CN106661064A - New crystal form of anticancer compound, preparation method and use thereof - Google Patents
New crystal form of anticancer compound, preparation method and use thereof Download PDFInfo
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- A61K31/66—Phosphorus compounds
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- 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
Disclosed are a crystal form of an anticancer compound (R)-3-[1-(2, 6-dichloro-3-fluorophenyl) ethoxy]-5-[3-fluorophenyl-1-dimethyl phosphine acyl-oxy-4-yl] pyridine-2-amine and preparation method thereof. The structural formula of the crystal form is as represented by formula I. The crystal form has a stable property, a high purity, no hygroscopicity and high bioavailability, and meets requirements for pharmaceutical preparation.
Description
The present invention relates to field of medicine and chemical technology, specifically related to a kind of crystal formation of anticancer compound (R) -3- [1- (2,6- bis- chloro- 3- fluorophenyls) 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 6 500 to 11 000, 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 type I compound, (± 0.2 °) in 2 θ of the crystal formation XRPD collection of illustrative plates is to show diffraction maximum at 6.63,7.64,10.38,11.38,12.07,13.23,15.48,16.90,
It is preferred that, (± 0.2 °) also in 2 θ of the crystal formation XRPD collection of illustrative plates is to show diffraction maximum at 19.47,20.06,20.83,22.43,24.26,26.18,29.74.
Particularly preferred, the crystal formation XRPD collection of illustrative plates is as shown in Figure 1.
Crystal formation of the present invention illustrates that sample is free of the crystallization water or adsorption solvent through thermogravimetric analysis (TGA), display sample from room temperature to 220 DEG C of holding constant weights.Subsequent sample starts weightlessness, has slowed down in about 400 DEG C of weightlessness, to 700 DEG C of weightlessness about 62% to 260 DEG C or so sample weight loss acutely.
Crystal formation of the present invention scans thermometric analysis (DSC) through differential, is shown in endothermic peak in the range of 180 DEG C~185 DEG C, and has at 182 ± 1 DEG C sharp absworption peak.
Type I compound is dissolved the present invention also aims to provide a kind of method for preparing the crystal formation, including with organic solvent, cooling crystallization is stirred, filters to obtain target crystal formation.
Another object of the present invention also resides in a kind of method for preparing the crystal formation of replacement that provides, including dissolves type I compound with organic solvent, adds anti-solvent stirring and crystallizing, filters to obtain target crystal formation.
Further, in above-mentioned preparation process, drying steps are also included after crystallization filtering, drying temperature is more than 25 DEG C, preferably more than 70 DEG C, more preferably more than 80 DEG C.
It is preferred that, the organic solvent is selected from acetonitrile, ethyl acetate and/or butyl acetate.
It is preferred that, the anti-solvent is selected from isopropyl ether, normal heptane and/or n-hexane.
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 purposes for providing the crystal formation or described pharmaceutical composition in antineoplastic is prepared
Crystal form purity provided by the present invention is high, and stability is good, and without drawing moist, bioavilability is high, is adapted to pharmaceutical preparation needs.
Fig. 1 is the XRPD collection of illustrative plates of the present invention (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.
Fig. 2 is the thermogravimetric analysis figure (TGA) of the present invention (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.
Fig. 3 is the differential scanning calorimeter figure (DSC) of the present invention (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.
Embodiment 1
By in type I compound crude product 5.0g input acetonitriles 70ml, 70 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 3.1g, and 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 ethyl acetate 100ml, 65 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 3.5g, after testing, and 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 ethyl acetate 175ml, then 60 DEG C of stirring in water bath dissolvings add isopropyl ether stirring and crystallizing 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal formation 4.3g, after testing, and 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 ethyl acetate 175ml, then 60 DEG C of stirring in water bath dissolvings add normal heptane stirring and crystallizing 2h.Filtering, 25 DEG C of vacuum drying obtain target crystal formation 4.7g, after testing, and 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 acetone 42ml, 60 DEG C of stirring in water bath dissolve, then natural cooling stirring and crystallizing 2h.Filtering, 80 DEG C of vacuum drying, 18 hours target crystal formation 4.2g derived above.After testing, its XRPD collection of illustrative plates coincide with Fig. 1 substantially, and all characteristic peaks are in error range.
Experimental example one, THERMAL STABILITY
Appropriate crystal formation of the present invention is taken, is respectively placed under condition of different temperatures, is sampled after 18 hours, detects its X-ray powder diffraction, as a result as shown in table 1：
Table 1
As seen from the above table, the present invention (R) -3- [1- (2, the chloro- 3- fluorophenyls of 6- bis-) ethyoxyl] -5- [3- fluorophenyl -1- dimethyl phosphine acyl-oxygen -4- bases] pyridine -2- amine crystal formation is under condition of different temperatures, its X-ray powder diffraction collection is without significant change, show that crystal formation does not change, show good thermal stability.
Experimental example two, influence factor experiment
Appropriate crystal formation of the present invention is taken, is respectively placed under the conditions of 60 DEG C of high temperature, high humidity RH92.5%, strong light 4500lx, in the 0th, sampling in 5,10 days, the loss on drying of sample, maximum single miscellaneous, always miscellaneous, isomers and content situation, testing result such as table 2 is detected.
Table 2
Experimental example three, accelerated test
Appropriate crystal formation of the present invention is taken, under conditions of being placed in temperature for 40 DEG C ± 2 DEG C, relative humidity 75% ± 5%, is placed 6 months.Sampled respectively at the 0th, 1,2,3, June, detect loss on drying, maximum single miscellaneous, total miscellaneous, isomers and the content situation of sample, testing result such as table 3.
Table 3
Experimental example four, long term test
Appropriate crystal formation of the present invention is taken, under conditions of being placed in temperature for 30 DEG C ± 2 DEG C, relative humidity 65% ± 5%, is placed 24 months.Respectively at the 0th, sampling in 3,6,9,12,18,24 months, detect loss on drying, maximum single miscellaneous, total miscellaneous, isomers and the content situation of sample, testing result such as table 4.
Table 4
From table 2-4, (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-form compounds high temperature, high humidity, strong light and accelerate 6 months, long-term 24 months experiment in, its every Testing index has no significant change, show that sample quality is stably and controllable, have good stability, convenient storage and transport are highly suitable as raw material and prepared for pharmaceutical preparation.
Experimental example five, 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 and fitted for crystal formation of the present invention
Amount, is 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-form compounds percentage weight increase be 0.02%, show that crystal formation of the present invention is moist without drawing, hardly influenceed and deliquescence by high humility.
Experimental example six, dissolubility
By Chinese Pharmacopoeia two note on the use experiments of version in 2010.The crystal formation of the present invention for being ground into fine powder is weighed, in the solvent for being placed in 25 DEG C of ± 2 DEG C of certain capacities, every strength shaking in 5 minutes 30 seconds；When observing the dissolving situation in 30 minutes, such as invisible particles of solute, that is, it is considered as and is completely dissolved.It the results are shown in Table 5.
Table 5
| Solvent | Example weight (g) | Solvent load (ml) | Dissolution phenomena | Conclusion |
| Methanol | 0.1 | 0.2 | It is completely dissolved | It is readily soluble |
| Acetone | 0.1 | 4.0 | It is completely dissolved | It is slightly molten |
| 0.1mol/L hydrochloric acid | 0.1 | 2.4 | It is completely dissolved | Dissolving |
As shown in Table 5, (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-form compounds have high-dissolvability, show that it has high bioavilability.
Claims (10)
- The crystal formation of type I compound, it is characterised in that (± 0.2 °) in 2 θ of the crystal formation XRPD collection of illustrative plates is to show diffraction maximum at 6.63,7.64,10.38,11.38,12.07,13.23,15.48,16.90,
- Crystal formation according to claim 1, it is characterised in that (± 0.2 °) also in 2 θ of the crystal formation XRPD collection of illustrative plates is to show diffraction maximum at 19.47,20.06,20.83,22.43,24.26,26.18,29.74.
- Crystal formation according to claim 1, it is characterised in that the crystal formation XRPD collection of illustrative plates is as shown in Figure 1.
- The method for preparing crystal formation described in claim 1-3 any one, including type I compound is dissolved with organic solvent, cooling crystallization is stirred, target crystal formation is filtered to obtain.
- The method for preparing crystal formation described in claim 1-3 any one, including type I compound is dissolved with organic solvent, anti-solvent stirring and crystallizing is added, target crystal formation is filtered to obtain.
- Preparation method according to any one of claim 4 or 5, it is characterised in that also include drying steps after filtering, it is preferred that drying temperature is more than 20 DEG C, preferably more than 70 DEG C, more preferably more than 80 DEG C.
- Preparation method according to any one of claim 4 or 5, it is characterised in that the organic solvent is selected from acetonitrile, ethyl acetate and/or butyl acetate.
- Preparation method according to claim 5, it is characterised in that the anti-solvent choosing From isopropyl ether, normal heptane and/or n-hexane.
- A kind of pharmaceutical composition, crystal formation and pharmaceutically acceptable carrier described in the claim 1-3 any one comprising therapeutically effective amount.
- The purposes of crystal formation or claim 9 described pharmaceutical composition in antineoplastic is prepared described in claim 1-3 any one, it is preferred that the tumour is lung cancer.
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| CN201410387596 | 2014-08-07 | ||
| CN2014103875965 | 2014-08-07 | ||
| PCT/CN2015/086408 WO2016019909A1 (en) | 2014-08-07 | 2015-08-07 | New crystal form of anticancer compound, preparation method and use thereof |
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| CN106661064A true CN106661064A (en) | 2017-05-10 |
| CN106661064B CN106661064B (en) | 2019-10-15 |
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Cited By (1)
| 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 |
|---|---|---|---|---|
| EP1603570A2 (en) * | 2003-02-26 | 2005-12-14 | Sugen, Inc. | 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/CN2015/086408 patent/WO2016019909A1/en active Application Filing
- 2015-08-07 CN CN201580034413.4A patent/CN106661064B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1603570A2 (en) * | 2003-02-26 | 2005-12-14 | Sugen, Inc. | Aminoheteroaryl compounds as protein kinase inhibitors |
| CN103265477A (en) * | 2003-02-26 | 2013-08-28 | 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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| CN106661064B (en) | 2019-10-15 |
| WO2016019909A1 (en) | 2016-02-11 |
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