WO2016131406A1

WO2016131406A1 - Crystal form of oral mitogen-activated protein kinase inhibitor and preparation method thereof

Info

Publication number: WO2016131406A1
Application number: PCT/CN2016/073770
Authority: WO
Inventors: 陈敏华; 张炎锋; 陆飞; 张晓宇
Original assignee: 苏州晶云药物科技有限公司
Priority date: 2015-02-16
Filing date: 2016-02-14
Publication date: 2016-08-25
Also published as: CN105566225A

Abstract

The present invention relates to a crystal form for treating melanoma and ovarian cancer and a preparation method thereof. The crystal form A and the crystal form B provided by the present invention have a good stability, the process purification effect thereof is significant, and the solubility and hygroscopicity thereof meet medicinal requirements. The preparation method of the crystal form is simple, the cost is low, and the future optimization and development of the drug has significant value.

Description

Crystal form of oral mitogen-activated protein kinase inhibitor and preparation method thereof

Technical field

The present invention relates to the field of chemical medicine, in particular to 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzene The crystal form of imidazolium-6-carboxamide and a preparation method thereof.

Background technique

Binimetinib (MEK162), an anticancer drug, is an oral mitogen-activated protein kinase inhibitor developed by Array Biopharma and is currently in Phase III clinical trials in the United States for the NRAS gene. Treatment of mutant melanoma, BRAF mutant melanoma, and patients with recurrent low-grade plasma ovarian cancer. The chemical name of the drug is: 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole- 6-carboxamide, the structural formula of which is represented by formula (I).

Different crystal forms of solid chemical drugs can cause differences in their solubility and stability, which affect the absorption and bioavailability of drugs, and can lead to differences in clinical efficacy. However, there is currently no correlation report on the crystal form of the compound of formula (I), and therefore it is necessary to perform a comprehensive systematic polymorphic screening of the compound of formula (I) to select the crystal form most suitable for development.

The inventors of the present invention surprisingly discovered two crystal forms of the compound of formula (I) during the course of the study. Moreover, the crystal form of the invention has good stability, solubility and wettability meet the requirements of medicinal requirements, and the preparation method is simple and the cost is low, which is of great value for the optimization and development of the drug in the future.

Summary of the invention

It is an object of the present invention to provide a crystalline form of the compound of formula (I), Form A.

The crystalline germanium provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 20.3 ° ± 0.2 °, 28.3 ° ± 0.2 °, and 11.1 ° ± 0.2 °.

Further, the crystal form A provided by the present invention is further characterized by an X-ray powder diffraction pattern of one or two of 2theta values of 16.2°±0.2°, 11.7°±0.2°, and 18.9°±0.2°. There are characteristic peaks at or at three locations; preferred crystal form A provided by the present invention is further characterized by an X-ray powder diffraction pattern having a value of 16.2° ± 0.2°, 11.7 ° ± 0.2 °, and 18.9 ° ± 0.2 °. There are characteristic peaks.

Further, the crystal form A provided by the present invention is further characterized by an X-ray powder diffraction pattern of one or two of 2theta values of 23.7°±0.2°, 9.4°±0.2°, and 22.7°±0.2°. There are characteristic peaks at or at three locations; preferred crystal form A provided by the present invention is further characterized by an X-ray powder diffraction pattern having a 2theta value of 23.7° ± 0.2°, 9.4 ° ± 0.2 °, 22.7 ° ± 0.2 °. There are characteristic peaks.

Further, the crystal form A provided by the present invention is further characterized in that the X-ray powder diffraction pattern is basically as shown in FIG. 1 . Shown.

The crystal form A provided by the present invention is characterized in that an endothermic peak begins to appear near the temperature of 221 ° C, and the differential scanning calorimetry chart is basically as shown in FIG. 2 .

The crystal form A provided by the present invention is characterized in that it has a weight loss gradient of about 0.7% when heated to 200 ° C, and its thermogravimetric analysis chart is basically as shown in FIG. 3 .

Further, the crystal form A provided by the present invention is characterized in that the crystal form A is an anhydride.

Another object of the present invention is to provide a process for the preparation of Form A, characterized in that a compound of the formula (I) is added to a positive solvent and added by an anti-solvent addition or added to a suitable crystallization solvent, and the temperature is lowered by volatilization, heating or Prepared by suspension stirring.

Further, the positive solvent used in the anti-solvent addition includes alcohols, ethers, ketones, hydrocarbyl nitriles, and amides, and the anti-solvents include alcohols, esters, halogenated alkanes, and water. Further, positive solvents include, but are not limited to, alcohols, ethers, ketones, acetonitrile, dimethylformamide, and antisolvents include, but are not limited to, ethanol, ethyl acetate, dichloromethane, and water.

The crystallization solvent used for volatilization, heating, cooling or suspension stirring includes alcohols, ketones, halogenated alkanes, alkanes, ethers, aromatic hydrocarbons, esters, carboxylic acids, hydrocarbyl nitriles, water, amides. A mixed solvent of one or more solvents. Among them, alcohols include, but are not limited to, methanol, ethanol, isopropanol, ketones including but not limited to methyl ethyl ketone, methyl isobutyl ketone, halogenated alkanes including but not limited to dichloromethane, chloroform, alkanes including but not limited to Heptane, octane, ethers include, but are not limited to, methyl tert-butyl ether, aromatic hydrocarbons including, but not limited to, toluene, xylene, esters including but not limited to ethyl acetate, isopropyl acetate, carboxylic acids including But not limited to acetic acid, hydrocarbyl nitriles include, but are not limited to, acetonitrile, and amides include, but are not limited to, dimethylformamide.

Another object of the invention is to provide a crystalline form of the compound of formula (I), Form B.

The crystalline germanium provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 25.3 ° ± 0.2 °, 18.7 ° ± 0.2 °, and 16.8 ° ± 0.2 °.

Further, the crystal form B provided by the present invention is further characterized by an X-ray powder diffraction pattern of one or two of 2theta values of 17.2°±0.2°, 29.7°±0.2°, and 32.5°±0.2°. There are characteristic peaks at or at three locations; preferred crystal form A provided by the present invention is further characterized by an X-ray powder diffraction pattern having a value of 17.2° ± 0.2°, 29.7° ± 0.2°, 32.5 ° ± 0.2°. There are characteristic peaks.

Further, the crystal form B provided by the present invention is further characterized in that the X-ray powder diffraction pattern is one or two of 2theta values of 25.7°±0.2°, 21.5°±0.2°, and 23.0°±0.2°. There are characteristic peaks at or at three locations; preferred crystal form A provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a 2theta value of 25.7° ± 0.2°, 21.5° ± 0.2°, 23.0 ° ± 0.2°. There are characteristic peaks.

Further, the crystal form B provided by the present invention is further characterized in that the X-ray powder diffraction pattern thereof is substantially as shown in FIG.

The crystal form B provided by the present invention is characterized in that an endothermic peak begins to appear near the temperature of 89 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG. 5 .

The crystal form B provided by the present invention is characterized in that it has a weight loss gradient of about 21.6% when heated to 120 ° C, and the thermogravimetric analysis chart is basically as shown in FIG. 6 .

Further, the present invention provides the crystalline form B, characterized in that the crystalline form B is a diacetic acid solvate.

Another object of the present invention is to provide a process for the preparation of Form B comprising dissolving a solid of the compound (I) in acetic acid In the process, the toluene solvent is added by an anti-solvent addition method, and the mixture is stirred and crystallized.

Still further, the present invention provides a pharmaceutical composition comprising an effective amount of Form A or Form B or a mixture thereof and a pharmaceutically acceptable excipient.

Further, in the pharmaceutical composition of the present invention, the crystalline form A or the crystalline form B of the compound of the formula (I) or a mixture thereof can be used for the preparation of a medicament for treating cancer, in particular, a pharmaceutical preparation for melanoma and ovarian cancer. .

The beneficial effects of the invention are:

At present, there is no patent or literature report on the crystal form of the compound of the formula (I), and the inventors of the present invention have solved this problem through research and found two crystal forms suitable for development.

The crystal form provided by the invention has good stability and remarkable process purification effect. It can well avoid drug storage and crystal transformation during development, thus avoiding changes in bioavailability and efficacy.

The crystal form provided by the invention has low wettability, meets the requirements of bioavailability and efficacy, does not require special drying conditions in the preparation process, simplifies the preparation process and post-treatment process of the drug, and is not easily affected by humidity, and the storage condition The requirements are not harsh, and it is convenient for long-term storage, which greatly reduces the cost of material storage and quality control, and has strong economic value.

DRAWINGS

Figure 1 is an XRPD pattern of Form A

Figure 2 is a DSC diagram of Form A

Figure 3 is a TGA diagram of Form A

Figure 4 is an XRPD pattern of Form B

Figure 5 is a DSC diagram of Form B

Figure 6 is a TGA diagram of Form B

Figure 7 is a ¹ H NMR chart of Form B

Figure 8 is a DVS diagram of Form A

Figure 9 is a comparison of XRPD under different conditions of Form A (XRPD before test from top to bottom, XRPD placed at 5 °C for 11 months, XRPD placed at 25 °C, 60% RH for 11 months, 11 months of XRPD placed at 40 ° C, 75% RH)

Figure 10 is a comparison of XRPD under different conditions of Form B (XRPD before test from top to bottom, XRPD placed at room temperature for 2 weeks)

detailed description

The invention is further illustrated by the following examples, but is not intended to limit the scope of the invention. Improvements in the method of preparation and use of the apparatus may be made by those skilled in the art within the scope of the claims, and such modifications are also considered to be within the scope of the invention. Therefore, the scope of the invention should be determined by the appended claims.

In the following examples, the test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer. The starting compounds of the formula (I) can be obtained by known preparation methods, for example, according to the patent CN101633645B.

The abbreviations used in the present invention are explained as follows:

XRPD: X-ray powder diffraction

DSC: Differential Scanning Calorimetry

TGA: Thermogravimetric analysis

¹ H NMR: liquid NMR

DVS: Dynamic moisture adsorption

The X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer. The method parameters of the X-ray powder diffraction described in the present invention are as follows:

X-ray reflection parameters: Cu, Kα

1.540598;

1.544426

Kα2/Kα1 intensity ratio: 0.50

Voltage: 45 volts (kV)

Current: 40 milliamps (mA)

Scan range: from 3.0 to 40.0 degrees

The differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000. The method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:

Scan rate: 10 ° C / min

Protective gas: nitrogen

The thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000. The method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:

Scan rate: 10 ° C / min

Protective gas: nitrogen

The dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.). The method parameters of the dynamic moisture adsorber are as follows:

Temperature: 25 ° C

Carrier gas, flow rate: N ₂ , 200 ml / min

Unit time quality change: 0.002% / minute

Relative humidity range: 0%RH-95%RH

Example 1

Process for the preparation of crystalline form A of the compound of formula (I):

10.2 mg of the compound of the formula (I) was dissolved in 1.8 mL of methanol, and filtered through a 0.45 μm nylon filter to obtain a clear liquid which was placed in a 1.5 mL vial and evaporated at room temperature to obtain a solid crystal form A.

The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 1, and its XRPD pattern is shown in Fig. 1.

Table 1

Example 2

12.0 mg of the compound of the formula (I) was added to 1.2 mL of tetrahydrofuran, stirred at room temperature for three days at a rate of 500 r/min, and centrifuged to obtain a solid form.

The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 2.

Table 2

Example 3

17.0 mg of the compound of the formula (I) was dissolved in 0.1 mL of dimethylformamide, and then 0.2 mL of water was slowly added dropwise with stirring, stirring was continued for two days, and centrifugation to obtain a solid was crystalline form A.

The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 3.

table 3

Example 4

The wettability test of the crystalline form A of the compound of formula (I):

About 10 mg of the crystalline form A of the present invention was subjected to dynamic moisture adsorption (DVS) to test its wettability at 25 °C. The experimental results are shown in Table 4. The DVS pattern of the results of the wettability experiment is shown in Fig. 8.

Table 4

Defining the characteristics of wettability and the definition of wettability weight gain (Chinese Pharmacopoeia 2010 edition Appendix XIX J drug wettability test guidelines, experimental conditions: 25 ° C ± 1 ° C, 80% relative humidity):

Deliquescence: absorb enough water to form a liquid

Very hygroscopic: the wetting weight gain is not less than 15%

Humidity: Wet weight gain is less than 15% but not less than 2%

Slightly wettability: wetting gain is less than 2% but not less than 0.2%

No or almost no wettability: wetting gain is less than 0.2%

The results showed that the crystalline form A of the present invention had a weight gain of 0.14% after equilibration at 80% humidity, and was of no or almost no wettability. This property indicates that the crystal form is not susceptible to humidity or deliquescence, facilitating its long-term storage placement.

Example 5

Stability test of crystalline form A of the compound of formula (I):

Take about 10 mg of the crystal form A sample and place it at 5 ° C for long-term stability (25 ° C, 60% RH) and accelerated stability (40 ° C, 75% RH). HPLC purity. The experimental results are shown in Table 5. The XRPD comparison chart under different conditions of Form A is shown in Figure 9 (from top to bottom, XRPD before test, XRPD at 11 °C for 11 months, XRPD for 11 months at 25 °C, 60% RH, 11 months of XRPD was placed at 40 ° C and 75% RH).

table 5

起始晶型Initial crystal form	条件condition	起始纯度Initial purity	放置时间Placement time	晶型Crystal form	化学纯度Chemical purity
晶型A Crystal form A	5℃5 ° C	98.94％98.94%	11月November	晶型A保持不变Form A remains unchanged	98.84％98.84%
晶型ACrystal form A	25℃、60％RH25 ° C, 60% RH	98.94％98.94%	11月November	晶型A保持不变Form A remains unchanged	98.85％98.85%
晶型ACrystal form A	40℃、75％RH40 ° C, 75% RH	98.94％98.94%	11月November	晶型A保持不变Form A remains unchanged	98.95％98.95%

The results show that the crystal form A of the formula (I) is stable at 5 ° C, long-term stable (25 ° C, 60% RH) and accelerated stability (40 ° C, 75% RH), and the sample is stable during the standing process, and the purity is almost unchanged. .

Example 6

Method for preparing crystalline form B of compound of formula (I):

249.3 mg of the solid of the compound of the formula (I) was dissolved in 4 mL of acetic acid, and then 13 mL of toluene was slowly added dropwise with stirring, stirred for three days, and filtered to obtain a crystal form B.

The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 6. Its XRPD diagram is shown in Figure 4.

Table 6

Example 7

Method for preparing crystalline form B of compound of formula (I):

15.2 mg of the solid of the compound of the formula (I) was dissolved in 0.2 mL of acetic acid, and then 0.5 mL of toluene was slowly added dropwise with stirring, stirred overnight, and filtered to obtain a crystal form B.

The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 7. Its DSC diagram is shown in Figure 5, and its TGA diagram is shown in Figure 6. The ¹ H NMR chart is shown in Figure 7, and the ¹ H NMR data is as follows:

^{1 H NMR (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 = 13.2 Hz, 1H), 7.11 (d, J = 9.4 Hz, 1H), 6.39 (td, J = 9.0, 3.2 Hz, 1H), 4.69 (s, 1H), 3.87 (d, J = 25.0 Hz) , 5H), 3.54 (s, 2H), 1.91 (s, 5H).

Table 7

Example 8

Method for preparing crystalline form B of compound of formula (I):

109.1 mg of the solid of the compound of the formula (I) was dissolved in 1.8 mL of acetic acid, and then 6.4 mL of toluene was slowly added dropwise with stirring, stirred overnight, and filtered to obtain a crystal form B.

The X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 8.

Table 8

Example 9

Stability test of the crystalline form B of the compound of formula (I):

The crystal form B sample was placed at room temperature and the XRPD and HPLC purity of the Form B sample was measured after two weeks. The experimental results are shown in Table 9. The XRPD comparison chart under different conditions of Form B is shown in Figure 10 (from top to bottom, XRPD before test, and XRPD for 2 weeks at room temperature).

Table 9

起始晶型Initial crystal form	条件condition	起始纯度Initial purity	放置时间Placement time	晶型Crystal form	化学纯度Chemical purity
晶型BForm B	室温Room temperature	99.53％99.53%	2个星期2 weeks	晶型B保持不变Form B remains unchanged	99.52％99.52%

The results show that the crystal form B of the compound of the formula (I) is stable at room temperature, and the purity is almost unchanged during the standing.

Example 10

Study on the purity of the crystalline form B of the compound of formula (I):

10.0 mg of the starting sample of the compound of the formula (I) was dissolved in 0.2 mL of acetic acid, and then 0.5 mL of toluene was slowly added dropwise with stirring, stirred overnight, and filtered to obtain a crystal form B. The purity of the starting sample of the compound of the formula (I) and the crystalline form B prepared in the present example were respectively measured by high performance liquid chromatography. The results are shown in Table 10:

Table 10

The results show that Form B significantly improves the chemical purity of the sample and effectively removes many impurities in the sample.

The above embodiments are merely illustrative of the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims

a crystalline form of a compound of formula (I),

It is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 20.3 ° ± 0.2 °, 28.3 ° ± 0.2 °, and 11.1 ° ± 0.2 °.
The crystal form A according to claim 1, further characterized by an X-ray powder diffraction pattern of one or two of a 2theta value of 16.2 ° ± 0.2 °, 11.7 ° ± 0.2 °, and 18.9 ° ± 0.2 °. Or three with characteristic peaks.
The crystal form A according to claim 2, wherein the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 16.2 ° ± 0.2 °, 11.7 ° ± 0.2 °, and 18.9 ° ± 0.2 °.
The crystal form A according to any one of claims 1 to 3, characterized in that the X-ray powder diffraction pattern is in the 2theta value of 23.7 ° ± 0.2 °, 9.4 ° ± 0.2 °, 22.7 ° ± 0.2 ° One or two or three have characteristic peaks.
The crystal form A according to claim 4, wherein the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 23.7 ° ± 0.2 °, 9.4 ° ± 0.2 °, and 22.7 ° ± 0.2 °.
Crystal Form A according to Claim 1 wherein the X-ray powder diffraction pattern is substantially identical to that of Figure 1.
Form A according to any one of claims 1 to 6, wherein the crystal form A is an anhydride.
A process for the preparation of a crystalline form A of a compound of the formula (I) according to any one of claims 1 to 7, wherein the preparation comprises adding a compound of the formula (I) to a positive solvent and adding the crystal by addition of an antisolvent. Type A; the positive solvent includes alcohols, ethers, ketones, hydrocarbyl nitriles, and amides, and the anti-solvent includes alcohols, esters, halogenated alkanes, and water.
The preparation method according to claim 8, wherein the positive solvent comprises an alcohol, an ether, a ketone, acetonitrile or dimethylformamide, and the anti-solvent comprises ethanol, ethyl acetate, dichloromethane. ,water.
A process for the preparation of a crystalline form A of a compound of the formula (I) according to any one of claims 1 to 7, wherein the preparation comprises adding a compound of the formula (I) to a crystallization solvent, and cooling by evaporation and heating. Or suspension stirring to obtain crystal form A, which is a mixed solvent of one or more solvents.
The preparation method according to claim 10, wherein the crystallization solvent comprises alcohols, ketones, halogenated alkanes, alkanes, ethers, aromatic hydrocarbons, esters, carboxylic acids, hydrocarbyl nitriles, A mixture of one or more solvents of water, amides.
The preparation method according to claim 11, wherein the alcohol is methanol, ethanol or isopropanol, the ketone is methyl ethyl ketone or methyl isobutyl ketone, and the halogenated alkane is dichloromethane, three. Methyl chloride, the alkane is n-heptane, octane, the ether is methyl tert-butyl ether, the aromatic hydrocarbon is toluene, xylene, and the ester is ethyl acetate, isopropyl acetate The carboxylic acid is acetic acid, the hydrocarbyl nitrile is acetonitrile, and the amide is dimethylformamide.
A crystalline form of a compound of formula (I) characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 25.3 ° ± 0.2 °, 18.7 ° ± 0.2 °, and 16.8 ° ± 0.2 °.
The crystal form B according to claim 13, wherein the X-ray powder diffraction pattern is at one or two of 2theta values of 17.2 ° ± 0.2 °, 29.7 ° ± 0.2 °, and 32.5 ° ± 0.2 °. Or three with characteristic peaks.
The crystal form B according to claim 14, wherein the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 17.2 ° ± 0.2 °, 29.7 ° ± 0.2 °, and 32.5 ° ± 0.2 °.
Crystal Form B according to any one of claims 13-15, characterized in that the X-ray powder diffraction pattern is in the 2theta value of 25.7 ° ± 0.2 °, 21.5 ° ± 0.2 °, 23.0 ° ± 0.2 ° One or two or three have characteristic peaks.
The crystal form B according to any one of claims 16 to 4, wherein the X-ray powder diffraction pattern has a characteristic peak at 2theta values of 25.7° ± 0.2°, 21.5° ± 0.2°, and 23.0 ° ± 0.2°. .
Crystal Form B according to claim 13 wherein the X-ray powder diffraction pattern is substantially identical to that of Figure 4.
Form B according to any one of claims 13-18, wherein the Form B is a diacetate solvate.
A process for the preparation of a crystalline form B of a compound of the formula (I) according to any one of claims 13 to 19, which comprises preparing a solid of the compound (I) dissolved in acetic acid by an anti-solvent addition method Toluene solvent was added, and the crystal form B was obtained by stirring and crystallization.
A pharmaceutical composition comprising an effective amount of the crystalline form A according to any one of claims 1 to 7 or the crystalline form B according to any one of claims 13 to 19 or both A mixture and a pharmaceutically acceptable excipient.
The pharmaceutical composition according to claim 21, wherein the crystalline form A according to any one of claims 1 to 7 or the crystalline form B or both according to any one of claims 13 to 19 The mixture is used to prepare a cancer treatment drug.
The pharmaceutical composition according to claim 22, wherein the crystalline form A according to any one of claims 1 to 7 or the crystalline form B or both according to any one of claims 13 to 19 A mixture of the compounds for use in the preparation of a pharmaceutical preparation for the treatment of melanoma and ovarian cancer.