CN103083666A - Drug composition, drug composition preparation and drug composition uses - Google Patents
Drug composition, drug composition preparation and drug composition uses Download PDFInfo
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Abstract
The invention belongs to the technical field of medicine, and discloses a drug composition comprising (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-yl)amino]phenyl)-2,3-dihydro-inden-5-amide sesquisulfate and chlormethine in a DNA alkylated cross-linking agent, wherein the drug composition is determined through scientific experiments, test results show that the chlormethine in the DNA alkylation cross-linking agent does not affect compound stability, and pharmacological test results show that the (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-yl)amino]phenyl)-2,3-dihydro-inden-5-amide sesquisulfate and the chlormethine provide a synergistic 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 the mankind the first killer.Classical treatment cancer drug is all 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 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 cancerous cell, is not present in normal cell.If so this protein kinase has been suppressed with a micromolecular compound, cancerous cell has just no longer been bred even 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 that growth that its can anticancer even can kill cancer cell, 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.
In treatment of cancer, the purpose 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 mechanism of action and the Dynamic tumor cell of antineoplastic agent, is to treat in recent years one of impressive progress in 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 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 nitrogen mustards in DNA alkylation cross-linking agent, evidence, in DNA alkylation cross-linking agent, without any impact, pharmacology test proves both have synergism to nitrogen mustards on compound stability.
The present invention realizes 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) 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, nitrogen mustards in the DNA alkylation cross-linking agent of 3-dihydroindene-5 an amide sesquisulfate and effective dose.In described DNA alkylation cross-linking agent, nitrogen mustards includes but not limited to: 61 pages of nitrogen mustardses to 84 pages of records in " cancer therapy drug molecular library " (Science Press) (Chen Qingqi writes) (in February, 2010).
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, in 3-dihydroindene-5 an amide sesquisulfate and DNA alkylation cross-linking agent, the nitrogen mustards weight ratio is 1-10:1-10.
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.
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 application in preparation treatment cancer drug.
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.
The pharmaceutical preparation of pharmaceutical composition preparation 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, loose dividing in little culture dish, thickness is 5mm approximately.Be placed on medicine strong illumination proof box (SHH-100GD, Chongqing immortality experimental apparatus factory; LHH-250GP, upper sea blue leopard testing equipment company limited), placed 10 days under illumination 4500Lx ± 500Lx condition, the 5th day and sampling in the 10th day, detect, result is compared with 0 month data.
(2) hot test: sample thief is placed in small beaker, the diaphragm seal sealing.Be placed on electric drying oven with forced convection (DHG-9023A, the permanent Science and Technology Ltd. in Shanghai one), placed 10 days under 60 ℃ ± 1 ℃ condition, in the 5th day and sampling detection in the 10th day, result was compared with 0 month data.
(3) high wet test: sample thief, be placed in small beaker, be placed in respectively and fill 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), placed 10 days under 25 ℃ ± 1 ℃ condition, in the 5th day and sampling detection in the 10th day, result was 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 D of Chinese Pharmacopoeia version in 2010)
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; Acetonitrile: water (0.5% triethylamine, phosphoric acid is regulated PH=6.5) is (35:65) mobile phase; 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 appropriate, adds dissolve with ethanol 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, and injection liquid chromatography respectively records chromatogram to main constituent peak retention time more than 3 times.In the need testing solution chromatogram, if any impurity peaks, 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 (two appendix ⅴ D of Chinese Pharmacopoeia version in 2010)
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; Acetonitrile: water (0.5% triethylamine, phosphoric acid is regulated PH=6.5) is (35:65) mobile phase; 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 calculating should be not less than 3000.The peak-to-peak separating degree of compound and catabolite should meet the requirements.
It is appropriate that algoscopy is got this product, adds dissolve with ethanol 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 in every 1ml, and precision measures 20 μ l injection liquid chromatographies, records chromatogram; Separately get (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 reference substance is appropriate, accurately weighed, add the mobile phase dissolving and quantitatively be diluted to the solution that approximately contains 40 μ g in every 1ml, measuring with method.Press external standard method with calculated by peak area, and get final product.
2. cyclophosphamide
(1) related substance: sample thief adds dissolve with ethanol complete, filters, and the filtrate concentrate drying obtains raw material 2, according to " related substance " detection method under 417 pages of cyclophosphamide items of the Pharmacopoeia of the People's Republic of China (2010 editions, two ones).
(2) assay: sample thief adds dissolve with ethanol complete, filters, and the filtrate concentrate drying obtains raw material 2, and is accurately weighed, according to " assay " detection method under 418 pages of cyclophosphamide 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: cyclophosphamide 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: (after 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: raw material 1 and raw material 2 are after hot conditions (60 ℃) 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
The 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), 40 ℃ ± 2 ℃, RH75% ± 5% condition is set carries out the accelerated test of 6 months, and regularly sampling detected in the 1st, 2,3,6 month, and 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 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 in pharmaceutical composition, two kinds of active component mix, 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 nitrogen mustards compound can make up.
Two, pharmacological experimental example
Experimental example 1
Antitumor action research in people's hepatocarcinoma HepG2 tumor model
1, laboratory animal: BALB/c nude mice, female, 6-8 week, body weight 18-22 g.
2, Experimental agents
1 group of Experimental agents: cyclophosphamide 50mg/kg;
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 an amide sesquisulfate 100mg/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 100mg/kg; Cyclophosphamide 50mg/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 150mg/kg; Cyclophosphamide 50mg/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 180mg/kg; Cyclophosphamide 20mg/kg;
3, experimental technique: the 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, PBS is resuspended to being fit to be used for tumor inoculation under BALB/c nude Corium Mus after concentration.Every Mus right side subcutaneous vaccination 2 * 10 during inoculating cell
6The HepG2 cell.Treat that tumor average volume reaches 150-200 mm
3The time, according to tumor size and Mouse Weight random packet, each Experimental agents group gastric infusion, every day 1 time, 4 weeks of successive administration, 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.The gross tumor volume computing formula is: major diameter * minor axis
2/ 2.
5, experimental result: see Table 5.
Table 5 pair HepG2 tumor inhibition effect
Annotate: compare * * P＜0.01 with matched group; Compare ##P＜0.01, #P＜0.05 with 2 groups of experiments.
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 10mg/kg.
2 groups of Experimental agents: uracil mustard 1mg/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 10mg/kg, uracil mustard 1mg/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 5mg/kg, uracil mustard 1mg/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 1mg/kg, uracil mustard 1mg/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 the rear tumor inoculation under the NOD/SCID Corium Mus that is used for matrigel 1:1.
(2) animal model and grouping
Every Mus right side subcutaneous vaccination 5 * 10 during inoculation
6The K562 cell.Treat that tumor average volume reaches 150-200 mm
3The time, 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; 5 groups of tail intravenously administrables of experiment 1-experiment 1 time every other day, amount 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, every 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: ifosfamide 150mg/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 20mg/kg, ifosfamide 150mg/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 20mg/kg, ifosfamide 100mg/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 20mg/kg, ifosfamide 80mg/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 20mg/kg, ifosfamide 100mg/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 after 10 d, when tumor is grown to approximately diameter 1 cm left and right, 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, shred in aseptic plate, put and add 4 ℃ of normal saline in 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.Go down to posterity again as stated above 3 times after it goes out tumor, become the standard lotus tumor Mus of going down to posterity.The Lewis lung cancer cancer source standard lotus tumor of getting 14 d after going down to posterity go down to posterity mice, Mice Inoculated as stated above.Approximately after 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.After inoculation, 4 all rear all disconnected necks are put to death mice.
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(mm
3)=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 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 pharmaceutical composition] phenyl)-2, nitrogen mustards in the DNA alkylation cross-linking agent of 3-dihydroindene-5 an amide sesquisulfate and effective dose.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into tablet or capsule.
Embodiment 2
A kind of pharmaceutical composition, (1S)-1-in 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 20g, melphalan 2g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into tablet or capsule.
Embodiment 3
A kind of pharmaceutical composition, (1S)-1-in 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 20g, bendamustine hydrochloride 25g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Embodiment 4
A kind of pharmaceutical composition, (1S)-1-in 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, bendamustine hydrochloride 100g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
Embodiment 5
A kind of pharmaceutical composition, (1S)-1-in 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 20g, chlorambucil 2g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into tablet or capsule.
Embodiment 6
A kind of pharmaceutical composition, (1S)-1-in 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, chlorambucil 2g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into tablet or capsule.
Embodiment 7
A kind of pharmaceutical composition, (1S)-1-in 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, chlorambucil 4g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into tablet or capsule.
Embodiment 8
A kind of pharmaceutical composition, (1S)-1-in 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 40g, glyforfin 250g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into tablet or capsule.
Embodiment 9
A kind of pharmaceutical composition, (1S)-1-in 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, glyforfin 80g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into tablet or capsule.
Embodiment 10
A kind of pharmaceutical composition, (1S)-1-in 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, glyforfin 100g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into tablet or capsule.
Embodiment 11
A kind of pharmaceutical composition, (1S)-1-in 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 20g, Po Nimositing 170g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into tablet or capsule.
Embodiment 12
A kind of pharmaceutical composition, (1S)-1-in 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 20g, Po Nimositing 150g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into tablet or capsule.
Embodiment 13
A kind of pharmaceutical composition, (1S)-1-in 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 20g, Po Nimositing 100g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into tablet or capsule.
Embodiment 14
A kind of pharmaceutical composition, (1S)-1-in 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 0.2g, EMP disodium salt 20g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into tablet or capsule.
Embodiment 15
A kind of pharmaceutical composition, (1S)-1-in 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 0.4g, EMP disodium salt 1.4g.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into pharmaceutical preparation.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into the ejection preparations such as aqueous injection, injectable powder or infusion solution.
The aforementioned pharmaceutical compositions effective ingredient adds pharmaceutic adjuvant to be prepared into tablet or capsule.
Described embodiment includes but not limited to above-mentioned.
Claims (11)
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, nitrogen mustards in 3-dihydroindene-5 an amide sesquisulfate and DNA alkylation cross-linking agent.
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, in 3-dihydroindene-5 an amide sesquisulfate and DNA alkylation cross-linking agent, the nitrogen mustards weight ratio is 1-10:1-10.
3. a kind of pharmaceutical composition according to claim 1 and 2, wherein in DNA alkylation cross-linking agent, nitrogen mustards comprises cyclophosphamide.
4. a kind of pharmaceutical composition according to claim 1 and 2, wherein in DNA alkylation cross-linking agent, nitrogen mustards comprises uracil mustard.
5. a kind of pharmaceutical composition according to claim 1 and 2, wherein in DNA alkylation cross-linking agent, nitrogen mustards comprises one or more in bendamustine hydrochloride, chlorambucil, melphalan, ifosfamide, glyforfin, EMP disodium salt, Po Nimositing.
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 6, wherein cancer comprises hepatocarcinoma, leukemia, pulmonary carcinoma.
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 8, wherein pharmaceutical preparation comprises ejection preparation or oral formulations.
10. the pharmaceutical preparation of a kind of pharmaceutical composition preparation according to claim 8, wherein pharmaceutical preparation comprises aqueous injection, infusion solution or injectable powder.
11. the pharmaceutical preparation of a kind of pharmaceutical composition preparation according to claim 8, wherein pharmaceutical preparation comprises tablet or capsule.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109810142A (en) * | 2019-03-12 | 2019-05-28 | 石家庄学院 | One kind matrine derivative of ligustrazine containing mustargen and its preparation method and application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010072166A1 (en) * | 2008-12-25 | 2010-07-01 | 北京美迪赛医药技术有限公司 | Preparation method of dihydroindene amide compounds,their pharmaceutical compositions containg compounds thereof and use as protein kinases inhibitor |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010072166A1 (en) * | 2008-12-25 | 2010-07-01 | 北京美迪赛医药技术有限公司 | Preparation method of dihydroindene amide compounds,their pharmaceutical compositions containg compounds thereof and use as protein kinases inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| 庄雅云等: "氮芥类抗肿瘤药物研究进展", 《中国药学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109810142A (en) * | 2019-03-12 | 2019-05-28 | 石家庄学院 | One kind matrine derivative of ligustrazine containing mustargen and its preparation method and application |
| CN109810142B (en) * | 2019-03-12 | 2021-09-14 | 石家庄学院 | Nitrogenous mustard ligustrazine matrine derivative and preparation method and application thereof |
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| CN103083666B (en) | 2016-02-10 |
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