CN105330697A - Crystal form of anticancer compound, and preparation method and application thereof - Google Patents
Crystal form of anticancer compound, and preparation method and application thereof Download PDFInfo
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- CN105330697A CN105330697A CN201410385774.0A CN201410385774A CN105330697A CN 105330697 A CN105330697 A CN 105330697A CN 201410385774 A CN201410385774 A CN 201410385774A CN 105330697 A CN105330697 A CN 105330697A
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Abstract
The invention discloses a crystal form of an anticancer compound, and a preparation method and application thereof. Specifically, the invention discloses a novel crystal form of the anticancer compound (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphonoyloxy-4-yl]pyridine-2-amine and a preparation method thereof. The structural formula of the novel crystal form is as shown in a formula I which is described in the specification. The crystal form is a crystal form D. An XRPD pattern of the crystal form has diffraction peaks as 2theta(+/- 0.2 DEG) is equal to 4.89, 7.82, 8.32, 11.69, 12.06, 13.05, 14.65, 15.26, 18.14 and 20.03. The crystal form has stable properties and is applicable to pharmaceutical preparations.
Description
Technical field
The present invention relates to crystal formation D of a kind of anticancer compound (R)-3-[1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group]-5-[3-fluorophenyl-1-dimethyl phosphine acyl-oxygen-4-base] pyridine-2-amine and preparation method thereof.
Background technology
Lung cancer is modal lung primary malignant tumor, is usually divided into nonsmall-cell lung cancer (NSCLC) and small cell lung cancer (SCLC).Lung cancer is the cancer that M & M is the highest, and nonsmall-cell lung cancer accounts for 80% ~ 85% of lung cancer sum, and its mortality ratio is up to 80% ~ 90%.According to the statistics of the World Health Organization (WHO), global lung cancer new cases 1332132 example in 2002, account for 12.4% of whole new cancer cases sum, occupy first, Third National coroner's inquest main result display Past 30 Years China lung cancer mortality that the Ministry of Health of China announces on April 29th, 2008 rises 465%, current lung cancer has replaced liver cancer becomes the first Death Cause for Malignant Tumors of China, accounts for 22.7% of mortality of malignant tumors.
5 years survival rates about 10% ~ 15% of developed country's lung cancer are then lower in China.If advanced NSCLC is not treated, median survival interval about 4 ~ 5 months, within 1 year, survival rate is lower than 10%, and the standard First-line chemotherapy scheme of advanced NSCLC is equivalent to best supportive treatment and effectively can extends median survival interval, improves 1 year survival rate.But at present the curative effect of chemotherapy seems to reach a platform, its objective efficient about 30%, median survival interval 8 ~ 9 months, 1 year survival rate 30% ~ 40%.Therefore, the focus that more effective and safe treatment means becomes current lung cancer research is found.Tumor cells targeted therapy is the treatment means for other biological approach.At present, the target therapeutic agent of NSCLC mainly contains EGF-R ELISA (EGFR) family group inhibitor, angiogenesis inhibitor, Mutiple Targets inhibitor, signal transduction inhibitor, inducer of apoptosis etc.CSCO (CSCO) executive committee General Board, famous clinical tumor expert professor Ma Jun point out: " owing to having disguise in early days; be Locally Advanced when most of Patients with Non-small-cell Lung finds or shift, the patients with lung cancer exceeding half can miss surgical engine meeting.Tradition chemicotherapy offer limited effectiveness, and with insufferable medicine toxic side effects, the number of times of usual chemicotherapy failure is more, and the effect of successive treatment is poorer.But the appearance of targeted drug, provides a kind of newly possibility to conquering lung cancer.”
Pfizer announced on August 26th, 2011, XALKORI (crizotinib) capsule of the said firm obtains FDA (Food and Drug Adminstration) FDA and ratifies, this is first and carries out the medicine of targeted therapy to Nucleophosmin-anaplastic lymphoma kinase (ALK), is used for the treatment of the detection method ratified by FDA and is diagnosed as the Locally Advanced of the ALK positive or the nonsmall-cell lung cancer of transfer.The curative effect system of XALKORI is based on objective remission rate (ORR).XALKORI while FDA ratifies fast in acquisition, Pfizer go on the market after clinical trial, be intended to do further assessment to the clinical efficacy of XALKORI.According to FDA about targeted therapy and the up-to-date instruction with diagnosis, Pfizer has carried out hand-in-glove with FDA and molecular diagnosis business department of Abbott Laboratories in clinical trial, guarantees that the diagnostic detection technology of XALKORI and Abbott Laboratories obtains simultaneously and evaluates and ratify.VysisALKBreakApartFISH (fluorescence in situ hybridization) the probe reagent box of the latter and molecular diagnosis business department of Abbott Laboratories, in order to find ALK fusion gene.The ALKFISH test kit of XALKORI and molecular diagnosis business department of Abbott Laboratories is simultaneously granted, also indicates that the tumour medicine of Pfizer or cancer immunotherapies are developed with granted first together with diagnostic detection scheme." by really understanding the driving gene of NSCLC, as ALK, we can select the most possible patient to therapeutic response.XALKORI is the brand-new road we providing a Probe into Future medicament research and development and cancer therapy, " the responsible official PaulBunn of cancer research department of UNIVERSITY OF COLORADO AT DENVER teaches and JamesDudley chief physician points out." XALKORI is the new drug of first the treatment lung cancer carrying out FDA approval 6 years more, and represent Treatment for Non-small Cell Lung Mode change, we turn to the Therapeutic mode by biomarker decision-making from machine-made treatment plan." in XALKORI clinical trial, testing program requires that the biomarker ALK fusion gene detected result of patient tumors is positive, to improve treating the possibility of making a response.This detection method first for lung cancer therapy can make investigator observe good therapeutic action in the patients screened in advance.Preliminary epidemiological study shows, in nonsmall-cell lung cancer, ALK positive rate is approximately 3-5%, means every year at the Patients with Non-small-cell Lung of nearly 6500 to 11000 the ALK positives of the U.S..Registered the targeted therapy of clinical trial by XALKORI, late in the positive Patients with Non-small-cell Lung of ALK, objective remission rate is 50 to 61%.
In the scholarly forecast 2008-2013 term, Chinese nonsmall-cell lung cancer (NSCLC) is treated market and will be doubled above, from 3.07 hundred million dollars to 6.48 hundred million dollars.The increase of colorectal cancer case treatment will speed up this growth.During urbanization and aging population will cause 2008-2018, Chinese nonsmall-cell lung cancer morbidity case increases by 47%, from 36.15 ten thousand to 53.13 ten thousand.The most significantly increase and will occur in city, here the nonsmall-cell lung cancer morbidity case in Future Ten year will increase by 72%, and in contrast, Rural areas only has the growth of 8%.Gefitinib (Iressa of AstraZeneca), erlotinib (Erlotinib of Roche), increasingly universal with targeted therapies such as Endostatins (rhEndostatin of Jiangsu first sign medicine company), and the release of new target therapeutic agent---rhuMAb-VEGF (Avastin of Roche) and cetuximab (Erbitux of Merck)---promotes the main power in Chinese nonsmall-cell lung cancer market during being 2008-2013.The market share of China of transnational company Treatment for Non-small Cell Lung will rise to 47% in 2013 from 34% in 2008.Introducing primarily of targeted drug increases and drives by this growth.Because low-price competition is fierce, the market that multinational chemotherapeutics will lose in China.Therefore, as " metoo " medicine of Crizotinib, type I compound will have wide market potential.
Drug crystal forms research and the solid-state research and development of medicine have very important meaning in pharmacy industry.Drug molecule has different solid form usually, comprises salt, polycrystalline, and eutectic is amorphous, hydrate and solvate; The different crystal forms of same drug molecule, at crystalline structure, stability, the properties such as producibility and bioavailability may there were significant differences, thus directly affect curative effect and the exploitability of medicine.Therefore, any one drug research and development, all needs to carry out comprehensive and systematic screening polymorph, finds crystal formation as much as possible, then uses various solid-state approach to carry out deep research to these crystal formations, thus finds the crystal formation of the most applicable exploitation.
Summary of the invention
The object of the present invention is to provide the new crystal of type I compound,
Preferably, described crystal formation is crystal formation D, and the XRPD collection of illustrative plates of this crystal formation is that 4.89,7.82,8.32,11.69,12.06,13.05,14.65,15.26,18.14,20.03 places have diffraction peak at 2 θ (± 0.2 °).
Preferred further, the XRPD collection of illustrative plates of described crystal formation D as shown in Figure 1.
Another object of the present invention is also to provide the method preparing described crystal formation, comprising:
1) type I compound is dissolved by organic solvent A;
2) anti-solvent A stirring and crystallizing is added, and
3) filter to obtain target crystal formation, preferably, this crystal formation is crystal formation D,
Optional, also comprise vacuum drying step after filtration.
Preferably, described organic solvent A is selected from methyl alcohol, ethanol and/or propyl carbinol.
Preferably, described anti-solvent A is selected from isopropyl ether, normal heptane and/or normal hexane.
Another object of the present invention is also the another kind of crystal formation providing formula I, i.e. crystal formation E, the XRPD collection of illustrative plates of this crystal formation is that 3.93,7.78,8.59,13.88,17.06,18.82,20.01,20.38,21.35,24.01,25.72 places have diffraction peak at 2 θ (± 0.2 °).
Preferably, the XRPD collection of illustrative plates of described crystal formation E as shown in Figure 2.
Another object of the present invention is also to provide the method preparing described crystal formation E, comprising:
1) type I compound is dissolved by organic solvent B;
2) anti-solvent B stirring and crystallizing is added, and
3) target crystal formation E is filtered to obtain,
Optional, also comprise vacuum drying step after filtration.
Preferably, described organic solvent B is Virahol and/or ethylene glycol.
Preferably, described anti-solvent B is isopropyl ether, methyl tertiary butyl ether and/or glycol dimethyl ether.
Preferably, described vacuum-drying is carried out at 20-50 DEG C, more preferably 20-30 DEG C, most preferably 25 DEG C.
Another object of the present invention is also to provide a kind of pharmaceutical composition, and described pharmaceutical composition comprises described crystal formation (as crystal formation D or crystal formation E) and pharmaceutically acceptable carrier.
Another object of the present invention is also to provide described crystal formation or described pharmaceutical composition, is preparing the application in antitumor drug, and preferably, described tumour is lung cancer.
Find through experiment, crystal form purity of the present invention is high, and stable in properties, meet pharmaceutical preparation needs.
Accompanying drawing explanation
Fig. 1 is the XRPD collection of illustrative plates of (R)-3-[1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group]-5-[3-fluorophenyl-1-dimethyl phosphine acyl-oxygen-4-base] pyridine-2-amine crystal formation D.
Fig. 2 is the XRPD collection of illustrative plates of (R)-3-[1-(the chloro-3-fluorophenyl of 2,6-bis-) oxyethyl group]-5-[3-fluorophenyl-1-dimethyl phosphine acyl-oxygen-4-base] pyridine-2-amine crystal formation E.
Embodiment
Embodiment 1
Dropped in methyl alcohol 30ml by type I compound crude product 5.0g, stirring and dissolving, then adds isopropyl ether 900ml stirring and crystallizing 2h.Filter, 25 DEG C of vacuum-dryings obtain target crystal formation D3.8g, and its crystal form X RPD collection of illustrative plates as shown in Figure 1.
Embodiment 2
Dropped in ethanol 40ml by type I compound crude product 5.0g, stirring and dissolving, then adds isopropyl ether 500ml stirring and crystallizing 2h.Filter, 25 DEG C of vacuum-dryings obtain target crystal formation D4.1g, and after testing, its crystal form X RPD collection of illustrative plates is basic and Fig. 1 is identical, and all characteristic peaks are all in limit of error.
Embodiment 3
Dropped in ethanol 40ml by type I compound crude product 5.0g, stirring and dissolving, then adds normal heptane 500ml stirring and crystallizing 2h.Filter, 25 DEG C of vacuum-dryings obtain target crystal formation D4.3g, and after testing, its crystal form X RPD collection of illustrative plates is basic and Fig. 1 is identical, and all characteristic peaks are all in limit of error.
Embodiment 4
Dropped into by type I compound crude product 5.0g in Virahol 50ml, 40 DEG C of stirring in water bath are dissolved, and after stirring cooling, add isopropyl ether 1000ml stirring and crystallizing 2h.Filter, 25 DEG C of vacuum-dryings obtain target crystal formation E2.8g, and its crystal form X RPD collection of illustrative plates as shown in Figure 2.
Embodiment 5
Dropped into by type I compound crude product 10.0g in Virahol 100ml, 40 DEG C of stirring in water bath are dissolved, and after stirring cooling, add isopropyl ether 2000ml stirring and crystallizing 2h.Filter, 25 DEG C of vacuum-dryings obtain target crystal formation E5.2g, and after testing, its crystal form X RPD collection of illustrative plates is basic and Fig. 2 is identical, and all characteristic peaks are all in limit of error.
Embodiment 6
Dropped into by type I compound crude product 30.0g in Virahol 100ml, 40 DEG C of stirring in water bath are dissolved, and after stirring cooling, add isopropyl ether 6000ml stirring and crystallizing 2h.Filter, 25 DEG C of vacuum-dryings obtain target crystal formation E15.8g, and after testing, its crystal form X RPD collection of illustrative plates is basic and Fig. 2 is identical, and all characteristic peaks are all in limit of error.
Experimental example one, crystal formation D stability study
With the crystal formation prepared by the embodiment of the present invention 1 for sample, under condition of different temperatures, detect the stability of crystal formation, result is as shown in table 1
Table 1
As seen from the above table, crystal formation D is good at 25 DEG C-100 DEG C condition stability inferiors.
Experimental example two, crystal formation E stability study
With the crystal formation prepared by the embodiment of the present invention 4 for sample, under condition of different temperatures, detect the stability of crystal formation, result is as shown in table 2
Table 2
As seen from the above table, crystal formation E is good at 25 DEG C-80 DEG C condition stability inferiors.
Claims (14)
1. a crystal formation for type I compound,
2. the crystal formation of type I compound according to claim 1, it is characterized in that, described crystal formation is crystal formation D, and the XRPD collection of illustrative plates of this crystal formation is that 4.89,7.82,8.32,11.69,12.06,13.05,14.65,15.26,18.14,20.03 places have diffraction peak at 2 θ (± 0.2 °).
3. the crystal formation of type I compound according to claim 2, is characterized in that, the XRPD collection of illustrative plates of described crystal formation D as shown in Figure 1.
4. the method for the crystal formation of the type I compound of preparation as described in claim 2-3 any one, comprising:
1) type I compound is dissolved by organic solvent A;
2) anti-solvent A stirring and crystallizing is added, and
3) target crystal formation D is filtered to obtain,
Optional, also comprise vacuum drying step after filtration.
5. the method for the crystal formation of the type I compound of preparation according to claim 4 as described in claim 2-3 any one, is characterized in that, described organic solvent A is selected from methyl alcohol, ethanol and/or propyl carbinol.
6. the method for the crystal formation of the type I compound of preparation according to claim 4 as described in claim 2-3 any one, is characterized in that, described anti-solvent A is selected from isopropyl ether, normal heptane and/or normal hexane.
7. the crystal formation of type I compound according to claim 1, it is characterized in that, described crystal formation is crystal formation E, and the XRPD collection of illustrative plates of this crystal formation is that 3.93,7.78,8.59,13.88,17.06,18.82,20.01,20.38,21.35,24.01,25.72 places have diffraction peak at 2 θ (± 0.2 °).
8. the crystal formation of type I compound according to claim 7, is characterized in that, the XRPD collection of illustrative plates of described crystal formation E as shown in Figure 2.
9. the method for the crystal formation of the type I compound of preparation as described in claim 7-8 any one, comprising:
1) type I compound is dissolved by organic solvent B;
2) anti-solvent B stirring and crystallizing is added, and
3) target crystal formation E is filtered to obtain,
Optional, also comprise vacuum drying step after filtration.
10. preparation method according to claim 9, wherein said organic solvent B is Virahol and/or ethylene glycol.
The method of the crystal formation of the type I compound of 11. preparations according to claim 9 as described in claim 7-8 any one, wherein said anti-solvent B is isopropyl ether, methyl tertiary butyl ether and/or glycol dimethyl ether.
12. preparation methods according to claim 4 or 9 any one, it is characterized in that, described vacuum-drying is carried out at 20-50 DEG C, preferred 20-30 DEG C, more preferably 25 DEG C.
13. 1 kinds of pharmaceutical compositions, comprise the crystal formation of claim 1-3 or the type I compound described in right 7-8 any one and pharmaceutically acceptable carrier.
Pharmaceutical composition described in the crystal formation of 14. type I compound according to claim 1-3 or claim 7-8 any one or claim 12, preparing the application in antitumor drug, preferably, described tumour is lung cancer.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1777427A (en) * | 2003-02-26 | 2006-05-24 | 苏根公司 | Aminoheteroaryl compounds as protein kinase inhibitors |
| CN102105150A (en) * | 2008-05-21 | 2011-06-22 | 阿里亚德医药股份有限公司 | Phosphorous derivatives as kinase inhibitors |
| CN103826641A (en) * | 2011-02-24 | 2014-05-28 | 江苏豪森药业股份有限公司 | Phosphorus containing compounds as protein kinase inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1777427A (en) * | 2003-02-26 | 2006-05-24 | 苏根公司 | Aminoheteroaryl compounds as protein kinase inhibitors |
| CN102105150A (en) * | 2008-05-21 | 2011-06-22 | 阿里亚德医药股份有限公司 | Phosphorous derivatives as kinase inhibitors |
| CN103826641A (en) * | 2011-02-24 | 2014-05-28 | 江苏豪森药业股份有限公司 | Phosphorus containing compounds as protein kinase inhibitors |
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