CN105566225A - Crystal forms of orally-taken mitogen-activated protein kinase inhibitor and preparation method of crystal forms - Google Patents
Crystal forms of orally-taken mitogen-activated protein kinase inhibitor and preparation method of crystal forms Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to a crystal form for treating melanoma and ovarian cancer and a preparation method of the crystal form, in particular to crystal forms of an orally-taken mitogen-activated protein kinase inhibitor and a preparation method of the crystal forms. The crystal form A and the crystal form B are good in stability and significant in process purification effect, and the solubility and hygroscopicity of the crystal form A and the crystal form B meet medication requirements. The preparation method of the crystal forms is simple and low in cost and has important value in optimization and development of the medicine in the future.
Description
Technical field
The present invention relates to chemical medicine, particularly relate to crystal formation of 5-[(4-bromo-2-fluorophenyl) is amino] the fluoro-N-of-4-(2-hydroxyl-oxethyl)-1-methyl isophthalic acid H-benzoglyoxaline-6-methane amide and preparation method thereof.
Background technology
PTS Binimetinib (MEK162) is the oral mitogen activated protein kinase of one (mitogen-activatedproteinkinase) inhibitor researched and developed by Ai Rui pharmacy (ArrayBiopharma), phase iii clinical trial is at present in the U.S., for NRAS gene mutation body melanoma, the treatment of BRAF gene mutation body melanoma and the rudimentary blood plasma ovarian cancer patients of recurrent.The chemical name of this medicine is: 5-[(4-bromo-2-fluorophenyl) is amino] the fluoro-N-of-4-(2-hydroxyl-oxethyl)-1-methyl isophthalic acid H-benzoglyoxaline-6-methane amide, its structural formula is such as formula shown in (I).
Solid chemical crystal formation is different, its solubleness can be caused different with stability, thus affect absorption and the bioavailability of medicine, and can cause the difference of clinical drug effect.But, there is no the relevant report of the crystal formation of formula (I) compound at present, therefore, be necessary to carry out comprehensive and systematic screening polymorph to formula (I) compound, select the crystal formation of the most applicable exploitation.
Two kinds of crystal formations of the formula that found (I) compound that the present inventor is surprised in research process.And stability of crystal form of the present invention is good, solubleness, draws and moistly meet medicinal requirements, and preparation method is simple, with low cost, to the optimization of this medicine following and exploitation, there is important value.
Summary of the invention
An object of the present invention is to provide the crystal formation of a kind of formula (I) compound, crystal form A.
Crystal formation Α provided by the invention, is characterized in that, its X-ray powder diffraction figure is that 20.3 ° ± 0.2 °, 28.3 ° ± 0.2 °, 11.1 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, crystal form A provided by the invention, is further characterized in that, its X-ray powder diffraction figure is that a place in 16.2 ° ± 0.2 °, 11.7 ° ± 0.2 °, 18.9 ° ± 0.2 ° or two places or three places have characteristic peak in 2theta value; Preferred crystal form A provided by the invention, is further characterized in that, its X-ray powder diffraction figure is that 16.2 ° ± 0.2 °, 11.7 ° ± 0.2 °, 18.9 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, crystal form A provided by the invention, is further characterized in that, its X-ray powder diffraction figure is that a place in 23.7 ° ± 0.2 °, 9.4 ° ± 0.2 °, 22.7 ° ± 0.2 ° or two places or three places have characteristic peak in 2theta value; Preferred crystal form A provided by the invention, is further characterized in that, its X-ray powder diffraction figure is that 23.7 ° ± 0.2 °, 9.4 ° ± 0.2 °, 22.7 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, crystal form A provided by the invention, is further characterized in that, its X-ray powder diffraction figure substantially as shown in Figure 1.
Crystal form A provided by the invention, is characterized in that, starts to occur endotherm(ic)peak near being heated to 221 DEG C, and its differential scanning calorimetric thermogram substantially as shown in Figure 2.
Crystal form A provided by the invention, is characterized in that, when being heated to 200 DEG C, have the weight loss gradient of about 0.7%, its thermogravimetric analysis figure substantially as shown in Figure 3.
Further, crystal form A provided by the invention, is characterized in that, crystal form A is anhydride.
Another object of the present invention is to provide the preparation method of crystal form A, it is characterized in that, formula (I) compound is added positive solvent and adds obtained by anti-solvent or add in suitable crystallization solvent, lowering the temperature or suspend to stir by volatilizing, heating obtains.
Further, the positive solvent wherein used by anti-solvent interpolation comprises alcohols, ethers, ketone, alkyl nitrile, amides, and anti-solvent comprises alcohols, ester class, haloalkane hydro carbons, water.Further, positive solvent includes but not limited to alcohols, ethers, ketone, acetonitrile, dimethyl formamide, and anti-solvent includes but not limited to ethanol, ethyl acetate, methylene dichloride, water.
Stirring crystallization solvent used of wherein volatilizing, heat cooling or suspend comprises the mixed solvent of one or more solvents in alcohols, ketone, haloalkane hydro carbons, alkanes, ethers, arene, ester class, carboxylic-acid, alkyl nitrile, water, amides.Wherein, alcohols includes but not limited to methyl alcohol, ethanol, Virahol, ketone includes but not limited to methylethylketone, mibk, halogenated alkane includes but not limited to methylene dichloride, trichloromethane, alkane includes but not limited to normal heptane, octane, ethers includes but not limited to methyl tertiary butyl ether, arene includes but not limited to toluene, dimethylbenzene, ester class includes but not limited to ethyl acetate, isopropyl acetate, carboxylic-acid includes but not limited to acetic acid, alkyl nitrile includes but not limited to acetonitrile, and amides includes but not limited to dimethyl formamide.
Another object of the present invention is to provide the crystal formation of a kind of formula (I) compound, crystal form B.
Crystal formation Β provided by the invention, is characterized in that, its X-ray powder diffraction figure is that 25.3 ° ± 0.2 °, 18.7 ° ± 0.2 °, 16.8 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, crystal form B provided by the invention, is further characterized in that, its X-ray powder diffraction figure is that a place in 17.2 ° ± 0.2 °, 29.7 ° ± 0.2 °, 32.5 ° ± 0.2 ° or two places or three places have characteristic peak in 2theta value; Preferred crystal form A provided by the invention, is further characterized in that, its X-ray powder diffraction figure is that 17.2 ° ± 0.2 °, 29.7 ° ± 0.2 °, 32.5 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, crystal form B provided by the invention, is further characterized in that, its X-ray powder diffraction figure is that a place in 25.7 ° ± 0.2 °, 21.5 ° ± 0.2 °, 23.0 ° ± 0.2 ° or two places or three places have characteristic peak in 2theta value; Preferred crystal form A provided by the invention, is further characterized in that, its X-ray powder diffraction figure is that 25.7 ° ± 0.2 °, 21.5 ° ± 0.2 °, 23.0 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, crystal form B provided by the invention, is further characterized in that, its X-ray powder diffraction figure substantially as shown in Figure 4.
Crystal form B provided by the invention, is characterized in that, starts to occur endotherm(ic)peak near being heated to 89 DEG C, and its differential scanning calorimetric thermogram substantially as shown in Figure 5.
Crystal form B provided by the invention, is characterized in that, when being heated to 120 DEG C, have the weight loss gradient of about 21.6%, its thermogravimetric analysis figure substantially as shown in Figure 6.
Further, crystal form B provided by the invention, is characterized in that, crystal form B is oxalic acid solvate.
Another object of the present invention is to provide the preparation method of crystal form B, comprises the dissolution of solid of (I) compound in acetic acid, adds toluene solvant by anti-solvent additive process, and stirring and crystallizing obtains.
Further, medicinal compositions provided by the invention, is characterized in that, described medicinal compositions includes the crystal form A of effective amount or crystal form B or its mixture and pharmaceutically acceptable vehicle.
Further, in medicinal compositions of the present invention, the crystal form A of formula (I) compound or crystal form B or its mixture can be used for preparing the purposes in Therapeutic cancer medicine, particularly melanoma and ovarian cancer preparation.
Beneficial effect of the present invention is:
There is no the crystal formation of patent or reported in literature formula (I) compound at present, the present inventor, by through research, breaches this difficult problem, have found the crystal formation that two kinds are applicable to exploitation.
Stability of crystal form provided by the invention is good, and technique refining effect is remarkable.Can avoid well occurring in medicament storage and performance history to turn brilliant, thus avoid the change of bioavailability and drug effect.
Crystal formation provided by the invention draws moist lower, meet bioavailability and drug effect requirement, without the need to special drying conditions in preparation technology, simplify preparation technology and the aftertreatment technology of medicine, and be not subject to humidity effect, require not harsh to condition of storage, be convenient to long storage periods, greatly reduce the cost of material storing and quality control aspect, there is very strong economic worth.
Accompanying drawing explanation
Fig. 1 is the XRPD figure of crystal form A
Fig. 2 is the DSC figure of crystal form A
Fig. 3 is the TGA figure of crystal form A
Fig. 4 is the XRPD figure of crystal form B
Fig. 5 is the DSC figure of crystal form B
Fig. 6 is the TGA figure of crystal form B
Fig. 7 is crystal form B
1hNMR schemes
Fig. 8 is the DVS figure of crystal form A
Fig. 9 is that under crystal form A different condition, XRPD comparison diagram (is followed successively by the XRPD before test from top to bottom, the XRPD of 11 months is placed under 5 DEG C of conditions, 25 DEG C, place the XRPD of 11 months under 60%RH condition, 40 DEG C, place the XRPD of 11 months under 75%RH condition)
Figure 10 is XRPD comparison diagram under crystal form B different condition (is followed successively by the XRPD before test from top to bottom, places the XRPD in 2 week under room temperature condition)
Embodiment
Below will set forth the present invention further by specific embodiment, but be not limited to protection scope of the present invention.Those skilled in the art can make improvements preparation method and use instrument in right, and these improvement also should be considered as protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
In following embodiment, the described test method condition that conveniently conditioned disjunction manufacturer advises usually is implemented.Initial formula (I) compound can be obtained by known preparation method, such as, prepare according to patent CN101633645B.
Being explained as follows of abbreviation used in the present invention:
XRPD:X ray powder diffraction
DSC: differential scanning calorimetric analysis
TGA: thermogravimetric analysis
1hNMR: liquid nucleus magnetic hydrogen spectrum
DVS: dynamic water is adsorbed
X-ray powder diffraction figure of the present invention gathers on PanalyticalEmpyreanX ray powder diffractometer.The method parameter of X-ray powder diffraction of the present invention is as follows:
X ray reflection parameter: Cu, K α
Kα1
1.540598；Kα2
1.544426
K α 2/K α 1 intensity: 0.50
Voltage: 45 KVs (kV)
Electric current: 40 milliampere(mA)s (mA)
Sweep limit: from 3.0 to 40.0 degree
Differential scanning calorimetric analysis of the present invention (DSC) figure gathers on TAQ2000.The method parameter of differential scanning calorimetric analysis of the present invention (DSC) is as follows:
Scanning speed: 10 DEG C/min
Shielding gas: nitrogen
Thermogravimetric analysis of the present invention (TGA) figure gathers on TAQ5000.The method parameter of thermogravimetric analysis of the present invention (TGA) is as follows:
Scanning speed: 10 DEG C/min
Shielding gas: nitrogen
Dynamic water absorption (DVS) figure of the present invention gathers on the Intrinsic dynamic water adsorption instrument produced by SMS company (SurfaceMeasurementSystemsLtd.).The method parameter of described dynamic water adsorption instrument is as follows:
Temperature: 25 DEG C
Carrier gas, flow velocity: N
2, 200 ml/min
Unit time quality change: 0.002%/minute
RH range: 0%RH-95%RH
Embodiment 1
The preparation method of formula (I) compound crystal form A:
By formula (I) compound dissolution of 10.2mg in 1.8mL methyl alcohol, filtered, obtain clear liquid and be positioned in 1.5mL bottle by the nylon filter of 0.45 μm, at room temperature volatilization obtains crystalline solid form A.
The X-ray powder diffraction data of the crystal formation that the present embodiment obtains are as shown in table 1, and its XRPD schemes as Fig. 1.
Table 1
Embodiment 2
The preparation method of formula (I) compound crystal form A:
Add in 1.2mL tetrahydrofuran (THF) by formula (I) compound of 12.0mg, at room temperature stir three days with the speed of 500r/min, the centrifugal solid that obtains is crystal form A.
The X-ray powder diffraction data of the crystal formation that the present embodiment obtains are as shown in table 2.
Table 2
Embodiment 3
The preparation method of formula (I) compound crystal form A:
By formula (I) compound dissolution of 17.0mg in 0.1mL dimethyl formamide, then slowly drip the water of 0.2mL while stirring, continue stirring two days, the centrifugal solid that obtains is crystal form A.
The X-ray powder diffraction data of the crystal formation that the present embodiment obtains are as shown in table 3.
Table 3
Embodiment 4
Formula (I) compound crystal form A draws moist experiment:
Under 25 DEG C of conditions, get crystal form A of the present invention and be about 10mg and carry out dynamic water absorption (DVS) and test it and draw moist.Experimental result is as shown in table 4.Draw the DVS figure of moist experimental result as shown in Figure 8.
Table 4
About drawing moist feature description and drawing defining (Chinese Pharmacopoeia version annex XIXJ medicine in 2010 draws moist test direction principle, experiment condition: 25 DEG C ± 1 DEG C, 80% relative humidity) of moist weightening finish:
Deliquescence: absorb enough water and divide formation liquid
Have draw moist: draw wet weightening finish and be not less than 15%
Have draw moist: draw wet weightening finish and be less than 15% but be not less than 2%
Slightly draw moist: draw wet weightening finish and be less than 2% but be not less than 0.2%
Nothing or almost moist without drawing: draw wet weightening finish and be less than 0.2%
Result shows, weightening finish 0.14% after crystal form A of the present invention balances under 80% humidity, belongs to nothing or almost moist without drawing.This character shows that this crystal formation is not subject to humidity effect or deliquescence, facilitates its long storage periods to place.
Embodiment 5
The stability experiment of formula (I) compound crystal form A:
Get crystal form A sample and be about that 10mg is uncovered is positioned over 5 DEG C respectively, under (25 DEG C, 60%RH) steady in a long-term and acceleration for stabilization (40 DEG C, 75%RH) condition, within 11 months, survey XRPD and the HPLC purity of crystal form A sample.Experimental result is as shown in table 5.Under crystal form A different condition, XRPD comparison diagram such as Fig. 9 (is followed successively by the XRPD before test from top to bottom, the XRPD of 11 months is placed under 5 DEG C of conditions, 25 DEG C, place the XRPD of 11 months under 60%RH condition, 40 DEG C, place the XRPD of 11 months under 75%RH condition).
Table 5
| Initial crystal formation | Condition | Initial purity | Storage period | Crystal formation | Chemical purity |
| Crystal form A | 5℃ | 98.94％ | November | Crystal form A remains unchanged | 98.84％ |
| Crystal form A | 25℃、60％RH | 98.94％ | November | Crystal form A remains unchanged | 98.85％ |
| Crystal form A | 40℃、75％RH | 98.94％ | November | Crystal form A remains unchanged | 98.95％ |
Result shows, formula (I) compound crystal form A is at 5 DEG C, and under (25 DEG C, 60%RH) steady in a long-term and acceleration for stabilization (40 DEG C, 75%RH) condition, in put procedure, sample is stablized, and purity is almost constant.
Embodiment 6
The preparation method of formula (I) compound crystal form B:
By the dissolution of solid of 249.3mg formula (I) compound in 4mL acetic acid, then slowly drip the toluene of 13mL while stirring, stir three days, filter and obtain crystal form B.
The X-ray powder diffraction data of the crystal formation that the present embodiment obtains are as shown in table 6.Its XRPD schemes as Fig. 4.
Table 6
Embodiment 7
The preparation method of formula (I) compound crystal form B:
By the dissolution of solid of 15.2mg formula (I) compound in 0.2mL acetic acid, then slowly drip the toluene of 0.5mL while stirring, stirring is spent the night, and filters and obtains crystal form B.
The X-ray powder diffraction data of the crystal formation that the present embodiment obtains are as shown in table 7.Its DSC schemes as Fig. 5, and its TGA schemes as Fig. 6.Its
1hNMR schemes as Fig. 7,
1hNMR data are as follows:
1HNMR(400MHz,DMSO-d6)δ11.94(s,2H),11.64(s,1H),8.38(s,1H),7.83(s,1H),7.71(s,1H),7.43(d,J＝13.2Hz,1H),7.11(d,J＝9.4Hz,1H),6.39(td,J＝9.0,3.2Hz,1H),4.69(s,1H),3.87(d,J＝25.0Hz,5H),3.54(s,2H),1.91(s,5H)。
Table 7
Embodiment 8
The preparation method of formula (I) compound crystal form B:
By the dissolution of solid of 109.1mg formula (I) compound in 1.8mL acetic acid, then slowly drip the toluene of 6.4mL while stirring, stirring is spent the night, and filters and obtains crystal form B.
The X-ray powder diffraction data of the crystal formation that the present embodiment obtains are as shown in table 8.
Table 8
Embodiment 9
The stability experiment of formula (I) compound crystal form B:
Under getting that crystal form B sample is uncovered and being positioned over room temperature condition, after fortnight, survey XRPD and the HPLC purity of crystal form B sample.Experimental result is as shown in table 9.Under crystal form B different condition, XRPD comparison diagram is as Figure 10 (be followed successively by the XRPD before test from top to bottom, place the XRPD in 2 week under room temperature condition).
Table 9
| Initial crystal formation | Condition | Initial purity | Storage period | Crystal formation | Chemical purity 12--> |
| Crystal form B | Room temperature | 99.53％ | 2 week | Crystal form B remains unchanged | 99.52％ |
Result shows, formula (I) compound crystal form B at ambient temperature, in put procedure, stablize, and purity is almost constant by sample.
Embodiment 10
The purity research of formula (I) compound crystal form B:
Be dissolved in 0.2mL acetic acid by 10.0mg formula (I) compound initial sample, then slowly drip the toluene of 0.5mL while stirring, stirring is spent the night, and filters and prepares crystal form B.The purity of the crystal form B that formula (I) compound initial sample and the present embodiment prepare is detected respectively with high performance liquid chromatograph.Result is as shown in table 10:
Table 10
Result shows, crystal form B significantly improves the chemical purity of sample and the plurality of impurities effectively eliminated in sample.
Above-described embodiment, only for technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences done according to spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (23)
1. a crystal formation Α for formula (I) compound,
It is characterized in that, its X-ray powder diffraction figure is that 20.3 ° ± 0.2 °, 28.3 ° ± 0.2 °, 11.1 ° ± 0.2 ° place has characteristic peak in 2theta value.
2. crystal form A according to claim 1, is further characterized in that, its X-ray powder diffraction figure is that a place in 16.2 ° ± 0.2 °, 11.7 ° ± 0.2 °, 18.9 ° ± 0.2 ° or two places or three places have characteristic peak in 2theta value.
3. crystal form A according to claim 2, is further characterized in that, its X-ray powder diffraction figure is that 16.2 ° ± 0.2 °, 11.7 ° ± 0.2 °, 18.9 ° ± 0.2 ° place has characteristic peak in 2theta value.
4. the crystal form A according to any one of claim 1-3, is further characterized in that, its X-ray powder diffraction figure is that a place in 23.7 ° ± 0.2 °, 9.4 ° ± 0.2 °, 22.7 ° ± 0.2 ° or two places or three places have characteristic peak in 2theta value.
5. crystal form A according to claim 4, is further characterized in that, its X-ray powder diffraction figure is that 23.7 ° ± 0.2 °, 9.4 ° ± 0.2 °, 22.7 ° ± 0.2 ° place has characteristic peak in 2theta value.
6. crystal form A according to claim 1, is characterized in that, its X-ray powder diffraction figure is substantially consistent with Fig. 1.
7. the crystal form A according to any one of claim 1-6, is characterized in that: described crystal form A is anhydride.
8. a preparation method of formula (I) the compound crystal form A as described in any one of claim 1-7, is characterized in that, preparation method comprises and formula (I) compound added positive solvent and adds obtained crystal form A by anti-solvent; Described positive solvent comprises alcohols, ethers, ketone, alkyl nitrile, amides, and described anti-solvent comprises alcohols, ester class, haloalkane hydro carbons, water.
9. preparation method according to claim 8, is characterized in that, described positive solvent comprises alcohols, ethers, ketone, acetonitrile, dimethyl formamide, and described anti-solvent comprises ethanol, ethyl acetate, methylene dichloride, water.
10. the preparation method of formula (I) the compound crystal form A as described in any one of claim 1-7, it is characterized in that, preparation method comprises and adds in crystallization solvent by formula (I) compound, by volatilization, heating cooling or the obtained crystal form A of the stirring that suspends, described crystallization solvent is the mixed solvent of one or more solvents.
11. preparation methods according to claim 10, it is characterized in that, described crystallization solvent comprises the mixing of one or more solvents of alcohols, ketone, haloalkane hydro carbons, alkanes, ethers, arene, ester class, carboxylic-acid, alkyl nitrile, water, amides.
12. preparation methods according to claim 11, it is characterized in that, described alcohols is methyl alcohol, ethanol, Virahol, and described ketone is methylethylketone, mibk, described halogenated alkane is methylene dichloride, trichloromethane, described alkane is normal heptane, octane, and described ethers is methyl tertiary butyl ether, and described arene is toluene, dimethylbenzene, described ester class is ethyl acetate, isopropyl acetate, described carboxylic-acid is acetic acid, and described alkyl nitrile is acetonitrile, and described amides is dimethyl formamide.
The crystal formation Β of 13. 1 kinds of formula (I) compounds, is characterized in that, its X-ray powder diffraction figure is that 25.3 ° ± 0.2 °, 18.7 ° ± 0.2 °, 16.8 ° ± 0.2 ° place has characteristic peak in 2theta value.
14. crystal form Bs according to claim 13, are further characterized in that, its X-ray powder diffraction figure is that a place in 17.2 ° ± 0.2 °, 29.7 ° ± 0.2 °, 32.5 ° ± 0.2 ° or two places or three places have characteristic peak in 2theta value.
15. crystal form Bs according to claim 14, are further characterized in that, its X-ray powder diffraction figure is that 17.2 ° ± 0.2 °, 29.7 ° ± 0.2 °, 32.5 ° ± 0.2 ° place has characteristic peak in 2theta value.
16. crystal form Bs according to any one of claim 13-15, are further characterized in that, its X-ray powder diffraction figure is that a place in 25.7 ° ± 0.2 °, 21.5 ° ± 0.2 °, 23.0 ° ± 0.2 ° or two places or three places have characteristic peak in 2theta value.
17. crystal form Bs according to any one of claim 16, be further characterized in that, its X-ray powder diffraction figure is that 25.7 ° ± 0.2 °, 21.5 ° ± 0.2 °, 23.0 ° ± 0.2 ° place has characteristic peak in 2theta value.
18. crystal form Bs according to claim 13, is characterized in that, its X-ray powder diffraction figure is substantially consistent with Fig. 4.
19. crystal form Bs according to any one of claim 13-18, is characterized in that: described crystal form B is oxalic acid solvate.
The preparation method of 20. 1 kinds of formula (I) compound crystal form B as described in any one of claim 13-19, it is characterized in that, preparation method comprises the dissolution of solid of (I) compound in acetic acid, add toluene solvant by anti-solvent additive process, stirring and crystallizing obtains crystal form B.
21. 1 kinds of medicinal compositionss, described medicinal compositions includes the crystal form A described in claim 1-7 any one of effective amount or the crystal form B described in claim 13-19 any one or both mixtures and pharmaceutically acceptable vehicle.
22. medicinal compositionss according to claim 21, is characterized in that, the described crystal form A described in claim 1-7 any one or the crystal form B described in claim 13-19 any one or both mixtures are for the preparation of Therapeutic cancer medicine.
23. medicinal compositionss according to claim 22, it is characterized in that, the described crystal form A described in claim 1-7 any one or the crystal form B described in claim 13-19 any one or both mixtures are for the preparation of the purposes in treatment melanoma and ovarian cancer preparation.
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| CN101486682A (en) * | 2002-03-13 | 2009-07-22 | 阵列生物制药公司 | N3 alkylated benzimidazole derivatives as MEK inhibitors |
| WO2013142182A2 (en) * | 2012-03-20 | 2013-09-26 | Novartis Pharma Ag | Combination therapy |
| WO2014063024A1 (en) * | 2012-10-19 | 2014-04-24 | Novartis Ag | Preparation of and formulation comprising a mek inhibitor |
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| CN101486682A (en) * | 2002-03-13 | 2009-07-22 | 阵列生物制药公司 | N3 alkylated benzimidazole derivatives as MEK inhibitors |
| WO2013142182A2 (en) * | 2012-03-20 | 2013-09-26 | Novartis Pharma Ag | Combination therapy |
| WO2014063024A1 (en) * | 2012-10-19 | 2014-04-24 | Novartis Ag | Preparation of and formulation comprising a mek inhibitor |
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