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

Abstract

Disclosed in the present invention are a crystal form of a compound, and a preparation method therefor and the use thereof. The compound has a structure as represented by formula I. The crystal form has high crystal purity, low hygroscopicity, good solid-state stability and good solubility, and is thus beneficial for the preparation and storage of a pharmaceutical formulation and has great application value and has the prospect of becoming a medicine. In addition, the results of clinical trials further show that the crystal form A of the compound as represented by formula I of the present invention has great pharmacokinetic properties, low clinical toxicity, good safety, high oral bioavailability and good therapeutic effects on various diseases.

Description

Crystalline form of a compound, and preparation method and application thereof TECHNICAL FIELD

[0001] The present application belongs to the field of polymorph research of pharmaceutical chemistry, and particularly relates to a crystalline form of a compound (4-[9-(6-aminopurinyl)]-2(S)-hydroxybutyric acid methyl ester, referred to as DZ2002) and a preparation method and application thereof. BACKGROUND

[0002] In the medical field, the crystalline form of a compound has an important influence on its drug performance. Different crystalline forms can result in significant differences in solubility, stability, bioavailability, and efficacy of the compound. Therefore, discovering and developing new crystalline forms of a compound is of great significance to improve the clinical application value of a drug.

[0003] 4-[9-(6-aminopurinyl)]-2(S)-hydroxybutyric acid methyl ester ([4-(6-Amino-purin-9-yl)-2(S)-hydroxy-butyric acid methyl ester, referred to as DZ2002) is a reversible inhibitor of S-Adenosyl-L-homocysteine hydrolase (SAHH). DZ2002 has been studied as a therapeutic agent for various diseases, including autoimmune diseases (such as psoriasis, vitiligo, dry eye, etc.), osteoarthritis, etc. (see CN100345545C, CN107550913A, CN112472703B, CN117442623A). In addition to the therapeutic activity, the solid state form (i.e., crystalline or amorphous form) of DZ2002 is also a key factor in evaluating its therapeutic agent.

[0004] However, there is no report on the crystalline form of DZ2002, and a preparation method and application thereof.

[0005] SUMMARY

[0006] In order to overcome the deficiencies of the prior art, the present application provides a crystalline form of a compound, and a preparation method and application thereof.

[0007] In a first aspect of the present application, a crystalline form A of a compound represented by formula I is provided:

[0008] The XRPD pattern of said crystalline Form A (using Cu-Ka radiation) has characteristic peaks at at least three (e.g. three, four, five, six, seven, eight, in particular all) of the positions 5.8°±0.2°, 10.2°±0.2°, 11.7°±0.2°, 15.1°±0.2°, 17.7°±0.2°, 18.1°±0.2°, 25.8°±0.2°, 29.8°±0.2° in terms of 2 Theta.

[0009] Further, the XRPD pattern of said crystalline Form A (using Cu-Ka radiation) has characteristic peaks at at least three (e.g. three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, in particular all) of the positions 8.7°±0.2°, 10.8°±0.2°, 14.2°±0.2°, 19.2°±0.2°, 20.3°±0.2°, 23.7°±0.2°, 24.0°±0.2°, 25.4°±0.2°, 28.3°±0.2°, 30.6°±0.2°, 31.6°±0.2°, 33.0°±0.2°, 34.6°±0.2°, 36.4°±0.2° in terms of 2 Theta.

[0010] Further, said crystalline Form A has an XRPD pattern substantially as shown in Figure 1.

[0011] Further, the TGA pattern of said crystalline Form A shows a weight loss of 6.56% ± 1% (e.g. 5.56, 6.00, 6.56, 7.00, 7.56%, in particular 6.56%) from 30°C to 100°C and / or a weight loss of 57.3% ± 1% (e.g. 56.3, 56.8, 57.3, 57.8, 58.3%, in particular 57.3%) from 190°C to 400°C.

[0012] In some embodiments of the application, the TGA pattern of said crystalline Form A shows a weight loss of 6.56% from 30°C to 100°C and / or a weight loss of 57.3% from 190°C to 400°C.

[0013] Further, the DSC pattern of said crystalline Form A has an endothermic peak at 70-100°C (e.g. 70, 75, 80, 85, 80, 95, 100°C, in particular 90.4 ± 3°C) and / or 160-170°C (e.g. 160, 165, 170°C in particular 164.4 ± 3°C).

[0014] In some embodiments of the application, the DSC pattern of said crystalline Form A has an endothermic peak at 90.4 ± 3°C and / or 164.4 ± 3°C.

[0015] Further, the crystal form A is a hydrate crystal form, in particular a monohydrate crystal form.

[0016] Further, the crystal form A is a columnar crystal under observation by a polarizing microscope.

[0017] Further, the crystal system of the single crystal of the crystal form A is monoclinic system; and the space group is P21.

[0018] Further, the cell parameters of the crystal form A are as follows: α = γ = 90°; β = 112.9890(10)°.

[0019] Further, the cell volume of the crystal form A is

[0020] Further, the number of molecules in the unit cell of the crystal form A is 4.

[0021] Further, the goodness of fit of the crystal form A is 1.034.

[0022] Further, the density of the crystal form A is 1.382 g / cm 3 .

[0023] In a second aspect of the present application, a preparation method of the crystal form A of the compound of formula I is provided, which comprises using the compound of formula I in amorphous form as a starting material, and using a suspension stirring method to prepare the crystal form A.

[0024] Further, the suspension stirring method is a room temperature suspension stirring method.

[0025] Further, the room temperature suspension stirring method comprises the following steps: suspending the amorphous starting material of the compound of formula I with a solvent, and stirring at room temperature (20-30°C, for example 21, 22, 23, 24, 25, 26, 27, 28, 29, 30°C, in particular 25°C) until solid precipitates.

[0026] Further, the solvent is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, methyl tert-butyl ether, toluene, n-heptane, n-hexane, diethyl ether, dichloromethane, trichloromethane, petroleum ether.

[0027] In some embodiments of the present application, the solvent is methyl tert-butyl ether.

[0028] In a third aspect of the present application, a pharmaceutical composition comprising the crystal form A of the compound of formula I and one or more pharmaceutically acceptable excipients is provided.

[0029] Further, the pharmaceutically acceptable excipient is selected from the group consisting of thickening agents, stabilizing agents, preservatives, binding agents, lubricating agents, disintegrating agents, bacteriostatic agents, suspending agents, solubilizing agents, fillers, antioxidants, buffers.

[0030] Further, the pharmaceutical composition can be administered by any suitable route of administration, such as gastrointestinal administration (e.g., oral, sublingual, rectal administration) or non-gastrointestinal administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, drip, respiratory tract administration, etc.).

[0031] Further, the pharmaceutical composition can be in any suitable dosage form, which is selected from the group consisting of oral dosage forms (e.g., tablets, powders, pills, granules, capsules, lozenges, syrups, liquids, emulsions, suspensions, etc.), injection dosage forms (e.g., injections for subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, intraarticular injection, etc.), skin administration dosage forms (e.g., external solution, lotion, ointment, plaster, paste, patch, etc.), mucous membrane administration dosage forms (e.g., eye drops, eye ointment, eye gel, nose drops, gargle, sublingual tablets, etc.), cavity administration dosage forms (e.g., suppositories, aerosols, effervescent tablets, drops, dripping pills, enema liquids, etc., for rectum, vagina, urethra, nasal cavity, ear canal, etc., for rectum, vagina, urethra, nasal cavity, ear canal, etc.), respiratory tract administration dosage forms (e.g., sprays, aerosols, powder sprays, etc.).

[0032] Preferably, the dosage form of the pharmaceutical composition is selected from the group consisting of tablets, powders, capsules, injections, ointments, eye drops, eye ointments, eye gels, enema liquids.

[0033] In some embodiments of the present application, the pharmaceutical composition is in oral dosage form, particularly in capsule form.

[0034] Further, the crystalline form A of the compound of formula I is used alone or in combination with other kinds of active ingredients.

[0035] Further, the subject of the pharmaceutical composition is a mammal, particularly a human.

[0036] Further, the pharmaceutical composition comprises a therapeutically effective amount of the crystalline form A of the compound of formula I.

[0037] Further, the pharmaceutical composition is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a capsule, tablet, or any other form suitable for administration; additionally, the unit dosage form can be a packaged preparation, such as a tablet, capsule, or powder packaged in a vial or ampule. The quantity of active component in such unit doses will generally be from 0.1 mg to 1000 mg, or more preferably from 1 mg to 500 mg, depending on the condition being treated, the potency of the active component, and the route of administration. If desired, the composition can also contain other suitable therapeutic agents.

[0038] In a fourth aspect, the present application provides a use of the crystalline form A of the compound of Formula I or the pharmaceutical composition of the third aspect of the present application in the preparation of a medicament for the prevention and / or treatment of a disease selected from the group consisting of autoimmune diseases, autoinflammatory diseases.

[0039] Further, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, multiple sclerosis, autoimmune encephalomyelitis, psoriasis, vitiligo, eczema, rheumatoid arthritis, Sjogren's syndrome, and the like.

[0040] Further, the autoimmune encephalomyelitis is experimental autoimmune encephalomyelitis.

[0041] Further, the Sjogren's syndrome is dry eye.

[0042] Further, the dry eye is a tear deficiency dry eye.

[0043] Further, the autoimmune disease can also be an autoimmune disease caused by the hyperactivity of Th1-mediated cellular immune response.

[0044] Further, the autoinflammatory disease is selected from the group consisting of inflammatory bowel disease (IBD), hereditary periodic fever syndrome, vasculitis, and the like.

[0045] Further, the inflammatory bowel disease is selected from the group consisting of Crohn's disease (CD), ulcerative colitis, and the like.

[0046] In a fifth aspect, the present application provides a use for the prevention and / or treatment of a disease, which comprises administering to a subject in need thereof the crystalline form A of the compound of Formula I of the first aspect of the present application or the pharmaceutical composition of the third aspect of the present application, wherein the disease is defined as in the fourth aspect of the present application.

[0047] Further, the subject is a mammal, particularly a human.

[0048] Further, the administration can employ any suitable route of administration, such as gastrointestinal administration (e.g., oral, sublingual, rectal administration) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, drip, respiratory tract administration, etc.).

[0049] The present application is based on the previous research results of the inventors, and through experimental research, a crystal of the crystal form A of the compound shown in formula I is further obtained, which has high crystalline purity, low hygroscopicity, good solid-state stability and good solubility, is beneficial to the preparation and storage of pharmaceutical preparations, has very good application value and drug-making prospects. In addition, the results of clinical trials have shown that the crystal form A of the compound shown in formula I of the present application has very good pharmacokinetic properties, low clinical toxicity, good safety, high oral bioavailability, and good therapeutic effect on various diseases. BRIEF DESCRIPTION OF DRAWINGS

[0050] Figure 1 shows the XRPD pattern of the crystal form A.

[0051] Figure 2 shows the DVS pattern of the crystal form A.

[0052] Figure 3 shows the Raman pattern of the crystal form A.

[0053] Figure 4 shows the IR pattern of the crystal form A.

[0054] Figure 5 shows the single crystal structure Ortep diagram of the crystal form A.

[0055] Figure 6 shows the DZ2002 whole blood concentration-time curve after administration of the preparation 1 in beagle dogs.

[0056] Figure 7 shows the DZA whole blood concentration-time curve after administration of the preparation 1 in beagle dogs.

[0057] Figure 8 shows the DZ2002 whole blood concentration-time curve after administration of the preparation 2 in beagle dogs.

[0058] Figure 9 shows the DZA whole blood concentration-time curve after administration of the preparation 2 in beagle dogs. DETAILED DESCRIPTION

[0059] Unless otherwise defined, all scientific and technical terms used in the present application have the same meanings as commonly understood by one of ordinary skill in the art to which the present application pertains.

[0060] The term "crystal form" is confirmed by X-ray powder diffraction patterns. Those skilled in the art will appreciate that the physical and chemical properties discussed herein can be characterized with experimental error that depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample, among other things. In particular, it is well known in the art that X-ray diffraction patterns will vary somewhat depending on the conditions of the instrument. In particular, it is noted that the relative intensities of the X-ray powder diffraction patterns can vary with experimental conditions, and therefore the order of peak intensities should not be used as the sole or determining factor. In fact, the relative intensities of the diffraction peaks in an XRPD pattern are related to the preferred orientation of the crystals, and the peak intensities shown herein are illustrative and not for absolute comparison. In addition, the experimental error in peak angles is typically 5% or less, and this error in angles should be taken into account, typically allowing for a ± 0.2° error. In addition, there can be a general shift in peak angles due to experimental factors such as sample thickness, and some shift is typically allowed. Thus, those skilled in the art will appreciate that the X-ray powder diffraction pattern of a crystal form of the application need not be identical to the X-ray powder diffraction pattern of the examples described herein, and that "XRPD pattern identical" does not mean absolutely identical, but that the peak positions can differ by ± 0.2° and that the peak intensities allow for some variability. Any crystal form having a pattern with peaks identical or similar to those in these patterns is within the scope of the application. Those skilled in the art will be able to compare the patterns set forth herein with the patterns of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms. In some embodiments, the crystal form A of the application is pure, single, and substantially free of any other crystal form. In the present application, "substantially free of" when used in reference to a new crystal form indicates that the crystal form contains less than 20% by weight of another crystal form, more preferably less than 10% by weight of another crystal form, more preferably less than 5% by weight of another crystal form, and more preferably less than 1% by weight of another crystal form.

[0061] It is noted that the numerical values and ranges recited in this disclosure are not to be taken literally, as the numerical values and ranges can be "floated" around the recited values due to variations in the manufacturing process and the like, and that those of ordinary skill in the art will be able to make such variations without the exercise of inventive capacity. In the present application, such "floats" around the recited numerical values that can be expected by those of ordinary skill in the art are represented by the term "about". When the term "about" is used in the present application in reference to a numerical value, and is intended to indicate that the value can vary by ± 10%, preferably ± 5%, more preferably ± 2%, and more preferably ± 1% of the recited value. For example, "about 10" is to be interpreted as meaning any value in the range of 9-11, preferably 9.5-10.5, more preferably 9.8-10.2, and more preferably 9.9-10.1.

[0062] It is further noted that in powder x-ray diffraction patterns, the specific crystal form of a crystalline compound is often characterized by a diffraction pattern in which the relative intensities of the peaks, especially at low angles, can vary due to preferred orientation effects resulting from differences in crystallization conditions, particle size, relative amounts of components in a mixture, and other testing conditions. Therefore, the relative intensities of the diffraction peaks are not characteristic of the crystal form in question, and the determination of identity with a known crystal form should be made by attention to the positions of the peaks rather than their relative intensities.

[0063] The term "room temperature" refers to a temperature of an article that is close to or the same as the temperature of the space in which the article is located, e.g., the location of a fume hood in which the article is located. Typically, room temperature is about 20 °C to about 30 °C, or about 22 °C to 27 °C, or about 25 °C.

[0064] The term "subject" refers to any animal or cell thereof, whether in vitro or in situ, treated according to the methods described herein. In particular, the aforementioned animal includes a mammal, e.g., a rat, a mouse, a guinea pig, a rabbit, a dog, a monkey, or a human, particularly a human.

[0065] The term "treatment" refers to preventing, curing, reversing, attenuating, alleviating, minimizing, inhibiting, arresting, and / or stopping one or more clinical symptoms of a disease after the onset of the disease.

[0066] The term "prevention" refers to avoiding, minimizing, or making it difficult for a disease to occur or develop by treatment before the onset of the disease.

[0067] The term "autoimmune disease" refers to a disease caused by an immune response of the body to self-antigens resulting in damage to self-tissues. The American Autoimmune Related Diseases Association has compiled a comprehensive list of autoimmune diseases.

[0068] The term "autoinflammatory disease" refers to an inflammatory disease directed against self-tissues, organs, and the pathogenesis is defined as an abnormal response of the body's innate immune system resulting in inflammatory damage to self-tissues (see, Li Chengrong, Autoinflammatory Diseases, Chinese Journal of Pediatrics, 2008, 46(11): 842-847).

[0069] The disclosures of various publications, patents and published patent specifications referenced herein are hereby incorporated by reference in their entireties.

[0070] The technical solutions of the present application will be described clearly and completely below in combination with the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by those skilled in the art without creative work fall within the scope of protection of the present application.

[0071] The DZ2002 bulk drug used in the embodiments can be prepared by the preparation methods (i) to (vi) in the specific embodiments of the patent document CN101456860A (i.e. DZ2002 crude product), which has the following structure:

[0072] The DZA described in the embodiments has the following structure:

[0073] Embodiment 1: Preparation and characterization of the crystal form of DZ2002

[0074] 1. Instruments and methods

[0075] 1.1 X-ray powder diffraction (XRPD)

[0076] Instrument model: Bruker D8 advance X-Ray diffractometer; target: Cu Kα (40KV, 40mA); sample-to-detector distance: 30cm; scanning range: 3°-40° (2theta value); scanning rate: 0.1 sec / step; scanning step: 0.02.

[0077] 1.2 Thermogravimetric analysis (TGA)

[0078] Instrument model: Netzsch TG 209F3; temperature range: 30-400℃; scanning rate: 10℃ / min; purge gas: 25mL / min; protective gas: 15mL / min.

[0079] 1.3 Differential scanning calorimetry (DSC)

[0080] Instrument model: Perkin Elmer 8500 DSC; temperature range: 50-200℃; scanning rate: 10℃ / min; nitrogen flow rate: 50ml / min.

[0081] 1.4 Dynamic vapor sorption (DVS)

[0082] Instrument model: SMS DVS Intrinsic; 0-95% RH; temperature: 25℃.

[0083] 1.5 Raman spectroscopy (Raman)

[0084] Instrument model: Thermo Scientific DXR Raman Microscope; laser detection wavelength: 532 nm; exposure intensity: 2 s 5 times.

[0085] 1.6 X-ray single crystal diffraction (SC-XRD)

[0086] X-ray generator: MO Ka; temperature: 100 K.

[0087] 2. Preparation of the crystal form of DZ2002

[0088] Preparation of crystal form A: About 25 mg of DZ2002 raw material was stirred with 1 ml of methyl tert-butyl ether (MTBE) at 25°C for at least 24 h, the solution was filtered, and the solid part was dried in air for 10 min. The solid part was subjected to XRPD detection, and if the observed XRPD spectrum was different from the raw material spectrum, the solid was further subjected to other characterizations (such as DSC, TGA, IR, DVS, etc.). The results showed that a new crystal form of DZ2002 was obtained, which was designated as crystal form A.

[0089] Preparation of crystal form B: About 25 mg of DZ2002 raw material was stirred with 1 ml of isopropyl acetate at 25°C for at least 24 h, the solution was filtered, and the solid part was dried in air for 10 min. The solid part was subjected to XRPD detection, and if the observed XRPD spectrum was different from the raw material spectrum, the solid was further subjected to other characterizations (such as DSC, TGA, IR, DVS, etc.). The results showed that a new crystal form of DZ2002 was obtained, which was designated as crystal form B.

[0090] 3. Characterization of the crystal form of DZ2002

[0091] 3.1 Results of XRPD of crystal form A

[0092] The XRPD spectrum is shown in Figure 1, and the XRPD diffraction peak data is shown in Table 1.

[0093] Table 1 XRPD diffraction peak data of crystal form A

[0094] 3.2 Results of TGA and DCS of crystal form A

[0095] The TGA spectrum showed that crystal form A had a weight loss of 6.56% at 80-90°C (equivalent to 1 molecule of water, the theoretical value was 6.69%, and the corresponding single crystal analysis data also showed that crystal form A contained one molecule of water), and the corresponding DSC also had a clear water melting peak. And from the DSC spectrum, it can be seen that the starting melting temperature of crystal form A was 160°C, and the decomposition temperature was 200°C.

[0096] 3.3 Results of DVS for Form A

[0097] The hygroscopicity of Form A was evaluated by sorption and desorption experiments of moisture between 0-95% relative humidity at 25°C.

[0098] The DVS profile is shown in Figure 2. Form A has a moisture uptake of only 1% in the range of 0-95% humidity, indicating that it is slightly hygroscopic.

[0099] 3.4 Results of Raman for Form A

[0100] The Raman spectrum is shown in Figure 3.

[0101] 3.5 Results of IR for Form A

[0102] The IR spectrum is shown in Figure 4.

[0103] 3.6 Single Crystal Data for Form A

[0104] Computer program used to solve the crystal structure: The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P 21, with Z = 4 for the formula unit, C 10 H 13 N5O3.H2O. The final anisotropic full-matrix least-squares refinement on F 2 of 364 variables, converged at R1 = 3.47% (observed data) and wR2 = 9.38% (all data). The goodness of fit was 1.034. The largest peak in the final difference electron density synthesis was The largest hole was The RMS deviation was From the final model, the calculated density is 1.382 g / cm 3 , F (000), 534 e - . (The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P 21, with Z = 4 for the formula unit, C 10 H 13 N5O3.H2O. The final anisotropic full-matrix least-squares refinement on F 2with 364 variables converged at R1 = 3.47% for the observed data and wR2 = 9.38% for all data. The goodness-of-fit was 1.034. The largest peak in the final difference electron density synthesis was 0.314 e A3 and the largest hole was- with an RMS deviation of 0.045 On the basis of the final model, the calculated density was 1.382 g / cm 3 and F(000), 534 e - .)

[0105] The single crystal data of crystal form A is shown in Table 2, and the single crystal structure Ortep diagram is shown in Figure 5.

[0106] Table 2 Single crystal data of crystal form A

[0107] Example 2: Pharmacokinetic study of crystal form of DZ2002

[0108] 1. Experimental animals

[0109] Beagles were obtained from Shanghai Jiagan Biotechnology Co., Ltd. (Experimental Animal Use License No. SYXK (Shanghai) 2020-0042) and were acclimated for 2 weeks in the dog housing room of the Shanghai Institute of Pharmaceutical Research Animal Center (room temperature 23-25°C) with a body weight of about 8 kg.

[0110] 2. Preparation of formulations

[0111] Formulation 1: Crystal form B powder was filled into capsules, 80 mg / capsule.

[0112] Formulation 2: Crystal form A powder was filled into capsules, 85.7 mg / capsule.

[0113] 3. Experimental grouping and administration method

[0114] Three dogs / group, numbered 1#, 2#, and 3# respectively. After 12 hours of fasting, a single oral dose was administered, with a dose of 1 capsule / dog. Food was given 4 hours after administration.

[0115] 4. Sample collection and processing

[0116] Blood sampling time points: 0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 11 h, 24 h.

[0117] The concentrations of DZ2002 and DZA in the plasma of beagle dogs were detected by LC-MS / MS method. The LC-MS / MS detection method is as follows:

[0118] Liquid chromatograph: Agilent 1290 infinity LC system

[0119] Mass spectrometer: TSQ Vantage mass spectrometer

[0120] LC-MS / MS analysis conditions:

[0121] Chromatographic column: Synergi 4μFusion RP, 5μm, 2.0×50mm ID;

[0122] Mobile phase A: H2O (0.2% ammonium formate; 0.04% formic acid);

[0123] Mobile phase B: CH3OH (0.2% ammonium formate; 0.04% formic acid);

[0124] Flow rate: 0.3 mL / min;

[0125] Injection volume: 3μL;

[0126] The elution program is shown in Table 3.

[0127] Table 3 Elution program

[0128] The parameters of Spray Voltage, Vaporizer Temp, Sheath gas, Aux gas, Capillary Temp and S-lens were optimized;

[0129] The m / z of DZ2002 is 252→136, and the fragmentation energy is 23V;

[0130] The m / z of DZA is 238→136, and the fragmentation energy is 23V;

[0131] 5、Experimental results

[0132] It was found that DZ2002 could be rapidly converted to DZA after in vivo absorption after administration. The drug concentration-time curves of each group are shown in Figures 6-9, and the main pharmacokinetic parameters are shown in Table 4.

[0133] Table 4 Pharmacokinetic parameters after administration of beagle dogs

[0134] Relative oral bioavailability (RF) of Formulation 1 = AUC 制剂1 / AUC 制剂2 * 100%. Thus, compared with Formulation 1 (Form B), Formulation 2 (Form A) has better oral bioavailability.

[0135] The above description is merely preferred embodiments of the present application, but not to limit the present application. Any modification, equivalent replacement, and the like made in the spirit and principle of the present application shall be included in the scope of protection of the present application.

[0136] The foregoing examples and methods described in the present application can vary based on the ability, experience and preference of the person skilled in the art.

[0137] The steps of the method in the present application are only listed in a certain order, which does not constitute any limitation on the order of the steps of the method.

Claims

1. A crystalline Form A of a compound of Formula I, characterized by, The XRPD pattern of said crystalline Form A has characteristic peaks at at least three of the following positions: 5.8°±0.2°, 10.2°±0.2°, 11.7°±0.2°, 15.1°±0.2°, 17.7°±0.2°, 18.1°±0.2°, 25.8°±0.2°, 29.8°±0.2° in terms of 2Θ:

2. The crystalline Form A of claim 1, characterized by, the XRPD pattern of said crystalline Form A has at least three characteristic peaks in positions of about 8.7°±0.2°, 10.8°±0.2°, 14.2°±0.2°, 19.2°±0.2°, 20.3°±0.2°, 23.7°±0.2°, 24.0°±0.2°, 25.4°±0.2°, 28.3°±0.2°, 30.6°±0.2°, 31.6°±0.2°, 33.0°±0.2°, 34.6°±0.2°, 36.4°±0.2° of the 2Θ values; Preferably, said crystalline Form A has an XRPD pattern substantially as shown in Figure 1.

3. The crystalline Form A of claim 1, characterized by, the TGA pattern of said crystalline Form A has a weight loss of 6.56%±1% from 30°C to 100°C and / or 57.3%±1% from 190°C to 400°C; Preferably, the TGA pattern of said crystalline Form A has a weight loss of 6.56% from 30°C to 100°C and / or 57.3% from 190°C to 400°C.

4. The crystalline Form A of claim 1, characterized by, the DSC pattern of said crystalline Form A has an endothermic peak at 70-100°C and / or 160-170°C; Preferably, the DSC pattern of said crystalline Form A has an endothermic peak at 90.4±3°C and / or 164.4±3°C.

5. The crystalline Form A of claim 1, characterized by, Said crystalline Form A is a hydrate crystalline form, in particular a monohydrate crystalline form; Preferably, said crystalline Form A is a columnar crystal. Preferably, the crystal system of the Form A is monoclinic; the space group is P21; the unit cell parameters are: a = y = 90°; β = 112.9890(10)°; the unit cell volume of crystal form A is The density of said crystalline Form A is 1.382 g / cm 3 .

6. A process for preparing a crystalline Form A of a compound of Formula I according to any one of claims 1 to 5, characterized in that, The preparation method comprises using a compound of Formula I in amorphous form as starting material, and preparing crystalline Form A by suspension stirring method.

7. The preparation method according to claim 6, characterized in that, The suspension stirring method is a room temperature suspension stirring method. Preferably, said room temperature suspension stirring method comprises the following steps: suspending the amorphous starting material of Formula I in a solvent, and stirring at 20-30°C until solid precipitates; preferably at 25°C. Preferably, said solvent is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, methyl tert-butyl ether, toluene, n-heptane, n-hexane, diethyl ether, dichloromethane, trichloromethane, petroleum ether, preferably methyl tert-butyl ether.

8. A pharmaceutical composition comprising the crystalline Form A of the compound of Formula I according to any one of claims 1-5 or prepared by the method according to any one of claims 6-7, and one or more pharmaceutically acceptable excipients.

9. Use of the crystalline Form A of the compound of Formula I according to any one of claims 1-5 or prepared by the method according to any one of claims 6-7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for the prevention and / or treatment of a disease selected from the group consisting of autoimmune diseases, autoinflammatory diseases.

10. Use according to claim 9, characterized in that, said autoimmune diseases are selected from the group consisting of systemic lupus erythematosus, multiple sclerosis, autoimmune encephalomyelitis, psoriasis, vitiligo, eczema, rheumatoid arthritis, Sjogren's syndrome; Preferably, said Sjogren's syndrome is dry eye syndrome; said autoinflammatory diseases are selected from the group consisting of inflammatory bowel disease, familial periodic fever syndrome, vasculitis; said inflammatory bowel disease is selected from the group consisting of Crohn's disease, ulcerative colitis.

Images