Crystal form iii of benzoxazinooxazolidinone compound otb-658, processes for its preparation, and compositions and uses thereof

Abstract

The application belongs to the field of pharmacy, and discloses a crystal form III of an oxazolidinone antibacterial candidate new drug OTB-658, a preparation method of the crystal form III, and a composition and application of the crystal form III. Specifically, the application relates to a crystal form III of N-(((3S,3aS)-8-fluoro-1-oxo-7-thiomorpholinyl-3a,4-dihydro-1H,3H-benzo[b]oxazol[3,4-d][1,4]oxazin-3-yl)methyl)acetamide, i.e. OTB-658, and a preparation method of the crystal form III. The crystal form III of OTB-658 is used as a pharmaceutical active ingredient to prepare a drug for treating and / or preventing a bacterial, in particular Mycobacterium tuberculosis, infectious disease.

Description

Technical Field

[0001] This invention belongs to the field of pharmacology, specifically relating to crystal form III of the benzoxazine oxazolidinone compound OTB-658, and pharmaceutical compositions comprising crystal form III as described herein. The crystal form or pharmaceutical composition described herein can be used to prepare remedies for treating and / or preventing bacterial, particularly Mycobacterium tuberculosis, infectious diseases. This invention also relates to a method for preparing crystal form III. Background Technology

[0002] OTB-658 is a novel oxazolidinone antibacterial drug candidate with independent intellectual property rights, developed by the Institute of Materia Medica, Chinese Academy of Medical Sciences. It is intended for the treatment of bacterial infectious diseases, including tuberculosis. Its chemical name is N-(((3S,3aS)-8-fluoro-1-oxo-7-thiomorpholino-3a,4-dihydro-1H,3H-benzo[b]oxazol[3,4-d][1,4]oxazin-3-yl)methyl)acetamide, and its structure is as follows:

[0003]

[0004] Reference 1 (Discovery of a Conformationally Constrained Oxazolidinone with Improved Safety and Efficacy Profiles for the Treatment of Multidrug-Resistant Tuberculosis. Journal of Medicinal Chemistry, 2020, 63(17):9316-9339) and Chinese Patent CN108727406A disclose the compound OTB-658 and its preparation method. Reference 2 (In Vitro and InVivo Activity of Oxazolidinone Candidate OTB-658 against Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy, 2021, 65(11):e0097421) evaluated the anti-tuberculosis activity of OTB-658, which showed good anti-tuberculosis activity in mice both in vitro and in vivo, especially significantly better than linezolid in mice.

[0005] Crystal form is an important physicochemical property of a compound and a significant factor affecting drug quality. Different crystal forms of the same drug can exhibit significant differences in properties, solubility, melting point, dissolution rate, and bioavailability. This can further affect its dissolution and absorption in vivo, and consequently, may influence the drug's clinical efficacy and safety to some extent. The crystal form of a compound can be determined using X-ray powder diffraction, thermal analysis (Differential Scanning Calorimeter, DSC; Thermogravimetric Analysis, TGA), and infrared spectroscopy (IR).

[0006] OTB-658 is a polymorphic compound. In Reference 1 (Discovery of a Conformationally Constrained Oxazolidinone with Improved Safety and Efficacy Profiles for the Treatment of Multidrug-Resistant Tuberculosis. Journal of Medicinal Chemistry, 2020, 63(17): 9316-9339), we reported single-crystal data for OTB-658 (see the main text and the jm0c00500_si_002.cif file in Supporting Information for details). This single crystal belongs to the monoclinic system, space group P21, and its cell parameters are: The unit cell volume is The single crystals were grown using a dichloromethane and methanol system, and each asymmetric unit cell contained (C) 17 H 20 FN3O4S)8·(CH3OH)6, that is, the asymmetric unit of the unit cell is composed of 8 OTB-658 molecules and 6 methanol molecules. Summary of the Invention

[0007] This invention provides a crystal form III of OTB-658, a candidate new oxazolidinone antibacterial drug of formula (I). The obtained OTB-658 crystal form has good quality stability and pharmacokinetic properties, which can meet the requirements of clinical use of pharmaceutical formulations.

[0008] On the one hand, the present invention provides a crystal form III of the compound shown in formula (I).

[0009]

[0010] The crystal form III has X-ray powder diffraction patterns with diffraction peaks at the following 2θ angles: 6.23°±0.2°, 10.20°±0.2°, 13.70°±0.2°, 14.50°±0.2°, 14.73°±0.2°, 18.35°±0.2°, 18.87°±0.2°, 20.89°±0.2°, 21.30°±0.2°, 21.69°±0.2°, 22.47°±0.2°, 23.23°±0.2°, and 25.14°±0.2°.

[0011] In some embodiments, the crystal form III of the present invention has X-ray powder diffraction patterns with diffraction peaks at the following 2θ angles: 6.23°±0.2°, 10.20°±0.2°, 11.56°±0.2°, 12.52°±0.2°, 13.34°±0.2°, 13.70°±0.2°, 14.50°±0.2°, 14.73°±0.2°, 15.48°±0.2°, 16.34°±0.2°, 17.01°±0.2°, 18.3°±0.2°. 5°±0.2°, 18.87°±0.2°, 19.66°±0.2°, 20.39°±0.2°, 20.60°±0.2°, 20.89°±0.2°, 21.30°±0.2°, 21.69°±0.2°, 22.47°±0.2°, 23.23°±0.2°, 24.44°±0.2°, 25.14°±0.2°, 28.65°±0.2°, 29.57°±0.2°, 30.13°±0.2°.

[0012] In some embodiments, the crystal form III of the present invention has the following characteristics: Figure 1 The X-ray powder diffraction pattern shown is shown.

[0013] In some embodiments, the differential scanning calorimetry curve of crystal form III of the present invention has an endothermic peak at 178.13℃±3℃.

[0014] In some embodiments, the crystal form III of the present invention has the following characteristics: Figure 2 The differential scanning calorimetry curve is shown.

[0015] On the other hand, the present invention provides a method for preparing crystal form III of the compound shown in formula (I), which includes the following steps:

[0016] (1) Dissolve the compound shown in formula (I) in a solvent by heating;

[0017] (2) Cooling to precipitate crystals;

[0018] (3) After filtration and drying, the crystal form III of the compound shown in formula (I) is obtained.

[0019] The solvent mentioned in step (1) is a single solvent or a mixture of two solvents, such as n-hexane, n-heptane, dichloromethane, ethyl acetate, butyl acetate, isopropyl acetate, anhydrous methanol, anhydrous ethanol, isopropanol, tert-butanol, 95% ethanol, acetonitrile, acetone, or water. A single solvent is preferred. Acetone is more preferred.

[0020] In step (1), the weight and volume ratio of the compound shown in formula (I) to the solvent is 1 g: 10-60 mL.

[0021] Preferred ratio: 1g: 10-30mL. More preferred ratio: 1g: 10-20mL.

[0022] In step (1), the heating temperature is between 40℃ and 90℃.

[0023] In step (2), the cooling temperature is 0℃~30℃. Preferably, it is 15℃~25℃.

[0024] In step (3), the drying temperature is 40℃~70℃.

[0025] A third aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of crystal form III of the compound of the first aspect of the present invention (I) and optionally one or more pharmaceutically acceptable excipients.

[0026] The fourth aspect of the present invention provides the use of crystal form III of the compound of the first aspect (I) of the present invention or the pharmaceutical composition of the third aspect of the present invention in the preparation of a medicament for treating and / or preventing infectious diseases, particularly infectious diseases caused by Mycobacterium tuberculosis. Detailed description of the invention:

[0028] Definitions and general terms

[0029] Unless otherwise stated, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety. Although any methods and substances similar to or identical to those described herein may be used in the practice or testing of this invention, preferred methods, apparatus, and substances are described herein.

[0030] X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions of XRPD spectra mainly depend on the structure of the crystal form and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is essentially as shown in the XRPD patterns provided in the accompanying drawings. At the same time, the measurement of 2θ in the XRPD spectrum can have experimental errors; the measurement of 2θ in the XRPD spectrum may differ slightly between different instruments and different samples, therefore the value of 2θ cannot be considered absolute. According to the instrument conditions used in the experiments of the present invention, there is an error tolerance of ±0.2° for the diffraction peaks.

[0031] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference as a function of temperature by continuously heating or cooling under programmed control. The melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form described in this invention is characterized by a DSC plot with characteristic peak positions, which is essentially as shown in the DSC plots provided in the accompanying drawings. However, DSC spectra can be subject to experimental errors; the peak positions and peak values ​​of DSC spectra may vary slightly between different instruments and different samples. Therefore, the peak position or peak value of the DSC endothermic peak cannot be considered absolute. Based on the instrument conditions used in the experiments according to this invention, the melting peak has an error tolerance of ±3°C.

[0032] In the context of this invention, the 2θ values ​​in X-ray powder diffraction patterns are all expressed in degrees ( ° (in units of )

[0033] As described herein, the term "effective amount" refers to a dosage of medicine that can achieve the desired therapeutic effect on the disease or condition described in this invention in a subject.

[0034] As described herein, the term "pharmaceutically acceptable" means something that is not biologically or otherwise undesirable. For example, when describing "pharmaceuticalally acceptable excipients," it means that the excipient is physiologically acceptable to the subject.

[0035] As described herein, the term "pharmaceutical composition" can also refer to a "composition" which can be used to treat the disease or condition described in this invention in subjects, particularly mammals.

[0036] The “treatment” of the disease includes:

[0037] (1) Prevention of the disease, that is, preventing the development of clinical symptoms of the disease in mammals that are exposed to or susceptible to the disease but do not experience or show symptoms of the disease.

[0038] (2) Inhibit the disease, that is, stop or reduce the progression of the disease or its clinical symptoms.

[0039] (3) To alleviate the disease, that is, to restore the disease or its clinical symptoms.

[0040] "Therapeutic effective amount" refers to the amount of crystal form III of the compound of formula (I) sufficient to achieve therapeutic effect when administered to a mammal for the purpose of treating a disease. The therapeutic effective amount will vary depending on the crystal form III of the compound of formula (I), the disease to be treated and its severity, and factors such as the age, weight, and sex of the mammal. Therapeutic effective amount may also refer to any amount of crystal form III of the compound of formula (I) sufficient to achieve the desired beneficial effect, including disease prevention, disease inhibition, or disease ablation as described in (1)-(3) above. For example, the amount of crystal form III of the compound of formula (I) may be between 0.1-250 mg / kg, or preferably, 0.5-100 mg / kg, or more preferably, 1-50 mg / kg, or even more preferably, 2-20 mg / kg. Preferably, the amount of crystal form III of the compound of formula (I) is administered to the mammal twice daily. More preferably, the amount of crystal form III of the compound of formula (I) is administered to the mammal once daily. More preferably, the amount of the compound of formula (I) in crystal form III is administered to mammals once a week or every two weeks.

[0041] As described herein, the term "disease and / or symptom" refers to a physical condition of the subject that relates to the disease and / or symptom described in this invention. For example, the disease and / or symptom described in this invention refers to bacterial infectious diseases, particularly tuberculosis infectious diseases.

[0042] As described herein, the term "subject" may refer to a patient or other animal, particularly a mammal, such as a human, dog, monkey, cow, horse, etc., that receives a crystal form III of the compound of formula (I) of the present invention or a pharmaceutical composition thereof to treat the disease or condition described herein.

[0043] Another aspect of the invention relates to pharmaceutical compositions using crystal form III of the compound represented by formula (I) of the invention as the active ingredient. Such pharmaceutical compositions can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be formulated by combining crystal form III of the compound represented by formula (I) of the invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants.

[0044] The crystal form III of the compound represented by formula (I) in this invention or a pharmaceutical composition containing it can be administered in unit dose form via the enteric or non-enteric route, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0045] Dosage forms can be liquid, solid, or semi-solid. Liquid dosage forms can include solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms can include tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, pellets, suppositories, films, patches, aerosols, and sprays, etc.; semi-solid dosage forms can include ointments, gels, and pastes, etc.

[0046] The crystal form III of the compound shown in formula (I) of this invention can be formulated into ordinary formulations, sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0047] To formulate the crystal form III of the compound shown in formula (I) of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, and solubilizers. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose, croscarmellose sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and cosolvents can be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0048] Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0049] To formulate the drug delivery unit into capsules, the active ingredient, crystal form III of the compound of formula (I) of the present invention, can be mixed with a diluent and a solubilizer, and the mixture can be placed directly into hard capsules or soft capsules. Alternatively, the active ingredient, crystal form III of the compound of formula (I) of the present invention, can be first formed into granules or microspheres with a diluent, a binder, and a disintegrant, and then placed into hard capsules or soft capsules. The diluents, binders, wetting agents, disintegrants, and solubilizers used to prepare tablets of crystal form III of the compound of formula (I) of the present invention can also be used to prepare capsules of crystal form III of the compound of formula (I) of the present invention.

[0050] To prepare the crystal form III of the compound shown in formula (I) of this invention into an injection, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of commonly used solubilizers, co-solvents, pH adjusters, and osmotic pressure adjusters can be added. Solubilizers or co-solvents can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; pH adjusters can be phosphates, acetates, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure adjusters can be sodium chloride, mannitol, glucose, phosphates, acetates, etc. If preparing a lyophilized powder injection, mannitol, glucose, etc., can also be added as a support.

[0051] In addition, colorants, preservatives, flavorings, tasters or other additives may be added to pharmaceutical preparations if necessary.

[0052] To achieve the purpose of medication and enhance the therapeutic effect, the drug or drug composition of the present invention can be administered using any known method of administration.

[0053] The crystal form III of the compound shown in formula (I) of the present invention, or the composition thereof, can be taken alone or in combination with other therapeutic or symptomatic drugs. When the crystal form III of the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0054] Beneficial technical effects

[0055] The inventors have discovered that the crystal form III of the oxazolidinone antibacterial drug OTB-658 of formula (I) provided by the present invention has good stability and pharmacokinetic properties under high temperature, high humidity and light, which can meet the requirements of clinical use of pharmaceutical preparations.

[0056] In reference 1 (Discovery of a Conformationally Constrained Oxazolidinone with Improved Safety and Efficacy Profiles for the Treatment of Multidrug-Resistant Tuberculosis. Journal of Medicinal Chemistry, 2020, 63(17):9316-9339), we reported single-crystal data for OTB-658 (see the main text and the jm0c00500_si_002.cif file in SupportingInformation for details). The reported single crystal belongs to the monoclinic system, space group P21, with cell parameters: a = 12.150(1) Å, b = 26.738(3) Å, c = 23.805(1) Å, and a cell volume of 7713.78(16) Å. 3 Because the single crystal described in Reference 1 was cultured using a dichloromethane and methanol system, each asymmetric unit cell contains (C... 17 H 20 FN3O4S)8·(CH3OH)6, meaning that the asymmetric unit cell of the stated unit cell consists of 8 OTB-658 molecules and 6 methanol molecules. We performed X-ray powder diffraction analysis on this single crystal (see...). Figure 3 In this invention, the X-ray powder diffraction pattern of crystal form III is completely different from that of the single crystal. Furthermore, because the single crystal contains methanol, an ICH-defined Group II solvent (a solvent that is non-genotoxic but carcinogenic in animals), those skilled in the art know that methanol is a toxic solvent, and its residue limits in active pharmaceutical ingredients (APIs) are strictly regulated. Crystal form III in this invention does not contain this toxic solvent. Attached Figure Description

[0057] Figure 1 X-ray powder diffraction pattern of OTB-658 crystal form III.

[0058] Figure 2 Differential scanning calorimetry (DSC) curve of OTB-658 crystal form III.

[0059] Figure 3 X-ray powder diffraction pattern of a single crystal of OTB-658 reported in Reference 1. Detailed Implementation

[0060] The specific embodiments of the present invention will be described in further detail below with reference to the accompanying drawings and examples. The following examples are for illustrative purposes only and are not intended to limit the scope of the invention.

[0061] This invention relates to OTB-658 crystal form III, characterized by X-ray powder diffraction and differential scanning calorimetry.

[0062] X-ray powder diffraction analysis: A Bruker D8-Advances X-ray diffractometer (Germany) was used. X-ray powder diffraction patterns were obtained using Cu-Ka radiation (45 kV 40 mA). Powdered samples were prepared into thin layers on a single-crystal silicon sample holder, placed on a rotating sample stage, and analyzed in 0.02° increments within the range of 3°–50°. Data was collected using Data Collector software, processed using HighScore Plus software, and read using Data Viewer software.

[0063] Differential Scanning Calorimetry (DSC): Detection was performed using a Mettler DSC 3 differential scanning calorimeter. Differential scanning calorimetry was performed using a TA Q2000 module with a thermal analysis controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1–5 mg of sample was accurately weighed into a specially designed aluminum crucible with a lid, and sample analysis was performed using a linear heating device at 10 °C / min, from room temperature to approximately 250 °C. The DSC chamber was purged with dry nitrogen during the procedure.

[0064] Example 1

[0065] Take 1g of OTB-658 and place it in a 100mL single-necked flask. Add 12.5mL of acetone, heat to reflux until completely dissolved, clarify, cool down, stir and cool to 19℃, filter, wash twice with a small amount of acetone, dry and compact, place in a petri dish, and dry at 40℃ for 4h to obtain 617mg of white fine powder, yield 61.7%.

[0066] Example 2

[0067] Pharmacokinetics of OTB-658 crystal form III

[0068] Five male SD rats (Beijing Vital River Laboratory Animal Technology Co., Ltd.), weighing 170-190g, were used. A 2.5mg / mL suspension was prepared with 0.5% CMC for oral administration via gavage. Blood samples were collected from the orbital venous plexus at 5, 15, 30 min, 1, 2, 4, 6, 8, 12, and 24 h after oral administration of OTB-658 (25mg / 10mL / kg). A standard curve was established based on the sample concentration. The concentration of the test sample in the plasma was determined using LC / MS / MS in MRM mode, and quantitative analysis was performed. Based on the drug concentration-time curve, plasma pharmacokinetic parameters were calculated using WinNonlin software. Specific results are shown in Table 1.

[0069] Table 1. PK parameters of crystal form III of the present invention

[0070]

[0071] Experimental conclusion:

[0072] As can be seen from Table 1, the crystal form III of the present invention has a long half-life and a very high exposure level.

[0073] Example 3

[0074] Stability test of OTB-658 crystal form III at high temperature: Take an appropriate amount of OTB-658 crystal form III sample and put it into a flat weighing bottle, spread it into a thin layer of ≤5mm thickness, and place it at 60℃ for 10 days.

[0075] High humidity test: Take an appropriate amount of OTB-658 crystal form III sample and put it into a flat weighing bottle, spread it into a thin layer of ≤5mm thickness, and place it at 25℃ and 92.5%RH for 10 days.

[0076] Light exposure experiment: Take an appropriate amount of OTB-658 crystal form III sample and put it into a flat weighing bottle, spread it into a thin layer of ≤5mm thickness, and place it under light intensity of 5000lx for 10 days.

[0077] After stability tests under high temperature, high humidity, and light exposure, the OTB-658 crystal form III sample was observed for color changes, and the sample purity was determined by HPLC. See Table 2.

[0078] Table 2 Initial state of crystal form III of the present invention and experimental results after exposure to high temperature, high humidity and light.

[0079]

[0080] Experimental conclusion:

[0081] As shown in Table 2, after stability tests under high temperature, high humidity, and light, the appearance and purity of the crystal form III of the present invention did not change significantly, indicating that the crystal form III has good stability and is suitable for pharmaceutical use.

Claims

1. The crystal form of the compound shown in formula (I), wherein, The crystal form is crystal form III. The characteristic feature is that the X-ray powder diffraction pattern of crystal form III has diffraction peaks at the following 2θ angles: 6.23°±0.2°, 10.20°±0.2°, 13.70°±0.2°, 14.50°±0.2°, 14.73°±0.2°, 18.35°±0.2°, 18.87°±0.2°, 20.89°±0.2°, 21.30°±0.2°, 21.69°±0.2°, 22.47°±0.2°, 23.23°±0.2°, and 25.14°±0.2°.

2. The crystal form according to claim 1, wherein, The X-ray powder diffraction pattern of crystal form III shows diffraction peaks at the following 2θ angles: 6.23°±0.2°, 10.20°±0.2°, 11.56°±0.2°, 12.52°±0.2°, 13.34°±0.2°, 13.70°±0.2°, 14.50°±0.2°, 14.73°±0.2°, 15.48°±0.2°, 16.34°±0.2°, 17.01°±0.2°, and 18.35°±0.2°. , 18.87°±0.2°, 19.66°±0.2°, 20.39°±0.2°, 20.60°±0.2°, 20.89°±0.2°, 21.30°±0.2°, 21.69°±0.2°, 22.47°±0.2°, 23.23°±0.2°, 24.44°±0.2°, 25.14°±0.2°, 28.65°±0.2°, 29.57°±0.2°, 30.13°±0.2°.

3. The crystal form according to claim 1, wherein, Crystal form III has the X-ray powder diffraction pattern shown in Figure 1.

4. The crystal form according to claim 1, wherein, The differential scanning calorimetry curve of crystal form III has an endothermic peak at 178.13℃±3℃.

5. The crystal form according to claim 1, wherein, Crystal form III has the differential scanning calorimetry curve shown in Figure 2.

6. A method for preparing the crystal form according to any one of claims 1-5, characterized in that, Includes the following steps: (1) The compound shown in formula (I) is heated and dissolved in a solvent; (2) Cooling to precipitate crystals; (3) After filtration and drying, the crystal form III of the compound shown in formula (I) is obtained. The solvent is acetone.

7. The method according to claim 6, characterized in that, In step (1), the weight and volume ratio of the compound shown in formula (I) to the solvent is 1 g: 10~60 mL.

8. The method according to claim 6, characterized in that, In step (1), the heating temperature is between 40℃ and 90℃.

9. The method according to claim 6, characterized in that, In step (2), the cooling temperature is 0℃~30℃.

10. The method according to claim 6, characterized in that, In step (3), the drying temperature is 40℃~70℃.

11. A pharmaceutical composition comprising a therapeutically and / or preventively effective amount of the crystal form according to any one of claims 1-5 and optionally one or more pharmaceutically acceptable excipients.

12. Use of the crystal form according to any one of claims 1-5 or the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating and / or preventing bacterial infectious diseases.

13. The use according to claim 12, wherein, The infectious disease mentioned is an infectious disease caused by Mycobacterium tuberculosis.

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