
2-iodo-5-nitro-pyrimidine (0.425g 1.69mmol) is dissolved in DMF (20mL), add successively cesium carbonate (0.826g, 2.54mmol) with 4-hydroxy-n-picoline-2-methane amide (0.2g, 1.31mmol).Stirring at room 2 hours is poured reaction mixture into solution of potassium carbonate, with ethyl acetate extraction twice, merges organic layer, and concentrating under reduced pressure gets brown solid (0.25g, 77.9%).
Embodiment 7
The preparation of 5-amino-2-((2-(methylamino formyl radical) pyridine-4-) oxygen) pyrimidine
5-nitro-2-((2-(methylamino formyl radical) pyridine-4-) oxygen) pyrimidine (0.25g, 0.91mmol) and Ra/Ni (0.1g) add in the methyl alcohol (20mL) stirred overnight at room temperature in nitrogen atmosphere.Filter, filtrate decompression concentrates.Product gets faint yellow solid (0.12g, 54.1%) with silicagel column purifying (eluent DCM/MeOH=8/1).
Embodiment 8
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((2-(2-methylamino formyl radical pyridine-4-) oxygen) pyrimidine-5-) preparation of urea
With reference to embodiment 2, make with 5-amino-2-((2-(methylamino formyl radical) pyridine-4-) oxygen) pyrimidine.1HNMR(CD
3OD)：δ＝2.97(s，3H)，δ＝7.38(m，1H)，δ＝7.52(d，1H)，δ＝7.66(m，1H)，δ＝7.87(d，1H)，δ＝7.99(d，1H)，δ＝8.61(d，1H)，δ＝8.82(s，2H)。m/e＝466.80。
Embodiment 9
The preparation of 2-bromo-5-((2-(methylamino formyl radical) pyridine-4-) oxygen) pyrazine
With reference to embodiment 6, with 2,5-two bromo-pyrazines make.
Embodiment 10
The preparation of 2-(4-methoxybenzyl amido)-5-((2-(methylamino formyl radical) pyridine-4-) oxygen) pyrazine
(0.2g 0.65mmol) joins in the 4-methoxybenzylamine (15eq) pyrazine 2-bromo-5-((2-(methylamino formyl radical) pyridine-4-) oxygen), adds CuI (0.1eq), Cs then successively
2CO
3(2.0eq), 125 ℃ were stirred 1 hour.Add ETHYLE ACETATE and water, layering, organic layer is used MgSO
4Drying, concentrating under reduced pressure, product gets faint yellow solid (77mg, 32%) with the silicagel column purifying.
Embodiment 11
The preparation of 2-amino-5-((2-(methylamino formyl radical) pyridine-4-) oxygen) pyrazine
(77mg 0.22mmol) is dissolved in TFA to 2-(4-methoxybenzyl amido)-5-((2-(methylamino formyl radical) pyridine-4-) oxygen) pyrazine, and 110 ℃ were stirred 3 hours, and underpressure distillation solvent, product use the silicagel column purifying, must faint yellow solid (30mg, 55%).
Embodiment 12
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((5-(2-methylamino formyl radical pyridine-4-) oxygen) pyrazine-2-) preparation of urea
With reference to embodiment 2, make with 2-amino-5-((2-(methylamino formyl radical) pyridine-4-) oxygen) pyrazine.1HNMR(DMSO-d6)：δ＝2.95(s，3H)，δ＝7.29(m，1H)，δ＝7.55(m，1H)，δ＝7.70(m，1H)，δ＝7.75(d，1H)，δ＝8.06(d，1H)，δ＝8.27(s，1H)，δ＝8.56(d，1H)，δ＝8.68(d，1H)。m/e＝466.80。
Embodiment 13
The preparation of 4-((2-nitrothiophene-5-) oxygen)-N-methyl-pyridine-2-carboxamide
(0.8g is 1.0eq) with N-methyl-4-pyridone-2-methane amide (1.0eq) and Cs for 5-bromo-2-nitrothiophene
2CO
3Be dissolved in the dry DMF, stirred 18 hours under the room temperature.Reaction mixture dilutes with ETHYLE ACETATE, adds the water extraction, tells organic phase, and water layer is used ethyl acetate extraction, merges organic layer, washing, MgSO
4Drying, concentrating under reduced pressure.Product with silicagel column purifying (PE/EA=10/1) 4-((2-nitrothiophene-5-) oxygen)-N-methyl-pyridine-2-carboxamide (0.3g, 32%).
Embodiment 14
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((5-(2-methylamino formyl radical pyridine-4-) oxygen) thiophene-2-) preparation of urea
(0.3g 1.0eq) is dissolved in THF to 4-((2-nitrothiophene-5-) oxygen)-N-methyl-pyridine-2-carboxamide, adds Raney's nickel; Logical hydrogen stirred 2 hours under the room temperature, added 4-chloro-3-trifluoromethylbenzene based isocyanate; Stirred 1 hour under the room temperature, concentrate, product is with silicagel column purifying (DCM/MeOH=50/1); N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea (0.07g, 15%) of 5-(2-methylamino formyl radical pyridine-4-) oxygen) thiophene-2-).1HNMR(DMSO-d6)：δ＝2.77(d，3H)，δ＝6.40(d，1H)，δ＝6.63(d，1H)，δ＝7.26(m，1H)，δ＝7.55(m，2H)，δ＝7.65(m，1H)，δ＝8.04(s，1H)，δ＝8.53(d，1H)，δ＝8.76(d，1H)，δ＝9.31(s，1H)，δ
Embodiment 15
3, the preparation of 5-two bromo-2-nitrothiophenes
Under-20 ℃, 3, the 5-dibromo thiophene (3.0g, 1.0eq) and H
2SO
4Mixture in add HNO3 (2.5eq), 0 ℃ was stirred 20 minutes, filter, drying under reduced pressure, faint yellow solid (3.5g, 98%).
Embodiment 16
The preparation of 4-((3-bromo-2-nitrothiophene-5-) oxygen)-N-methyl-pyridine-2-carboxamide
With reference to embodiment 13, with 3, the preparation of 5-two bromo-2-nitrothiophenes.
Embodiment 17
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((3-bromo-5-(2-methylamino formyl radical pyridine-4-) oxygen) thiophene-2-) preparation of urea
With reference to embodiment 14, make with 4-((3-bromo-2-nitrothiophene-5-) oxygen)-N-methyl-pyridine-2-carboxamide.1HNMR(DMSO-d6)：δ＝2.78(d，3H)，δ＝7.13(s，1H)，δ＝7.17(m，1H)，δ＝7.48(m，1H)，δ＝7.58(s，2H)，δ＝7.99(m，1H)，δ＝8.53(d，1H)，δ＝8.77(d，1H)，δ＝9.22(s，1H)，δ＝9.68(s，1H)。m/e＝549.75。
Embodiment 18
The preparation of 4-((3-cyanic acid-2-nitrothiophene-5-) oxygen)-N-methyl-pyridine-2-carboxamide
4-((3-bromo-2-nitrothiophene-5-) oxygen)-N-methyl-pyridine-2-carboxamide (0.37g, 1.0eq) and CuCN (1.5eq) add DMF, 160 ℃ were stirred 30 minutes, were chilled to room temperature, with ETHYLE ACETATE dilution, brine wash, MgSO
4Drying, concentrating under reduced pressure.Product is used the silicagel column purifying, 4-((3-cyanic acid-2-nitrothiophene-5-) oxygen)-N-methyl-pyridine-2-carboxamide (0.13g, 41%).
Embodiment 19
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((3-cyanic acid-5-(2-methylamino formyl radical pyridine-4-) oxygen) thiophene-2-) preparation of urea
With reference to embodiment 14, make with 4-((3-cyanic acid-2-nitrothiophene-5-) oxygen)-N-methyl-pyridine-2-carboxamide.1HNMR(DMSO-d6)：δ＝2.56(d，3H)，δ＝7.28(s，1H)，δ＝7.34(m，1H)，δ＝7.57(d，1H)，δ＝7.68(s，2H)，δ＝7.82(d，1H)，δ＝8.17(d，1H)，δ＝8.48(s，1H)。m/e＝496.60。
Embodiment 20
The preparation of 5-iodo-thiazolamine
5-chloro-thiazolamine (2.0g, 14.8mmol) and NaI (4.0g, (45%, 30mL), 80 ℃ were stirred 24 hours, were chilled to room temperature, added DCM and water respectively, divided water-yielding stratum, and organic layer is used Na 26.7mmol) to be dissolved in hydroiodic acid HI
2SO
4Drying, concentrating under reduced pressure.(PE/EA (10/1) gets 5-iodo-thiazolamine (0.195g, 5.8%) to product with the silicagel column purifying.
Embodiment 21
The preparation of 4-((thiazolamine-5-) oxygen)-N-picoline-2-methane amide
(0.4g, 1.77mmol) (0.268g 1.77mmol) is dissolved in DMF (30mL) to 5-iodo-thiazolamine, adds Cs with N-methyl-4-pyridone-2-methane amide
2CO
3(1.1g 3.37mmol), stirred under the room temperature 16 hours, concentrating under reduced pressure, product purification, 4-((thiazolamine-5-) oxygen)-N-picoline-2-methane amide (0.077g, 17.4%)
Embodiment 22
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((5-(2-methylamino formyl radical pyridine-4-) oxygen) thiazole-2-) preparation of urea
With reference to embodiment 2, make with 4-((thiazolamine-5-) oxygen)-N-picoline-2-methane amide.1HNR(DMSO-d6)：δ＝2.78(d，3H)，δ＝7.33(d，1H)，δ＝7.36(s，1H)，δ＝7.60(m，4H)，δ＝8.07(s，1H)，δ＝8.55(d，1H)，δ＝8.78(d，1H)，δ＝9.41(s，1H)。m/e＝471.80。
Claims (9)
1. formula (I) compound or its pharmacy acceptable salt:
Wherein:
R
1, R
2And R
3Be selected from halogen; Cyanic acid; Hydroxyl; Replace or unsubstituted C1-C6 straight chain; The C1-C6 branched-chain alkyl; The C3-C7 naphthenic base; The C6-C10 aryl; Contain one or more N of being selected from; S; The C6-C10 heteroaryl of O atom or C6-C10 heterocyclic radical; Wherein, Substituting group is selected from amino; Halogen; The C1-C6 alkyl; Hydroxyl; The C1-C6 alkoxyl group; Nitro; Cyanic acid; Sulfydryl; The C1-C6 alkylthio; Halogen-C1-C6 alkylthio; Heterocyclic radical; Heteroaryl; The heterocyclic radical alkyl; Heteroaryl C1-C6 alkyl; C1-C6 alkyloyl or formamyl
The A ring is for replacing or non-substituted pyrimidyl, pyrazinyl, pyridyl, thienyl or thiazolyl, and substituting group is selected from halogen, cyanic acid or hydroxyl.
2. formula (I) compound according to claim 1 or its pharmacy acceptable salt is characterized in that halogen is selected from fluorine, chlorine, bromine or iodine.
3. following compound or its pharmacy acceptable salt:
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 4-(2-methylamino formyl radical pyridine-4-) oxygen) pyrimidine-2-);
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 6-(2-methylamino formyl radical pyridine-4-) oxygen) pyrimidine-4-);
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 2-(2-methylamino formyl radical pyridine-4-) oxygen) pyrimidine-5-);
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 5-(2-methylamino formyl radical pyridine-4-) oxygen) pyrazine-2-);
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 5-(2-methylamino formyl radical pyridine-4-) oxygen) thiophene-2-);
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 3-bromo-5-(2-methylamino formyl radical pyridine-4-) oxygen) thiophene-2-);
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 3-cyanic acid-5-(2-methylamino formyl radical pyridine-4-) oxygen) thiophene-2-);
N-(4-chloro-3-trifluoromethyl) phenyl-N '-((urea of 5-(2-methylamino formyl radical pyridine-4-) oxygen) thiazole-2-).
4. according to any described compound of claim 1-3, it is formula (I) compound pharmacy acceptable salt, is selected from:
A) subsalt of organic acid and mineral acid; Said organic acid and mineral acid are selected from hydrochloric acid, Hydrogen bromide, sulfuric acid; Phosphoric acid, methylsulfonic acid, three fluosulfonic acid, Phenylsulfonic acid, tosic acid, 1-naphthalene sulfonic aicd, 2-naphthene sulfonic acid, acetate; Trifluoroacetic acid, oxysuccinic acid, tartrate, Hydrocerol A, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, phenylacetic acid or tussol; With
B) hydrogen salt of the organic and mineral alkali of cation, said positively charged ion are selected from alkali metal cation, alkaline earth metal cation, ammonium ion, aliphatic substituted ammonium ion or the substituted ammonium ion of aromatics.
5. be used to treat the pharmaceutical composition of cancer, comprise suitable carriers on any described compound of claim 1-3 or its pharmacy acceptable salt and the physiology.
6. any described compound of claim 1-3 or its pharmacy acceptable salt are used to make the purposes of the medicine that suppresses the kinase mediated cancerous cells growth of VEGFR-2.
7. any described compound of claim 1-3 or its pharmacy acceptable salt are treated the purposes on the Cancerous disease medicine in preparation.
The process of claim 7 wherein, wherein said cancer is substantive cancer, kidney cancer, lung cancer, breast cancer, liver cancer, ovarian cancer, pancreatic cancer, thyroid cancer, bladder cancer, leukemia, adenocarcinoma, melanoma, gastrointestinal cancer, colorectal cancer, endocrine cancer, kidney cancer, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), mesothelioma cancer, angiosarcoma, adrenal cortical carcinoma, endometrial cancer and glial tumors.
9. the described purposes of claim 8, wherein said cancer is kidney, liver cancer, lung cancer, lung cancer, colorectal carcinoma, gastrointestinal cancer, mammary cancer, gastrointestinal cancer and angiosarcoma.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2014040243A1 (en) * | 2012-09-12 | 2014-03-20 | 湖南有色凯铂生物药业有限公司 | N-substituted phenyl-n'-substituted heterocyclic urea compound and application thereof as anticancer medicament |
| CN107613984A (en) * | 2015-05-25 | 2018-01-19 | 和记黄埔医药（上海）有限公司 | Medical composition and its use |
| CN108440404A (en) * | 2018-05-08 | 2018-08-24 | 西安凯伦生物科技有限公司 | Antitumor drug and its preparation method and application with multiple kinase inhibitory activity |
| CN113292515A (en) * | 2021-06-04 | 2021-08-24 | 沈阳药科大学 | Urea compound containing piperazine group and preparation method and application thereof |
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| WO2006125540A1 (en) * | 2005-05-27 | 2006-11-30 | Bayer Healthcare Ag | Combination therapy comprising a diaryl urea compound and a pi3, akt kinase or mtor inhibitors (rapamycins) for cancer treatment |
| CN101475513A (en) * | 2009-01-20 | 2009-07-08 | 中国药科大学 | Raf and HDAC small molecular double inhibitor, and preparation and use thereof |
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| WO2006125540A1 (en) * | 2005-05-27 | 2006-11-30 | Bayer Healthcare Ag | Combination therapy comprising a diaryl urea compound and a pi3, akt kinase or mtor inhibitors (rapamycins) for cancer treatment |
| CN101475513A (en) * | 2009-01-20 | 2009-07-08 | 中国药科大学 | Raf and HDAC small molecular double inhibitor, and preparation and use thereof |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014040243A1 (en) * | 2012-09-12 | 2014-03-20 | 湖南有色凯铂生物药业有限公司 | N-substituted phenyl-n'-substituted heterocyclic urea compound and application thereof as anticancer medicament |
| CN107613984A (en) * | 2015-05-25 | 2018-01-19 | 和记黄埔医药（上海）有限公司 | Medical composition and its use |
| CN107613984B (en) * | 2015-05-25 | 2021-04-30 | 和记黄埔医药（上海）有限公司 | Pharmaceutical composition and use thereof |
| CN108440404A (en) * | 2018-05-08 | 2018-08-24 | 西安凯伦生物科技有限公司 | Antitumor drug and its preparation method and application with multiple kinase inhibitory activity |
| CN113292515A (en) * | 2021-06-04 | 2021-08-24 | 沈阳药科大学 | Urea compound containing piperazine group and preparation method and application thereof |
| CN113292515B (en) * | 2021-06-04 | 2022-05-20 | 沈阳药科大学 | Urea compound containing piperazine group and preparation method and application thereof |
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