CN101653608B - Pharmaceutical composition containing hepatocyte growth factor receptor inhibitor and histone deacetylase inhibitor and application thereof - Google Patents
Pharmaceutical composition containing hepatocyte growth factor receptor inhibitor and histone deacetylase inhibitor and application thereof Download PDFInfo
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- CN101653608B CN101653608B CN 200810135516 CN200810135516A CN101653608B CN 101653608 B CN101653608 B CN 101653608B CN 200810135516 CN200810135516 CN 200810135516 CN 200810135516 A CN200810135516 A CN 200810135516A CN 101653608 B CN101653608 B CN 101653608B
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Abstract
The invention relates to a pharmaceutical composition containing a hepatocyte growth factor receptor (cMet) inhibitor and a histone deacetylase (HDAC) inhibitor, and application of the pharmaceutical composition in the preparation of medicaments for treating intestinal cancer, sarcoma, glioma, liver cancer, lung cancer, stomach 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 pharmaceutical composition and the application in the medicine of preparation treatment intestinal cancer, sarcoma, glioma, hepatocarcinoma, pulmonary carcinoma, gastric cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate thereof of C-MET HGFr (cMet) inhibitor and histon deacetylase (HDAC) (HDAC) inhibitor.
Background technology
World Health Organization's investigation report shows that 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 colon cancer is one of common malignant tumor, and is the highest with 40-50 year age group sickness rate.The morbidity of colon cancer and environment, living habit, especially diet style is relevant.It is generally acknowledged that high fat diet and cellulose deficiency are main pathogenic factors.Along with growth in the living standard, the change of dietary structure, the sickness rate of colon cancer is year by year ascendant trend; Sarcoma is to derive from mesenchymal tissue, comprises the malignant tumor of connective tissue and muscle, multiple skin, subcutaneous, periosteum and the long bone of limbs two ends be born in, and osteosarcoma comparatively commonly wherein, fatality rate and disability rate are high.Osteosarcomatous paathogenic factor comprises mainly that inherited genetic factors, benign cancerate, infection etc., its sickness rate amplification speed, and be rejuvenation trend; Glioma is to betide neuroectodermal tumor, and it originates from neural Interstitial cell, is the intracranial common cancer, accounts for the 35-60% of intracranial tumor.
The antitumor drug that has gone on the market at present is more, and such as alkylating agent medicine, antimetabolite, antitumor antibiotics, immunomodulator etc., but medicine is because toxicity is larger 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 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 cMet inhibitor that grinds or entered clinical research PF-02341066, SGX523 or PHA665752 etc. are arranged.
Antibiotic FR 901228 has inhibition tumor cell propagation, cell cycle arrest, Cell differentiation inducing activity and promotes apoptotic effect.There have been at present the multiple Antibiotic FR 901228s such as SAHA, MS-275, FK228 to enter clinical research.
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 targeted therapy for many target spots and will not only be intended to reduce or delay chemical sproof appearance, reduce toxicity, and obtains 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 the application in the medicine of preparation treatment intestinal cancer, sarcoma, glioma, hepatocarcinoma, pulmonary carcinoma, gastric cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate thereof, be specially the pharmaceutical composition that contains C-MET HGFr (cMet) inhibitor and Antibiotic FR 901228 and the application for the treatment of the medicine of intestinal cancer, sarcoma, glioma, hepatocarcinoma, pulmonary carcinoma, gastric 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 Antibiotic FR 901228 of the present invention, described C-MET HGFr (cMet) inhibitor can be the medicine of the cMet inhibitor of any structure type, such as PF-02341066, SGX523 or PHA665752, wherein, SGX-523 has applied for that by the research and development of SGX Pha rmaceuticals company the I phase is clinical; PHA-665752 is researched and developed by Sugen company.
CMet inhibitor in the pharmaceutical composition of the present invention is preferably: PF-02341066, its structural formula are I.
In the 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.
Antibiotic FR 901228 can be the Antibiotic FR 901228 medicine of any structure type during the present invention used; such as hydroximic acid, cyclic peptide, benzamides, fatty acid etc.; be specifically as follows but be not limited to as, trichostatin (TSA), suberoylanilidehydroxamic acid (SAHA), depsipeptide (FK228), apicidin, MS-275, sodium butyrate, phenylbutyrate sodium.Wherein, MS-275 is researched and developed by Beyer Co., Ltd, and it is clinical to carry out the II phase.
Antibiotic FR 901228 of the present invention is preferably SAHA, and wherein SAHA is JMC, 38,8,1995,1411-1413 and JMC, and the formula II chemical compound of putting down in writing among 48,15,2005, the 5047-5051:
The present invention contains in the pharmaceutical composition of C-MET HGFr (cMet) inhibitor and Antibiotic FR 901228, and the mol ratio of C-MET HGFr (cMet) inhibitor PF-02341066 and Antibiotic FR 901228 is 0.1-5.0:0.1-5.0; Further preferred molar ratio is 0.5-2.0:0.75-2.0.
The present invention contain C-MET HGFr (cMet) inhibitor and Antibiotic FR 901228 pharmaceutical composition can for the preparation of the treatment various tumors medicine, described tumor includes but not limited to intestinal cancer, sarcoma, glioma, hepatocarcinoma, pulmonary carcinoma, gastric cancer, cerebroma, cancer of pancreas, ovarian cancer, breast carcinoma or carcinoma of prostate.
The pharmaceutical composition of the preferred C-MET HGFr of the present invention (cMet) inhibitor and Antibiotic FR 901228 is for the preparation of the application in treatment colon cancer, sarcoma and the gliomatous medicine.
In the application of pharmaceutical composition of the present invention for the preparation of the medicine for the treatment of colon cancer, the mol ratio of described PF-02341066 and SAHA is preferably 0.75-1.5:1.0-2.0; The mol ratio of PF-02341066 and SAHA is 1.0-1.5:1.5-2.0 more preferably; Mol ratio the best of PF-02341066 and SAHA is 1.5:2.0.
The present composition is in the application of the medicine of preparation treatment sarcoma, and the mol ratio of described PF-02341066 and SAHA is 0.5-1.5:0.75-1.5; The mol ratio of PF-02341066 and SAHA is preferably 1.0-1.5:1.0-1.5; Mol ratio the best of PF-02341066 and SAHA is 1.5:1.5.
The present composition is in the application of the gliomatous medicine of preparation treatment, and the mol ratio of described PF-02341066 and SAHA is 1.0-2.0:0.75-1.5; The mol ratio of PF-02341066 and SAHA is 1.5-2.0:1.0-1.5 more preferably; Mol ratio the best of PF-02341066 and SAHA is 2.0:1.5.
Contain C-MET HGFr (cMet) inhibitor and Antibiotic FR 901228 compositions in preparation treatment intestinal cancer, sarcoma, glioma, hepatocarcinoma, pulmonary carcinoma, gastric 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 simultaneously administration, C-MET HGFr (cMet) inhibitor and Antibiotic FR 901228 can be contained in same pharmaceutical preparation such as tablet or the capsule, also C-MET HGFr (cMet) inhibitor and Antibiotic FR 901228 can be made respectively preparation, as making respectively tablet or capsule, and the mode that adopts this area routine is with their packings or combine, and 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, C-MET HGFr (cMet) inhibitor can be made respectively different preparations with Antibiotic FR 901228, and the mode that adopts this area routine is with their packings or combine, then the patient takes according to the sequencing of package insert indication, 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 to 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 respectively different preparations with Antibiotic FR 901228; and the mode that adopts this area routine is with their packings or combine; then the patient takes according to the chi sequence of package insert indication, perhaps this pharmaceutical composition is prepared into the controlled release preparation that C-MET HGFr (cMet) inhibitor and Antibiotic FR 901228 intersection discharges.
C-MET HGFr (cMet) inhibitor and Antibiotic FR 901228 compositions are in preparation treatment intestinal cancer, sarcoma, glioma, hepatocarcinoma, pulmonary carcinoma, gastric cancer, cerebroma, cancer of pancreas, ovarian cancer, in the application of the medicine of breast carcinoma or carcinoma of prostate, C-MET HGFr in the described compositions (cMet) inhibitor and Antibiotic FR 901228 can be used or simultaneously with the using in order of any priority, as C-MET HGFr (cMet) inhibitor and Antibiotic FR 901228 being taken to the patient simultaneously; Also can first Antibiotic FR 901228 be taken, then be taken to C-MET HGFr (cMet) inhibitor medicaments to the patient, or take first Antibiotic FR 901228, then take C-MET HGFr (cMet) inhibitor medicaments, 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 Antibiotic FR 901228; the pharmaceutical preparation that the present invention preferably makes gastrointestinal administration with C-MET HGFr (cMet) inhibitor and Antibiotic FR 901228, 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 Antibiotic FR 901228 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.
Among the present invention; the preparation method of compositions does not have any restriction; C-MET HGFr (cMet) inhibitor and Antibiotic FR 901228 can directly be mixed and then made 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 among 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 C-MET HGFr (cMet) inhibitor and HT-29 (colon cancer cell line) is killed in the Antibiotic FR 901228 combination; the test of U2-OS (sarcoma cell strain) and D37 (neuroglial cytoma strain); results suggest; C-MET HGFr of the present invention (cMet) inhibitor and Antibiotic FR 901228 combined therapy colon cancer; sarcoma and glioma 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: HT-29 (colon cancer cell line), U2-OS (sarcoma cell strain) and D37 (neuroglial cytoma 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; C-MET HGFr (cMet) inhibitor PF-02341066 is synthesized into reference to patent WO2007066187; The synthesized reference document of Antibiotic FR 901228 SAHA is: J.Med.Chem., 1995,38,1411-1413.
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,-20 ℃ of lower preservations, 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 for subsequent use.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 the RPMI1640 culture medium that contains 10% calf serum, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO
2Damp condition under cultivate, in the previous day of dosing, carry out cell inoculation 2 * 10 at six orifice plates
5Then/hole adds the as stated above medicinal composition solution of preparation 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.Because dead cell comes off from incubator enter the 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 the 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 ,-20 ℃ of lower preservations.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 the RPMI1640 culture medium that contains 10% calf serum, 100kU/L penicillin, 100mg/L streptomycin, 37 ℃, 5%CO
2Damp condition under cultivate, in the previous day of dosing, carry out cell inoculation 2 * 10 at six orifice plates
5Then/hole adds as stated above each component solution of the pharmaceutical composition of preparation with any order 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, 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 the 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.
In the drug regimen shown in the lower tabulation 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 SAHA promote the test of HT-29 cell death, see Table 2.
Table 2
Cause in the test of colon cancer cell line HT-29 cell death at the investigation related compound, find 20% cell death of when using 1.5 μ MPF-02341066 or lower concentration, 2.0 μ MSAHA or lower concentration separately, also only having an appointment; (1.0 μ MPF-02341066+1.5 μ MSAHA) then produces obvious synergism when both share under low concentration, causes about 60% cancer cell death; When both share with the ratio of 1.5 μ MPF-02341066+2.0 μ MSAHA, then produce more significantly synergism, cause about 90% cancer cell death.
The PF-02341066 of embodiment 2 different proportions and the combination Synergistic of SAHA promote the test of U2-OS cell death, see Table 3.
Table 3
Cause in the test of sarcoma cell strain U2-OS cell death at the investigation related compound, find when using 1.5 μ MPF-02341066 or lower concentration, 1.0 μ MSAHA or lower concentration separately, to only have the seldom cell death of amount; Even also only have an appointment 15% cell death when increasing concentration to the 1.5 μ MSAHA of single medicine; (1.0 μ MPF-02341066+1.0 μ M SAHA) then produces obvious synergism when both share under low concentration, causes about 60% cancer cell death; When both share with the ratio of 1.5 μ MPF-02341066+1.5 μ M SAHA, then produce more significantly synergism, cause about 90% cancer cell death.
The PF-02341066 of embodiment 3 different proportions and the combination Synergistic of SAHA promote the test of D37 cell death, see Table 4.
Table 4
Cause in the test of neuroglial cytoma strain D37 cell death at the investigation related compound, find the 10-20% cell death of when using 2.0 μ MPF-02341066 or lower concentration, 1.5 μ MSAHA or lower concentration separately, also only having an appointment; (1.5 μ MPF-02341066+1.0 μ M SAHA) then produces obvious synergism 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+1.5 μ MSAHA, then produce more significantly synergism, cause about 85% cancer cell death.
Claims (12)
1. one kind is used for the treatment of intestinal cancer, sarcoma, gliomatous pharmaceutical composition; it is characterized in that containing hepatocyte growth factor receptor inhibitor PF-02341066 and Antibiotic FR 901228 SAHA, the mol ratio of described PF-02341066 and SAHA is 0.5-2.0:0.75-2.0.
2. the application of pharmaceutical composition claimed in claim 1 in preparation treatment intestinal cancer, sarcoma, gliomatous medicine.
3. application according to claim 2 is characterized in that, in the application of the medicine for preparing the treatment colon cancer, the mol ratio of described PF-02341066 and SAHA is 0.75-1.5:1.0-2.0.
4. application according to claim 3 is characterized in that, in the application of the medicine for preparing the treatment colon cancer, the mol ratio of described PF-02341066 and SAHA is 1.0-1.5:1.5-2.0.
5. application according to claim 4 is characterized in that, in the application of the medicine for preparing the treatment colon cancer, the mol ratio of described PF-02341066 and SAHA is 1.5:2.0.
6. application according to claim 2 is characterized in that, in the application of the medicine for preparing the treatment sarcoma, the mol ratio of described PF-02341066 and SAHA is 0.5-1.5:0.75-1.5.
7. application according to claim 6 is characterized in that, in the application of the medicine for preparing the treatment sarcoma, the mol ratio of described PF-02341066 and SAHA is 1.0-1.5:1.0-1.5.
8. application according to claim 7 is characterized in that, in the application of the medicine for preparing the treatment sarcoma, the mol ratio of described PF-02341066 and SAHA is 1.5:1.5.
9. application according to claim 2 is characterized in that, in the application of the gliomatous medicine of preparation treatment, the mol ratio of described PF-02341066 and SAHA is 1.0-2.0:0.75-1.5.
10. application according to claim 9 is characterized in that, in the application of the gliomatous medicine of preparation treatment, the mol ratio of described PF-02341066 and SAHA is 1.5-2.0:1.0-1.5.
11. application according to claim 10 is characterized in that, in the application of the gliomatous medicine of preparation treatment, the mol ratio of described PF-02341066 and SAHA is 2.0:1.5.
12. application according to claim 2 is characterized in that, the hepatocyte growth factor receptor inhibitor PF-02341066 in the described pharmaceutical composition and Antibiotic FR 901228 SAHA use or using in order with any priority simultaneously.
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| CN101653608B true CN101653608B (en) | 2013-02-13 |
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