CN106459111A - Crystal form of anticancer compound and preparation method and use thereof - Google Patents
Crystal form of anticancer compound and preparation method and use thereof Download PDFInfo
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- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
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Abstract
The present invention relates to a crystal form of an anticancer compound (R)-3-[1-(2,6-dichloro-3-fluorophenyl) ethoxy]-5-[3-fluorophenyl-1-dimethyl phosphonooxy-4-yl] pyridine-2-amine and preparation method thereof, the structural formula thereof being represented by formula I. The crystal form has good stability, low hygroscopicity, and good fluidity and satisfies pharmaceutical preparation application requirements.
Description
The present invention relates to crystal formation of a kind of anticancer compound (R) -3- [1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethyoxyl] -5- [3- fluorophenyl -1- dimethyl phosphine acyl-oxygen -4- bases] pyridine -2- amine and preparation method thereof.
Lung cancer is most common lung's primary malignant tumor, is generally divided into non-small cell lung cancer (NSCLC) and ED-SCLC (SCLC).Lung cancer is morbidity and mortality highest cancer, and non-small cell lung cancer accounts for the 80%~85% of lung cancer sum, and its death rate is up to 80%~90%.According to the World Health Organization (WHO) statistics, global lung cancer new cases 1332132 in 2002, account for the 12.4% of whole new cancer cases sums, occupy first, the Third National coroner's inquest main result that the Ministry of Public Health of China announces on April 29th, 2008 shows that Past 30 Years China lung cancer mortality rises 465%, current lung cancer has been substituted liver cancer as the first Death Cause for Malignant Tumors of China, accounts 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, 1 year survival rate is less than 10%, and the standard First-line chemotherapy scheme of advanced NSCLC can effectively extend median survival interval equivalent to optimal supportive treatment, improve 1 year survival rate.But the curative effect of current chemotherapy seems to reach a platform, its objective effective percentage about 30%, median survival interval 8~9 months, 1 year survival rate 30%~40%.Therefore, finding more effective and safety treatment means turns into a focus of current lung cancer research.Tumor cells targeted therapy is the treatment means for other biological approach.At present, NSCLC target therapeutic agent mainly has EGF-R ELISA (EGFR) family group inhibitor, angiogenesis inhibitors, 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：" because early stage has disguise, most of Patients with Non-small-cell Lung have been Locally Advanceds when finding or shifted that the patients with lung cancer more than half can miss operative chance.Traditional chemicotherapy offer limited effectiveness, and with being difficult to
The medicine toxicity stood, the number of times of usual chemicotherapy failure is more, and the effect of successive treatment is poorer.But the appearance of targeted drug, a kind of new possibility is provided to lung cancer is conquered.”
Pfizer announced on the 26th in August in 2011, XALKORI (crizotinib) capsule of the said firm obtains FDA (Food and Drug Adminstration) FDA approvals, this is first medicine that targeted therapy is carried out to anaplastic lymphoma kinase (ALK), and the positive Locally Advanceds of ALK or the non-small cell lung cancer of transfer are diagnosed as by the FDA detection methods ratified for treating.XALKORI curative effect system is based on objective remission rate (ORR).XALKORI is while acquisition FDA quickly ratifies, clinical test after Pfizer is listed, it is intended to do further assessment to XALKORI clinical efficacy.According to FDA on targeted therapy and with the newest instruction of diagnosis, Pfizer has carried out hand-in-glove in clinical test with FDA and molecule diagnosis business department of Abbott Laboratories, it is ensured that the diagnosis detection technique of XALKORI and Abbott Laboratories is evaluated and ratified simultaneously.The latter is Vysis ALK Break Apart FISH (FISH) probe reagent box that Abbott Laboratories' molecule diagnoses business department, to find ALK fusion gene.XALKORI and the ALK FISH kits of Abbott Laboratories molecules diagnosis business department are simultaneously granted, also indicate Pfizer tumour medicine or cancer immunotherapies developed first together with diagnosis detection scheme with it is granted." by really understanding NSCLC driving gene, such as ALK, we can select the most possible patient to therapeutic response.XALKORI is the brand-new road for we providing a Probe into Future medicament research and development and treatment of cancer, " the director Paul Bunn of cancer research department of UNIVERSITY OF COLORADO AT DENVER professor and James Dudley chief physicians point out." XALKORI is the new drug for first treatment lung cancer for carrying out FDA approvals 6 years more, represents Treatment for Non-small Cell Lung Mode change, we are being diverted through the Therapeutic mode of biomarker decision-making from machine-made therapeutic scheme." in XALKORI clinical tests, testing program requires that the biomarker ALK fusion gene testing result of patient tumors is the positive, to improve the possibility made a response to treatment.This detection method for lung cancer therapy can make researcher observe good therapeutic effect in the patients screened in advance first.Preliminary epidemiological study shows that ALK positive rates are about 3-5% in non-small cell lung cancer, it is meant that the annual Patients with Non-small-cell Lung positive in about 6500 to 11000, U.S. ALK.The targeted therapy of clinical test is registered 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 terms, Chinese non-small cell lung cancer (NSCLC) treatment market will double the above, from 3.07 hundred million dollars to 6.48 hundred million dollars.Colorectal cancer case is controlled
The increase for the treatment of will accelerate this increase.During urbanization and aging population will cause 2008-2018, Chinese non-small cell lung cancer morbidity case increases by 47%, from 36.15 ten thousand to 53.13 ten thousand.Most obvious increase will occur in city, and following 10 years non-small cell lung cancer morbidity case will increase by 72% herein, and in contrast, rural area only has 8% growth.Gefitinib (Iressa of AstraZeneca), Erlotinib (Erlotinib of Roche), it is increasingly widespread with the targeted therapy such as Endostatin (rhEndostatin of Jiangsu first sign medicine company), and the release --- bevacizumab (Avastin of Roche) and cetuximab (Erbitux of Merck) --- of new target therapeutic agent promotes the main power in China's non-small cell lung cancer market during being 2008-2013.The market share of China of trans-corporation Treatment for Non-small Cell Lung will rise to 47% in 2013 from 34% in 2008.This growth drives mainly being increased by the introducing of targeted drug.Because low-price competition is fierce, the chemotherapeutics of trans-corporation will be lost in the market of China.Therefore, as Crizotinib " me too " medicines, type I compound will have wide market potential.
Drug crystal forms are studied and medicine solid-state is researched and developed in pharmacy industry with very important meaning.Drug molecule generally has different solid forms, including salt, and polycrystalline, eutectic is amorphous, hydrate and solvate；The different crystal forms of same drug molecule, in crystal structure, stability, the properties such as productibility and bioavilability might have significant difference, so as to directly affect the curative effect and exploitability of medicine.Therefore, any one drug research and development, is required for carrying out comprehensive and systematic screening polymorph, finds crystal formation as much as possible, then carries out in-depth study to these crystal formations using various solid-state approach, so as to find the crystal formation for being best suitable for exploitation.
The content of the invention
It is an object of the invention to provide a kind of crystal formation of formula (I) compound
It is preferred that, the crystal formation is crystal formation A, and (± 0.2 °) in 2 θ of its XRPD collection of illustrative plates is to have diffraction maximum at 7.86,9.60,11.76,12.37,14.68,19.61,20.02,21.19,23.76,24.89.
It is furthermore preferred that the XRPD collection of illustrative plates of the crystal formation A is as shown in Figure 1.
Another object of the present invention also resides in offer and prepares the formula (I) compound crystal form A's
Method, including with organic solvent A dissolution type (I) compound, stir cooling crystallization, filter to obtain target crystal formation.
Another object of the present invention also resides in a kind of method for preparing the formula (I) compound crystal form A of replacement that provides, including with organic solvent B dissolution type (I) compound, adds anti-solvent A stirring and crystallizings, filter to obtain target crystal formation.
It is preferred that, the organic solvent A is selected from tetrahydrofuran and/or acetone.
It is preferred that, the organic solvent B is selected from dichloromethane and/or chloroform, and the anti-solvent A is selected from isopropyl ether, normal heptane and/or n-hexane.
Another object of the present invention also resides in the crystal formation B of offer formula (I) compound, the crystal formation is crystal formation B, and (± 0.2 °) in 2 θ of its XRPD collection of illustrative plates is to have diffraction maximum at 6.82,10.14,11.25,12.55,13.50,14.90,16.27,19.78,25.21.
It is preferred that, the XRPD collection of illustrative plates of the crystal formation B is as shown in Figure 2.
Type I compound is dissolved the present invention also aims to provide the method that one kind prepares the formula (I) compound crystal form B, including with organic solvent C, cooling crystallization is stirred, filters to obtain target crystal formation, optional, vacuum drying step is also included after filtering.
Another object of the present invention also resides in a kind of method for providing the formula of replacement (I) compound crystal form B, including dissolving type I compound with organic solvent D, anti-solvent B crystallizations are added, target crystal formation is filtered to obtain, optional, vacuum drying step is also included after filtering.
It is preferred that, the vacuum drying temperature is 20-40 DEG C, most preferably more preferably 20-30 DEG C, 25 DEG C.
It is preferred that, the organic solvent C is selected from isopropanol and/or n-butanol.
It is preferred that, the organic solvent D is selected from isopropanol, acetone and/or 2- butanone, and it is normal heptane or n-hexane that the anti-solvent B, which is selected from,.
Another object of the present invention also resides in a kind of pharmaceutical composition of offer, the crystal formation and pharmaceutically acceptable carrier comprising therapeutically effective amount.
Another object of the present invention also resides in the effect for providing above-mentioned crystal formation or pharmaceutical composition for preparing antineoplastic, it is preferred that for preparing the application in treatment lung-cancer medicament.
Crystal form purity provided by the present invention is high, and stability is good, low in hygroscopicity, good fluidity, is adapted to pharmaceutical preparation needs.
Fig. 1 is (R) -3- [1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethyoxyl] -5- [3- fluorophenyl -1- dimethyl phosphine acyl-oxygen -4- bases] pyridine -2- amine crystal formations A XRPD collection of illustrative plates；
Fig. 2 is (R) -3- [1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethyoxyl] -5- [3- fluorophenyl -1- dimethyl phosphine acyl-oxygen -4- bases] pyridine -2- amine crystal formations B XRPD collection of illustrative plates.
Embodiment 1
By in type I compound crude product 5.0g input acetone 42ml, 60 DEG C of stirring in water bath dissolve, then natural cooling stirring and crystallizing 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal formation A 4.1g.After testing, its XRPD collection of illustrative plates is as shown in Figure 1.
Embodiment 2
By in type I compound crude product 5.0g input tetrahydrofurans 150ml, 60 DEG C of stirring in water bath dissolve, then natural cooling stirring and crystallizing 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal formation A3.6g.After testing, its XRPD collection of illustrative plates coincide with Fig. 1 substantially, and all characteristic peaks are in error range.
Embodiment 3
By in type I compound crude product 5.0g input dichloromethane 30ml, then stirring and dissolving adds isopropyl ether 100ml stirring and crystallizings 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal formation A4.4g.After testing, its XRPD collection of illustrative plates coincide with Fig. 1 substantially, and all characteristic peaks are in error range.
Embodiment 4
By in type I compound crude product 5.0g input dichloromethane 30ml, then stirring and dissolving adds normal heptane 100ml stirring and crystallizings 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal formation A4.5g.After testing, its XRPD collection of illustrative plates coincide with Fig. 1 substantially, and all characteristic peaks are in error range.
Embodiment 5
By in type I compound crude product 5.0g input isopropanols 30ml, 60 DEG C of stirring in water bath dissolve, then natural cooling stirring and crystallizing 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal formation B4.3g.After testing, its XRPD collection of illustrative plates is as shown in Figure 2.
Embodiment 6
By in type I compound crude product 5.0g input isopropanols 50ml, normal heptane 150ml stirring and crystallizings 2h is then added.Filtering, 25 DEG C of vacuum drying obtain target crystal formation B 4.3g.After testing, its XRPD collection of illustrative plates coincide with Fig. 2 substantially, and all characteristic peaks are in error range.
Embodiment 7
By in type I compound crude product 5.0g input acetone 150ml, then 40 DEG C of stirring in water bath dissolvings add normal heptane 1200ml stirring and crystallizings 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal formation B 4.4g.After testing, its XRPD collection of illustrative plates coincide with Fig. 2 substantially, and all characteristic peaks are in error range.
Experimental example one, crystal formation A stability studies
Using the crystal formation prepared by the embodiment of the present invention 1 as sample, the stability of crystal formation is detected under condition of different temperatures, as a result as shown in table 1
Table 1
| Temperature | 25℃ | 45℃ | 60℃ |
| Crystal formation | A | A | A |
As seen from the above table, crystal formation A has good stability under the conditions of 25 DEG C -60 DEG C
Experimental example two, crystal formation B stability studies
Using the crystal formation prepared by the embodiment of the present invention 5 as sample, the stability of crystal formation is detected under condition of different temperatures, as a result as shown in table 2
Table 2
| Temperature | 20℃ | 30℃ | 50℃ |
| Crystal formation | B | B | B |
As seen from the above table, crystal formation B has good stability under the conditions of 20 DEG C -50 DEG C
Experimental example three, draw moist
According to《Medicine draws moist test guideline》(two J of annex Ⅺ Ⅹ of Chinese Pharmacopoeia 2010 edition) carry out draws moist test.Dry tool plug glass measuring cup (external diameter is 50mm, a height of 15mm) is taken, is placed in experiment the previous day in ± 1 DEG C of thermostatic drier of suitable 25 DEG C (placing ammonium chloride saturated solution in bottom), accurately weighed weight (m1)；Take for crystal formation of the present invention in right amount, be laid in above-mentioned measuring cup, the thickness of test sample is typically about 1mm, accurately weighed weight (m2)；Measuring cup is open, and placed 24 hours with same be placed under the conditions of above-mentioned constant temperature and humidity of bottle cap；Cover measuring cup lid, precise weighing (m3).
Draws moist test criterion is as follows：
Deliquescence：Absorb enough moisture formation liquid
Easily draw moist：X% >=15%；
Have and draw moist：2%≤X% ＜ 15%；
Slightly draw moist：0.2%≤X% ＜ 2%；
Nothing is moist almost without drawing：X% ＜ 0.2%.
According to above method, measure (R) -3- [1- (2 of the present invention, the chloro- 3- fluorophenyls of 6- bis-) ethyoxyl] -5- [3- fluorophenyl -1- dimethyl phosphine acyl-oxygen -4- bases] pyridine -2- amine crystal formation A compounds percentage weight increase be 0.3%, the percentage weight increase of crystal formation B compounds is 1.0%, show that crystal formation A of the present invention and crystal formation B slightly have and draw moist, hardly influenceed and deliquescence by high humility.
Example IV, mobility
Appropriate crystal formation A and crystal formation B of the present invention are taken, angle of repose measure is carried out.
Fixed funnel method determines angle of repose.Funnel is fixed on certain altitude H, powder is placed in funnel, it is in heaps to be that nature is flowed down, has just been released to the top of cone untill hopper outlet, determined the radius r of circular cone bottom surface, calculated angle of repose.Angle of repose=arc tg (H/r).Measurement result is arranged in table 3.
| Crystal formation | Angle of repose (°) |
| Crystal formation A | 26.4 |
| Crystal formation B | 23.6 |
As a result show, crystal formation crystal formation A of the present invention, crystal formation B has less angle of repose, illustrate that the mobility of crystal formation of the present invention is higher.
Claims (16)
- The crystal formation of formula (I) compound
- The crystal formation of formula (I) compound according to claim 1, it is characterized in that, the crystal formation is crystal formation A, and (± 0.2 °) in 2 θ of its XRPD collection of illustrative plates is to have diffraction maximum at 7.86,9.60,11.76,12.37,14.68,19.61,20.02,21.19,23.76,24.89.
- The crystal formation of formula (I) compound according to claim 2, it is characterised in that the XRPD collection of illustrative plates of the crystal formation A is as shown in Figure 1.
- The method for preparing formula (I) the compound crystal form A described in any one of claim 1 or 2, including with organic solvent A dissolution type (I) compound, stir cooling crystallization, filter to obtain target crystal formation.
- The method for preparing formula (I) the compound crystal form A described in any one of claim 1 or 2, including with organic solvent B dissolution type (I) compound, add anti-solvent A stirring and crystallizings, filter to obtain target crystal formation.
- Preparation method according to claim 4, it is characterised in that the organic solvent A is selected from tetrahydrofuran and/or acetone.
- Preparation method according to claim 5, it is characterised in that the organic solvent B is selected from dichloromethane and/or chloroform, the anti-solvent A is selected from isopropyl ether, normal heptane and/or n-hexane.
- The crystal formation of formula (I) compound according to claim 1, it is characterised in that The crystal formation is crystal formation B, and (± 0.2 °) in 2 θ of its XRPD collection of illustrative plates is to have diffraction maximum at 6.82,10.14,11.25,12.55,13.50,14.90,16.27,19.78,25.21.
- The crystal formation of formula (I) compound according to claim 8, it is characterised in that the XRPD collection of illustrative plates of the crystal formation B is as shown in Figure 2.
- The method for preparing formula (I) the compound crystal form B described in any one of claim 8 or 9, including type I compound is dissolved with organic solvent C, cooling crystallization is stirred, target crystal formation is filtered to obtain, optional, vacuum drying step is also included after filtering.
- The method for preparing formula (I) the compound crystal form B described in any one of claim 8 or 9, including type I compound is dissolved with organic solvent D, anti-solvent B crystallizations are added, target crystal formation is filtered to obtain, optional, vacuum drying step is also included after filtering.
- Preparation method according to claim 10, it is characterised in that the organic solvent C is selected from isopropanol and/or n-butanol.
- Preparation method according to claim 11, it is characterised in that the organic solvent D is selected from isopropanol, acetone and/or 2- butanone, and it is normal heptane or n-hexane that the anti-solvent B, which is selected from,.
- Preparation method according to claim 10 or 11, it is characterised in that the vacuum drying temperature is 20-40 DEG C, most preferably preferably 20-30 DEG C, 25 DEG C.
- Crystal formation and pharmaceutically acceptable carrier described in a kind of pharmaceutical composition, the claim 1-3 comprising therapeutically effective amount or claim 8-9 any one.
- Crystal formation described in claim 1-3 or claim 8-9 any one or claim 4 described pharmaceutical composition are used for the effect for preparing antineoplastic, it is preferred that for preparing treatment lung-cancer medicament.
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| CN2014103879881 | 2014-08-07 | ||
| CN201410387988 | 2014-08-07 | ||
| PCT/CN2015/086410 WO2016019910A1 (en) | 2014-08-07 | 2015-08-07 | Crystal form of anticancer compound and preparation method and use thereof |
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| CN106459111A true CN106459111A (en) | 2017-02-22 |
| CN106459111B CN106459111B (en) | 2019-05-31 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110317265A (en) * | 2018-03-28 | 2019-10-11 | 江苏豪森药业集团有限公司 | Angiomax crystal form A and preparation method thereof |
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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- 2015-08-07 WO PCT/CN2015/086410 patent/WO2016019910A1/en active Application Filing
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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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110317265A (en) * | 2018-03-28 | 2019-10-11 | 江苏豪森药业集团有限公司 | Angiomax crystal form A and preparation method thereof |
| CN110317265B (en) * | 2018-03-28 | 2023-03-10 | 江苏豪森药业集团有限公司 | Bivalirudin crystal form A and preparation method thereof |
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| WO2016019910A1 (en) | 2016-02-11 |
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