CN103083666B - A kind of pharmaceutical composition and preparation thereof and purposes - Google Patents
A kind of pharmaceutical composition and preparation thereof and purposes Download PDFInfo
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- CN103083666B CN103083666B CN201110332013.5A CN201110332013A CN103083666B CN 103083666 B CN103083666 B CN 103083666B CN 201110332013 A CN201110332013 A CN 201110332013A CN 103083666 B CN103083666 B CN 103083666B
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Abstract
The invention belongs to medical art, the invention discloses the pharmaceutical composition that in (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates and DNA alkylation cross-linking agent, nitrogen mustards forms; This pharmaceutical composition is determined by the experiment of science.Test proves, in DAN alkylation cross-linking agent, nitrogen mustards is on compound stability without any impact, and pharmacology test proves, the two has synergism.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of pharmaceutical composition containing dihydroindene amide compound and preparation thereof and purposes.
Background technology
Cancer (cancer), medical terminology, also known as malignant tumor (malignantneoplasm), is not normal by control growth and proliferation of cell mechanism and disease that is that cause.Cancer is the formidable enemy of human health.According to statistics, in China, from 2007, cancer exceeded cardiovascular disease becomes the mankind first killer.Classical Therapeutic cancer medicine is all cytotoxic chemotherapeutics, such as cisplatin (cisplatin), carboplatin (carboplatin), paclitaxel (paclitaxel), pemetrexed (pemetrexed), gemcitabine (gemcitabine) etc., these medicines can not act on cancerous cell in specific manner, except killing cancerous cell, normal cell can also be killed, 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 the dosage and time that human body can bear.In such a situa-tion, most of cancerous cell can not be killed, and can only be controlled.Once after drug withdrawal, cancerous cell starts again breeding, occurs recurrence or diffusion, causes death.
Along with biological development, scientists finds in recent years, causes the reason of cancer to be the sudden change of gene.The gene of sudden change creates a kind of protein and is called protein kinase.This protein kinase is only present in cancerous cell, is not present in normal cell.If so this protein kinase with a micromolecular compound to inhibit, cancerous cell is just no longer bred even dead, but Normocellular growth is unaffected.This micromolecular compound just as the anticarcinogen of a new generation, can be called targeting medicine.The feature of targeting anticarcinogen is that its growth of anticancer even can kill cancerous cell, but does not suppress Normocellular growth or kill normal cell, and consequently toxic and side effects is less than classical chemotherapeutic, can long-term taking.At present, external drugmaker has developed several such targeting anticarcinogen, such as imatinib mesylate (gleevec), Iressa (iressa), Erlotinib (tarceva) and SU11248 (sutent) etc., they are all very effective to the various cancer for the treatment of, 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) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates belong to kinases inhibitor, may be used for treating various cancer.
In treatment of cancer, the object of drug combination is to heighten the effect of a treatment, and reduces the generation of untoward reaction.Carrying out reasonable drug combination according to the mechanism of action of antineoplastic agent and Dynamic tumor cell, is one of impressive progress for the treatment of in recent years in tumor.Along with the further investigation of targeted anticancer medicine, researcher is wished cytotoxic drug and targeting anticarcinogen conbined usage, to solving the problem.
Summary of the invention
For these reasons, applicant is by the test of science, determine compound (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates can combine with nitrogen mustards in DNA alkylation cross-linking agent, test proves, in DNA alkylation cross-linking agent nitrogen mustards on compound stability without any impact, pharmacology test proves, the two has synergism.
The present invention is realized by following proposal.
Compound of the present invention (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate structural formulas are as follows:
（Ⅰ）。
A kind of pharmaceutical composition, pharmaceutical composition includes nitrogen mustards in (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates of effective amount and the DNA alkylation cross-linking agent of effective dose.In described DNA alkylation cross-linking agent, nitrogen mustards includes but not limited to: 61 pages to the 84 pages nitrogen mustardses recorded in " anti-tumor drug molecule storehouse " (Science Press) (Chen Qingqi writes) (in February, 2010).
A kind of pharmaceutical composition, wherein in (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates and DNA alkylation cross-linking agent, nitrogen mustards weight ratio is 1-10:1-10.
Aforementioned pharmaceutical compositions can also comprise cytotoxic drug or targeting anticarcinogen, or other active component.
Aforementioned pharmaceutical compositions can also comprise pharmacy acceptable pharmaceutic adjuvant.
In DNA alkylation cross-linking agent described above, nitrogen mustards includes but not limited to cyclophosphamide.
Nitrogen mustards in DNA alkylation cross-linking agent described above but be not limited to uracil mustard.
In DNA alkylation cross-linking agent described above, nitrogen mustards includes but not limited to following: one or more in bendamustine hydrochloride, chlorambucil, melphalan, ifosfamide, glyforfin, EMP disodium salt, Po Nimositing.
In DNA alkylation cross-linking agent described above, nitrogen mustards also comprises nitrogen mustards in the DNA alkylation cross-linking agent of clinical research.
Pharmaceutical composition described above is preparing the application in Therapeutic cancer medicine.
Described cancer includes but not limited to hepatocarcinoma, pulmonary carcinoma, leukemia, carcinoma of prostate, ovarian cancer, intestinal cancer, melanoma, incidence cancer, lymphatic cancer, cerebroma etc.
Pharmaceutical preparation prepared by pharmaceutical composition described above.
Pharmaceutical preparation described above includes but not limited to ejection preparation or oral formulations.
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, loosen and divide in little culture dish, thickness is about 5mm.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), place 10 days under illumination 4500Lx ± 500Lx condition, the 5th day and sampling in the 10th day, detect, result was compared with 0 month data.
(2) hot test: sample thief, is placed in small beaker, and diaphragm seal seals.Be placed on electric drying oven with forced convection (DHG-9023A, the permanent Science and Technology Ltd. in Shanghai one), place 10 days under 60 DEG C ± 1 DEG C condition, detect in the 5th day and sampling in the 10th day, result is compared with 0 month data.
(3) high wet test: sample thief, is placed in small beaker, is placed in respectively and fills NaCl saturated solution and KNO
3the close drying device of saturated solution, damp condition is respectively RH75%.It is placed in respectively electric drying oven with forced convection (DHG-9023A, the permanent Science and Technology Ltd. in Shanghai one), places 10 days under 25 DEG C ± 1 DEG C condition, detect in the 5th day and sampling in the 10th day, result is 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) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates
(1) related substance: high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D)
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; Acetonitrile: water (0.5% triethylamine, phosphoric acid regulates PH=6.5) (35:65) is mobile phase; Determined wavelength is 220nm, and number of theoretical plate calculates by the U.S. enlightening of sulphuric acid should be not less than 3000 for Ni Feng.
Algoscopy sample thief is appropriate, and add dissolve with ethanol completely, filter, residue is dry, obtains raw material 1, and raw material 1 adds mobile phase and makes the sample solution of every 1ml containing 200 μ g, as need testing solution; Precision measures 0.5ml, puts in 100ml measuring bottle, is diluted to scale with mobile phase, shake up, in contrast solution.Get contrast solution 20 μ l injection liquid chromatography, conditioning instrumentation sensitivity, makes the peak height of main constituent chromatographic peak be about 20 ~ 25% of full scale; Precision measures need testing solution and each 20 μ l of reference substance solution, respectively injection liquid chromatography, and record chromatogram is to main constituent peak retention time more than 3 times.If any impurity peaks in need testing solution chromatogram, the peak area sum of each impurity peaks must not be greater than contrast solution main peak area (0.5%), 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 (Chinese Pharmacopoeia version in 2010 two annex V D)
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; Acetonitrile: water (0.5% triethylamine, phosphoric acid regulates PH=6.5) (35:65) is mobile phase; Determined wavelength is 265nm, number of theoretical plate calculates should be not less than 3000 by (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate peak.Compound and the peak-to-peak separating degree of catabolite should meet the requirements.
It is appropriate that algoscopy gets this product, adds dissolve with ethanol completely, filter, residue is dry, obtains raw material 1, accurately weighed, raw material 1 adds mobile phase and dissolves and be quantitatively diluted to the solution about containing sample 40 μ g in every 1ml, and precision measures 20 μ l injection liquid chromatographies, record chromatogram; Separately get (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate reference substances are appropriate, accurately weighed, add mobile phase dissolve and be quantitatively diluted to the solution about containing 40 μ g in every 1ml, be measured in the same method.By external standard method with calculated by peak area, to obtain final product.
2. cyclophosphamide
(1) related substance: it is complete that sample thief adds dissolve with ethanol, and filter, filtrate concentrate drying, obtains raw material 2, according to " related substance " detection method under the Pharmacopoeia of the People's Republic of China (2010 editions, two) 417 pages of cyclophosphamide items.
(2) assay: it is complete that sample thief adds dissolve with ethanol, and filter, filtrate concentrate drying, obtains raw material 2, accurately weighed, according to " assay " detection method under the Pharmacopoeia of the People's Republic of China (2010 editions, two) 418 pages of cyclophosphamide items.
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) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 50mg; Raw material 2: cyclophosphamide 200mg; Raw material 1 and raw material 2 are mixed completely, obtains test specimen.
Result of the test: in table 1, table 2, table 3.
Table 1 strong illumination (4500Lx ± 500Lx) influence factor result of the test
Test brief summary: raw material 1 and raw material 2 are through strong illumination (4500Lx ± 500Lx) after 10 days, and content and related substance have no significant change.
Table 2 hot conditions (60 DEG C) influence factor's result of the test
Test brief summary: raw material 1 and raw material 2 are after hot conditions (60 DEG C) heating, and indices is all without significant change, and quality meets the requirements of the standard.
Table 3 super-humid conditions (RH75%) influence factor result of the test
Test brief summary: raw material 1 and raw material 2 are under super-humid conditions (RH92.5%), and indices is all without significant change, and quality meets the requirements of the standard.
(2) accelerated test
1, experimental condition
Sample thief, is placed in climatic chamber (KBWF240, Chinese medical instrument), arranges 40 DEG C ± 2 DEG C, RH75% ± 5% condition carries out the accelerated test of 6 months, and in the 1st, within 2,3,6 months, regularly sample detection, result is compared with 0 month data.
2, detection method and standard
With test ().
3, test specimen
With test (one) sample.
Result of the test is in Table table 4.
Table 4 accelerated test (40 DEG C, RH75%) result
Test brief summary: pharmaceutical composition Raw of the present invention accelerates 6 months under high temperature 40 DEG C, 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): aforementioned stable test shows, in pharmaceutical composition after two kinds of active component mixing, have no effect each other, absolutely prove that (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates and nitrogen mustards compound can combine.
Two, pharmacological experimental example
Experimental example 1
Antitumor action research in people hepatocarcinoma HepG2 tumor model
1, laboratory animal: BALB/cnude mice, female, 6-8 week, body weight 18-22g.
2, Experimental agents
Experimental agents 1 group: cyclophosphamide 50mg/kg;
Experimental agents 2 groups: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 100mg/kg;
Experimental agents 3 groups: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 100mg/kg; Cyclophosphamide 50mg/kg;
Experimental agents 4 groups: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 150mg/kg; Cyclophosphamide 50mg/kg;
Experimental agents 5 groups: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 180mg/kg; Cyclophosphamide 20mg/kg;
3, experimental technique: HepG2 cell culture is containing 10% hyclone, in the DMEM culture fluid of 100U/ml penicillin and 100 μ g/ml streptomycins.Collect the HepG2 cell of exponential phase, for tumor inoculation under BALB/cnude Corium Mus after the resuspended extremely applicable concentration of PBS.Subcutaneous vaccination 2 × 10 on the right side of every Mus during inoculating cell
6hepG2 cell.Treat that tumor average volume reaches 150-200mm
3time, according to tumor size and Mouse Weight random packet, each Experimental agents group gastric infusion, every day 1 time, successive administration 4 weeks, calculates gross tumor volume, carries out statistical analysis; Statistical analysis: experimental result with mean+/-standard error (
± s) represent, two groups compare with EXCEL software t inspection organize between analysis.Gross tumor volume computing formula is: major diameter × minor axis
2/ 2.
5, experimental result: in table 5.
Table 5 pair HepG2 tumor inhibition effect
Note: compare * * P<0.01 with matched group; ##P<0.01 is compared, #P<0.05 with experiment 2 groups.
Experimental example 2
Antitumor action research in people's chronic myelocytic leukemia K562 tumor model
1, laboratory animal: NOD/SCID mice, female, 6-8 week, body weight 18-22g.
2, Experimental agents:
Experimental agents 1 group: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 10mg/kg.
Experimental agents 2 groups: uracil mustard 1mg/kg.
Experimental agents 3 groups: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 10mg/kg, uracil mustard 1mg/kg.
Experimental agents 4 groups: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 5mg/kg, uracil mustard 1mg/kg.
Experimental agents 5 groups: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 1mg/kg, uracil mustard 1mg/kg.
3, experimental technique and step
(1) cell
K562 cell culture is containing 10% hyclone, in the RPMI-1640 culture fluid of 100U/ml penicillin and 100 μ g/ml streptomycins.Collect the K562 cell of exponential phase, PBS is resuspended to applicable concentration and for tumor inoculation under NOD/SCID Corium Mus after mixing with matrigel1:1.
(2) animal model and grouping
Subcutaneous vaccination 5 × 10 on the right side of every Mus during inoculation
6k562 cell.Treat that tumor average volume reaches 150-200mm
3time, according to tumor size and Mouse Weight random packet, often organize 8 animals.Gross tumor volume computing formula is: major diameter × minor axis
2/ 2.Matched group gives normal saline, 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) represent, two groups compare with EXCEL software t inspection organize between analysis.
4, experimental result: in table 6.
Table 6 pair K562 tumor inhibition effect
Note: compare * * P<0.01 with matched group; ##P<0.01 is compared, #P<0.05 with experiment 1 group.
Experimental example 3
On the impact of mice lung cancer
1, laboratory animal: C57BL/6 mouse inbred lines, female, 6-8 week, body weight 18-22g.
2, tumor strain: Lewis lung cancer cell strain (3LL), is stored in C57BL/6 Mice Body, within every 2 weeks, goes down to posterity 1 time.
3, Experimental agents:
Experimental agents 1 group: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 20mg/kg.
Experimental agents 2 groups: ifosfamide 150mg/kg.
Experimental agents 3 groups: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 20mg/kg, ifosfamide 150mg/kg.
Experimental agents 4 groups: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 20mg/kg, ifosfamide 100mg/kg.
Experimental agents 5 groups: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 20mg/kg, ifosfamide 80mg/kg.
Experimental agents 6 groups: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 20mg/kg, ifosfamide 100mg/kg, gefitinib 5mg/kg.
4, experimental technique
Tumor-bearing model is set up: trophophase Lewis lung cancer cell (3LL cell) of taking the logarithm, and when trypan exclusion stain living cell counting number reaches 95%-100%, centrifugal segregation culture medium, with normal saline adjustment cell concentration is
1 × 10
7/ mL, gets 1mL syringe and extracts tumor cell suspension to be inoculated in the right axil of mice subcutaneous, every only inoculation 0.2mL tumor cell suspension.Subcutaneous tumor can be touched after about 10d, when tumor grows to about diameter about 1cm, tumor-bearing mice is put to death in neck dislocation, in 75% alcohol-pickled 5min, in superclean bench, strip tumor tissues from armpit is subcutaneous, reject fibrous capsule and slough, shred in sterilized petri dishes, put in tissue grinder and add 4 DEG C of normal saline, grind filtration gently and make tumor cell suspension.0.4% trypan blue counting, cell viability >95%, adjusts cell concentration to be 5 × 10
6individual/mL.Get above-mentioned tumor cell suspension 0.2mL(containing oncocyte number 10
6individual) to be inoculated in the right armpit of mice subcutaneous.Go out after tumor to go down to posterity again as stated above 3 times until it, become standard lotus tumor and to go down to posterity Mus.The Lewis lung cancer cancer source standard lotus tumor of getting 14d after going down to posterity goes down to posterity mice, as stated above Mice Inoculated.After about 6d, can touch Subcutaneous tumor, volume is about 100-200mm
3, start to carry out random packet.
Grouping and medication: with random method by postvaccinal mice group, often organize 10 mices, and Experimental agents group and normal saline group are all about 100-200mm in the rear 6d(Subcutaneous tumor of inoculation
3) starting administration, intraperitoneal injection, the molten inequalities such as normal saline group, observe mouse diet, activity and general status every day.After inoculation, after 4 weeks, all disconnected neck puts to death mice.
Final gross tumor volume: after putting to death mices after 4 weeks, complete stripping tumor body is also weighed, with most major diameter and the perpendicular minor axis of vernier caliper measurement tumor block, according to formula V(mm
3)=0.52 × major diameter × minor axis
2calculate gross tumor volume.
5, experimental result: in table 7.
Table 7 is heavy and volume impact on transplantable lung cancer tumor
Note: compare * * P<0.01 with normal saline group, * P<0.05; #P<0.05 is compared with Experimental agents 1 group; & P<0.05 is compared with Experimental agents 2 groups.
Experiment conclusion: above-mentioned pharmacological experiment illustration understands that the application's pharmaceutical composition has the effect of good Therapeutic cancer, than being used alone arbitrary compound, all has better effect, illustrates that pharmaceutical composition of the present invention has collaborative pharmacological action.
Three, embodiment is prepared
Embodiment 1
A kind of pharmaceutical composition, nitrogen mustards in (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates of effective dose and the DNA alkylation cross-linking agent of effective dose is contained in pharmaceutical composition.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into tablet or capsule.
Embodiment 2
A kind of pharmaceutical composition, (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2 in pharmaceutical composition, 3-dihydroindene-5 amide sesquisulfate 20g, melphalan 2g.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into tablet or capsule.
Embodiment 3
A kind of pharmaceutical composition, (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2 in pharmaceutical composition, 3-dihydroindene-5 amide sesquisulfate 20g, bendamustine hydrochloride 25g.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
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-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2 in pharmaceutical composition, 3-dihydroindene-5 amide sesquisulfate 10g, bendamustine hydrochloride 100g.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
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-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2 in pharmaceutical composition, 3-dihydroindene-5 amide sesquisulfate 20g, chlorambucil 2g.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into tablet or capsule.
Embodiment 6
A kind of pharmaceutical composition, (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2 in pharmaceutical composition, 3-dihydroindene-5 amide sesquisulfate 10g, chlorambucil 2g.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into tablet or capsule.
Embodiment 7
A kind of pharmaceutical composition, (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2 in pharmaceutical composition, 3-dihydroindene-5 amide sesquisulfate 10g, chlorambucil 4g.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into tablet or capsule.
Embodiment 8
A kind of pharmaceutical composition, (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2 in pharmaceutical composition, 3-dihydroindene-5 amide sesquisulfate 40g, glyforfin 250g.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into tablet or capsule.
Embodiment 9
A kind of pharmaceutical composition, (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2 in pharmaceutical composition, 3-dihydroindene-5 amide sesquisulfate 10g, glyforfin 80g.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into tablet or capsule.
Embodiment 10
A kind of pharmaceutical composition, (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2 in pharmaceutical composition, 3-dihydroindene-5 amide sesquisulfate 10g, glyforfin 100g.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into tablet or capsule.
Embodiment 11
A kind of pharmaceutical composition, (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2 in pharmaceutical composition, 3-dihydroindene-5 amide sesquisulfate 20g, Po Nimositing 170g.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into tablet or capsule.
Embodiment 12
A kind of pharmaceutical composition, (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2 in pharmaceutical composition, 3-dihydroindene-5 amide sesquisulfate 20g, Po Nimositing 150g.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into tablet or capsule.
Embodiment 13
A kind of pharmaceutical composition, (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2 in pharmaceutical composition, 3-dihydroindene-5 amide sesquisulfate 20g, Po Nimositing 100g.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into tablet or capsule.
Embodiment 14
A kind of pharmaceutical composition, (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2 in pharmaceutical composition, 3-dihydroindene-5 amide sesquisulfate 0.2g, EMP disodium salt 20g.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into tablet or capsule.
Embodiment 15
A kind of pharmaceutical composition, (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2 in pharmaceutical composition, 3-dihydroindene-5 amide sesquisulfate 0.4g, EMP disodium salt 1.4g.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into pharmaceutical preparation.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant and is prepared into tablet or capsule.
Described embodiment includes but not limited to above-mentioned.
Claims (7)
1. a pharmaceutical composition, it is characterized in that pharmaceutical composition consists of: nitrogen mustards in (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates and DNA alkylation cross-linking agent; Wherein in (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates and DNA alkylation cross-linking agent, nitrogen mustards weight ratio is 1-10:1-10; Wherein in DNA alkylation cross-linking agent, nitrogen mustards is: cyclophosphamide, uracil mustard or ifosfamide.
2. a kind of pharmaceutical composition according to claim 1 is preparing the application in Therapeutic cancer medicine.
3. application according to claim 2, wherein cancer comprises hepatocarcinoma, leukemia, pulmonary carcinoma.
4. a kind of pharmaceutical composition according to claim 1, is characterized in that pharmaceutical composition is prepared into pharmaceutical preparation.
5. a kind of pharmaceutical composition according to claim 4, its pharmaceutical formulations comprises ejection preparation or oral formulations.
6. a kind of pharmaceutical composition according to claim 4, its pharmaceutical formulations comprises aqueous injection, infusion solution or injectable powder.
7. a kind of pharmaceutical composition according to claim 4, its pharmaceutical formulations comprises tablet or capsule.
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Effective date of registration: 20170808 Address after: 150025, No. 29, Beijing Road, Limin economic and Technological Development Zone, Hulan District, Heilongjiang, Harbin Patentee after: Harbin Yu Heng Pharmaceutical Co., Ltd. Address before: 100016 B87, G 21, Jiuxianqiao, Beijing, Chaoyang District Co-patentee before: Harbin Gloria Pharmaceuticals Co., Ltd. Patentee before: Beijing Medconxin Pharmaceutical Technology Co., Ltd. |