CN107137408A - A kind of CDK4/6 inhibitor combines the purposes in the medicine for preparing treatment breast cancer with arimedex - Google Patents
A kind of CDK4/6 inhibitor combines the purposes in the medicine for preparing treatment breast cancer with arimedex Download PDFInfo
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- CN107137408A CN107137408A CN201710110337.1A CN201710110337A CN107137408A CN 107137408 A CN107137408 A CN 107137408A CN 201710110337 A CN201710110337 A CN 201710110337A CN 107137408 A CN107137408 A CN 107137408A
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- 0 CC(C)(C)*C(N(CC1)CCC1C(CC1)CN=C1NC(N=C(CC(C)=C1C(C)=O)N(C2CCCC2)C1=O)=N)=O Chemical compound CC(C)(C)*C(N(CC1)CCC1C(CC1)CN=C1NC(N=C(CC(C)=C1C(C)=O)N(C2CCCC2)C1=O)=N)=O 0.000 description 1
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
Combine the purposes in the medicine for preparing treatment breast cancer with arimedex the present invention relates to a kind of CDK4/6 inhibitor.Specifically, CDK4/6 inhibitor of the present invention is compound A or its officinal salt, and arimedex is one or more of in formestane, Exemestane, Fadrozole, Letrozole, Vorozole, Anastrozole.
Description
Technical field
Combine the present invention relates to a kind of CDK4/6 inhibitor with arimedex and preparing the medicine for the treatment of breast cancer
In purposes.
Background technology
Breast cancer is one of most common malignant tumour of women, high with the incidence of disease, has much invasion, but course advancement is slow
Slowly, Chinese population association 2010 year 2 month issues in Beijing on the 1st《Chinese mammary gland disease survey report》, report display, China city
The death rate of city area breast cancer increases 38.91%, and breast cancer, which has become, threatens WomanHealth maximum disease, at present
In at least 156 kinds of breast cancer medicines for grinding and listing, wherein 68% is target therapeutic agent, numerous studies find tumour with it is thin
Born of the same parents' cycle is unusual related, and the mass mutation of mitogenic signals albumen and antimitotic signal protein defect are led in tumour cell
Cause Proliferative Disorders；Simultaneously all there is genomic instability (GIN) and genome unstability (CIN) in most of tumour, this
Three kinds of basic cell cycle defects are all directly or indirectly caused by the out of control of CDKs.Cyclin dependent kinase (CDK,
Cyclin Dependent Kinase) inhibitor is increasingly becoming popular target.
The a generation two generations CDK inhibitor developed at present is a lot, two generation medicines of greatest concern include Pfizer companies and
The CDK4/6 inhibitor PD-0332991 of Onyx companies joint development, its activity by suppressing CDK4/6 suppresses Rb phosphoric acid
Change, E2F-Rb compounds is detained in endochylema, block the startup of cell cycle.Clinical test results (NCT00721409) show
Show, the progresson free survival phase (Progression-free survival, PFS) of the patient of Letrozole single therapy is 7.5 months,
And the patient of Letrozole and the treatment of PD-0332991 drug combinations then extends to 26.1 months its progresson free survival phase, this is significantly excellent
Gesture obtains extensive concern.
WO2014183520 discloses a series of CDK4/6 suppressions that meet formula (I) formula similar to PD-0332991 structures
Preparation, inhibitory activity and high selectivity with significant CDK4/6, and these expected compounds are possibly used for a series of swollen
Knurl, and can be used in combination with a series of existing antitumor agents, including formula A compounds as follows, its chemistry
Entitled 6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- bases) amino) pyrido [2,3-d] is phonetic
Pyridine -7 (8H) -one：
But above-mentioned document does not have and specifically discloses when which compound is combined with any antitumor agent and can obtain
Preferable effect, more it is not anticipated that some specific combination modes can obtain synergy.
The content of the invention
The present invention is it has surprisingly been found that compound A or its officinal salt are achieved when being used in combination with arimedex
Significant synergy, so as to complete the present invention.
One aspect of the present invention provides compound A or its officinal salt is combined with arimedex in preparation treatment breast
Purposes in the medicine of gland cancer.Described arimedex can be formestane, Exemestane, Fadrozole, Letrozole, volt
Chlorazol, Anastrozole, preferably Letrozole.
Wherein described breast cancer is preferably that estrogen receptor positive (ER+), and/or human epidermal growth factor receptor 2 are cloudy
The breast cancer of property (HER2-)；The Locally Advanced or metastatic breast cancer of more preferably above-mentioned phenotype.
In the present invention, compound A is in actual use, preferably the form of its officinal salt, can be various organic acids
Or the addition salts of inorganic acid, wherein particularly preferred isethionate, its structure is as follows：
It is highly preferred that the compound A of present invention isethionate exists in the form of the crystallization of I types, Cu-Ka spokes are used
Penetrate, obtain the X-ray powder diffraction collection represented with 2 θ angles and interplanar distance, the I types crystallization has as shown in Figure 1
X-ray powder diffraction collection, wherein in about 4.17 (21.17), 8.26 (10.69), 9.04 (9.77), 10.78 (8.20),
12.38 (7.14), 14.01 (6.32), 18.50 (4.79), 18.89 (4.70), 20.69 (4.29), 21.58 (4.11), 23.87
And there is characteristic peak 28.15 (3.17) (3.73).
Described I crystal has good stability through being tested under illumination, high temperature and super-humid conditions, and dissolubility, bioavilability
Better than compound A in itself.
In the present invention, every consumption per day (in terms of compound A) scope of compound A or its officinal salt can be 0.1mg/
Kg~1000mg/kg, preferably 0.5~10mg/kg, more preferably 0.5~5mg/kg.For the adult mankind, preferably with compound A
Meter, per consumption per day 1mg~1000mg, preferably 10~500mg, most preferably 30 to 300mg.
In the present invention, for the adult mankind, every consumption per day of arimedex is 1~100mg, preferably 1~
10mg, more preferably 1~5mg.
In yet other embodiments, compound A or its officinal salt and arimedex are with spy
Fixed part by weight is used in combination, and such as 1~1000：1, preferably 10~100：1, more preferably 20~80：1.
Heretofore described is used in combination, and does not limit compound A or its officinal salt and arimedex is same
When apply, can also the two successively apply；In addition, in order to which medication is convenient, also compound A can be made with arimedex
Pharmaceutical composition.
Brief description of the drawings
Fig. 1：Show the XRD spectrum of the I crystal of compound A isethionate；
Fig. 2：Show the DSC collection of illustrative plates figures of the I crystal of compound A isethionate；
Fig. 3：PD-0332991, compound A are alone or share subcutaneous to human breast carcinoma MCF-7/ARO nude mouses with Letrozole
The curative effect of transplantable tumor；
Fig. 4：PD-0332991, compound A are alone or share the influence to lotus knurl nude mouse body weight with Letrozole；
Fig. 5：PD-0332991, compound A are alone or share subcutaneous to human breast carcinoma MCF-7/ARO nude mouses with Letrozole
The curative effect (tumour photo) of transplantable tumor.
Embodiment
It is used to further describe the present invention with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.
Experiment tester used
1st, DSC is composed
INSTRUMENT MODEL：Mettler Toledo DSC 1Staree System
Purge gass：Nitrogen
Heating rate：10.0℃/min
Temperature range：40-400℃
2nd, x-ray diffraction pattern
INSTRUMENT MODEL：Bruker D8Focus X-ray powder diffraction instrument
Ray：Monochromatic Cu-K alpha rays (λ=1.5406)
Scan mode：The θ of θ/2, scanning range：2-40°
Voltage：40KV, electric current：40mA
Embodiment 1：6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- bases) amino) pyridine
And the preparation of [2,3-d] pyrimidine -7 (8H) -one isethionate
Step 1：6- ((6- (1- vinyl butyl ethers base) -8- cyclopenta -5- methyl -7- carbonyl -7,8- dihydro pyridos [2,
3-d] pyrimidine -2-base) amino) -5', 6'- dihydros-[3,4'- bipyridyls] -1'(2'H)-t-butyl formate preparation
Under argon gas protection, by (10g, 29.06mmol) 2- amino -6- (1- fourths oxyethylene group) -8- cyclopenta -5- methyl pyrroles
Pyridine simultaneously [2,3-d] pyrimidine -7 (8H) -one (by WO2014183520 disclose method prepare), cesium carbonate (14.22g,
43.75mmol)、Pd2(dba)3Double diphenylphosphine -9, the 9- dimethyl xanthenes of (2.12g, 2.31mmol), 4,5- (2.69g,
4.69mmol) put into 125.00g dioxane in three mouthfuls of reaction bulbs, backflow is heated to after stirring, raw material is slowly added dropwise
4- (6- chloropyridine -3- bases) -5,6- dihydropyridines -1 (2H)-carboxylic acid tert-butyl ester (10.34g, 35.00mmol, it is auspicious purchased from Yancheng City
Health medication chemistry Co., Ltd) and dioxane (65.62g, 0.74mol) mixed liquor (time for adding about 5h).Drip Bi Jixu
Return stirring reacts 1~1.5h, and TLC monitoring raw material 2- amino -6- (1- fourths oxyethylene group) -8- cyclopenta -5- picolines are simultaneously
[2,3-d] pyrimidine -7 (8H) -one reaction (solvent completely：Petroleum ether：Ethyl acetate=2:1, raw material Rf=0.6, product Rf=
0.7), terminating reaction.Reaction solution is cooled to room temperature, and filtering, filter cake is washed with dichloromethane 17.19g × 3.By filtrate in 65 DEG C
It is concentrated under reduced pressure dry.Residue adds the dissolving of 137.50g dichloromethane, adds 56.25g purified waters, and point liquid, aqueous phase uses 68.75g again
Dichloromethane is extracted.Merge organic phase, anhydrous sodium sulfate drying, filtering, filter cake is washed with 23.44g dichloromethane, and filtrate is in 45 DEG C
It is concentrated under reduced pressure into oily liquids.150g acetone solutions are added, about 2h, ice-water bath stir about 3h is stirred at room temperature.Filtering, filter cake is with cold
Acetone 25g × 4 are washed, and 8~10h of reduced pressure at room temperature obtains solid about 14.84g, yield：80~92%, HPLC detection purity are not
Less than 90%.ESI/MS:[M+H]=601.43.
Step 2：(((6- acetyl group -8- cyclopenta -5- methyl -7- carbonyl -7,8- dihydro pyridos [2,3-d] are phonetic by 6- by 4-
Pyridine -2- bases) amino) pyridin-3-yl) and piperidines -1- t-butyl formates preparation
By 6- ((6- (1- vinyl butyl ethers base) -8- cyclopenta -5- methyl -7- carbonyl -7,8- dihydro pyridos [2,3-d]
Pyrimidine -2-base) amino) -5', 6'- dihydros-[3,4'- bipyridyl] -1'(2'H)-t-butyl formate (14.84g, 24.69mmol)
Put into 75g acetic acid in three mouthfuls of reaction bulbs, lead to argon gas protection.10%Pd/C (5g) is added, hydrogen is replaced three times, in 50 under stirring
~60 DEG C of atmospheric hydrogenations react 30~32h.HPLC methods monitor intermediate state surplus (6- ((6- (1- vinyl butyl ethers base) -8- rings
Amyl group -5- methyl -7- carbonyl -7,8- dihydro pyridos [2,3-d] pyrimidine -2-base) amino) -5', 6'- dihydros-[3,4'- joins pyrrole
Pyridine] -1'(2'H)-t-butyl formate takes off normal-butyl protection but the intermediate that is not reduced of double bond) ＜ 0.3%, terminating reaction.
Reaction solution is cooled to room temperature, is filtered after the displacement of system argon gas, filter cake is washed with 37.50g dichloromethane.By filtrate in 65 DEG C of decompressions
It is concentrated to dryness.Residue argon gas protection 50g absolute ethyl alcohols backflow mashing 0.5h, naturally cools to room temperature, ice bath is stirred under stirring
Mix about 4h.Filtering, filter cake is washed with cold absolute ethyl alcohol 12.50g × 2.Gained wet product adds dichloromethane 31.25g stirrings, filtering
Insoluble matter, is slowly added to isopropanol 118.75g, ice bath stir about 3h, 8~10h is dried under reduced pressure after filtering to be consolidated under filtrate stirring
Body about 8.75g, yield：60~72%, HPLC detection purity are not less than 98%.ESI/MS:[M+H]=547.26.
Step 3：6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- bases) amino) pyrido
The preparation of [2,3-d] pyrimidine -7 (8H) -one isethionate
By 4- (6- ((6- acetyl group -8- cyclopenta -5- methyl -7- carbonyl -7,8- dihydro pyrido [2,3-d] pyrimidines -2-
Base) amino) pyridin-3-yl) piperidines -1- t-butyl formates (8.75g, 15.94mmol) and 56.25g absolute methanols put into three mouthfuls
In reaction bulb, stir.80% isethionic acid (8.81g, 55.94mmol) and water 0.94g are dissolved in 13.75g without water beetle
In alcohol, it is added drop-wise in above-mentioned solution, solution becomes clarification.Drop, which finishes, is heated to reflux stirring reaction 3~3.5h, TLC detection raw material reaction
(petroleum ether completely：Ethyl acetate=1:1, raw material Rf=0.3, product Rf=0), terminating reaction is filtered while hot.Under filtrate stirring
Triethylamine (4.00g, 39.38mmol) is added dropwise, Bi Jixu stir about 1h, ice bath stir about 3h is dripped.Filtering, filter cake is with cold without water beetle
Alcohol 7.19g × 2 are washed, and 40 DEG C are dried under reduced pressure 6~8h and obtain solid about 7.97g, yield：82~93%, HPLC detection purity is not low
In 98%.TOF-MS:[M+H]=447.2503 (6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -
2- yls) amino) pyrido [2,3-d] pyrimidine -7 (8H) -one combines hydrionic quasi-molecular ions).The X- of the crystallized sample is penetrated
Line diffraction spectrogram is shown in Fig. 1.The crystallization is in about 4.17 (21.17), 8.26 (10.69), 9.04 (9.77), 10.78 (8.20),
12.38 (7.14), 14.01 (6.32), 18.50 (4.79), 18.89 (4.70), 20.69 (4.29), 21.58 (4.11), 23.87
And there is characteristic peak at 28.15 (3.17) places (3.73).DSC spectrograms are shown in Fig. 2, there is melting endothermic peak near 324 DEG C, and this crystal formation is determined
Justice is I crystal.Through testing under illumination, high temperature and super-humid conditions, the crystal formation has good stability.
Embodiment 2：Compound A and PD-0332991 is alone or shares naked to human breast carcinoma MCF-7/ARO small with Letrozole
The comparative studies of mouse subcutaneous transplantation knurl curative effect.
1 test medicine
Medicine name：PD-0332991 isethionate is yellow crystalline powder, is disclosed according to CN1835951B
Method prepare；Compound A isethionate is white powder, is prepared by embodiment 1；Letrozole is white powder
End, is provided by Hengrui Medicine Co., Ltd., Jiangsu Prov..
Compound method：Compound A isethionate is prepared with 50mM citric acids+0.5%CMC+0.5%Tween80；
PD-0332991 isethionate is prepared with the distilled water containing 0.1%Tween 80；Letrozole is with containing 20%PEG's 400
Distilled water is prepared and diluted.
2 experimental animals
BALB/cA-nude nude mouses, 6-7 weeks, ♀, purchased from Shanghai Ling Chang bio tech ltd.Production licence
Number：SCXK (Shanghai) 2013-0018；Animal quality certification number 2013001811147.Feeding environment：SPF grades.
3 experimental procedures
Nude mouse subcutaneous vaccination human breast carcinoma MCF-7/ARO cells, after after tumour growth to 100-250mm3, by animal with
Machine is grouped (D0).Dosage and dosage regimen are shown in Table 1.Solvent group gavage 50mM citric acids+0.5%CMC+0.5%Tween
80 solution；2-3 knurl volume is surveyed weekly, claims mouse weight, record data.Gross tumor volume (V) calculation formula is：
V=1/2 × a × b2 wherein a, b represent length and width respectively.
T/C (%)=(T-T0)/(C-C0) 100 wherein T, C is the gross tumor volume at the end of experiment；T0, C0 open for experiment
The gross tumor volume during beginning.
4 result of the tests
MCF-7 Breast Cancer Cell expresses ERs, but does not express aromatizing enzyme, MCF-7 cells Stable transfections people virtue
MCF-7/ARO cells are named as after sweetening treatment enzyme.PD-0332991, compound A (100mg/kg, PO, QD × 21) to MCF-7/ARO
The growth of nude mouse subcutaneous transplantation knurl has certain inhibitory action, and tumour inhibiting rate is respectively 32% and 31%, but is not reaching to statistics
Learn significant difference (P>0.05, compared with solvent)；Letrozole is 29% to MCF-7/ARO tumour inhibiting rate；PD-0332991, change
Compound A is shared with Letrozole, and tumour inhibiting rate is improved, and is respectively increased to 46% and 54%, and has statistical significant difference
(P<0.05, compared with solvent).Tumor-bearing mice can be resistant to very well to above medicine, not have the symptoms such as Body weight loss；PD-
0332991st, compound A and Letrozole share toxicity and are not also significantly increased.As a result illustrate, PD-0332991, compound A are with coming
Bent azoles is shared has synergy for the MCF-7/ARO subcutaneous transplantation knurls with treatment estrogen receptor positive and expression aromatizing enzyme
Effect；After being combined with Letrozole, becoming apparent for compound A tumour inhibiting rate lifting brings up to 54% by the 31% of single medicine；And
PD-0332991 tumour inhibiting rate only increases to 46% by 32%.
Claims (13)
1. compound A or its officinal salt combine the purposes in the medicine for preparing treatment breast cancer with arimedex,
2. purposes according to claim 1, wherein the arimedex is stubborn selected from formestane, Exemestane, method
One or more, preferably Letrozole in azoles, Letrozole, Vorozole, Anastrozole.
3. purposes according to claim 1, wherein described breast cancer is the breast cancer of estrogen receptor positive (ER+).
4. purposes according to claim 1, wherein described breast cancer is that human epidermal growth factor receptor 2 is negative
(HER2-) breast cancer.
5. purposes according to claim 1, wherein described breast cancer is Locally Advanced or metastatic breast cancer.
6. purposes according to claim 1, wherein described compound A officinal salt is isethionate.
7. purposes according to claim 6, wherein described isethionate exists with I types crystal form, uses Cu-
Ka is radiated, and obtains the X-ray powder diffraction collection represented with 2 θ angles and interplanar distance, and the I types crystallization has such as Fig. 1 institutes
The X-ray powder diffraction collection shown, wherein in about 4.17 (21.17), 8.26 (10.69), 9.04 (9.77), 10.78
(8.20), 12.38 (7.14), 14.01 (6.32), 18.50 (4.79), 18.89 (4.70), 20.69 (4.29), 21.58
(4.11), there is characteristic peak 23.87 (3.73) and 28.15 (3.17).
8. the daily amount ranges of purposes according to claim 1, wherein compound A or its officinal salt are 0.1mg/kg
~1000mg/kg, preferably 0.5~10mg/kg, more preferably 0.5~5mg/kg.
9. every consumption per day 1mg~1000mg of purposes according to claim 1, wherein compound A or its officinal salt, excellent
Select 10~500mg, most preferably 30 to 300mg.
10. purposes according to claim 1, wherein every consumption per day of the arimedex is 1~100mg, it is excellent
Select 1~10mg, more preferably 1~5mg.
11. purposes according to claim 1, wherein compound A or its officinal salt are with arimedex with specific
Part by weight be 1~1000：1, preferably 10~100：1, more preferably 20~80：1.
12. a kind of pharmaceutical composition, contain compound A or its officinal salt and arimedex and pharmaceutically acceptable
Carrier, preferably described arimedex be Letrozole.
13. pharmaceutical composition according to claim 12, wherein compound A or its officinal salt and arimedex
Using specific part by weight as 1~1000：1, preferably 10~100：1, more preferably 20~80：1.
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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 |
| WO2020156446A1 (en) | 2019-01-30 | 2020-08-06 | 江苏恒瑞医药股份有限公司 | Use of composition containing cdk4/6 inhibitor in combination with anastrozole in preparation of medicament for treating tumor diseases |
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| WO2020156446A1 (en) | 2019-01-30 | 2020-08-06 | 江苏恒瑞医药股份有限公司 | Use of composition containing cdk4/6 inhibitor in combination with anastrozole in preparation of medicament for treating tumor diseases |
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| US20220125792A1 (en) * | 2019-01-30 | 2022-04-28 | Jiangsu Hengrui Medicine Co., Ltd. | Use of composition containing cdk4/6 inhibitor in combination with anastrozole in preparation of medicament for treating tumor diseases |
| 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 |
| WO2023046200A1 (en) * | 2021-09-27 | 2023-03-30 | 正大天晴药业集团股份有限公司 | Combined pharmaceutical composition of cdk4/6 inhibitor and aromatase inhibitor |
| WO2023109741A1 (en) * | 2021-12-13 | 2023-06-22 | 轩竹生物科技股份有限公司 | Pharmaceutical composition for treating cancer |
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