CN107382873A - A kind of preparation method for the medicine olaparib for treating oophoroma - Google Patents
A kind of preparation method for the medicine olaparib for treating oophoroma Download PDFInfo
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- CN107382873A CN107382873A CN201710781802.4A CN201710781802A CN107382873A CN 107382873 A CN107382873 A CN 107382873A CN 201710781802 A CN201710781802 A CN 201710781802A CN 107382873 A CN107382873 A CN 107382873A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
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Abstract
The present invention relates to a kind of preparation method for the medicine olaparib for treating oophoroma, it comprises the following steps：1) olaparib crude product is added to the in the mixed solvent of dimethyl carbonate and isopropyl ether, is slowly heated to 45~50 DEG C, insulated and stirred 30min, 60~65 DEG C is continuously heating to, stirring, dissolving crude product, obtains crude product solution；2) activated carbon is added into crude product solution, is decolourized, filtering, collects filtrate；3) slow cooling, filtrate temperature is down to 30~35 DEG C, is incubated, stirring；4) 5 DEG C and following, 150 revs/min of mixing speed of control are cooled the filtrate to again, and addition crystal seed, after controlling temperature and mixing speed growing the grain 2h, filtering, the filter cake mixed solvent of a small amount of dimethyl carbonate and isopropyl ether flushing is dry, obtains olaparib.Preparation method technique provided by the invention is simple, and yield and purity are high, especially di-substituted to significantly reduce, while applicant surprisingly has found that obtained olaparib hygroscopicity significantly reduces.
Description
Technical field
The present invention relates to a kind of preparation method of known drug, specifically a kind of preparation method of olaparib, category
In field of medicine preparing technology.
Background technology
Olaparib, entitled 4- [3- (4- cyclopropane carbonyl piperazine -1- carbonyls) -4- the luorobenzyls] -2H- phthalazines -1- of chemistry
Ketone, the entitled Olaparib of English, structural formula are as shown in Equation 1：
Olaparib (Olaparib) is the KuDOS drugmakers of wholly-owned subsidiary by AstraZeneca (AstraZeneca)
A kind of small molecule of research and development, is a kind of potent PARP inhibitors, and it promotes tumour by suppressing DNA of tumor cell injury repair
Apoptosis, the effect of so as to strengthen radiotherapy and alkylating agent and platinum-based chemotherapy, it is mainly used in treating mastocarcinoma gene
No.1 or the gene mutation cancer of No. two (BRCA-1 or BRCA-2) (being primarily present in breast cancer, oophoroma and prostate cancer).It is difficult to understand
La Pani can selectivity act on tumour cell, normal cell is due to remaining double-strand repair function without destroyed.Cancer
Cell is because two allele are all lacked or are mutated, and double-strand repair function is lost, and cell is finally dead, this new medicine
Treatment to refractory neoplasm brings hope.
In the preparation process of olaparib, disubstituted impurity in products as shown in Equation 2 can be produced, the impurity is by closing
Introduce into the impurity piperazine in the raw material (cyclopropane carbonyl piperazine) of olaparib, produced in olaparib prepares condensation step
It is raw, it is generally existing.And olaparib and olaparib dimer similar in property, both are difficult to separate, and directly affect Austria
La Pani quality.
Chinese patent CN201610100873.9 adds concentrate the mixed solution that water and monohydric alcohol are formed, and backflow is molten
Solution, filtering, stirring and crystallizing, filters and high-purity olaparib is produced after drying.The monohydric alcohol is selected from methanol, ethanol, isopropyl
One or more of mixing in alcohol, preferably methanol and/or ethanol.
Olaparib is mixed backflow with solvent by Chinese patent CN201510757797.4, and the saturation for obtaining olaparib is molten
Liquid；The solvent is preferably the one or more in normal propyl alcohol, isopropanol, n-butanol and the tert-butyl alcohol.
Chinese patent CN101528714B discloses synthesis and the process for purification of a kind of olaparib, and it uses ethanol crystallization
Or ethanol/water system recrystallization carries out refined method to olaparib.
Chinese patent CN201510535431.2 provides a kind of process for purification of olaparib, A) olaparib crude product is existed
Dissolved in amide solvent, obtain olaparib crude product solution；B) by the step A) obtained olaparib crude product solution enters
Row crystallization, obtain olaparib highly finished product.The process for purification that the invention provides employs amide solvent, and amide solvent is to double
Substitution product impurity has preferable solubility, while the solvent also has certain dissolubility to olaparib, therefore olaparib is received
Rate decreases.
Although above-mentioned preparation method has preferable elimination effect to most of impurity in olaparib, for disubstituted
This special impurities of product are almost without scavenging action, it is therefore necessary to develop a kind of new preparation method to obtain Austria of high-purity
La Pani.
The present inventor surprisingly has found to use solvent carbonic acid two after substantial amounts of research has been carried out to bulk drug olaparib
Methyl esters and isopropyl ether mixed solution combination rising temperature for dissolving, cooling crystallization etc. can effectively remove the disubstituted product of olaparib, product
Purity is improved to 99.99%, while applicant surprisingly has found that obtained olaparib hygroscopicity significantly reduces.
The content of the invention
It is an object of the invention to provide a kind of preparation method for the medicine olaparib for treating oophoroma, the present invention provides
Process for purification can effectively remove disubstituted impurity in products, improve purity.
The present invention provides a kind of preparation method for the medicine olaparib for treating oophoroma, comprises the following steps：
1) olaparib crude product is added to the in the mixed solvent of dimethyl carbonate and isopropyl ether, is slowly heated to 45~50
DEG C, insulated and stirred, 60~65 DEG C are continuously heating to, stirring, dissolving crude product, obtains crude product solution；
2) activated carbon is added into crude product solution, is decolourized, filtering, collects filtrate；
3) slow cooling, filtrate temperature is down to 30~35 DEG C, is incubated, stirring；
4) 5 DEG C and following, control mixing speed are cooled the filtrate to again, add crystal seed, control temperature and mixing speed are supported
After brilliant 2h, filtering, filter cake is rinsed with the mixed solvent of a small amount of dimethyl carbonate and isopropyl ether, is dried, is obtained olaparib.
The present invention is selected 45~50 DEG C, 60~65 DEG C of two major temperatures, crude product carried out fully molten by process optimization
Solution, 30~35 DEG C, 5 DEG C of selection and following two major temperature gradients carry out cooling crystallization, are maintained at product more times
Crystal growth Metastable zone, avoids impurity in Crystallization Process and is wrapped in lattice and separate out together, passes through the side that this kind controls crystallization
Formula, can effectively remove the disubstituted product of olaparib, and product purity is improved to 99.99%.
Preferably, the volume ratio of dimethyl carbonate and isopropyl ether is 1.0-1.5 in step 1):1, the olaparib
The mass volume ratio of crude product and mixed solvent is 1 (g)：7-8(mL).
Preferably, 60~65 DEG C are continuously heating in step 1).
Preferably, the mixing speed described in step 1) is 110 revs/min, and mixing time is 30min.
Preferably, the addition of olaparib crystal seed is the 2.0wt% of olaparib crude product in step 4).
Preferably, mixing speed described in step 4) is 150 revs/min.
It is further preferred that in step 1), the volume ratio of dimethyl carbonate and isopropyl ether is 1.2:1.
Compared with prior art, the invention has the advantages that：
The preparation method of olaparib provided by the present invention employs the mixed solvent of dimethyl carbonate and isopropyl ether, energy
It is enough to have preferable solubility to disubstituted impurity, but, provided by the invention process for purification poor to the dissolubility of olaparib
The disubstituted impurity in products in olaparib can not only be effectively removed, and also has preferably to remove to other impurity and imitates
Fruit.Test result indicates that the content for the disubstituted impurity of olaparib that preparation method provided by the invention obtains only has
0.004%, always miscellaneous is 0.01%, while applicant surprisingly has found that obtained olaparib hygroscopicity significantly reduces.
Embodiment
The content of the invention of the present invention is described further below by specific embodiment, but does not therefore limit this hair
Bright content.
Embodiment 1
By olaparib crude product 10g, be added to 70mL dimethyl carbonates and isopropyl ether mixed solvent (dimethyl carbonate and
The volume ratio of isopropyl ether is 1.0:1) in, 45~50 DEG C are slowly heated to, with 110 revs/min of mixing speed insulated and stirred
30min, 60~65 DEG C are continuously heating to, 30min is stirred with 110 revs/min of mixing speed, dissolving crude product, it is molten to obtain crude product
Liquid；Activated carbon is added into crude product solution, is decolourized, filtering, collects filtrate；Slow cooling, filtrate temperature is down to 30~35 DEG C,
Insulation, 110 revs/min of mixing speed is controlled, stir 30min；5 DEG C and following, control mixing speed 150 are cooled the filtrate to again
Rev/min, crystal seed 0.2g is added, after controlling 150 revs/min of growing the grain 2h of temperature and mixing speed, filtering, a small amount of carbonic acid of filter cake
The mixed solvent of dimethyl ester and isopropyl ether rinses, and filters, is dried under reduced pressure, obtains olaparib 9.75g, yield 97.5%.
The olaparib obtained to the present embodiment carries out HPLC (high performance liquid chromatography) detections, the Aura that this example obtains
Pa Buddhist nun purity 99.98%, disubstituted impurity 0.004%, total miscellaneous 0.014%.
Embodiment 2
By olaparib crude product 10g, be added to 75mL dimethyl carbonates and isopropyl ether mixed solvent (dimethyl carbonate and
The volume ratio of isopropyl ether is 1.2:1) in, 45~50 DEG C are slowly heated to, with 110 revs/min of mixing speed insulated and stirred
30min, 60~65 DEG C are continuously heating to, 30min is stirred with 110 revs/min of mixing speed, dissolving crude product, it is molten to obtain crude product
Liquid；Activated carbon is added into crude product solution, is decolourized, filtering, collects filtrate；Slow cooling, filtrate temperature is down to 30~35 DEG C,
Insulation, 110 revs/min of mixing speed is controlled, stir 30min；5 DEG C and following, control mixing speed 150 are cooled the filtrate to again
Rev/min, crystal seed 0.2g is added, after controlling 150 revs/min of growing the grain 2h of temperature and mixing speed, filtering, a small amount of carbonic acid of filter cake
The mixed solvent of dimethyl ester and isopropyl ether rinses, and filters, is dried under reduced pressure, obtains olaparib 9.8g, yield 98%.
The olaparib obtained to the present embodiment carries out HPLC (high performance liquid chromatography) detections, the Aura that this example obtains
Pa Buddhist nun purity 99.99%, disubstituted impurity 0.002%, total miscellaneous 0.010%.
Embodiment 3
By olaparib crude product 10g, be added to 80mL dimethyl carbonates and isopropyl ether mixed solvent (dimethyl carbonate and
The volume ratio of isopropyl ether is 1.5:1) in, 45~50 DEG C are slowly heated to, with 110 revs/min of mixing speed insulated and stirred
30min, 60~65 DEG C are continuously heating to, 30min is stirred with 110 revs/min of mixing speed, dissolving crude product, it is molten to obtain crude product
Liquid；Activated carbon is added into crude product solution, is decolourized, filtering, collects filtrate；Slow cooling, filtrate temperature is down to 30~35 DEG C,
Insulation, 110 revs/min of mixing speed is controlled, stir 30min；5 DEG C and following, control mixing speed 150 are cooled the filtrate to again
Rev/min, crystal seed 0.2g is added, after controlling 150 revs/min of growing the grain 2h of temperature and mixing speed, filtering, a small amount of carbonic acid of filter cake
The mixed solvent of dimethyl ester and isopropyl ether rinses, and filters, is dried under reduced pressure, obtains olaparib 9.68g, yield 96.8%.
The olaparib obtained to the present embodiment carries out HPLC (high performance liquid chromatography) detections, the Aura that this example obtains
Pa Buddhist nun purity 99.99%, disubstituted impurity 0.003%, total miscellaneous 0.012%.
Embodiment 4
By olaparib crude product 10g, be added to 70mL dimethyl carbonates and isopropyl ether mixed solvent (dimethyl carbonate and
The volume ratio of isopropyl ether is 1.2:1) in, 45~50 DEG C are slowly heated to, with 110 revs/min of mixing speed insulated and stirred
30min, 60~65 DEG C are continuously heating to, 30min is stirred with 110 revs/min of mixing speed, dissolving crude product, it is molten to obtain crude product
Liquid；Activated carbon is added into crude product solution, is decolourized, filtering, collects filtrate；3) slow cooling, filtrate temperature is down to 30~35
DEG C, insulation, 110 revs/min of mixing speed is controlled, stir 30min；5 DEG C and following, control mixing speed are cooled the filtrate to again
150 revs/min, crystal seed 0.2g is added, after controlling 150 revs/min of growing the grain 2h of temperature and mixing speed, filtering, filter cake is with a small quantity
The mixed solvent of dimethyl carbonate and isopropyl ether rinses, and filters, is dried under reduced pressure, obtains olaparib 9.72g, yield 97.2%.
The olaparib obtained to the present embodiment carries out HPLC (high performance liquid chromatography) detections, the Aura that this example obtains
Pa Buddhist nun purity 99.99%, disubstituted impurity 0.004%, total miscellaneous 0.013%.
Comparative example 1
By 10.0g olaparib crude products, 75mLN is added to, in N- dimethyl acetamides, be heated to 85~90 DEG C, stirring,
After dissolving crude product, continue to stir 1.5h, obtain crude product solution；0.05g activated carbons are added into crude product solution, insulation is decolourized,
Insulation filtering, collects filtrate；Slow cooling insulation, stirs 30min to 30~35 DEG C, filters, is dried under reduced pressure, obtains 8.13g Auras
Pa Buddhist nun's fine work, yield：81.3%.The olaparib purity 99.93% that this comparative example obtains, disubstituted impurity 0.03% are total miscellaneous
0.07%.
Comparative example 2
Olaparib crude product 10g is added in 75mL ethanol, is slowly heated to 45~50 DEG C, with 110 revs/min
Mixing speed insulated and stirred 30min, is continuously heating to 60~65 DEG C, and 30min, crude product are stirred with 110 revs/min of mixing speed
Dissolving, obtains crude product solution；Activated carbon is added into crude product solution, is decolourized, filtering, collects filtrate；Slow cooling, by filtrate temperature
Degree is down to 30~35 DEG C, insulation, controls 110 revs/min of mixing speed, stirs 30min；5 DEG C and less are cooled the filtrate to again,
150 revs/min of mixing speed is controlled, adds crystal seed 0.2g, after controlling 150 revs/min of growing the grain 2h of temperature and mixing speed, mistake
Filter, filter cake are rinsed with the mixed solvent of a small amount of ethanol, filter, be dried under reduced pressure, obtain olaparib 8.25g, yield 82.5%.
The olaparib obtained to this comparative example carries out HPLC (high performance liquid chromatography) detections, Austria that this comparative example obtains
La Pani purity is 99.48%, disubstituted impurity 0.22%, total miscellaneous 0.51%.
Comparative example 3
By olaparib crude product 10g, it is added in 18.7mL water, 56.3mL ethanol, is slowly heated to 45~50 DEG C, with
110 revs/min of mixing speed insulated and stirred 30min, is continuously heating to 60~65 DEG C, is stirred with 110 revs/min of mixing speed
30min is mixed, dissolving crude product, obtains crude product solution；Activated carbon is added into crude product solution, is decolourized, filtering, collects filtrate；Slowly
Cooling, filtrate temperature is down to 30~35 DEG C, insulation, 110 revs/min of mixing speed is controlled, stirs 30min；Filtrate is dropped again
Temperature is to 5 DEG C and following, controls 150 revs/min of mixing speed, adds crystal seed 0.2g, controls 150 revs/min of temperature and mixing speed
After clock growing the grain 2h, filtering, filter cake is rinsed with the mixed solvent of a small amount of second alcohol and water, is filtered, is dried under reduced pressure, obtains olaparib
8.75g, yield 87.5%.
The olaparib obtained to this comparative example carries out HPLC (high performance liquid chromatography) detections, Austria that this comparative example obtains
La Pani purity is 99.11%, disubstituted impurity 0.37%, total miscellaneous 0.88%.
Comparative example 4
By olaparib crude product 10g, the mixed solvent (volume of chloroform and petroleum ether of 75mL chloroforms and petroleum ether is added to
Than for 1.2:1) in, 45~50 DEG C are slowly heated to, with 110 revs/min of mixing speed insulated and stirred 30min, continues to heat up
To 60~65 DEG C, 30min is stirred with 110 revs/min of mixing speed, dissolving crude product, obtains crude product solution；Into crude product solution
Activated carbon is added, is decolourized, filtering, collects filtrate；3) slow cooling, filtrate temperature is down to 30~35 DEG C, insulation, control is stirred
110 revs/min of speed, stir 30min；5 DEG C and following, 150 revs/min of mixing speed of control, addition are cooled the filtrate to again
After crystal seed 0.2g, 150 revs/min of growing the grain 2h of control temperature and mixing speed, filtering, filter cake a small amount of dimethyl carbonate and isopropyl
The mixed solvent of ether rinses, and filters, is dried under reduced pressure, obtains olaparib 8.26g, yield 82.6%.
The olaparib obtained to this comparative example carries out HPLC (high performance liquid chromatography) detections, Austria that this comparative example obtains
La Pani purity 99.89%, disubstituted impurity 0.07%, total miscellaneous 0.10%.
Comparative example 5
By olaparib crude product 10g, be added to 75mL ethyl acetate and petroleum ether mixed solvent (chloroform and petroleum ether
Volume ratio is 1.2:1) in, 45~50 DEG C are slowly heated to, with 110 revs/min of mixing speed insulated and stirred 30min, is continued
60~65 DEG C are warming up to, 30min is stirred with 110 revs/min of mixing speed, dissolving crude product, obtains crude product solution；It is molten to crude product
Activated carbon is added in liquid, is decolourized, filtering, collects filtrate；3) slow cooling, filtrate temperature is down to 30~35 DEG C, is incubated, control
110 revs/min of mixing speed, stir 30min；5 DEG C and following, 150 revs/min of mixing speed of control are cooled the filtrate to again,
Add crystal seed 0.2g, after control temperature and mixing speed 150 revs/min of growing the grain 2h, filtering, filter cake with a small amount of dimethyl carbonate with
The mixed solvent of isopropyl ether rinses, and filters, is dried under reduced pressure, obtains olaparib 9.12g, yield 91.2%.
The olaparib obtained to this comparative example carries out HPLC (high performance liquid chromatography) detections, Austria that this comparative example obtains
La Pani purity 99.93%, disubstituted impurity 0.04%, total miscellaneous 0.07%.
Preparation method provided by the invention can effectively remove disubstituted production it can be seen from above example and comparative example
Thing impurity and other impurities, gained olaparib purity are high.Determined using cassette moisture teller, olaparib of the present invention contains
Water is 0.18%-0.21%.
Experimental example：Draws moist test
According to the medicine draws moist test guideline of 2015 editions general rules of Chinese Pharmacopoeia 9103.
Specific test method is as follows：
Dry tool plug glass measuring cup (external diameter 50mm, a height of 15mm) is taken, suitable 25 are placed in experiment the previous day
(design temperature is 25 DEG C for DEG C of ± 1 DEG C thermostatic drier (placing ammonium chloride or ammonium sulfate saturated solution in bottom) or growth cabinet
± 1 DEG C, relative humidity is 80% ± 2%) in, accurately weighed weight (m1).
Take test sample appropriate, be laid in above-mentioned measuring cup, test sample thickness is about 1mm, accurately weighed weight (m2).
Measuring cup is open, and with bottle cap with being placed under the conditions of above-mentioned constant temperature and humidity 24 hours.
Cover measuring cup lid, accurately weighed weight (m3).
Percentage weight increase=(m3-m2)/(m2-m1) × 100%
Draw moist feature description with drawing defining for moist weightening
Deliquescence：Absorb enough moisture and form liquid.
It is great draw it is moist：Draw wet weightening and be not less than 15%.
Have draw it is moist：Draw wet weightening less than 15% but not less than 2%.
Slightly draw moist：Draw wet weightening less than 2% but not less than 0.2%.
Nothing is moist almost without drawing：Draw wet weightening and be less than 0.2%.
Result of the test is shown in Table 1-1 and table 1-2
Table 1-1 trial target draws moist test results
| Project | Trial target 1 | Trial target 2 | Trial target 3 | Trial target 4 | Trial target 5 | Trial target 6 |
| Draw wet weightening (%) | 0.02 | 0.03 | 0.02 | 0.02 | 0.04 | 0.03 |
Table 1-2 reference substance draws moist test results
Reference substance 1：The olaparib prepared with reference to the A embodiments 1,2 of patent CN 105439961.
Reference substance 2：The olaparib prepared with reference to patent CN 105254572A embodiments 1-3.
Reference substance 3：The olaparib prepared with reference to patent CN101528714A embodiments 1,3,5.
Reference substance 4：The olaparib prepared with reference to patent CN101821242A embodiments 1-5.
Reference substance 5：The olaparib prepared with reference to patent CN106554315A embodiments 1.
Reference substance 6：The olaparib prepared with reference to the A embodiments 1-4 of patent CN 105985294.
Reference substance 7：The olaparib prepared with reference to the A embodiments 1-4 of patent CN 105061328.
Reference substance 8：The olaparib prepared with reference to the A embodiments one, two, three of patent CN 105085407.
Reference substance 9：The olaparib prepared with reference to the A embodiments 1-4 of patent CN 105503739.
Reference substance 10：The olaparib prepared with reference to patent CN 105820126 A embodiments 4-1,4-2,4-3.
Reference substance 11：Reference literature J.Am.Chem.Soc.2014, olaparib made from 136,6142-6147.
Reference substance 12：Reference literature J.Med.Chem., 2008,51：Olaparib made from 6581-6591.
Reference substance 13：With reference to Nanjing University of Technology's Master's thesis in 2012《Olaparib and the like study on the synthesis》Report
Olaparib made from the method in road.
It was found from experimental result, compared with olaparib of the prior art, the olaparib moisture absorption prepared by the present invention
Property significantly improve, it is moist almost without drawing, be advantageous to improve preparation stability.
Claims (6)
- A kind of 1. preparation method for the medicine olaparib for treating oophoroma, it is characterised in that the preparation of described olaparib Method comprises the following steps：1) olaparib crude product is added to the in the mixed solvent of dimethyl carbonate and isopropyl ether, is slowly heated to 45~50 DEG C, Insulated and stirred, 60~65 DEG C are continuously heating to, stirring, dissolving crude product, obtains crude product solution；2) activated carbon is added into crude product solution, is decolourized, filtering, collects filtrate；3) slow cooling, filtrate temperature is down to 30~35 DEG C, is incubated, stirring；4) 5 DEG C and following, control mixing speed, addition crystal seed, control temperature and mixing speed growing the grain 2h are cooled the filtrate to again Afterwards, filter, filter cake is rinsed with the mixed solvent of a small amount of dimethyl carbonate and isopropyl ether, is dried, is obtained olaparib.
- A kind of 2. preparation method of medicine olaparib for treating oophoroma according to claim 1, it is characterised in that step It is rapid 1) in the volume ratio of dimethyl carbonate and isopropyl ether be 1.0-1.5:1, the quality of the olaparib crude product and mixed solvent Volume ratio is 1 (g)：7-8(mL).
- A kind of 3. preparation method of medicine olaparib for treating oophoroma according to claim 1, it is characterised in that step It is rapid 1) described in mixing speed be 110 revs/min, mixing time is 30min.
- A kind of 4. preparation method of medicine olaparib for treating oophoroma according to claim 1, it is characterised in that step It is rapid 4) in olaparib crystal seed addition be olaparib crude product 2.0wt%.
- A kind of 5. preparation method of medicine olaparib for treating oophoroma according to claim 1, it is characterised in that step It is rapid 4) described in mixing speed be 150 revs/min.
- A kind of 6. preparation method of medicine olaparib for treating oophoroma according to claim 1, it is characterised in that step It is rapid 1) in, the volume ratio of dimethyl carbonate and isopropyl ether is 1.2:1.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10662178B2 (en) | 2018-01-31 | 2020-05-26 | Apotex Inc. | Crystalline form of Olaparib |
| CN111494385A (en) * | 2020-05-13 | 2020-08-07 | 黑龙江中医药大学 | Medicine for treating ovarian cancer and preparation method and application thereof |
| CN113215168A (en) * | 2021-04-29 | 2021-08-06 | 华中科技大学同济医学院附属同济医院 | Marker for cancer cell drug resistance, preparation combination for reversing cancer cell drug resistance and application thereof |
-
2017
- 2017-09-02 CN CN201710781802.4A patent/CN107382873A/en not_active Withdrawn
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10662178B2 (en) | 2018-01-31 | 2020-05-26 | Apotex Inc. | Crystalline form of Olaparib |
| CN111494385A (en) * | 2020-05-13 | 2020-08-07 | 黑龙江中医药大学 | Medicine for treating ovarian cancer and preparation method and application thereof |
| CN111494385B (en) * | 2020-05-13 | 2021-01-12 | 黑龙江中医药大学 | Medicine for treating ovarian cancer and preparation method and application thereof |
| CN113215168A (en) * | 2021-04-29 | 2021-08-06 | 华中科技大学同济医学院附属同济医院 | Marker for cancer cell drug resistance, preparation combination for reversing cancer cell drug resistance and application thereof |
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Application publication date: 20171124 |