CN101653607A - Pharmaceutical composition containing hepatocyte growth factor receptor inhibitor and mitogen extracellular kinase inhibitor and application thereof - Google Patents
Pharmaceutical composition containing hepatocyte growth factor receptor inhibitor and mitogen extracellular kinase inhibitor and application thereof Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition containing a hepatocyte growth factor receptor (cMet) inhibitor and a mitogen extracellular kinase (MEK) inhibitor, and application of the pharmaceutical composition in the preparation of medicaments for treating liver cancer, lung cancer, stomach cancer, intestinal cancer, brain tumors, pancreatic cancer, ovarian cancer, mammary cancer or prostate cancer. The pharmaceutical composition has significant synergistic effect, improves the treatment effect of the medicaments, reduces the administration dose and reduces side effects.
Description
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 the pharmaceutical composition and the application in the medicine of preparation treatment hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate thereof of hepatocyte growth factor receptor inhibitor and mitogen extracellular kinase inhibitor.
Background technology
World Health Organization's investigation report shows that global cancer condition is serious day by day, 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 of 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 one of human modal malignant tumor for occurring in the epithelial canceration of hepatocyte and stones in intrahepatic bile duct; Cancer of pancreas is one of higher digestive system tumor of grade malignancy, and sickness rate is ascendant trend year by year.Because onset concealment lacks effective method of early diagnosis, often reach an advanced stage when making a definite diagnosis or shift, the patients with terminal median survival interval is no more than six months, and the treatment new method of therefore studying cancer of pancreas is extremely urgent.
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 because toxicity is bigger mostly, and patient does not tolerate.The Study on Molecular Mechanism that develops along with the generation to tumor is more and more clearer, and the multiple malignant tumor of molecular targeted treatment has been subjected to paying close attention to widely and paying much attention to.Molecular targeted agents selectivity height, wide spectrum are effective, and its safety is better than the cytotoxicity chemotherapeutics, are the new directions of present oncotherapy field development.
Hepatocyte growth factor (Hepatocyte growth factor, HGF) by with have the ability that promotes cell division, motion and shaping after special receptor (C-MET HGFr cMet) on its target cell combines.CMet is a proto-oncogene cMet encoded protein, 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 the after birth, and the biological effect by signal transduction pathway performance HGF in the 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 hepatocyte growth factor receptor inhibitor that grinds or entered clinical research PF-02341066, SGX523 or PHA665752 etc. are arranged.
Mitogen activated protein kinase (mitogen-activated protein kinase, MAPK) cascade is the important channel of cell signalling, the various kinds of cell external signal of raising (as somatomedin, cytokine, the tumour promotion factor) can be passed on to nucleus step by step by phosphoric acid activation, and activate multiple nuclear factor, as C-myc, C-jun etc. participate in cell and grow, grow, divide, reach various physiological processes such as differentiation, and play an important role in malignant transformation of cells and evolution.As important ring---mitogen extracellular kinase (the mitogenextracellular kinase in the MAPK signal transduction pathway, MEK) can be by activation such as multiple somatomedin, inflammatory factor and environmental stress reactions, the propagation that causes cell, therefore, mek inhibitor becomes a new direction of antitumor drug research.
Along with the progress of oncomolecularbiology, the molecular targeted treatment of tumor 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 single signal transduction pathway, but a plurality of signal transduction pathway concur, therefore drug combination carries out targeted therapy at many target spots and will not only be intended to reduce or delay chemical sproof appearance, reduce toxicity, and by multiple medicine the synergism that cancerous cell kills and wounds is obtained better therapeutic.
Summary of the invention
At above technological deficiency, the invention provides a kind of pharmaceutical composition and the application in the medicine of preparation treatment hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate thereof, be specially pharmaceutical composition that contains C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor and the application for the treatment of the medicine of hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate in preparation thereof.
In the pharmaceutical composition that contains C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor of the present invention, described C-MET HGFr (cMet) inhibitor can be the medicine of the hepatocyte growth factor receptor inhibitor of any structure type, as PF-02341066, SGX523 or PHA665752, wherein, SGX-523 has applied for that by the research and development of SGXPharmaceuticals company the I phase is clinical; PHA-665752 is researched and developed by Sugen company.
In the pharmaceutical composition of the present invention, described hepatocyte growth factor receptor inhibitor is preferably PF-02341066, and structural formula is formula I:
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.
Among the present invention, described mitogen extracellular kinase inhibitor can be for the medicine of the mitogen extracellular kinase inhibitor of any structure type, as U0126, ARRY-142886, CI-1040 or PD325901, wherein, PD-325901 is by Pfizer company research and development, and it is clinical to carry out the II phase at present; CI-1040 is researched and developed by Pfizer company.
In the pharmaceutical composition of the present invention, described mitogen extracellular kinase inhibitor is preferably U0126 or ARRY-142886 or its combination, and wherein ARRY-142886 is the chemical compound of the formula II that put down in writing among the WO03/077914;
In the pharmaceutical composition of the present invention, described component is not limited to said medicine itself, can also be the salt of their analog, derivant and organic or inorganic thereof.
The present invention contains in the pharmaceutical composition of C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor, and the mol ratio of described C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor is 0.1-5.0: 0.05-2.0; The mol ratio of further preferred C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor is 0.5-2.0: 0.15-1.0.
The pharmaceutical composition that the present invention contains C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor can be used to prepare the medicine for the treatment of various tumors, and described tumor includes but not limited to hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate.
The pharmaceutical composition of C-MET HGFr of the present invention (cMet) inhibitor and mitogen extracellular kinase inhibitor is preferred for preparing the application in the medicine for the treatment of hepatocarcinoma or cancer of pancreas.
In the application that pharmaceutical composition of the present invention is used for preparing the medicine for the treatment of hepatocarcinoma, C-MET HGFr (cMet) inhibitor is preferably PF-02341066, and mitogen extracellular kinase inhibitor is preferably ARRY-142886; Wherein, the mol ratio of described PF-02341066 and ARRY-142886 is 0.5-2.0: 0.15-0.5, being preferably PF-02341066 and ARRY-142886 mol ratio is 1.0-2.0: 0.25-0.5, and best is that PF-02341066 and ARRY-142886 mol ratio are 2.0: 0.5.
The present composition is in the application of the medicine of preparation treatment cancer of pancreas, described C-MET HGFr (cMet) inhibitor is preferably PF-02341066, mitogen extracellular kinase inhibitor is preferably ARRY-142886, wherein, the mol ratio of described PF-02341066 and ARRY-142886 is 0.5-2.0: 0.25-1.0.
Pharmaceutical composition of the present invention is in the application of the medicine of preparation treatment AsPC-1 type cancer of pancreas, and the mol ratio of described PF-02341066 and ARRY-142886 is 1.0-2.0: 0.25-1.0; The mol ratio of preferred PF-02341066 and ARRY-142886 is 1.5-2.0: 0.5-1.0; The mol ratio that the best is preferably PF-02341066 and ARRY-142886 is 2.0: 1.0.
Wherein in the application of the medicine for preparing treatment Hs766T type cancer of pancreas, the mol ratio of described PF-02341066 and ARRY-142886 is 0.5-1.5: 0.25-1.0; The mol ratio of preferred PF-02341066 and ARRY-142886 is 1.0-1.5: 0.5-1.0; The mol ratio that the best is preferably PF-02341066 and ARRY-142886 is 1.5: 1.0.
Contain C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor compositions in preparation treatment hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, cerebroma, 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, C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor can be contained in in a kind of pharmaceutical preparation such as tablet or the capsule, also C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor can be made preparation respectively, as making tablet or capsule respectively, and the mode that adopts this area routine is with their packings or combine, and the patient takes simultaneously according to the indication of package insert then; In the scheme of the medicament of the present composition being made administration successively, C-MET HGFr (cMet) inhibitor can be made different preparations respectively with mitogen extracellular kinase inhibitor, and the mode that adopts this area routine is with their packings or combine, the patient takes according to the sequencing of package insert indication then, or two kinds of compositions in the above-mentioned composition are made a kind of preparation of controlled release, a kind of composition in elder generation's release composition, and then the another kind of composition in the release composition, the patient only need take this controlled release composition preparation; In the scheme of the medicament that the present composition is prepared into the intersection administration, C-MET HGFr (cMet) inhibitor can be made different preparations respectively with mitogen extracellular kinase inhibitor, and the mode that adopts this area routine is with their packings or combine, the patient takes according to the chi sequence of package insert indication then, the controlled release preparation that perhaps this preparation of pharmaceutical compositions is become C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor intersection to discharge.
C-MET HGFr of the present invention (cMet) inhibitor and mitogen extracellular kinase inhibitor compositions are in the application of the medicine of preparation treatment hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate, C-MET HGFr in the described compositions (cMet) inhibitor and mitogen extracellular kinase inhibitor can use or simultaneously with the using in order of any priority, as C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor being taken to the patient simultaneously; Also can earlier mitogen extracellular kinase inhibitor be taken, be taken then to C-MET HGFr (cMet) inhibitor medicaments to the patient, or take mitogen extracellular kinase inhibitor earlier, take C-MET HGFr (cMet) inhibitor medicaments then, the interval of taking for both does not have special requirement, but the interval of preferably taking two kinds of medicines is no more than one day; Perhaps two kinds of medicines replace administration.
Among the present invention, can adopt the method for this area routine to be prepared into the pharmaceutical preparation that is suitable for gastrointestinal administration or parenteral administration C-MET HGFr of the present invention (cMet) inhibitor and mitogen extracellular kinase inhibitor, the pharmaceutical preparation that the present invention preferably makes gastrointestinal administration with C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor, its dosage form can be conventional tablet or capsule or controlled release, slow releasing preparation.In the pharmaceutical preparation of C-MET HGFr of the present invention (cMet) inhibitor and mitogen extracellular kinase inhibitor compositions, according to different dosage forms and preparation specification, the content of described compositions in preparation can be 1-99% in mass, is preferably 10%-90%; The adjuvant that preparation uses can adopt the adjuvant of this area routine, reacts or the curative effect that do not influence medicine of the present invention is a prerequisite with the discord present composition; The preparation method of described preparation can adopt the preparation method of this area routine to be prepared.
Among the present invention, C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor preparation of compositions method do not have any restriction, C-MET HGFr (cMet) inhibitor and mitogen extracellular kinase inhibitor can directly mix makes preparation then, or respectively and/or corresponding auxiliary material mix and to make preparation respectively, and then be packaging together, or mix and then mix and make preparation with corresponding auxiliary material respectively according to the mode of this area routine.
The dosage of the pharmaceutical composition among the present invention can carry out suitable variation according to the dosage form difference of administration object, route of administration or medicine, but is prerequisite to guarantee that this pharmaceutical composition can reach effective blood drug level in mammalian body.
The present invention has carried out C-MET HGFr (cMet) inhibitor respectively and mitogen extracellular kinase inhibitor makes up the test of killing HepG2 (hepatoma cell strain), AsPC-1, Hs766T (pancreas cancer cell strain), results suggest, C-MET HGFr of the present invention (cMet) inhibitor and mitogen extracellular kinase inhibitor combined therapy hepatocarcinoma, cancer of pancreas have significant cooperative effect, not only improved the curative effect of medicine, and 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: HepG2 (hepatoma cell strain), AsPC-1 (pancreas cancer cell strain), Hs766T (pancreas cancer cell strain) are all available from American Type Culture Collection (ATCC), Rockville, MD, USA.
Medicine: institute's pharmaceutical composition is all by following method 1 or 2 described preparations of method in following examples; Mitogen extracellular kinase inhibitor ARRY-142886 is synthesized into reference to patent WO03/077914; C-MET HGFr (cMet) inhibitor PF-02341066 is synthesized into reference to patent WO2007066187.
Method 1: each component of accurate weighing corresponding pharmaceutical compositions, dissolve respectively with dimethyl sulfoxide, be made into the stock solution of 10mM separately, preserve down at-20 ℃, be diluted to suitable concentration with fresh culture medium during use, the solution of each component of 1 microlitre of respectively asking for then mixes standby.In all tests, the ultimate density of dimethyl sulfoxide is answered≤5g/L, so that do not influence cell activity.
With all cells in RPMI 1640 culture medium that contain 10% calf serum, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO
2Damp condition cultivate down, in the previous day of dosing, on six orifice plates, carry out cell inoculation 2 * 10
5/ hole adds the pharmaceutical composition solution of preparation as stated above then in cell, make each component reach its working concentration, 1-6 in specifically seeing Table.
After the dosing 5 days, measure cell death by trypan blue (Trypan Blue), cell turns into 10 minutes by carrying out pancreatin at 37 ℃ with trypsin sodium/EDTA.Dead cell comes off from incubator and enters the culture medium, by all cells of centrifugal collection under 1200 rev/mins, and then with culture medium suspended sediment again, mixes with the trypan blue dyestuff.After the dyeing, count with optical microscope and hematimeter.Dyed the blue dead cell of counting by dyestuff.500 cells of picked at random are counted, and dead cell is recently expressed with the percentage that accounts for the grand total cell.
Method 2: each component of accurate weighing corresponding pharmaceutical compositions, dissolve respectively with dimethyl sulfoxide, be made into the stock solution of 10mM separately, preserve down at-20 ℃.Be diluted to suitable concentration with fresh culture medium during use, the solution for standby of each component of 1 microlitre of respectively asking for then.In all tests, the ultimate density of dimethyl sulfoxide is answered≤5g/L, so that do not influence cell activity.
With all cells in RPMI 1640 culture medium that contain 10% calf serum, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO
2Damp condition cultivate down, in the previous day of dosing, on six orifice plates, carry out cell inoculation 2 * 10
5/ hole adds each component solution of the pharmaceutical composition of preparation as stated above with any order then in cell, make each component reach its working concentration, 7-9 in specifically seeing Table.
After the dosing 5 days, 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 the culture medium,, and then, mix with the trypan blue dyestuff with culture medium suspended sediment again by all cells of centrifugal collection under 1200 rev/mins.After the dyeing, count with optical microscope and hematimeter.Dyed the blue dead cell of counting by dyestuff.500 cells of picked at random are counted, and dead cell is recently expressed with the percentage that accounts for the grand total cell.
Tabulate down in the drug regimen shown in 1, the combination of 1-6 is by method 1 preparation; 7-9 is by method 2 preparations.
Table 1
The PF-02341066 of embodiment 1 different proportion and the combination Synergistic of ARRY-142886 promote the test of HepG2 cell death, see Table 2.
Table 2
Cause in the test of hepatoma cell strain HepG2 cell death at the investigation related compound, find when using 2.0 μ M PF-02341066 or lower concentration, 0.25 μ M ARRY-142886 or lower concentration separately, to have only very a spot of cell death; Even when increasing concentration to the 0.5 μ MARRY-142886 of single medicine, 20% cell death of also only having an appointment; (1.0 μ M PF-02341066+0.25 μ M ARRY-142886) then produces the obvious synergistic effect when both share under low concentration, causes about 60% cancer cell death; When both share with the ratio of 2.0 μ M PF-02341066+0.5 μ MARRY-142886, then produce obvious synergistic effect more, cause about 100% cancer cell death.
The PF-02341066 of embodiment 2 different proportions and ARRY-142886 combination Synergistic promote the AsPC-1 cell death, see Table 3.
Table 3
Cause in the test of pancreas cancer cell strain AsPC-1 cell death at the investigation related compound, find when using 1.5 μ M PF-02341066 or lower concentration, 0.5 μ M ARRY-142886 or lower concentration separately, to have only very a spot of cell death; Even only have an appointment the 15-20% cell death when increasing concentration to the 2.0 μ MPF-02341066 of single medicine or 1.0 μ M ARRY-142886; (1.5 μ M PF-02341066+0.5 μ M ARRY-142886) then produces the obvious synergistic effect when both share under low concentration, causes about 60% cancer cell death; When both share with the ratio of 2.0 μ MPF-02341066+1.0 μ M ARRY-142886, then produce obvious synergistic effect more, cause about 90% cancer cell death.
The PF-02341066 of embodiment 3 different proportions and ARRY-142886 combination Synergistic promote the Hs766T cell death, see Table 4.
Table 4
Cause in the test of pancreas cancer cell strain Hs766T cell death at the investigation related compound, find when using 1.5 μ M PF-02341066 or lower concentration, 1.0 μ M ARRY-142886 or lower concentration separately, to have only very a spot of cell death; And when both share with the ratio of 1.5 μ M PF-02341066+1.0 μ M ARRY-142886, then produce the obvious synergistic effect, cause about 85% cancer cell death.
Claims (15)
1, a kind of pharmaceutical composition is characterized in that containing hepatocyte growth factor receptor inhibitor and mitogen extracellular kinase inhibitor.
2, pharmaceutical composition according to claim 1 is characterized in that, the mol ratio of described hepatocyte growth factor receptor inhibitor and mitogen extracellular kinase inhibitor is 0.1-5.0: 0.05-2.0.
3, pharmaceutical composition according to claim 2 is characterized in that, the mol ratio of described hepatocyte growth factor receptor inhibitor and mitogen extracellular kinase inhibitor is 0.5-2.0: 0.15-1.0.
4, pharmaceutical composition according to claim 3 is characterized in that, described hepatocyte growth factor receptor inhibitor is PF-02341066, SGX523 or PHA665752; Mitogen extracellular kinase inhibitor is U0126, ARRY-142886, PD325901 or CI-1040.
5, the application of the arbitrary described pharmaceutical composition of claim 1-4 in the medicine of preparation treatment hepatocarcinoma, pulmonary carcinoma, gastric cancer, intestinal cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate.
6, application according to claim 5 is characterized in that, in the application of the medicine for preparing treatment hepatocarcinoma, described PF-02341066 and ARRY-142886 mol ratio are 0.5-2.0: 0.15-0.5.
7, application according to claim 6 is characterized in that, in the application of the medicine for preparing treatment hepatocarcinoma, described PF-02341066 and ARRY-142886 mol ratio are 1.0-2.0: 0.25-0.5.
8, application according to claim 7 is characterized in that, in the application of the medicine for preparing treatment hepatocarcinoma, described PF-02341066 and ARRY-142886 mol ratio are 2.0: 0.5.
9, application according to claim 5 is characterized in that, in the application of the medicine for preparing the treatment cancer of pancreas, described PF-02341066 and ARRY-142886 mol ratio are 0.5-2.0: 0.25-1.0.
10, application according to claim 9 is characterized in that, in the application of the medicine for preparing treatment AsPC-1 type cancer of pancreas, described PF-02341066 and ARRY-142886 mol ratio are 1.0-2.0: 0.25-1.0.
11, application according to claim 10 is characterized in that, in the application of the medicine for preparing treatment As PC-1 type cancer of pancreas, described PF-02341066 and ARRY-142886 mol ratio are 1.5-2.0: 0.5-1.0.
12, application according to claim 11 is characterized in that, in the application of the medicine for preparing treatment AsPC-1 type cancer of pancreas, described PF-02341066 and ARRY-142886 mol ratio are 2.0: 1.0.
13 application according to claim 9 is characterized in that, in the application of the medicine for preparing treatment Hs766T type cancer of pancreas, described PF-02341066 and ARRY-142886 mol ratio are 0.5-1.5: 0.25-1.0.
14, application according to claim 13 is characterized in that, in the application of the medicine for preparing treatment Hs766T type cancer of pancreas, described PF-02341066 and ARRY-142886 mol ratio are 1.0-1.5: 0.5-1.0.
15, application according to claim 14 is characterized in that, in the application of the medicine for preparing treatment Hs 766T type cancer of pancreas, described PF-02341066 and ARRY-142886 mol ratio are 1.5: 1.0.
16, application according to claim 5 is characterized in that, hepatocyte growth factor receptor inhibitor in the described pharmaceutical composition and mitogen extracellular kinase inhibitor use or using in order with any priority simultaneously.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664954A (en) * | 2012-09-17 | 2014-03-26 | 杨育新 | Compounds for treating traumatic brain injury diseases and application thereof |
| WO2014056566A1 (en) * | 2012-10-11 | 2014-04-17 | Merck Patent Gmbh | Combination of a 6-oxo-1,6-dihydro-pyridazine derivative having anti-cancer activity with a mek inhibitor |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL233493B1 (en) * | 2002-03-13 | 2019-10-31 | Array Biopharma Inc | N3 alkylated benzimidazole derivatives as MEK inhibitors |
| ATE488237T1 (en) * | 2005-12-05 | 2010-12-15 | Pfizer Prod Inc | METHOD FOR TREATING ABNORMAL CELL GROWTH |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664954A (en) * | 2012-09-17 | 2014-03-26 | 杨育新 | Compounds for treating traumatic brain injury diseases and application thereof |
| WO2014056566A1 (en) * | 2012-10-11 | 2014-04-17 | Merck Patent Gmbh | Combination of a 6-oxo-1,6-dihydro-pyridazine derivative having anti-cancer activity with a mek inhibitor |
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