CN107929276A - A kind of taxol and CDKS kinase inhibitor drug combination compositions - Google Patents
A kind of taxol and CDKS kinase inhibitor drug combination compositions Download PDFInfo
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- CN107929276A CN107929276A CN201711489598.5A CN201711489598A CN107929276A CN 107929276 A CN107929276 A CN 107929276A CN 201711489598 A CN201711489598 A CN 201711489598A CN 107929276 A CN107929276 A CN 107929276A
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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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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Abstract
A kind of taxol and CDKS kinase inhibitor drug combination compositions provided by the invention, include active ingredient and pharmaceutically acceptable auxiliary material, it is characterised in that：The active ingredient is made of the CDK4/6 kinase inhibitors shown in taxol and Formulas I or its pharmaceutically acceptable salt, and taxol and the mass ratio of CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt are (2 8) in the active ingredient：1.The pharmaceutical composition anticancer therapeutic is good, toxic side effect is low；Since CDK4/6 kinase inhibitors are to the sensitiveness of taxol, both generate synergistic effect by drug combination, so as to reduce the Clinical practice dosage of capecitabine, reduce heavy dose and use 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 taxol and CDKS kinase inhibitor drug combination compositions.
Background technology
Taxol, English name Paclitaxel, alias taxol, Paclitaxe, Paclitaxe, chemical name 5 β, 20- epoxy -1,2 α,
4,7 β, 10 β, 13 α--13 [(2 ' R, 3 ' S)-N- of hexahydroxy taxane -11- alkene -9- ketone -4,10- diacetate esters -2- benzoic ethers
Benzoyl -3- phenylisoserines ester], molecular weight 853.92, molecular formula C47H51NO14.It is new breast cancer, is led to
Cross promotion tubulin polymerization and suppress depolymerization, keep tubulin to stablize, suppress cell mitogen.Experiment in vitro proves Japanese yew
Alcohol has significant radiosensitizing effect, it may be possible to cell is terminated in G2 the and M phases to radiotherapy sensitivity, clinic is primarily adapted for use in
Oophoroma and breast cancer, also have certain curative effect to lung cancer, colorectal cancer, melanoma, incidence cancer, lymthoma, brain tumor.
Another problem of generally existing is most antitumor agent with serious toxicity in treatment of cancer.Although
Traditional antineoplastic, such as taxol and taxol, have the resistance to the action of a drug and serious toxicity, but due to because they can be reduced
Tumour, these medicines are still very important in treatment of cancer.
Although the combination of anticancer 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 the drug therapy of improvement cancer.Although for example, there is the combination chemotherapy based on taxol in clinical treatment
Scheme, but to ultimately result in 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, the novel compositions approach that exploitation is used to deliver the known anticancer agents with different mechanism of action is the important of this area
It is progressive.Work can be played in the case of some combinations although being related to the scheme of the combination of the anticancer with different mechanism of action
With, but other combinations of the identical mode for anticancer may not work, and such combination may not always produce tool
There is the combination of beneficial therapeutic effect.
The content of the invention
Technical problem：The defects of in order to solve the prior art, the present invention provides a kind of taxol and CDKS kinase inhibitions
Agent drug combination compositions.
Technical solution：A kind of taxol and CDKS kinase inhibitor drug combination compositions provided by the invention, comprising
Active ingredient and pharmaceutically acceptable auxiliary material, it is characterised in that：The active ingredient is as shown in taxol and Formulas I
CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt form, taxol and CDK4/6 kinase inhibitors in the active ingredient
Or the mass ratio of its pharmaceutically acceptable salt is 1：(2-8)；Wherein, CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt
Chemical formula 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, taxol and the matter of CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt in the active ingredient
Amount is than being 1：(3-6).
Taxol and the mass ratio of CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt are 1 in the active ingredient：
5。
Present invention also offers the CDK4/6 kinase inhibitors shown in taxol and Formulas I or its pharmaceutically acceptable salt composition
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.
Beneficial 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 the CDK4/6 kinase inhibitors shown in Formulas I add the antitumor life of taxol
Long bioactivity, the two synergistic effect of combination with antitumor propagation, thirsts for exploitation into a line of clinically anti-pancreatic cancer
Medication.
(2) toxic side effect is low.Since CDK4/6 kinase inhibitors are to the sensitiveness of taxol, both generate drug combination
Synergistic effect, so as to reduce the Clinical practice dosage of capecitabine, is reduced heavy dose of secondary using poison caused by capecitabine
Effect, improves safety clinical treatment index, has preferable potential applicability in clinical practice.
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 are weighed in reaction bulb, the dissolving of 30m dichloromethane is added, is slowly added dropwise at 0 DEG C dissolved with 4g
(BOC)2The dichloromethane solution of O, drips and finishes, 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, filtering, is spin-dried for, obtains 2.98g grease.
It is 1 that gained grease is added 50ml volume ratios:1 DMF/ water mixed solvents dissolving, adds 0.41g2- amino -5- chloropyridines,
100 DEG C of reaction 8h, reaction terminate, and add water 20ml, ethyl acetate extraction, anhydrous sodium sulfate drying organic phase, filtering, is spin-dried for, and 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 20ml acetonitriles in reaction bulb by the chloro- 5- nitro-pyrimidines of 4- bis-, 1.935gDIPEA
Solution, is added dropwise the acetonitrile solution that 15ml is dissolved with 1.395g aniline, 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 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, is filtered, 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 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 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, reacts at room temperature 10h, after reaction, add
Enter frozen water, filter, ethyl acetate extraction, anhydrous sodium sulfate drying organic phase, filtering, is spin-dried for, and column chromatography purifying is made titled
Compound.
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 30ml anhydrous tetrahydro furans, reflux in reaction bulb
12h is reacted, after reaction, is cooled to room temperature, adds frozen 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, 1ml trifluoro second is slowly added dropwise
Acid, room temperature reaction overnight, after reaction, add 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 50ml volume ratios:1 methanol aqueous solution is molten
Solution, adds 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
For 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, adds 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,
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
Test result indicates 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
Compound of the 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 suppression 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 with 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
Support 24 it is small when after add sieved sample, cell is in 37 DEG C, 5%CO2Under the conditions of continue culture 48 it is small when after, add MTT continue
Cultivate 4 it is small when, it is dissolving crystallized with DMSO, be detected under microplate reader.It the results are shown in Table 3：
Table 3
The compound that can be seen that the present invention from above 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 suppression of 2 kinase activity of phase protein D, is control using palbociclib.
The compound and palbociclib of the present invention distinguishes 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 when reaction 1 is small at room temperature, the diluted Development of appropriateness is added to system
Reagent A.Room temperature the reaction was continued 1 it is small when, add Stop Reagent and terminate reaction.Excitation wavelength 400nm, while detect ripple
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 |
The compound that can be seen that the present invention from above experimental result there is preferable suppression 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, alcohol disappears
After on the outside of malicious tube wall, it 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% hyclone, and clean cryopreservation tube once, centrifuge tube is centrifuged into (1000rpm, 5min), supernatant discarding
Liquid, adds the DMEM culture mediums containing 10% hyclone of 37 DEG C of 2ml preheating, is transferred in blake bottle, be positioned over 37 DEG C,
50mL/L CO2Cultivated in the incubator of saturated humidity, and with 0.5% Trypsin Induced 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, 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, above operation all carry 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；
Taxol group：Every nude mice presses the taxol of weight gavage 30mg/kg, with 1% sodium cellulose glycolate solution
Gavage after suspension, one time a day；
Compound group one：Every nude mice presses the compound of the embodiment 1 of weight gavage 100mg/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 100mg/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 100mg/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 and the purple of 15mg/kg of weight gavage 75mg/kg
China fir alcohol, 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 and the purple of 15mg/kg of weight gavage 75mg/kg
China fir alcohol, 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 and the purple of 15mg/kg of weight gavage 75mg/kg
China fir alcohol, 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, separates transplantable tumor, claims knurl weight, tumour inhibiting rate=(control group knurl weight-control
Treatment group knurl weight)/control group knurl weight × 100%.Each group is averaged knurl weight and tumour inhibiting rate refers to table 5.
Table 5
| Group | Sample size | Knurl weight g | Inhibiting rate % |
| Blank control group | 10 | 1.39±0.69 | - |
| Taxol group | 10 | 1.21±0.54 | 12.95 |
| Compound group one | 10 | 0.94±0.31 | 32.37 |
| Compound group two | 10 | 0.91±0.29 | 34.53 |
| Compound group three | 10 | 0.92±0.28 | 33.81 |
| Joint group one | 10 | 0.29±0.21 | 79.14 |
| Joint group two | 10 | 0.25±0.20 | 82.01 |
| Joint group three | 10 | 0.26±0.22 | 81.29 |
Claims (6)
1. a kind of taxol and CDKS kinase inhibitor drug combination compositions, comprising active ingredient and pharmaceutically acceptable
Auxiliary material, it is characterised in that：The active ingredient can be connect as the CDK4/6 kinase inhibitors shown in taxol and Formulas I or its pharmacy
The salt received forms, and taxol and the mass ratio of CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt are in the active ingredient
1：(2-8)；Wherein, the chemical formula of CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt is：
2. a kind of taxol according to claim 1 and CDKS kinase inhibitor drug combination compositions, its feature exist
In：The pharmaceutically acceptable salt of CDK4/6 kinase inhibitors is the pyrimido-pyrimidine cyclohexadione compounds maleate shown in Formula II
Or the pyrimido-pyrimidine cyclohexadione compounds hydrobromate shown in formula III：
3. a kind of taxol according to claim 1 and CDKS kinase inhibitor drug combination compositions, its feature exist
In：Taxol and the mass ratio of CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt are 1 in the active ingredient：(3-6).
4. a kind of taxol according to claim 1 and CDKS kinase inhibitor drug combination compositions, its feature exist
In：Taxol and the mass ratio of CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt are 1 in the active ingredient：5.
5. the composition of the CDK4/6 kinase inhibitors or its pharmaceutically acceptable salt composition shown in taxol and Formulas I is controlled in preparation
Treat 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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