Crystal form of ethanesulfonyl phenylacetamide compound and preparation method and application thereof

Abstract

The invention discloses a crystal form of an ethanesulfonyl phenylacetamide compound as well as a preparation method and application of the crystal form. The invention provides a crystal form 1 of a compound as shown in a formula I. The crystal form 1 has diffraction peaks at 9.862 + / -0.2 degrees, 15.446 + / -0.2 degrees, 19.406 + / -0.2 degrees and 23.809 + / -0.2 degrees in an X-ray powder diffraction pattern represented by a 2 theta angle. The crystal form 1 provided by the invention has good stability. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a crystal form of an ethylsulfonylphenylacetamide compound, a preparation method thereof, and applications thereof. Background Art

[0002] Retinoic acid receptor-related orphan receptors (RORs) belong to a member of the nuclear receptor superfamily of ligand-dependent transcription factors and play important roles in a series of physiological and pathological processes such as reproductive development, circadian rhythm regulation, metabolic disorders, inflammation, and immune system regulation. RORs mainly include three members: RORα, RORβ, and RORγ. RORα is mainly distributed in the liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus, brain, and blood. RORβ is mainly distributed in the central nervous system, including the brain, retina, and pineal gland. RORγ is highly expressed in the thymus and is also distributed in the kidney, liver, heart, skeletal muscle, adipose tissue, testis, prostate, and pancreas. It is further divided into two subtypes, RORγ1 and RORγt (also known as RORγ2), according to different transcriptional splicing positions. The former is mainly expressed in the thymus, testis, pancreas, heart, liver, skeletal muscle, and kidney, while RORγt is only expressed in immune organs.

[0003] Th17 cells are a subtype of T helper cells, characterized by secreting interleukin 17 (IL-17) cytokines. They were initially considered to mainly play an immune function by recruiting neutrophils in the resistance to bacterial and fungal infections. Subsequent studies have found that Th17 cells play a key role in many murine autoimmune disease models, and increased levels of IL-17 can also be detected in some human autoimmune diseases, including Psoriasis, Multiple Sclerosis (MS), Rheumatoid Arthritis (RA), and Inflammatory Bowel Disease (IBD). The number of Th17 cells found in the tissues and peripheral blood samples of patients with autoimmune diseases is increased. Therefore, Th17 cells or the cytokines IL-17 they produce are closely related to the pathogenesis of autoimmune diseases and inflammation. Inhibiting the differentiation of Th17 cells can be used to treat related diseases.

[0004] Studies have shown that RORγt is a key regulatory factor for Th17 cell differentiation. Littman et al. first reported that RORγt is essential for the differentiation of naive CD4+ T cells into Th17 cells. Mice lacking RORγt lack lymphoid organs such as lymph nodes and Peyer's patches, and the process of T cell development and maturation is also affected. The number of various types of T cells is lower than that of normal mice. Regulating the activity of RORγt through small molecule compounds can directly affect the differentiation of Th17 cells. Inhibiting RORγt significantly reduces the level of the cytokine IL-17 secreted by Th17 cells. Therefore, RORγt can be used as a new target for the treatment of autoimmune diseases. Developing small molecule regulators of RORγt and using them to treat RORγt-mediated related diseases such as autoimmune diseases and inflammatory diseases is of great significance.

[0005] Chinese Patent CN114685363A discloses an ethylsulfonylphenylacetamide compound, 2-(4-(ethylsulfonyl)phenyl)-N-(6-(2-methyl-2-(pyridin-2-yl)propanoyl)pyridin-3-yl)acetamide, with the molecular formula C 24 H 25 N3O4S, and its structural formula is shown in Formula I: The solid obtained by the method of Example 7 is the following Crystal Form 2;

[0006]

[0007] Compound I has inhibitory activity against RORγt, can effectively inhibit the RORγt protein receptor, thereby regulating the differentiation of Th17 cells, inhibiting the production of IL-17, and further treating RORγt-mediated related autoimmune diseases, especially suitable for various diseases such as psoriasis, multiple sclerosis, atopic dermatitis, and inflammatory bowel disease.

[0008] In view of the importance of solid drug crystal forms and their stability in clinical treatment, in-depth study of the crystal form of the above Compound I is of great significance for developing drugs suitable for industrial production and having good biological activity. Summary of the Invention

[0009] The present invention provides Crystal Form 1 of a compound shown in Formula I, and its X-ray powder diffraction pattern expressed in 2θ angle has diffraction peaks at 9.862±0.2°, 15.446±0.2°, 19.406±0.2° and 23.809±0.2°;

[0010]

[0011] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form 1 expressed in 2θ angles further has diffraction peaks at one or more (e.g., 2, 3, 4, or 5) of 16.802±0.2°, 18.167±0.2°, 19.705±0.2°, 27.070±0.2°, and 27.629±0.2°.

[0012] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form 1 expressed in 2θ angles has diffraction peaks at 9.862±0.2°, 15.446±0.2°, 16.802±0.2°, 18.167±0.2°, 19.406±0.2°, 19.705±0.2°, 23.809±0.2°, 27.070±0.2°, and 27.629±0.2°.

[0013] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form 1 expressed in 2θ angles further has diffraction peaks at one or more (e.g., 2, 3, or 4) of 9.091±0.2°, 11.502±0.2°, 15.285±0.2°, and 17.729±0.2°.

[0014] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form 1 expressed in 2θ angles further has diffraction peaks at one or more of 15.884±0.2°, 18.773±0.2°, 20.414±0.2°, 20.922±0.2°, 22.881±0.2°, 23.202±0.2°, 24.050±0.2°, 24.568±0.2°, 25.490±0.2°, 25.769±0.2°, 26.491±0.2°, 27.852±0.2°, 30.331±0.2°, 30.477±0.2°, 33.450±0.2°, 34.311±0.2°, 34.813±0.2°, 37.472±0.2°, and 38.460±0.2°.

[0015] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form 1 expressed in 2θ angles further has diffraction peaks at one or more of 4.718±0.2°, 10.719±0.2°, 15.064±0.2°, 17.148±0.2°, 18.595±0.2°, 22.180±0.2°, 22.399±0.2°, 22.682±0.2°, 23.526±0.2°, 24.310±0.2°, 25.232±0.2°, 28.218±0.2°, 28.650±0.2°, 29.689±0.2°, 30.731±0.2°, 31.170±0.2°, 31.649±0.2°, 31.975±0.2°, 32.612±0.2°, 32.975±0.2°, 33.954±0.2°, 34.592±0.2°, 35.256±0.2°, 35.818±0.2°, 36.759±0.2°, 39.259±0.2°, and 39.494±0.2°.

[0016] In some embodiments of the present invention, the XRPD pattern of the crystalline form 1 is substantially as Figure 2 shown.

[0017] In some embodiments of the present invention, the weight loss of the crystalline form 1 is <0.40% during the process from 29.20°C to 150°C;

[0018] and / or, the differential scanning calorimetry curve of the crystalline form 1 has an endothermic peak at 183.47±5°C;

[0019] and / or, the moisture absorption weight gain of the crystalline form 1 at 80% RH is <0.2%;

[0020] and / or, the X-ray powder diffraction pattern is measured using Cu-Kα radiation spectrum.

[0021] In some embodiments of the present invention, the weight loss of the crystalline form 1 is about 0.2653% from 29.2°C to 150°C; preferably, the thermogravimetric analysis curve pattern of the crystalline form 1 is substantially as Figure 4 shown;

[0022] and / or, the differential scanning calorimetry pattern of the crystalline form 1 is substantially as Figure 6 shown;

[0023] and / or, the dynamic moisture sorption pattern of the crystalline form 1 is substantially as Figure 8 shown.

[0024] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form 1 in terms of 2θ angle has diffraction peaks at the diffraction angles shown in Table 1:

[0025] Table 1

[0026] Number Diffraction angle 2θ (±0.2°) Number Diffraction angle 2θ (±0.2°) Number Diffraction angle 2θ (±0.2°) 1 4.718 21 22.399 41 30.477 2 9.091 22 22.682 42 30.731 3 9.862 23 22.881 43 31.170 4 10.719 24 23.202 44 31.649 5 11.502 25 23.526 45 31.975 6 15.064 26 23.809 46 32.612 7 15.285 27 24.050 47 32.975 8 15.446 28 24.310 48 33.450 9 15.884 29 24.568 49 33.954 10 16.802 30 25.232 50 34.311 11 17.148 31 25.490 51 34.592 12 17.729 32 25.769 52 34.813 13 18.167 33 26.491 53 35.256 14 18.595 34 27.070 54 35.818 15 18.773 35 27.629 55 36.759 16 19.406 36 27.852 56 37.472 17 19.705 37 28.218 57 38.460 18 20.414 38 28.650 58 39.259 19 20.922 39 29.689 59 39.494 20 22.180 40 30.331 。

[0027] In some embodiments of the present invention, in the X-ray powder diffraction pattern of the crystalline form 1 in terms of 2θ angle, its diffraction peaks, d values and peak height percentages can be as shown in Table 2:

[0028] Table 2

[0029]

[0030]

[0031]

[0032] In the present invention, the target type used in the X-ray powder diffraction is a Cu target.

[0033] The present invention also provides a preparation method of the crystalline form 1 of the compound shown in Formula I as described above, which is Scheme 1, Scheme 2 or Scheme 3;

[0034] The said Scheme 1 includes the following steps: The compound shown in Formula I is slurried and crystallized in ethyl acetate, and the solid is collected to obtain the crystalline form 1 of the compound shown in Formula I. The volume-mass ratio of the ethyl acetate to the compound shown in Formula I is 5 - 50 mL / g;

[0035] The said Scheme 2 includes the following steps: The solution of the compound shown in Formula I is cooled to precipitate a solid, and the solid is collected to obtain the crystalline form 1 of the compound shown in Formula I. The solvent of the solution is a mixed solvent of acetone, methanol and water; the volume ratio of the acetone, methanol and water is 10:(2 - 4):(1 - 2); the volume-mass ratio of the mixed solvent to the compound shown in Formula I is 10 - 100 mL / g;

[0036] The said Scheme 3 includes the following steps: The crystalline form 2 of the compound shown in Formula I is suspended in a solvent for polymorph conversion to obtain the crystalline form 1 of the compound shown in Formula I;

[0037] The said solvent is 1, 2 or 3 of water, acetone and ethanol;

[0038] The X-ray powder diffraction pattern of crystalline form 2 of the compound represented by formula I, expressed in 2θ angle, has diffraction peaks at 9.743±0.2°, 12.042±0.2°, 15.062±0.2°, 15.285±0.2°, 17.908±0.2°, 18.146±0.2°, 19.531±0.2°, 20.029±0.2°, 21.307±0.2°, 23.251±0.2° and 25.254±0.2° (for example, in the X-ray powder diffraction pattern of crystalline form 2 of the compound represented by formula I, the diffraction peaks, d values and peak height percentages are as shown in Table 3 below). In some embodiments of the present invention, the above-described Scheme 1, Scheme 2 and Scheme 3 further include drying; preferably, the drying temperature is 55±5°C.

[0039] In some embodiments of the present invention, in Scheme 1, the volume-to-mass ratio of the mixed solvent to the compound represented by formula I is 10-20 mL / g; for example, 9.1 mL / g;

[0040] In some embodiments of the present invention, in Scheme 2, the volume-to-mass ratio of the mixed solvent to the compound represented by formula I can be 15.1 mL / g.

[0041] In some embodiments of the present invention, in Scheme 3, polymorph conversion is carried out under the seed crystal of crystalline form 1 of the compound represented by formula I.

[0042] In some embodiments of the present invention, in Scheme 3, the polymorph conversion temperature is room temperature, for example, 10-30°C.

[0043] The present invention provides crystalline form 2 of a compound represented by formula I, the X-ray powder diffraction pattern of which, expressed in 2θ angle, has diffraction peaks at 9.743±0.2°, 12.042±0.2°, 15.062±0.2°, 15.285±0.2°, 17.908±0.2°, 18.146±0.2°, 19.531±0.2°, 20.029±0.2°, 21.307±0.2°, 23.251±0.2° and 25.254±0.2°;

[0044]

[0045] In some embodiments of the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form 2 expressed in terms of 2θ angle further has diffraction peaks at one or more of 6.071±0.2°, 13.465±0.2°, 14.503±0.2°, 15.686±0.2°, 20.747±0.2°, 21.727±0.2°, 22.390±0.2°, 23.828±0.2° and 25.112±0.2°.

[0046] In some embodiments of the present invention, more preferably, the X-ray powder diffraction pattern of the crystalline form 2 expressed in terms of 2θ angle further has diffraction peaks at one or more of 8.991±0.2°, 14.125±0.2°, 15.867±0.2°, 16.870±0.2°, 18.786±0.2°, 24.087±0.2°, 26.211±0.2°, 26.511±0.2°, 27.051±0.2°, 27.879±0.2°, 28.247±0.2°, 28.431±0.2°, 28.895±0.2°, 29.909±0.2°, 30.517±0.2°, 30.811±0.2°, 31.653±0.2°, 31.928±0.2°, 32.170±0.2°, 33.355±0.2° and 36.674±0.2°.

[0047] In some embodiments of the present invention, preferably, in the X-ray powder diffraction pattern of the crystalline form 2 expressed in terms of 2θ angle, its diffraction peaks, d values and peak height percentages can also be as shown in Table 3:

[0048] Table 3

[0049]

[0050]

[0051]

[0052] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form 2 is substantially as Figure 3 shown.

[0053] In some embodiments of the present invention, during the process of 31.30°C to 150°C, the weight loss of the crystalline form 2 is ≤1.4%; preferably, the weight loss of the crystalline form 1 is about 1.394% during 31.30°C to 150°C.

[0054] In some embodiments of the present invention, the thermogravimetric analysis curve pattern of the crystalline form 2 is substantially as Figure 5 shown.

[0055] In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of polymorph 2 has an endothermic peak at 181.95 ± 5 °C.

[0056] In some embodiments of the present invention, the differential scanning calorimetry (DSC) pattern of polymorph 2 is substantially as Figure 7 shown.

[0057] In some embodiments of the present invention, the X-ray powder diffraction pattern is measured using Cu-Kα radiation.

[0058] The present invention also provides a method for preparing polymorph 2 of the compound represented by Formula I as described above, which comprises the following steps: the amorphous sample of the compound represented by Formula I is left standing open at 25 °C - 60% RH for 8 days, and the solid is collected to obtain polymorph 2 of the compound represented by Formula I.

[0059] The present invention also provides a method for preparing polymorph 2 of the compound represented by Formula I as described above, which comprises the following steps: the amorphous sample of the compound represented by Formula I is left standing open at RT - 12% RH or RT - 58% RH for 8 days, and the solid is collected to obtain polymorph 2 of the compound represented by Formula I.

[0060] The present invention provides an amorphous form of the compound represented by Formula I, the X-ray powder diffraction pattern of which has no obvious sharp diffraction peaks.

[0061] Preferably, the amorphous form has an XRPD pattern as shown in Figure 1 the appendix.

[0062] The present invention also provides a method for preparing the amorphous form of the compound represented by Formula I as described above, which comprises the following steps: the compound represented by Formula I is suspended in a mixed solvent of acetone and tetrahydrofuran, heated to dissolve completely and then filtered, the filtrate is concentrated under reduced pressure to dryness at 40 °C - 60 °C, and the solid is collected to obtain the amorphous sample of the compound represented by Formula I.

[0063] The volume ratio of acetone to tetrahydrofuran is preferably (5:1 to 4:1). The volume-to-mass ratio of the mixed solvent to the compound represented by Formula I is preferably 20 - 100 mL / g; for example, 60 mL / g.

[0064] The present invention also provides a pharmaceutical composition, which comprises Substance X and at least one pharmaceutical excipient; Substance X is polymorph 1 of the compound represented by Formula I as described above or its amorphous form.

[0065] The selection of the pharmaceutical excipient varies depending on the administration route and the characteristics of the action, and generally can be conventional fillers, diluents, binders, wetting agents, disintegrants, lubricants, emulsifiers, suspending agents, etc. in the art.

[0066] The described pharmaceutical composition can be administered by oral, injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, buccal, rectal, urethral, vaginal, nasal, inhalation or topical routes, and the preferred route is oral.

[0067] The present invention provides an application of the foregoing crystalline form 1, amorphous form or the foregoing pharmaceutical composition of the compound shown in formula I in the preparation of a drug, and the drug is used for preventing or treating diseases related to the RORγt protein receptor.

[0068] In some embodiments of the present invention, the diseases related to the RORγt protein receptor are selected from one or more of psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, systemic lupus erythematosus, Behcet's disease and chronic obstructive pulmonary disease.

[0069] The present invention provides a pharmaceutical solid dispersion, which comprises the compound shown in formula I as described above and a pharmaceutical carrier.

[0070] Preferably, the compound I is the amorphous form of the compound shown in formula I as described above.

[0071] Preferably, the mass ratio of the crystalline form 1 of the compound shown in formula I to the pharmaceutical carrier is 1:(2 - 4), for example, 1:3.

[0072] Preferably, the pharmaceutical carrier is hypromellose acetate succinate.

[0073] Preferably, the particle size of the pharmaceutical solid dispersion is ≤100 mesh sieve.

[0074] The present invention provides a solid dispersion of the crystalline form 1 of the compound shown in formula I, which comprises compound I and hypromellose acetate succinate;

[0075]

[0076] In some embodiments of the present invention, in the solid dispersion of the crystalline form 1 of compound I, the mass ratio of compound I to hypromellose acetate succinate is 1:(2 - 4), for example, 1:3.

[0077] The present invention also provides a preparation method of a pharmaceutical solid dispersion, which comprises the following steps: extruding the compound shown in formula I as described above and a pharmaceutical carrier by the melting method to obtain the pharmaceutical solid dispersion.

[0078] Preferably, the compound shown in formula I is preferably the crystalline form or amorphous form of the compound shown in formula I. The crystalline form of the compound shown in formula I is preferably the crystalline form 1 shown in formula I as described above.

[0079] Preferably, the pharmaceutical carrier is hypromellose acetate succinate.

[0080] Preferably, the temperature of the melting method is 180 - 200 °C, such as 190 °C.

[0081] The present invention also provides a method for preparing a solid dispersion of polymorph 1 of the compound shown in Formula I as described above, which comprises the following steps: extruding the above-mentioned Compound I and hypromellose acetate succinate by the melting method to obtain the solid dispersion of polymorph 1 of the compound shown in Formula I.

[0082] Preferably, the temperature of the melting method is 180 - 200 °C, such as 190 °C.

[0083] In some embodiments of the present invention, the method for preparing the solid dispersion of the compound shown in Formula I as described above comprises the following steps:

[0084] Weigh polymorph 1 of Compound I and hypromellose acetate succinate (HPMCAS) according to a mass ratio of 1:3, mix them evenly to obtain a mixed powder; set the temperature of the main heating section of the hot melt extruder to 190 °C, turn on the heating, and when the equipment reaches the set temperature and is stable, add the mixed powder into the feeding hopper; gradually increase the rotation speed of the automatic feeder and the screw speed. When both the rotation speed of the feeder and the screw speed reach 25 rpm for the feeder speed and 300 rpm for the screw speed, start collecting the hot melt extrudate, and use a multi-functional pulverizer to pulverize the extrudate. After pulverization, sieve the sample through a 100-mesh sieve to obtain the solid dispersion of polymorph 1 of Compound I.

[0085] In some embodiments of the present invention, the method for preparing the solid dispersion of polymorph 1 of the compound shown in Formula I as described above comprises the following steps:

[0086] Weigh polymorph 1 of Compound I and hypromellose acetate succinate (HPMCAS) according to a mass ratio of 1:3, mix them evenly to obtain a mixed powder for hot melt extrusion; set the temperature of the main heating section of the hot melt extruder to 190 °C, turn on the heating, and when the equipment reaches the set temperature and is stable, add the mixed powder into the feeding hopper; gradually increase the rotation speed of the automatic feeder and the screw speed, and pay attention to coordinated adjustment to ensure that the material does not accumulate in the twin-screw; when both the rotation speed of the feeder and the screw speed reach the target values (feeder speed: 25 rpm, screw speed: 300 rpm), start collecting the hot melt extrudate. The extrudate is transparent; use a multi-functional pulverizer to pulverize the extrudate. After pulverization, sieve the sample through a 100-mesh sieve to obtain the solid dispersion of polymorph 1 of Compound I.

[0087] The present invention also provides a pharmaceutical solid dispersion prepared by the above method for preparing the pharmaceutical solid dispersion.

[0088] The present invention also provides a pharmaceutical composition, which comprises the above-mentioned drug solid dispersion and at least one pharmaceutical excipient.

[0089] The present invention also provides a pharmaceutical composition, which comprises substance X and at least one pharmaceutical excipient; the substance X is a solid dispersion of the crystalline form 1 of the compound shown in formula I as described above.

[0090] The selection of the pharmaceutical excipient varies depending on the administration route and action characteristics, and usually can be conventional fillers, diluents, binders, wetting agents, disintegrants, lubricants, emulsifiers, suspending agents, etc. in the art.

[0091] The pharmaceutical composition can be administered by oral, injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, buccal, rectal, urethral, vaginal, nasal, inhalation or topical routes, and the preferred route is oral.

[0092] The present invention provides an application of the solid dispersion shown in formula I as described above or the pharmaceutical composition as described above in the preparation of a drug, and the drug is used for preventing or treating diseases related to the RORγt protein receptor.

[0093] In some embodiments of the present invention, the diseases related to the RORγt protein receptor are selected from one or more of psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, systemic lupus erythematosus, Behcet's disease and chronic obstructive pulmonary disease.

[0094] In the present invention, "solid dispersion" has the same meaning as "solid dispersion body".

[0095] On the basis of not violating the common sense in the art, the above preferred conditions can be arbitrarily combined to obtain various preferred examples of the present invention.

[0096] The reagents and raw materials used in the present invention are all commercially available.

[0097] The positive and progressive effects of the present invention are as follows: the crystalline form 1 of the present invention has high stability and low hygroscopicity, and can be used for treating TNBS-induced colitis;

[0098] The crystalline form 1, amorphous form and drug solid dispersion body of the present invention have excellent pharmacokinetics. Description of the Drawings

[0099] Figure 1 It is the X-ray powder diffraction pattern of the amorphous sample obtained in Example 1;

[0100] Figure 2 It is the X-ray powder diffraction pattern of the crystalline form 1 obtained in Example 2;

[0101] Figure 3X-ray powder diffraction pattern of crystalline form 2 obtained in Example 4;

[0102] Figure 4 Thermogravimetric analysis chart of crystalline form 1 obtained in Example 2;

[0103] Figure 5 Thermogravimetric analysis chart of crystalline form 2 obtained in Example 4;

[0104] Figure 6 Differential scanning calorimetry chart of crystalline form 1 obtained in Example 2;

[0105] Figure 7 Differential scanning calorimetry chart of crystalline form 2 obtained in Example 4;

[0106] Figure 8 Dynamic water adsorption chart of crystalline form 1 obtained in Example 2;

[0107] Figure 9 Dynamic water adsorption chart of crystalline form 2 obtained in Example 4;

[0108] Figure 10 X-ray powder diffraction pattern of the mixed sample in the crystalline form transformation experiment in Effect Example 1;

[0109] Figure 11 X-ray powder diffraction pattern of the crystalline form transformation experiment in water in Effect Example 1;

[0110] Figure 12 X-ray powder diffraction pattern of the crystalline form transformation experiment in ethanol in Effect Example 1;

[0111] Figure 13 X-ray powder diffraction pattern of the crystalline form transformation experiment in acetone in Effect Example 1;

[0112] Figure 14 X-ray powder diffraction comparison chart of the stability experiment in Effect Example 2;

[0113] Figure 15 Differential scanning calorimetry comparison chart of the stability experiment in Effect Example 2.

[0114] Figure 16 Differential scanning calorimetry comparison chart of the stability experiment in Example 5 Detailed implementation manners

[0115] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0116] Instruments and methods for data collection:

[0117] The X-ray powder diffraction pattern described in this application was collected on a Bruker D8 Advance Diffractometer X-ray powder diffractometer.

[0118] The technical specifications of the instrument are as follows:

[0119] The wavelength of the copper target is Kα radiation (40 KV, 40 mA), θ-2θ goniometer, nickel filter, Lynxeye detector.

[0120] Collection software: Diffrac Plus XRD Commander

[0121] Calibration substance: corundum (Al2O3)

[0122] Analysis software: MDI Jade

[0123] The accessories are as follows:

[0124]

[0125] The parameters are as follows:

[0126] Detection angle 3° - 40° 2θ / 3 - 30° 2θ (hot stage XRPD) Step size 0.02° 2θ Speed <![CDATA[0.2s.step -1 > Amount of sample detected > 2 mg Remarks Unless otherwise specified, the sample is not ground before detection

[0127] The differential scanning calorimetry (DSC) data described in this application were collected from a TA Instruments Q200 differential scanning calorimeter. The instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. Usually, 0.5 mg - 5 mg of the sample is placed in an aluminum crucible (covered without punching holes), and the sample is heated from room temperature to 220 °C or 250 °C at a heating rate of 10 °C / min under the protection of dry N2 at 50 mL / min. At the same time, the TA software records the heat change of the sample during the heating process. In this application, the melting point is reported according to the starting temperature.

[0128] The thermogravimetric analysis (TGA) data described in this application were collected from a TA Instruments Q500 thermogravimetric analyzer. The instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. Usually, 1 - 10 mg of the sample is placed in a platinum crucible, and in a segmented high-resolution detection mode, the sample is heated from room temperature to 350 °C or 400 °C at a heating rate of 10 °C / min under the protection of dry N2 at 40 mL / min. At the same time, the TA software records the weight change of the sample during the heating process.

[0129] The dynamic moisture sorption graphs described in this application were collected on a TA Instruments Q5000 dynamic moisture sorption instrument. The instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. The method parameters for the dynamic moisture sorption test described in this invention are as follows:

[0130] Temperature: 25 °C

[0131] Protective gas and flow rate: N2, 10 mL / min

[0132] Minimum dm / dt equilibrium time: 15 minutes

[0133] Maximum equilibrium time: 90 minutes

[0134] Relative humidity range: 0%RH - 80%RH - 0%RH

[0135] Relative humidity gradient: 10% (0%RH - 80%RH - 0%RH)

[0136] Preparation of the amorphous sample of Compound I in Example 1

[0137] Weigh the Compound I sample (100 mg), add acetone (5 mL) and tetrahydrofuran (1 mL), heat until dissolved and clarified, then filter. The filtrate is concentrated to dryness under reduced pressure at 60 °C to obtain the amorphous sample.

[0138] Preparation of Crystal Form 1 of Compound I in Example 2

[0139] Disperse the Compound I sample (33 g) in ethyl acetate (300 mL), heat to reflux with stirring for 18 hours, slowly cool to room temperature under stirring, filter by suction, and dry the filter cake. The obtained solid sample is Crystal Form 1 of Compound I.

[0140] Preparation of Crystal Form 1 of Compound I in Example 3

[0141] Disperse the Compound I sample (10.21 g) in a mixed solvent of acetone (100 mL), methanol (34 mL) and water (20 mL), heat to reflux with stirring until the system is clarified, slowly cool to room temperature under stirring, precipitate solids, filter by suction and dry to obtain a solid sample, which is Crystal Form 1 of Compound I.

[0142] After testing, the X-ray powder diffraction data of the solids obtained in Example 2 and Example 3 are shown in Table 6, and their X-ray powder diffraction patterns are as Figure 2 shown, and their TGA patterns are as Figure 4 shown, and their DSC patterns are as Figure 6As shown, the results indicate that the obtained solid product is Crystal Form 1 described in this application. The TGA data shows that the crystal form sample has a weight loss of approximately 0.2653% from 29.20 °C to 150 °C, and there is a single melting endothermic peak at 183.47 °C (peak temperature) in the DSC.

[0143] Table 6

[0144]

[0145]

[0146] Hygroscopicity test of Crystal Form 1

[0147] Take about 9.698 mg of Crystal Form 1 and test its hygroscopicity using a dynamic vapor sorption (DVS) instrument. The experimental results are shown in Table 7. The DVS diagram of the hygroscopicity experiment is as Figure 8 shown.

[0148] Table 7 Hygroscopicity experiment of Crystal Form 1

[0149]

[0150]

[0151] Regarding the description of hygroscopicity characteristics and the definition of hygroscopic weight gain (Guiding Principles for Drug Hygroscopicity Tests, Appendix XIX J of Chinese Pharmacopoeia 2010 Edition, experimental conditions: 25 °C ± 1 °C, 80% relative humidity):

[0152] Deliquescence: Absorbing sufficient moisture to form a liquid

[0153] Highly hygroscopic: Hygroscopic weight gain not less than 15%

[0154] Hygroscopic: Hygroscopic weight gain less than 15% but not less than 2%

[0155] Slightly hygroscopic: Hygroscopic weight gain less than 2% but not less than 0.2%

[0156] Non - or almost non - hygroscopic: Hygroscopic weight gain less than 0.2%.

[0157] Preparation of Compound I Crystal Form 2 in Example 4

[0158] Take 30 mg of the amorphous sample and let it stand open at 25 °C - 60% RH for 8 days. The collected solid is Crystal Form 2 of Compound I.

[0159] After testing, the X - ray powder diffraction data of the solid obtained in Example 4 is shown in Table 8, and its X - ray powder diffraction pattern is as Figure 3 shown, its TGA diagram is as Figure 5 shown, and its DSC diagram is as Figure 7As shown, the results indicate that the obtained solid product is Crystal Form 2 described in this application. The TGA data shows that the crystal form sample has a weight loss of approximately 1.394% from 31.30 °C to 150 °C, and there is a single melting endothermic peak at 181.95 °C (peak temperature) in the DSC.

[0160] Table 8

[0161]

[0162]

[0163] Hygroscopicity Test of Crystal Form 2

[0164] Take about 2.3020 mg of Crystal Form 2 and test its hygroscopicity using a dynamic vapor sorption (DVS) instrument. The experimental results are shown in Table 9. The DVS diagram of the hygroscopicity experiment is as Figure 9 shown.

[0165] Table 9 Hygroscopicity Experiment of Crystal Form 2

[0166]

[0167]

[0168] Preparation of Solid Dispersion of Compound I in Example 5

[0169] Weigh Crystal Form 1 of Compound I and hypromellose acetate succinate (HPMCAS) according to a mass ratio of 1:3, mix them evenly to obtain a mixed powder for hot melt extrusion. Set the temperature of the main heating section of the hot melt extruder to 190 °C, turn on the heating, and when the equipment reaches the set temperature and stabilizes, add the mixed powder into the feeding hopper. Gradually increase the rotation speed of the automatic feeder and the screw speed, and pay attention to coordinated adjustment to ensure that the material does not accumulate in the twin-screw. When the rotation speeds of both the feeder and the screw reach the target values (feeder rotation speed: 25 rpm, screw rotation speed: 300 rpm), start collecting the hot melt extrudate, and the extrudate is transparent. Use a multi-functional pulverizer to pulverize the extrudate, and pass the pulverized sample through a 100-mesh sieve to obtain the solid dispersion of Compound I.

[0170] Perform X-ray powder diffraction on the obtained solid, as shown in Figure 16 , and it is detected that the form of Compound I in the solid dispersion of Compound I is amorphous.

[0171] Effect Example 1: Crystal Form Conversion Experiment

[0172]

[0173] The X-ray powder diffraction pattern of the mixed sample in the crystal form conversion experiment is as Figure 10 shown.

[0174] As Figure 11 shown, after 4 days of crystallization slurry of the mixed sample of polymorph 1 and polymorph 2 in water at room temperature, polymorph 2 was transformed into polymorph 1.

[0175] As Figure 12 shown, after 4 days of crystallization slurry of the mixed sample of polymorph 1 and polymorph 2 in ethanol at room temperature, polymorph 2 was transformed into polymorph 1.

[0176] As Figure 13 shown, after 4 days of crystallization slurry of the mixed sample of polymorph 1 and polymorph 2 in acetone at room temperature, polymorph 2 was transformed into polymorph 1.

[0177] Conclusion: Polymorph transformation experiments were carried out on polymorph 1 and polymorph 2. The experimental results showed that at room temperature, the most stable polymorph in water, acetone and ethanol was polymorph 1.

[0178] Effect Example 2: Study on the Stability of Polymorph 1

[0179]

[0180]

[0181] Conclusion:

[0182] Under the four conditions of long-term, accelerated, high humidity and high temperature, as Figure 14 shown, by comparing the X-ray powder diffraction patterns of the samples, polymorph 1 did not change and no polymorph transformation occurred.

[0183] Under the four conditions of long-term, accelerated, high humidity and high temperature, as Figure 15 shown, by comparing the differential scanning calorimetry diagrams of the samples, the melting points of polymorph 1 did not change.

[0184] Effect Example 3: Absorption of Polymorph 1 of Compound I and Solid Dispersion of Compound I in Rats after Administration

[0185] SD rats (provided by Sino-British SIPPR Lab Animal Ltd, Shanghai), three rats in each group, were given Compound I Polymorph 1 by intravenous injection and intragastric administration respectively (see Table 9). For the intravenous injection group, 0.4 mL of blood was collected from the fundus venous plexus of rats before administration and at 0.033 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. For the intragastric administration group, 0.4 mL of blood was collected from the fundus venous plexus of rats before administration and at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. The blood samples were centrifuged at 8000 rpm for 5 min to separate the upper plasma. 40 μL of the plasma sample was added to 400 μL of methanol containing internal standard to precipitate proteins, vortexed for 1 min, centrifuged at 18000 g at 4 °C for 10 min, and 400 μL of the supernatant was injected into a 96-well plate. The injection volume was 1 μL and the plasma drug concentration was detected by LC / MS / MS, and then the corresponding pharmacokinetic parameters were calculated, as shown in Table 10.

[0186] Table 9 Animal grouping and drug administration

[0187]

[0188] Note: Solutol is polyethylene glycol stearate 15, Saline is normal saline, and DI water is ultrapure water

[0189] Table 10 Pharmacokinetic parameters after injection / intragastric administration of Polymorph 1

[0190]

[0191]

[0192] Conclusion: In this experiment, after intravenous injection of Compound I Polymorph 1 and intragastric administration of the solid dispersion of Compound I respectively, the results showed that the half-life of the latter part of Compound I Polymorph 1 by intravenous injection was 0.19 h, and the bioavailability of the solid dispersion of Compound I by intragastric administration was 1.24%.

[0193] Polymorph 1 in Table 9 above was obtained according to the preparation method of Example 2, and the solid dispersion of Compound I was obtained according to the preparation method of Example 5.

[0194] Effect Example 4: Tissue distribution of rats after administration of the solid dispersion of Compound I

[0195] SD rats (provided by Sino - British SIPPR Lab Animal Ltd, Shanghai), 3 rats per time point, were given the solid dispersion of Compound I (see Table 11) by gavage. The gavage group collected plasma, stomach, duodenum, jejunum, colon, rectum, apical blood, portal vein plasma, liver and other tissues and organs at 0.25 h, 1 h, 2 h, and 4 h. Blood samples were centrifuged at 6800 g for 6 min to separate the upper plasma. 30 μL of plasma sample was added to 300 μL of methanol containing internal standard to precipitate proteins, vortexed for 1 min, centrifuged at 18000 g at 4 °C for 10 min, and 400 μL of the supernatant was injected into a 96 - well plate with an injection volume of 1 μL for detection in LC / MS / MS to obtain plasma drug concentrations, and then the corresponding pharmacokinetic parameters were calculated, as shown in Table 13.

[0196] Tissue samples were homogenized with 50% MeOH (1:5). 40 μL of the homogenate was added to 400 μL of methanol containing internal standard to precipitate proteins, vortexed for 1 min, centrifuged at 18000 g at 4 °C for 10 min, and 400 μL of the supernatant was injected into a 96 - well plate with an injection volume of 1 μL for detection in LC / MS / MS to obtain tissue drug concentrations, as shown in Table 12.

[0197] Table 11 Animal grouping and drug administration

[0198]

[0199] Note: DI water is ultrapure water, and the solid dispersion of Compound I was prepared according to the description in Effect Example 3.

[0200] Table 12 Plasma and tissue drug concentrations after gavage administration of the solid dispersion of Compound I

[0201]

[0202]

[0203] Conclusion: In this experiment, after the solid dispersion of Compound I was given by gavage, the results showed that the solid dispersion of Compound I was widely distributed in the gastrointestinal tract after gavage administration, and the amount of drug entering the bloodstream was extremely small.

[0204] Effect Example 5: The solid dispersion of Compound I significantly improved the TNBS - induced rat colitis model

[0205] Fifty 6 - week - old male SD rats, weighing about 200 g, were randomly divided into 5 groups (Table 13), with 10 rats in each group.

[0206] The rats in the Sham group and the model group were gavaged with blank excipients (hydroxypropyl methylcellulose acetate succinate, HPMCAS) twice a day at an interval of 8 hours, starting from Day -1 and ending on Day 5.

[0207] The positive drug Mesalamine group and the solid dispersion group of Compound I were administered from Day -1 to the end of Day 5, and Day 6 was the experimental endpoint.

[0208] Rats in the model group: On experimental Day 0, SD rats weighing about 200 g were anesthetized with 3.2 ml of 1.25% avertin anesthetic (Easycheck, M2910). Rats in the model group and each dose administration group were rectally perfused with 1 ml of 1% TNBS solution (final concentration 50% ethanol).

[0209] Rats in the Sham group were rectally perfused with an equal volume of 50% ethanol. During the experiment, the body weight of the animals was measured daily, and the fecal traits and occult blood scores of the rats were determined for calculating the disease activity index (DAI) (Table 14).

[0210] At the experimental endpoint, after the animals were euthanized with CO2, blood was quickly collected from the heart to prepare serum, which was stored at -80 °C. The colon (from anus to cecum) was collected, photographed and the length of the colon was measured. The fat and connective tissues around the colon were removed, and the contents and cecum were removed and weighed. Then the rat colon was longitudinally dissected, and half of the colon tissue was taken in the Swiss roll form (such as the rectal segment, and the parts of each animal needed to be unified), fixed with neutral polyformaldehyde fixative for subsequent histopathological H&E staining, and a professional pathological score was given to the staining results by a pathologist (Table 15). The other half of the colon tissue was used for intestinal mucosa collection, homogenized and its protein concentration was detected.

[0211] Table 13. Animal grouping and dosing regimen

[0212]

[0213] Note: The positive drug is Mesalamine; PO is oral administration, BID is twice a day, QD is once a day;

[0214] The solid dispersion of Compound I (the solid dispersion of Compound I in Example 5) was dissolved in ultrapure water for administration.

[0215] Table 14. DAI scoring criteria

[0216] Score Percentage of weight loss Stool character Occult blood or bloody stool 0 0 Normal Negative occult blood 1 1～5 Soft stool Weak positive occult blood 2 6～10 Loose stool Positive occult blood 3 11～20 Watery stool Bloody stool 4 >20 Very watery stool Massive bloody stool

[0217] Table 15. Colon tissue pathological scoring criteria

[0218] Score Crypt structure Immune cell infiltration Muscular layer sclerosis Goblet cell Crypt abscess 0 Normal Normal Normal Present Normal 1 Slightly distorted Slight infiltration Slight fibrosis Absent Abscess 2 Distorted Infiltration Fibrosis - - 3 Severely distorted Massive infiltration Highly fibrotic - -

[0219] Table 16. Body weight changes

[0220]

[0221] Note: *P<0.05, **P<0.01, ***p<0.001, ****P<0.0001 vs. model group. Analyzed by two-way ANOVA and compared between groups using Dunnett’s test.

[0222] Table 17. Disease activity score

[0223]

[0224] Note: *P<0.05, **P<0.01, ***p<0.001, ****P<0.0001 vs. model group. Analyzed by two-way ANOVA and compared between groups using Dunnett’s test.

[0225] Table 18. Colon parameters

[0226]

[0227]

[0228] Note: *P<0.05, ****P<0.0001 vs. model group. Analyzed by one-way ANOVA and compared between groups using Dunnett’s test.

[0229] Table 19. Pathological score of rat colon tissue

[0230]

[0231] Note: ****P<0.0001 vs. model group. Analyzed by one-way ANOVA and compared between groups using Dunnett’s test.

[0232] Results: Combining the data from the In-life experiment and pathological analysis, the solid dispersion of Compound I of this patent: orally administered at 5 mg / kg and 5 mg / kg (twice a day) can significantly relieve TNBS-induced colitis and show a good dose-dependence, such as body weight (Table 16) and disease severity (Table 17).

[0233] It is manifested as slowing down the weight loss of rats with enteritis and improving the conditions of diarrhea and bloody stools in rats, reversing the reduction of the length-to-weight ratio of the colon in rats with enteritis (Table 18), and reducing the loss of crypt structure and infiltration of inflammatory cells, etc. (Table 19).

[0234] Conclusion: The solid dispersion of Compound I significantly alleviates the symptoms of TNBS-induced rat colitis model at a dose as low as 5 mg / kg (twice a day), showing the potential for treating inflammatory bowel disease.

Claims

1. Polymorph 1 of a compound represented by Formula I, characterized in that, Its X-ray powder diffraction pattern expressed in terms of 2θ has diffraction peaks at 9.862 ± 0.2°, 15.446 ± 0.2°, 19.406 ± 0.2° and 23.809 ± 0.2°; 2. The crystalline form 1 of the compound shown in Formula I as described in claim 1, characterized in that, Its X-ray powder diffraction pattern expressed in terms of 2θ has diffraction peaks at 9.862 ± 0.2°, 15.446 ± 0.2°, 16.802 ± 0.2°, 18.167 ± 0.2°, 19.406 ± 0.2°, 19.705 ± 0.2°, 23.809 ± 0.2°, 27.070 ± 0.2° and 27.629 ± 0.2°; 3. The crystalline form 1 of the compound shown in formula I as described in claim 2, characterized in that, The X-ray powder diffraction pattern of the said crystalline form 1 expressed in terms of 2θ also has diffraction peaks at one or more of 9.091 ± 0.2°, 11.502 ± 0.2°, 15.285 ± 0.2° and 17.729 ± 0.2°; 4. The crystalline form 1 of the compound shown in Formula I as described in claim 3, characterized in that, The X-ray powder diffraction pattern of the said crystalline form 1 expressed in terms of 2θ also has diffraction peaks at one or more of 15.884 ± 0.2°, 18.773 ± 0.2°, 20.414 ± 0.2°, 20.922 ± 0.2°, 22.881 ± 0.2°, 23.202 ± 0.2°, 24.050 ± 0.2°, 24.568 ± 0.2°, 25.490 ± 0.2°, 25.769 ± 0.2°, 26.491 ± 0.2°, 27.852 ± 0.2°, 30.331 ± 0.2°, 30.477 ± 0.2°, 33.450 ± 0.2°, 34.311 ± 0.2°, 34.813 ± 0.2°, 37.472 ± 0.2° and 38.460 ± 0.2°; 5. The crystalline form 1 of the compound shown in Formula I as described in claim 4, characterized in that, The X-ray powder diffraction pattern of the said crystalline form 1 expressed in terms of 2θ also has diffraction peaks at one or more of 4.718 ± 0.2°, 10.719 ± 0.2°, 15.064 ± 0.2°, 17.148 ± 0.2°, 18.595 ± 0.2°, 22.180 ± 0.2°, 22.399 ± 0.2°, 22.682 ± 0.2°, 23.526 ± 0.2°, 24.310 ± 0.2°, 25.232 ± 0.2°, 28.218 ± 0.2°, 28.650 ± 0.2°, 29.689 ± 0.2°, 30.731 ± 0.2°, 31.170 ± 0.2°, 31.649 ± 0.2°, 31.975 ± 0.2°, 32.612 ± 0.2°, 32.975 ± 0.2°, 33.954 ± 0.2°, 34.592 ± 0.2°, 35.256 ± 0.2°, 35.818 ± 0.2°, 36.759 ± 0.2°, 39.259 ± 0.2° and 39.494 ± 0.2°; 6. The crystalline form 1 of the compound represented by formula I as described in any one of claims 1-5, characterized in that, The X-ray powder diffraction pattern of the said crystalline form 1 expressed in terms of 2θ also has diffraction peaks at the diffraction angles shown below:

7. The polymorphic form 1 of the compound represented by formula I according to any one of claims 1-6, characterized in that, It satisfies one or more of the following conditions: (1) The said crystalline form 1 has a weight loss of < 0.40% during the process from 29.2°C to 150°C; (2) The differential scanning calorimetry curve of the crystalline form 1 has an endothermic peak at 183.47 ± 5 °C; (3) The moisture absorption weight gain of the crystalline form 1 at 80% RH is <0.2%; (4) The X-ray powder diffraction pattern described is measured using Cu-Kα radiation; (5) In the X-ray powder diffraction pattern of the crystalline form 1 expressed in 2θ angle, its diffraction peaks, d values, and peak height percentages are as follows:

8. The crystalline form 1 of the compound represented by formula I according to any one of claims 1-7, characterized in that, It satisfies one or more of the following conditions: (1) The crystalline form 1 loses about 0.2653% of its weight from 29.20 °C to 150 °C; preferably, the thermogravimetric analysis curve pattern of the crystalline form 1 is basically as shown in Figure 4; (2) The differential scanning calorimetry pattern of the crystalline form 1 is basically as shown in Figure 6; (3) The dynamic moisture adsorption pattern of the crystalline form 1 is basically as shown in Figure 8; (4) The XRPD pattern of the crystalline form 1 is basically as shown in Figure 2.

9. A method for preparing polymorph 1 of the compound represented by Formula I as described in any one of claims 1-8, characterized in that, It is Scheme 1, Scheme 2, or Scheme 3; The said Scheme 1 includes the following steps: The compound shown in Formula I is slurried and crystallized in ethyl acetate, and the solid is collected to obtain the crystalline form 1 of the compound shown in Formula I. The volume-to-mass ratio of the ethyl acetate to the compound shown in Formula I is 5 - 50 mL / g; The said Scheme 2 includes the following steps: The solution of the compound shown in Formula I is cooled to precipitate a solid, and the solid is collected to obtain the crystalline form 1 of the compound shown in Formula I. The solvent of the solution is a mixed solvent of acetone, methanol, and water; the volume ratio of the acetone, methanol, and water is 10:(2 - 4):(1 - 2); the volume-to-mass ratio of the mixed solvent to the compound shown in Formula I is 10 - 100 mL / g; The said Scheme 3 includes the following steps: The crystalline form 2 of the compound shown in Formula I is suspended in a solvent for polymorph conversion to obtain the crystalline form 1 of the compound shown in Formula I; The said solvent is one, two, or three of water, acetone, and ethanol; The X-ray powder diffraction pattern of the crystalline form 2 of the compound shown in Formula I expressed in 2θ angle has diffraction peaks at 9.743 ± 0.2 °, 12.042 ± 0.2 °, 15.062 ± 0.2 °, 15.285 ± 0.2 °, 17.908 ± 0.2 °, 18.146 ± 0.2 °, 19.531 ± 0.2 °, 20.029 ± 0.2 °, 21.307 ± 0.2 °, 23.251 ± 0.2 °, and 25.254 ± 0.2 °.

10. The preparation method of crystal form 1 of the compound shown in formula I as described in claim 9, characterized in that, It satisfies one or more of the following conditions: (1) Scheme 1 and Scheme 2 also include drying; preferably, the drying temperature is 55 ± 5 °C; (2) In Scheme 1, the volume-to-mass ratio of the mixed solvent to the compound shown in Formula I is 10 - 20 mL / g; for example, 9.1 mL / g; (3) In Scheme 2, the volume-to-mass ratio of the mixed solvent to the compound shown in Formula I is 15.1 mL / g; (4) In Scheme 3, the polymorph conversion is carried out under the seed crystal of the crystalline form 1 of the compound shown in Formula I; (5) In Scheme 3, the temperature of the polymorph conversion is 10 - 30 °C.

11. An amorphous form of a compound represented by Formula I, characterized in that, Its X-ray powder diffraction pattern has no obvious sharp diffraction peaks; preferably, the amorphous substance has an XRPD pattern as shown in Figure 1; 12. A pharmaceutical solid dispersion, characterized in that, It includes the compound shown by Formula I above and a pharmaceutical carrier; 13. The pharmaceutical solid dispersion according to claim 12, characterized in that ， It satisfies one or more of the following conditions: (1) Compound I is the amorphous form of the compound shown by Formula I; (2) The mass ratio of crystalline form 1 of the compound shown by Formula I to the pharmaceutical carrier is 1:(2 - 4), for example, 1:3; (3) The pharmaceutical carrier is hypromellose acetate succinate; (4) The particle size of the pharmaceutical solid dispersion is ≤ 100 mesh sieve.

14. The pharmaceutical solid dispersion according to claim 13, wherein It includes Compound I and hypromellose acetate succinate; Preferably, in the solid dispersion of crystalline form 1 of Compound I, the mass ratio of Compound I to hypromellose acetate succinate is 1:(2 - 4), for example, 1:

3.

15. A method for preparing a pharmaceutical solid dispersion, characterized in that, It includes the following steps: extruding the compound shown by Formula I and the pharmaceutical carrier by the melting method to obtain the pharmaceutical solid dispersion; Preferably, the compound shown by Formula I is the crystalline form or amorphous form of the compound shown by Formula I; the crystalline form of the compound shown by Formula I is preferably crystalline form 1 shown by Formula I in any one of Claims 1 - 8; Preferably, the pharmaceutical carrier is hypromellose acetate succinate; Preferably, the temperature of the melting method is 180 - 200 °C, for example, 190 °C.

16. A pharmaceutical solid dispersion prepared by the preparation method of the pharmaceutical solid dispersion as described in Claim 15.

17. A pharmaceutical composition, characterized in that, It includes Substance X and at least one pharmaceutical excipient; Substance X is crystalline form 1 of the compound shown by Formula I in any one of Claims 1 - 8, the amorphous form of the compound of Formula I as described in Claim 11, or the pharmaceutical solid dispersion in any one of Claims 12 - 14 and 16.

18. Use of crystalline form 1 of the compound shown by Formula I in any one of Claims 1 - 8, the amorphous form of the compound of Formula I as described in Claim 11, or the pharmaceutical solid dispersion in any one of Claims 12 - 14 and 16 in the preparation of a drug for preventing or treating diseases related to the RORγt protein receptor; Preferably, the diseases related to the RORγt protein receptor are selected from one or more of psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, systemic lupus erythematosus, Behcet's disease, and chronic obstructive pulmonary disease.

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