CN102942530A - Novel anti-tumor compound and medication composition thereof - Google Patents
Novel anti-tumor compound and medication composition thereof Download PDFInfo
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- CN102942530A CN102942530A CN 201210485055 CN201210485055A CN102942530A CN 102942530 A CN102942530 A CN 102942530A CN 201210485055 CN201210485055 CN 201210485055 CN 201210485055 A CN201210485055 A CN 201210485055A CN 102942530 A CN102942530 A CN 102942530A
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Abstract
The invention belongs to the pharmaceutical field, and relates to a novel anti-tumor compound with protein tyrosine kinase inhibitory activities, a preparation method of the compound and applications of the compound in treatment of diseases mediated by c-Met or symptoms mediated by the c-Met, and cancers or other proliferative diseases. The novel anti-tumor compound is an N-(2-fluorine-4-{[2, 3-bi-(methyl oxyl) quinoxaline-4-group] oxyl} phenyl)-N'-(4-mesyl phenyl) cyclopropane-1, 1-dimethyl acrylamide compound or pharmaceutically acceptable salt, a hydrate and/or a solvate of the compound. The invention further relates to an application of the compound in manufacturing of medications for treating cancers. The cancers are breast, respiratory tract, brain, reproductive organ, digestive tract, urinary tract, eye, liver, skin, head or neck, thyroid gland and parathyroid gland cancers or distant metastases of solid tumors. The invention further relates to a medication composition which comprises the N-(2-fluorine-4-{[2, 3-bi-(methyl oxyl) quinoxaline-4-group] oxyl} phenyl)-N'-(4-mesyl phenyl) cyclopropane-1, 1-dimethyl acrylamide compound or the pharmaceutically acceptable hydrate or solvate of the compound and a pharmaceutically acceptable excipient.
Description
Technical field
The present invention relates to have protein tyrosine kinase and suppress active new a kind of new antitumoral compounds; be N-(2-fluoro-4-{[2; two (the methyl oxygen base) quinoxalines-4-yl of 3-] the oxygen base } phenyl)-N '-(4-methylsulfonyl phenyl) cyclopropane-1; 1-diformamide compound; its preparation method and be used for the treatment of disease or the illness, particularly cancer of c-Met-mediation and the purposes of other proliferative disease of c-Met-mediation.
Background technology
Cancer is one of disease of modal wide-scale distribution.In 2002, the whole world surpasses 4,400,000 people and is diagnosed with mammary cancer, colorectal carcinoma, ovarian cancer, lung cancer or prostate cancer, and surpass 2,500,000 people and die from these pathogenic diseases (Globocan 2002Report, http://www-dep.iarc.fr/globocan/downloads.htm).Only in the U.S., expectation had in 2005 to surpass 1,250,000 newly-increased case and have above 500000 people dies from cancer.It is the cancer of colon (～100000), lung (～170000), mammary gland (～210000) and prostate gland (～230000) that great majority in these newly-increased cases are estimated.Expectation all increases approximately 15% at sickness rate and the prevalence rate of Future Ten year cancer, shows 1.4% average growth rate.
The generation of cancer can have many modes, and this is one of very difficult reason of their treatment.A kind of mode is the conversion that cell passes through cancer protein, and cancer protein derives from normal cell protein matter by genetic mutation, transforms to cause the non-physiology activation of these protein.The protein of a family in many cancer proteins source is Tyrosylprotein kinase (for example, the src kinases), particularly receptor tyrosine kinase (RTKs).In the past twenty years, permitted the importance of signal in the mammalian cell growth regulating that many-sided research has confirmed receptor tyrosine kinase (RTK)-mediation.Recently, the selectivity micromolecular inhibitor of clinical use Tyrosylprotein kinase has been obtained achievement as antineoplastic agent.
The c-Met acceptor also is receptor tyrosine kinase.Identified its oncogenic potential in the early 1980s, from the human osteosarcoma cell line of chemical induction, be separated at that time the Met of sudden change, described clone contains the kinase domain [C.S.Cooper etc., Nature 311:29-33 (1984)] of the Met gene that the dimerization domain with its N-end condenses.
Cell Met albumen is the different dimerization transmembrane protein [G.A.Rodrigues etc., Mol.Cell Biol.11:2962-70 (1991)] that synthesizes strand 190kd precursor.This precursor carries out cracking in the cell with α-chain of forming 50kd and the beta chain of 145kd after amino-acid residue 307, the two connects by disulfide linkage.α-chain is extracellular fully, and beta chain can be crossed over plasma membrane.Beta chain is comprised of the sema structural domain of N-end, and this structural domain is regulated ligand binding with α-chain.The remainder of the outer functional domain of beta chain is comprised of halfcystine enrichment structural domain and four immunoglobulin domains, and it is cross-film zone and cell intracellular domain subsequently.The cell intracellular domain contains nearly film territory, kinase domain and C-end structure territory, and it regulates downstream signal.In case ligand binding, induce the dimerization of acceptor, kinase domain is by the activation ring of membrane-proximal region territory (Y1003), kinases (Y1234 and Y1235) and the cascade activation of the tyrosine autophosphorylation step in carboxyl-end structure territory (Y1349 and Y1356).The Y1349 of phosphorylation and Y1356 comprise the required many substrates in conjunction with adaptor protein of downstream c-Met signalling and stop site [C.Ponzetto etc., Cell 77:261-71 (1994)].C-Met one of the most important substrate that signals is support (scaffolding) adaptor protein Gab1, it is combined with Y1349 or Y1356 by unusual Tyrosine O-phosphate binding site (term mbs:met binding site), causes the interior signal of cell of unique prolongation.Another important substrate is adaptor protein Grb2.According to cellular environment, these joint things are regulated the activation of signal pathway in the various cells, for example pass through those of ERK/MAPK, PI3K/Akt, Ras, JNK, STAT, NF κ B and beta-catenin signalling.
By pHGF (HGF) (also being called dispersion factor) and splice variant activation thereof, this is its known unique biologic activity part [L.Naldini etc., Oncogene 6:501-4 (1991)] to c-Met uniquely.HGF has unique structure, the similarity of the proteolytic ferment of its demonstration and Profibrinolysin family.It is comprised of the amino of non-enzymic activity-end structure territory, is four kringle structural domains and serine protease homology structural domain after amino-end structure territory.Similar to c-Met, HGF be synthesized into nonactive strand precursor (front-HGF), (for example, the Profibrinolysin activator is connected extracellular cracking and be converted into the active alpha that disulphide connects-and beta chain heterodimer to nonactive strand precursor with thrombin by serine protease.In conjunction with heparan sulfate proteoglycan, this makes it keep mainly being combined with extracellular matrix and limiting its diffusion to HGF with high-affinity.Crystal structure analysis shows that HGF forms dimer, and it is in case be combined the dimerization of namely inducing acceptor with c-Met.
HGF is expressed by mesenchymal cell, its with particularly in epithelial cell the c-Met of wide expression be combined in various tissues and comprise in epithelial cell, endotheliocyte, neuronal cell and the hematopoietic cell and cause pleiotropy.This effect generally includes a kind of or whole of following phenomenon: i) stimulate mitotic division to occur; By hepatocellular mitogenic activity is identified HGF; Ii) stimulate intrusion and migration; In experimental technique independently, based on the inducing action of its cell mobility (" dispersion "), HGF is accredited as dispersion factor; And iii) stimulate form that (tubule generation) occurs.HGF induces the formation of branch tubule in collagen stroma from Madin-Darby canine kidney(cell line).In addition, show that from the mouse of genetic modification and the evidence of cell culture test c-Met can be used as the survival acceptor and Cell protection avoids apoptosis [N.Tomita etc., Circulation 107:1411-1417 (2003); S.Ding etc., Blood 101:4816-4822 (2003); Q.Zeng etc., J.Biol.Chem.277:25203-25208 (2002); N.Horiguchi etc., Oncogene 21:1791-1799 (2002); A.Bardelli etc., Embo are (1996) J.15:6205-6212; P.Longati etc., Cell Death Differ.3:23-28 (1996); E.M.Rosen, Symp.Soc.Exp.Biol.47:227-234 (1993)].The coordination of these biological processes of HGF is carried out and can be produced special genetic program, and it is called as " invasive growth ".
Under normal operation, c-Met and HGF particularly are absolutely necessary for the growth of placenta and liver and the myoblastic directional migration of four limbs body segment for the fetal development of mouse.The heredity of c-Met or HGF gene is interrupted causing identical phenotype, and this shows the interaction of their uniquenesses.People understand less to the physiological role of c-Met/HGF in the adult organism body, but experimental evidence shows that they are relevant with wound healing, tissue regeneration, hemoposieis and tissue homeostasis.
The discriminating of cancer protein TPR-MET is the most important hint that c-Met may play a role in tumour occurs.Other important source of evidence is in many different experimental techniques.The induced expression tumour of crossing of c-Met or HGF occurs and metastatic phenotype (when expressing in nude mice) in people and the mouse cell line.The tumour that the transgenosis of c-Met or HGF is crossed the induced expression mouse occurs.
More enjoyably, for example the missense mutation of c-Met or the sudden change of activated receptor have been identified in lung cancer, cancer of the stomach, liver cancer, head and neck cancer, ovarian cancer and the cancer of the brain sporadic with heredity corpora mammillaria kidney (HPRC) and other cancer type.Importantly, the specificity c-Met of HPRC family sudden change and disease isolation form cause-effect relationship [L.Schmidt etc., Nat.Genet.16:68-73 (1997) between c-Met activation and the human cancer; B.Zbar etc., Adv.Cancer Res.75:163-201 (1998)].Have that the activation sudden change of strong activity of conversion is positioned at activation ring (D1228N/H and Y1230H/D/C) and contiguous P+1 encircles (M1250T).Have been found that other weak sudden change is near the catalysis ring and at the A of kinase domain leaf.In addition, in lung tumor, observed some sudden change in the nearly film of the c-Met territory, its not direct activation kinases, but by making protein tolerate stabilizing protein [M.Kong-Beltran etc., Cancer Res.66:283-9 (2006) to ubiquitination and degraded subsequently; T.E.Taher etc., J.Immunol.169:3793-800 (2002); P.Peschard etc., Mol.Cell 8:995-1004 (2001)].Be enjoyably, the wettability that increases in the somatic mutation of c-Met and the various cancers with shift widely relevant.When the frequency lower (being lower than 5%) of kind of system and somatic mutation, observed other main mechanism, in the situation that is not having sudden change, it causes the c-Met signal to take off adjusting by paracrine or autocrine mechanism.For example produce in the osteosarcoma or rhabdosarcoma of HGF at physiology in the tumour that derives from mesenchymal cell, and in the glioblastoma multiforme in ectoderm source and breast cancer, observed the paracrine activation.
Yet modal case is that wherein c-Met crosses the cancer of expression, such as what observe in the cancer of colon, pancreas, stomach, mammary gland, prostate gland, ovary and liver.For example, by gene amplification expression can occur, as observing in stomach and lung tumor cell system.Recently, in the lung tumor cell system that obtains the inhibiting resistance of EGF acceptor, detect crossing of c-Met and express [J.A.Engelmann etc., Science 316:1039-1043 (2007)].Some crosses the also coexpression HGF of epithelium tumor that expresses c-Met, thereby causes autocrine c-Met/HGF stimulating ring and evade the needs of the HGF in mesenchymal cell source.
Generally speaking, have been found that regardless of its concrete mechanism the abnormal activation of c-Met common relevant with prognosis mala [J.G.Christensen etc., Cancer Lett.225:1-26 (2005)] in the human cancer.
In a word, carried out many confirmations c-Met and be studying in the external and body of important cancer target spot, comprehensively tabulation can be checked at http://www.vai.org/met [C.Birchmeier etc., Nat.Rev.Mol.Cell Biol.4:915-25 (2003)].Adopt many strategies to weaken Met unusual in people's tumour and signaled, comprised HGF antagonist and micromolecular inhibitor etc.Present many micromolecular inhibitors are in the clinical development, for example ARQ-197 (Arqule), foretinib (XL-880, Exelixis/GSK) and PH-2341066 (Pfizer); They have been carried out summarizing [J.J.Cui, Expert Opin.Ther.Patents 17:1035-45 (2007)] recently.
WO 2005/030140A1 has described a class N-(2-fluoro-4-{[2; two (the methyl oxygen base) quinoxalines-4-yl of 3-] the oxygen base } phenyl)-N '-(4-methylsulfonyl phenyl) cyclopropane-1; the 1-diformamide; it has obvious c-Met and Ret suppresses active, and discloses its preparation method.N-(2-fluoro-4-{[2, two (the methyl oxygen base) quinoxalines-4-yl of 3-] the oxygen base } phenyl)-N '-(4-methylsulfonyl phenyl) cyclopropane-1, the 1-diformamide, compound structure (hereinafter to be referred as Compound I) as shown below:
(Compound I).
WO 2005/030140A1 has also described a class N-[3-fluoro-4-({ 6-(methyl oxygen base)-7-[(3-morpholine-4-base propyl group) oxygen base] quinolyl-4 } the oxygen base) phenyl]-N '-(4-fluorophenyl) cyclopropane-1, the 1-diformamide, it has obvious c-Met and Ret suppresses active, and discloses its preparation method.N-[3-fluoro-4-(6-(methyl oxygen base)-7-[(3-morpholine-4-base propyl group) and the oxygen base] quinolyl-4 } the oxygen base) phenyl]-N '-(4-fluorophenyl) cyclopropane-1, the 1-diformamide, compound structure (hereinafter to be referred as Compound I I) as shown below:
(Compound I I).
Surprisingly, the applicant finds in research, on the improved basis of above-claimed cpd, has been found that now than the more superior c-Met IC of above-claimed cpd
50A kind of novel compound of value, and represented the prospect of significantly improved treatment tumour.
Summary of the invention
Thus, in one aspect in, the present invention relates to N-(2-fluoro-4-{[2, two (the methyl oxygen base) quinoxalines-4-yl of 3-] oxygen base } phenyl)-N '-(4-methylsulfonyl phenyl) cyclopropane-1,1-diformamide compound:
The compounds of this invention can also their form of salt, hydrate and/or solvate exist.
Be used for the pharmacy acceptable salt that salt of the present invention is preferably the compounds of this invention (for example, referring to S.M.Berge etc., " Pharmaceutical Salts ", J.Pharm.Sci.1977,66,1-19).
The hydrate of the compounds of this invention or their salt is the stoichiometry combination of compound or salt and water, for example, and semihydrate, monohydrate or dihydrate.
The solvate of the compounds of this invention or their salt is the coatings of stoichiometric composition of compound or salt and solvent, the solvate that the organic solvent of for example commonly using with this area is combined.
The most preferred preparation method of the present invention in an embodiment.
Another aspect; another object of the present invention is to provide a kind of N-of preparation (2-fluoro-4-{[2; two (the methyl oxygen base) quinoxalines-4-yl of 3-] the oxygen base } phenyl)-N '-(4-methylsulfonyl phenyl) cyclopropane-1, the method for 1-diformamide, it comprises following step:
(1), 2,3-dimethyl-5-chloro-quinoxaline and 2-fluoro-4-nitrophenoxy etherificate, reduction are obtained 2-fluoro-4-(2,3-dimethoxy quinoxaline-4-base oxygen base)-phenyl amine;
(2), cyclopropane dicarboxylic acid and the methylsulfonyl aniline condensation obtained 1-(4-methylsulfonyl phenyl amino formyl radical)-cyclopropane-carboxylic acid, then under the oxalyl chloride condition, prepare 1-(4-methylsulfonyl phenyl amino formyl radical)-cyclopropanecarbonyl-acyl chlorides;
(3), step (1) and the condensation under the salt of wormwood condition of step (2) products therefrom obtain target product N-(2-fluoro-4-{[2; two (the methyl oxygen base) quinoxalines-4-yl of 3-] the oxygen base } phenyl)-N '-(4-methylsulfonyl phenyl) cyclopropane-1, the 1-diformamide.
Shown in the figure specific as follows:
Described compound N-(2-fluoro-4-{[2, two (the methyl oxygen base) quinoxalines-4-yl of 3-] the oxygen base } phenyl)-N '-(4-methylsulfonyl phenyl) cyclopropane-1, the 1-diformamide can also with other pharmaceutically acceptable acid salt, these examples that can accept acid comprise the acid salt that forms with mineral acid and organic acid, and described mineral acid is hydrochloric acid, trifluoroacetic acid, Hydrogen bromide, nitric acid, ammonium sulfate, sulfuric acid, perchloric acid, hydrofluoric acid, hydroiodic acid HI, phosphoric acid and similarly acid for example; Described organic acid is tartrate for example, FUMARIC ACID TECH GRADE, phenylformic acid, methylsulfonic acid, Phenylsulfonic acid, butene dioic acid, tosic acid, toxilic acid, fumaric acid, succsinic acid, acetic acid, oxysuccinic acid, half fumaric acid, Citric Acid, Succinic Acid, xitix, acetic acid, lactic acid, propanedioic acid, oxalic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, glycine, Methionin, arginine, ornithine, L-glutamic acid, aspartic acid, 1, the 2-ethionic acid, the 2-ethylenehydrinsulfonic acid, the 4-chlorobenzenesulfonic acid, the 2-naphthene sulfonic acid, the 4-toluenesulphonic acids, camphorsulfonic acid, glucoheptonic acid, 4,4 '-methylene-bis-(3-hydroxyl-2-alkene-1-carboxylic acid), the 3-phenylpropionic acid, trimethylacetic acid, tert.-butylacetic acid, dodecyl sulphate, glyconic acid, hydroxynaphthoic acid, Whitfield's ointment, stearic acid and muconic acid and similarly acid.
The compounds of this invention preferably is combined into malate with oxysuccinic acid, more preferably is combined into (L)-malate with (L)-oxysuccinic acid.
Described compound N-(2-fluoro-4-{[2; two (the methyl oxygen base) quinoxalines-4-yl of 3-] the oxygen base } phenyl)-N '-(4-methylsulfonyl phenyl) cyclopropane-1; the 1-diformamide can also with other pharmaceutically acceptable base addition salt; these examples comprise the base addition salt that forms when the acid proton in being present in parent compound is replaced by metal ion, and described metal ion is sodium salt, sylvite, lithium salts, ammonium salt, calcium salt, magnesium salts, molysite, zinc salt, mantoquita, manganese salt, aluminium salt and analogue for example.Concrete salt is ammonium salt, sylvite, sodium salt, calcium salt and magnesium salts.The salt that is derived from pharmaceutically acceptable organic nontoxic alkali includes, but not limited to the salt of primary amine, secondary amine and tertiary amine, the amine of replacement comprises the amine of naturally occurring replacement, cyclammonium and deacidite.The example of organic bases comprises Isopropylamine, Trimethylamine 99, diethylamine, triethylamine, tripropyl amine, thanomin, DMAE, 2-DEAE diethylaminoethanol, dicyclohexylamine, Methionin, arginine, Histidine, caffeine, PROCAINE HCL, PHARMA GRADE, sea bar amine, choline, trimethyl-glycine, quadrol, glycosamine, methylglucosamine, Theobromine, purine, piperazine, piperidines, N-ethylpiperidine, tromethane, N-METHYL-ALPHA-L-GLUCOSAMINE, versamid 900 and analogue.Exemplary organic bases is Isopropylamine, diethylamine, thanomin, Trimethylamine 99, dicyclohexylamine, choline and caffeine.
The method of using
Compound of the present invention is receptor tyrosine kinase, particularly the establishment agent of the active or expression of c-Met receptor tyrosine kinase.In addition, the compounds of this invention be characterized as high permeability in the epithelial cell of intestines, promote these compounds after per os gives from GI absorption.The compound useful as therapeutics of therefore, expection formula (I).
Therefore, in another embodiment, it is relevant with the c-Met kinase activity or by the method for the illness of its mediation to the invention provides in the patient of this treatment of needs treatment, comprises the above defined the compounds of this invention that gives patient's significant quantity.In certain embodiments, the illness relevant with the c-Met kinase activity is cell proliferation disorders, particularly cancer.
Term " treatment " or " processing " are conventional the uses as described herein, for example, take resist, alleviate, reduce, alleviate, improve disease or illness for example the situation of cancer as processing or the nursing of purpose to the experimenter.
Term " experimenter " or " patient " comprise suffering from cell proliferation disorders or other organism that can be benefited by the administration of the compounds of this invention, for example mankind or non-human animal.The preferred mankind comprise suffering from or be easy to suffer from cell proliferation disorders as described herein or the human patients of correlation behavior.Term " non-human animal " comprises vertebrates, for example, and Mammals, for example non-human primate, sheep, ox, dog, cat, and rodent, for example mouse, and non-human mammal, such as chicken, Amphibians, Reptilia etc.
Term " relevant with c-Met or by the illness of c-Met mediation " comprises with c-Met active relevant or relate to the disease of c-Met activity, and for example the activity of c-Met is excessively strong, and with the illness of these diseases.The example of " relevant with c-Met or by the illness of c-Met mediation " comprises the illness that is caused by the c-Met overstimulation because of sudden change among unusual a large amount of c-Met or the c-Met, perhaps the illness because suddenling change among unusual a large amount of c-Met or the c-Met and being caused by unusual a large amount of c-Met activity.
Term " activity of c-Met is excessively strong " refers to normally not express the cells c-Met of c-Met, the cell that does not perhaps normally have active c-Met produces the c-Met activity, perhaps cause the c-Met of the increase of undesirable cell proliferation to express, perhaps cause the sudden change of c-Met constitutively activate.
Term " cell proliferation disorders " comprises the illness that relates to the undesirable or uncontrolled propagation of cell.The compounds of this invention can be used for cell proliferation and/or the cytodifferentiation such as prevention, inhibition, prevention, reduction, control, and/or produces natural death of cerebral cells.The method comprises the patient who needs it, comprise Mammals (comprising the mankind), the compounds of this invention of a certain amount of effective treatment or prevention illness, or its pharmacy acceptable salt, isomer, polymorphic form, metabolite, hydrate or solvate.
Cell proliferation among the present invention or hyper-proliferative illness include but not limited to, for example, psoriasis, keloid and cutaneous other propagation, bone obstacle, blood vessel originality or vascular proliferation obstacle, pulmonary hypertension, fibrosis obstacle, proliferation of glomerular mesangial cells disease, polyp of colon, POLYCYSTIC KIDNEY DISEASE, benign prostate propagation (BPH) and solid tumor, for example mammary gland, respiratory tract, brain, reproductive organ, digestive tube, urinary tract, eye, liver, skin, head and neck, Tiroidina, parathyroid cancer and their far-end shift.These obstacles also comprise lymphoma, sarcoma and leukemia.
The example of breast cancer includes but not limited to wettability duct carcinoma, wettability lobular carcinoma, ductal carcinoma in situ and LCIS.
The example of respiratory cancer includes but not limited to small cell lung cancer and nonsmall-cell lung cancer and bronchial adenoma and pleura pulmonary blastoma.
The example of the cancer of the brain includes but not limited to brain stem and hypothalamus neurospongioma, cerebellum and large cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma and neuroectodermal tumor and pinealoma.
The tumour of male reproductive organ includes but not limited to prostate cancer and carcinoma of testis.Female reproductive organ's tumour includes but not limited to the cancer of uterine endometrium, uterine cervix, ovary, vagina and vulva, and the sarcoma in uterus.
Gastral tumour includes but not limited to the cancer of anus, colon, colorectum, esophagus, gall-bladder, stomach, pancreas, rectum, small intestine and sialisterium.
The tumour of urinary tract includes but not limited to bladder cancer, penile cancer, kidney, carcinoma of renal pelvis, carcinoma of ureter, urethral carcinoma and heredity and sporadic corpora mammillaria kidney.
The eye cancer includes but not limited to intraocular melanoma and retinoblastoma.
The example of liver cancer includes but not limited to hepatocellular carcinoma (being with or without the hepatocellular carcinoma that the plumage stratiform changes), cholangiocarcinoma (intrahepatic cholangiocarcinoma) and the liver cell cholangiocarcinoma that mixes.
Skin carcinoma includes but not limited to squamous cell carcinoma, Kaposis sarcoma, malignant melanoma, merkel's cells skin carcinoma and non-melanoma skin cancer.
Head and neck cancer includes but not limited to cancer, lip and oral carcinoma and the squamous cell of larynx, hypopharynx, nasopharynx, oropharynx.
Lymphoma includes but not limited to the lymphoma of AIDS associated lymphoma, non-Hodgkin′s lymphomas, cutaneous T cell lymphoma, Burkitt lymphoma, lymphogranulomatosis and central nervous system.
Sarcoma includes but not limited to soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma and rhabdosarcoma.
Leukemia includes but not limited to acute myeloid leukemia, acute lymphoblastic leukemia, lymphocytic leukemia, chronic granulocytic leukemia and hairy cell.
Can use the fibrosis proliferative disorders of the compounds of this invention and method treatment, be that the extracellular matrix abnormal formation comprises pulmonary fibrosis, atherosclerosis, restenosis, liver cirrhosis and proliferation of glomerular mesangial cells disease, comprise ephrosis for example glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy.
Can comprise tumor growth, retinopathy by people or other mammiferous other illness that gives the compounds of this invention treatment, the macula lutea degenerative change, rheumatoid arthritis, psoriatic that comprises diabetic retinopathy, ischemic retinal venous occlusion, retinopathy of prematurity and age-dependent with epidermis under blister form relevant epidermolysis illness, comprise bullous pemphigoid, erythema multiforme and dermatitis herpetiformis.
Above-mentioned disease is characterized in the mankind fully, but also is present in other animal with the similar cause of disease, can treat by giving pharmaceutical composition of the present invention.
The compounds of this invention can be used as independent medicament administration, and perhaps with one or more other therapeutical agent Combined Preparation, wherein said associating does not cause unacceptable deleterious effect.This combination therapy comprises the single medicine preparation that contains the compounds of this invention and one or more other therapeutical agents, and gives the compounds of this invention and various other therapeutical agent with drug alone dosage form separately.For example, can be with the compounds of this invention and therapeutical agent with for example together administration of Tablet and Capsula of single oral dosage form composition, perhaps can be with every kind of medicine with independent preparation administration.
When using independent preparation, the compounds of this invention and one or more other therapeutical agents are (for example simultaneously) or in separately staggered time (for example continuous) administration basically simultaneously.
Especially, the compounds of this invention can be fixed or independent combination and other antineoplastic agent uses, for example the antineoplastic agent of alkylating agent, metabolic antagonist, plant origin, hormonotherapy agent, topoisomerase enzyme inhibitor, camptothecin derivative, kinase inhibitor, targeted drug, antibody, Interferon, rabbit and/or biological response modifier, anti-angiogenic compounds and other tumour medicine.In this respect, hereinafter be the non-limiting tabulation of second exemplary drugs that can be used in combination with the compounds of this invention:
Alkylating agent, include but not limited to mustargen N-oxide compound, endoxan, ifosfamide, phosphinothioylidynetrisaziridine, ranomustine, nimustine, Temozolomide, altretamine, apaziquone, brostailicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, Mafosfamide, bendamustine and mitolactol; The alkylated compound of platinum-coordination includes but not limited to, cis-platinum, carboplatin, eptaplatin, lobaplatin, S 254, oxaliplatin and Satraplatin;
Metabolic antagonist, include but not limited to methotrexate, the Ismipur riboside, mercaptopurine, 5 FU 5 fluorouracil makes up separately or with folinic acid, Tegafur, doxifluridine, carmofur, cytosine arabinoside, cytosine arabinoside octadecyl phosphoric acid salt, enocitabine, gemcitabine, fludarabine, 5-azacytidine, capecitabine, CldAdo, Clofarex, Decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, melphalan, Nelzarabine, Nolatrexed, ocfosfite, pemetrexed disodium, pentostatin, pelitrexol, Raltitrexed, triapine, trimetrexate, vidarabine, vincristine(VCR) and vinorelbine;
The hormonotherapy agent, include but not limited to, Exemestane, leuprorelin acetate, Anastrozole, doxercalciferol, fadrozole, formestane, 11-beta hydroxyl steroid dehydrogenase type 1 inhibitor, 17-α hydroxylase/17,20 lyase inhibitors are Abiraterone acetate for example, the 5-alpha reductase inhibitor is finasteride and epristeride for example, anti-estrogens is Tamoxifen Citrate and fulvestrant for example, Trelstar, toremifene, raloxifene, Lasofoxifene, letrozole, anti-androgens is bicalutamide for example, flutamide, mifepristone, Nilutamide, Casodex and Mifepristone class and combination thereof;
The antitumorigenic substance of plant origin comprises, for example, is selected from those of mitotic inhibitor, esperamicin for example, and for example husky dagger-axe is grand, ixabepilone and epothilone B, vinealeucoblastine(VLB), Vinflunine, docetaxel and taxol;
The cytotoxicity topoisomerase enzyme inhibitor, include but not limited to aclarubicin, Dx, amonafide, belotecan, camptothecine, 10-hydroxycamptothecine, 9-aminocamptothecin, diflomotecan, irinotecan, Hycamtin, edotecarin, epimbicin, Etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirambicin, pixantrone, rubitecan, sobuzoxane, tafluposide and combination thereof;
Immune substance comprises for example interferon alpha of Interferon, rabbit, Intederon Alpha-2a, interferon alpha-b, interferon beta, interferon-gamma-1a and interferon-gamma-n1, with other immunostimulant for example L19-IL2 and other IL2 derivative, filgrastim, lentinan, Schizophyllan, TheraCys, ubenimex, rIL-2, alemtuzumab, BAM-002, Dacarbazine, daclizumab, denileukin, gemtuzumab, ozogamicin, ibritumomab, Imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), Sch-39300, Sargramostim, tasonermin, teceleukin, Thymosin-Alpha1, tositumomab, Vimlizin, epratuzumab, mitumomab, oregovomab, Victibix and Provenge;
Biological response modifier is for modifying for example histocyte survival of life entity defense mechanism or biologically, growth or differentiation so that they have the reagent of anti-tumor activity; This class reagent comprises, for example, and krestin, lentinan, sizofiran, molten chain bacterium, ProMune and ubenimex;
Anti-angiogenic compounds, include but not limited to that Acitretin, aflibercept, angiostatin, aplidine, asentar, Ah former times are for Buddhist nun, rhuMAb-VEGF, brivanib alaninat, cilengtide, combretastatin, endostatin, fenretinide, Halofuginone, pazopanib, ranibizumab, rebimastat, recentin, regorafenib, removab, Revlimid, Xarelto, squalamine, Sutent, lapatinibditosylate, Thalidomide, ukrain, PTK787 and vitaxin;
Antibody includes but not limited to, trastuzumab, Cetuximab, rhuMAb-VEGF, Rituximab, ticilimumab, ipilimumab, lumiliximab, catumaxomab, atacicept, oregovomab and alemtuzumab;
The VEGF inhibitor, for example, sorafenib, regorafenib, rhuMAb-VEGF, sunitinib, recentin, axitinib, aflibercept, telatinib, brivanib alaninate, vatalanib, pazopanib and Ranibizumab;
EGFR (HER1) inhibitor, for example, Cetuximab, panitumumab, vectibix, gefitinib, erlotinib and Zactima;
The HER2 inhibitor, for example, lapatinib, tratuzumab and pertuzumab;
MTOR inhibitors, for example, temsirolimus, sirolimus/rapamycin and everolimus;
The c-Met inhibitor;
PI3K and AKT inhibitor;
CDK inhibitor, for example roscovitine and flavopiridol;
Spindle assembly checkpoint inhibitor and target antimitotic agent, for example PLK inhibitor, Aurora inhibitor (for example, Hesperadin), check point kinase inhibitor and KSP inhibitor;
Hdac inhibitor, for example, panobinostat, vorinostat, MS275, belinostat and LBH589;
HSP90 and HSP70 inhibitor;
Proteasome inhibitor, for example bortezomib and carfilzomib;
The serine/threonine kinase inhibitor comprises mek inhibitor and Raf inhibitor, for example sorafenib;
Farnesyl transferase inhibitor for example, tipifamib;
Tyrosine kinase inhibitor for example comprises dasatinib, nilotibib, regorafenib, bosutinib, sorafenib, rhuMAb-VEGF, sunitinib, cediranib, axitinib, aflibercept, telatinib, imatinib mesylate, brivanibalaninate, pazopanib, ranibizumab, vatalanib, Cetuximab, panitumumab, vectibix, gefitinib, erlotinib, lapatinib, tratuzumab, pertuzumab and c-Kit inhibitor;
The Vitamin D Receptor agonist;
Bcl-2 protein inhibitor, for example obatoclax, Ao Limosen sodium and gossypol;
Cluster of differentiation 20 receptor antagonists, for example, Rituximab;
Ribonucleotide reductase inhibitors, for example, gemcitabine;
Neoplasm necrosis apoptosis induction ligand acceptor 1 agonist, for example, mapatumumab;
The 5-hydroxytryptamine receptor antagonist, for example, rEV598, xaliprode, palonosetron hydrochloride, granisetron, Zindol and AB-1001;
Integrin inhibitor comprises α 5-beta 1 integrin inhibitor, for example, and E7820, JSM 6425, volociximab and endostatin;
Androgen receptor antagonists, for example comprise abolon, Fluoxymesterone, Synrotabs, Prost-aid, andromustine, bicalutamide, flutamide, apo-cyproterone, apo-flutamide, chlormadinone acetate, cyproterone acetate, Tabi, cyproterone acetate and Nilutamide;
Aromatase inhibitor, for example, Anastrozole, letrozole, testolactone, Exemestane, amino aminoglutethimide and formestane;
Matrix metallo-proteinase inhibitor;
Other carcinostatic agent for example comprises, alitretinoin, Polyinosinic-polycytidylic acid, the atrasentan bexarotene, bortezomib, bosentan, calcitriol, exisulind, fotemustine, Ibandronic acid, miltefosine, mitoxantrone, I-Asparaginase, Procarbazine, Dacarbazine, hydroxyurea, pegaspargase, pentostatin, Tazarotene, velcade, gallium nitrate, canfosfamide, darinaparsin and vitamin A acid.
In preferred embodiments, the compounds of this invention can for example other kinase inhibitor (for example, EGFR inhibitor), mTOR inhibitors and angiogenesis inhibitor be united use with chemotherapy (being cytotoxic agent), hormone antagonist and/or targeted therapy.
The compounds of this invention can also be combined with radiotherapy and/or surgical operation and be used for cancer therapy.
In addition, the compounds of this invention uses with himself or in composition, is used for research and diagnosis or with the reference standard etc. that performs an analysis, these all are well known in the art.
Pharmaceutical composition and methods for the treatment of
In yet another aspect, the invention provides the compounds of this invention that comprises as hereinbefore defined and the pharmaceutical composition of pharmaceutically acceptable carrier.
In yet another aspect, the invention provides the method for pharmaceutical compositions.The method comprises comprising at least a the compounds of this invention is as hereinbefore defined mixed with at least a pharmaceutically acceptable carrier, and makes the composition that obtains become the step of suitable form of medication.
The compounds of this invention can whole body and/or local onset.For this purpose, its mode that can be fit to is used, for example oral, parenteral, lung, nose, hypogloeeis, tongue, oral cavity, rectum, through skin, conjunctiva, ear or as implant or support.
For these application approaches, the application mode administration that the compounds of this invention active ingredient can be fit to.
Useful oral application form comprises fast and/or discharges with improved form the application form of active ingredient, for example tablet (dressing and coated tablet for example do not have enteric coating), capsule, sugar coated tablet, granule, pilule, powder, emulsion agent, suspensoid, solution and aerosol.
Can implement parenteral application and avoid absorption step (in the intravenously, intra-arterial, heart, in the backbone or in the lumbar vertebrae) or comprise absorption (intramuscular, subcutaneous, intracutaneous, through skin or intraperitoneal).Useful parenteral application form comprises injection formulations and the infusion preparation with solution, suspensoid, emulsion agent, freeze-dried and sterilized powder form.
The form that is applicable to other application approach comprises, for example, the tablet of inhalable drug form (comprising powdery inhalation, sprays), nasal drop, solution or sprays, tongue, hypogloeeis or orally administering or capsule, suppository, ear and ophthalmic preparation, capsule for vagina agent, aqueous suspensions (lotion, shake mixture), lipotropy suspensoid, ointment, ointment, emulsion, paste, face powder, implant or support.
In preferred embodiments, provide as hereinbefore defined the pharmaceutical composition that comprises the compounds of this invention with the form that is applicable to oral administration.In a more preferred embodiment, provide as hereinbefore defined the pharmaceutical composition that comprises the compounds of this invention with the form that is applicable to intravenously administrable.
The compounds of this invention active ingredient itself can be converted into described application form according to known way.This can carry out with inert non-toxic, pharmaceutically suitable vehicle.These comprise, especially carrier (for example Microcrystalline Cellulose), solvent (for example liquid macrogol), emulsifying agent (for example sodium lauryl sulphate), dispersion agent (for example polyvinylpyrrolidone), synthetic or natural biological copolymer (for example albumin), stablizer (for example antioxidant for example xitix), tinting material (for example inorganic pigment for example ferric oxide) or taste and/or smell corrigent.
In another embodiment, the invention provides the method that treatment needs patient's cell proliferation disorders of this treatment, comprise the compounds of this invention as hereinbefore defined that gives patient's significant quantity.In certain embodiments, cell proliferation disorders is cancer.
In yet another aspect, the invention provides the compounds of this invention of as mentioned definition for the preparation of the purposes of the pharmaceutical composition for the treatment of or prevention cell proliferation disorders.In certain embodiments, cell proliferation disorders is cancer.
When the compounds of this invention gives the human and animal as medicine, they can himself or as the pharmaceutical composition administration, described pharmaceutical composition contains for example activeconstituents and the pharmaceutically acceptable carrier of 0.1-99.5% (more preferably 0.5-90%).
No matter select which kind of route of administration, the compounds of this invention (hydrate forms that can be suitable is used) and/or pharmaceutical composition of the present invention can be mixed with pharmaceutically acceptable formulation by ordinary method well known by persons skilled in the art.
The actual dose level of activeconstituents and administration time-histories can change in the pharmaceutical composition of the present invention, reach the therapeutic response that needs and to the amount of the avirulent activeconstituents of patient in order to obtain for particular patient, composition and administering mode.Exemplary dosage range be every day 0.01-100mg/kg or every day 0.1-150mg/kg.
In certain embodiments, the compounds of this invention can be united use with conventional tumor chemotherapeutic drug.The conventional treatment scheme that is used for leukemia and other tumour comprises radiation, medicine or the combination of the two.
The compounds of this invention is treated effective antiproliferative amount or is prevented determining of effective antiproliferative amount, can by utilizing known technology and observing the result who under analogue, obtains, easily be realized by doctor or animal doctor (" attending doctor ") as those skilled in the art.Severity and the employed specific compound of the needs of patients that dosage can be judged according to the attending doctor, the symptom for the treatment of change.In determining the effective antiproliferative amount for the treatment of or dosage, the effective antiproliferative amount of prevention or dosage, the attending doctor can consider many factors, includes but not limited to: related concrete cell proliferation disorders; Pharmacodynamic profile and administering mode and the approach of concrete medicament; Needed treatment time-histories; Mammiferous kind; Its size, age and general health; Related disease specific; The degree of disease or severity; The reaction of individual patient; The particular compound that gives; Administering mode; The biological utilisation feature of the preparation that gives; Selected dosage; The kind (be the compounds of this invention and other jointly give the interaction of therapy) of simultaneously treatment; And other correlation circumstance.
Treatment can use the lower dosage that is lower than the compound optimal dose initial.After this, the increase that dosage can be by a small margin is until reach in this case best effect.Between having made things convenient for, if necessary, total per daily dose can be divided into several parts of administrations in one day.Expect the effective antiproliferative amount for the treatment of of the present invention or prevent effective antiproliferative amount not wait to about 100mg/kg/ days from about 0.01 milligram of every kg body weight every day (mg/kg/ days).
The preferred dose of the compounds of this invention is the maximal dose that the patient can stand and not produce serious side effects.Exemplarily, the compounds of this invention can about 0.01mg/kg to about 100mg/kg body weight, about 0.01mg/kg about 10mg/kg body weight or the about 0.1mg/kg dosed administration of about 10mg/kg body weight extremely extremely.The intermediate range of the numerical value of above enumerating also is a part of the present invention.
Except as otherwise noted, the hereinafter percentages calculation among test and the embodiment; Umber is calculated by weight.Be used for solvent ratios, Dilution ratio and the concentration of report liquid/liquid solution separately based on volumeter.
Embodiment
Only the present invention will be further described for following examples, but the present invention is not played the effect of restriction.
Preparation method of the present invention is as shown below:
2,3-dimethyl-5-chloro-quinoxaline and 2-fluoro-4-nitrophenoxy etherificate, reduction are obtained 2-fluoro-4-(2,3-dimethoxy quinoxaline-4-base oxygen base)-phenyl amine; The cyclopropane dicarboxylic acid with the methylsulfonyl aniline condensation is obtained 1-(4-methylsulfonyl phenyl amino formyl radical)-cyclopropane-carboxylic acid, then under the oxalyl chloride condition, prepare 1-(4-methylsulfonyl phenyl amino formyl radical)-cyclopropanecarbonyl-acyl chlorides; The two condensation under the salt of wormwood condition obtains N-(2-fluoro-4-{[2; two (the methyl oxygen base) quinoxalines-4-yl of 3-] the oxygen base } phenyl)-N '-(4-methylsulfonyl phenyl) cyclopropane-1; the 1-diformamide; obtain N-(2-fluoro-4-{[2 with the malate salify again; two (the methyl oxygen base) quinoxalines-4-yl of 3-] the oxygen base } phenyl)-N '-(4-methylsulfonyl phenyl) cyclopropane-1, the 1-diformamide-(L)-malate.
Embodiment 1: preparation 2,3-dimethyl-5-(2-fluoro-4-nitrophenoxy)-quinoxaline
In reaction flask, add 5-chloro-2,3-dimethoxy-quinoxaline (52g), 2-fluoro-4-nitrophenol (50g), 4-dimethylaminopyridine (6.1g) and 2,6-lutidine (260g).Solution is heated to 147 ℃, and after 20 hours, the HPLC detection reaction is finished.Reaction solution was cooled to room temperature, adds methyl alcohol (350ml), adds subsequently 5% wet chemical, with reaction solution stir about 2 hours.The gained solid precipitation is filtered, wash with water, and at room temperature dry 12 hours, title compound 24g obtained, purity 95.4%.
Embodiment 2: preparation 2-fluoro-4-(2,3-dimethoxy quinoxaline-4-base oxygen base)-phenyl amine
The solution that will contain potassium formiate (32g), formic acid (20g) and water (100ml) joins 2,3-dimethoxy-4 '-(2-fluoro-4-nitrophenoxy)-quinoxaline (52g), 10% palladium/carbon (3g) in 60 ℃ of mixing solutionss of THF (260ml).Carry out described adding, reacting liquid temperature is maintained at about 60 ℃, and the HPLC detection reaction is complete, filters.The concentrated partial solvent that boils off, cooling obtains the product precipitation.By the filtered and recycled product, wash with water, dry to obtain title compound 20g, purity 96.9% under the vacuum.
Embodiment 3: preparation 1-(4-methylsulfonyl phenyl amino formyl radical)-cyclopropane-carboxylic acid
The control rate of addition makes reacting liquid temperature not be higher than 10 ℃, triethylamine (53ml) is added drop-wise to cyclopropane-1, in THF (400ml) solution of 1-dicarboxylic acid (7g).With about 30 minutes of solution stirring, then add thionyl chloride (66ml), keep reacting liquid temperature to be lower than 10 ℃.When adding is finished, so that reacting liquid temperature is no more than the solution that 10 ℃ speed adds the THF (160ml) of 4-methylsulfonyl aniline (63g).With mixture stir about 4 hours, then use isopropyl acetate (400ml) dilution.This solution is sequentially with 4% aqueous sodium hydroxide solution, saturated sodium-chloride water solution washing.Decompression concentrated solution adds normal heptane subsequently, obtains solid precipitation.Filter, then dry under vacuum, obtain title compound (7g).
Embodiment 4: preparation 1-(4-methylsulfonyl phenyl amino formyl radical)-cyclopropanecarbonyl-acyl chlorides
Under the ice bath, oxalyl chloride (7g) is joined (4-methylsulfonyl phenyl amino formyl radical)-encircle third and play carboxylic acid acid (15g) solution in THF (80ml) and DMF 1mL mixture, reacted 3 hours, this solution is used for next step.
Embodiment 5 preparation N-(2-fluoro-4-{[2, two (the methyl oxygen base) quinoxalines-4-yl of 3-] the oxygen base } phenyl)-N '-(4-methylsulfonyl phenyl) cyclopropane-1, the 1-diformamide
So that reacting liquid temperature is no more than 30 ℃ speed; to join from the solution that contains 1-(4-methylsulfonyl phenyl amino formyl radical)-cyclopropanecarbonyl-acyl chlorides of preceding step 2-fluoro-4-(2,3-dimethoxy quinoxaline-4-base oxygen base)-phenyl amine (20g) and the mixture of salt of wormwood (25g) in THF (180ml) and water (80ml).(generally in 10 minutes) add entry (2kg) when reaction is finished.Mixture 15-30 ℃ of stir about 10 hours, is obtained the product precipitation.The filtered and recycled product, with the mixing solutions washing of THF and water, 65 ℃ of dryings are about 12 hours under vacuum, obtain title compound (free alkali, 32g).LC/MS：[M+H]：581.6.
Embodiment 6: preparation N-(2-fluoro-4-{[2, two (the methyl oxygen base) quinoxalines-4-yl of 3-] the oxygen base } phenyl)-N '-(4-methylsulfonyl phenyl) cyclopropane-1, the 1-diformamide-(L)-malate
The solution of (L)-oxysuccinic acid (15g) in water (18ml) is joined 30g N-(2-fluoro-4-{[2; two (the methyl oxygen base) quinoxalines-4-yl of 3-] the oxygen base } phenyl)-N '-(4-methylsulfonyl phenyl) cyclopropane-1; the solution of 1-diformamide free alkali in the THF of 230ml; batch temperature is maintained at about 25 ℃; then add gac; and the gained mixture heating up refluxed; add entry (50ml) this moment; then filter reaction mixture; add subsequently Virahol (260ml); and make it cool to room temperature; the filtered and recycled product is used washed with isopropyl alcohol, and in about 65 ℃ of vacuum-dryings; obtain compound 35g, purity: 99.2%.
Embodiment 5: bio-evaluation
The confirmation of the activity of the compounds of this invention can by well known in the art external, exsomatize and in vivo test realizes.For example, in order to confirm the activity of the compounds of this invention, can use following test.
The test of kinases specific detection:
Kinase activity and compound inhibition ability adopt in following three kinds of detection modes one or more to investigate, and wherein, the concentration of ATP is close with various kinase whose Michaelis-Menton constant (Km value).The dose-response experiment is carried out at the 384-microtiter plate, investigates 10 kinds of different inhibitor concentration.The data obtained carries out match with following formula:
Y＝Min+(Max-Min)/(1+(X/IC
50)^H)
In the formula, Y is observes signal values, and X is inhibitor concentration, and Min is the background signal of (0% enzymic activity) during without enzyme, the signal of (100% enzymic activity) when Max is the unrestraint agent, IC
50Be the concentration of the suppressed half inhibitor of enzyme, H is the Hill coefficient.
C-Met detects
The c-Met biochemical activity adopts luciferase coupling chemoluminescence kinase assay method (LCCA) to estimate.Measure the per-cent of remaining ATP behind the kinase reaction as kinase activity.Adopt luciferase-fluorescein-coupling chemoluminescence method to detect remaining ATP.Particularly, in 20 μ L buffer solution system (20mM Tris-HCl pH7.5,10mM MgCl2,0.02%Triton X-100,100mM DTT, 2mM MnCl2) add medicine to be measured in, 1 μ M ATP, 1 μ Mpoly-EY and 10nM c-Met (the people c-Met kinase domain P948-S1343 of baculovirus expression) also begin timing.Hatch adding 20 μ l luciferase-fluorescein mixed solutions after 2 hours under the room temperature, measure with Wllac Victor2 enzyme micro-plate reader.Luciferase-fluorescein mixed solution contains 50mM HEPES, pH 7.8,8.5 μ g/ml oxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4%Triton X-100,0.25mg/ml coenzyme A, 63 μ M AMP, the luciferase of 28 μ g/ml fluoresceins and 40,000 units.
KDR detects:
The KDR biochemical activity adopts luciferase coupling chemoluminescence kinase assay method (LCCA) to assess.Measure remaining ATP per-cent behind the kinase reaction as kinase activity.Adopt luciferase-fluorescein-coupling chemoluminescence method to detect remaining ATP.For this test, in 20 μ L buffer solution system (20mM Tris-HCl pH7.5,10mM MgCl
2, 0.01%Triton X-100,1mM DTT, 3mM MnCl
2) middle adding medicine to be measured, 3 μ M ATP, 1.6 μ Mpoly-EY and 5nM KDR (the people KDR kinase domain D807-V1356 of baculovirus expression) also begin timing.Hatch adding 20 μ l luciferase-fluorescein mixed solutions after 4 hours under the room temperature, measure with Wllac Victor2 enzyme micro-plate reader.Luciferase-fluorescein mixed solution contains 50mM HEPES, pH 7.8,8.5 μ g/ml oxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4%Triton X-100,0.25mg/l coenzyme A, 63 μ M AMP, the luciferase of 28 μ g/ml fluoresceins and 40,000 units.
The representational IC of the compounds of this invention
50Value is listed in the table below 1, also is listed in the table below for the contrasting data from compound relevant, nonfluorinated on the structure of prior art (referring to WO 2005/030140) in addition:
Table 1
| The embodiment numbering | KDR?IC 50[nM] | c-Met?IC 50[nM?] |
| The compounds of this invention | 0.018 | 0.09 |
| The compounds of this invention-(L)-malate | 0.015 | 0.07 |
| Compound I among the WO 2005/030140 | 0.13 | 0.62 |
| Compound I I among the WO 2005/030140 | 0.081 | 0.45 |
Embodiment 6: the embodiment relevant with pharmaceutical composition
Pharmaceutical composition of the present invention can followingly be set forth:
Aseptic intravenous solution:
Use sterile injectable water to prepare the 5mg/ml solution of compound required for the present invention, if need to would regulate pH.With aseptic 5% glucose solution dilution is used for administration 1-2mg/ml, and as venoclysis administration in about 60 minutes.
The lyophilized powder that is used for intravenously administrable:
Can use (i) 100-1000mg compound required for the present invention as lyophilized powder, (ii) 32-327mg/ml Trisodium Citrate and (iii) the 300-3000mg Dextran 40 prepare sterile preparation.Use sterile injectable salt solution or 5% glucose that preparation is reconstructed into the concentration of 10-20mg/ml, it further is diluted to 0.2-0.4mg/ml with salt solution or 5% glucose, the administration in 15-60 minute as intravenous injection or venoclysis.
The intramuscular suspension agent:
Can prepare following solution or suspension and be used for intramuscular injection: 50mg/ml water-insoluble compound required for the present invention; The 5mg/ml Xylo-Mucine; The 4mg/mL tween 80; 9mg/ml sodium-chlor; 9mg/ml benzylalcohol.
Hard-shell capsule:
Prepare a large amount of unit capsules by two sections hard gelatin capsules of filling standard, each is equipped with the Powdered activeconstituents of 100mg, 150mg lactose, 50mg Mierocrystalline cellulose and 6mg Magnesium Stearate.
Soft gelatin capsule:
The preparation activeconstituents is at digestible oil mixture in soya-bean oil, oleum gossypii seminis or the sweet oil and be injected into the soft gelatin capsule that contains the 100mg activeconstituents in the molten gelatin with formation by positive-displacement pump for example.Washing and dry capsule.Activeconstituents can be dissolved in the mixture of polyoxyethylene glycol, glycerine and sorbyl alcohol, with the preparation can be miscible with water medicinal mixture.
Tablet:
Prepare a large amount of tablets by ordinary method, so that dose unit is silicon-dioxide, 5mg Magnesium Stearate, 275mg Microcrystalline Cellulose, 11mg starch and the 98.8mg lactose of 100mg activeconstituents, 0.2mg colloidal state.Can use suitable moisture and anhydrous dressing to improve palatability, improve outward appearance and stability or to postpone absorption.
In order to be aware and understand purpose, slightly described aforementioned invention in detail by example explanation and embodiment.With reference to various specific embodiments and technical description the present invention.Yet, should be appreciated that, can make many variations and modification, remain in the spirit and scope of the invention simultaneously.It will be apparent to those skilled in the art that and change and revise and to implement within the scope of the appended claims.Therefore, be appreciated that above-mentioned specification sheets is intended that Illustrative and nonrestrictive.Therefore, the scope of the invention should not determine with reference to above-mentioned specification sheets, and the full breadth of the equivalent that should advocate with reference to claims and this claim is determined.All patents, patent application and the publication that the application quotes for all purposes this by reference integral body incorporate into, indicate so individually as each independent patent, patent application or publication.
Claims (10)
1. a N-(2-fluoro-4-{[2, two (the methyl oxygen base) quinoxalines-4-yl of 3-] oxygen base } phenyl)-N '-(4-methylsulfonyl phenyl) cyclopropane-1,1-diformamide, or its pharmacy acceptable salt, hydrate and/or solvate.
2. compound according to claim 1; it is characterized in that described salt is N-(2-fluoro-4-{[2; two (the methyl oxygen base) quinoxalines-4-yl of 3-] the oxygen base } phenyl)-N '-(4-methylsulfonyl phenyl) cyclopropane-1, the 1-diformamide-(L)-malate.
3. the method for the preparation of the described compound of claim 1 is characterized in that comprising the steps:
(1), 2,3-dimethyl-5-chloro-quinoxaline and 2-fluoro-4-nitrophenoxy etherificate, reduction are obtained 2-fluoro-4-(2,3-dimethoxy quinoxaline-4-base oxygen base)-phenyl amine;
(2), cyclopropane dicarboxylic acid and the methylsulfonyl aniline condensation obtained 1-(4-methylsulfonyl phenyl amino formyl radical)-cyclopropane-carboxylic acid, then under the oxalyl chloride condition, prepare 1-(4-methylsulfonyl phenyl amino formyl radical)-cyclopropanecarbonyl-acyl chlorides;
(3), step (1) and the condensation under the salt of wormwood condition of step (2) products therefrom obtain target product N-(2-fluoro-4-{[2; two (the methyl oxygen base) quinoxalines-4-yl of 3-] the oxygen base } phenyl)-N '-(4-methylsulfonyl phenyl) cyclopropane-1, the 1-diformamide.
4. be used for the treatment of or compound or its pharmacy acceptable salt, hydrate and/or the solvate of prophylactic claim 1 or 2.
5. claim 1 or 2 described compounds or its pharmacy acceptable salt, hydrate and/or solvate are for the preparation of the purposes in the pharmaceutical composition for the treatment of or prevention cell proliferation disorders.
6. the purposes of claim 5, wherein this cell proliferation disorders is cancer.
7. pharmaceutical composition comprises claim 1 or 2 described compounds or its pharmacy acceptable salt, hydrate and/or solvate, and pharmaceutically acceptable vehicle.
8. the pharmaceutical composition of claim 7 also comprises one or more other therapeutical agents.
9. the pharmaceutical composition of claim 8, wherein other therapeutical agent is antineoplastic agent.
10. purposes claimed in claim 5, wherein this cancer is that the far-end of mammary gland, respiratory tract, brain, reproductive organ, digestive tube, urinary tract, eye, liver, skin, head or neck, Tiroidina, parathyroid cancer or solid tumor shifts.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831707A (en) * | 2016-12-28 | 2017-06-13 | 杭州市西溪医院 | As the benzheterocycle analog derivative and its medical application of c Met kinase inhibitors |
| EP3299369A4 (en) * | 2015-05-21 | 2018-05-02 | Shanghai Institute of Materia Medica, Chinese Academy of Sciences | Pyrido-azaheterecydic compound and preparation method and use thereof |
| CN108026035A (en) * | 2015-09-02 | 2018-05-11 | 陈昆锋 | Compound with Protein-tyrosine-phosphatase SHP-1 agonist activities |
| CN114605391A (en) * | 2022-02-21 | 2022-06-10 | 广州六顺生物科技股份有限公司 | Quinoxaline derivative and preparation method and application thereof |
-
2012
- 2012-11-26 CN CN 201210485055 patent/CN102942530A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3299369A4 (en) * | 2015-05-21 | 2018-05-02 | Shanghai Institute of Materia Medica, Chinese Academy of Sciences | Pyrido-azaheterecydic compound and preparation method and use thereof |
| US10710996B2 (en) | 2015-05-21 | 2020-07-14 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Pyrido-azaheterecydic compound and preparation method and use thereof |
| CN108026035A (en) * | 2015-09-02 | 2018-05-11 | 陈昆锋 | Compound with Protein-tyrosine-phosphatase SHP-1 agonist activities |
| CN106831707A (en) * | 2016-12-28 | 2017-06-13 | 杭州市西溪医院 | As the benzheterocycle analog derivative and its medical application of c Met kinase inhibitors |
| CN106831707B (en) * | 2016-12-28 | 2019-09-20 | 杭州市西溪医院 | Benzheterocycle analog derivative and its medical application as c-Met kinase inhibitor |
| CN114605391A (en) * | 2022-02-21 | 2022-06-10 | 广州六顺生物科技股份有限公司 | Quinoxaline derivative and preparation method and application thereof |
| CN114605391B (en) * | 2022-02-21 | 2024-01-26 | 广州六顺生物科技股份有限公司 | Quinoxaline derivative, preparation method and application thereof |
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Application publication date: 20130227 |