CN102408426B - Substituted aromatic urea compound and application as anticancer medicament thereof - Google Patents
Substituted aromatic urea compound and application as anticancer medicament thereof Download PDFInfo
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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
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Abstract
The invention relates to substituted aromatic urea compounds as shown in formula (I) or (II) which can be used as a VEGFR-2 kinase inhibitor, and their application in preparation of medicaments for treating VEGFR-2 mediated diseases. Formula 1, Formula 2, are disclosed, wherein, R1, R2 and R3 are selected from trifluoromethyl or trifluoromethoxy.
Description
Invention field
The present invention relates to the aryl urea compound as the replacement of kinase inhibitor such as VEGFR-2, and they are for the preparation of the purposes in the disease mediated medicine of kinases such as treatment VEGFR-2.
Background technology
Along with the further investigation to oncomolecularbiology, become the important component part of antineoplaston by the targeted therapy method that multiple carcinogenic protein kinases is suppressed, and in all kinds of tumor treatment, obtained major progress.In cell, protein kinase is by passing on and amplification message growth, differentiation and the apoptosis of control cell to the phosphorylation of upstream 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 by 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 the combination of Urogastron (EGF) and cytolemma upper epidermis growth factor receptors (EGFR), EGFR is in SH2 position, the position of its phosphorylation and adapter protein GRB2 (growth factor receptor-bound protein 2) combination, recruiting guanylic acid exchange factor SOS albumen and Ras is combined on the adjacent inner cell film, GTP substitutes the GDP of being combined with Ras and intensifies Ras, 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 is combined 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, enter in the nucleus and direct activating transcription factor, start the biological procedureses such as growth, differentiation and apoptosis of cell.In case excessive activation takes place this path, 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 may be activated by different upstreams albumen or suppress and form an extremely complicated network regulation structure.For example, the Raf on the Raf/MEK/ERK signal path and ERK also can bring into play its signal transduction regulating effect by the mode that does not rely on Ras; The activity of Ras can cause that also the minimizing of GTP hydrolysis improves by 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 the downstream, S6kinase (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 more than 50 kind of known oncogene, major part is protein kinase gene (Manning et al.Sicence, 2002,298,1912).The cancer gene is in repressed state usually, but when they undergo mutation or by abnormal activation after, for example under the effect of chemical toxicant, long-term ultraviolet lighting or radioactive substance, oncogene can excessively be expressed kinases, or the kinases of expressing 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).At kinases out of control on the cell signal path or somatomedin etc. as drug target, research and development small molecules or macromole inhibitor, 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.Adi jel; 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 have unusual high C-raf activity 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 kinase inhibitor usually can while antagonism B-ref, C-raf and B-raf-V600E.Xarelto (Sorafenib) by Bayer research and development is in the RAF kinase inhibitor 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 growth and transfer (the Keating GM of anticancer by while antagonism RAF kinases and several vasculogenesis growth factor acceptor (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-inducible factor-1 α, HIF-1 α); HIF-1 α stimulates the expression of cell growth factors such as VEGF and PDGF-β synthetic again, and the new vessel that participates in tumor tissues generates.In addition, most kidney tool EGFR expresses, and the expression degree is relevant with prognosis, and HIF-1 α is combined with EGFR by activating the effect of TGF-α generation autocrine, thereby promotes cell proliferation and existence.The no matter combination of which kind of somatomedin and its acceptor, all need usually by 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 namely proposed growth and the transfer (metastasis) that vasculogenesis theory (Angiogenesis) is explained tumour.Their experiment shows the vascular endothelial growth factor inhibitor, 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, cancer cells secretes acceptor (VEGFR) combination that vascular endothelial growth factor (VEGF) and cell are touched, 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 moved forward, increases, forms canalization vascular circle and new basilar membrane, finally forms new vessel.Document shows that further multiple different somatomedin participates in newborn tumor vascular formation simultaneously; Except VEGF, also have Thr6 PDGF BB (Platelet-derived growth factor, PDGF) and fibroblast growth factor (Fibroblast Growth Factor, FGF) etc.Somatomedins such as the PDGF of cancer cells secretion and FGF help the formation of new vessel by 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, vascular stroma imperfection, perviousness height, so tumour cell is penetrated in the blood, spreads and be attached to that growth and breeding forms cancer metastasis (metastasis) 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 mainly participates in newborn vasculolymphatic formation (Lymphangiogenesis), in the process that cancer shifts by lymphsystem, play the part of important role, these acceptors can increase and the target spot (Steven A.Stacker.Lymphangiogenesis in Cancer metastasis, Springer.2009 pp.27-) that shifts as the antagonism parenchymal tumor.
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 examples have all proved with small molecules or macromolecular drug and suppressed the curative effect that kinases or somatomedin 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 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) medicine for treatment (Gambacorti-Passerini C.Lancet Oncology 2008,9 (600): 600), imatinib has proved the feasibility of kinase inhibitor for treating cancer first, 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 growth and the division of cell by the bcr-abl kinases of overexpression in the antagonism leukaemia cancer cell; Its while is the kinase whose activity of antagonism c-kit also, and shows that clinically it to the curative effect of gi tract Leydig's cell tumor, 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.
Gefitinib (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 Gefitinib.2004, Tarceva (erlotinib) was developed jointly in Genentech and OSI 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 for the treatment of and sequential therapy.Gefitinib and Tarceva are EGF-R ELISA (EGFR) inhibitor, the antagonism cell surface is striden the combination of EGFR acceptor and Urogastron (EGF) on the film and is suppressed signalling channels such as Raf/MEK/ERK (the Raymond E of EGFR transduction, Faivre S, Armand J.Drugs 2000,60Suppl 1:15-23; Discussion41-2).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 for the treatment of kidney (RCC), Sutent is by antagonizing vessel endothelium cell growth factor acceptor (VGEFR), and the formation of anticancer new vessel delays 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 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, B, Hidalgo M.Curr.Opin.Investig.Drugs 2006,7:501-512).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 is clinical to be the rapamycin derivative sirolimus (Temsirolimus) of U.S. Hui Shi pharmaceutical development with the mTOR inhibitor, is the medicine for treatment of kidney by FDA approval in 2007.
Lapatinibditosylate (Lapatinib) is 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.Cancerresearch 2004,64 (18): 6652-9) in 2010 again.
Because kinase whose high homology and diversity, the small molecules cancer therapy drug of research and development mostly is multiple kinase inhibitor greatly at present, different with former worry fortunately, and lower kinases selectivity does not influence the curative effect of medicine; On the contrary, preferred multiple kinase inhibitor may be more conducive to resist complex genesis, various informative cancer, and can use by a medicine more.
Different with small molecules kinase inhibitor multiplicity is that normally only at the special inhibitor of single target spot in the cell signal passage, a plurality of clinical examples 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 somatomedin (VGEF) specifically, suppresses the formation of cancer new vessel, and can promote chemotherapeutics to infiltration (the Los M et al.The Oncologist 2007,12 (4): 443-50) of 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 come the signalling channel of anticancer growth division by the combination with EGF-R ELISA (EGFR).Cetuximab (IgG1) and handkerchief Buddhist nun monoclonal antibody (IgG2) belong to the different subtype of immunoglobulin (Ig), and there is fine distinction in they at anticancer mechanism, and except 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 example full proof with kinase inhibitor antagonism cancer cells signalling channel out of control, the feasibility for the treatment of various cancers.Yet cancer is one of the most complicated disease, and each organ of health all may form the different cancer of structure organizations by various mechanism, and a lot of cancers are that the 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 diversity of form structure make its treatment various challenges abrim all the time, 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 constantly development structure novelty, different, the better novel targeted medicine of drug effect of function, carry out the preferably combination of medicine according to signal path and cancer genetics information, improve the curative effect of cancer therapy.
Vascular endothelial growth factor (VEGF) is most important cell growth factor in the tumor-blood-vessel growth process, tumor vessel is extremely sensitive to VEGF, VEGF mRNA concentration is higher than normal cell significantly in a lot of tumour cells, these tumours comprise lung cancer (Mattern et al.Br.J Cancer 1996,73,93,1), thyroid carcinoma (Viglietto et al.Oncogene 1995,11,1569), mammary cancer (Brown et al.Human Pathol.1995,26,86) Wei Intestinal cancer (Brown et al.Cancer Res.1993,53,4727; Suzuki et al.Cancer Res.1996,56,3004), kidney and bladder cancer (Brown et al.Am.J Palhol.1993,143L 1255), ovarian cancer (Olson et al.Cancer Res.1994,54,1255), cervical cancer (Guidi et al.J Nat ' l Cancer30Inst.1995,87,12137) and angiosarcoma (Hashimoto et al.Lab.Invest.1995,73,859) and multiple intracranial tumors (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 inhibitor (as 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.
WO-2004007458 discloses one group of 2-alkanamine nicotinamide derivates as VEGFR, PDGFR and Kit inhibitor, is used for the treatment of non-squamous nonsmall-cell lung cancer in clinical three phases test, and other indication comprises essence cancer Wei Intestinal cancer, colorectal carcinoma, internal secretion cancer, mammary cancer and lung cancer.
WO-2004113304 discloses one group of indazole, benzisoxa azoles and benzothiazole derivant as CSFR-1, PDGFR, Flt3, Kit, VEGFR-1, VEGFR-2, VEGFR-3 inhibitor, in clinical three phases test, be used for the treatment of liver cancer, second phase is clinical in nonsmall-cell lung cancer, 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 derivatives as Kit, PDGFR section acceptor, VEGFR-1, VEGFR-2, VEGFR-3 inhibitor, in clinical three phases test, be used for the treatment of kidney, other clinical experiment comprises mammary cancer, colorectal carcinoma Wei Intestinal cancer, nonsmall-cell lung cancer and liver cancer etc.
WO-200102369 discloses one group of indazole derivatives as CSFR-1, PDGF, VEGF-1, VEGF-2 and VEGF-3 inhibitor, in clinical three phases test, be used for the treatment of kidney, second phase clinical experiment Bao Kuo Inter skin cancer, angiosarcoma, adrenal cortical adenocarcinoma and liver cancer etc.
WO-200232872 discloses one group of novel quinoline-urea derivatives as VEGFR-2, VEGFR-3, FGFR1-4 and RET inhibitor, be used for the treatment of thyroid carcinoma in clinical three phases test, 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 inhibitor are used for the treatment of melanoma.
Chinese patent CN101475513A, CN101260106A and CN101735215A also disclose the purposes of three kinds of raf kinase inhibitor substituted bisarylurea compounds on the treatment cancer.
The invention summary
The present invention relates to general formula (I) (II) compound or its pharmacy acceptable salt, and treatment patient's method, this method comprises to the patient uses general formula (I) (II) compound or its pharmacy acceptable salt that suppresses kinases significant quantities such as VEGFR-2.
The present invention relates to the aryl urea compound of kinase whose replacements such as a kind of VEGFR-2 of inhibition, it is (II) described compound or its pharmacy acceptable salt of general formula (I):
Formula (I)
Formula (II)
Wherein:
R
1, R
2And R
3Can be connected individually or simultaneously and form a substituting group, disubstituted or three substituting group products on the phenyl ring;
R
1, R
2And R
3Further be selected from halogen, cyano group, hydroxyl, replacement or unsubstituted alkyl, alkoxyl group, cycloalkyl, aryl, heteroaryl or heterocyclic radical respectively;
R
1, R
2And R
3Further be selected from halogen, cyano group, hydroxyl, replacement or unsubstituted low alkyl group, lower alkoxy, low-grade cycloalkyl, C6-C20 aryl, C6-C20 heteroaryl or C6-C20 heterocyclic radical respectively;
R
1, R
2And R
3Further be selected from halogen, cyano group, hydroxyl, replacement or unsubstituted C1-C6 straight chain, C1-C6 branched-chain alkyl, C3-C7 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl respectively or contain the C6-C10 heterocyclic radical of one or more N of being selected from, S, O atom;
R
1, R
2And R
3More preferably fluorine, chlorine, methyl, ethyl, cyano group, hydroxyl, the tertiary butyl, cyclopropyl or cyclobutyl, phenyl, pyridyl, pyrryl or piperazinyl;
R
1, R
2And R
3Can also be preferably cyano group, hydroxyl, trifluoromethyl, methoxyl group or trifluoromethoxy.
Described halogen is selected from fluorine, chlorine, bromine or iodine, preferred fluorine or iodine.
Described substituting group is selected from amino, halogen, C1-C6 alkyl, hydroxyl, C1-C6 alkoxyl group, nitro, cyano group, 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 be replaced.
The preferred particular compound of the present invention or its pharmacy acceptable salt have:
N-(3-trifluoromethyl-4-chlorine) phenyl-N '-(4-(8-methylamino--1,7-naphthyridines-4-oxygen base) phenyl) urea N-(3-trifluoromethyl-4-chlorine) phenyl-N '-(3-(8-methylamino--1,7-naphthyridines-4-oxygen base) phenyl) urea
The present invention relates to formula (I) (II) compound or its pharmacy acceptable salt, these salt are selected from:
A) subsalt of organic acid and mineral acid, described 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, acetic acid, trifluoroacetic acid, oxysuccinic acid, tartrate, citric acid, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, phenylacetic acid or tussol; With
B) acid salt of the organic and mineral alkali of cation, described positively charged ion are selected from the ammonium ion of alkali metal cation, alkaline earth metal cation, ammonium ion, aliphatic series replacement or the ammonium ion that aromatics replaces.
The present invention is used for the treatment of the pharmaceutical composition of cancer, comprises (II) suitable carriers on compound or its pharmacy acceptable salt and the physiology of formula (I).
Compound of the present invention or its pharmacy acceptable salt can be used for making the purposes of the medicine that suppresses kinase mediated cancerous cells growth such as VEGEFR-2 and shift.
Compound of the present invention or its pharmacy acceptable salt can also be in the purposes for preparing on the treatment Cancerous disease medicine.
Cancer of the present invention comprises essence cancer, kidney, lung cancer, mammary cancer, liver cancer, ovarian cancer, carcinoma of the pancreas, thyroid carcinoma, bladder cancer, leukemia, gland cancer, melanoma, Wei Intestinal cancer, colorectal carcinoma, internal secretion cancer, kidney, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), Inter skin cancer, angiosarcoma, adrenal cortical adenocarcinoma, carcinoma of endometrium and neurospongioma etc.Especially treating effective cancer is kidney, liver cancer, lung cancer, lung cancer, colorectal carcinoma, Wei Intestinal cancer, mammary cancer, Wei Intestinal cancer and angiosarcoma etc.
In the context of content of the present invention, unless otherwise indicated, otherwise be used for to describe herein general formula (I) (II) generic term of compound have 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 maximum values, preferred 1 to 6 and comprise the group of 6 carbon atoms of maximum value at the most, and described 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, cyano group, lower alkoxy, C
3-C
7Cycloalkyl, amino or single-or two-low-grade alkyl amino replace.
Halogen-low alkyl group, halogen-lower alkoxy, halogen-lower alkylthio etc. refer to have moieties, wherein moieties is replaced the substituting group that replaces to fully by the halogen list.Halogen-low alkyl group, halogen-lower alkoxy are included within the lower alkoxy of low alkyl group, replacement of replacement.
The preferred fluorine of halogen, chlorine, bromine or iodine, more preferably fluorine, chlorine or bromine, particularly fluorine.
Phenyl generally is unsubstituted phenyl or the phenyl that replaced by 1-5, preferred 1 or 2 substituting group.Suitable substituting group includes but not limited to amino; single-or the amino (wherein low-grade alkyl substituent can be unsubstituted or further as above those listed substituting groups of alkyl be replaced) that replaces of two-low alkyl group; halogen; low alkyl group; the low alkyl group that replaces; hydroxyl; lower alkoxy; the lower alkoxy that replaces; nitro; cyano group; sulfydryl; lower alkylthio; halogen-lower alkylthio; heterocyclic radical; heteroaryl; the heterocyclic radical alkyl; heteroarylalkyl; low-grade alkane acidyl; formamyl and N-list-or N; the formamyl that N-two-low alkyl group replaces, wherein low-grade alkyl substituent can be unsubstituted or further be replaced.
Be R1, the R2 of phenyl and the preferred unsubstituted phenyl of R3 or the phenyl that replaced by one or more substituting groups, preferred three at the most, a preferred substituting group.The substituting group that R1, R2 and R3 phenyl are even more important comprises amino, list-or the lower alkylthio of lower alkoxy, nitro, cyano group, sulfydryl, lower alkylthio and the replacement of the low alkyl group of two-low-grade alkyl amino (wherein alkyl is unsubstituted or substituted), halogen, low alkyl group, replacement, hydroxyl, lower alkoxy, replacement.
R for phenyl
1, R
2And R
3Preferred unsubstituted phenyl or the phenyl that is replaced by one or two identical or different substituting group, described 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, for example trifluoromethoxy or 1,1,2,2-tetrafluoro oxyethyl group; More preferably by the phenyl of a substituting group replacement, described substituting group is selected from low alkyl group unsubstituted or that replace, preferable methyl, halogen-low alkyl group, for example trifluoromethyl, the unsubstituted or lower alkoxy that replaces, preferred methoxyl group and halogen-lower alkoxy, preferred trifluoromethoxy.
Important R1, R2 and R3 phenyl comprise the phenyl that unsubstituted phenyl and lower alkoxy replace, the phenyl that preferred wherein lower alkoxy replaces.
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 amino that replaces of two-low alkyl group, wherein alkyl is unsubstituted or by halogen, hydroxyl, nitro, cyano group, lower alkoxy, C
3-C
7Cycloalkyl, 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 low alkyl group unsubstituted or that replace.Heterocyclic radical comprises morpholino, parathiazan generation, piperidyl, piperazinyl etc.
Pharmacy acceptable salt preferred formula (I) is the pharmaceutically useful acid salt of compound (II).This class salt is (II) compound formation of the formula (I) by having basic nitrogen atom for example, acid salt for example, the preferred acid salt that 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; acetic acid for example; propionic acid; sad; capric acid; dodecylic acid; oxyacetic acid; lactic acid; the 2-hydroxybutyric acid; glyconic acid; fumaric acid; Succinic Acid; hexanodioic acid; pimelic acid; suberic acid; nonane diacid; oxysuccinic acid; tartrate; citric acid; saccharic acid; tetrahydroxyadipic acid; amino acid; L-glutamic acid for example; aspartic acid; sarcosine; ethanoylaminoethanoic acid; N-ethanoyl l-asparagine; the N-acetylcysteine; pyruvic acid; etheric acid; phosphoserine; 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; the 5-trimethoxybenzoic acid; the 2-phenoxy benzoic acid; the 2-acetoxy-benzoic acid; the 4-aminosallcylic acid; phthalic acid; phenylacetic acid; glucuronic acid; galacturonic acid; methane-or ethane-sulfonic acid; the 2-hydroxyethanesulfonic acid; ethane-1; the 2-disulfonic acid; Phenylsulfonic acid; the 2-naphthene sulfonic acid; 1; the 5-naphthalene disulfonic acid; N-cyclohexyl thionamic acid; the N-methyl-; the N-ethyl-or N-propyl group-thionamic acid; or other organic protonic acid, for example xitix.
The present invention relates to the aryl urea compound compound as the replacement of kinase inhibitor such as VEGER-2, and they are for the preparation of the purposes in the disease mediated medicine of kinases such as treatment VEGFR-2.
Described patient is Mammals, generally is the people.
Compound of the present invention can be used for treating mammalian cancer, preferred human cancer includes but not limited to malignant melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, liver cancer, lung cancer, kidney, carcinoma of the pancreas, glioblastoma, spinal cord proliferative disease, mesothelioma, Wei Intestinal cancer, mammary cancer and angiosarcoma etc.Compound of the present invention also can be used for treating the inflammatory diseases that kinases such as VEGFR-2 mediate, and comprises rheumatoid arthritis, retinopathy (comprising diabetic retina neural disease and macular degeneration), cardiovascular disorder and metabolic trouble.
General formula of the present invention (I) (II) compound or its pharmacy acceptable salt has aforesaid valuable pharmacological character.
A) subsalt of organic acid and mineral acid, described 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, acetic acid, trifluoroacetic acid, oxysuccinic acid, tartrate, citric acid, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, phenylacetic acid and tussol; With
B) acid salt of the organic and mineral alkali of cation, described positively charged ion is selected from alkali metal cation, alkaline earth metal cation, ammonium ion, the ammonium ion that the ammonium ion that aliphatic series replaces and aromatics replace.
General formula of the present invention (I) (II) compound pharmacy acceptable salt is pharmaceutically useful acid salt.This class salt is (II) compound formation of the formula (I) by having basic nitrogen atom for example, acid salt for example, preferably acid salt, the especially pharmacologically acceptable salt that forms 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; methylsulfonic acid for example; three fluosulfonic acid; Phenylsulfonic acid; tosic acid; 1-naphthalene sulfonic aicd; the 2-naphthene sulfonic acid; acetic acid; trifluoroacetic acid; oxysuccinic acid; tartrate; citric acid; 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; the 2-hydroxybutyric acid; glyconic acid; Succinic Acid; hexanodioic acid; pimelic acid; suberic acid; nonane diacid; saccharic acid; tetrahydroxyadipic acid; perhaps amino acid; L-glutamic acid for example; aspartic acid; sarcosine; ethanoylaminoethanoic acid; N-ethanoyl l-asparagine; the N-acetylcysteine; pyruvic acid; etheric acid; phosphoserine; 2-or 3-Phosphoric acid glycerol esters; hydroxymaleic acid; methyl-maleic acid; naphthenic acid; 1-or 3-hydroxyl naphthalene-2-formic acid; 3; 4; the 5-trimethoxybenzoic acid; the 2-phenoxy benzoic acid; the 2-acetoxy-benzoic acid; the 4-aminosallcylic acid; phthalic acid; phenylacetic acid; glucuronic acid; galacturonic acid; methane-or ethane-sulfonic acid; the 2-hydroxyethanesulfonic acid; ethane-1; the 2-disulfonic acid; 1; the 5-naphthalene disulfonic acid; N-cyclohexyl thionamic acid; the N-methyl-; the 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 kinase inhibitor etc.; Cytotoxic drug, metabolic antagonist for example is as purine and pyrimidine analogue metabolic antagonist; Antimitotic drug such as microtubule are stablized medicine and antimitotic alkaloid; The platinum coordination complex; Antitumor antibiotics; Alkylating agent, for example mustargen and nitrosourea; Increta, adrenal corticoid class for example, 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 raised in other side and tumour cell or the compound of acceptor, for example ATP and GTP phosphodiesterase inhibitor, kinases inhibitor, Serine for example, Threonine and tyrosine kinase inhibitor, for example Abelson protein tyrosine kinase and various somatomedin, their acceptor and its kinase inhibitor, for example epidermal growth factor receptor kinase inhibitor, the vascular endothelial growth factor receptor kinase inhibitor, fibroblast growth factor inhibitor, IGF-1 inhibitor and platelet derived growth factor receptor kinase inhibitor etc.; Methionine(Met) aminopeptidase inhibitor, proteinase inhibitor, cyclooxygenase inhibitors, for example cyclo-oxygenase-1 or-2 inhibitor, 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 the 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 ground) treatment people, and is used for the treatment of other warm-blooded animal, commercial useful warm-blooded animal for example, and rodent for example, as mouse, rabbit or rat, or cavy.
The present invention also comprises the pharmaceutical composition that comprises the carrier that general formula (I) (II) approves on compound and the physiology.
The compounds of this invention can be by 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, described composition 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.Described vehicle is inert diluent for example, calcium 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, 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, provides long-term continuous action.For example, can adopt time-delay material such as glyceryl monostearate or distearin.Described compound also can be made solid, releases form soon.
Oral preparations can also be hard gelatin capsule, activeconstituents wherein mixes mutually with for example inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, 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.Described vehicle is suspension agent, Xylo-Mucine for example, methylcellulose gum, hydroxypropyl-methylcellulose gum, sodiun alginate, Polyvinylpyrolidone (PVP), tragakanta and Sudan Gum-arabic; Dispersion agent or wetting agent can be natural phospholipids, Yelkin TTS for example, or the condensation product of oxyethane and lipid acid, polyoxyethylene stearic acid ester for example, 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 ethyl p-hydroxybenzoate 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 and one or more sanitass mix.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 by being suspended in activeconstituents peanut oil, sweet oil, sesame oil or peanut wet goods vegetables oil or such as preparing in the mineral oil such as whiteruss.This oily suspensions can contain thickening material, for example beeswax, paraffinum durum or hexadecanol.In order to improve mouthfeel, can add above-mentioned sweeting agent and spices.Described composition can be guaranteed the quality such as antioxidants such as xitix by adding.
The form of pharmaceutical composition of the present invention can also be O/w emulsion.Oil phase can be such as sweet oil or peanut wet goods vegetables oil or mineral oil 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 Isosorbide Dinitrate; The condensation product of described partial ester and oxyethane, for example single oleic acid Sorbitan ethoxylate.Described emulsion also can contain sweeting agent and spices.
Also sweeting agent obtain syrup and elixirs such as available for example glycerine, polypropylene glycol, sorbyl alcohol or sucrose.This class 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 by conventional mixing, granulation, moulding, dissolving or freeze drying process preparation.
The preferred solution that uses activeconstituents, also can use suspension or dispersion in addition, especially wait the aqueous solution, dispersion or the suspension opened, for example only containing active substance or containing active substance and carrier for example under the situation of the lyophilised compositions of N.F,USP MANNITOL, these formulations can prepare before use.Pharmaceutical composition can be sterilized and/or be comprised vehicle, 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 by conventional dissolving or freeze drying process preparation.Described solution or suspension can comprise for example Xylo-Mucine, carboxymethyl cellulose, dextran, polyvinylpyrrolidone or gelatin or solubilizing agent Tween 80 for example of tackify material.
Suspension in oil comprises conventional vegetables oil, synthetic oil or the semi-synthetic oil of injection purpose of being used for as oily components.Can mention as liquid aliphatic acid esters especially, its comprise have 8 to 22, especially the longer chain fatty acid of 12 to 22 carbon atoms is as acid constituents, for example lauric acid, tridecanoic acid, tetradecanoic acid, pentadecylic acid, palmitinic acid, margaric acid, 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 antioxidant, for example vitamin-E, β-Hu Luobusu or 3,5-, two-tertiary butyl-4-hydroxy toluene.The alkoxide component of these fatty acid 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 ethylene glycol and glycerine.Therefore, the example of the fatty acid ester that can mention has: ethyl oleate, Isopropyl myristate, Wickenol 111 etc., but vegetables oil especially, for example oleum gossypii seminis, Prunus amygdalus oil, sweet oil, sesame oil, soya-bean oil and more particularly peanut oil.
The preparation of injectable composition is carried out with ordinary method under aseptic condition, is introduced in ampoule for example or the bottle and the sealing of container is also carried out with ordinary method under aseptic condition.
Being used for Orally administered pharmaceutical composition can for example obtain by the 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 as lactose, sucrose, N.F,USP MANNITOL or Sorbitol Powder, cellulosics and/or calcium phosphate for example tricalcium phosphate or secondary calcium phosphate, also has tackiness agent, for example starch such as corn, wheat, rice or yam starch, methylcellulose gum, Vltra tears, Xylo-Mucine and/or polyvinylpyrrolidone, and/or if desired, disintegrating agent, above-mentioned starch for example, also have carboxymethyl starch, 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, 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 use priming, described priming can contain gum arabic, talcum powder, polyvinylpyrrolidone, polyoxyethylene glycol and/or titanium dioxide, or the dressing solution of use in suitable organic solvent or solvent mixture, perhaps for the preparation of enteric coating, use the solution of suitable cellulosics, for example cellulose acetate phthalate or hydroxypropylmethylcellulose phthalate.Can add tinting material or pigment in tablet or the drageeing dressing, 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 acid ester of fatty oil, paraffin oil or liquid macrogol or ethylene glycol or propylene glycol 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 dextran, 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 by adding suitable solvent before parenteral is used.
The solution of using for for example parenteral also can be used with the transfusion form.Preferred sanitas has for example antioxidant such as xitix or microbicide such as Sorbic Acid or phenylformic acid.
All use general formulas (I) (II) in the treatment plan of 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 often in conventional administration.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, i.e. and (II) the day administration number of times of compound or its salt of pharmaceutically approving of therapeutic modality in certain fate and general formula (I), those skilled in the art can determine 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 by for example hereinafter described general method by known compound (or with the raw material that can be made by known compound as initiator).Can hereinafter described common method measure the kinase whose activity of each compound inhibition VEGFR-2.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 general reacting flow chart as described below.
Scheme 1
Scheme 2
Part pharmacological testing method is as follows
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 (fluorescence resonance energy transfer) method.Experiment is carried out at the 384-microwell plate, and cumulative volume is 10ul, sample compound, n-compound or water (contrast) and VEGFR-2 kinases is blended in to contain Hepes/Tris (pH7.4), EGTA/Tris, MgCl earlier
2, DTT and Tween 20 buffered soln.Phosphorylation reaction (begins behind Ulight-CAGAGAIETDKEYYTVKD (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 microplate reader (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 for example
50Be respectively 47nM and 94nM.
Embodiment
Below further explain and describe content of the present invention by embodiment, but embodiment is not to be construed as limiting the scope of the invention.
Embodiment 1
4-chloro-8-methylamino--1, the preparation of 7-naphthyridines
With 4,8-, two chloro-1, (500mg 3.1mmol) adds MeNH to the 7-naphthyridines
2THF solution (2M, 3.0eq) in, 100 ℃ were stirred 6 hours.Decompression steams solvent, adds ethyl acetate and K
2CO
3Solution, layering, organic layer MgSO
4Drying, concentrating under reduced pressure, gained solid directly carry out next step reaction.
Embodiment 2
4-((4-amino-benzene) oxygen base)-8-methylamino--1, the preparation of 7-naphthyridines
4-chloro-8-methylamino--1, (100mg 0.9mmol) is dissolved in DMSO to the 7-naphthyridines, adds t-BuOK (1.1eq), and stirring at room 30 minutes adds 4-amino-phenol (1.0eq), and 60 ℃ were stirred 2 hours, and were cooled to room temperature.Add ethyl acetate and water, layering, organic layer concentrating under reduced pressure, the white solid of silicagel column purifying (120mg, 50%).
Embodiment 3
The preparation of N-(3-trifluoromethyl-4-chlorine) phenyl-N '-(4-(8-methylamino--1,7-naphthyridines-4-oxygen base) phenyl) urea
4-((4-amino-benzene) oxygen base)-8-methylamino--1, (120mg 0.44mmol) is dissolved in methylene dichloride with 3-trifluoromethyl-4-chloro-phenyl-isocyanic ester (1.0eq) to the 7-naphthyridines, stirring at room 4 hours, decompression steams solvent, and the silicagel column purifying gets white solid (60mg, 33%).1HNMR(DMSO-d
6)：δ＝2.98(d，3H)，δ＝6.72(d，1H)，δ＝7.07(d，1H)，δ＝7.21(d，2H)，δ＝7.59(m，5H)，δ＝7.95(d，1H)，δ＝8.09(d，1H)，δ＝8.53(d，1H)，δ＝8.98(s，1H)，δ＝9.18(s，1H)。m/e＝487.86。
Embodiment 4
4-((3-amino-benzene) oxygen base)-8-methylamino--1, the preparation of 7-naphthyridines
With reference to embodiment 2, make with the 3-amino-phenol.1HNMR(DMSO-d
6)：δ＝2.98(d，3H)，δ＝6.72(d，1H)，δ＝7.07(d，1H)，δ＝7.21(d，2H)，δ＝7.59(m，5H)，δ＝7.95(d，1H)，δ＝8.09(d，1H)，δ＝8.53(d，1H)，δ＝8.98(s，1H)，δ＝9.18(s，1H)。m/e＝487.86。
Embodiment 5
The preparation of N-(3-trifluoromethyl-4-chlorine) phenyl-N '-(3-(8-methylamino--1,7-naphthyridines-4-oxygen base) phenyl) urea
With reference to embodiment 3, with 4-((3-amino-benzene) oxygen base)-8-methylamino--1, the 7-naphthyridines makes.1HNMR(CDCl
3)：δ＝3.18(d，3H)，δ＝6.68(d，1H)，δ＝6.84(s，1H)，δ＝7.08(s，1H)，δ＝7.18(d，2H)，δ＝7.26(m，3H)，δ＝7.57(m，1H)，δ＝7.73(d，2H)，δ＝7.97(m，2H)，δ＝8.44(d，1H)。m/e＝487.86。
Claims (9)
1. formula (I), (II) compound or its pharmacy acceptable salt:
Formula (I)
Formula (II)
Wherein, R
1, R
2And R
3Be selected from fluorine, chlorine, bromine, trifluoromethyl or trifluoromethoxy.
2. following compound or its pharmacy acceptable salt:
N-(3-trifluoromethyl-4-chlorine) phenyl-N '-(4-(8-methylamino--1,7-naphthyridines-4-oxygen base) phenyl) urea
N-(3-trifluoromethyl-4-chlorine) phenyl-N '-(3-(8-methylamino--1,7-naphthyridines-4-oxygen base) phenyl) urea.
3. according to each described compound or its pharmacy acceptable salt among the claim 1-2, be selected from: formula (I), (II) salt as described below:
The subsalt of organic acid and mineral acid, described 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, acetic acid, trifluoroacetic acid, oxysuccinic acid, tartrate, citric acid, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, phenylacetic acid or tussol.
4. the pharmaceutical composition that is used for the treatment of cancer comprises among the claim 1-2 suitable carriers on each described compound or its pharmacy acceptable salt and the physiology.
Among the claim 1-2 each described compound or its pharmacy acceptable salt for the manufacture of the purposes of the medicine that suppresses the kinase mediated disease of VEGFR-2.
Among the claim 1-2 each described compound or its pharmacy acceptable salt for the manufacture of the purposes of the medicine that suppresses the kinase mediated cancerous cells growth of VEGFR-2 and shift.
7. each described compound of claim 1-2 or its pharmacy acceptable salt are in the purposes for preparing on the treatment Cancerous disease medicine.
8. the described purposes of claim 7, wherein said cancer is kidney, lung cancer, liver cancer, ovarian cancer, bladder cancer, leukemia, gland cancer, melanoma, gastrointestinal cancer, internal secretion cancer, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), carcinoma mesothelial, angiosarcoma, carcinoma of endometrium or neurospongioma.
9. the described purposes of claim 7, wherein said cancer is mammary cancer, carcinoma of the pancreas, thyroid carcinoma, adrenal cortical adenocarcinoma or colorectal carcinoma.
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| CN102408426B (en) * | 2011-09-14 | 2013-07-10 | 湖南有色凯铂生物药业有限公司 | Substituted aromatic urea compound and application as anticancer medicament thereof |
| CN110028444B (en) * | 2019-05-28 | 2022-02-11 | 沈阳药科大学 | 1-aryl-3- [4- (pyridine-2-yl methoxy) phenyl ] urea compound and application thereof |
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|---|---|---|---|---|
| CA2503445C (en) * | 2002-10-24 | 2012-07-31 | Merck Patent Gesellschaft Mit Beschraenkter Haftung | Methylene urea derivatives as raf-kinase inhibitors |
| CN1972925A (en) * | 2004-01-30 | 2007-05-30 | 默克专利有限公司 | Substituted bisarylurea derivatives |
| CA2581516C (en) * | 2004-10-12 | 2013-06-11 | Astrazeneca Ab | Quinazoline derivatives |
| AU2006247315A1 (en) * | 2005-05-18 | 2006-11-23 | Wyeth | 4, 6-diamino-[1,7] naphthyridine-3-carbonitrile inhibitors of Tpl2 kinase and methods of making and using the same |
| AU2009267161B2 (en) * | 2008-07-03 | 2014-11-06 | Merck Patent Gmbh | Naphthyridininones as Aurora kinase inhibitors |
| EA201290073A1 (en) * | 2009-08-24 | 2013-01-30 | Эсэпиен Фармасьютикалз, Инк. | UREA COMPOUNDS CONTAINING 5,6-BICYCLIC HETEROARYL AS KINAZ INHIBITORS |
| CN102408426B (en) * | 2011-09-14 | 2013-07-10 | 湖南有色凯铂生物药业有限公司 | Substituted aromatic urea compound and application as anticancer medicament thereof |
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- 2011-09-14 CN CN2011102708783A patent/CN102408426B/en not_active Expired - Fee Related
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2012
- 2012-09-12 WO PCT/CN2012/081296 patent/WO2013037292A1/en active Application Filing
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| Publication number | Publication date |
|---|---|
| WO2013037292A1 (en) | 2013-03-21 |
| CN102408426A (en) | 2012-04-11 |
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