CN105777651A - Crystal form of poly adenosinediphosphate-ribose polymerase (PARP) inhibitor, preparation method for crystal form and medicinal use of crystal form - Google Patents
Crystal form of poly adenosinediphosphate-ribose polymerase (PARP) inhibitor, preparation method for crystal form and medicinal use of crystal form Download PDFInfo
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- CN105777651A CN105777651A CN201510982228.XA CN201510982228A CN105777651A CN 105777651 A CN105777651 A CN 105777651A CN 201510982228 A CN201510982228 A CN 201510982228A CN 105777651 A CN105777651 A CN 105777651A
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- FDLYAMZZIXQODN-UHFFFAOYSA-N O=C(C1CC1)N(CC1)CCN1C(c1cc(CC(c2ccccc22)=NNC2=O)ccc1F)=O Chemical compound O=C(C1CC1)N(CC1)CCN1C(c1cc(CC(c2ccccc22)=NNC2=O)ccc1F)=O FDLYAMZZIXQODN-UHFFFAOYSA-N 0.000 description 1
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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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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention relates to a crystal form of a poly adenosinediphosphate-ribose polymerase (PARP) inhibitor, a preparation method for the crystal form and medicinal use of the crystal form and particularly relates to a novel crystal form of the PARP inhibitor, i.e., 4-[3-(4-cyclopropanylcarbonyl-piperazin-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one, a preparation method for the novel crystal form, a pharmaceutical composition of the novel crystal form and use of the novel crystal form in cancer treatment. The novel crystal form provided by the invention is good in reproducibility, is stable and readily available and is applicable to drug development.
Description
Technical field
The present invention relates to medicinal chemistry arts, be specifically related to a kind of polyadenylic acid diphosphonic acid phosphoribosynltransferase (PARP) inhibitor and 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-] novel crystal forms of-2H-phthalazines-1-ketone, preparation method and medical usage.
Background technology
4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone is oral polyadenylic acid diphosphonic acid phosphoribosynltransferase (PARP) inhibitor of the one developed by AstraZeneca company, treatment for cancer, including the ovarian cancer of BRCA sudden change, gastric cancer, the breast carcinoma of BRCA sudden change, nonsmall-cell lung cancer (NSCLC) and carcinoma of prostate, this product gets permission listing in December, 2014 at US and European.
4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone can pass through to block DNA damage reparation, causes DNA damage to accumulate, finally kills tumor cell；In addition, moreover it is possible to increase cell to the sensitivity of foreign DNA damage factor in other, suppress angiogenesis, strengthen Normocellular immunity, thus resisting the invasion of cancerous cell, its structural formula is as follows:
Patent CN101528714B is authorized to protect 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-the 4-]-2H-phthalazines-1-ketone of crystal form A form, its powder X-ray RD characteristic peak 2 θ ° (± 0.1 °) is 12.0, 17.8, 21.1, 22.3, 29.2, 10.5, 14.0, 21.7, 24.3 with 26.1, this crystal formation can be obtained by following two method: crystallization gained 4-in dichloromethane and acetonitrile [3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone is processed by method one successively with second alcohol and water, it is drying to obtain crystal form A；Method two is to be suspended in water and C1-2 alcohol mixture by 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone, cools down and adds crystal form A kind crystalline substance, products therefrom is drying to obtain crystal form A after being heated to reflux；nullThis patent also discloses the solvate crystal formation of 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone，Solvate crystal formation originates from that solution is saturated and crystallization trial，From dichloromethane、Ethyl acetate、Methanol、Ethanol、Isopropanol、2-butanone、T-butyl methyl ether、Toluene、Oxolane、Water、Hexamethylene、Cyclopropyl methyl ketone、1,2-dichloroethanes、Trifluoroacetic Acid Ethyl Ester、Fluorobenzene hexafluoroisopropanol、Methyl nonafluorobutyl ether、2-methyl isophthalic acid-propanol、Nitrocarbol.、Propionitrile、Trichloro ethylene、α α α-benzotrifluoride、Heptane and acetonitrile etc. obtain，Usual solvents compound crystal formation is included on lower column position and has 2 θ ° of (± 0.1 °) characteristic peak: 7.0-7.5、10.1-10.6、15.1-15.6、18.5-19.0、21.0-21.5、24.8-25.3 and 27.0-27.5.
Patent CN101821242B is authorized to protect 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-the 4-]-2H-phthalazines-1-ketone of crystal formation L-shaped formula; this crystal formation be in the organic solvent optionally having maximum 30%v/v water pulp crystal form A or the mixture gained of crystal form A and crystal formation L; its powder X-ray RD characteristic peak 2 θ ° (± 0.1 °) is: 14.4,17.2,17.5,18.8 and 23.0, also has the additional peak of following 2 θ ° (± 0.1 °): 10.4,13.6 and 25.1.
Summary of the invention
It is an object of the invention to provide the novel crystal forms of a kind of 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone, at this by its called after crystal form B.
This crystal formation can be identified by the method for its characteristic X-ray powder diffraction (XRD) collection of illustrative plates.
This crystal formation can by being characterized by characteristic X-ray powder diffraction pattern, its θ ° of (± 0.2 °) peak of powder X-ray RD characteristic peak 2 is: 6.34,6.75,8.21,12.61,14.97,16.33,19.59 and 22.00, and wherein said X-ray powder diffraction pattern uses CuKα1Radiation obtains.
Preferably, the diffracting spectrum of this crystal formation is as shown in Figure 1.
In order to allow experimental error, above-mentioned 2 θ are considered as must accurately to ± 0.2 degree of 2 θ value, that is, when the crystal formation whether crystallized sample of given 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-the 4-]-2H-phthalazines-1-ketone of assessment is the present invention, the 2 θ values through laboratory observation to sample, as drop on eigenvalue ± 0.2 degree of 2 θ in, it is considered that identical with above-mentioned eigenvalue.
Another aspect of the present invention further relates to the method preparing the crystal form B of 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone (Formulas I), and the method comprises the steps:
I a certain amount of 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone is suspended in the water as solvent of certain volume ratio and the mixture of alcohol by ()；
(ii) suspension is heated to reflux molten clear rear filtered while hot；
(iii) filtrate is put and at a certain temperature, stand crystallize；
(iv) stirring of precipitation solid being smashed, filter, namely filtration cakes torrefaction obtains 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone (Formulas I) crystal form B.
Preferably, in step (i), 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone and the mass volume ratio (g:ml) of solvent are selected from 1g:3ml～1g:9ml, preferred 1g:4ml～1g:6ml, more preferably 1g:5ml.
Preferably, 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone is suspended in a certain proportion of C by step (i)1-3In the mixed solution of alcohol and water composition.C1-3Alcohol is selected from methanol, ethanol, propanol and/or isopropanol, it is preferable that methanol and ethanol, more preferably ethanol.
Preferably, in step (i), the volume ratio of water and alcohol is selected from 3:1～1:3, it is preferable that 2:1～1:2, more preferably 1:1.
Preferably, step (iii) stands recrystallization temperature selected from 10～40 DEG C, it is preferable that 20～30 DEG C, more preferably 23～27 DEG C.
Published 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-the 4-]-2H-phthalazines-1-ketone crystal form B of the present invention is a kind of stable crystal formation, this crystal form samples crystal formation and have related substance all to remain stable in influence factor's (high temperature, high humidity and illumination) is 30 days, it does not have any change occurs；Meanwhile, the physicochemical properties that this crystal formation can also keep good under grinding condition are stable, and these character are highly beneficial to preparation.
Another object of the present invention is to provide the pharmaceutical composition containing 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone crystal form B.
It addition, another object of the present invention also resides in the application providing 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone crystal form B or the pharmaceutical composition containing crystal form B at preparation treatment cancer drug.Preferably, described cancer includes the ovarian cancer of BRCA sudden change, gastric cancer, the breast carcinoma of BRCA sudden change, nonsmall-cell lung cancer (NSCLC) and carcinoma of prostate.
Another object of the present invention also resides in provides the pharmaceutical composition containing 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone crystal form B as active component and other therapeutic component of pharmaceutical carrier, diluent or excipient and selectivity existence.The compositions of the present invention is suitable to oral administration, and dosage form includes tablet and capsule.
The present invention develops the novel crystal forms of a kind of 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone, this crystal formation favorable reproducibility, is stably easy to get, and is suitable for drug development.
Inventor is through verification experimental verification, 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone crystal form B is a kind of stable crystal formation, and the sample of this crystal formation at least physical state and chemical state can not change in 10 days at 50 DEG C；Under grinding the pressure with 10MPa, physicochemical properties are stable simultaneously, and these character are highly beneficial to preparation.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction pattern of formula I crystal form B.
Detailed description of the invention
In order to further illustrate the present invention, below in conjunction with specific embodiment, the present invention is specifically addressed, but protection scope of the present invention is not limited to specific embodiment.
Embodiment 1:
25ml single port bottle adds 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-the 4-]-2H-phthalazines-1-ketone of 2g, add 10ml ethanol/water solution (ethanol: water=1:1, v:v) rearmounted 90 DEG C of oil baths reflux molten clearly, filter, filter filter is put 25 DEG C and is stood overnight, precipitate out a large amount of solid, filter after stirring, filter cake is put 80 DEG C of drying under reduced pressure and is obtained 1.45g4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone crystal form B in 20 hours, and its XRD figure is composed as shown in Figure 1.
Embodiment 2:
25ml single port bottle adds 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-the 4-]-2H-phthalazines-1-ketone of 2g, add 10ml ethanol/water solution (ethanol: water=1:2, v:v) rearmounted 90 DEG C of oil baths reflux molten clearly, filter, filter filter is put 25 DEG C and is stood overnight, precipitate out a large amount of solid, filtering after stirring, filter cake is put 80 DEG C of drying under reduced pressure and is obtained 1.48g4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone in 20 hours.After testing, its XRD figure spectrum is coincide with Fig. 1 substantially.
Embodiment 3:
25ml single port bottle adds 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-the 4-]-2H-phthalazines-1-ketone of 2g, add 10ml methanol/water solution (methanol: water=1:1, v:v) rearmounted 90 DEG C of oil baths reflux molten clearly, filter, filter filter is put 25 DEG C and is stood overnight, precipitate out a large amount of solid, filtering after stirring, filter cake is put 80 DEG C of drying under reduced pressure and is obtained 1.2g4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone in 20 hours.After testing, its XRD figure spectrum is coincide with Fig. 1 substantially.
Embodiment 4:
25ml single port bottle adds 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-the 4-]-2H-phthalazines-1-ketone of 2g, add 10ml isopropanol/water solution (isopropanol: water=1:1, v:v) rearmounted 100 DEG C of oil baths reflux molten clearly, filter, filter filter is put 25 DEG C and is stood overnight, precipitate out a large amount of solid, filtering after stirring, filter cake is put 80 DEG C of drying under reduced pressure and is obtained 1.43g4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone in 20 hours.After testing, its XRD figure spectrum is coincide with Fig. 1 substantially.
Experimental example 1: the crystal formation comparative study before and after sample stability test
Method sequential system according to embodiment 1, for sample, makes X-ray powder diffraction under long-time stability (temperature 30 DEG C, humidity 65%) condition respectively after placing six months, analyze X-ray powder diffraction pattern and compare with initial data.Data are more respectively in Table 1:
Table 1: the X-ray powder diffraction data contrast table of sample long-time stability
Conclusion: contrast above-mentioned XRD spectra, there is not obvious change in 2 θ values of diffraction maximum.After three batch samples are placed six months under long-time stability (temperature 30 DEG C, humidity 65%) condition, crystal formation does not change.
Experimental example two: the crystal formation comparative study before and after grinding
Method sequential system according to embodiment 1 is for sample, and carries out test as follows:
(1) directly grind 5 minutes；
(2) the direct micropowder of raw material.
Above two sample carrying out X-ray powder diffraction test respectively, and data and initial data is compared, Data Comparison is in Table 2:
Table 2: sample is milled, X-ray powder diffraction data contrast table before and after micropowder
| Sequence number | Initial 2 θ (°) | Data 2 θ (°) after grinding | Data 2 θ (°) after micropowder |
| 1 | 6.42 | 6.47 | 6.39 |
| 2 | 6.84 | 6.88 | 6.81 |
| 3 | 8.29 | 8.34 | 8.28 |
| 4 | 10.32 | 10.32 | 10.27 |
| 5 | 12.73 | 12.76 | 12.68 |
| 6 | 13.65 | 13.71 | 13.64 |
| 7 | 15.06 | 15.11 | 15.05 |
| 8 | 16.41 | 16.47 | 16.39 |
| 9 | 18.69 | 18.73 | 18.70 |
| 10 | 19.74 | 19.75 | 19.63 |
| 11 | 20.77 | 20.83 | 20.73 |
| 12 | 21.97 | 22.07 | 22.01 |
| 13 | 23.00 | 23.06 | 22.95 |
| 14 | 26.26 | 26.30 | 26.19 |
Conclusion: sample is when directly grinding with micropowder, and crystal formation does not change.
Investigate data it can be seen that stability of crystal form of the present invention is done well from sample stability, be suitable for medicine quality standard.
Experimental example three: the comparative study before and after sample stability test
Sample prepared by the method according to embodiment 1, detects investigation project respectively after placing six months under long-time stability (temperature 30 DEG C ± 2 DEG C, humidity 65% ± 5%) condition, and Data Comparison is in Table 3:
Table 3: sample long-time stability Data Comparison table
Conclusion: sample has good stability long-term when.
Experimental example four: sample preparation becomes the dissolution outcome research of 50mg specification capsule
Sample prepared by the method according to embodiment 1, prepare into the capsule of 50mg specification, investigating sample dissolution respectively in 0.1mol/LHCl solution, pH4.5 acetate buffer solution (containing 1% tween), pH6.8 phosphate buffer (containing 1% tween) and purified water (containing 1% tween), Data Comparison is in Table 4:
Table 4 made products is containing the dissolution data (n=6) in the water of 1% tween, pH4.5 and pH6.8 buffer
Table 5 made products dissolution data (n=6) in 0.1mol/LHCl solution
Conclusion: sample preparation becomes the dissolution result of 50mg specification capsule to show: 1. product is in the pH4.5 acetate buffer solution containing 1% tween, pH6.8 phosphate buffer and purified water, and the dissolution of 45min is all higher than 90%；2. in 0.1mol/L hydrochloric acid, product capsule shells 1h just starts disintegrate, and release is relatively slow, finally also can almost dissolution is complete.Therefore, the finished dosage form that this crystal formation is made is adopted to disclosure satisfy that medication demand.
Claims (11)
- The crystal formation of 1.4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone, it including at least 2 θ ° of (± 0.2 °) characteristic peaks is in X-ray powder diffraction pattern:
Peak 2θ°(±0.2°) 1 6.34 2 6.75 3 8.21 4 12.61 5 14.97 6 16.33 7 19.59 8 22.00 - 2. crystal formation according to claim 1, it is characterised in that the XRPD collection of illustrative plates of described crystal formation is as shown in Figure 1.
- 3. the method for 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone crystal formation described in preparation any one of claim 1-2, the method comprises the steps:I) a certain amount of 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone is suspended in the water as solvent of certain volume ratio and the mixture of alcohol；Ii) suspension is heated to reflux molten clear rear filtered while hot；Iii) filtrate is put and at a certain temperature, stand crystallize；Iv) stirring of precipitation solid being smashed, filter, namely filtration cakes torrefaction obtains 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone crystal formation.
- 4. method according to claim 3, it is characterized in that, in step i), 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone is 1g:3ml～1g:9ml with the mass volume ratio (g:ml) of solvent, preferred 1g:4ml～1g:6ml, more preferably 1g:5ml.
- 5. method according to claim 3, it is characterised in that 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone is suspended in a certain proportion of C1-3In the mixed solution of alcohol and water composition.
- 6. method according to claim 5, it is characterised in that described C1-3Alcohol is selected from methanol, ethanol, propanol and/or isopropanol, it is preferable that methanol and ethanol, more preferably ethanol.
- 7. method according to claim 5, it is characterised in that the volume ratio of water and alcohol is 3:1～1:3, it is preferable that 2:1～1:2, more preferably 1:1.
- 8. method according to claim 3, it is characterised in that step iii) in stand the temperature of crystallize selected from 10～40 DEG C, it is preferable that 20～30 DEG C, more preferably 23～27 DEG C.
- 9. comprise the pharmaceutical composition of 4-described in any one of claim 1-2 [3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone crystal formation.
- 10. pharmaceutical composition according to claim 9, it is characterised in that described compositions makes tablet or capsule.
- 11. the application that 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-the 4-]-2H-phthalazines-1-ketone crystal formation according to any one of claim 1-2 is in preparation treatment cancer drug, preferably, described cancer is selected from the ovarian cancer of BRCA sudden change, gastric cancer, the breast carcinoma of BRCA sudden change, nonsmall-cell lung cancer and carcinoma of prostate.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI639593B (en) * | 2016-08-24 | 2018-11-01 | 台灣神隆股份有限公司 | Processes for preparing olaparib |
| US10662178B2 (en) | 2018-01-31 | 2020-05-26 | Apotex Inc. | Crystalline form of Olaparib |
| WO2024188265A1 (en) * | 2023-03-13 | 2024-09-19 | 江苏豪森药业集团有限公司 | Use of piperidine alkene compound in preparation of drug for treating cancer |
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| CN101528714A (en) * | 2006-10-17 | 2009-09-09 | 库多斯药物有限公司 | Polymorphic form of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2h-phthalazin-1-one |
| CN101821242A (en) * | 2007-10-17 | 2010-09-01 | 库多斯药物有限公司 | 4- [3- (4-cyclopropanecarbonyl-piperazine-i-carbony_, -fluoro-benzyl] -2h-phthalaz in-1-one |
| CN102238945A (en) * | 2008-10-07 | 2011-11-09 | 阿斯利康(英国)有限公司 | Pharmaceutical formulation 514 |
| CN103130723A (en) * | 2011-11-30 | 2013-06-05 | 成都地奥制药集团有限公司 | Poly (aenosine diphosphate glucose pyrophospheralase (ADP)-ribose) polymerase inhibitor |
| CN106137998A (en) * | 2015-03-30 | 2016-11-23 | 江苏豪森药业集团有限公司 | Aura handkerchief Buddhist nun's pharmaceutical composition and preparation method thereof |
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| CN101528714A (en) * | 2006-10-17 | 2009-09-09 | 库多斯药物有限公司 | Polymorphic form of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2h-phthalazin-1-one |
| CN101821242A (en) * | 2007-10-17 | 2010-09-01 | 库多斯药物有限公司 | 4- [3- (4-cyclopropanecarbonyl-piperazine-i-carbony_, -fluoro-benzyl] -2h-phthalaz in-1-one |
| CN102238945A (en) * | 2008-10-07 | 2011-11-09 | 阿斯利康(英国)有限公司 | Pharmaceutical formulation 514 |
| CN103130723A (en) * | 2011-11-30 | 2013-06-05 | 成都地奥制药集团有限公司 | Poly (aenosine diphosphate glucose pyrophospheralase (ADP)-ribose) polymerase inhibitor |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI639593B (en) * | 2016-08-24 | 2018-11-01 | 台灣神隆股份有限公司 | Processes for preparing olaparib |
| US10662178B2 (en) | 2018-01-31 | 2020-05-26 | Apotex Inc. | Crystalline form of Olaparib |
| WO2024188265A1 (en) * | 2023-03-13 | 2024-09-19 | 江苏豪森药业集团有限公司 | Use of piperidine alkene compound in preparation of drug for treating cancer |
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Application publication date: 20160720 |