Crystal form of naphthalimide compound and preparation method therefor and use thereof

Abstract

The present invention relates to a crystal form of a naphthalimide compound represented by formula (I) and a preparation method therefor and a use thereof. The crystal form of the present invention has low hygroscopicity and excellent stability, and is suitable for use as a drug.

Description

Crystal form of naphthamide compound, and preparation method and use thereof TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a crystal form of naphthamide compound, and a preparation method and use thereof. BACKGROUND

[0002] Compound (I) is first disclosed in CN104860885A, and a structural formula is shown in the following formula (I),

[0003] Compound (I) is a VEGFR / CSF1R dual-target inhibitor with excellent activity, and can inhibit tumor cell angiogenesis and promote tumor immunity to exert an anti-tumor effect. Compound (I) can be used for preparing a drug for preventing and / or treating a disease related to abnormal angiogenesis, and / or a drug as a VEGFR-2 inhibitor, and / or a drug for preventing and / or treating a disease related to a CSF1R kinase signal transduction pathway, and / or a drug as a CSF1R kinase inhibitor. The disease related to abnormal angiogenesis is selected from the group consisting of a tumor, rheumatoid arthritis, age-related macular degeneration and psoriasis; and the tumor includes lung cancer, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, kidney cancer, glioma (such as glioblastoma, astrocytoma, medulloblastoma), melanoma, head and neck cancer, bladder cancer, cervical cancer, cholangiocarcinoma, nasopharyngeal carcinoma, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, fibromyosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastasis, meningioma and lymphoma. SUMMARY

[0004] There is no crystal form of compound (I) in the prior art. The inventors finally obtain a crystal form with low hygroscopicity, good stability and suitable for industrial production through a large number of experimental researches on the crystal form of compound (I), and the crystal form is suitable for raw drug production, storage and use.

[0005] In a first aspect, the present application provides a crystal form A of compound (I), characterized in that a powder X-ray diffraction pattern expressed by a 2θ angle (°) using Cu-Kα radiation has characteristic diffraction peaks at the following positions: 8.4±0.2°, 15.4±0.2°, 17.0±0.2°, 17.8±0.2°, 22.5±0.2°, 25.9±0.2°,

[0006] In some embodiments of the application, the Form A is characterized by a powder X-ray diffraction pattern, expressed in angles 2 theta (°), using Cu-Kalpharadiation, having characteristic diffraction peaks at the following positions: 8.4 ± 0.2°, 14.0 ± 0.2°, 15.4 ± 0.2°, 17.0 ± 0.2°, 17.8 ± 0.2°, 22.5 ± 0.2°, 25.9 ± 0.2°.

[0007] In some embodiments of the application, the Form A is characterized by a powder X-ray diffraction pattern, expressed in angles 2 theta (°), using Cu-Kalpharadiation, having characteristic diffraction peaks at the following positions: 8.4 ± 0.2°, 14.0 ± 0.2°, 15.4 ± 0.2°, 17.0 ± 0.2°, 17.8 ± 0.2°, 18.6 ± 0.2°, 19.7 ± 0.2°, 22.5 ± 0.2°, 25.9 ± 0.2°.

[0008] In some embodiments of the application, the Form A is characterized by a powder X-ray diffraction pattern, expressed in angles 2 theta (°), using Cu-Kalpharadiation, having characteristic diffraction peaks at the following positions: 8.4 ± 0.2°, 14.0 ± 0.2°, 15.4 ± 0.2°, 17.0 ± 0.2°, 17.8 ± 0.2°, 18.6 ± 0.2°, 19.7 ± 0.2°, 22.5 ± 0.2°, 24.1 ± 0.2°, 25.3 ± 0.2°, 25.9 ± 0.2°.

[0009] In some embodiments of the application, the Form A is characterized by a powder X-ray diffraction pattern, expressed in angles 2 theta (°), using Cu-Kalpharadiation, having characteristic diffraction peaks at the following positions: 8.4 ± 0.2°, 11.3 ± 0.2°, 14.0 ± 0.2°, 15.4 ± 0.2°, 17.0 ± 0.2°, 17.8 ± 0.2°, 18.6 ± 0.2°, 19.7 ± 0.2°, 22.5 ± 0.2°, 24.1 ± 0.2°, 25.3 ± 0.2°, 25.9 ± 0.2°.

[0010] In some embodiments of the application, the Form A is characterized by a powder X-ray diffraction pattern, expressed in angles 2 theta (°), using Cu-Kalpharadiation, having characteristic diffraction peaks at the following positions: 8.4 ± 0.2°, 11.3 ± 0.2°, 14.0 ± 0.2°, 14.8 ± 0.2°, 15.4 ± 0.2°, 17.0 ± 0.2°, 17.8 ± 0.2°, 18.6 ± 0.2°, 19.7 ± 0.2°, 21.9 ± 0.2°, 22.5 ± 0.2°, 24.1 ± 0.2°, 24.6 ± 0.2°, 25.3 ± 0.2°, 25.9 ± 0.2°.

[0011] In some embodiments of the application, the Form A is characterized by a powder X-ray diffraction pattern, expressed in terms of 2 theta angle (°), having characteristic diffraction peaks at 8.4 ± 0.2°, 11.3 ± 0.2°, 14.0 ± 0.2°, 14.8 ± 0.2°, 15.4 ± 0.2°, 17.0 ± 0.2°, 17.8 ± 0.2°, 18.6 ± 0.2°, 19.7 ± 0.2°, 21.9 ± 0.2°, 22.5 ± 0.2°, 24.1 ± 0.2°, 24.6 ± 0.2°, 25.3 ± 0.2°, 25.9 ± 0.2°, 26.7 ± 0.2°, 27.8 ± 0.2°, using Cu-Kalpharadiation.

[0012] In some embodiments of the application, the Form A is characterized by a powder X-ray diffraction pattern, expressed in terms of 2 theta angle (°), having characteristic diffraction peaks at 8.4 ± 0.2°, 15.4 ± 0.2°, 17.0 ± 0.2°, 17.8 ± 0.2°, 22.5 ± 0.2°, 25.9 ± 0.2°; optionally further comprising 14.0 ± 0.2°, further optionally 25.3 ± 0.2°, more further optionally 24.1 ± 0.2°, more further optionally 18.6 ± 0.2°, using Cu-Kalpharadiation.

[0013] In some embodiments of the application, the Form A is characterized by a powder X-ray diffraction pattern, expressed in terms of 2 theta angle (°), having characteristic diffraction peaks at 8.4 ± 0.2°, 11.3 ± 0.2°, 14.0 ± 0.2°, 14.8 ± 0.2°, 15.4 ± 0.2°, 17.0 ± 0.2°; optionally further comprising 17.8 ± 0.2°, further optionally 18.6 ± 0.2°, more further optionally 19.7 ± 0.2°, more further optionally 21.9 ± 0.2°, using Cu-Kalpharadiation.

[0014] In some embodiments of the application, the Form A is characterized by a powder X-ray diffraction pattern, expressed in terms of 2 theta angle (°), having characteristic diffraction peaks at 8.4 ± 0.2°, 15.4 ± 0.2°, 17.0 ± 0.2°, 17.8 ± 0.2°, 22.5 ± 0.2°, 26.0 ± 0.2°; optionally further comprising 14.0 ± 0.2°, further optionally 18.6 ± 0.2°, 19.8 ± 0.2°, more further optionally 24.1 ± 0.2°, 25.3 ± 0.2°, more further optionally 11.3 ± 0.2°, more further optionally 14.8 ± 0.2°, 21.9 ± 0.2°, 24.7 ± 0.2°, more further optionally 26.7 ± 0.2°, 27.8 ± 0.2°, using Cu-Kalpharadiation.

[0015] In some embodiments of the application, the Form A is characterized by a powder X-ray diffraction pattern, expressed in terms of 2 theta (°) angles, having characteristic diffraction peaks at 8.4 ± 0.2°, 15.4 ± 0.2°, 17.0 ± 0.2°, 17.8 ± 0.2°, 22.5 ± 0.2°, 26.0 ± 0.2°; optionally further comprising 14.0 ± 0.2°, further optionally 25.3 ± 0.2°, more further optionally 24.1 ± 0.2°, again more further optionally 18.6 ± 0.2°, yet more further optionally 11.3 ± 0.2°, 14.8 ± 0.2°, 19.8 ± 0.2°, still more further optionally 21.9 ± 0.2°, using Cu-Ka radiation.

[0016] In some embodiments of the application, the Form A has a powder X-ray diffraction pattern substantially as shown in Figure 1 or Figure 2, using Cu-Ka radiation.

[0017] In some embodiments of the application, the Form A has a unit cell parameters of: α = 90(10)°, β = 90.122(10)°, γ = 90(10)°, } using Mo Kα radiation, belongs to triclinic system, P-21 space group.

[0018] In some embodiments of the application, the Form A has an endothermic peak at about 262.5 ± 5°C, for example about 262.5 ± 4°C, 262.5 ± 3°C, 262.5 ± 2°C, 262.5 ± 1°C, or 262.5 ± 0.5°C, as measured by differential scanning calorimetry.

[0019] In some embodiments of the application, the Form A is an anhydrate.

[0020] In a second aspect, the present application provides a method for preparing the Form A as described above, comprising:

[0021] dissolving the crude compound (I) in solvent 1, then adding or adding to solvent 2, stirring to crystallize to obtain the Form A of compound (I),

[0022] wherein the solvent 1 includes but is not limited to N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, acetonitrile, nitromethane, diethyl ether, n-hexane;

[0023] The solvent 2 includes but is not limited to methanol, ethanol, isopropanol, n-propanol, n-butanol, sec-butanol, n-hexanol, tetrahydrofuran, methyl tert-butyl ether.

[0024] In some embodiments of the present application, the above preparation method, the solvent 1 is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone; preferably N,N-dimethylacetamide, dimethyl sulfoxide.

[0025] In some embodiments of the present application, the above preparation method, the solvent 2 is selected from the group consisting of methanol, n-hexanol, tetrahydrofuran, preferably methanol, tetrahydrofuran.

[0026] In some embodiments of the present application, the above preparation method, the solvent 1 is selected from the group consisting of acetonitrile, nitromethane, diethyl ether, n-hexane, and the solvent 2 is tetrahydrofuran; or the solvent 1 is dimethyl sulfoxide, and the solvent 2 is methanol.

[0027] In some embodiments of the present application, the above preparation method, the temperature of dissolving is 20-60℃, preferably 20-30℃ or 45-55℃.

[0028] In some embodiments of the present application, the above preparation method, the temperature of crystallization is 0-40℃, preferably 20-30℃.

[0029] In some embodiments of the present application, the above preparation method, the volume ratio of solvent 1 to solvent 2 is 1:(2-5), preferably 1:(3-5).

[0030] In some embodiments of the present application, the above preparation method, the mass-volume ratio (g / mL) of crude compound (I) to solvent 1 is 1:(1-1000), preferably 1:(2-700).

[0031] The present application provides a preparation method of the above crystal form A. Specifically, the preparation method of the crystal form A comprises:

[0032] Dissolving crude compound (I) in solvent 1, then adding or adding to solvent 2, stirring and crystallizing to obtain crystal form A of compound (I), wherein

[0033] The solvent 1 is dimethyl sulfoxide, the solvent 2 is methanol, preferably, compound (I) crude is dissolved in solvent 1 to obtain a solution of compound (I) in solvent 1, then solvent 2 is added to the solution; the temperature of the dissolution is 20-60°C, preferably 20-30°C or 45-55°C; the temperature of the crystallization is 0-40°C, preferably 20-30°C; the volume ratio of solvent 1 to solvent 2 is 1:(2-5), preferably 1:(3-5); the mass volume ratio (g / mL) of compound (I) crude to solvent 1 is 1:(1-1000), preferably 1:(2-700), 1:(2-100), preferably 1:(2-10); the crystallization time is at least 0.1 hour, for example, 0.2 hour to 56 days, or 0.5 hour-28 days, or 8 hours-21 days, or 12 hours-14 days, or 1 day-7 days, or 0.5 hour-2.5 hours; or

[0034] The solvent 1 is selected from one of acetonitrile, nitromethane, diethyl ether, and n-hexane, the solvent 2 is tetrahydrofuran, preferably, compound (I) crude is dissolved in solvent 1 to obtain a solution of compound (I) in solvent 1, then the solution is added to solvent 2; the temperature of the dissolution is 20-60°C, preferably 20-30°C or 45-55°C; the temperature of the crystallization is 0-40°C, preferably 20-30°C; the volume ratio of solvent 1 to solvent 2 is 1:(2-5), preferably 1:(3-5); the mass volume ratio (g / mL) of compound (I) crude to solvent 1 is 1:(1-1000), preferably 1:(2-700), 1:(100-700), preferably 1:(500-700); the crystallization time is at least 0.1 hour, for example, 0.2 hour to 56 days, or 0.5 hour-28 days, or 8 hours-21 days, or 12 hours-14 days, or 1 day-7 days, or 0.5 hour-2.5 hours.

[0035] In some embodiments of the present application, the above preparation method, the separation step comprises separating the obtained crystal form A from the crystallization solution by using suitable methods such as filtration, centrifugation, etc.

[0036] In some embodiments of the present application, the above preparation method, in consideration of removing free solvent from the product, after the separation step, further comprises a drying step, and the drying method can use any suitable known method, preferably vacuum drying. The specific drying conditions are, for example, the temperature is preferably 30-70°C, further preferably 35-60°C, more preferably 40-50°C; the drying time is preferably 4-20h, more preferably 5-12h. Regardless of the drying means used, the residual amount of solvent in the obtained product should meet the quality standards.

[0037] The compound (I) crude product described in the present application can be prepared by using the known method disclosed in CN104860885A, or any known method disclosed in other prior art.

[0038] In a third aspect, the present application also provides a pharmaceutical composition comprising the crystal form A described above, and optionally a pharmaceutically acceptable carrier. In some embodiments of the present application, the pharmaceutical composition comprises a therapeutically effective amount of the crystal form A described above, and optionally a pharmaceutically acceptable carrier.

[0039] The pharmaceutical composition described above can be prepared into clinically acceptable formulations, such as oral formulations, injection formulations, topical administration formulations, external use formulations, etc., preferably oral formulations. The oral formulations are preferably solid formulations, such as tablets, capsules, granules, oral solutions, etc. These formulations can be prepared by using corresponding excipients known to those skilled in the art, and using corresponding known pharmaceutical preparation techniques.

[0040] In a fourth aspect, the present application also provides the use of the crystal form A described above or the pharmaceutical composition described above in the preparation of a medicament for preventing and / or treating diseases related to abnormal vascular proliferation, and / or for preventing and / or treating diseases benefiting from VEGFR-2 inhibition and / or CSF1R kinase inhibition, and / or for use as a VEGFR-2 inhibitor, and / or for preventing and / or treating diseases related to CSF1R kinase signal transduction pathway, and / or for use as a CSF1R kinase inhibitor.

[0041] In some embodiments of the present application, the diseases related to abnormal vascular proliferation are selected from the group consisting of tumors, rheumatoid arthritis, age-related macular degeneration and psoriasis; and the tumors are preferably selected from the group consisting of lung cancer, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, kidney cancer, glioma, melanoma, head and neck cancer, bladder cancer, cervical cancer, cholangiocarcinoma, nasopharyngeal carcinoma, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, fibromyosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastasis, meningioma and lymphoma. The glioma is preferably selected from the group consisting of glioblastoma, astrocytoma and medulloblastoma.

[0042] The "patient" in the use described above includes all members of the animal kingdom, including but not limited to mammals (e.g., mice, rats, cats, monkeys, dogs, etc.) and humans.

[0043] Definitions and explanations

[0044] The following terms and phrases, as used herein, are intended to have the following meanings unless otherwise indicated. A particular phrase or term should not be construed to be indefinite or unclear unless specifically defined, but should be construed in accordance with the ordinary meaning. When a trade name appears herein, it is intended to designate the active ingredient of that product.

[0045] As used herein, and unless otherwise indicated, the term "2Θ, 2Θ angle or 2Θ angle" means the diffraction angle, in ° or degrees.

[0046] As used herein, and unless otherwise indicated, the term "crystallization temperature, drying temperature" means the temperature in °C or degrees Celsius, and can have an error range of ±10, ±5, ±4, ±3, ±2, or ±1 °C.

[0047] As used herein, and unless otherwise indicated, the term "therapeutically effective amount" means a sufficient amount of a drug or pharmaceutical agent to achieve the intended effect without undue adverse side effects. In embodiments of the present application, the amount of a given drug to be administered to a patient in accordance with the present application will depend on factors such as the particular dosage form being used, the type and severity of the disease or condition, and the unique characteristics of the subject or host being treated (e.g., weight), but the dosage can be routinely determined in accordance with methods known in the art, taking into account the particular circumstances, including, for example, the specific drug being used, the route of administration, the condition being treated, and the subject or host being treated. For a pharmaceutical composition of the present application, which comprises a therapeutically effective amount of a compound of the present application and a pharmaceutically acceptable carrier, the "therapeutically effective amount" means that the weight of the compound of the present application is 1-99%, e.g., 20-80%, 30-70%, or 45-55%, and the weight of the pharmaceutically acceptable carrier is 99-1%, e.g., 80-20%, 70-30%, or 55-45%, based on the weight of the pharmaceutical composition. Pharmaceutically acceptable carriers are well known in the art and are not described here.

[0048] The term "substantially as shown in the figure" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks in the powder X-ray diffraction pattern or the DSC pattern or the crystal shape pattern of the crystalline particles of a certain crystal form are present in the given pattern. Further, as the content of a certain crystal form in a product gradually decreases, some of the diffraction peaks attributed to the crystal form in the powder X-ray diffraction pattern thereof can be less due to the detection sensitivity of the instrument. In addition, for any given crystal form, there can be slight errors in the position of the peaks, which is also known in the field of crystallography. For example, due to changes in temperature when analyzing the sample, movement of the sample or calibration of the instrument, the position of the peaks can shift, and the measurement error of the 2θ value is usually about ±0.2°. Therefore, when determining the structure of each crystal form, this error should be taken into account, and the term "substantially" or "substantially as shown in the figure" is also intended to cover such differences in the position of the diffraction peaks.

[0049] The present application will be described in detail below by way of examples, which can be used without further purification.

[0050] The solvent used in the present application can be commercially available.

[0051] Technical effects

[0052] The crystal form of the present application has the following beneficial effects:

[0053] The crystal form of the present application has low hygroscopicity.

[0054] The crystal form of the present application has excellent stability. BRIEF DESCRIPTION OF DRAWINGS

[0055] Figure 1: XRPD spectrum of the crystal form A of compound (I) obtained in Example 1.

[0056] Figure 2: XRPD spectrum of the crystal form A of compound (I) obtained in Test Example 4.

[0057] Figure 3: XRPD spectrum of the crystal form B of compound (I) obtained in Example 4.

[0058] Figure 4: DSC analysis pattern of crystal form A.

[0059] Figure 5: DSC analysis pattern of crystal form B. DETAILED DESCRIPTION

[0060] 1. X-ray powder diffractometer (XRPD)

[0061] Instrument model: Bruker D2 Advance X-ray diffractometer

[0062] Measurement conditions: CuKa radiation, graphite monochromator (40KV, 150mA), scan range: 3°-40°2θ, scan speed: 0.15s, step 0.02°.

[0063] 2. Thermogravimetric analyzer (TGA)

[0064] Instrument model: Netzsch TG 209F3 thermogravimetric analyzer

[0065] Temperature range: 30-400°C

[0066] Scanning rate: 10°C / min

[0067] Purge gas: 25 mL / min

[0068] Protective gas: 15 mL / min.

[0069] 3. Differential scanning calorimetry (DSC) analysis

[0070] Instrument model: TA DSC Q2000 differential scanning calorimeter

[0071] Temperature range: 40-300°C

[0072] Scanning rate: 10°C / min

[0073] Nitrogen flow rate: 50 mL / min.

[0074] 4. Dynamic vapor sorption (DVS) analysis

[0075] Instrument model: SMS DVS Intrinsic

[0076] Temperature: 25°C

[0077] Humidity range: 0-95% RH

[0078] The preferred embodiments of the present application will be described in detail below with reference to the accompanying drawings. The embodiments are provided to better illustrate the content of the present application, but the content of the present application is not limited to the embodiments. Non-essential improvements and modifications of the embodiments by those skilled in the art according to the above content of the application still fall within the protection scope of the present application.

[0079] Preparation example: preparation of crude compound (I)

[0080] The crude compound (I) was prepared according to CN104860885A example 21, which was a white solid. The obtained solid sample was subjected to X-ray powder diffraction test, and the result was amorphous.

[0081] Preparation of crystalline form A of compound (I)

[0082] The crude compound (I) 2 g was added to a reaction bottle, 4.4 mL of dimethyl sulfoxide was added, heated to 45-55 °C and stirred to dissolve, 20 mL of methanol was added, cooled to room temperature (20-30 °C), and stirred to crystallize for 0.5-2.5 h to obtain 1.6 g of white crystals with a purity of 99.5% by HPLC. Polarized light photograph showed that the obtained crystal was rhombic block crystal. The sample was tested by powder X-ray diffraction and showed that it was crystalline form A, the spectrum is shown in Figure 1, and the data results are shown in Table 1.

[0083] Table 1: Powder-X-ray diffraction peak data of sample of crystalline form A of Example 1

[0084] The sample was tested by TGA and showed no weight loss before 300 °C, indicating that crystalline form A did not contain crystal water.

[0085] Preparation of single crystal of crystalline form A of Example 2

[0086] An appropriate amount of sample obtained in Example 1 was dissolved in ethanol / isopropanol (v / v = 1:1), and single crystals of crystalline form A were obtained by evaporation at 2-8 °C. The single crystal data are shown in Table 2:

[0087] Table 2: Single crystal diffraction data of crystalline form A

[0088] Preparation of crystalline form A of compound (I) of Example 3

[0089] The following describes another method for preparing crystalline form A: about 3 mg of the sample of Preparation Example was weighed, dissolved in solvent 1 (2 mL), and then added to solvent 2 (6 mL), and left at room temperature (25 °C) for one week to obtain white crystals. The results are shown in Table 3:

[0090] Table 3: Test results for preparation of crystalline form A of Example 3

[0091] Preparation of crystalline form B of compound (I) of Example 4

[0092] About 3 mg of the sample of Preparation Example 1 was taken, 1 mL or 0.5 mL of ethanol and 0.5 mL of water were added, mixed and dissolved, and left at 25 °C to slowly evaporate to dryness, to obtain a solid. The sample was tested by powder X-ray diffraction and showed that it was crystalline form B, the spectrum is shown in the figure, and the data results are shown in Table 4:

[0093] Table 4: Powder-X-ray characteristic peak data of crystalline form B of Example 4

[0094] The sample was subjected to TGA test, which showed that it was a monohydrate crystal form.

[0095] Test Example 1: Differential Scanning Calorimetry (DSC) Test

[0096] The sample of crystal form A of Example 1 and the sample of crystal form B of Example 4 were subjected to DSC test, and the results are shown in Table 5:

[0097] Table 5: DSC test results of crystal form A and crystal form B

[0098] Test Example 2: Hygroscopicity test of crystal form

[0099] The dynamic vapor sorption instrument (DVS) was used to investigate the water adsorption and desorption of the crystal form samples at 25°C under 0-95% relative humidity, so as to determine the hygroscopicity of various crystal forms.

[0100] The following table is the definition and range of hygroscopicity of drugs in Chinese Pharmacopoeia 2010 edition after equilibrium at 25°C and 80% RH.

[0101] Table 6: Hygroscopicity test results of crystal form A and crystal form B

[0102] Test Example 3: Stability test of crystal form

[0103] The sample of crystal form A of Example 1 was taken in an appropriate amount and placed at 40°C / 75% RH and 25°C / 60% RH for 7 days, respectively, and no crystal form conversion occurred.

[0104] Test Example 4: Stability test of crystal form A after pulverization

[0105] The sample of crystal form A of Example 1 was taken in an appropriate amount and pulverized using an experimental jet mill, the feeding speed was 0.5-0.8 M bar, the pulverization gas pressure was 0.5-0.8 M bar, and the sample after pulverization was subjected to XRPD test, and no crystal form change occurred, the spectrum is shown in the drawing, and the data results are shown in the table.

[0106] Table: Powder-X-ray diffraction peak data of crystal form A after jet pulverization

[0107] Comparative Example:

[0108] During the development process, the inventors found that compound (I) could not be crystallized into a solid or only amorphous or mixed crystals could be obtained under various crystal research methods and different experimental conditions. Exemplary schemes include but are not limited to the following comparative examples:

[0109] Comparative Example 1: Cooling crystallization method

[0110] About 6 mg of the sample from Preparation 1 was weighed, dissolved in solvent after addition of solvent, warmed to 50°C to dissolve, cooled to room temperature, filtered, and crystallized by standing at 4°C and -20°C.

[0111] Antisolvent crystallization method of Comparative Example 2

[0112] About 3 mg of the sample from Preparation 1 was weighed, dissolved in solvent 1 (2 mL), and then added to solvent 2 (6 mL), and allowed to stand at room temperature for one week.

[0113] Evaporative crystallization method of Comparative Example 3

[0114] About 3 mg of the sample from Preparation 1 was weighed, dissolved in the appropriate solvent (solvent 1 + solvent 2 + solvent 3 (if solvent 3 was used)), and allowed to evaporate to dryness at the appropriate temperature, open to the atmosphere.

Claims

1. A crystalline Form A of Compound (I) characterized by, The powder X-ray diffraction pattern using Cu-Ka radiation, expressed in terms of 2 theta angles (°), has characteristic diffraction peaks at the following positions: 8.4 ± 0.2°, 15.4 ± 0.2°, 17.0 ± 0.2°, 17.8 ± 0.2°, 22.5 ± 0.2°, 25.9 ± 0.2°, 2. The crystalline Form A of claim 1, characterized by, a powder X-ray diffraction pattern, expressed in angles 2 theta (°), using Cu-Ka radiation, has characteristic diffraction peaks at the following positions: 8.4±0.2°, 14.0±0.2°, 15.4±0.2°, 17.0±0.2°, 17.8±0.2°, 22.5±0.2°, 25.9±0.2°, or a powder X-ray diffraction pattern, expressed in angles 2 theta (°), using Cu-Ka radiation, has characteristic diffraction peaks at the following positions: 8.4±0.2°, 14.0±0.2°, 15.4±0.2°, 17.0±0.2°, 17.8±0.2°, 18.6±0.2°, 19.7±0.2°, 22.5±0.2°, 25.9±0.2°, or a powder X-ray diffraction pattern, expressed in angles 2 theta (°), using Cu-Ka radiation, has characteristic diffraction peaks at the following positions: 8.4±0.2°, 14.0±0.2°, 15.4±0.2°, 17.0±0.2°, 17.8±0.2°, 18.6±0.2°, 19.7±0.2°, 22.5±0.2°, 24.1±0.2°, 25.3±0.2°, 25.9±0.2°, or a powder X-ray diffraction pattern, expressed in angles 2 theta (°), using Cu-Ka radiation, has characteristic diffraction peaks at the following positions: 8.4±0.2°, 11.3±0.2°, 14.0±0.2°, 15.4±0.2°, 17.0±0.2°, 17.8±0.2°, 18.6±0.2°, 19.7±0.2°, 22.5±0.2°, 24.1±0.2°, 25.3±0.2°, 25.9±0.2°, or a powder X-ray diffraction pattern, expressed in angles 2 theta (°), using Cu-Ka radiation, has characteristic diffraction peaks at the following positions: 8.4±0.2°, 11.3±0.2°, 14.0±0.2°, 14.8±0.2°, 15.4±0.2°, 17.0±0.2°, 17.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.9±0.2°, 22.5±0.2°, 24.1±0.2°, 24.6±0.2°, 25.3±0.2°, 25.9±0.2°, or a powder X-ray diffraction pattern, expressed in angles 2 theta (°), using Cu-Ka radiation, has characteristic diffraction peaks at the following positions: 8.4±0.2°, 11.3±0.2°, 14.0±0.2°, 14.8±0.2°, 15.4±0.2°, 17.0±0.2°, 17.8±0.2°, 18.6±0.2°, 19.7±0.2°, 21.9±0.2°, 22.5±0.2°, 24.1±0.2°, 24.6±0.2°, 25.3±0.2°, 25.9±0.2°, 26.7±0.2°, 27.8±0.2°, or The powder X-ray diffraction pattern of the Form A is substantially as shown in FIG. 1 or FIG. 2 using Cu-Ka radiation.

3. The crystalline Form A of any one of claims 1-2, characterized by, Its single crystal uses Mo Kα radiation, belongs to triclinic crystal system, P-21 space group, and its cell parameter is:

4. Crystal form A as described in any one of claims 1-3, characterized in that, The endothermic peak is measured by differential scanning calorimetry at about 262.5±5°C, for example, about 262.5±4°C, 262.5±3°C, 262.5±2°C, 262.5±1°C, or 262.5±0.5°C.

5. Crystal form A as described in any one of claims 1-4, characterized in that, The Form A is an anhydrate.

6. A method for preparing the Form A of any one of claims 1-5, comprising: dissolving the crude compound (I) in solvent 1, then adding or adding to solvent 2, stirring to crystallize to obtain the Form A of compound (I), wherein the solvent 1 includes but is not limited to N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, acetonitrile, nitromethane, diethyl ether, n-hexane, preferably the solvent 1 is selected from: N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, more preferably the solvent 1 is selected from: N,N-dimethylacetamide, dimethyl sulfoxide; the solvent 2 includes but is not limited to methanol, ethanol, isopropanol, n-propanol, n-butanol, sec-butanol, n-hexanol, tetrahydrofuran, methyl tert-butyl ether, preferably the solvent 2 is selected from: methanol, n-hexanol, tetrahydrofuran, more preferably the solvent 2 is selected from: methanol, tetrahydrofuran; preferably, the crystallization temperature is 0-40°C, preferably 20-30°C; preferably, the volume ratio of solvent 1 to solvent 2 is 1:(2-5), preferably 1:(3-5); preferably, the mass volume ratio (g / mL) of crude compound (I) to solvent 1 is 1:(1-1000), preferably 1:(2-700).

7. A pharmaceutical composition comprising the Form A of any one of claims 1-5, and optionally a pharmaceutically acceptable carrier.

8. Use of the Form A of any one of claims 1-5 or the pharmaceutical composition of claim 7 in the manufacture of a medicament for the prevention and / or treatment of a disease associated with abnormal vascular proliferation, and / or for the prevention and / or treatment of a disease that benefits from VEGFR-2 inhibition and / or CSF1R kinase inhibition, and / or for use as a VEGFR-2 inhibitor, and / or for the prevention and / or treatment of a disease associated with the CSF1R kinase signaling pathway, and / or for use as a CSF1R kinase inhibitor; for example, the disease is selected from: tumor, rheumatoid arthritis, age-related macular degeneration, and psoriasis; the tumor is preferably: lung cancer, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, kidney cancer, glioma, melanoma, head and neck cancer, bladder cancer, cervical cancer, cholangiocarcinoma, nasopharyngeal carcinoma, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, fibromyosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastasis, meningioma, and lymphoma; the glioma is preferably glioblastoma, astrocytoma, medulloblastoma.

9. A method for preventing and / or treating a disease associated with abnormal vascular proliferation, and / or for preventing and / or treating a disease that benefits from VEGFR-2 inhibition and / or CSF1R kinase inhibition, and / or for preventing and / or treating a disease associated with CSF1R kinase signaling pathway, comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline Form A of any one of claims 1-5 or the pharmaceutical composition of claim 7; For example, the disease is selected from the group consisting of tumor, rheumatoid arthritis, age-related macular degeneration and psoriasis; the tumor is preferably lung cancer, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, renal cancer, glioma, melanoma, head and neck cancer, bladder cancer, cervical cancer, cholangiocarcinoma, nasopharyngeal carcinoma, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, fibromyosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastasis, meningioma and lymphoma; the glioma is preferably glioblastoma, astrocytoma, medulloblastoma.

10. The crystalline Form A of any one of claims 1-5 or the pharmaceutical composition of claim 7 for use in preventing and / or treating a disease associated with abnormal vascular proliferation, and / or for preventing and / or treating a disease that benefits from VEGFR-2 inhibition and / or CSF1R kinase inhibition, and / or for preventing and / or treating a disease associated with CSF1R kinase signaling pathway, and / or for use as a VEGFR-2 inhibitor, and / or for use as a CSF1R kinase inhibitor; For example, the disease is selected from the group consisting of tumor, rheumatoid arthritis, age-related macular degeneration and psoriasis; the tumor is preferably lung cancer, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, renal cancer, glioma, melanoma, head and neck cancer, bladder cancer, cervical cancer, cholangiocarcinoma, nasopharyngeal carcinoma, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, fibromyosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastasis, meningioma and lymphoma; the glioma is preferably glioblastoma, astrocytoma, medulloblastoma.

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