Crystalline forms of nucleoside compounds

Abstract

The present invention provides a crystalline form of a nucleoside compound, which is crystalline form I of ATV014, which has good solubility and thermal stability, and has a better bioavailability and dissolution curve in certain formulations. Its good permeability and thermal stability make it suitable for use in certain pharmaceutical formulations.

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical technology and relates to a crystalline form of a nucleoside compound. [Background technology]

[0002] The novel coronavirus is an enveloped, single-stranded RNA virus belonging to the βcoronavirus genus. Similar to SARS and MERS, the SARS-CoV-2 genome encodes nonstructural proteins, including 3C-like protease (3CL), papain-like protease (PL), helicase, and RNA-dependent RNA polymerase (RdRp). Structural proteins include spike glycoproteins and accessory proteins. The novel coronavirus infects human respiratory epithelial cells by binding to the angiotensin-converting enzyme (ACE2) receptor on the surface of the cells. After entering the host cell, the virus disassembles, releasing the nucleocapsid and viral RNA into the cytoplasm. The open reading frame (ORF1a / b) at the 5' end of the viral RNA encodes polyproteins (pp1a and pp1ab), which play important roles in the processing and maturation of enzymes required for viral replication. pp1a and pp1ab are cleaved by papain-like protease (PLpro) and 3C-like protease (3CLpro), producing nonstructural proteins, including RNA-dependent RNA polymerase and helicase, which play crucial roles in the transcription and replication of SARS-CoV-2. Currently, the coronavirus surface spike glycoproteins used for receptor recognition and the key proteins involved in replication and transcription, 3CLpro, PLpro, and RdRp, are four attractive targets for antiviral drug development.

[0003] Through the applicant's previous research on remdesivir and its precursor compound GS-441524 (Li, et al., J. Med. Chem. 2020), the applicant discovered that GS-441524 had superior antiviral activity to remdesivir in in vivo mouse activity tests. Compound GS-441524 has a similar mechanism of action to remdesivir but exhibits superior safety. Accordingly, the applicant has filed a patent application (application number or patent number 202011000517.2) describing the use of compound GS-441524 as an agent for the prevention, mitigation, and / or treatment of SARS-CoV-2.

[0004] The compound represented by formula ATV014 is a derivative of compound GS-441524, and the inventors' research has found that the compound represented by formula ATV014 has better activity and bioavailability than compound GS-441524. [ka]

[0005] A single drug may exist in different solid forms, and different solid forms of the same drug may differ significantly in terms of appearance, solubility, melting point, dissolution rate, biological efficacy, etc., which may have different effects on the stability, bioavailability, and therapeutic effect of the drug. Therefore, there is a need for new solid forms of ATV014 with better physicochemical properties, in particular, relatively high solubility, good stability, or high bioavailability. Summary of the Invention

[0006] In order to solve the above problems, the present invention provides the following technical solutions. In a first aspect, there is provided a crystalline form of the compound represented by formula (ATV014). The crystalline form has good physical and chemical stability, low hygroscopicity, which is advantageous for long-term storage, good solubility and thermal stability, and a better bioavailability and dissolution curve in certain formulations. Its good solubility and thermal stability make it suitable for use in certain pharmaceutical formulations. In a second aspect, a pharmaceutical composition comprising the crystalline form is provided. In a third aspect, there is provided a use of said crystalline form or said pharmaceutical composition. In a fourth aspect, there is provided a method for producing said crystalline form.

[0007] In a first aspect, there is provided a crystalline form of a compound of formula (ATV014). In the present invention, the compound represented by formula (ATV014) is named ATV014. [ka]

[0008] The present invention specifically contemplates the existence of multiple solid forms of ATV014 and has discovered crystalline Form I of the compound ATV014, which has an X-ray powder diffraction pattern substantially as shown in Figure 1, and in some embodiments, a differential scanning calorimetry curve for Form I substantially as shown in Figure 2. In some embodiments, the thermogravimetric analysis pattern for Form I of ATV014 is substantially as shown in Figure 2.

[0009] In some embodiments, crystalline Form I of compound ATV014 has at least one, or at least two, or all of properties (a) through (c). (a) The X-ray powder diffraction pattern of crystalline form I is essentially as shown in FIG. (b) The differential scanning calorimetry curve of crystalline form I is essentially that shown in FIG. (c) The thermogravimetric analysis pattern of crystalline form I is essentially as shown in FIG.

[0010] In some embodiments, the crystalline Form I of ATV014 has the following characteristics: (a) The X-ray powder diffraction pattern of crystalline form I is essentially as shown in FIG. (b) The differential scanning calorimetry curve of crystalline form I is essentially that shown in Figure 2. (c) The thermogravimetric analysis pattern of crystalline form I is approximately the same as that shown in Figure 2.

[0011] In some embodiments, crystalline Form I of ATV014 has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, or at least six 2θ degree reflections, the maxima of which and the XRPD pattern are approximately as shown in FIG. 1.

[0012] In some embodiments, the XRPD diffraction angles 2θ of crystalline Form I of ATV014 have characteristic peaks at 9.69±0.2°, 9.84±0.2°, and 18.70±0.2°.

[0013] In some embodiments, the X-ray powder diffraction pattern of Form I of ATV014 has characteristic peaks at diffraction angles 2θ of 9.69±0.2°, 18.70±0.2°, and 23.88±0.2°, and at one, two, or three of the following diffraction angles 2θ: 9.84±0.2°, 17.74±0.2°, and 19.38±0.2°.

[0014] In some embodiments, the X-ray powder diffraction pattern of ATV014 crystalline Form I has characteristic peaks at diffraction angles 2θ±0.2° of 9.69, 18.70, and 23.88, and one or two of the following diffraction angles 2θ: 9.84±0.2°, 17.74±0.2°, and 19.38±0.2°.

[0015] In some embodiments, the X-ray powder diffraction pattern of Form I of ATV014 has characteristic peaks at diffraction angles 2θ±0.2° of 9.69±0.2°, 9.84±0.2°, 17.74±0.2°, 18.70±0.2°, 19.38±0.2°, and 23.88±0.2°, and at diffraction angles 2θ±0.2°, and at one of 13.19±0.2°, 15.61±0.2°, and 21.31±0.2°.

[0016] In some embodiments, the X-ray powder diffraction pattern of Form I of ATV014 has characteristic peaks at diffraction angles 2θ of 9.69±0.2°, 9.84±0.2°, 17.74±0.2°, 18.70±0.2°, 19.38±0.2°, and 23.88±0.2°, and two of the following characteristic peaks at diffraction angles 2θ: 13.19±0.2°, 15.61±0.2°, and 21.31±0.2°.

[0017] In some embodiments, the X-ray powder diffraction pattern of Form I of ATV014 has diffraction angles 2θ of 9.69±0.2°, 9.84±0.2°, 13.19 ±0.2°, 15.61±0.2°, 17.74±0.2°, 18.70±0.2°, 19.38±0.2°, 21.31±0.2°, and 23.88±0.2°.

[0018] In some embodiments, the X-ray powder diffraction pattern of crystalline Form I of ATV014 has diffraction angles 2θ of 9.69±0.2°, 9.84±0.2°, 13.19 It has characteristic peaks at at least three positions among 15.61±0.2°, 17.74±0.2°, 18.70±0.2°, 19.38±0.2°, 21.31±0.2°, and 23.88±0.2°.

[0019] In some embodiments, the X-ray powder diffraction pattern of Form I of ATV014 has diffraction angles 2θ of 9.69±0.2°, 9.84±0.2°, 13.19 It has characteristic peaks at diffraction angles 2θ of 17.41±0.2° and 26.01±0.2°, 15.61±0.2°, 17.74±0.2°, 18.70±0.2°, 19.38±0.2°, 21.31±0.2° and 23.88±0.2°, and has characteristic peaks at diffraction angles 2θ of 17.41±0.2° and 26.01±0.2°.

[0020] In some embodiments, the X-ray powder diffraction pattern of Form I of ATV014 has diffraction angles 2θ of 9.69±0.2°, 9.84±0.2°,13.19 It has characteristic peaks at diffraction angles 2θ of 17.41±0.2° and 26.01±0.2°.

[0021] In some embodiments, the X-ray powder diffraction pattern of Form I of ATV014 has diffraction angles 2θ of 9.69±0.2°, 9.84±0.2°, 13.19 ±0.2°, 15.61±0.2°, 17.41±0.2°, 17.74±0.2°, 18.70±0.2°, 19.38±0.2°, 21.31±0.2°, 23.88±0.2°, and 26.01±0.2°.

[0022] In some embodiments, the X-ray powder diffraction pattern of Form I of ATV014 has diffraction angles 2θ of 9.69±0.2°, 9.84±0.2°, 13.19 ±0.2°, 15.61±0.2°, 17.41±0.2°, 17.74±0.2°, 18.70±0.2°, 19.38±0.2°, 21.31±0.2°, 23.88±0.2°, and 26.01±0.2°.

[0023] In some embodiments, the differential scanning calorimetry curve for crystalline Form I of ATV014 has an endothermic peak at about 212°C to about 238°C. In some embodiments, the differential scanning calorimetry curve for crystalline Form I of ATV014 has an endothermic peak at about 220°C to about 235°C. In some embodiments, the differential scanning calorimetry curve for crystalline Form I of ATV014 has an endothermic peak with a peak value of 226°C to 230°C. In some embodiments, the differential scanning calorimetry curve for crystalline Form I of ATV014 essentially resembles the differential scanning calorimetry curve of Figure 2.

[0024] In some embodiments, the differential scanning calorimetry curve for crystalline Form I of ATV014 shows a melting point of 225.14±5°C.

[0025] In some embodiments, the thermogravimetric analysis curve for Crystalline Form I of ATV014 shows a weight loss of less than 1% from about 30°C to about 200°C. In some embodiments, the thermogravimetric analysis curve for Crystalline Form I of ATV014 shows a weight loss of less than 0.5% from 30°C to 200°C. In some embodiments, the thermogravimetric analysis curve for Crystalline Form I of ATV014 shows a weight loss of less than 1% from 100°C to 200°C. In some embodiments, the thermogravimetric analysis curve for Crystalline Form I of ATV014 shows a weight loss of less than 0.5% from 100°C to 200°C. In some embodiments, the thermogravimetric analysis curve for Crystalline Form I of ATV014 essentially resembles the thermogravimetric analysis curve of FIG. 2.

[0026] In some embodiments, the crystalline Form I of ATV014 is essentially pure.

[0027] The novel crystalline form provided by the present invention has not been reported yet. Through research, the inventors of the present invention have overcome this difficulty and found a novel crystalline form suitable for development. The novel crystalline form has better stability and solubility, and a more stable crystalline form is of great significance for improving the quality of drugs.

[0028] The novel crystalline form provided by the present invention has good stability and is not susceptible to deliquescence under humid conditions, which is convenient for long-term storage and storage of drugs. The crystalline form provided by the present invention has good stability, remarkable refinement effect, and effectively prevents the occurrence of crystallization during drug storage and development, thereby avoiding changes in bioavailability and efficacy, and has great economic value.

[0029] In a second aspect, a pharmaceutical composition comprising the crystalline form is provided.

[0030] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of ATV014 crystalline Form I and pharmaceutically acceptable auxiliary materials or excipients. Typically, a therapeutically effective amount of ATV014 crystalline Form I is mixed or contacted with one or more medicinal auxiliary materials to prepare a pharmaceutical composition or formulation, prepared by methods well known in the pharmaceutical arts. The pharmaceutical composition or formulation can be used to treat a disease associated with a viral infection, or to prevent, alleviate, and / or treat symptoms, such as a disease associated with SARS-CoV-2.

[0031] In some embodiments, a pharmaceutical composition comprising the free base of ATV014, wherein at least 80% of the free base of the compound ATV014 is ATV014 crystalline Form I. In some embodiments, a pharmaceutical composition comprising the free base of ATV014, wherein at least 90% of the ATV014 free base is ATV014 crystalline Form I. In some embodiments, a pharmaceutical composition comprising the free base of ATV014, wherein at least 95% of the ATV014 free base is ATV014 crystalline Form I. In some embodiments, a pharmaceutical composition comprising the free base of ATV014, wherein at least 99% of the ATV014 free base is ATV014 crystalline Form I.

[0032] In a third aspect, there is provided a use of said crystalline form or said pharmaceutical composition.

[0033] Use of said crystalline form or said pharmaceutical composition in the manufacture of a medicament for the prevention, alleviation and / or treatment of a disease or symptom associated with a viral infection.

[0034] The virus is selected from a coronavirus, which in some embodiments is selected from SARS-CoV-2 or a variant thereof.

[0035] The compounds of the present invention, including crystalline form I of ATV014, can be used to treat diseases associated with viral infections, or in methods for preventing, alleviating, and / or treating symptoms of diseases such as those associated with SARS-CoV-2.

[0036] In a fourth aspect, there is provided a method for preparing crystalline Form I of ATV014, which comprises dissolving ATV014 in a good solvent, which may be any solid form of ATV014, followed by adding an anti-solvent to precipitate crystals, filtering and drying to obtain the crystalline form.

[0037] Dissolving ATV014 in a good solvent may be dissolving ATV014 in a good solvent under room temperature conditions.

[0038] In some embodiments, the good solvent is selected from dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, tetrahydrofuran, dichloromethane, methanol, or a combination thereof. The anti-solvent is selected from water, methyl tert-butyl ether, or a combination thereof. In some embodiments, the good solvent is dimethyl sulfoxide, N-methylpyrrolidone, or a combination thereof, and the anti-solvent is water. In some embodiments, the good solvent is dimethyl sulfoxide and the anti-solvent is water. In some embodiments, the good solvent is N-methylpyrrolidone and the anti-solvent is water. In some embodiments, the good solvent is tetrahydrofuran and the anti-solvent is water, methyl tert-butyl ether, or a combination thereof. In some embodiments, the good solvent is a mixed solvent of dichloromethane and methanol, and the anti-solvent is methyl tert-butyl ether. [Effects of the Invention]

[0039] Compared with the prior art, the present invention has the following technical advantages: (1) The crystalline form I of ATV014 provided by the present invention does not change in crystalline form and chemical purity even when left under hygroscopic conditions, and has good physical and chemical stability. (2) According to the DVS results, the crystalline form I of ATV014 has low hygroscopicity, which is advantageous for long-term storage. (3) The crystalline form I of ATV014 provided by the present invention has good solubility and thermal stability, and has better bioavailability and dissolution curve in certain formulations. Its good solubility and thermal stability make it suitable for use in certain drug formulations.

[0040] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings:

[0041] The term "crystalline form" refers to one unique regular arrangement and / or conformation of molecules in a compound lattice.

[0042] The term "essentially pure" refers to a crystalline form that is substantially free of one or more other crystalline forms, where the purity of the crystalline form is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%, or the crystalline form comprises other crystalline forms that represent less than 20%, less than 10%, less than 5%, less than 3%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% of the total volume or weight percentage of the crystalline form.

[0043] "Substantially free" of one or more other crystalline forms means that the content of other crystalline forms is less than 20%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% of the total volume or weight.

[0044] The term "essentially as shown" in an X-ray powder diffraction pattern means that at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern appear in those figures.

[0045] The term "anti-solvent" refers to a solvent that promotes a solution to reach a state of supersaturation or crystallization. In some embodiments, ATV014 has a solubility in the anti-solvent of less than 0.001 g / L, less than 0.01 g / L, less than 0.1 g / L, less than 0.2 g / L, less than 0.3 g / L, less than 0.4 g / L, less than 0.5 g / L, less than 0.6 g / L, less than 0.8 g / L, less than 1 g / L, less than 2 g / L, less than 3 g / L, less than 4 g / L, less than 5 g / L, less than 6 g / L, less than 7 g / L, less than 8 g / L, less than 9 g / L, or less than 10 g / L.

[0046] The term "peak or characteristic peak" of the data in the patterns and / or figures refers to a feature that those skilled in the art would not attribute to background noise.

[0047] All numbers in the present invention are approximations, regardless of whether or not phrases such as "about" or "approximately" are used. The numerical value of a number may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15%, 20%, etc. Whenever a number having a value of N is disclosed, any number having a value of N±1%, N±2%, N±3%, N±5%, N±7%, N±8%, N±10%, N±15%, or N±20% is expressly disclosed, where "±" means addition or subtraction. The lower limit R of a numerical range L and upper limit R U Whenever R is disclosed, any number within the disclosed range is expressly disclosed. Specifically, R = R L +K*(R U -R L ), where K is a variable from 1% to 100% in 1% increments, i.e., 1%, 2%, 3%, 4%, 5%, 50%, 51%, 52%, 95%, 96%, 97%, 98%, 99%, or 100%. Specifically, numerical ranges defined by two R values ​​are expressly disclosed herein.

[0048] "Room temperature" in the present invention refers to ambient temperature, and is a temperature from about 10°C to about 40°C. In some embodiments, "room temperature" refers to a temperature from about 20°C to about 30°C. In some embodiments, "room temperature" refers to a temperature from about 25°C to about 30°C. In some embodiments, "room temperature" refers to 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, etc.

[0049] The term "treatment," as used herein, unless otherwise specified, means reversing, alleviating, inhibiting the progression of, or preventing the disease, disorder, or one or more symptoms of such disease, disorder, to which the term applies. As used herein, the term "treatment" refers to the act of treating as defined above as "treatment."

[0050] In the context of the present invention, "crystalline Form I of ATV014" is synonymous with "crystalline Form I of the free base of ATV014". [Brief explanation of the drawings]

[0051] [Figure 1] 1 is an X-ray powder diffraction pattern of crystalline form I of ATV014 prepared in an example of the present invention. [Figure 2] 1 shows a differential scanning calorimetry pattern (DSC) and a thermogravimetric analysis pattern (TGA) of crystalline form I of ATV014, an example of the present invention. [Figure 3] 1 is an XRPD overlay map of a stability test sample of crystalline form I of ATV014, an example of the present invention. [Figure 4] 1 is an XRPD overlay map of the remaining solid after solubility measurement of crystalline form I of ATV014, an example of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0052] In order for those skilled in the art to better understand the technical solutions of the present invention, several non-limiting embodiments are further disclosed below to describe the present invention in more detail.

[0053] All reagents used in the present invention are commercially available or prepared by the methods described herein.

[0054] Instrument Parameters Unless otherwise specified in the parameters, all of the following analyses are performed at room temperature.

[0055] X-ray powder diffraction studies X-ray powder diffraction patterns were collected using a Bruker D8 Advance X-ray diffractometer (Germany) equipped with an autosampler using a zero-background sample disc. The radiation source was Cu kα (λ = 1.5418 Å), with the light pipe voltage set at 40 kV and the light pipe current set at 40 mA. The X-ray divergence slit was 0.6 mm. An appropriate amount of sample was taken and gently pressed with a clean glass slide under ambient conditions onto the center of the zero-background sample disc to obtain a flat surface, and the zero-background sample shelf was then fixed. The sample was subjected to diffraction analysis over a range of 3–40° (2θ) with a scan step of 0.02° (2θ). The software used for data collection was DIFFRAC.COMMANDER, and data were analyzed and presented using DIFFRAC.EVA.

[0056] Differential scanning calorimetry curve (DSC) Samples are subjected to DSC analysis on aluminum discs with perforated lids using a TA Instrument Discovery DSC 250 instrument. The sample (approximately 2-5 mg) is weighed onto the aluminum disc, capped with Tzero, the sample weight is precisely recorded, and the sample is transferred to the instrument for measurement. The instrument is purged with nitrogen at 50 mL / min. Data is collected between 25°C and 300°C at a heating rate of 10°C / min. Data is analyzed and displayed in TRIOS.

[0057] Thermogravimetric analysis (TGA) Samples were analyzed by TGA on a TA Instrument Discovery TGA 55 instrument with an open aluminum disc. A 2-5 mg sample was placed on a pre-equilibrated aluminum sample disc and heated from ambient temperature to 300°C at 10°C / min. The sample chamber was maintained with a nitrogen gas flow of 25 mL / min. In the TGA pattern, the horizontal axis represents temperature (°C) and the vertical axis represents the percentage of weight loss (Weight (%)).

[0058] Dynamic Water Sorption Analysis (DVS) Obtain moisture adsorption / desorption data for the sample using DVS Intrinsic. Place 10-50 mg of sample in the sample chamber and automatically weigh it. Set the parameters according to Table 1 to analyze the sample hygroscopicity.

[0059] [Table 1]

[0060] Detection of crystalline forms by high performance liquid chromatography (HPLC) Liquid chromatography is performed using an Agilent HPLC 1260 series.

[0061] [Table 2]

[0062] The above various dosage forms of drugs can be prepared by conventional methods in the pharmaceutical field. In the present invention, the compound structures indicated by the abbreviations of some compounds are shown in Table 3.

[0063] [Table 3]

[0064] In describing the experimental details, certain abbreviations and acronyms are used, most of which will be understood by those skilled in the art, and the following table contains a list of these abbreviations and acronyms:

[0065] [Table 4]

[0066] The compound of formula (ATV014) of the present invention can be prepared by referring to the methods disclosed in the prior art, for example, by the methods disclosed in Examples 1-3 of Chinese Patent CN2021106212456, or by the methods in the following Examples.

[0067] Example 1 Preparation of ATV014 [ka]

[0068] A 500 mL reactor was equipped with a stirrer, a thermometer, and a constant pressure dropping funnel. Add acetone (300 mL) dried over magnesium sulfate, and then add 2,2-dimethoxypropane (17 g, 0.16 mol). Add concentrated sulfuric acid (2.4 mL, 0.04 mol) dropwise to the mixture at room temperature. After 5 minutes, the addition is complete and the solid begins to dissolve. The temperature is raised to 45 °C and the reaction is continued for 4 hours. Monitor the reaction for completion by HPLC (OD-3 column, mobile phase: n-hexane / isopropanol = 80:20, flow rate: 0.8 mL / min, sample injection volume: 1 μL). Stop the reaction, cool in an ice bath, add solid NaHCO3 (10 g) and water (30 mL), adjust the pH to 7-8 with sodium bicarbonate, remove the solvent by distillation under reduced pressure, and dilute the residue with ethyl acetate (300 mL). Wash the ethyl acetate layer with water (80 mL) and saturated brine (80 mL), and dry over anhydrous sodium sulfate. The mixture was filtered under reduced pressure, and the filtrate was distilled under reduced pressure until about 100 mL of solvent remained. The residue was slowly poured into petroleum ether cooled in an ice bath and vigorously stirred to wash out a large amount of white solid. The mixture was filtered under suction to obtain 10.5 g of compound 1 as a white solid, with a yield of 91%.

[0069] Dissolve 150 g of compound 1 in 15 mL of dichloromethane, add cyclohexanecarboxylic acid and 554.0 mg of 4-dimethylaminopyridine, and stir for 10 minutes. Then add 10.2 g of dicyclohexylcarbodiimide and stir at room temperature for 24 hours. Separate compound 2 (white solid) by column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain compound 2. Dissolve compound 2 in 30 mL of 37% aqueous hydrochloric acid and 150 mL of tetrahydrofuran. Stir for 6 hours. Add sodium carbonate to adjust the pH to 8. Remove the organic solvent by rotary evaporation to obtain ATV014 (white solid).

[0070] Example 2 Preparation of ATV014 Crystalline Form I General method: At room temperature, add approximately 26 mg of ATV014 (the sample prepared in Example 1) to a certain amount of solvent. After the sample is completely dissolved, slowly add a certain amount of antisolvent (poor solvent) dropwise to cause antisolvent precipitation. Filter and dry to obtain the corresponding ATV014 crystalline form I. The experimental results are shown in Table 5.

[0071] [Table 5]

[0072] ATV014 crystalline form I is an amorphous form. The X-ray powder diffraction pattern of crystalline form I is shown in Figure 1, and the complete absorption peaks are listed in Tables 6 to 8. The differential scanning calorimetry curve of crystalline form I is essentially shown in Figure 2. The thermogravimetric analysis pattern of crystalline form I is essentially shown in Figure 2. Crystalline Form I of ATV014 has diffraction peaks at the following 2θ angles when measured by an X-ray powder diffractometer using Cu—K radiation.

[0073] [Table 6]

[0074] [Table 7]

[0075] [Table 8]

[0076] Example 3 Solid State Stability Studies Crystalline Form I of ATV014 with lot number 41579-025-C1 obtained in Example 2 was used in a solid state stability study, and was examined for XRPD and purity under the conditions shown in Table 9. The experimental results are shown in Table 9, and the XRPD overlay pattern is shown in Figure 3. Crystalline Form I of ATV014 was found to be 40 o C / 75%RH, 60 o After being stored at C and 92.5% RH for 7 days, its physical and chemical properties remain stable.

[0077] [Table 9]

[0078] Example 4 Solubility Measurement Based on the results of the salt formation screening study, the solubility of ATV014 crystalline Form I, lot number 41579-025-C5 obtained in Example 2, was measured at 37°C in FaSSIF, FeSSIF, SGF, and water at 0.5 hours, 2 hours, and 24 hours. The solubility and pH results are shown in Table 10. The solubility is pH-dependent, with higher solubility at lower pH. The solubility of ATV014 crystalline Form I in SGF is at most approximately 2.9 mg / mL. The solubility in water is at least approximately 0.005 mg / mL. During the solubility measurements, the XRPD pattern of the remaining solid was consistent with ATV014 crystalline Form I, and the crystalline form did not change. The XRPD pattern is shown in Figure 4.

[0079] [Table 10]

[0080] Example 5: Characterization of Crystal Form I of ATV014 Crystalline Form I of ATV014 obtained with lot number 41579-025-C5 in Example 2 was analyzed by polarized light microscopy (PLM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic moisture sorption (DVS), and the results are shown in Table 11.

[0081] [Table 11]

[0082] The method of the present invention has been described by a preferred embodiment, and it is clear that those skilled in the art can modify or appropriately modify and combine the methods and uses described herein to implement and apply the technology of the present invention within the content, spirit and scope of the present invention. Those skilled in the art can appropriately improve the implementation of process parameters by referring to the content of this specification. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in the present invention.

Claims

1. A crystal of ATV014, the structure of which is shown in formula ATV014, 【Chemistry 1】 The crystalline form of ATV014 is crystalline form I, and the X-ray powder diffraction pattern of crystalline form I of ATV014 has characteristic peaks at diffraction angles 2θ of 9.69±0.2°, 9.84±0.2°, 17.74±0.2°, 18.70±0.2°, 19.38±0.2°, and 23.88±0.2°.

2. 2. The crystal of ATV014 according to claim 1, wherein the X-ray powder diffraction pattern of the crystalline form I of ATV014 further has characteristic peaks at one, two or three of the diffraction angles 2θ of 13.19±0.2°, 15.61±0.2° and 21.31±0.2°.

3. 2. The crystal of ATV014 according to claim 1, wherein the X-ray powder diffraction pattern of the crystalline form I of ATV014 further has characteristic peaks at one or two of the diffraction angles 2θ of 13.19±0.2°, 15.61±0.2°, and 21.31±0.2°.

4. 2. The crystalline form I of ATV014 according to claim 1, wherein the X-ray powder diffraction pattern of the crystalline form I of ATV014 has characteristic peaks at diffraction angles 2θ of 9.69±0.2°, 9.84±0.2°, 13.19±0.2°, 15.61±0.2°, 17.74±0.2°, 18.70±0.2°, 19.38±0.2°, 21.31±0.2°, and 23.88±0.2°.

5. 5. The crystal of ATV014 according to claim 4, wherein the X-ray powder diffraction pattern of the crystalline form I of ATV014 further has characteristic peaks at one or two of the diffraction angles 2θ of 17.41±0.2° and 26.01±0.2°.

6. 6. A crystalline form of ATV014 according to any one of claims 1 to 5, wherein the X-ray powder diffraction pattern of the crystalline form I of ATV014 has characteristic peaks at diffraction angles 2θ of 9.69±0.2°, 9.84±0.2°, 13.19±0.2°, 15.61±0.2°, 17.41±0.2°, 17.74±0.2°, 18.70±0.2°, 19.38±0.2°, 21.31±0.2°, 23.88±0.2°, and 26.01±0.2°.

7. The ATV014 crystal according to claim 1, wherein a differential scanning calorimetry curve of the crystalline form I of ATV014 has an endothermic peak at 212°C to 238°C, or a differential scanning calorimetry curve of the crystalline form I of ATV014 has an endothermic peak at 220°C to 235°C, or a differential scanning calorimetry curve of the crystalline form I of ATV014 has an endothermic peak at a peak value of 226°C to 230°C.

8. The ATV014 crystal according to claim 1, wherein the weight loss of the crystalline form I of ATV014 at 30°C to 200°C in a thermogravimetric analysis curve is less than 1%, or the weight loss of the crystalline form I of ATV014 at 30°C to 200°C in a thermogravimetric analysis curve is less than 0.5%.

9. A method for producing the crystal of ATV014 according to any one of claims 1 to 8, comprising dissolving ATV014 in a good solvent, wherein the ATV014 is any solid form of ATV014, and after the solution is clarified, adding an anti-solvent to precipitate the crystal, filtering and drying to obtain crystalline form I of ATV014; A method for producing crystals of ATV014, characterized in that the good solvent is dimethyl sulfoxide, N-methylpyrrolidone, or a combination thereof, and the anti-solvent is water, or the good solvent is tetrahydrofuran, and the anti-solvent is water, methyl tert-butyl ether, or a combination thereof, or the good solvent is a mixed solvent of dichloromethane and methanol, and the anti-solvent is methyl tert-butyl ether.

10. 1. A pharmaceutical composition comprising: A pharmaceutical composition comprising a therapeutically effective amount of a crystal of the compound ATV014 according to any one of claims 1 to 8 and a pharmaceutically acceptable excipient.

11. Use of a crystal of compound ATV014 according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 10 in the manufacture of a medicament for the prevention, alleviation and / or treatment of a disease or symptom associated with infection with a virus that is SARS-CoV-2 or a mutant strain thereof.

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