CN105330697B - A kind of crystal form of anticancer compound and its preparation method and application - Google Patents
A kind of crystal form of anticancer compound and its preparation method and application Download PDFInfo
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- CN105330697B CN105330697B CN201410385774.0A CN201410385774A CN105330697B CN 105330697 B CN105330697 B CN 105330697B CN 201410385774 A CN201410385774 A CN 201410385774A CN 105330697 B CN105330697 B CN 105330697B
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Abstract
The invention discloses crystal forms of a kind of anticancer compound and its preparation method and application.Specifically, the invention discloses a kind of anticancer compound (R) -3- [1- (2, the chloro- 3- fluorophenyl of 6- bis-) ethyoxyl] -5- [3- fluorophenyl -1- dimethyl phosphine acyl-oxygen -4- base] pyridine -2- amine novel crystal forms and preparation method thereof, its structural formula is as shown in formula I, the crystal form is crystal form D, and the XRPD map of the crystal form is to have diffraction maximum at 4.89,7.82,8.32,11.69,12.06,13.05,14.65,15.26,18.14,20.03 at (± 0.2 °) of 2 θ.Crystal form property of the present invention is stablized, and pharmaceutical preparation application is suitable for.
Description
Technical field
The present invention relates to a kind of anticancer compound (R) -3- [1- (the chloro- 3- fluorophenyl of 2,6- bis-) ethyoxyl] -5- [3- fluorobenzene
Base -1- dimethyl phosphine acyl-oxygen -4- base] pyridine -2- amine crystal form D and preparation method thereof.
Background technique
Lung cancer is most common lung's primary malignant tumor, is generally divided into non-small cell lung cancer (NSCLC) and cellule
Lung cancer (SCLC).Lung cancer is the highest cancer of morbidity and mortality, and non-small cell lung cancer account for lung cancer sum 80%~
85%, the death rate is up to 80%~90%.According to the statistics of the World Health Organization (WHO), global lung cancer neopathy in 2002
Example 1332132, the 12.4% of whole new cancer cases sums is accounted for, occupies first, the Ministry of Public Health, China public affairs on April 29th, 2008
The Third National coroner's inquest main result of cloth shows that Past 30 Years China lung cancer mortality rises 465%, at present lung cancer
Liver cancer has been substituted as China first place Death Cause for Malignant Tumors, has accounted for the 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, survival rate was lower than 10% within 1 year, and the standard First-line chemotherapy scheme of advanced NSCLC is equivalent to most preferably
Supportive treatment can effectively extend median survival interval, improve 1 year survival rate.But the curative effect of current chemotherapy seems that reaching one puts down
Platform, objective effective percentage about 30%, median survival interval 8~9 months, 1 year survival rate 30%~40%.Therefore, finding more has
The treatment means of effect and safety become a hot spot of current lung cancer research.Tumor cells targeted therapy is for other biological
The treatment means of approach.Currently, the target therapeutic agent of NSCLC mainly has the inhibition of EGF-R ELISA (EGFR) family
Agent, angiogenesis inhibitors, multiple target point inhibitor, signal transduction inhibitor, inducer of apoptosis etc..Chinese Anti-Cancer Association's clinic is swollen
Tumor cooperation Professional Committee (CSCO) executive committee General Board, famous clinical tumor expert professor Ma Jun point out: " by
There is concealment in early stage, most of Patients with Non-small-cell Lung have been Locally Advanceds when finding or have shifted, and are more than half
Patients with lung cancer can miss operative chance.Traditional chemicotherapy offer limited effectiveness, and with insufferable drug toxicity, usually
The number of chemicotherapy failure is more, and the effect of successive treatment is poorer.But the appearance of targeted drug provides one kind to lung cancer is conquered
Newly may."
Pfizer announced that XALKORI (crizotinib) capsule of the said firm obtains U.S.'s food on August 26th, 2011
Product drug administration FDA approval, this is first drug that targeted therapy is carried out to anaplastic lymphoma kinase (ALK), is used for
Treatment is diagnosed as the Locally Advanced of the ALK positive or the non-small cell lung cancer of transfer by the detection method that FDA ratifies.XALKORI
Curative effect system be based on objective remission rate (ORR).XALKORI is while acquisition FDA quickly ratifies, after Pfizer is being listed
Clinical test, it is intended to which further assessment is done to the clinical efficacy of XALKORI.According to FDA about targeted therapy and with diagnosis
Newest instruction, Pfizer have carried out hand-in-glove with FDA and molecular diagnosis business department, Abbott Laboratories in clinical test, it is ensured that
The diagnosis detection technique of XALKORI and Abbott Laboratories is evaluated and is ratified simultaneously.The latter, that is, molecular diagnosis business department, Abbott Laboratories
Vysis ALK Break Apart FISH (fluorescence in situ hybridization) probe reagent box, to find ALK fusion gene.
XALKORI and the ALK FISH kit of molecular diagnosis business department, Abbott Laboratories are granted simultaneously, also indicate the tumour medicine of Pfizer
Or cancer immunotherapies for the first time with diagnosis detection scheme together with carry out exploitation and it is granted." by the driving base for really understanding NSCLC
Cause, such as ALK, we can choose out the most possibly patient to therapeutic response.XALKORI, which is that we provide one, to be explored not
Carry out the brand-new road of medicament research and development and treatment of cancer, " the responsible person Paul of cancer research department, UNIVERSITY OF COLORADO AT DENVER
Bunn professor and James Dudley chief physician point out." XALKORI is first treatment lung cancer for carrying out FDA approval 6 years more
New drug represents Treatment for Non-small Cell Lung Mode change, we are diverted through biology from machine-made therapeutic scheme
The treatment mode of marker decision." in XALKORI clinical test, testing program requires the biomarker ALK of patient tumors
Fusion testing result is the positive, to improve a possibility that making a response to treatment.It is used for this inspection of lung cancer therapy for the first time
Survey method can make researcher observe good therapeutic effect in the patients screened in advance.Preliminary epidemiology is ground
Study carefully and show that ALK positive rate is about 3-5% in non-small cell lung cancer, it is meant that every year in the U.S. about 6500 to 11000
The Patients with Non-small-cell Lung of the name ALK positive.The targeted therapy of clinical test is registered by XALKORI, late the ALK positive is non-
In Patients With Small Cell Carcinoma of The Lung, objective remission rate is 50 to 61%.
In the scholarly forecast 2008-2013 term, Chinese non-small cell lung cancer (NSCLC) treatment market will double with
On, from 3.07 hundred million dollars to 6.48 hundred million dollar.The increase of colorectal cancer case treatment will accelerate this growth.Urbanization and population
During aging will lead to 2008-2018, Chinese non-small cell lung cancer morbidity case increases by 47%, from 36.15 ten thousand to 53.13
Ten thousand.Most apparent increase will occur in city, and following 10 years non-small cell lung cancer morbidity cases will increase by 72% herein, with
This is on the contrary, rural area only has 8% growth.Gefitinib (Iressa of AstraZeneca), Erlotinib (special sieve of Roche
It is triumphant) and the targeted therapies such as Endostatin (rhEndostatin of Jiangsu first sign medicine company) it is increasingly widespread, and new target therapeutic agent pushes away
--- bevacizumab (Avastin of Roche) and cetuximab (Erbitux of Merck) --- is during being 2008-2013 out
Push the main power in Chinese non-small cell lung cancer market.The market share of China, trans-corporation Treatment for Non-small Cell Lung will be from
34% in 2008 rises to 47% in 2013.This growth will mainly be increased by the introducing of targeted drug and be driven.Due to
Low-price competition is fierce, and the chemotherapeutics of trans-corporation will lose in the market of China.Therefore, as " the me of Crizotinib
Too " drug, type I compound will have wide market potential.
Drug crystal forms research and the research and development of drug solid-state have very important meaning in pharmacy industry.Drug molecule usually has not
Same solid forms, including salt, polycrystalline, eutectic is amorphous, hydrate and solvate；The not isomorphous of same drug molecule
Type, in crystal structure, stability, the properties such as productibility and bioavilability might have significant difference, thus directly
Influence the curative effect and exploitability of drug.Therefore, any one drug research and development requires to carry out comprehensive and systematic polymorphic sieve
Choosing, finds crystal form as much as possible, then in-depth study is carried out to these crystal forms using various solid-state approach, to find most
It is suitble to the crystal form of exploitation.
Summary of the invention
The purpose of the present invention is to provide the novel crystal forms of type I compound,
Preferably, the crystal form is crystal form D, the XRPD map of the crystal form at (± 0.2 °) of 2 θ is 4.89,7.82,8.32,
11.69, there is diffraction maximum at 12.06,13.05,14.65,15.26,18.14,20.03.
It is further preferred that the XRPD map of the crystal form D is as shown in Figure 1.
Another object of the present invention also resides in the method for providing and preparing the crystal form, comprising:
1) type I compound is dissolved with organic solvent A；
2) anti-solvent A stirring and crystallizing is added, and
3) target crystal form is filtered to obtain, it is preferred that the crystal form is crystal form D,
Optional, it also include vacuum drying step after filtering.
Preferably, the organic solvent A is selected from methanol, ethyl alcohol and/or n-butanol.
Preferably, the anti-solvent A is selected from isopropyl ether, normal heptane and/or n-hexane.
Another object of the present invention, which also resides in, provides another crystal form of compound of formula I, i.e. crystal form E, the XRPD of the crystal form
Map (± 0.2 °) of 2 θ for 3.93,7.78,8.59,13.88,17.06,18.82,20.01,20.38,21.35,24.01,
25.72 there is diffraction maximum at place.
Preferably, the XRPD map of the crystal form E is as shown in Figure 2.
Another object of the present invention also resides in the method for providing and preparing the crystal form E, comprising:
1) type I compound is dissolved with organic solvent B；
2) anti-solvent B stirring and crystallizing is added, and
3) target crystal form E is filtered to obtain,
Optional, it also include vacuum drying step after filtering.
Preferably, the organic solvent B is isopropanol and/or ethylene glycol.
Preferably, the anti-solvent B is isopropyl ether, methyl tertiary butyl ether(MTBE) and/or glycol dimethyl ether.
Preferably, the vacuum drying is carried out at 20-50 DEG C, more preferable 20-30 DEG C, most preferably 25 DEG C.
Another object of the present invention, which also resides in, provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the crystal form
(such as crystal form D or crystal form E) and pharmaceutically acceptable carrier.
Another object of the present invention, which also resides in, provides the crystal form or described pharmaceutical composition, in the preparation of antitumor drugs
Application, it is preferred that the tumour be lung cancer.
Through experiments, it was found that crystal form purity of the invention is high, and property is stablized, and pharmaceutical preparation needs are met.
Detailed description of the invention
Fig. 1 is (R) -3- [1- (the chloro- 3- fluorophenyl of 2,6- bis-) ethyoxyl] -5- [3- fluorophenyl -1- dimethyl phosphine acyl-oxygen -
4- yl] pyridine -2- amine crystal form D XRPD map.
Fig. 2 is (R) -3- [1- (the chloro- 3- fluorophenyl of 2,6- bis-) ethyoxyl] -5- [3- fluorophenyl -1- dimethyl phosphine acyl-oxygen -
4- yl] pyridine -2- amine crystal form E XRPD map.
Specific embodiment
Embodiment 1
Type I compound crude product 5.0g is put into methanol 30ml, stirring and dissolving, isopropyl ether 900ml stirring analysis is then added
Brilliant 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal form D 3.8g, and crystal form XRPD map is as shown in Figure 1.
Embodiment 2
Type I compound crude product 5.0g is put into ethyl alcohol 40ml, stirring and dissolving, isopropyl ether 500ml stirring analysis is then added
Brilliant 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal form D 4.1g, and through detecting, crystal form XRPD map coincide with Fig. 1 substantially,
All characteristic peaks are in error range.
Embodiment 3
Type I compound crude product 5.0g is put into ethyl alcohol 40ml, stirring and dissolving, normal heptane 500ml stirring analysis is then added
Brilliant 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal form D 4.3g, and through detecting, crystal form XRPD map coincide with Fig. 1 substantially,
All characteristic peaks are in error range.
Embodiment 4
Type I compound crude product 5.0g is put into isopropanol 50ml, 40 DEG C of stirring in water bath dissolutions after stirring is cooling, are added
Isopropyl ether 1000ml stirring and crystallizing 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal form E 2.8g, crystal form XRPD map as schemed
Shown in 2.
Embodiment 5
Type I compound crude product 10.0g is put into isopropanol 100ml, 40 DEG C of stirring in water bath dissolutions add after stirring is cooling
Enter isopropyl ether 2000ml stirring and crystallizing 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal form E 5.2g, through detecting, crystal form
XRPD map coincide with Fig. 2 substantially, and all characteristic peaks are in error range.
Embodiment 6
Type I compound crude product 30.0g is put into isopropanol 100ml, 40 DEG C of stirring in water bath dissolutions add after stirring is cooling
Enter isopropyl ether 6000ml stirring and crystallizing 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal form E 15.8g, through detecting, crystal form
XRPD map coincide with Fig. 2 substantially, and all characteristic peaks are in error range.
Experimental example one, crystal form D stability study
Using crystal form prepared by the embodiment of the present invention 1 as sample, the stability of crystal form, knot are detected under condition of different temperatures
Fruit is as shown in table 1
Table 1
As seen from the above table, crystal form D has good stability under the conditions of 25 DEG C -100 DEG C.
Experimental example two, crystal form E stability study
Using crystal form prepared by the embodiment of the present invention 4 as sample, the stability of crystal form, knot are detected under condition of different temperatures
Fruit is as shown in table 2
Table 2
As seen from the above table, crystal form E has good stability under the conditions of 25 DEG C -80 DEG C.
Claims (8)
1. the crystal form of type I compound, which is characterized in that the crystal form is crystal form D, and the XRPD map of the crystal form is in 2 θ ± 0.2 °
4.89, there is diffraction maximum at 7.82,8.32,11.69,12.06,13.05,14.65,15.26,18.14,20.03,
2. the crystal form of type I compound according to claim 1, which is characterized in that XRPD map such as Fig. 1 of the crystal form D
It is shown.
3. the method for preparing the crystal form of the type I compound as described in claim 1-2 any one, comprising:
1) type I compound is dissolved with organic solvent A；
2) anti-solvent A stirring and crystallizing is added, and
3) target crystal form D is filtered to obtain,
Optional, it also include vacuum drying step after filtering,
Wherein, the organic solvent A is selected from methanol, ethyl alcohol and/or n-butanol；
The anti-solvent A is selected from isopropyl ether, normal heptane and/or n-hexane；
The vacuum drying is carried out at 20-50 DEG C.
4. preparation method according to claim 3, which is characterized in that the vacuum drying is carried out at 20-30 DEG C.
5. preparation method according to claim 3, which is characterized in that the vacuum drying is carried out at 25 DEG C.
6. a kind of pharmaceutical composition, the crystal form comprising type I compound of any of claims 1 or 2 and pharmaceutically acceptable load
Body.
7. the crystal form or claim 6 described pharmaceutical composition of type I compound according to claim 1 or 2 are anti-in preparation
Application in tumour medicine.
8. the crystal form or claim 6 described pharmaceutical composition of type I compound according to claim 1 or 2 are preparing lung
Application in cancer drug.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: Jiangsu best Pharmaceutical Co.,Ltd. Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: Jiangsu best Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. |
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