Crystal form of deuterated compound and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a crystal form I and a crystal form II of [[(12aR)-12-[(11S)-7, 8-difluoro-6, 11-dihydrodibenzo [C, e] thiocycloheptane-11-yl]-6, 8-dioxo-3, 4, 6, 8, 12, 12a-hexahydro-1H-[1, 4] oxazino [3, 4-c] pyridino [2, 1-f] [1, 2, 4] triazine-7-yl] oxo] methyl (ethyl-d5) carbonate, a preparation method of the crystal forms and a pharmaceutical composition comprising the crystal forms. The invention further relates to application of the crystal form or the pharmaceutical composition containing the crystal form in preparation of drugs for preventing, treating, treating or relieving influenza virus infection diseases of patients, and the crystal form has the properties of good stability, pharmacokinetics and the like, so that the drugs can be better formed.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and relates to a crystal form of a deuterated compound and its use, specifically to the crystal form of [[(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[c,e]thiepten-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl]oxo]methyl (ethyl-d5) carbonate and a pharmaceutical composition containing the crystal form, and further relates to their use in the preparation of drugs. Background Art

[0002] When influenza virus invades host cells, the replication and transcription in host cells are inseparable from the catalysis of RNA polymerase. Among them, cap-dependent nucleic acid PA endonuclease is an enzyme necessary for synthesizing viral mRNA. By inhibiting cap-dependent nucleic acid PA endonuclease, the transcription process of influenza virus can be selectively blocked, so as to achieve the purpose of preventing, treating or alleviating influenza in patients.

[0003] Currently, commonly used anti-influenza virus drugs include: ion channel m2 inhibitors, such as amantadine and methyl amantadine; neuraminidase inhibitors, such as oseltamivir, zanamivir, peramivir, etc.; other drugs, such as moroxydine and ribavirin.

[0004] Chinese Patent Application CN116284048A discloses the compound [[(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[c,e]thiepten-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl]oxo]methyl (ethyl-d5) carbonate (Compound I), which can prevent, treat, or alleviate influenza virus infection diseases in patients.

[0005] Different salt forms and solid forms of drug active ingredients may affect the properties of drugs and the development of preparations, and ultimately affect the pharmacological properties of preparation products. Therefore, studying the salt forms or solid forms of drug active ingredients is crucial for improving the development difficulty of drug preparations and the pharmacological properties of preparation products. Summary of the Invention

[0006] The present invention provides a crystal form of a compound of formula I, a method for preparing the crystal form, and a pharmaceutical composition comprising the crystal form. The present invention also relates to the use of the crystal form or the pharmaceutical composition comprising the crystal form in the preparation of a medicament for preventing, treating, alleviating or reducing influenza virus infection diseases in patients. Among them, the crystal form has good stability, pharmacokinetics and other properties, and thus can be better formulated into a drug.

[0007] In a first aspect, the present invention provides a crystal form of a compound represented by formula I, wherein the crystal form is crystal form I and crystal form II.

[0008] Among them, the X-ray powder diffraction pattern of crystal form I contains diffraction peaks at the following 2θ angles: 4.317° ± 0.2°, 8.538° ± 0.2°, 17.038° ± 0.2°, 21.556° ± 0.2°, 25.620° ± 0.2°, 29.979° ± 0.2°, 34.378° ± 0.2°; the relative intensity of the diffraction peak at 2θ = 21.556° ± 0.2° does not exceed 20%, and the relative intensity of the diffraction peak at 2θ = 34.378° ± 0.2° is not less than 10%; the X-ray powder diffraction pattern of crystal form II contains diffraction peaks at the following 2θ angles: 5.979° ± 0.2°, 8.258° ± 0.2°, 8.797° ± 0.2°, 11.862° ± 0.2°, 14.342° ± 0.2°, 16.159° ± 0.2°, 17.561° ± 0.2°, 19.258° ± 0.2°, 21.660° ± 0.2°, 23.380° ± 0.2°, 25.119° ± 0.2°, 25.798° ± 0.2°, 27.060° ± 0.2°, 27.422° ± 0.2°, 29.899° ± 0.2°.

[0009] In some embodiments, the X-ray powder diffraction pattern of Form I comprises diffraction peaks at the following 2θ angles: 4.317° ± 0.2°, 8.538° ± 0.2°, 10.680° ± 0.2°, 13.378° ± 0.2°, 14.479° ± 0.2°, 15.817° ± 0.2°, 17.038° ± 0.2°, 18.478° ± 0.2°, 20.019° ± 0.2°, 21.319° ± 0.2°, 21.556° ± 0.2°, 23.381° ± 0.2°, 25.620° ± 0.2°, 27.500° ± 0.2°, 29.019° ± 0.2°, 29.519° ± 0.2°, 29.979° ± 0.2°, 31.561° ± 0.2°, 33.711° ± 0.2°, 34.378° ± 0.2°, 35.842° ± 0.2°, 37.721° ± 0.2°, 38.803° ± 0.2°, 39.661° ± 0.2°, 41.660° ± 0.2°, 43.340° ± 0.2°, 45.538° ± 0.2°, 47.739° ± 0.2°; wherein the relative intensity of the diffraction peak at 2θ angle of 21.556° ± 0.2° does not exceed 20%, and the relative intensity of the diffraction peak at 2θ angle of 34.378° ± 0.2° is not less than 10%;

[0010] The X-ray powder diffraction pattern of the crystalline form II contains diffraction peaks at the following 2θ angles: 5.979° ± 0.2°, 7.202° ± 0.2°, 8.258° ± 0.2°, 8.797° ± 0.2°, 9.499° ± 0.2°, 10.137° ± 0.2°, 11.862° ± 0.2°, 12.503° ± 0.2°, 13.920° ± 0.2°, 14.342° ± 0.2°, 15.218° ± 0.2°, 16.159° ± 0.2°, 17.140° ± 0.2°, 17.561° ± 0.2°, 17.880° ± 0.2°, 19.258° ± 0.2°, 20.339° ± 0.2°, 21.660° ± 0.2°, 22.161° ± 0.2°, 23.380° ± 0.2°, 23.862° ± 0.2°, 24.160° ± 0.2°, 25.119° ± 0.2°, 25.798° ± 0.2°, 26.482° ± 0.2°, 27.060° ± 0.2°, 27.422° ± 0.2°, 28.138° ± 0.2°, 28.662° ± 0.2°, 29.899° ± 0.2°, 31.441° ± 0.2°, 32.701° ± 0.2°, 33.961° ± 0.2°, 34.781° ± 0.2°, 35.739° ± 0.2°, 37.160° ± 0.2°, 37.525° ± 0.2°, 39.084° ± 0.2°, 47.080° ± 0.2°, 48.924° ± 0.2°.

[0011] In some embodiments, the crystalline form I has an X-ray powder diffraction pattern substantially as Figure 1 shown; the crystalline form II has an X-ray powder diffraction pattern substantially as Figure 4 shown;

[0012] In Figure 1Among them, the X-ray powder diffraction pattern of the crystalline form I contains diffraction peaks at the following 2θ angles: 4.317° ± 0.2°, 8.538° ± 0.2°, 10.022° ± 0.2°, 10.680° ± 0.2°, 11.680° ± 0.2°, 12.777° ± 0.2°, 13.378° ± 0.2°, 13.978° ± 0.2°, 14.479° ± 0.2°, 14.762° ± 0.2°, 15.817° ± 0.2°, 17.038° ± 0.2°, 18.478° ± 0.2°, 19.678° ± 0.2°, 20.019° ± 0.2°, 20.636° ± 0.2°, 21.319° ± 0.2°, 21.556° ± 0.2°, 23.381° ± 0.2°, 25.620° ± 0.2°, 27.060° ± 0.2°, 27.500° ± 0.2°, 29.019° ± 0.2°, 29.519° ± 0.2°, 29.979° ± 0.2°, 30.739° ± 0.2°, 31.561° ± 0.2°, 32.584° ± 0.2°, 33.711° ± 0.2°, 34.378° ± 0.2°, 34.941° ± 0.2°, 35.842° ± 0.2°, 37.000° ± 0.2°, 37.721° ± 0.2°, 38.803° ± 0.2°, 39.082° ± 0.2°, 39.661° ± 0.2°, 41.199° ± 0.2°, 41.660° ± 0.2°, 43.340° ± 0.2°, 43.800° ± 0.2°, 44.546° ± 0.2°, 45.538° ± 0.2°, 47.739° ± 0.2°, 48.222° ± 0.2; among which, the relative intensity of the diffraction peak at 2θ angle of 21.556° ± 0.2° does not exceed 20%, and the relative intensity of the diffraction peak at 2θ angle of 34.378° ± 0.2° is not less than 10%;

[0013] In Figure 4Among them, the X-ray powder diffraction pattern of polymorph II contains diffraction peaks at the following 2θ angles: 5.979° ± 0.2°, 7.202° ± 0.2°, 8.258° ± 0.2°, 8.797° ± 0.2°, 9.499° ± 0.2°, 10.137° ± 0.2°, 11.361° ± 0.2°, 11.862° ± 0.2°, 12.503° ± 0.2°, 13.134° ± 0.2°, 13.920° ± 0.2°, 14.342° ± 0.2°, 15.218° ± 0.2°, 15.538° ± 0.2°, 16.159° ± 0.2°, 17.140° ± 0.2°, 17.561° ± 0.2°, 17.880° ± 0.2°, 18.960° ± 0.2°, 19.258° ± 0.2°, 20.339° ± 0.2°, 20.761° ± 0.2°, 21.660° ± 0.2°, 22.161° ± 0.2°, 22.856° ± 0.2°, 23.380° ± 0.2°, 23.862° ± 0.2°, 24.160° ± 0.2°, 25.119° ± 0.2°, 25.798° ± 0.2°, 26.482° ± 0.2°, 26.722° ± 0.2°, 27.060° ± 0.2°, 27.422° ± 0.2°, 28.138° ± 0.2°, 28.662° ± 0.2°, 29.365° ± 0.2°, 29.899° ± 0.2°, 31.441° ± 0.2°, 32.162° ± 0.2°, 32.701° ± 0.2°, 33.961° ± 0.2°, 34.781° ± 0.2°, 35.739° ± 0.2°, 36.311° ± 0.2, 37.160° ± 0.2°, 37.525° ± 0.2°, 38.060° ± 0.2°, 38.555° ± 0.2°, 39.084° ± 0.2°, 41.039° ± 0.2°, 42.138° ± 0.2°, 42.980° ± 0.2°, 43.558° ± 0.2°, 44.220° ± 0.2°, 47.080° ± 0.2°, 48.924° ± 0.2°.

[0014] In some embodiments, the differential scanning calorimetry (DSC) curve of polymorph I contains endothermic peaks at 184.4 °C and 232.0 °C; the DSC curve of polymorph II contains endothermic peaks at 206.4 °C and 231.6 °C.

[0015] In some embodiments, polymorph I has a differential scanning calorimetry (DSC) curve substantially as Figure 2 shown; polymorph II has a DSC curve substantially as Figure 5 shown; or polymorph I has a DSC curve substantially as Figure 3The thermogravimetric analysis diagram shown; the crystal form II has substantially as Figure 6 the thermogravimetric analysis diagram shown.

[0016] In a second aspect, the present invention provides a method for preparing the crystal form II, comprising:

[0017] Step 1: Add the compound of formula I into a solvent;

[0018] Step 2: Heat and stir until clear;

[0019] Step 3: Cool to room temperature to precipitate a solid, and filter to obtain crystal form II;

[0020] wherein the solvent is methanol or ethanol.

[0021] In a third aspect, the present invention provides a method for preparing the crystal form I, characterized in that the method comprises:

[0022] Step 1: Add the compound of formula I into a good solvent;

[0023] Step 2: After heating to the reflux temperature of the solvent and stirring until clear, add a poor solvent;

[0024] Step 3: Cool to room temperature to precipitate a solid, and filter to obtain crystal form I;

[0025] wherein the good solvent is methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, acetone; the poor solvent is water or n-heptane.

[0026] In a fourth aspect, the present invention provides a pharmaceutical composition comprising the crystal form I or crystal form II and a pharmaceutically acceptable carrier, excipient, adjuvant, diluent or the like.

[0027] In a fifth aspect, the present invention provides the use of the crystal form or pharmaceutical composition in the preparation of a drug for preventing, treating, treating or alleviating influenza virus infection diseases in patients.

[0028] The preparation of the crystal form described in the present invention is described in detail in the Examples section, and the pharmacokinetic experiments and stability experiments of the crystal form are provided. It has been proven that the crystal form described in the present invention has good stability and pharmacokinetic properties. Description of the Drawings

[0029] Figure 1 is the X-ray powder diffraction (XRD) pattern of crystal form I of the compound of formula I;

[0030] Figure 2 is the differential scanning calorimetry (DSC) pattern of crystal form I of the compound of formula I;

[0031] Figure 3It is the thermogravimetric analysis (TGA) diagram of Crystal Form I of the compound of Formula I;

[0032] Figure 4 It is the X-ray powder diffraction (XRD) diagram of Crystal Form II of the compound of Formula I;

[0033] Figure 5 It is the differential scanning calorimetry (DSC) diagram of Crystal Form II of the compound of Formula I;

[0034] Figure 6 It is the thermogravimetric analysis (TGA) diagram of Crystal Form II of the compound of Formula I;

[0035] Figure 7 It is the X-ray powder diffraction (XRD) diagram of Crystal Form III of the compound of Formula I;

[0036] Figure 8 It is the X-ray powder diffraction (XRD) diagram of Crystal Form IV of the compound of Formula I;

[0037] Figure 9 It is the X-ray powder diffraction (XRD) diagram of Crystal Form V of the compound of Formula I. Detailed implementation manners

[0038] The X-ray powder diffraction analysis method used in the present invention: SmartLab diffractometer produced by Rigaku Corporation, Japan; Cu radiation, voltage 40 kV, current 30 mA; scanning range 3° - 50°, scanning step 0.02°, scanning speed 10° / min; peak searching through XRD analysis software Jade; obtaining diffraction peak angle-intensity data.

[0039] The TGA analysis method used in the present invention: Using a thermogravimetric analyzer Q500 to detect and analyze the weight loss of the sample during heating, with a nitrogen purge gas flow rate of 60 mL / min in the sample chamber, heating from room temperature to 400 °C at a heating rate of 10 °C / min, and data analysis software TA Universal Analysis.

[0040] The DSC analysis method used in the present invention is: Using a differential scanning calorimeter Q2000 to analyze the thermal properties of the sample, with a nitrogen purge gas flow rate of 50 mL / min in the sample chamber. Equilibrating at 40 °C, heating from 25 °C to 250 °C at a heating rate of 10 °C / min, and data analysis software TA Universal Analysis.

[0041] The term "comprising" is an open-ended expression, that is, it includes the content specified in the present invention, but does not exclude other aspects of the content.

[0042] The description of terms such as "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0043] In the present invention, h represents hour; min represents minute; g represents gram; both mL and ml represent milliliter; RRT represents relative retention time.

[0044] "Room temperature" in the present invention refers to a temperature ranging from about 10 °C to about 40 °C. In some embodiments, "room temperature" refers to a temperature ranging from about 20 °C to about 30 °C; in other embodiments, "room temperature" refers to 20 °C, 22.5 °C, 25 °C, 27.5 °C, etc.

[0045] In the present invention, the expressions such as "Compound I", "the compound shown in Formula I", and "Formula I" represent the same compound.

[0046] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further elaborate on the present invention.

[0047] The compound of Formula I [[(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[c,e]thiepten-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl]oxo]methyl (ethyl-d5) carbonate was prepared according to the synthesis method in the examples of Chinese Patent Application CN116284048A.

[0048] The reagents used in the present invention can all be purchased from the market or can be prepared by the methods described in the present invention.

[0049] Example 1 Preparation of Crystal Form I

[0050] Add 3.0 g of the compound of formula I to a 100 ml three-necked flask, then add 93 ml of absolute ethanol, heat up to the reflux temperature and stir until dissolved clearly. At the reflux temperature, while stirring, add 135 ml of purified water dropwise to the reaction flask, cool to room temperature and stir. Crystals precipitate out, and filter to obtain 2.8 g of white solid (yield 93%).

[0051] Its spectrum was identified by X-ray powder diffraction analysis to be consistent with Figure 1 basically the same.

[0052] Preparation of Crystal Form II in Example 2

[0053] Add 3.0 g of the compound of formula I to a 100 ml three-necked flask, then add 63 ml of methanol, heat up to dissolve, stir and cool to room temperature to precipitate crystals, filter to obtain 2.6 g of white solid (yield 87%).

[0054] Its spectrum was identified by X-ray powder diffraction analysis to be consistent with Figure 4 basically the same.

[0055] Preparation of Crystal Form III in Example 3

[0056] Add 3.0 g of the compound of formula I to a 100 ml three-necked flask, add 6 ml of dichloromethane, stir at room temperature until the solid dissolves clearly, and add 3 ml of n-heptane dropwise to the reaction flask while stirring to precipitate crystals, filter to obtain 2.7 g of off-white solid (yield 90%).

[0057] Its spectrum was identified by X-ray powder diffraction analysis to be consistent with Figure 7 basically the same.

[0058] Preparation of Crystal Form IV in Example 4

[0059] Add 2.0 g of the compound of formula I to a 100 ml three-necked flask, add 8 ml of N-methylpyrrolidone, stir until dissolved clearly, then add 14 ml of purified water dropwise to the reaction flask to precipitate crystals, filter to obtain 2.7 g of off-white solid (yield 90%).

[0060] Its spectrum was identified by X-ray powder diffraction analysis to be consistent with Figure 8 basically the same.

[0061] Preparation of Crystal Form V in Example 5

[0062] Add 2.0 g of the compound of formula I to a 100 ml three-necked flask, add 10 ml of tetrahydrofuran, stir until dissolved clearly, then add 20 ml of purified water dropwise to the reaction flask to precipitate crystals, filter to obtain 2.7 g of off-white solid (yield 90%).

[0063] Its spectrum was identified by X-ray powder diffraction analysis to be consistent with Figure 9 basically the same.

[0064] Example 6 Pharmacokinetic Experiment of the Crystal Forms of the Invention

[0065] Pharmacokinetic Experiment Method

[0066] Use methylcellulose (MC) to prepare suspensions of polymorph I and polymorph II of the compound of formula I of the present invention respectively, and orally administer them to SD rats by gavage. The SD rats are supplied with the sample at 1 mg / kg, with three animals in each group. Before dosing (0 h), 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after dosing, about 0.2 mL of blood is collected from the orbital cavity, centrifuged at 1700 g for 10 min to separate the plasma, and the blood drug concentration is determined by LC-MS / MS method. When the measured concentration value is lower than 80% of the lower limit of quantitation of the analyte, it is counted as not detected (counted as zero) or lower than the lower limit of quantitation (counted as ND). Before reaching the peak, it is counted as zero, and after reaching the peak, it is counted as ND. The pharmacokinetic parameters are calculated using Phoenix win nonlin 8.0 software. max Before reaching the peak, it is counted as zero, and after reaching the peak, it is counted as ND. The pharmacokinetic parameters are calculated using Phoenix win nonlin 8.0 software.

[0067] The main pharmacokinetic parameters are shown in Table 1 below:

[0068] Table 1 Main Pharmacokinetic Parameters of the Crystal Forms of the Invention

[0069]

[0070] As can be seen from Table 1, the exposure amounts of polymorph I and polymorph II of the present invention in rats are relatively large, and they have good pharmacokinetic properties.

[0071] Example 7 Stability Experiment

[0072] (1) High-temperature experiment: Take an appropriate amount of the test sample and put it into a flat weighing bottle, spread it into a thin layer with a thickness of ≤5 mm, and place it at 60 °C for 30 days. Samples are taken on the 5th, 10th, and 30th days to observe the color change of the sample, and the purity of the sample is detected by HPLC;

[0073] (2) High-humidity experiment: Take an appropriate amount of the test sample and put it into a flat weighing bottle, spread it into a thin layer with a thickness of ≤5 mm, and place it at 25 °C and RH 90% ± 5% for 10 days. Samples are taken on the 5th and 10th days to observe the color change of the sample, and the purity of the sample is detected by HPLC;

[0074] (3) Light experiment: Take an appropriate amount of the test sample and put it into a flat weighing bottle, spread it into a thin layer with a thickness of ≤5 mm, and place it in an open light box (with ultraviolet light). Samples are taken after placing it for 10 days under the conditions of illuminance 5000 ± 500 lx and ultraviolet lamp energy 90 μw / cm2 to observe the color change of the sample, and the purity of the sample is detected by HPLC.

[0075] Table 2 Stability Experiment Data of Polymorph I of the Invention

[0076]

[0077]

[0078] Verified by experiments, both polymorph I and polymorph II of the present invention can achieve similar stability effects. Under the conditions of light, high temperature and high humidity, there are no obvious changes in the crystal form, purity, specific rotation, appearance, loss on drying and impurity content of polymorph I and polymorph II. Compared with the solid of the compound of formula I prepared by the synthesis method in the examples of Chinese Patent CN116284048A, and polymorph III, polymorph IV and polymorph V, polymorph I and polymorph II are more suitable for pharmaceutical use, which is beneficial to ensuring the effectiveness and safety of drugs. Among them, the specific stability experimental data of polymorph I of the present invention can be seen in Table 2.

[0079] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the technical principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A crystalline form of a compound as shown in formula I, wherein the crystalline form is crystalline form I and crystalline form II, in, The X-ray powder diffraction pattern of the crystalline form I comprises the following diffraction peaks at 2θ angles: 4.317°±0.2°, 8.538°±0.2°, 17.038°±0.2°, 21.556°±0.2°, 25.620°±0.2°, 29.979°±0.2°, 34.378°±0.2°; wherein the relative intensity of the diffraction peak at 2θ angle of 21.556°±0.2° is not more than 20%, and the relative intensity of the diffraction peak at 2θ angle of 34.378°±0.2° is not less than 10%; The X-ray powder diffraction pattern of the crystalline form II comprises the following diffraction peaks at 2θ angles: 5.979°±0.2°, 8.258°±0.2°, 8.797°±0.2°, 11.862°±0.2°, 14.342°±0.2°, 16.159°±0.2°, 17.561°±0.2°, 19.258°±0.2°, 21.660°±0.2°, 23.380°±0.2°, 25.119°±0.2°, 25.798°±0.2°, 27.060°±0.2°, 27.422°±0.2°, and 29.899°±0.2°.

2. The crystal form according to claim 1, characterized in that The X-ray powder diffraction pattern of the crystalline form I comprises the following diffraction peaks at 2θ angles: 4.317°±0.2°, 8.538°±0.2°, 10.680°±0.2°, 13.378°±0.2°, 14.479°±0.2°, 15.817°±0.2°, 17.038°±0.2°, 18.478°±0.2°, 20.019°±0.2°, 21.319°±0.2°, 21.556°±0.2°, 23.381°±0.2°, 25.620°±0.2°, 27.500°±0.2°, 29.019°±0.2°, 29.519°±0.2°, 29.979°±0.2°, 31. 561°±0.2°, 33.711°±0.2°, 34.378°±0.2°, 35.842°±0.2°, 37.721°±0.2°, 38.803°±0.2°, 39.661°±0.2°, 41.660°±0.2°, 43.340°±0.2°, 45.538°±0.2°, 47.739°±0.2°; wherein the relative intensity of the diffraction peak at 2θ angle of 21.556°±0.2° is not more than 20%, and the relative intensity of the diffraction peak at 2θ angle of 34.378°±0.2° is not less than 10%; the X-ray powder diffraction pattern of the crystalline form II comprises the following diffraction peaks at 2θ angles: 5.979°±0.2°, 7.2 02°±0.2°, 8.258°±0.2°, 8.797°±0.2°, 9.499°±0.2°, 10.137°±0.2°, 11.862°±0.2°, 12.503°±0.2°, 13.920°±0.2°, 14.342°±0.2°, 15.218°±0.2°, 1 6.159°±0.2°, 17.140°±0.2°, 17.561°±0.2°, 17.880°±0.2°, 19.258°±0.2°, 20.339°±0.2°, 21.660°±0.2°, 22.161°±0.2°, 23.380°±0.2°, 23.862°±0.2° .2°, 24.160°±0.2°, 25.119°±0.2°, 25.798°±0.2°, 26.482°±0.2°, 27.060°±0.2°, 27.422°±0.2°, 28.138°±0.2°, 28.662°±0.2°, 29.899°±0.2°, 31.4 41°±0.2°, 32.701°±0.2°, 33.961°±0.2°, 34.781°±0.2°, 35.739°±0.2°37.160°±0.2°, 37.525°±0.2°, 39.084°±0.2°, 47.080°±0.2°, 48.924°±0.2°.

3. The crystal form according to claim 1, characterized in that The crystalline form I has an X-ray powder diffraction pattern substantially as shown in FIG1 ; the crystalline form II has an X-ray powder diffraction pattern substantially as shown in FIG4 .

4. The crystal form according to claim 1, characterized in that The differential scanning calorimetry diagram of the crystalline form I comprises endothermic peaks at 184.4°C and 232.0°C; the differential scanning calorimetry diagram of the crystalline form II comprises endothermic peaks at 206.4°C and 231.6°C.

5. The crystal form according to claim 1, characterized in that The crystalline form I has a differential scanning calorimetry diagram substantially as shown in Figure 2; the crystalline form II has a differential scanning calorimetry diagram substantially as shown in Figure 5; or the crystalline form I has a thermogravimetric analysis diagram substantially as shown in Figure 3; the crystalline form II has a thermogravimetric analysis diagram substantially as shown in Figure 6.

6. A method for preparing the crystalline form II according to any one of claims 1 to 5, characterized in that the method include: Step 1, adding the compound of formula I into a solvent; Step 2: Heat and stir until dissolved; Step 3, cooling to room temperature to precipitate solid, filtering to obtain Form II; The solvent is methanol or ethanol.

7. A method for preparing the crystalline form I according to any one of claims 1 to 5, characterized in that: Methods include: Step 1, adding the compound of formula I into a good solvent; Step 2, heating to the solvent reflux temperature, stirring and clarifying, and then adding a poor solvent; Step 3, cooling to room temperature to precipitate solid, filtering to obtain Form I; The good solvent is methanol, ethanol, isopropanol, acetonitrile, ethyl acetate and acetone; the poor solvent is water and n-heptane.

8. A pharmaceutical composition, characterized in that It comprises the crystalline form I or crystalline form II according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier, excipient, adjuvant, diluent or a combination thereof.

9. Use of the crystal form according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing, treating, curing or alleviating influenza virus infection in patients.

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