CN108210508A - A kind of antineoplastic pharmaceutical compositions - Google Patents
A kind of antineoplastic pharmaceutical compositions Download PDFInfo
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- CN108210508A CN108210508A CN201711489600.9A CN201711489600A CN108210508A CN 108210508 A CN108210508 A CN 108210508A CN 201711489600 A CN201711489600 A CN 201711489600A CN 108210508 A CN108210508 A CN 108210508A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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Abstract
A kind of antineoplastic pharmaceutical compositions provided by the invention, include active constituent and pharmaceutically acceptable auxiliary material, it is characterised in that：The active constituent is made of the CDK4/6 kinase inhibitors shown in gemcitabine and Formulas I or its pharmaceutically acceptable salt, and gemcitabine and the mass ratio of CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt are (2 8) in the active constituent：1.The pharmaceutical composition anticancer therapeutic is good, toxic side effect is low；Since CDK4/6 kinase inhibitors are to the sensibility of gemcitabine, the two drug combination produces synergistic effect, so as to reduce the Clinical practice dosage of capecitabine, it reduces large dosage and uses toxic side effect caused by capecitabine, safety clinical treatment index is improved, there is preferable potential applicability in clinical practice.
Description
Technical field
The invention belongs to chemical medicine, a kind of antineoplastic pharmaceutical compositions.
Background technology
Cyclin-dependent kinase (cyclin-dependent kinase, CDK) is a kind of serine/threonine kinase
Enzyme as the CDK-cyclin compounds that intracellular important signal transducers and period plain (cyclin) are formed, participates in thin
The growth of born of the same parents, proliferation, suspend mode or into apoptosis.CDK families include 1-13, wherein, CDK4 and CDK6 connection cyclin D families
Race (cyclin D1, D2, D3) forms CDK4/6-Cyclin D compounds, makes to include Retinoblastoma Protein
After a series of substrate phosphorylations including (Retinoblastoma protein, Rb), release is in connection and by its inhibition
Albumen, such as transcription factor E2F, E2F are further activated and are transcribed some genes necessary into the S phases, realize cell cycle
The propulsion of different phases and transformation.It is existing research shows that, CDK4/6 specificity activation it is close with the proliferation of some tumours
Correlation has Rb, the abnormal generally existing of cyclin D-CDK4/6-INK4-Rb accesses in about 80% human tumor.Therefore,
CDK4/6 inhibitor is researched and developed, to obtain the anti-tumor medicine of high-efficiency low-toxicity, has become antitumor drug research and development
Hot spot.Wherein, the palbociclib of Pfizer's exploitation inhibits the IC of CDK4 and CDK650Value is respectively 11 and 15nmol/L.
In experiment in vitro, palbociclib can inhibit the growth of the tumours such as tumor-bearing mice breast cancer, lung cancer, colon cancer, and can make to swell
Knurl is shunk back, and toxic side effect is small, shows good application prospect.The appearance of Palbociclib has evoked CDK4/6 inhibitor
Research boom.
Another problem of generally existing is most of antitumor agent along with serious toxicity in treatment of cancer.Although
Traditional antineoplastic, such as gemcitabine and taxol have drug resistance and serious toxicity, but due to because they can subtract
Few tumour, these drugs are still very important in treatment of cancer.
Although the combination of anticancer agent has been demonstrated there is great progress in modality of cancer treatment, for difficult to treat
Or the treatment of the cancer to showing treatment resistance as the conventional anti-neoplastic agent of monotherapy, still there are some unsatisfied demands
With the space of drug therapy for improving cancer.Although for example, there is the combined chemotherapy based on gemcitabine to control in clinical treatment
Treatment scheme, but to eventually lead to cancer of pancreas prognosis very poor for drug resistance of tumor, and median survival interval is only 3-6 months, and survival rate is less than within 5 years
5%.Therefore, exploitation is the important of this field for delivering the novel compositions approach of the known anticancer agents with different role mechanism
Progress.Work can be played in the case of certain combinations although being related to the scheme of the anticancer agent combination with different role mechanism
With, but identical mode may not work for other combinations of anticancer agent, and such combination may not always generate tool
There is the combination of beneficial therapeutic effect.
Invention content
Technical problem：The defects of in order to solve the prior art, the present invention provides a kind of antineoplastic pharmaceutical compositions.
Technical solution：A kind of antineoplastic pharmaceutical compositions provided by the invention, comprising active constituent and pharmaceutically acceptable
Auxiliary material, it is characterised in that：The active constituent is as the CDK4/6 kinase inhibitors or its pharmacy shown in gemcitabine and Formulas I
Acceptable salt forms, gemcitabine and the matter of CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt in the active constituent
Amount is than being (2-8)：1；Wherein, the chemical formula of CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt is：
As an improvement, the pharmaceutically acceptable salt of CDK4/6 kinase inhibitors is the pyrimido-pyrimidine diones shown in Formula II
Pyrimido-pyrimidine cyclohexadione compounds hydrobromate shown in compound maleate or formula III：
As an improvement, gemcitabine and CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt in the active constituent
Mass ratio is (3-5)：1.
Gemcitabine and the mass ratio of CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt are in the active constituent
4：1.
The present invention also provides the CDK4/6 kinase inhibitors shown in gemcitabine and Formulas I or its pharmaceutically acceptable salt groups
Into composition prepare treatment with prevention cancer drug in application.
Wherein, the cancer include but not limited to breast cancer, colorectal cancer, oophoroma, prostate cancer, lung cancer, liver cancer,
Cancer of pancreas.
Advantageous effect：Compared with prior art, pharmaceutical composition of the present invention have the following advantages that and significantly into
Step：
(1) anticancer therapeutic is good.Present invention discover that increase gemcitabine antitumor for the CDK4/6 kinase inhibitors shown in Formulas I
The bioactivity of growth, synergistic effect of the two combination with antitumor proliferation, thirsts for exploitation into the one of clinically anti-pancreatic cancer
Line medication.
(2) toxic side effect is low.Since CDK4/6 kinase inhibitors are to the sensibility of gemcitabine, the two drug combination generates
Synergistic effect so as to reduce the Clinical practice dosage of capecitabine, reduces large dosage and uses poison caused by capecitabine
Side effect improves safety clinical treatment index, has preferable potential applicability in clinical practice.
Specific embodiment
The present invention is further illustrated below.
Embodiment 1 1- phenyl -3- methyl -7- (5- piperazinyl pyridine -2- bases amino) pyrimido [4,5-d] pyrimidine -2,4
The synthesis of (1H, 3H)-diketone
The synthesis of step 1 1- tertbutyloxycarbonyls -4- (2-aminopyridine -5- bases) piperazine
3.15g Piperazine anhydrous is weighed in reaction bulb, the dissolving of 30m dichloromethane is added in, is slowly added dropwise at 0 DEG C dissolved with 4g
(BOC)2The dichloromethane solution of O is dripped and is finished, and reacts at room temperature 2h, and filtering is evaporated off solvent, adds water 10ml, filters, and adds in aqueous solution
Sodium carbonate to saturation, dichloromethane extracts 3 times, collects organic phase, sodium sulphate drying, and filtering is spin-dried for, obtains 2.98g grease.
It is 1 that gained grease is added in 50ml volume ratios:1 DMF/ water mixed solvents dissolving, adds in 0.41g2- amino -5- chloropyridines,
100 DEG C of reaction 8h, reaction terminate, and add water 20ml, ethyl acetate extraction, and anhydrous sodium sulfate drying organic phase is filtered, is spin-dried for, makes
Obtain title compound.
LC-MS m/z:[M+H]+=279.
The synthesis of step 2 4- phenylamino -2- chlorine pyrimidine -5- Ethyl formates
3.315g 2 is weighed, it is molten to add in 20ml acetonitriles in reaction bulb by bis- chloro- 5- nitro-pyrimidines of 4-, 1.935gDIPEA
The acetonitrile solution that 15ml is dissolved with 1.395g aniline is added dropwise in solution, and drop finishes, and flow back 2h, after reaction, is cooled to room temperature, and filters,
Drying, obtains title compound.
LC-MS m/z:[M+H]+=278.
Step 3 2- (5- (N- tert-butoxycarbonyl-piperazine -1- bases) pyridine -2- bases amino) -4- anilino-pyrimidine -5- formic acid
The synthesis of ethyl ester
Claim 4.185g step 1 gains, 3.96g step 2 gains add in the dissolving of 100ml acetonitriles, reflux in reaction bulb
3h is reacted, after reaction, is cooled to room temperature, is filtered, ethyl acetate extraction, anhydrous sodium sulfate drying organic phase filters, rotation
It is dry, title compound is made.
LC-MS m/z:[M+H]+=520.
Step 4 2- (5- (N- tert-butoxycarbonyl-piperazine -1- bases) pyridine -2- bases amino) -4- anilino-pyrimidine -5- formic acid
Synthesis
5.19g step 3 gains are weighed in reaction bulb, add in 50ml tetrahydrofurans and 20ml 1M sodium hydroxide solutions,
50 DEG C of reaction 3h, after reaction, are cooled to room temperature, dilute hydrochloric acid tune pH to acidity, filter, ethyl acetate extraction, anhydrous slufuric acid
Sodium dries organic phase, and filtering is spin-dried for, and title compound is made.
LC-MS m/z:[M+H]+=492.
Step 5 2- (5- (N- tert-butoxycarbonyl-piperazine -1- bases) pyridine -2- bases amino) -4- anilino- -5- methylaminos
The synthesis of formylpyrimidin
4.91g step 4 gains are weighed, 2.58gDIPEA is in reaction bulb, after adding in the dissolving of 15ml anhydrous DMFs, in batches
4.56gHATU is slowly added to, after reacting at room temperature 2h, 1.32g methylamine hydrochlorides is added in, reacts at room temperature 10h, after reaction, add
Enter ice water, filter, ethyl acetate extraction, anhydrous sodium sulfate drying organic phase is filtered, is spin-dried for, and column chromatography purifying is made titled
Close object.
LC-MS m/z:[M+H]+=505.
Step 6 1- phenyl -3- methyl -7- (5- (N- tert-butoxycarbonyl-piperazine -1- bases) pyridine -2- bases amino) pyrimido
The synthesis of [4,5-d] pyrimidine -2,4 (1H, 3H)-diketone
2.52g step 5 gains are weighed, 1.38g potassium carbonate adds in 30ml anhydrous tetrahydro furans, reflux in reaction bulb
12h is reacted, after reaction, is cooled to room temperature, adds in ice water 20ml, ethyl acetate extraction, anhydrous sodium sulfate dries organic phase,
Filtering, is spin-dried for, and title compound is made in column chromatography purifying.
LC-MS m/z:[M+H]+=531.
Step 7 1- phenyl -3- methyl -7- (5- piperazinyl pyridine -2- bases amino) pyrimido [4,5-d] pyrimidine -2,4
The synthesis of (1H, 3H)-diketone
0.53g step 6 gains are weighed in reaction bulb, the dissolving of 5ml dichloromethane is added in, 1ml trifluoro second is slowly added dropwise
Acid, room temperature reaction overnight, after reaction, add in saturation, sodium bicarbonate solution tune pH to neutrality, dichloromethane extraction is received
Collect organic phase, column chromatography purifies to obtain title compound.
1H NMR(400MHz,CDCl3,δppm):7.81(s,1H),7.50-7.45(m,4H),7.19-7.16(m,2H),
6.81-6.79(m,2H),4.09(s,1H),3.76(s,3H),3.41-3.38(m,4H),3.17-3.19(m,4H),2.17(s,
1H)。LC-MS m/z:[M+H]+=431.
Embodiment 2 1- phenyl -3- methyl -7- (5- piperazinyl pyridine -2- bases amino) pyrimido [4,5-d] pyrimidine -2,4
The synthesis of (1H, 3H)-dione maleate
1 compound of 10.78g embodiments is weighed in reaction bulb, it is 2 to add in 50ml volume ratios:1 methanol aqueous solution is molten
Solution adds in 2.9g maleic acids, is warming up to 45 DEG C of stirring 0.5h, after being cooled to room temperature, cool overnight in refrigerator, and filtering, volume ratio
It is 2:1 methanol water washing, drying, obtains title compound.
Embodiment 3 1- phenyl -3- methyl -7- (5- piperazinyl pyridine -2- bases amino) pyrimido [4,5-d] pyrimidine -2,4
The synthesis of (1H, 3H)-diketone hydrobromate
1 compound of 15g embodiments is weighed in reaction bulb, the dissolving of 50ml dichloromethane is added in, adds in 5.9g hydrobromic acids, rise
Temperature after being cooled to room temperature, removes solvent under reduced pressure, obtains title compound to 45 DEG C of stirring 0.5h.
1 stability experiment of experimental example
4 parts of the compound of 1g embodiments 1 to 3 is weighed, respectively under the conditions of illumination 4500Lx, under the conditions of RH70%75 DEG C,
It is placed under room temperature 1 month with RH70% under the conditions of RH70%60 DEG C, experimental result is shown in Table 1.
Table 1
The experimental results showed that the compound of the embodiment of the present invention 2 and 3 has very high stability.
2 solubility experiment of experimental example
Solubility is measured using HPLC methods, experimental result is shown in Table 2.
Table 2
| Water | |
| 1 compound of embodiment | 3.2mg/ml |
| 2 compound of embodiment | 152.9mg/ml |
| 3 compound of embodiment | 95.3mg/ml |
3 cell in vitro activity rating of experimental example
The compound of the present invention prepared by above example, after each compound is dissolved to 10mM with DMSO, with complete training
Foster base is diluted to 50 μM, after being then diluted to 10 μM with the complete medium containing 0.1%DMSO, 10 times of dilutions successively, and totally 10
Concentration.
The inhibition to tumor cell lines such as breast carcinoma cell strain MDA-231, breast cancer cell line mcf-7s is measured with mtt assay
Effect.Mtt assay with the relevant dehydrogenases of NADP can make exogenous MTT be reduced into slightly solubility using existing in living cells mitochondria
Bluish violet crystal, and be deposited in cell, and dead cell is without this function.Again in dimethyl sulfoxide (DMSO) (DMSO) dissolving cell
Purple crystal thing, its OD values indirect reaction its amount of viable cell is measured at 570nm wavelength with enzyme-linked immunosorbent assay instrument.By tumour
Cell MCF-7 (human breast cancer cell), MDA-231 (human breast cancer cell) are planted on 96 orifice plates into 4000/200 μ L/ holes, training
Sieved sample is added in after supporting 24 hours, cell is in 37 DEG C, 5%CO2Under the conditions of continue culture 48 hours after, add in MTT continue
Culture 4 hours, it is dissolving crystallized with DMSO, it is detected under microplate reader.It the results are shown in Table 3：
Table 3
Can be seen that the compound of the present invention from more than experimental result has higher inhibitory activity to breast cancer cell.
4 vitro kinase activity of experimental example is evaluated
Compound prepared by this experiment test embodiment of the present invention is to CDK4/ cyclin D1s and CDK6/ cell weeks
The inhibition of 2 kinase activity of phase protein D is control using palbociclib.
The compound of the present invention and palbociclib distinguish 3 times of serial dilutions since 1 μM, totally 10 concentration.
CDK4/ cyclin D1s and CDK6/ Cyclin D2s are obtained by directly buying kit.CDK4/
Cyclin D1 and CDK6/ Cyclin D2s use after being diluted to suitable concentration with kinase dilution liquid respectively.Kinases
Sunstrate containing peptide, HEPES (pH7.5), BRIJ-35, MgCl in dilution2And EDTA.CDK4phospho-
Peptide substrate and CDK6phospho-peptide substrate are used separately as the control of 100% phosphorylation, are not added with
ATP is compareed as 0% phosphorylation.After reacting 1 hour at room temperature, the diluted Development of appropriateness is added in system
Reagent A.The reaction was continued 1 hour for room temperature, adds in Stop Reagent and terminates reaction.Excitation wavelength 400nm, while detect wave
A length of 445nm (coumarin) and the fluorescence intensity of 520nm (fluorescein).It the results are shown in Table 4.
Table 4
| Compound | CDK4 kinases IC50(nM) | CDK6 kinases IC50(nM) |
| palbociclib | 15.3 | 18.2 |
| 1 compound of embodiment | 16.0 | 12.3 |
| 2 compound of embodiment | 16.4 | 12.9 |
| 3 compound of embodiment | 16.9 | 15.4 |
Can be seen that the compound of the present invention from more than experimental result there is preferable inhibition to live CDK4 and CDK6 kinases
Property.
Experimental example 5
Human pancreatic carcinoma PANC-1 cell line after taking out cryopreservation tube, puts into 37 DEG C of water-baths, shakes defrosting 2min, and alcohol disappears
It after on the outside of malicious tube wall, is transferred in super-clean bench, pipe inner cell is transferred in centrifuge tube, 5ml37 DEG C of preheating of addition contains
The DMEM culture mediums of 10% fetal calf serum, and it is primary to clean cryopreservation tube, and centrifuge tube is centrifuged (1000rpm, 5min), is discarded supernatant
Liquid adds the DMEM culture mediums containing 10% fetal calf serum of 37 DEG C of 2ml preheating, is transferred in culture bottle, be positioned over 37 DEG C,
50mL/L CO2It is cultivated in the incubator of saturated humidity, and with 0.5% trypsin digestion and routine passage.
SPF grades of BALB/c-nu nude mouses, 6 week old, male, 18~20g of weight.Take the human pancreas in exponential phase
Cancer cell PANC-1 is inoculated in the right oxter of nude mice, and every mouse about injects 2 × 106 cells, after 3 generation of continuous passage, when the 4th generation
When growth of transplanted human was to 3 weeks, tumor bearing nude mice is put to death, fresh tumor tissue is taken, is cut into volume about 8mm3Tumor mass is inoculated in experiment nude mice
Right side oxter, more than operate and all carried out under aseptic condition in super-clean bench.
The 8th day tumour is in locally surviving and growing to diameter about 0.5cm after plant, by the successful Transplanted tumor model mouse of modeling
Stochastic averagina is divided into four groups, and every group 8, each group carries out treatment 3 weeks by the tested material of following dosage respectively：
Blank control group：Every 1% sodium cellulose glycolate solution 0.1ml/10g of nude mice gavage, one time a day；
Gemcitabine group：Every nude mice presses the gemcitabine of weight gavage 800mg/kg, with 1% sodium cellulose glycolate
Gavage after solution is suspended, one time a day；
Compound group one：Every nude mice presses the compound of the embodiment 1 of weight gavage 120mg/kg, with 1% methylol
Gavage after sodium cellulosate solution is suspended, one time a day；
Compound group two：Every nude mice presses the compound of the embodiment 2 of weight gavage 120mg/kg, with 1% methylol
Gavage after sodium cellulosate solution is suspended, one time a day；
Compound group three：Every nude mice presses the compound of the embodiment 3 of weight gavage 120mg/kg, with 1% methylol
Gavage after sodium cellulosate solution is suspended, one time a day；
Joint group one：Every nude mice presses the compound of embodiment 1 of weight gavage 75mg/kg and the Ji of 300mg/kg
His shore of west, gavage after being suspended with 1% sodium cellulose glycolate solution, one time a day.
Joint group two：Every nude mice presses the compound of embodiment 2 of weight gavage 75mg/kg and the Ji of 300mg/kg
His shore of west, gavage after being suspended with 1% sodium cellulose glycolate solution, one time a day.
Joint group three：Every nude mice presses the compound of embodiment 3 of weight gavage 75mg/kg and the Ji of 300mg/kg
His shore of west, gavage after being suspended with 1% sodium cellulose glycolate solution, one time a day.
The 2nd day after administration, each group animal is put to death, detaches transplantable tumor, claims knurl weight, tumour inhibiting rate=(control group knurl weight-it controls
Treatment group knurl weight)/control group knurl weight × 100%.Each group average knurl weight and tumour inhibiting rate refer to table 5.
Table 5
| Group | Sample size | Knurl weight g | Inhibiting rate % |
| Blank control group | 10 | 1.39±0.69 | - |
| Gemcitabine group | 10 | 1.16±0.66 | 16.55 |
| Compound group one | 10 | 0.89±0.28 | 35.97 |
| Compound group two | 10 | 0.87±0.26 | 37.41 |
| Compound group three | 10 | 0.86±0.26 | 38.13 |
| Joint group one | 10 | 0.32±0.21 | 76.98 |
| Joint group two | 10 | 0.30±0.19 | 78.41 |
| Joint group three | 10 | 0.29±0.18 | 79.14 |
Claims (6)
1. a kind of antineoplastic pharmaceutical compositions include active constituent and pharmaceutically acceptable auxiliary material, it is characterised in that：Described
Active constituent is made of the CDK4/6 kinase inhibitors shown in gemcitabine and Formulas I or its pharmaceutically acceptable salt, the activity
Gemcitabine and the mass ratio of CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt are (2-8) in ingredient：1；Wherein,
The chemical formula of CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt is：
2. a kind of antineoplastic pharmaceutical compositions according to claim 1, it is characterised in that：The medicine of CDK4/6 kinase inhibitors
Acceptable salt is learned as the pyrimido-pyrimidine shown in the pyrimido-pyrimidine cyclohexadione compounds maleate or formula III shown in Formula II
Cyclohexadione compounds hydrobromate：
3. a kind of antineoplastic pharmaceutical compositions according to claim 1, it is characterised in that：Ji Xita in the active constituent
Shore and the mass ratio of CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt are (3-5)：1.
4. a kind of antineoplastic pharmaceutical compositions according to claim 1, it is characterised in that：Ji Xita in the active constituent
Shore and the mass ratio of CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt are 4：1.
5. prepared by the composition of the CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt composition shown in gemcitabine and Formulas I
Treatment and the application in prevention cancer drug.
6. application as claimed in claim 5, it is characterised in that：The cancer include but not limited to breast cancer, colorectal cancer,
Oophoroma, prostate cancer, lung cancer, liver cancer, cancer of pancreas.
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| CN110143948A (en) * | 2019-06-21 | 2019-08-20 | 上海博悦生物科技有限公司 | CDK4/6 inhibitor, its pharmaceutical composition, preparation method and application |
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| CN110143948A (en) * | 2019-06-21 | 2019-08-20 | 上海博悦生物科技有限公司 | CDK4/6 inhibitor, its pharmaceutical composition, preparation method and application |
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