CN101836991B

Movatterモバイル変換

Info

Publication number: CN101836991B
Application number: CN 200910129318
Authority: CN
Inventors: 赵镭
Original assignee: Dinkum International Investment Hong Kong Co ltd
Current assignee: Dinkum International Investment Hong Kong Co ltd
Priority date: 2009-03-19
Filing date: 2009-03-19
Publication date: 2013-05-22
Anticipated expiration: 2029-03-19
Also published as: CN101836991A

Abstract

本发明涉及一种含有索拉非尼、肝细胞生长因子受体(cMet)抑制剂与表皮生长因子受体(EGFR)酪氨酸激酶抑制剂的药物组合物及其在制备治疗肺癌、结肠癌、肝癌、肾癌、胃癌、脑瘤、肉瘤、胰腺癌、卵巢癌、乳腺癌或前列腺癌的药物中的应用，本发明药物组合物具有显著的协同效应，提高了药物的疗效，降低了给药剂量，减少了副作用的发生。The present invention relates to a pharmaceutical composition containing sorafenib, a hepatocyte growth factor receptor (cMet) inhibitor and an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and an application thereof in preparing a medicine for treating lung cancer, colon cancer, liver cancer, kidney cancer, gastric cancer, brain tumor, sarcoma, pancreatic cancer, ovarian cancer, breast cancer or prostate cancer. The pharmaceutical composition of the present invention has a significant synergistic effect, improves the efficacy of the medicine, reduces the dosage, and reduces the occurrence of side effects.

Description

Contain pharmaceutical composition and the application thereof of Sorafenib, cMet inhibitor and EGFR tyrosine kinase inhibitor

Technical field

The present invention relates to a kind of pharmaceutical composition and the application in the medicine of preparation treatment cancer thereof, be specifically related to contain pharmaceutical composition and the application in the medicine of preparation Hepatoma therapy, pulmonary carcinoma, colon cancer, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate thereof of Sorafenib, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor.

Background technology

World Health Organization's investigation report shows, global cancer condition is day by day serious, and 20 years from now on new patients' number will be increased to 1,500 ten thousand by present every year 1000 ten thousand, because the number that cancer is dead also will be by increasing to 1,000 ten thousand 6,000,000 of every year.Wherein primary hepatocarcinoma is the canceration that occurs in hepatocyte and intrahepatic biliary epithelium cell, is one of modal malignant tumor of the mankind; Pulmonary carcinoma is common malignant tumor, comes from bronchiolar epitheliums at different levels, is divided into cell lung cancer and nonsmall-cell lung cancer; Along with growth in the living standard, the change of dietary structure, the sickness rate of colon cancer is ascendant trend year by year.

The antitumor drug that has gone on the market at present is more, and as alkylating agent medicine, antimetabolite, antitumor antibiotics, immunomodulator etc., but medicine is larger due to toxicity mostly, and patient does not tolerate.Along with the Study on Molecular Mechanism to the genesis of tumor is more and more clearer, the molecular targeted therapy Several Kinds of Malignancy has been subject to paying close attention to widely and paying much attention to.The molecular targeted agents selectivity is high, wide spectrum is effective, and its safety is better than the cytotoxicity chemotherapeutics, is the new direction of present therapeutic field of tumor development.

Hepatocyte growth factor (Hepatocyte growth factor, HGF) by with its target cell on special receptor (C-MET HGFr cMet) in conjunction with after have the ability that promotes cell division, motion and shaping.CMet is the albumen of proto-oncogene cMet coding, is the transmembrane receptor that a class has the autonomy phosphorylation activity.HGF and cMet in conjunction with after induce cMet receptor tyrosine phosphorylation on after birth, and the biological effect by signal transduction pathway performance HGF in various kinds of cell, the generation of tumor cell, migrate and transfer process in brought into play important effect.Therefore, the activity that suppresses cMet may play important intervention effect to generation, invasion and attack and the transfer of tumor cell.At the cMet inhibitor that grinds or entered clinical research, PF-02341066, SGX523 or PHA665752 etc. are arranged.

Sorafenib is a kind of many target spots inhibitors of kinases by Bayer and the common development of ONYX, targeting is serine/threonine kinase receptor and tyrosine kinase receptor in tumor cell and tumor vessel, suppress tumor growth by suppressing the Raf/MEK/ERK signal transduction path, simultaneously also by suppressing to generate with new vessels the activity of relevant tyrosine kinase receptor, block tumor neovasculature generation, indirectly the growth of inhibition tumor cell.Sorafenib is 800mg/ days at the dosage that the clinical dosage that uses is taken as per day for adults at present.Yet Sorafenib has more untoward reaction, as, " toxic and side effects of Sorafenib and processing thereof ", what " cancer progression magazine " July in 2007, the 5th the 4th phase of volume 370-373 page was put down in writing, untoward reaction comprises brothers' syndrome, tired, diarrhoea, dermal toxicity and gastrointestinal reaction etc., and often causes the interruption of drug administration or reduce drug dose.Therefore seek the focus of cancer therapy drug for studying at present that therapeutic effect is better, side effect is low.

EGF-R ELISA (epidermal growth factor receptor, EGFR) plays an important role in the genesis of tumor, after it and ligand binding, inspires cascade reaction and causes cell proliferation, angiogenesis, transfer and apoptosis to suppress.Comprise in the multiple entities tumor of nonsmall-cell lung cancer, the normal mistake of EGFR gene expressed, and the expression of this gene is relevant with the poor prognosis of some tumor.The endocellular metabolism zone of epidermal growth factor recipient tyrosine kinase inhibitor and ATP reversibility competition tyrosine kinase, the autophosphorylation of inhibitory enzyme and the transmission of downstream signal.The medicine that has gone on the market is just like gefitinib (Gefitinib, Iressa), erlotinib (Erlotinib, Taceva) be approved for the treatment of advanced Non-small cell lung, no significant difference on Overall survival synergism do not appear, in the therapeutic scheme that associating gefitinib or erlotinib and carboplatin+paclitaxel/cisplatin+gemcitabine is used for advanced Non-small cell lung.

Along with the progress of oncomolecularbiology, the tumor molecular targeted therapy has become the focus of tumor research, has brought into play important effect in the treatment of kinds of tumors.Yet, the biological behaviour of most of tumor is arranged by the single signal pathway, but a plurality of signal transduction pathway concur, therefore drug combination carries out for many target spots appearance, the reduction toxicity that targeted therapy will not only be intended to reduce or delay drug resistance, especially rational three coupling medicines will be obtained better curative effect by the synergism that multi-medicament kills and wounds cancerous cell.

Summary of the invention

for above technological deficiency, the invention provides a kind of pharmaceutical composition and preparing Hepatoma therapy, pulmonary carcinoma, colon cancer, pulmonary carcinoma, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, application in the medicine of breast carcinoma or carcinoma of prostate, be specially and contain Sorafenib, the pharmaceutical composition of C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor is in preparation treatment pulmonary carcinoma, colon cancer, hepatocarcinoma, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, application in the medicine of breast carcinoma or carcinoma of prostate.

The present invention contains in the pharmaceutical composition of Sorafenib, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor, and described hepatocyte growth factor receptor inhibitor is PF-02341066, SGX523 or PHA665752 and corresponding analog, derivant etc.; Epidermal growth factor recipient tyrosine kinase inhibitor is gefitinib, erlotinib, Canertinib or PKI166 and corresponding analog, derivant etc.

Sorafenib described in pharmaceutical composition of the present invention (English name: Sorafenib) be 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-uride] phenoxy group }-the pyridine-2-carboxylic acids methylamine, its structural formula is I.

In the present invention, Sorafenib is not limited to this medicine itself, can also be its pharmaceutically useful salt, the analog of the derivant of Sorafenib or the various Sorafenibs disclosed in the WO2000041698 patent application; The present invention simultaneously can also replace with Sorafenib the other medicines of many target spots inhibitors of kinases in using.

Described C-MET HGFr (cMet) inhibitor in pharmaceutical composition of the present invention can be the medicine of the cMet inhibitor of any structure type, as PF-02341066, SGX523 or PHA665752, wherein, SGX-523 has applied for that by the research and development of SGX Pharmaceuticals company the I phase is clinical; PHA-665752 is by the research and development of Sugen company.

C-MET HGFr in pharmaceutical composition of the present invention (cMet) inhibitor is preferably: PF-02341066, its structural formula are II.

In pharmaceutical composition of the present invention, described component is not limited to PF-02341066 medicine itself, can also be its pharmaceutically useful salt, the analog of the derivant of PF-02341066 or the various PF-02341066 disclosed in the WO2007066187 patent application.

In the present invention, described EGF-R ELISA (EGFR) tyrosine kinase inhibitor can be the medicine of the epidermal growth factor recipient tyrosine kinase inhibitor of any structure type, as gefitinib, erlotinib, Canertinib or PKI166, wherein, Canertin b is the EGFR tyrosine kinase inhibitor, by the research and development of Pfizer company; PKI166, the EGFR tyrosine kinase inhibitor is by the research and development of Pfizer company.

Pharmaceutical composition epidermal growth factor receptor tyrosine kinase inhibitor of the present invention is preferably gefitinib or erlotinib or its combination, and wherein erlotinib is the compound of the formula III put down in writing in US5747498;

In pharmaceutical composition of the present invention, described component is not limited to said medicine itself, can also be the salt of their analog, derivant, free alkali and other organic or inorganic.

The present invention contains in the pharmaceutical composition of Sorafenib, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor, and the mol ratio of Sorafenib, hepatocyte growth factor receptor inhibitor and epidermal growth factor recipient tyrosine kinase inhibitor is 0.2-10.0: 0.3-3.0: 1.5-15; The present invention further mol ratio of preferred described Sorafenib, hepatocyte growth factor receptor inhibitor and epidermal growth factor recipient tyrosine kinase inhibitor is 0.5-6.0: 0.75-1.5: 3.0-7.5.

The present invention contain Sorafenib, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor pharmaceutical composition can for the preparation of the treatment various tumors medicine, described tumor includes but not limited to hepatocarcinoma, pulmonary carcinoma, colon cancer, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate.

The pharmaceutical composition of the preferred Sorafenib of the present invention, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor is for the preparation of the application in the medicine of Hepatoma therapy, pulmonary carcinoma and colon cancer.

In the application of the present invention in the medicine of preparation Hepatoma therapy, described Sorafenib, hepatocyte growth factor receptor inhibitor PF-02341066 and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib mol ratio are 0.5-1.5: 0.75-1.5: 3.0-7.5; Being preferably Sorafenib, PF-02341066 and erlotinib mol ratio is 1.0-1.5: 1.0-1.5: 5.0-7.5; More preferably Sorafenib, PF-02341066 and erlotinib mol ratio are 1.5: 1.5: 7.5.

In the application of the present invention in the medicine of preparation treatment pulmonary carcinoma, colon cancer, described Sorafenib, hepatocyte growth factor receptor inhibitor PF-02341066 and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib mol ratio are 3.0-6.0: 0.75-1.5: 3.0-7.5; Being preferably Sorafenib, PF-02341066 and erlotinib mol ratio is 4.0-6.0: 1.0-1.5: 5.0-7.5; More preferably Sorafenib, PF-02341066 and erlotinib mol ratio are 6.0: 1.5: 7.5.

contain Sorafenib, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor compositions are at the preparation Hepatoma therapy, pulmonary carcinoma, colon cancer, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, in the application of the medicine of breast carcinoma or carcinoma of prostate, in the scheme of the medicament of the present composition being made administration simultaneously, Sorafenib, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor can be contained in same pharmaceutical preparation such as tablet or capsule, also can be with Sorafenib, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor are made respectively preparation, as making respectively tablet or capsule, and adopt the mode of this area routine that their are packed or combine, then the patient takes simultaneously according to the indication of package insert, in the scheme of the medicament of the present composition being made successively administration, can be with Sorafenib, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor are made respectively different preparations, and adopt the mode of this area routine that their are packed or combine, then the patient takes according to the sequencing of package insert indication, or three kinds of compositions in above-mentioned composition are made a kind of preparation of controlled release, a kind of composition in first release composition, and then the another kind of composition in release composition, and then discharge the third composition, the patient only need to take this controlled release composition preparation, in the scheme of the medicament that the present composition is prepared into the intersection administration, can be with Sorafenib, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor are made respectively different preparations, and adopt the mode of this area routine that their are packed or combine, then the patient takes according to the chi sequence of package insert indication, perhaps this pharmaceutical composition is prepared into Sorafenib, the controlled release preparation that C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor intersection discharge.

contain Sorafenib, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor compositions are at the preparation Hepatoma therapy, pulmonary carcinoma, colon cancer, renal carcinoma, gastric cancer, cerebroma, sarcoma, cancer of pancreas, ovarian cancer, in application in the medicine of breast carcinoma or carcinoma of prostate, Sorafenib in described compositions, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor can use or using in order with any priority simultaneously, as can be with Sorafenib, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor are taken to the patient simultaneously, also can first take wherein a kind of, then use simultaneously or take another two kinds of medicines with the order of any priority, the interval of taking for the three does not have special requirement, but the interval of preferably taking three kinds of medicines is no more than one day, perhaps three kinds of medicines replace administration.

in the present invention, can be with the Sorafenib in the present invention, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor adopt the method for this area routine to be prepared into the pharmaceutical preparation that is suitable for gastrointestinal administration or parenteral administration, the present invention is preferably with Sorafenib, the pharmaceutical preparation that C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor are made gastrointestinal administration, its dosage form can be conventional tablet or capsule, or controlled release, slow releasing preparation.In the pharmaceutical preparation of Sorafenib of the present invention, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor compositions, according to different dosage forms and preparation specification, the content of described compositions in preparation can be counted 1-99% for quality, is preferably 10%-90%; The adjuvant that preparation uses can adopt the adjuvant of this area routine, take the discord present composition react or the curative effect that do not affect medicine of the present invention as prerequisite; The preparation method of described preparation can adopt the preparation method of this area routine to be prepared.

In the present invention, the preparation method of compositions does not have any restriction, Sorafenib, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor three can carry out direct mixing and then make preparation, or respectively and/or corresponding adjuvant mix and make respectively preparation, and then be packaging together according to the mode of this area routine, or mix and then mix and make preparation with corresponding adjuvant respectively.

The dosage of the pharmaceutical composition in the present invention can carry out suitable variation according to the dosage form difference of administration object, route of administration or medicine, but to guarantee that this pharmaceutical composition can reach effective blood drug level as prerequisite in mammalian body.

the present invention has carried out respectively Sorafenib, C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor both and three's combination arbitrarily kill Hep3B (hepatoma cell strain), A549 (lung cancer cell line), the test of HCT-116 (colon cancer cell line), results suggest, Sorafenib of the present invention, three joint groups of C-MET HGFr (cMet) inhibitor and EGF-R ELISA (EGFR) tyrosine kinase inhibitor close Hepatoma therapy, pulmonary carcinoma and colon cancer have significant cooperative effect, the one pack system medicine or two joint groups that obviously are better than in them close, greatly improved the curative effect of medicine, reduced dosage, reduced the generation of side effect.

The specific embodiment

The invention will be further elaborated with the following Examples, but the present invention is not limited to this.

Embodiment

Reagent and method:

Cell: Hep3B (hepatoma cell strain), A549 (lung cancer cell line), HCT-116 (colon cancer cell line) are all available from American Type Culture Collection (ATCC), Rockville, MD, USA.

Medicine: in following examples, institute's pharmaceutical composition is all by following method 1 or method 2 is described prepares; C-MET HGFr (cMet) inhibitor PF-02341066 is synthesized into reference to patent WO2007066187; Sorafenib is synthesized into reference to patent US2003207872; EGF-R ELISA (EGFR) tyrosine kinase inhibitor erlotinib is synthesized into reference to patent US5747498.

Method 1: each component of the accurate corresponding pharmaceutical composition of weighing, dissolve respectively with dimethyl sulfoxide, be made into separately the stock solution of 10mM, preserve under-20 ℃, be diluted to suitable concentration with fresh culture medium during use, the solution of each component of 1 microlitre of then respectively asking for mixes standby.In all tests, the ultimate density of dimethyl sulfoxide is answered≤5g/L, in order to do not affect the activity of cell.

With all cells in RPMI 1640 culture medium that contain 10% calf serum, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO₂Damp condition under cultivate, in the previous day of dosing, carry out cell inoculation 2 * 10 on six orifice plates⁵Then/hole adds the medicinal composition solution of preparation as stated above in cell, make each component reach its working concentration, 1-18 in specifically seeing Table.

After drug treating, measure cell death by trypan blue (Trypan Blue), cell turns into 10 minutes by carrying out pancreatin at 37 ℃ with trypsin sodium/EDTA.Because dead cell comes off from incubator enter culture medium, by all cells of centrifugal collection under 1200 rev/mins, and then with culture medium Eddy diffusion precipitate, mix with the trypan blue dyestuff.After dyeing, count with optical microscope and hematimeter.By the dead cell of counting of dyes au bleu.Choose at random 500 cells and count, dead cell is recently expressed with the percentage that accounts for the grand total cell.

Method 2: each component of the accurate corresponding pharmaceutical composition of weighing, dissolve respectively with dimethyl sulfoxide, be made into separately the stock solution of 10mM, preserve under-20 ℃.Be diluted to suitable concentration with fresh culture medium during use, the solution for standby of each component of 1 microlitre of then respectively asking for.In all tests, the ultimate density of dimethyl sulfoxide is answered≤5g/L, in order to do not affect the activity of cell.

With all cells in RPMI 1640 culture medium that contain 10% calf serum, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO₂Damp condition under cultivate, in the previous day of dosing, carry out cell inoculation 2 * 10 on six orifice plates⁵Then/hole adds each component solution of the pharmaceutical composition of preparation as stated above with any order in cell, make each component reach its working concentration, 19-36 in specifically seeing Table.

In drug regimen shown in lower list 1, the combination of 1-18 prepares by method 2 by the combination of method 1, the 19-36.

Table 1

Sequence number	PF-02341066 (micromole)	Sorafenib (micromole)	Erlotinib (micromole)
				1	0.75	0.5
2	0.75		3.0
				3		0.5	3.0
4	0.75	0.5	3.0
				5	1.0	1.0
6	1.0		5.0
				7		1.0	5.0
8	1.0	1.0	5.0
				9	1.5	1.5

10	1.5		7.5
				11		1.5	7.5
12	1.5	1.5	7.5
				13	0.75	3.0
14	0.75		3.0
				15		3.0	3.0
16	0.75	3.0	3.0
				17	1.0	4.0
18	1.0		5.0
				19		4.0	5.0
20	1.0	4.0	5.0
				21	1.5	6.0
22	1.5		7.5
				23		6.0	7.5
24	1.5	6.0	7.5
				25	0.75	3.0
26	0.75		3.0
				27		3.0	3.0
28	0.75	3.0	3.0
				29	1.0	4.0
30	1.0		5.0
				31		4.0	5.0
32	1.0	4.0	5.0
				33	1.5	6.0
34	1.5		7.5
				35		6.0	7.5
36	1.5	6.0	7.5

The combination Synergistic of PF-02341066, Sorafenib and the erlotinib of embodiment 1 different proportion promotes the test of Hep3B cell death, sees Table 2.

Table 2

in the investigation related compound causes the test of hepatoma cell strain Hep3B cell death, find when using separately 1.0 μ M PF-02341066, 1.5 μ M Sorafenib, 7.5 when μ M erlotinib or lower concentration, almost acellular death, even any two kinds when share under low concentration of above-mentioned three kinds of medicines, only have 1.0 μ M PF-02341066+1.0 μ M Sorafenibs, 1.0 μ M PF-02341066+5.0 μ M erlotinib share and can cause approximately 20% cell death, and the i.e. 1.0 μ M Sorafenibs+5.0 almost acellular death of μ M erlotinib of another kind of combination, but (1.0 μ M PF-02341066+1.0 μ M Sorafenib+5.0 μ M erlotinibs) produce obvious synergism when these three kinds of medicines share under above-mentioned low concentration, cause approximately 50% cancer cell death, when above-mentioned three kinds of medicines make up respectively under higher concentration in twos, can cause approximately 34% cancer cell death when also only having 1.5 μ M PF-02341066+1.5 μ M Sorafenibs to share, all the other two kinds combinations are that 1.5 μ MPF-02341066+7.5 μ M erlotinibs and 1.5 μ M Sorafenibs+7.5 μ M erlotinibs only cause the cell death of 10-25%, (1.5 μ M PF-02341066+1.5 μ M Sorafenib+7.5 μ M erlotinibs) produce more significant synergism when the three share, and cause 92% cancer cell death.

The combination Synergistic of PF-02341066, Sorafenib and the erlotinib of embodiment 2 different proportions promotes the test of A549 cell death, sees Table 3.

Table 3

In the investigation related compound causes the test of lung cancer cell line A549 cell death, find when use 1.5 μ M PF-02341066 separately, 4.0 μ M Sorafenibs, 5.0 μ M erlotinibs or lower concentration, only have an appointment 10% cell death, even any two kinds when share under low concentration of above-mentioned three kinds of medicines also only are no more than 15% cell death; But (1.0 μ M PF-02341066+4.0 μ M Sorafenib+5.0 μ M erlotinibs) produce obvious synergism when these three kinds of medicines share under above-mentioned low concentration, cause approximately 40% cancer cell death; When above-mentioned three kinds of medicines make up respectively under higher concentration in twos, can cause approximately 27% cancer cell death when also only having 1.5 μ M PF-02341066+6.0 μ M Sorafenibs to share, all the other two kinds combinations are that 1.5 μ MPF-02341066+7.5 μ M erlotinibs and 6.0 μ M Sorafenibs+7.5 μ M erlotinibs only cause approximately 15% cell death, (1.5 μ M PF-02341066+6.0 μ M Sorafenib+7.5 μ M erlotinibs) produce more significant synergism when the three share, and cause 93% cancer cell death.

The combination Synergistic of PF-02341066, Sorafenib and the erlotinib of embodiment 3 different proportions promotes the test of HCT116 cell death, sees Table 4.

Table 4

In the investigation related compound causes the test of colon cancer cell line HCT116 cell death, find when use 1.5 μ M PF-02341066 separately, 4.0 μ M Sorafenibs, 5.0 μ M erlotinibs or lower concentration, only have an appointment 10% cell death, even any two kinds when share under low concentration of above-mentioned three kinds of medicines, 10% the cell death of also only having an appointment; But (1.0 μ M PF-02341066+4.0 μ M Sorafenib+5.0 μ M erlotinibs) produce obvious synergism when these three kinds of medicines share under above-mentioned low concentration, cause approximately 44% cancer cell death; When above-mentioned three kinds of medicines make up respectively under higher concentration in twos, can cause approximately 25% cancer cell death when also only having 1.5 μ M PF-02341066+6.0 μ M Sorafenibs to share, all the other two kinds combinations are that 1.5 μ MPF-02341066+7.5 μ M erlotinibs and 6.0 μ M Sorafenibs+7.5 μ M erlotinibs only cause being no more than 20% cell death, (1.5 μ M PF-02341066+6.0 μ M Sorafenib+7.5 μ M erlotinibs) produce more significant synergism when the three share, and cause 92% cancer cell death.

Claims

1. a pharmaceutical composition that is used for the treatment of hepatocarcinoma, pulmonary carcinoma, colon cancer, is characterized in that, described compositions contains Sorafenib, hepatocyte growth factor receptor inhibitor PF-02341066 and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib.

2. pharmaceutical composition according to claim 1, it is characterized in that, the mol ratio of described Sorafenib, hepatocyte growth factor receptor inhibitor PF-02341066 and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib is 0.2-10.0:0.3-3.0:1.5-15.

3. pharmaceutical composition according to claim 2, it is characterized in that, the mol ratio of described Sorafenib, hepatocyte growth factor receptor inhibitor PF-02341066 and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib is 0.5-6.0:0.75-1.5:3.0-7.5.

4. the application of the arbitrary described pharmaceutical composition of claim 1-3 in the medicine of preparation Hepatoma therapy, pulmonary carcinoma, colon cancer.

5. application according to claim 4, it is characterized in that, in application in the medicine of preparation Hepatoma therapy, described Sorafenib, hepatocyte growth factor receptor inhibitor PF-02341066 and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib mol ratio are 0.5-1.5:0.75-1.5:3.0-7.5.

6. application according to claim 5, it is characterized in that, in application in the medicine of preparation Hepatoma therapy, described Sorafenib, hepatocyte growth factor receptor inhibitor PF-02341066 and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib mol ratio are 1.0-1.5:1.0-1.5:5.0-7.5.

7. application according to claim 4, it is characterized in that, in application in the medicine of preparation treatment pulmonary carcinoma, colon cancer, described Sorafenib, hepatocyte growth factor receptor inhibitor PF-02341066 and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib mol ratio are 3.0-6.0:0.75-1.5:3.0-7.5.

8. application according to claim 7, it is characterized in that, in application in the medicine of preparation treatment pulmonary carcinoma, colon cancer, described Sorafenib, hepatocyte growth factor receptor inhibitor PF-02341066 and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib mol ratio are 4.0-6.0:1.0-1.5:5.0-7.5.

9. application according to claim 4, it is characterized in that, the Sorafenib in described pharmaceutical composition, hepatocyte growth factor receptor inhibitor PF-02341066 and epidermal growth factor recipient tyrosine kinase inhibitor erlotinib use or using in order with any priority simultaneously.