CN109553581A - Replace carbamide compound, its pharmaceutically acceptable salt or its solvate, its application, drug and pharmaceutical composition - Google Patents

Replace carbamide compound, its pharmaceutically acceptable salt or its solvate, its application, drug and pharmaceutical composition Download PDF

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CN109553581A
CN109553581A CN201910114715.2A CN201910114715A CN109553581A CN 109553581 A CN109553581 A CN 109553581A CN 201910114715 A CN201910114715 A CN 201910114715A CN 109553581 A CN109553581 A CN 109553581A
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compound
acceptable salt
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carbamide compound
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陆瑞燕
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Guangzhou Six Shun Biological Polytron Technologies Inc
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Abstract

The present invention provides a kind of substitution carbamide compound, its pharmaceutically acceptable salt or its solvate.The present invention also provides described substitution carbamide compound, its pharmaceutically acceptable salt or its solvates to prepare the application in drug or pharmaceutical composition for regulating and controlling kinase activity or treatment and kinase-associated conditions as the application of the inhibitor of one of MET, VEGFR, PDGFR and RET or in the application and described substitution carbamide compound, its pharmaceutically acceptable salt or its solvate for preparing two or more the multiple target point inhibitor in MET, VEGFR, PDGFR and RET.The present invention also provides a kind of for treating the drug or pharmaceutical composition of angiogenesis abnormal diseases.Shown in the substituted urea compound structure such as formula (I), R1Selected from methoxyl group or deuterated methoxyl group；R2Selected from methyl, deuterated methyl,In any one structure；R3Any one in F, Cl, Br, I.

Description

Replace carbamide compound, its pharmaceutically acceptable salt or its solvate, its application, Drug and pharmaceutical composition
Related application
This application claims filed on 09 25th, 2018, application No. is 2018111165044, entitled " substituted urea The Chinese patent Shen of conjunction object, its pharmaceutically acceptable salt or its solvate, pharmaceutical composition, preparation method and applications " Priority please, is incorporated herein by reference in its entirety.
Technical field
The invention belongs to biomedicine technical field, be related to a kind of substitution carbamide compound, its pharmaceutically acceptable salt or Its solvate, its application, drug and pharmaceutical composition.
Background technique
Cancer is a series of diseases characterized by abnormal cell hyperplasia out of control and diffusion, is to seriously endanger human health One of principal disease, according to WHO Report, whole world cancer patient increases by 10,000,000 people every year, dead about 7,000,000 people, To the year two thousand twenty, cancer patient every year will newly-increased 20,000,000 people.Currently, there are 1,600,000 people's cancer strickens, while about 130 in China every year Ten thousand people die of cancer, and cancer is just becoming the mankind " the second killer " for being only second to cardiovascular disease.
With the development of molecular biology, great progress is achieved for the molecular mechanism of action of tumor development, A variety of receptor tyrosine kinase families are had proven at present and its ligand plays crucial adjustment effect in Tumor angiogenesis, such as MET, VEGFR, BRAF, PDGFR and RET.
RET is a proto-oncogene, and full name: RET proto-oncogene is long-armed positioned at No. 10 autosomes (10q11.2), overall length 60kb include 21 exons, encode the tyrosine kinase receptor superfamily RET egg of 1100 amino acid It is white, in normal neuron, sympathetic nerve and parasympathetic ganglion, parafollicular cells of thyroid gland, adrenal gland myelocyte, urogenital tract Cell, Testicular Germ Cell have expression.Can be activated after RET protein activation downstream signal path (comprising RAS, MAPK, ERK, PI3K, AKT etc.), lead to cell Proliferation, migration and differentiation.The activated mutant of RET gene and the malignant tumour of people are related, including 2 type of multiple endocrine neoplasia (multiple endocrine neoplasiatype II, MEN2), thyroid papillary carcinoma (papillary thyroid carcinomas, PTC), congenital megacolon and adenocarcinoma of lung etc., different mutation types can Lead to the difference of tumor invasion ability.Preliminary studies have shown that the signal transduction pathway that it is mediated is more unique.3 kinds of RET gene prominent It is related to the generation of mankind's kinds cancer to become type: 1, there are RET gene and other genes are a variety of heavy for papillary adenocarcinoma of thyroid Row；2, multiple endocrine neoplasia type 2, there are 7 site point mutation for familial inheritance medullary carcinoma of thyroid gland etc.；3, lung cancer RET base Because of fusion.In recent years for the structure function of RET albumen, the research of influence of the RET gene mutation to RET protein function is by pass Note.With going deep into RET gene mutation research, RET should can become the target spot that kinds of tumors is precisely treated.
Vascular endothelial growth factor receptor (VEGFR) is a kind of tyrosine kinase transmembrane glycoprotein, it is by 7 class Ig The extracellular region of structural domain composition；Tyrosine kinase domain district's groups are at including VEGFR-1 in one transmembrane structure area and cytoplasm (Flt-1), 3 kinds of VEGFR-2 (KDR/Flk-1), VEGFR-3 (Flt-4) receptors.The extracellular fragment of VEGFR is in conjunction with VEGF Region, the two combine rear VEGFR conformation to change, and lead to Receptor dimerization, and intracellular section of tyrosine site occurs from phosphoric acid Change, activates the signal transduction pathway in downstream.Wherein VEGFR-1 is mainly distributed on vascular endothelial cell, thin in macrophage, monokaryon Also there is expression in born of the same parents, candidate stem cell, can be combined with VEGF-A, VEGF-B and PlGF-1.Compared with VEGFR-2, VEGFR-1 with The affinity of VEGF is 10 times high, but cannot activate the signal of endothelial cell proliferation.VEGFR-1 promotees blood vessel life probably as VEGF At reversed regulatory factor play a role, VEGFR-1 also have mediate monocyte emigration, endothelial progenitor cells are enlisted, promotion is made The biological functions such as hemocytoblast survival.VEGFR-2 is mainly distributed in vascular endothelial cell and candidate stem cell, but some Non-endothelial cells type also has expression.VEGFR-2 can be in conjunction with VEGF-A, VEGF-C, VEGF-D, VEGF-E.VEGF stimulation The nucleus formation of the proliferation of endothelial cell, the permeability for increasing blood vessel and new blood vessel mainly passes through combination and activation VEGFR-2 Come what is realized.VEGFR-3 is mainly expressed in lymphatic endothelial cells, and also expression is in the cells such as monocyte, macrophage. VEGFR-3 can be in conjunction with VEGF-C and VEGF-D.VEGFR-3 participates in maintaining the survival of lymphatic endothelial cells, and promotes it Proliferation and migration, it is related with tumour cell lymph node transfer.
The experimental results show VEGFR overexpression in many cancerous tissues, including liver cancer, lung cancer, colon cancer, ovum Nest cancer, breast cancer etc. serve key in the growth and transfer of tumour, it is possible to by blocking or interfering VEGFR signal transduction pathway controls tumour growth.Using VEGFR as the anti-tumor drug of target and traditional tumor therapeutic agent Compared to there is very big advantage.Under normal physiological conditions, people's angiogenesis is only in the physiological activities such as wound healing and menstrual cycle In work, so using anti-angiogenic medicaments treat tumour, to human toxicity act on it is small；The growth and migration of tumour rely on In the generation of a large amount of new vessels, the antitumous effect of wide spectrum can achieve using VEGFR as target spot；It is different from tumour cell, blood There is endothelial cell genetic stability to be not likely to produce so being considered as ideal therapy target to anti-angiogenic medicaments Resistance；And endothelial cell directly contacted with blood make drug be more easier reach vascular endothelial cell.
In addition, vascular endothelial growth factor (VEGF) during the pathological change of Retinal vascular disease, is in high table Up to state；The clinical test of anti-vegf treatment confirms that treatment can be such that choroidal neovascularization reduces, fluid seepage is reduced, Neovascular age-related macular degeneration, the choroidal neovascularization of the various causes of disease, diabetes and vein obstruction cause Macular edema, retinopathy of prematurity and neovascular glaucoma treatment in, anti-vegf treatment shows preferable Validity.Therefore, the inhibitor of VEGFR is also used for retinal vessel and forms disease, neovascular glaucoma and sugar in addition to tumour Urinate the treatment that the relevant blood vessels such as characteristic of disease retinopathy generate abnormal diseases.
It is raw that platelet derived growth factor (Platelet-derived Growth Factor, PDGF) belongs to blood vessel endothelium Long factor family, active enhancing are of great significance in cancer and leukaemia, are atherosclerosis initial phases The most strong mitogeneic factor of one of important factor in order and hepatic stellate cells.PDGFR is a kind of tyrosine kinase receptor, tool Have protein hydroxyphenylaminopropionic acid kinase activity, in conjunction with ligand PDGF after, pass through special tyrosine residue dephosphorylation and start And amplified signal, promote actin rearrangement and plays the physiological actions such as mitogenesis, chemotactic.The mistake of PDGF and PDGFR race Express, at present reduction closely related with a series of diseases such as malignant tumour, atherosclerosis, arterial restenosis and fibrosis etc. The mode of PDGF signal transduction mainly inhibits PDGFR, blocks its tyrosine kinase phosphorylation and downstream signal transduction.In recent years Studies have shown that the growth of tumour is angiogenesis-dependent, tumour cell can generate a variety of angiogenic factors, in tumour Generation, development, play a significant role in invasion and transfer process.PDGF expression is closely related with the angiogenesis of tumour, swells Oncocyte is by release PDGF Angiogensis, and PDGF can also raise vascular endothelial growth factor (Vascular Endothelial Growth Factor, VEGF) expression, VEGF is also important angiogenic factors, can mediate indirectly Angiogenesis.Inside and outside experimental study shows in oophoroma, kidney, lung cancer, brain tumor, prostate cancer, breast cancer, Colon and rectum In the kinds of tumors such as cancer, the overexpression of PDGF is all detected.In addition, the activation of PDGF signal path can increase tumor stroma Interstitial fluid body pressure (interstitial fluid pressure, IFP), IFP, which increases, to be prevalent in solid tumor mass, It is serious that anti-tumor drug is hindered effectively to transport tumour cell, reduce intake of the tumor tissues to drug.Currently, PDGFR master Will be as antitumor target spot, the research and development of PDGFR inhibitor is also current research hotspot, using PDGFR as target spot Drug has the advantages that highly selective and toxic side effect is small, but also has simultaneously and can only inhibit and be difficult to thoroughly kill tumour cell Defect.
Interstitial epidermis transforming factor (Mesenchymal to epithelial transition factor, MET) gene Encoded albumen MET size is about 170k Da, is about 190k Da after glycosylation modified, is formed eventually by shear action Two polypeptide chains connected by disulfide bond, i.e. α chain (50k Da) and β chain (140k Da).MET belongs to RON subtribe, be scattering because Sub or the only known hepatocyte growth factor (HGF) receptor.MET albumen is led to by the only subunit of 50kD and the B subunit of 145kD The connected heterodimer of disulfide bond is crossed, extracellular domain and Intracellular domain are divided into.Extracellular domain includes 3 different structural domains of function: being covered It covers the end the N- ligand binding domain (region SEMA) of entire ol chain and part B chain, have the cystine enrichment region of 4 conservative disulfide bond Domain and immunoglobulin like domain.Intracellular domain is equally made of 3 regulatory regions: having the close of Tyrl003 phosphorylation site Spanning domain, the tyrosine kinase catalyst structure domain for having Tyrl234 and Tyrl235 phosphorylation site and have Tyrl349 and The multi-functional bond area in the one end c of Tyrl356 combination tyrosine.After HGF is in conjunction with Met extracellular domain, phosphoric acid occurs for induction MET Change, various kinds of cell mesenchymal factor is raised in the multi-functional region in the end C-, such as GABl (growth factor receptor binding protein precursor -1), GAB2 (growth factor receptor binding protein precursor -2) etc. further attracts the molecules such as SHP2, P13K to be incorporated in this, thus activates RAS/ MAPK, P13K/AKT, JAK/STAT access etc., to regulate and control the growth of cell, migration, proliferation and survival.With research Deeply, MET has been found unconventionality expression or gene magnification in Several Kinds of Malignancy, and the prognosis with tumor patient has closely Relationship.Gene magnification or highly expressed phenomenon is all presented in MET gene in many primary tumors, including lung cancer, gastric cancer, knot are directly Intestinal cancer, liver cancer etc..61% non-small cell lung cancer (Non-small cell lung cancer, NSCLC) and 35% in lung cancer Small Cell Lung Cancer (Small cell lung cancer, SCLC) has MET gene magnification phenomenon and MET gene copy number is high NSCLC patient's prognosis is relatively poor.Recently as the deep and extension studied in terms of tumour MET, gradually become anti- The important target spot of oncotherapy has good antitumous effect, MET especially for the inhibitor of HGF/MET targeted therapy The exploitation of target spot inhibitor has huge market value.
Therapy based on target is considered as the developing direction of the following treatment of cancer.Marketed drug Sorafenib is (mostly lucky Beauty) and it is happy cut down for Buddhist nun (Lenvatinib, E7080), both drugs are the multi-kinase inhibitors of targeting vegf receptor, and It is a kind of multiple target point kinase inhibitor, but its tumor-inhibiting action is to be improved.
Summary of the invention
In view of this, it is desirable to provide a kind of substitution carbamide compound with tumor-inhibiting action more outstanding, it can pharmaceutically connect The salt received or its solvate, its application, drug and pharmaceutical composition.
The present invention provides a kind of substitution carbamide compound, its pharmaceutically acceptable salt or its solvate, structure such as formula (I) It is shown:
Wherein:
R1Selected from methoxyl group or deuterated methoxyl group；
R2Selected from methyl, deuterated methyl,In any one structure；
R3Any one in F, Cl, Br, I.
R in one of the embodiments,3Selected from F or Cl.
The pharmaceutically acceptable salt is the basic salt of organic acid or inorganic acid in one of the embodiments,.
The solvate is hydrate in one of the embodiments,.
The present invention also provides the substitution carbamide compound, its pharmaceutically acceptable salt or its solvates to prepare The application of the inhibitor of one of MET, VEGFR, PDGFR and RET, or preparing two in MET, VEGFR, PDGFR and RET The application of kind or two or more multiple target point inhibitor.
The present invention also provides the substitution carbamide compound, its pharmaceutically acceptable salt or its solvates to use in preparation In regulation kinase activity or treatment and the application in the drugs of kinase-associated conditions or pharmaceutical composition, the kinases include MET, One of VEGFR, PDGFR and RET or a variety of.
The present invention also provides a kind of for treating the drug or pharmaceutical composition of angiogenesis abnormal diseases, including according to institute Substitution carbamide compound, its pharmaceutically acceptable salt or its solvate and the acceptable carrier of physiology stated.
The angiogenesis abnormal diseases include cancer, retinal vessel formation disease, new life in one of the embodiments, At least one of neovascular glaucoma, diseases associated with inflammation and diabetic retinopathy.
The cancer includes breast cancer, respiratory cancer, the cancer of the brain, genital cancer, alimentary canal in one of the embodiments, Cancer, carcinoma of urethra, cancer eye, liver cancer, cutaneum carcinoma, head and/or neck cancer, lymthoma, sarcoma, leukaemia, thyroid cancer, parathyroid carcinoma And/or their distant metastases.
The cancer is one of colorectal cancer, the cancer of the esophagus, gastric cancer and liver cancer or more in one of the embodiments, Kind.
Substitution carbamide compound, its pharmaceutically acceptable salt or its solvate provided by the invention, by with diformazan Oxygroup replaces, or the quinazoline structure replaced respectively by the alkoxy of methoxyl group and the heterocycle containing morpholine with there is cyclopropyl and substitution Or unsubstituted phenyl replace urea structure connection, the substitution carbamide compound experiments prove that can effectively inhibit MET, VEGFR, One or more enzymatic activity in PDGFR and RET has excellent tumor-inhibiting action.Utilize the substitution carbamide compound, its pharmacy Upper acceptable salt or its solvate can be used as kinase inhibitor, prepare drug or pharmaceutical composition, treatment and blood vessel shape At abnormal relevant disease.
Particularly, due to the heterogeneity of tumour and the complexity for the treatment of of cancer, the small-molecule drug of single target spot is only capable of needle It is effective to small part tumour, and it is also easy to produce drug resistance, therapeutic effect is not good enough.Multiple target point inhibitor can improve treatment to a certain extent Effect extends drug resistance generation time, and the therapy of more targets is considered as the developing direction of the following treatment of cancer.It is provided by the invention to take It can be used as the multiple target point of MET, VEGFR, PDGFR and RET for carbamide compound, its pharmaceutically acceptable salt or its solvate Inhibitor has broad application prospects in the therapy of more targets of cancer.
Detailed description of the invention
Fig. 1 is concentration-effect relation curve of the RMI 9918 to hERG potassium channel；
Fig. 2 is concentration-effect relation curve of compound of the embodiment of the present invention I-1 to hERG potassium channel；
Fig. 3 is concentration-effect relation curve of compound of the embodiment of the present invention I-2 to hERG potassium channel；
Fig. 4 is suppression result figure of compound of the embodiment of the present invention I-2 to KYSE-410 cancer of the esophagus mouse tumor volume；
Fig. 5 is compound of embodiment of the present invention I-2 between weight result of variations figure KYSE-410 cancer of the esophagus mouse administration phase；
Fig. 6 is suppression result of compound of the embodiment of the present invention I-2 to HT-29 colorectal cancer mouse tumor volume；
Fig. 7 is suppression result figure of compound of the embodiment of the present invention I-2 to BGC-823 gastric carcinoma mouse gross tumor volume；
Fig. 8 is suppression result figure of compound of the embodiment of the present invention I-2 to SMMC-7721 liver cancer mouse gross tumor volume.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, right with reference to the accompanying drawings and embodiments The present invention is further elaborated.It should be appreciated that described herein, specific examples are only used to explain the present invention, not For limiting the present invention.
The embodiment of the present invention provides a kind of substitution carbamide compound, the compound, and structural formula is as follows:
Wherein:
R1Selected from methoxyl group or deuterated methoxyl group；
R2Selected from methyl, deuterated methyl,In any one structure；
R3Any one in F, Cl, Br, I.
Substitution carbamide compound includes active group A and active group B described in the embodiment of the present invention.Active group A has two Methoxy substitution, or the quinazoline ring structure replaced respectively by the alkoxy of methoxyl group and the heterocycle containing morpholine.Active group B has Cyclopropyl and phenyl substituted urea structure substituted or unsubstituted.The active group A connects knot by oxygen with the active group B It closes, the substitution carbamide compound has excellent tumor-inhibiting action, especially as the multiple target point inhibitor for adjusting kinase activity, uses In adjust cell activity, such as proliferation, differentiation, apoptosis, migration and chemotactic, more specifically can effectively inhibit MET, The enzymatic activity of VEGFR, PDGFR and RET, so that disease extremely relevant to vascularization is effectively treated, especially with blood vessel The abnormal hyperplasia of formation.
The embodiment of the present invention also provide in vivo receive oxidation, reduction, hydrolysis, engagement etc. metabolism and show described in take For the active compound of carbamide compound, or receives the metabolism such as oxidation, reduction, hydrolysis in vivo and generate the substituted urea The compound for closing object, as the solvate of its pharmaceutically acceptable salt and these compounds is also included within the present invention In, preferably their hydrate.
Preferably, the pharmaceutically acceptable salt is the basic salt of organic acid or inorganic acid；More preferably hydrochloride, hydrogen Bromate, hydriodate, sulfate, phosphate, acetate, trifluoroacetate, rhodanate, maleate, hydroxymaleic acid Salt, glutarate, mesylate, esilate, benzene sulfonate, tosilate, benzoate, salicylate, phenylacetic acid Salt, cinnamate, lactate, malonate, pivalate, succinate, fumarate, malate, mandelate, winestone Hydrochlorate, gallate, gluconate, laruate, palmitate, pectate, picrate, citrate or it Combination.
The substitution carbamide compound, R3Any one in F, Cl, Br, I.In one embodiment, the R3Preferably F or Cl, the substitution carbamide compound can be selected from any one in following structural formula:
Substitution carbamide compound described in the embodiment of the present invention can be prepared by a variety of methods, and the embodiment of the present invention provides one kind The preparation method of the substitution carbamide compound with higher yields, comprising the following steps:
(1) compound (Ic) is obtained by compound (Ia) and (Ib) reaction；
(2) compound (Ie) is obtained by compound (Ic) and (Id) reaction；
(3) the substitution carbamide compound is obtained by compound (Ie) and compound (If) reaction；
Wherein, R1Selected from methoxyl group or deuterated methoxyl group；
R2Selected from methyl, deuterated methyl,In any one structure；
R3Any one in F, Cl, Br, I.
Compound (Ia) and compound (Ib) are medicine intermediate, can be obtained by purchase.Compound (Ia) in step (1) Amidation obtains compound (Ic) under the conditions of base catalysis with compound (Ib).Basic catalyst used can be organic base or nothing Machine alkali, it is preferred that the basic catalyst is at least one of sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine；It is used molten Agent can be selected from tetrahydrofuran and water mixed solvent, ethyl alcohol and water mixed solvent, acetone and water mixed solvent and methylene chloride At least one, wherein the volume ratio of the in the mixed solvent, organic solvent and water is 1:10 to 10:1；Reaction temperature is -10 DEG C~50 DEG C.
Amidation under the conditions of base catalysis of compound (Ic) and compound (Id) obtains compound (Ie) in step (2). Compound (Id) is cyclopropylamine, can be obtained by purchase.Basic catalyst used can be organic base or inorganic base, it is preferred that institute Stating basic catalyst is at least one of sodium bicarbonate, sodium carbonate, potassium carbonate, triethylamine；Solvent for use is preferably tetrahydro furan It mutters, at least one of methylene chloride and acetonitrile；Reaction temperature is 10 DEG C~70 DEG C.
Compound (If) is medicine intermediate, can be obtained by purchase.Compound (Ie) and compound (If) in step (3) Etherificate obtains the substitution carbamide compound under the conditions of base catalysis, and used catalyst is highly basic, it is preferred that the base catalysis Agent is at least one of sodium hydroxide, potassium hydroxide sodium, sodium hydride；Solvent for use is preferably N,N-dimethylformamide or two Methyl sulfoxide, reaction temperature are 30 DEG C~130 DEG C.
The embodiment of the present invention also provides described substitution carbamide compound, its pharmaceutically acceptable salt or its solvate and exists The application of the inhibitor of one of MET, VEGFR, PDGFR and RET is prepared, or in preparation MET, VEGFR, PDGFR and PET Two or more multiple target point inhibitor application.
The VEGF includes one of VEGFR1, VEGFR2 and VEGFR3 or a variety of.The PDGFR includes PDGFR α And/or PDGFR β.
The embodiment of the present invention also provide the substitution carbamide compound, its pharmaceutically acceptable salt, its solvate or Using one or more inhibition agent inhibitors of its MET, VEGFR, BRAF, PDGFR and/or RET in preparation for regulating and controlling kinases The drug of activity or treatment with kinase-associated conditions or the application in pharmaceutical composition.Described pharmaceutical composition includes the substitution The effective component and physiology of carbamide compound or the compound pharmaceutically acceptable salt or their solvate composition can connect The carrier received.
Described pharmaceutical composition can further comprise other drugs activating agent.
The others pharmaceutically active agents include but is not limited at least one of to be exemplified below: PD-1, PD-L1, coming that Spend amine, Aldesleukin, interferon, Amrubicin, arsenic trioxide, U-18496, capecitabine, carboplatin, Kang Shi get, west Not interleukin, daunorubicin, Chlorambucil, cis-platinum, Cladribine, Cladribine, clodronic acid pamidronic acid, cyclophosphamide, arabinose born of the same parents Glycosides, floxuridine, Fluconazole, fludarabine, 5- fluorodeoxyuridine monophosphate, 5 FU 5 fluorouracil, gemcitabine, Ji are appropriate Monoclonal antibody, imatinib mesylate, idarubicin, ifosfamide, interferon-' alpha ', interferon-' alpha ' 2, interferon α-2 A, interferon-' alpha '- 2B, interferon alfa-n1, Alferon N, interferon beta, interferon gamma -1a, interleukin 2, intron A, Iressa, according to vertical For health, citric acid Evacet, Temozolomide,.
The angiogenesis abnormal diseases include cancer, neovascular glaucoma, retinal vessel formation disease, diabetes Property retinopathy, diseases associated with inflammation.The diseases associated with inflammation includes arthritis deformans, rheumatic arthritis, chronic eczema, retardance Allergic reaction.
Preferably, the angiogenesis abnormal diseases are cancer.The cancer includes breast cancer, respiratory cancer, the cancer of the brain, life Grow organ cancer, digestive system cancer, carcinoma of urethra, cancer eye, liver cancer, cutaneum carcinoma, head and/or neck cancer, lymthoma, sarcoma, leukaemia, first shape Gland cancer, parathyroid carcinoma and/or their distant metastases.It is furthermore preferred that the cancer is colorectal cancer, the cancer of the esophagus and gastric cancer One of or it is a variety of.
Preferably, the breast cancer is aggressive duct carcinoma, aggressive lobular carcinoma, in situ ductal carcinoma or in situ lobular carcinoma； The respiratory cancer is Small Cell Lung Cancer, non-small cell lung cancer, bronchial adenoma or pleuropulinonary blastoma；The cancer of the brain is brain Dry tumor, now glioma, cerebellar astrocytoma, cerebral astrocytoma, medulloblastoma, ependymoma, nerve are outer Germinal layer or pinealoma.The reproductive organs tumour is prostate cancer, carcinoma of testis, carcinoma of endometrium, cervical carcinoma, oophoroma, yin Road cancer, carcinoma of vulva or sarcoma of uterus；The digestive system cancer is cancer of anus, colon cancer, colorectal cancer, cancer of the esophagus, gallbladder cancer, stomach Cancer, cancer of pancreas, the carcinoma of the rectum, carcinoma of small intestine or glandula cancer；The carcinoma of urethra is bladder cancer, carcinoma of penis, kidney, carcinoma of renal pelvis, ureter Cancer or carcinoma of urethra；The cancer eye is intraocular melanoma or retinoblastoma；The liver cancer is hepatocellular carcinoma, with or without fibre Tie up hepatocellular carcinoma, cholangiocarcinoma or the mixed hepatocellular cholangiocarcinoma of plate variation；The cutaneum carcinoma is squamous cell carcinoma, Ka Jibo Sarcoma, chromoma, Merkel cell skin cancer or non-melanoma cutaneum carcinoma；The head and neck cancer is laryngocarcinoma, hypopharyngeal cancer, nose Pharynx cancer, oropharyngeal cancer, lip cancer or carcinoma of mouth；The lymthoma is AIDS associated lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell Lymthoma, Hodgkin's disease or central nervous system lymphoma；The sarcoma is soft tissue sarcoma, osteosarcoma, malignant fibrous group Knit cytoma, lymphosarcoma or rhabdomyosarcoma；The leukaemia be acute myeloid leukemia, acute lymphoblastic leukemia, Chronic lymphocytic leukemia, chronic myelogenous leukemia or hairy cell leukemia.
Under normal conditions, with the substitution carbamide compound of the embodiment of the present invention, its pharmaceutically acceptable salt, its solvate Or with its combination of compositions using cytotoxicity inhibitor and/or inhibition of cell proliferation and/or tumour immunotherapy and/ Or gene therapy can realize at least one of following purpose:
Preferably effect is generated compared with being administered alone one of both in terms of reducing tumour growth or even being eliminated tumour Power；
Reduce the dosage of monotherapy activating agent to be administered；
It is easier to be had compared with the therapy of independent activating agent and other certain combined therapies by patient tolerance than monotherapy There is less harmful drug complication；
More kinds of various cancers types can be treated in mammal especially people；
Higher response rate is generated in the patient treated；
Reach the longer time-to-live in the patient treated compared with the embolic chemotherapy of standard；
Tumor development is set to need the longer time；
Compared with the antagonism example generated when known antitumor activity agent is used in combination, generated effect and tolerance knot Fruit is good at least as when being administered alone activating agent.
Embodiment 1
Compound I-1 1- (the chloro- 4- of 2- ((6,7- dimethoxyquinazoline -4- base) oxygroup) phenyl) -3- cyclopropyl urea Synthetic route is as follows:
Synthetic method:
(1) the chloro- phenol of 4- amino -2- (12.7g, 0.1mol) and sodium bicarbonate (16.8g, 0.2mol) are added to tetrahydro It in furans (100ml) and water (100ml), is stirred at room temperature, is allowed in uniform suspension (solution A).By phenyl chloroformate (18.8g, 0.12mol), which is dissolved in tetrahydrofuran (50mL), forms solution (solution B).Solution B is added dropwise into solution A, drips Room temperature is stirred to react after finishing, and is tracked and is reacted by TLC, is analyzed to identify after the reaction was completed, post-processed.The step of post-processing, wraps It includes: reaction solution being stood into liquid separation, water phase is extracted with 100mL ethyl acetate, and organic phase is used saturated common salt water washing 3 times again, added Anhydrous sodium sulfate is dry, filters, and the solid that filtrate decompression is concentrated to get adds ethyl acetate (50mL) to be heated to reflux dissolved clarification, then plus stone Oily ether (100mL), which is down to, is stirred at room temperature crystallization 5 hours, and the crystal of precipitation filters dry that compound (I-1c) 15.3g, yield are 62%.
(2) will to compound (I-1c) (12.4g, 0.05mol), cyclopropylamine (5.7g, 0.1mol) and triethylamine (5g, It 0.05mol) is added in acetonitrile (150mL), 50 DEG C of heating stirring reactions are tracked by TLC and reacted, are analyzed to identify reaction and complete Afterwards, it is post-processed.The step of post-processing includes: to be cooled to room temperature, and filtering, filter cake is washed with a small amount of acetonitrile, obtained solid 45 DEG C vacuum drying obtains compound (I-1e) 9.03g, yield 86%.
(3) by compound (I-1e) (5.88g, 0.028mol), chloro- 6, the 7- dimethoxyquinazoline of 4- (4.49g, 0.02mol) be added in DMF (50mL) with sodium hydroxide (0.96g, 0.24mol), the reaction of 50 DEG C of heating stirrings, by TLC with Track reaction, is analyzed to identify after the reaction was completed, is post-processed.The step of post-processing includes: that 100mL is added into reaction solution Water stirs lower room temperature crystallization, filters, filter cake purifying water washing 2 times.Obtained solid mashing in ethyl alcohol (250mL), filters, It is dried in vacuo to obtain compound (I-1) 7.13g, yield 86%.
The nuclear magnetic data of obtained compound (I-1) are as follows: 1H NMR (400MHz, DMSO) δ (ppm): 8.61 (s, 1H), 8.25(d,1H),8.00(s,1H),7.59(s,1H),7.54(d,1H),7.43(s,1H),7.30(dd,1H),7.22(d, 1H),4.11-3.96(m,6H),2.69-2.60(m,1H),0.72(q,2H),0.56-0.40(m,2H)；ESI-MS (m/z): 415.2[M+1]。
Embodiment 2
Compound I-2 1- (the fluoro- 4- of 2- ((6,7- dimethoxyquinazoline -4- base) oxygroup) phenyl) -3- cyclopropyl urea Synthetic route is as follows:
Synthetic method can refer to embodiment 1, and equivalents ratio and reaction condition are constant in step (1) and step (2), step (3) reactant equivalent is constant in, and reaction condition is 40 DEG C of heating stirring reactions.The step of post-processing includes: into reaction solution 100mL water is added, stirs lower room temperature crystallization, filters, filter cake purifying water washing 2 times.Obtained solid is beaten in ethyl alcohol (200mL) Slurry filters, is dried in vacuo to obtain compound (I-2) 6.05g, yield 76%.
The nuclear magnetic data of obtained compound (I-2) are as follows: 1H NMR (400MHz, DMSO) δ (ppm): 8.62 (s, 1H), 8.26(d,1H),8.03(s,1H),7.62(s,1H),7.55(d,1H),7.43(s,1H),7.32(d,1H),7.20(d,1H), 4.12-3.96(m,6H),2.70-2.60(m,1H),0.73(q,2H),0.57-0.41(m,2H)；ESI-MS(m/z):399[M+ 1]。
Embodiment 3
Compound I-3 1- (the chloro- 4- of 2- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinazoline -4- base) oxygroup) benzene Base) -3- cyclopropyl urea synthetic route it is as follows:
Synthetic method can refer to embodiment 1, and equivalents ratio and reaction condition are constant in step (1) and step (2), step (3) reactant equivalent is constant in, and reaction condition is 50 DEG C of heating stirring reactions.The step of post-processing includes: to be concentrated under reduced pressure to remove 50mL water is added into reaction solution for about 40mL DMF solvent, stirs lower room temperature crystallization, filters, filter cake purifying water washing 2 It is secondary.Obtained solid recrystallization in ethyl alcohol (100mL), filters, 45 DEG C are dried in vacuo to obtain compound (I-3) 4.86g, yield 46%.
The nuclear magnetic data of obtained compound (I-3) are as follows:1H NMR (400MHz, DMSO) δ (ppm): 8.61 (s, 1H), 8.25(d,1H),8.00(s,1H),7.59(s,1H),7.54(d,1H),7.43(s,1H),7.30(d,2.5Hz,1H),7.22 (d,1H),4.31(t,2H),4.08(s,3H),3.71-3.77(m,4H),2.60-2.65(m,2H),2.44-2.57(m,5H), 2.07-2.18 (m, 2H), 0.72 (q, J=6.5Hz, 2H), 0.56-0.40 (m, 2H)；ESI-MS(m/z):528.2[M+1].
Embodiment 4
Compound I-4 1- (the fluoro- 4- of 2- ((6- methoxyl group -7- (3- morpholine propoxyl group) quinazoline -4- base) oxygroup) benzene Base) -3- cyclopropyl urea synthetic route it is as follows:
Synthetic method can refer to embodiment 1, and equivalents ratio and reaction condition are constant in step (1) and step (2), step (3) reactant equivalent is constant in, and reaction condition is 70 DEG C of heating stirring reactions.The step of post-processing includes: to be concentrated under reduced pressure to remove 50mL water is added into reaction solution for about 40mL DMF solvent, stirs lower room temperature crystallization, filters, filter cake purifying water washing 2 It is secondary.Obtained solid recrystallization in ethyl alcohol (150mL), filters, 45 DEG C are dried in vacuo to obtain compound (I-4) 7.36g, yield 72%.
The nuclear magnetic data of obtained compound (I-4) are as follows:1H NMR (400MHz, DMSO) δ (ppm): 8.56 (s, 1H), 8.12-8.19(m,2H),7.54(d,1H),7.39(d,1H),7.30-7.33(m,1H),7.07-7.09(m,1H),6.80(m, 1H),4.25(t,2H),3.99(s,3H),3.64-3.70(m,4H),2.53-2.58(m,2H),2.39-2.50(m,5H), 2.05-2.16(m,2H),0.65(m,2H),0.42(m,2H)；ESI-MS(m/z):512.2[M+1].
Embodiment 5
Compound I-5 1- (the chloro- 4- of 2- ((6- methoxyl group -7- (2- morpholine ethyoxyl) quinazoline -4- base) oxygroup) benzene Base) -3- cyclopropyl urea synthetic route it is as follows:
Synthetic method and post-processing can refer to embodiment 3, obtain obtaining compound (I-5), yield 46%.
The nuclear magnetic data of obtained compound (I-5) are as follows:1H NMR (400MHz, DMSO) δ (ppm): 8.60 (s, 1H), 8.24(d,1H),8.01(s,1H),7.61(s,1H),7.55(d,1H),7.42(s,1H),7.31(m,1H),7.21(d,1H), 4.25-4.32(m,2H),4.11-3.96(m,6H),3.66-3.73(m,4H),2.85-2.94(m,2H),2.69-2.54(m, 5H),0.72(q,2H),0.56–0.40(m,2H)；ESI-MS(m/z):514.2[M+1].
Embodiment 6
Compound I-6 1- (the fluoro- 4- of 2- ((6- methoxyl group -7- (2- morpholine propoxyl group) quinazoline -4- base) oxygroup) benzene Base) -3- cyclopropyl urea synthetic route it is as follows:
Synthetic method and post-processing can refer to embodiment 4, obtain obtaining compound (I-6), yield 72%.
The nuclear magnetic data of obtained compound (I-6) are as follows:1H NMR (400MHz, DMSO) δ (ppm): 8.57 (s, 1H), 8.14-8.19(m,2H),7.56(d,1H),7.41(d,1H),7.31-7.35(m,1H),7.08-7.10(m,1H),6.82(m, 1H),4.28-4.35(m,2H),3.97-3.99(m,6H),3.69-3.77(m,4H),2.88-2.98(m,2H),2.73–2.57 (m,5H),0.65(m,2H),0.42(m,2H)；ESI-MS(m/z):498.2[M+1].
Experimental example 1 replaces carbamide compound I-1~I-6 to the external activity Inhibition test of enzyme
Using the Z '-LYTE of Thermo Fisher scientificTMDetection replaces carbamide compound I-1~I-6 to various The inhibitory effect of enzymatic activity.Kinases used in detection be it is commercially available, detection method is according to Z '-LYTETMConventional practices into Row.
(1) each reagent and preparation condition:
1,1 × kinase buffer liquid A (50mM HEPES (pH 7.5), 0.01%BRIJ-35,10mM MgCl2,4mM MnCl2,1mM EGTA,2mM DTT)
1 × kinase buffer liquid B (50mM HEPES (pH 7.5), 0.01%BRIJ-35,10mM MgCl2,1mM EGTA)
In kinase reaction, using 1 × kinase buffer liquid A or 1 × kinase buffer liquid B dilution ATP solution, substrate, enzyme and change Close object.
2, untested compound working solution
The compound accurate weighing that embodiment 1-6 is obtained is added dimethyl sulfoxide (DMSO) solvent and forms mother liquor, then Untested compound I-1~I-6 solution is prepared to required concentration using kinase buffer liquid；
3,4 × ATP (adenosine triphyosphate) working solution
4 times that ATP extremely reacts final concentration are prepared with 1 × kinase buffer liquid B.
4、2×Z’-LYTETMPeptide substrates/enzyme working solution
VEGFR1 enzyme/peptide substrates mixed liquor:
2 times that peptide substrates Tyr 04 and VEGFR1 enzyme extremely react final concentration are prepared with 1 × kinase buffer liquid A.Final kinases 10 μ L VEGFR1 enzymes/peptide substrates mixed liquor when reaction includes 2.64ng-12.5ng VEGFR1 and 2 μM of Tyr 04,50mM HEPES (pH 7.5), 0.01%BRIJ-35,10mM MgCl2,2mM MnCl2,1mM EGTA,1mM DTT。
VEGFR3 enzyme/peptide substrates mixed liquor:
2 times that peptide substrates Tyr 04 and VEGFR3 enzyme extremely react final concentration are prepared with 1 × kinase buffer liquid A.Final kinases 10 μ L VEGFR3 enzymes/peptide substrates mixed liquor when reaction includes 2ng-20ng VEGFR3,2 μM of Tyr 04 and 50mM HEPES (pH 7.5), 0.01%BRIJ-35,10mM MgCl2, 2mM MnCl2,1mM EGTA,1mM DTT。
VEGFR2 enzyme/peptide substrates mixed liquor:
2 times that peptide substrates Tyr 01 and VEGFR2 enzyme extremely react final concentration are prepared with 1 × kinase buffer liquid B.Final kinases 10 μ L VEGFR2 enzymes/peptide substrates mixed liquor when reaction includes 0.75ng-15ng VEGFR2,2 μM of Tyr 01 and 50mM HEPES (pH 7.5), 0.01%BRIJ-35,10mM MgCl2,1mM EGTA。
PDGFR α enzyme/peptide substrates mixed liquor:
2 times that peptide substrates Tyr 04 and PDGFR α enzyme extremely react final concentration are prepared with 1 × kinase buffer liquid A.Final kinases 10 μ L PDGFR α enzymes/peptide substrates mixed liquor when reaction includes 1.54ng-22.6ng PDGFR α, 2 μM of Tyr 04,50mM HEPES (pH7.5), 0.01%BRIJ-35,10mM MgCl2,2mM MnCl2, 1mM EGTA, 1mM DTT.
PDGFR β enzyme/peptide substrates mixed liquor:
2 times that peptide substrates Tyr 04 and PDGFR β enzyme extremely react final concentration are prepared with 1 × kinase buffer liquid A.Final kinases 10 μ L PDGFR β enzymes/peptide substrates mixed liquor when reaction includes 7ng-50ng PDGFR β, 2 μM of Tyr 04,50mM HEPES (pH7.5), 0.01%BRIJ-35,10mM MgCl2, 2mM MnCl2,1mM EGTA,1mM DTT。
RET enzyme/peptide substrates mixed liquor:
2 times that peptide substrates Tyr 02 and RET enzyme extremely react final concentration are prepared with 1 × kinase buffer liquid B.Final kinase reaction When 10 μ L RET enzymes/peptide substrates mixed liquor include 0.49ng-3.64ng RET, 2 μM of Tyr02 and 50mM HEPES (pH 7.5), 0.01%BRIJ-35,10mM MgCl2,1mM EGTA。
MET enzyme/peptide substrates mixed liquor:
2 times that peptide substrates Tyr 06 and MET enzyme extremely react final concentration are prepared with 1 × kinase buffer liquid B.Final kinase reaction When MET enzyme/peptide substrates mixed liquor include 0.49ng-7.84ng MET, 2 μM of Tyr 06 and 50mM HEPES (pH 7.5), 0.01%BRIJ-35,10mM MgCl2,1mM EGTA。
Wherein, HEPES is N- (2- ethoxy) piperazine-N'-2- ethane sulfonic acid, and BRIJ-35 is dodecyl polyethylene glycol Ether, EGTA are bis- (the 2- amino-ethyl ether) tetraacethyls of ethylene glycol, and Tyr is tyrosine, and Ser is serine, and DTT is two sulphur threoses Alcohol, it be extracellular regulated protein kinase -2, Thr is threonine that MEK1, which is mitogen original activated protein kinase -1, ERK2,.
(2) Z '-LYTETMScreening scheme and determination condition are as follows:
The diluted untested compound of addition buffer in 384 orifice plates, enzyme/peptide substrates mixed liquor, ATP (adenine core Guanosine triphosphate), 30 second disks are shaken, 1 hour progress kinase reaction of incubated at room temperature；
Fluorescence-enhancing agent is added in every hole, is incubated at room temperature 1 hour；
It reads fluorescence intensity data at each hole 445nm and 520nm respectively using fluorescence analyser, data is handled, It obtains replacing carbamide compound to the inhibiting rate of VEGFR1, VEGFR2, VEGFR3, PDGFR α, PDGFR β, RET and MET enzymatic activity IC50Value.
Specifically, the data processing method are as follows: arrange the data read using fluorescence analyser, according to formula Calculate the ratio (Ratio445/520) of fluorescence intensity at each hole 445nm and 520nm and the relative inhibition in each hole.The suppression Rate IC processed50Value is that the active sample comprising compound carries out the relative inhibition detected after concentration dilution, is made by Xlfit software Figure is asked to obtain.
Experimental result is as shown in table 1:
Maximum inhibition of the 1 compound I-1~I-6 of table to enzyme
By above-mentioned experimental result it is found that substitution carbamide compound I-1~I-6 provided in an embodiment of the present invention to VEGFR1, VEGFR2, VEGFR3, PDGFR α, PDGFR β, RET and MET 503nhibiting concentration IC50Value shows described in nanomole rank Carbamide compound I-1~I-6 is replaced to all have VEGFR1, VEGFR2, each target spot of VEGFR3, PDGFR α, PDGFR β, RET and MET Stronger combination, can effective inhibitory enzyme activity under extremely low concentration.
Experimental example 2 replaces inhibition of the carbamide compound I-1 and I-2 to hERG (potassium-channel)
(1) experimental procedure:
1, cell prepares
HEK-293 cell (deriving from Military Medical Science Institute) is rinsed with PBS (phosphate buffered saline solution), is used Tryple (pancreatin substitute) solution carries out digestion separation, with DMEM culture medium (Dulbecco's modified eagle Medium so that cell is suspended again and be stored in spare in centrifuge tube.Before Patch-clamp techniques, cell is added dropwise in the filling of glass bottom In the culture dish of chute or 35mm, it is ensured that cell has certain density and cell is in single discrete state.
2, electrophysiologic testing
HERG electric current is recorded using whole-cell patch-clamp recording technique, above-mentioned ready cell suspension is taken to be added in culture dish, It is placed on inverted microscope objective table, after cell is adherent, with extracellular fluid perfusion；
Glass microelectrode draws two step of instrument by microelectrode and draws, and charging in electrode after liquid that it enters water power resistance value is 2M Ω -5M Ω；After establishing whole-cell recording technique pattern, holding command potential is -80mV, gives depolarizing voltage to+60mV, time-histories is 850ms, then repolarization to -50mV, time-histories 1275ms, draws hERG tail current.It is repeated once pulse protocol within every 15 seconds, Through entire experiment；
After electric current is stable by the way of continuous perfusion administration extracellular from low concentration to high concentration.Since low concentration, hold Continue perfusion to efficacy stability, then carries out the perfusion of next concentration.The substituted urea of Example 1 and Example 2 of the present invention preparation Object I-1 and I-2 is closed respectively as test sample, test sample is dissolved in DMSO, is diluted to required concentration, test 5 with extracellular fluid To the blocking effect of hERG tail current, positive control is RMI 9918 for the test sample of a various concentration and 4 concentration positive controls (Terfenadine), to heart toxic side effect.
(2) data collection and analysis
Stimulation granting and signal acquisition are carried out by PatchMadter software；Patch clamp amplifier amplified signal, is filtered into 10KHz.Use the further data analysis of the carry out such as FitMaster, EXCEL and SPASS 21.0 and curve matching.Data with Means standard deviation indicates.In data handling, when judging the blocking effect to hERG, by the peak value of tail current and its baseline into Row correction.The effect of each compound under various concentration is indicated with the inhibiting rate of wake flow.Inhibiting rate=100 × (preceding tail current is administered Peak value-administration rear molding current peak)/preceding tail current peak value % is administered.Using the concentration of tester as horizontal axis, with normalized Electric current inhibiting rate is the longitudinal axis, makees concentration effect curve, obtains the 503nhibiting concentration IC of tester through Hill equation model50Numerical value.
(3) experimental result
Experimental result is as shown in Fig. 1~3 and table 2, substitution carbamide compound I-1 provided in an embodiment of the present invention and I-2 pairs The IC of hERG electric current50Value is all larger than 30 μM, does not have apparent inhibiting effect to the channel hERG, illustrates provided in an embodiment of the present invention Compound I-1 and I-2 acardia toxicity.
The IC of table 2 compound I-1, I-2 to hERG electric current50Value
Compound or positive reference substance IC50(μM) It completes sample size (N)
I-1 >30 2
I-2 >30 2
RMI 9918 (positive control) 0.042 3
It is detected using zoopery and replaces the anti-tumor activity of carbamide compound I-2 in vivo, and won with card and cut down for Buddhist nun and Le It is compareed for Buddhist nun, the tumour is the cancer of the esophagus, colorectal cancer tumour, gastric cancer, liver cancer.
Experimental example 3 replaces the anti esophageal cancer tumor promotion of carbamide compound I-2 in vivo
1, the foundation of tumor model
By KYSE-410 esophageal cancer cell (the deriving from Military Medical Science Institute) DMEM in high glucose for containing 10% fetal calf serum In 37 DEG C, 5%CO2Routine culture in incubator grows to 80% or more fusion rate to cell and reaches institute after passing three generations in vitro When requirement, cell is collected in digestion, is suspended with matrigel 1:1.To about 2 × 106A stomach cancer cell, esophageal cancer cell, colorectal cancer Cell is injected into oxter on the left of every nude mouse respectively.
2, experimental animal grouping and administration
To tumour growth to 100mm3~300mm3Afterwards, animal is grouped, every group 6 at random, is fed by different form of medication It supports, is respectively as follows:
(1) model group: 0.5% sodium carboxymethylcellulose solvent of daily stomach-filling；
(2) tested group 1 of compound I-2: the compound I-2 solution of daily stomach-filling 3mg/kg (mouse weight)；
(3) tested group 2 of compound I-2: the compound I-2 solution of daily stomach-filling 5mg/kg (mouse weight)；
(4) tested group 3 of compound I-2: the compound I-2 solution of daily stomach-filling 10mg/kg (mouse weight)；
(5) tested group 4 of compound I-2: the compound I-2 solution of daily stomach-filling 20mg/kg (mouse weight)；
(6) positive controls 1: the pleasure of daily stomach-filling 10mg/kg (mouse weight) is cut down for Buddhist nun's solution；
(7) positive controls 2: the pleasure of daily stomach-filling 30mg/kg (mouse weight) is cut down for Buddhist nun's solution.
It is primary every the weighing of identical time, weight, the gross tumor volume of mouse are recorded, and calculate relative tumour volume (RTV).Wherein, RTV calculation formula is RTV=Vt/V0, wherein VtIt is the t days after representing administration gross tumor volumes, V0It is to start The gross tumor volume on the same day is administered.
Experimental result is as shown in Figure 4 and Figure 5, and compound I-2 is from low dosage (3mg/kg) to high dose as can be seen from Figure 4 The positive drug pleasure that (20mg/kg) is all better than large dosage to the inhibiting effect of the cancer of the esophagus is cut down for Buddhist nun (10mg/kg and 30mg/kg), says The anti esophageal cancer tumor effect of bright compound I-2 is cut down better than pleasure for Buddhist nun；Fig. 5 shows the experimental mice body for giving compound I-2 It keeps stablizing again, and giving happy cut down for the experimental mice of Buddhist nun has apparent weight loss, illustrates the safety ratio of compound I-2 Finding pleasure in, it is more preferable for Buddhist nun to cut down, less side effects.
Experimental example 4 replaces the anti-colorectal carcinoma tumor promotion of carbamide compound I-2 in vivo
1, the foundation of tumor model
By HT-29 colorectal cancer cell (derive from Military Medical Science Institute) with the DMEM in high glucose containing 10% fetal calf serum in 37 DEG C, 5%CO2Routine culture in incubator, after passing three generations in vitro, needed for growing to 80% or more fusion rate to cell and reach When amount, cell is collected in digestion, is suspended with matrigel 1:1.To about 2 × 106A stomach cancer cell, esophageal cancer cell, colorectal cancer are thin Born of the same parents are injected into oxter on the left of every nude mouse respectively.
2, experimental animal grouping and administration
To tumour growth to 100mm3~300mm3Afterwards, animal is grouped, every group 6 at random, is fed by different form of medication It supports, is respectively as follows:
(1) model group: 0.5% sodium carboxymethylcellulose solvent of daily stomach-filling；
(2) tested group 1 of compound I-2: the compound I-2 solution of daily stomach-filling 2mg/kg (mouse weight)；
(3) tested group 2 of compound I-2: the compound I-2 solution of daily stomach-filling 5mg/kg (mouse weight)；
(4) tested group 3 of compound I-2: the compound I-2 solution of daily stomach-filling 10mg/kg (mouse weight)；
(5) positive controls: the pleasure of daily stomach-filling 10mg/kg (mouse weight) is cut down for Buddhist nun's solution.
It is primary every the weighing of identical time, weight, the gross tumor volume of mouse are recorded, and calculate relative tumour volume (RTV).Wherein, RTV calculation formula is RTV=Vt/V0, wherein VtIt is the t days after representing administration gross tumor volumes, V0It is to start The gross tumor volume on the same day is administered.
Experimental result is as shown in fig. 6, compound I-2 is from low dosage (2mg/kg) to high dose as can be seen from Figure 6 The positive drug pleasure that (10mg/kg) is all better than large dosage to the inhibiting effect of colorectal cancer is cut down for Buddhist nun (10mg/kg), illustrates compound The anti-colorectal carcinoma tumor effect of I-2 is cut down also superior to pleasure for Buddhist nun.
Experimental example 5 replaces the anti-gastric cancer tumor promotion of carbamide compound I-2 in vivo
1, the foundation of tumor model
By BGC-823 stomach cancer cell (deriving from Military Medical Science Institute) with the DMEM in high glucose containing 10% fetal calf serum in 37 DEG C, 5%CO2Routine culture in incubator grows to 80% or more fusion rate to cell and reaches aequum after passing three generations in vitro When, cell is collected in digestion, is suspended with matrigel 1:1.To about 2 × 106A stomach cancer cell, esophageal cancer cell, colorectal cancer cell It is injected into oxter on the left of every nude mouse respectively.
2, experimental animal grouping and administration
To tumour growth to 100mm3~300mm3Afterwards, animal is grouped, every group 6 at random, is fed by different form of medication It supports, is respectively as follows:
(1) model group: 0.5% sodium carboxymethylcellulose solvent of daily stomach-filling；
(2) tested group 1 of compound I-2: the compound I-2 solution of daily stomach-filling 3mg/kg (mouse weight)；
(3) tested group 2 of compound I-2: the compound I-2 solution of daily stomach-filling 5mg/kg (mouse weight)；
(4) tested group 3 of compound I-2: the compound I-2 solution of daily stomach-filling 10mg/kg (mouse weight)；
(5) positive controls: the card of daily stomach-filling 30mg/kg (mouse weight) is rich to replace Buddhist nun's solution.
It is primary every the weighing of identical time, weight, the gross tumor volume of mouse are recorded, and calculate relative tumour volume (RTV).Wherein, RTV calculation formula is RTV=Vt/V0, wherein VtIt is the t days after representing administration gross tumor volumes, V0It is to start The gross tumor volume on the same day is administered.
Experimental result is as shown in fig. 7, compound I-2 is from low dosage (3mg/kg) to high dose as can be seen from Figure 7 The positive drug card that (10mg/kg) is all better than large dosage to the inhibiting effect of gastric cancer is rich for Buddhist nun (30mg/kg), illustrates compound I-2 Anti- non-tumor effect rich better than card replace Buddhist nun.
Embodiment 6 replaces the anti-liver cancer and anti-tumor promotion of carbamide compound I-2 in vivo
1, the foundation of tumor model
By SMMC-7721 liver cancer cells (derive from Military Medical Science Institute) with the DMEM in high glucose containing 10% fetal calf serum in 37 DEG C, 5%CO2Routine culture in incubator, after passing three generations in vitro, needed for growing to 80% or more fusion rate to cell and reach When amount, cell is collected in digestion, is suspended with matrigel 1:1.To about 2 × 106A stomach cancer cell, esophageal cancer cell, colorectal cancer are thin Born of the same parents are injected into oxter on the left of every nude mouse respectively.
2, experimental animal grouping and administration
To tumour growth to 100mm3~300mm3Afterwards, animal is grouped, every group 6 at random, is fed by different form of medication It supports, is respectively as follows:
(1) model group: 0.5% sodium carboxymethylcellulose solvent of daily stomach-filling；
(2) tested group 1 of compound I-2: the compound I-2 solution of daily stomach-filling 5mg/kg (mouse weight)；
(3) tested group 2 of compound I-2: the compound I-2 solution of daily stomach-filling 10mg/kg (mouse weight)；
(4) positive controls: the pleasure of daily stomach-filling 10mg/kg (mouse weight) is cut down for Buddhist nun's solution.
Experimental results are shown in figure 8, and compound I-2 is from low dosage (3mg/kg) to high dose as can be seen from Figure 8 (10mg/kg) has strong inhibiting effect to gastric cancer, and cut down more happy than positive drug of compound I-2 is replaced in high dose 10mg/kg Buddhist nun has stronger internal anti-liver cancer and anti-tumor effect.
Each technical characteristic of embodiment described above can be combined arbitrarily, for simplicity of description, not to above-mentioned reality It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited In contradiction, all should be considered as described in this specification.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously Limitations on the scope of the patent of the present invention therefore cannot be interpreted as.It should be pointed out that for those of ordinary skill in the art For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to guarantor of the invention Protect range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.

Claims (10)

1. a kind of substitution carbamide compound, its pharmaceutically acceptable salt or its solvate, which is characterized in that structure such as formula (I) It is shown:
Wherein:
R1Selected from methoxyl group or deuterated methoxyl group；
R2Selected from methyl, deuterated methyl,In any one structure；
R3Any one in F, Cl, Br, I.
2. substitution carbamide compound according to claim 1, its pharmaceutically acceptable salt or its solvate, feature exist In R3Selected from F or Cl.
3. it is according to claim 1 replace carbamide compound pharmaceutically acceptable salt, which is characterized in that it is described pharmaceutically Acceptable salt is the basic salt of organic acid or inorganic acid.
4. the solvate according to claim 1 for replacing carbamide compound, which is characterized in that the solvate is hydration Object.
5. substitution carbamide compound according to any one of claim 1 to 4, its pharmaceutically acceptable salt or its solvent close Object the inhibitor for preparing one of MET, VEGFR, PDGFR and RET application, or preparation MET, VEGFR, PDGFR and The application of two or more multiple target point inhibitor in RET.
6. substitution carbamide compound according to any one of claim 1 to 4, its pharmaceutically acceptable salt or its solvent close Object is in preparation for regulating and controlling kinase activity or treating and the application in the drug of kinase-associated conditions or pharmaceutical composition, feature It is, the kinases includes one of MET, VEGFR, PDGFR and RET or a variety of.
7. a kind of for treating the drug or pharmaceutical composition of angiogenesis abnormal diseases, which is characterized in that including according to right It is required that substitution carbamide compound, its pharmaceutically acceptable salt described in any one of 1 to 4 or its solvate and physiology can connect The carrier received.
8. drug according to claim 7 or pharmaceutical composition, which is characterized in that the angiogenesis abnormal diseases include Cancer, retinal vessel form at least one in disease, neovascular glaucoma, diseases associated with inflammation and diabetic retinopathy Kind.
9. drug according to claim 8 or pharmaceutical composition, which is characterized in that the cancer includes breast cancer, breathing Road cancer, the cancer of the brain, genital cancer, digestive system cancer, carcinoma of urethra, cancer eye, liver cancer, cutaneum carcinoma, head and/or neck cancer, lymthoma, meat Tumor, leukaemia, thyroid cancer, parathyroid carcinoma and/or their distant metastases.
10. drug according to claim 8 or pharmaceutical composition, which is characterized in that the cancer is colorectal cancer, oesophagus One of cancer, gastric cancer and liver cancer are a variety of.
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