CN103006665A - Medicine composition, and preparation and application thereof - Google Patents
Medicine composition, and preparation and application thereof Download PDFInfo
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- CN103006665A CN103006665A CN2011102834589A CN201110283458A CN103006665A CN 103006665 A CN103006665 A CN 103006665A CN 2011102834589 A CN2011102834589 A CN 2011102834589A CN 201110283458 A CN201110283458 A CN 201110283458A CN 103006665 A CN103006665 A CN 103006665A
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Abstract
The invention belongs to the technical field of medicines, and discloses a medicine composition composed of (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-pyrimidine-2-yl)amino]phenyl)-2,3-dihydroindene-5-amide sesquisulfate and a taxanes microtubule inhibitor. The medicine composition is determined through scientific experiments. As a result of experiments, the taxanes microtubule inhibitor has no influence on the stability of the compound. As a result of pharmacological test, the two components provide a synergetic effect.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of pharmaceutical composition and preparation and purposes that contains the dihydroindene amide compound.
Background technology
Cancer (cancer), medical terminology also claim malignant tumor (malignant neoplasm), are not normal by control growth and proliferation of cell mechanism and disease that cause.Cancer is the formidable enemy of human health.According to statistics, in China, cancer surpassed cardiovascular disease from 2007 becomes human the first killer.Classical treatment cancer drug all is the cytotoxicity chemotherapeutic, cisplatin (cisplatin) for example, carboplatin (carboplatin), paclitaxel (paclitaxel), pemetrexed (pemetrexed), gemcitabine (gemcitabine) etc., these medicines can not act on cancerous cell in specific manner, except kill cancer cell, can also kill normal cell, cause alopecia, erythrocyte reduces, the toxic and side effects such as vomiting and weight loss.For this reason, these medicines can only be given to dosage and the time that human body can bear.Under such condition, most of cancerous cell can not be killed, and can only be controlled.In case after the drug withdrawal, cancerous cell begins again breeding, recurrence or diffusion appear, cause death.
Along with biological development, scientists is found in recent years, and the reason that causes cancer is the sudden change of gene.The gene of sudden change has produced a kind of protein and has been called protein kinase.This protein kinase only is present in the cancerous cell, is not present in the normal cell.If so this protein kinase has been suppressed with a micromolecular compound, cancerous cell has just no longer been bred even is dead, but Normocellular growth is unaffected.This micromolecular compound just can be used as the anticarcinogen of a new generation, is called the targeting medicine.The characteristics of targeting anticarcinogen are growth even the energy kill cancer cell of its energy anticancer, but do not suppress Normocellular growth or kill normal cell, and consequently toxic and side effects is less than classical chemotherapeutic, but long-term taking.At present, external drugmaker has developed several such targeting anticarcinogens, such as imatinib mesylate (gleevec), Iressa (iressa), Erlotinib (tarceva) and SU11248 (sutent) etc., they are all very effective to treating various cancers, and toxic and side effects is less than classical anticarcinogen.Patent WO2010/072166A1 discloses (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate belongs to kinases inhibitor, can be used for the treatment of various cancers.
The purpose of drug combination is to heighten the effect of a treatment in the treatment of cancer, reduces the generation of untoward reaction.Mechanism of action and Dynamic tumor cell according to antineoplastic agent carry out reasonable drug combination, are to treat in recent years one of impressive progress in the tumor.Along with the further investigation of targeted anticancer medicine, researcher wishes cytotoxic drug and targeting anticarcinogen are united use, to addressing the above problem.
Summary of the invention
For these reasons, the applicant is by the test of science, determine chemical compound (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate can make up with the taxanes microtubule inhibitors, evidence, without any impact, pharmacology test proves the taxanes microtubule inhibitors on compound stability, and the two has synergism.
The present invention realizes by following proposal.
Chemical compound of the present invention (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate structural formula is as follows:
A kind of pharmaceutical composition, pharmaceutical composition comprises effective dose (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2, the taxanes microtubule inhibitors of 3-dihydroindene-5 an amide sesquisulfate and effective dose.Described taxanes microtubule inhibitors includes but not limited to: 205 pages of taxanes microtubule inhibitors to 216 pages of records in " cancer therapy drug molecular library " (Science Press) (Chen Qingqi writes) (in February, 2012).
A kind of pharmaceutical composition, (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino wherein] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate and taxanes microtubule inhibitors weight ratio are 1-10:1-20.
Aforementioned pharmaceutical compositions can also comprise cytotoxic drug or targeting anticarcinogen, perhaps other active component.
Aforementioned pharmaceutical compositions can also comprise pharmacy acceptable pharmaceutic adjuvant.
Taxanes microtubule inhibitors described above includes but not limited to paclitaxel.
Taxanes microtubule inhibitors described above includes but not limited to docetaxel (Docetaxel).
Taxanes microtubule inhibitors described above also comprises one or more in the bearing taxanes that extraction obtains in the Ramulus et folium taxi cuspidatae.Described Ramulus et folium taxi cuspidatae is extracted the bearing taxanes that obtains and includes but not limited to following: Cephalomannine, paclitaxel C, 10-deacetylate Bakating III, Bakating III, 10-deacetyl taxol, 7-xylose paclitaxel, 10-remove acetyl Cephalomannine, 10-deacetyl taxol C, 7-xylose paclitaxel C, 9-hydroxyl-13-acetyl group Bakating III etc.
Taxanes microtubule inhibitors described above also comprises the taxanes microtubule inhibitors of clinical research.
Pharmaceutical composition described above application in preparation treatment cancer drug.
Described cancer includes but not limited to breast carcinoma, pulmonary carcinoma, carcinoma of prostate, ovarian cancer, intestinal cancer, melanoma, incidence cancer, lymphatic cancer, cerebroma.
The pharmaceutical preparation of pharmaceutical composition preparation described above.
Pharmaceutical preparation described above includes but not limited to ejection preparation.
Pharmaceutical preparation described above includes but not limited to aqueous injection, infusion solution or injectable powder.
One, stability test
(1) influence factor's test
1, experimental condition
(1) exposure experiments to light: sample thief, loose dividing in little culture dish, thickness is 5mm approximately.Be placed on the proof box of medicine strong illumination (SHH-100GD, Chongqing immortality experimental apparatus factory; LHH-250GP, upper sea blue leopard testing equipment company limited), under illumination 4500Lx ± 500Lx condition, placed 10 days, the 5th day and sampling in the 10th day, detect, the result compares with 0 month data.
(2) hot test: sample thief places small beaker, the diaphragm seal sealing.Be placed on electric drying oven with forced convection (DHG-9023A, Shanghai one permanent Science and Technology Ltd.), placed 10 days under 60 ℃ ± 1 ℃ condition, in the 5th day and sampling detection in the 10th day, the result compared with 0 month data.
(3) high wet test: sample thief, place small beaker, place respectively to fill NaCl saturated solution and KNO
3The close drying device of saturated solution, damp condition is respectively RH75%.It is placed respectively electric drying oven with forced convection (DHG-9023A, Shanghai one permanent Science and Technology Ltd.), placed 10 days under 25 ℃ ± 1 ℃ condition, in the 5th day and sampling detection in the 10th day, the result compared with 0 month data.
2, detection method
1. (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate
(1) related substance: high performance liquid chromatography (two appendix ⅴ of Chinese Pharmacopoeia version in 2010 D)
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; Acetonitrile: water (0.5% triethylamine, phosphoric acid is regulated pH=6.5) is mobile phase (35:65); The detection wavelength is 220nm, and number of theoretical plate calculates for Ni Feng by the U.S. enlightening of sulphuric acid should be not less than 3000.
The algoscopy sample thief is an amount of, and the adding dissolve with methanol is complete, filters, and residue is dry, obtains raw material 1, and raw material 1 adds mobile phase and makes the sample solution that every 1ml contains 200 μ g, as need testing solution; Precision measures 0.5ml, puts in the 100ml measuring bottle, is diluted to scale with mobile phase, shakes up, in contrast solution.Get contrast solution 20 μ l injection liquid chromatographies, regulate instrumental sensitivity, make the peak height of main constituent chromatographic peak be about 20～25% of full scale; Precision measures each 20 μ l of need testing solution and reference substance solution, injection liquid chromatography respectively, and the record chromatogram is to main constituent peak retention time more than 3 times.If any impurity peaks, the peak area sum of each impurity peaks must not be greater than contrast solution main peak area (0.5%) in the need testing solution chromatogram, and wherein single impurity peak area must not be greater than 0.3 times (0.15%) of contrast solution main peak area.
(2) assay: high performance liquid chromatography (two appendix ⅴ of Chinese Pharmacopoeia version in 2010 D)
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; Acetonitrile: water (0.5% triethylamine, phosphoric acid is regulated PH=6.5) is mobile phase (35:65); The detection wavelength is 265nm, number of theoretical plate is by (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate peak calculates and should be not less than 3000.The peak-to-peak separating degree of chemical compound and catabolite should meet the requirements.
It is an amount of that algoscopy is got this product, and the adding dissolve with methanol is complete, filters, residue is dry, obtains raw material 1, and is accurately weighed, raw material 1 adds the mobile phase dissolving and quantitatively is diluted to the solution that approximately contains sample 40 μ g among every 1ml, and precision measures 20 μ l injection liquid chromatographies, the record chromatogram; It is an amount of that other gets reference substance, accurately weighed, adds the mobile phase dissolving and quantitatively be diluted to the solution that approximately contains 40 μ g among every 1ml, measures with method.Press external standard method with calculated by peak area, and get final product.
2. paclitaxel
(1) related substance: it is complete that sample thief adds dissolve with methanol, filters, and the filtrate concentrate drying obtains raw material 2, according to " related substance " detection method under 1007 pages of paclitaxel items of the Pharmacopoeia of the People's Republic of China (2010 editions, two ones).
(2) assay: it is complete that sample thief adds dissolve with methanol, filters, and the filtrate concentrate drying obtains raw material 2, and is accurately weighed, according to " assay " detection method under 1007 pages of paclitaxel items of the Pharmacopoeia of the People's Republic of China (2010 editions, two ones).
3, test specimen
Test specimen: raw material 1:(1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 50mg; Raw material 2: paclitaxel 200mg; Raw material 1 and raw material 2 are mixed fully, obtain test specimen.
Result of the test: see Table 1, table 2, table 3.
Table 1 strong illumination (the influence factor's result of the test of 4500Lx ± 500Lx)
The test brief summary: (behind the 4500Lx ± 500Lx) 10 days, content and related substance have no significant change through strong illumination for raw material 1 and raw material 2.
Table 2 hot conditions (60 ℃) influence factor's result of the test
The test brief summary: after raw material 1 and raw material 2 mixed, after hot conditions (60 ℃) heating, indices was all without significant change, and quality meets the requirements of the standard.
Table 3 super-humid conditions (RH75%) influence factor result of the test
The test brief summary: after raw material 1 and raw material 2 mixed, under super-humid conditions (RH92.5%), indices was all without significant change, and quality meets the requirements of the standard.
(2) accelerated test
1, experimental condition
Sample thief places in the climatic chamber (KBWF240, Chinese medical instrument), 40 ℃ ± 2 ℃, RH75% ± 5% condition is set carries out 6 months accelerated test, and regularly sampling detected in the 1st, 2,3,6 month, and the result compares with 0 month data.
2, detection method and standard
With test ().
3, test specimen
With test (one) sample.
Result of the test sees Table table 4.
Table 4 accelerated test (40 ℃, RH75%) result
The test brief summary: pharmaceutical composition Raw of the present invention accelerated 6 months under 40 ℃ of high temperature, high humidity RH75% condition, through 0,1,2,3,6 month sample analysis, sample size has no obvious decline, and related substance has no remarkable increase, does not also detect new catabolite.
Conclusion (of pressure testing): the aforementioned stable test shows, after two kinds of active component mix in the pharmaceutical composition, have no effect each other, prove absolutely (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate and paclitaxel analog compound can make up.
Two, pharmacological experimental example
Experimental example 1
Effect to Human Prostate Cancer PC-3 Cell Line
1, cell and condition of culture: human prostata cancer PC-3 cell culture adds 100 U/ml penicillins and 100 mg/L streptomycins in the RPMI1640 culture medium that contains 10% calf serum.Cellar culture under 37 ℃, the condition of 50 ml/L CO2.Fetching is counted approximately 5 * 106/ml passage and being inoculated in 24 orifice plates of trophophase, continues to cultivate behind 12 h stand-by.
2, Experimental agents
1 group of Experimental agents: docetaxel 6.7 * 10-5g/L;
2 groups of Experimental agents: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 6.7 * 10-5g/L;
3 groups of Experimental agents: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 6.7 * 10-5g/L; Docetaxel 6.7 * 10-5g/L;
4 groups of Experimental agents: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 6.7 * 10-5g/L; Docetaxel 6.7 * 10-4g/L;
5 groups of Experimental agents: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 6.7 * 10-5g/L; Docetaxel 13.4 * 10-4g/L;
3, experimental technique: 5 * 106/L cell is inoculated in 96 orifice plates, and every hole 200 μ l are after the adherent growth, be divided into different experiments medicine group, 24 h and 48 h are managed in every component other places, and every kind of concentration or compatibility are established parallel repetition 7 holes, repeated experiments 3 times, and set up the blank group that does not add any medicine.After abandoning supernatant, every hole adds the MTT of the 5g/L of the new preparation of 200 μ l, and 37 ℃ are continued to hatch 4h, abandon the dimethyl sulfoxide (DMSO) that supernatant adds 150 μ l, in DG3022 type microplate reader, measures absorbance (A) at 490 nm wavelength behind the mixing.Inhibition rate of tumor cell=(1-experimental port A value/control wells A value) * 100%.
5, experimental result: see Table 5.
The growth inhibited effect of table 5 pair PC-3 cell
Annotate: compare * * P＜0.01, * P＜0.05 with 1 group of Experimental agents; Compare ##P＜0.01, #P＜0.05 with 2 groups of Experimental agents.
Experimental example 2
Antitumor action research in people's chronic myelocytic leukemia K562 tumor model
1, laboratory animal: the NOD/SCID mice, female, 6-8 week, body weight 18-22 g.
2, Experimental agents:
1 group of Experimental agents: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 90mg/kg.
2 groups of Experimental agents: docetaxel 10mg/kg.
3 groups of Experimental agents: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 90mg/kg, docetaxel 10mg/kg.
4 groups of Experimental agents: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 40mg/kg, docetaxel 10mg/kg.
5 groups of Experimental agents: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 25mg/kg, docetaxel 10mg/kg.
3, experimental technique and step
(1) cell
The K562 cell culture is containing 10% hyclone, in the RPMI-1640 culture fluid of 100 U/ml penicillins and 100 μ g/ml streptomycins.Collect the K562 cell of exponential phase, PBS is resuspended to being fit to concentration and mixing rear for tumor inoculation under the NOD/SCID Corium Mus with matrigel 1:1.
(2) animal model and grouping
Every Mus right side subcutaneous vaccination 5 * 106 K562 cells during inoculation.When treating that tumor average volume reaches 150-200 mm3, according to tumor size and Mouse Weight random packet, every group of 8 animals.The gross tumor volume computing formula is: major diameter * minor axis 2/2.Matched group gives normal saline, and intraperitoneal administration 1 time every other day, amounts to 14 days; Experiment 1-tests 5 groups of tail intravenously administrables, 1 time every other day, amounts to 14 days.Calculate gross tumor volume, carry out statistical analysis; Statistical analysis: experimental result with mean+/-standard error (
± s) expression, two groups relatively organize with EXCEL software t check between analysis.
4, experimental result: see Table 6.
Table 6 pair K562 tumor inhibition effect
Annotate: compare * * P＜0.01 with matched group; Compare ##P＜0.01, #P＜0.05 with 1 group of experiment.
Experimental example 3
Impact on mice lung cancer
1, laboratory animal: the C57BL/6 mouse inbred lines, female, 6-8 week, body weight 18-22 g.
2, tumor strain: Lewis lung cancer cell strain (3LL), be stored in the C57BL/6 Mice Body, per 2 weeks go down to posterity 1 time.
3, Experimental agents:
1 group of Experimental agents: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 20mg/kg.
2 groups of Experimental agents: Cephalomannine 20mg/kg.
3 groups of Experimental agents: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 18mg/kg, Cephalomannine 2mg/kg.
4 groups of Experimental agents: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 15mg/kg, Cephalomannine 5mg/kg.
5 groups of Experimental agents: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 12mg/kg, Cephalomannine 8mg/kg.
6 groups of Experimental agents: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 10mg/kg, Cephalomannine 2mg/kg, gefitinib 5mg/kg.
4, experimental technique
Tumor-bearing model is set up: the trophophase Lewis lung cancer cell (3LL cell) of taking the logarithm, when trypan blue exclusion method living cell counting number reaches 95%-100%, centrifugal removal culture medium, take normal saline adjust cell concentration as
1 * 10
7/ mL gets 1 mL syringe and extracts the tumor cell suspension to be inoculated in the right axil of mice subcutaneous, every inoculation 0.2 mL tumor cell suspension.Approximately can touch Subcutaneous tumor behind 10 d, when treating that tumor is grown to approximately the diameter 1 cm left and right sides, tumor-bearing mice is put to death in the neck dislocation, in 75% alcohol-pickled 5 min, in superclean bench, from the subcutaneous tumor tissues that strips of armpit, reject fibrous capsule and slough, in aseptic plate, shred, put and add 4 ℃ of normal saline in the tissue grinder, grind gently to filter and make tumor cell suspension.0.4% trypan blue counting, cell viability〉95%, transferring cell concentration is 5 * 10
6Individual/mL.Get above-mentioned tumor cell suspension 0.2 mL(and contain oncocyte several 10
6Individual) to be inoculated in the right armpit of mice subcutaneous.After it goes out tumor, go down to posterity again as stated above 3 times, become the standard lotus tumor Mus of going down to posterity.Get go down to posterity after the Lewis lung cancer cancer source standard lotus tumor of 14 d go down to posterity mice, as stated above Mice Inoculated.Approximately behind the 6d, can touch Subcutaneous tumor, volume is 100-200 mm approximately
3, begin to carry out random packet.
Grouping and medication: with random method with postvaccinal mice group, every group of 10 mices, Experimental agents group and normal saline group be the about 100-200 mm of the 6th d(Subcutaneous tumor after inoculation all
3) the beginning administration, intraperitoneal injection, the molten inequalities such as normal saline group are observed mice diet, activity and general status every day.4 all rear all disconnected necks are put to death mice after the inoculation.
Final gross tumor volume: after putting to death mices after 4 weeks, completely peel off the tumor body and weigh, with major diameter and the perpendicular minor axis of vernier caliper measurement tumor piece, according to formula V(mm3)=0.52 * major diameter * minor axis
2Calculate gross tumor volume.
5, experimental result: see Table 7.
Table 7 is heavy and volume impact on pulmonary carcinoma transplanted tumor tumor
Annotate: compare * * P＜0.01, * P＜0.05 with the normal saline group; Compare #P＜0.05 with 1 group of Experimental agents; Compare ﹠amp with 2 groups of Experimental agents; P＜0.05.
Experiment conclusion: above-mentioned pharmacological experiment illustration understands the effect that the application's pharmaceutical composition has good treatment cancer, than the arbitrary chemical compound of independent use, all has better effect, illustrates that pharmaceutical composition of the present invention has collaborative pharmacological action.
Three, Preparation Example
Embodiment 1
A kind of pharmaceutical composition, contain (the 1S)-1-(4-methylpiperazine-1-yl) of effective dose-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino in the pharmaceutical composition] phenyl)-2, the paclitaxel of 3-dihydroindene-5 an amide sesquisulfate and effective dose.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Embodiment 2
A kind of pharmaceutical composition, (1S)-1-in the pharmaceutical composition (4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 10g, docetaxel 10g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Embodiment 3
A kind of pharmaceutical composition, (1S)-1-in the pharmaceutical composition (4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 10g, docetaxel 25g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Embodiment 4
A kind of pharmaceutical composition, (1S)-1-in the pharmaceutical composition (4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 10g, docetaxel 95g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Embodiment 5
A kind of pharmaceutical composition, (1S)-1-in the pharmaceutical composition (4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 10g, docetaxel 200g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Embodiment 6
A kind of pharmaceutical composition, (1S)-1-in the pharmaceutical composition (4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 10g, docetaxel 1g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Embodiment 7
A kind of pharmaceutical composition, (1S)-1-in the pharmaceutical composition (4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 10g, paclitaxel 3.5g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Embodiment 8
A kind of pharmaceutical composition, (1S)-1-in the pharmaceutical composition (4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 10g, paclitaxel 9g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Embodiment 9
A kind of pharmaceutical composition, (1S)-1-in the pharmaceutical composition (4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 10g, Bakating III 10g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Embodiment 10
A kind of pharmaceutical composition, (1S)-1-in the pharmaceutical composition (4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 10g, Bakating III 2g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Embodiment 11
A kind of pharmaceutical composition, (1S)-1-in the pharmaceutical composition (4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 10g, 7-xylose paclitaxel C 15g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Embodiment 12
A kind of pharmaceutical composition, (1S)-1-in the pharmaceutical composition (4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 10g, 7-xylose paclitaxel C 5g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Embodiment 13
A kind of pharmaceutical composition, (1S)-1-in the pharmaceutical composition (4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 10g, 10-deacetyl taxol 2g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Embodiment 14
A kind of pharmaceutical composition, (1S)-1-in the pharmaceutical composition (4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 10g, 10-deacetyl taxol 10g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Embodiment 15
A kind of pharmaceutical composition, (1S)-1-in the pharmaceutical composition (4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate 10g, 10-deacetyl taxol 18g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Described embodiment includes but not limited to above-mentioned.
Claims (10)
1. pharmaceutical composition, it is characterized in that pharmaceutical composition comprises (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate and taxanes microtubule inhibitors.
2. a kind of pharmaceutical composition according to claim 1, (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino wherein] phenyl)-2,3-dihydroindene-5 an amide sesquisulfate and taxanes microtubule inhibitors weight ratio are 1-10:1-20.
3. a kind of pharmaceutical composition according to claim 1 and 2, wherein the taxanes microtubule inhibitors comprises paclitaxel.
4. a kind of pharmaceutical composition according to claim 1 and 2, wherein the taxanes microtubule inhibitors comprises docetaxel.
5. a kind of pharmaceutical composition according to claim 1 and 2, wherein the taxanes microtubule inhibitors comprises one or more in the bearing taxanes that extraction obtains in the Ramulus et folium taxi cuspidatae.
6. the application of a kind of pharmaceutical composition according to claim 1 and 2 in preparation treatment cancer drug.
7. application according to claim 7, wherein cancer comprises leukemia, pulmonary carcinoma, carcinoma of prostate.
8. the pharmaceutical preparation of a kind of pharmaceutical composition preparation according to claim 1 and 2.
9. the pharmaceutical preparation of a kind of pharmaceutical composition preparation according to claim 9, wherein pharmaceutical preparation comprises ejection preparation.
10. the pharmaceutical preparation of a kind of pharmaceutical composition preparation according to claim 9, wherein pharmaceutical preparation comprises aqueous injection, infusion solution or injectable powder.
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| CN2011102834589A CN103006665A (en) | 2011-09-22 | 2011-09-22 | Medicine composition, and preparation and application thereof |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101759683A (en) * | 2008-12-25 | 2010-06-30 | 北京美迪赛医药技术有限公司 | Preparation method of hydrindene amide compound, medical composition comprising hydrindene amide compound and application thereof as protein kinase inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101759683A (en) * | 2008-12-25 | 2010-06-30 | 北京美迪赛医药技术有限公司 | Preparation method of hydrindene amide compound, medical composition comprising hydrindene amide compound and application thereof as protein kinase inhibitor |
Non-Patent Citations (1)
| Title |
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| 王伟等: "紫杉醇合成的研究", 《植物学通报》 * |
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Application publication date: 20130403 |