WO2025140327A1 - CRYSTAL FORM OF THYROID HORMONE β RECEPTOR MODULATOR - Google Patents

Abstract

The present invention relates to a polymorph of a compound that can be used as a thyroid hormone β receptor modulator, a preparation method therefor and a use thereof, and a pharmaceutical composition containing the polymorph. The use is a use in the preparation of drugs for treating various thyroid-related diseases.

Description

A crystal form of thyroid hormone beta receptor modulator Technical Field

The present application relates to the field of biomedicine, and specifically to polymorphs of compounds and pharmaceutical compositions and uses thereof.

Background Art

Thyroid hormones are necessary for normal growth and development of the human body. Insufficient or excessive secretion of thyroid hormones can cause diseases. When the thyroid gland is underactive, physical and intellectual development are affected, which can cause cretinism. When adults have thyroid dysfunction, myxedema can occur. When the thyroid gland is overactive, symptoms such as nervousness, irritability, tremors, increased heart rate, and increased cardiac output can occur. Thyroid hormones can promote the oxidation of substances, increase oxygen consumption, increase basal metabolic rate, and increase heat production.

The biological activity of thyroid hormones is mediated by thyroid hormone receptors (TRs). Thyroid hormone receptors belong to the superfamily of nuclear receptors. TR has a ligand binding domain, a DNA binding domain, and an amino-terminal domain. There are four subtypes of TR, namely TRα1, TRα2, TRβ1, and TRβ2. Among them, the heart is mainly TRα1, and the liver is mainly TRβ1. The mRNA expression of TRβ2 is mostly limited to the pituitary gland and hypothalamus. TRα1, TRβ1, and TRβ2 can bind to thyroid hormones and produce corresponding physiological effects. TRα2 does not bind to thyroid hormones.

Taking full advantage of the advantages of thyroid hormone in increasing metabolic rate, oxygen consumption and heat release can bring therapeutic benefits, such as treating obesity. Hyperthyroidism is often accompanied by increased food intake, but also an overall increase in basal metabolic rate (BMR), accompanied by a weight loss of about 15%; while hypothyroidism is often accompanied by a weight gain of 25-30%. Most patients who use T3 to treat hypothyroidism experience weight gain. In addition, thyroid hormone can also reduce serum low-density lipoprotein (LDL) (Journal of Molecular and Celluar Cardiology 37(2004):1137-1146). Existing studies have shown that hyperthyroidism can significantly reduce serum total cholesterol, mainly because thyroid hormone increases the expression of liver LDL receptors, thereby promoting the metabolism of cholesterol to bile acid; hypothyroidism is related to hypercholesterolemia. Therefore, thyroid hormone may reduce the occurrence of atherosclerosis and other cardiovascular diseases.

The use of thyroid hormones to treat diseases is often accompanied by side effects of supraphysiological doses due to individual differences, including heart problems (mainly tachycardia), muscle weakness, and excessive weight loss, and long-term use is also accompanied by bone loss. By modifying thyroid hormones, the adverse effects of thyroxine itself can be reduced, while retaining its beneficial effects, so as to develop appropriate drugs and treat the corresponding diseases: obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver diseases (fatty liver, NASH, NAFLD, etc.), cardiovascular diseases (atherosclerosis, etc.), thyroid diseases (hypothyroidism, thyroid cancer, etc.), and other related diseases.

The compound 2-(3,5-dichloro-4-((5-hydroxy-4-isopropylpyrimidin-2-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione disclosed in WO2021244582A1 is a novel thyroid hormone β receptor modulator having a structure of formula I.

The compound can be used to treat thyroid hormone-related diseases, such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver diseases (fatty liver, NASH, NAFLD, etc.), cardiovascular diseases (atherosclerosis, etc.), and thyroid diseases (hypothyroidism, thyroid cancer, etc.).

Summary of the invention

One of the purposes of the present application is to provide polymorphs of the compound of formula I (2-(3,5-dichloro-4-((5-hydroxy-4-isopropylpyrimidin-2-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione). The various crystal forms prepared in the present application can be identified and distinguished from other crystal forms by conventional crystal form characterization methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). By studying the properties of the crystal forms described in the present application, it was unexpectedly found that the various crystal forms of the present application have the advantages of good solubility, low hygroscopicity and/or good stability, and are suitable as pharmaceutical crystal forms.

The present application provides a crystalline form M of a compound represented by formula I,

In certain embodiments, in the X-ray powder diffraction pattern obtained using Cu Kα radiation, the crystalline form M shows characteristic diffraction peaks at diffraction angles 2θ of 6.58±0.2°, 10.15°±0.2°, 12.11±0.2°, 15.59±0.2°, 19.16±0.2°, and 26.98±0.2°.

In certain embodiments, in the X-ray powder diffraction pattern obtained using Cu Kα radiation, the crystalline form M shows characteristic diffraction peaks at diffraction angles 2θ of 6.58±0.2°, 10.15°±0.2°, 11.38°±0.2°, 12.11±0.2°, 14.04°±0.2°, 14.67°±0.2°, 15.59±0.2°, 19.16±0.2°, and 26.98±0.2°.

In certain embodiments, in the X-ray powder diffraction pattern obtained using CuKα radiation, the crystalline form M shows characteristic diffraction peaks at diffraction angles 2θ of 6.58±0.2°, 10.15°±0.2°, 11.38°±0.2°, 12.11±0.2°, 14.04°±0.2°, 14.67°±0.2°, 15.59±0.2°, 19.16±0.2°, 20.67°±0.2°, 22.94°±0.2°, 24.37°±0.2°, 26.98°±0.2°, and 27.37°±0.2°.

In certain embodiments, the X-ray powder diffraction pattern of the crystalline form M is substantially the same as that of FIG. 1 .

In certain embodiments, the crystalline Form M shows substantially no weight loss when heated to about 30° C.-180° C. in a thermogravimetric analysis test ( FIG. 2 ).

In certain embodiments, the crystalline form M shows an endothermic peak at about 205-210° C. in a differential scanning calorimetry test.

In some specific embodiments, the DSC spectrum of the crystalline form M is substantially the same as that of FIG. 3 .

The present application provides a crystalline form N of a compound represented by formula I.

In certain embodiments, in the PXRD powder diffraction pattern obtained using CuKα radiation and expressed in terms of a diffraction angle of 2θ, the crystalline form N shows characteristic diffraction peaks at 6.28±0.2°, 10.21°±0.2°, 12.29±0.2°, 15.81±0.2°, 18.96±0.2°, and 26.42±0.2°.

In certain embodiments, in the PXRD powder diffraction pattern obtained using CuKα radiation and expressed in a diffraction angle of 2θ, the crystalline form N shows characteristic diffraction peaks at 6.28±0.2°, 10.21°±0.2°, 12.29±0.2°, 14.16±0.2°, 14.67±0.2°, 15.20±0.2°, 15.81±0.2°, 18.96±0.2°, and 26.42±0.2°.

In certain embodiments, in the PXRD powder diffraction pattern obtained using CuKα radiation and expressed as a diffraction angle 2θ, the crystalline form N shows characteristic diffraction peaks at 6.28±0.2°, 10.21°±0.2°, 12.29±0.2°, 14.16±0.2°, 14.67±0.2°, 15.20±0.2°, 15.81±0.2°, 18.96±0.2°, 19.85°±0.2°, 20.63°±0.2°, 23.01°±0.2°, 26.42°±0.2°, and 28.54°±0.2°.

In certain embodiments, the X-ray powder diffraction pattern of the crystalline Form N is substantially the same as FIG. 4 .

In certain embodiments, the crystalline Form N shows substantially no weight loss when heated to about 30° C.-180° C. in a thermogravimetric analysis test ( FIG. 5 ).

In certain embodiments, the crystalline form N shows an endothermic peak at about 204-207° C. in a differential scanning calorimetry test.

In certain specific embodiments, the DSC spectrum of the crystalline form N is substantially the same as that of FIG. 6 .

The present application provides a hydrate crystal form O of the compound represented by formula I, wherein the water content of the hydrate crystal form O is that of a hemihydrate.

The single crystal of Form O was prepared and the crystal structure information was measured by single crystal X-ray diffraction. The crystallographic parameters of Form O (M = 838.44 g/mol) are: triclinic system, P-1 space group, α＝95.276(3)°，β＝106.113(4)°，γ＝109.816(4)°. Unit cell volume The number of molecules in the unit cell is Z = 2, and the unit cell density is ρ _calc = 1.513 g/cm ³ .

In certain embodiments, in the PXRD powder diffraction pattern obtained using CuKα radiation and represented by a diffraction angle 2θ, the crystalline form O shows characteristic diffraction peaks at 8.14±0.2°, 8.68°±0.2°, 9.11±0.2°, 14.01±0.2°, 24.11±0.2°, and 26.57±0.2°.

In certain embodiments, in the PXRD powder diffraction pattern obtained using CuKα radiation and expressed as a diffraction angle 2θ, the crystalline form O shows characteristic diffraction peaks at 8.14±0.2°, 8.68°±0.2°, 9.11±0.2°, 11.82±0.2°, 12.21±0.2°, 13.34±0.2°, 14.01±0.2°, 24.11±0.2°, and 26.57±0.2°.

In certain embodiments, in the PXRD powder diffraction pattern obtained using Cu-Kα radiation and expressed as a diffraction angle 2θ, the crystalline form O shows characteristic diffraction peaks at 8.14±0.2°, 8.68°±0.2°, 9.11±0.2°, 11.82±0.2°, 12.21±0.2°, 13.34±0.2°, 14.01±0.2°, 16.20°±0.2°, 20.30°±0.2°, 20.75°±0.2°, 21.12°±0.2°, 24.11°±0.2°, and 26.57±0.2°.

In certain embodiments, the X-ray powder diffraction pattern of the crystalline Form O is substantially the same as that of FIG. 7 .

In certain embodiments, the crystal form O shows a weight loss of 2.14% in the range of 40-140°C in a thermogravimetric analysis test ( FIG. 8 ). Based on the weight loss temperature and weight loss, it is inferred that the crystal form O is a hemihydrate (theoretical weight loss is 2.19%), which is consistent with the single crystal results and the DSC results.

In certain embodiments, the Form O shows a broad endothermic peak in the range of 60-140°C in a differential scanning calorimetry test, which is a desolvation peak, and a sharp endothermic peak at 174-177°C, which is a melting peak, indicating that Form O is a solvate, and is confirmed to be a hemihydrate based on the single crystal results.

In certain embodiments, the DSC spectrum of the crystalline form O is substantially the same as that of FIG. 9 .

Another object of the present application is to provide a pharmaceutical composition comprising the above-mentioned polymorph.

Another object of the present application is to provide the use of the above-mentioned polymorph or pharmaceutical composition in the preparation of a drug for preventing or treating diseases related to the action of thyroid hormone beta receptor agonists.

Another object of the present application is to provide the use of the above-mentioned polymorph or pharmaceutical composition in the preparation of a drug for preventing or treating thyroid hormone-related diseases, such as obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, thyroid cancer, metabolic syndrome, cardiovascular disease, coronary artery disease, myocardial infarction, ventricular dysfunction, heart failure, fatty liver, cirrhosis, diabetes, fatty hepatitis, non-alcoholic fatty hepatitis, non-alcoholic fatty liver disease, atherosclerosis, or hypothyroidism.

Those skilled in the art can easily perceive other aspects and advantages of the present application from the detailed description below. In the detailed description below, only exemplary embodiments of the present application are shown and described. As will be appreciated by those skilled in the art, the content of the present application enables those skilled in the art to modify the disclosed specific embodiments without departing from the spirit and scope of the invention to which the present application relates. Accordingly, the description in the drawings and specification of the present application is merely exemplary and not restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 X-ray powder diffraction pattern of Form M

Figure 2 Thermogravimetric analysis of Form M

Figure 3 Differential scanning calorimetry analysis of Form M

Figure 4 X-ray powder diffraction pattern of Form N

Figure 5 Thermogravimetric analysis of Form N

Figure 6 Differential scanning calorimetry analysis of Form N

Figure 7 X-ray powder diffraction pattern of Form O

Figure 8 Thermogravimetric analysis of Form O

Figure 9 Differential scanning calorimetry analysis of Form O

Figure 10 Schematic diagram of the asymmetric unit of the single crystal sample of Form O

Figure 11 X-ray powder diffraction pattern of Form A

Figure 12 Differential scanning calorimetry analysis of Form A

Figure 13 X-ray powder diffraction pattern of amorphous

Example

The present invention will be further described below through specific examples, but it is not intended to limit the scope of protection of the present invention. Those skilled in the art may make improvements to the preparation method and the use of the instrument within the scope of the claims, and these improvements should also be regarded as the scope of protection of the present invention. Therefore, the scope of protection of the patent of the present invention shall be based on the attached claims.

The abbreviations used in the present invention are explained as follows:
XRPD: X-ray powder diffraction
DSC: Differential Scanning Calorimetry
TGA: Thermogravimetric analysis
DVS: Dynamic Vapor Sorption
HPLC: High Performance Liquid Chromatography
RH: Relative Humidity Instruments and Methods
1. X-ray powder diffraction (XRPD)
1.1 Test conditions
XRPD was measured by Empyrean X-ray diffractometer at room temperature using Cu Kα radiation (I _Kα1 :
I _Kα2 =0.5, λ ₁ =1.540598, λ ₂ =1.544426). Specific instrument parameters are shown in Table 1.

Table 1 Instrument parameters

2. Differential Scanning Calorimetry (DSC)

2.1 Test conditions

DSC was measured using NETZSCH DSC 214Nevio differential scanning calorimeter. The specific test conditions were as follows: temperature range: 40°C - 250°C, heating rate: 10°C/min, aluminum crucible, gas atmosphere: N2, gas flow rate: 50mL/min.

3. Thermogravimetric analysis (TGA)

3.1 Test conditions

TGA was determined by Mettler's TGA 2 thermogravimetric analysis. The specific test conditions were as follows: temperature range: 30°C - 800°C, heating rate: 10°C/min, alumina crucible, gas atmosphere: N2, gas flow rate: 50mL/min.

Unless otherwise specified in the examples, the room temperature is 20°C to 30°C.

Example 1

500 mg of the compound of formula I was weighed into a reaction container, 5 mL of n-heptane was added, slurried at 80°C for 2 hours, transferred to room temperature and allowed to stand for 0.5 hours, filtered, the filter cake was washed with 2.5 mL of n-heptane, and the obtained solid was dried at 80°C for 10 hours, with a yield of 92%.

X-ray powder diffraction (XRPD) analysis confirmed that the crystalline form was Form M. The X-ray powder diffraction data are shown in Table 2, and the diffraction pattern is shown in FIG1 .

The crystal form M in the thermogravimetric analysis test (TGA) is shown in Figure 2. Figure 2 shows that the crystal form M has substantially no weight loss when heated to about 30°C-180°C.

The crystal form M in the differential scanning calorimetry (DSC) test is shown in Figure 3. Figure 3 shows that there is an endothermic peak at about 205-210°C.

Table 2 X-ray powder diffraction data of Form M

Example 2

Weigh 326 mg of the raw material into a reaction container, add 1 mL of ethyl acetate, dissolve at 80°C, add 10 mL of n-hexane dropwise, keep warm for 10 min, transfer to room temperature and stir, filter after 30 min, and dry. The obtained solid was confirmed to be Form N by X-ray powder diffraction (XRPD) detection.

Through XRPD detection, the X-ray powder diffraction data of Form N are shown in Table 3, and its diffraction pattern is shown in FIG4 .

The crystal form N in the thermogravimetric analysis test (TGA) is shown in Figure 5. Figure 5 shows that the crystal form M has almost no weight loss when heated to about 30°C-180°C, indicating that the crystal form N is a polymorph (non-solvate), which is consistent with the DSC results. There is a small amount of weight loss (about 1.21%) around 200°C, and the decomposition temperature of the crystal form N is 322.72°C (extrapolated starting point).

The crystal form N in the differential scanning calorimetry (DSC) test is shown in Figure 6. Figure 6 shows that there is an endothermic peak at about 204-207°C.

Table 3 X-ray powder diffraction data of Form N

Example 3

Weigh 1.000 g of the raw material into a reaction container, add 5 mL of ethyl acetate and stir to dissolve, slowly add 50 mL of n-heptane, stir and crystallize for 4 hours, then filter and dry. The obtained solid was confirmed to be Form O by X-ray powder diffraction (XRPD) detection, and the yield was 73.0%.

Through XRPD detection, the X-ray powder diffraction data of Form O are shown in Table 4, and its diffraction pattern is shown in FIG7 .

Table 4 X-ray powder diffraction data of Form O

The crystal form O in the thermogravimetric analysis test (TGA) is shown in Figure 8. Figure 8 shows that the weight loss in the range of 40-140°C is 2.14%. Based on the weight loss temperature and weight loss, it is inferred that the crystal form O is a hemihydrate (theoretical weight loss is 2.19%), which is consistent with the single crystal results and DSC results.

The crystal form O in the differential scanning calorimetry (DSC) test is shown in Figure 9. Figure 9 shows that there is a broad endothermic peak in the range of 60-140°C, which is a desolvation peak, and a sharp endothermic peak at 174-177°C, which is a melting peak, indicating that the crystal form O is a solvate, which is confirmed to be a hemihydrate according to the single crystal results.

Single crystals of Form O were obtained, and the crystal structure information was measured by single crystal X-ray diffraction. The single crystal data were collected at room temperature (293.15K) using a CCD Xcalibur Nova X-ray instrument and multi-layer scanning was performed using a graphite monochromator Mo Kα ray (λ＝0.71073). Olex2 software was used for unit cell refinement and data processing, and ShelXT was used for crystal structure analysis and refinement.

The crystallographic parameters of Form O (M = 838.44 g/mol) are: triclinic system, P-1 space group, α＝95.276(3)°，β＝106.113(4)°，γ＝109.816(4)°，unit cell volume The number of molecules in the unit cell is Z = 2, and the unit cell density is ρ _calc = 1.513 g/cm ³ . The main crystallographic parameters are shown in Table 5.

Table 5 Main crystallographic parameters of Form O

The schematic diagram of the asymmetric unit of the single crystal sample molecule is shown in Figure 10. One asymmetric unit structure contains 2 structural molecules of the compound of formula I and 1 water molecule, that is, the stoichiometric ratio of the structural molecules of the compound of formula I and the water molecules in the crystal form O is 2:1, which is confirmed to be a hemihydrate.

Example 4

Weigh 50 mg of the compound of formula I into a weighing bottle, add 2 mL of isopropyl acetate at room temperature and shake to dissolve, seal the bottle with a film and let it stand at room temperature to slowly evaporate and crystallize to obtain a yellow solid, which is characterized as Form A.

The XRPD analysis showed that the X-ray powder diffraction data of Form A are shown in Table 6, and its diffraction pattern is shown in Figure 11.

Table 6 X-ray powder diffraction data of Form A

Thermogravimetric analysis (TGA) of the crystalline form A showed that the crystalline form A lost about 2.48% of its weight when heated to about 30° C.-180° C.

The crystal form A in the differential scanning calorimetry (DSC) test is shown in Figure 12. Figure 12 shows that the crystal form A has endothermic peaks at about 175.1°C and 205.6°C in the differential scanning calorimetry test.

Embodiment 5:

The compound of formula I was obtained according to the method described in Example 6 of WO2021244582A1, and was characterized as amorphous by PXRD, and its diffraction pattern is shown in Figure 13. The amorphous form loses about 7% weight when heated to about 30°C-180°C in a thermogravimetric analysis test (TGA), and has endothermic peaks at about 120.7°C and 206.1°C in a differential scanning calorimetry test (DSC).

Example 6: Moisture absorption test

The test method uses a dynamic vapor sorption instrument (DVS) to investigate the hygroscopicity. The specific detection method is to weigh 20-50 mg of the sample to be tested and place it in the sample tray of the instrument, and change the relative humidity of the environment according to the program to determine the mass change during the water vapor adsorption and desorption process. The program is set to increase the relative humidity from 10% RH to 98% RH in a gradient of 10%, and then gradually decrease from 98% RH to 10% RH in a gradient of 10%. The balance is based on the mass change rate being less than 0.002. The results of the hygroscopicity study of crystal forms M, N, O, A and amorphous are shown in Table 7.

Table 7 Hygroscopicity study results

Example 7: Solubility Test

Test method: Weigh an excess amount of the sample to be tested into a centrifuge tube, add 1-5 mL of pH 1.0-pH 8.0 medium respectively, shake in a 37°C water bath for 24 hours, filter with a filter head, and measure the solubility of the filtrate by HPLC. The results are shown in Table 8.

Table 8 Equilibrium solubility data

Embodiment 8:

According to the method described in Examples 2-11 of CN117209480A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, and Form L of the compound of Formula I were obtained respectively. The obtained compounds were subjected to thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), and the type of crystal form was determined. The results are shown in Table 9.

Table 9 TGA and DSC test results of Form B-Form L

Crystalline Form B, Crystalline Form C, Crystalline Form D, Crystalline Form E, Crystalline Form F, Crystalline Form G, Crystalline Form H, Crystalline Form J, Crystalline Form K, and Crystalline Form L are all solvates of the compound of Formula I, which have problems such as residual solvents, complex quality control, and poor operability, and have no advantages in drug development.

Example 9: Stability Test

Test method: Take the compound of formula I with different crystal forms, place it in a clean container, place it under high humidity, high temperature and light conditions for 30 days, take samples on the 0th, 5th, 10th and 30th days, and detect its crystal form; place it under accelerated conditions for 30 days, take samples on the 0th and 30th days, and detect its crystal form. The results are detailed in Table 10.

Table 10 Crystal stability study

Claims (10)

A crystalline form M of 2-(3,5-dichloro-4-((5-hydroxy-4-isopropylpyrimidin-2-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, characterized in that, in an X-ray powder diffraction pattern obtained using CuKα radiation, characteristic peaks are shown at diffraction angles 2θ of 6.58±0.2°, 10.15°±0.2°, 12.11±0.2°, 15.59±0.2°, 19.16±0.2°, and 26.98±0.2°; preferably, the crystalline form M has characteristic peaks at diffraction angles 2θ of 6.58±0.2°, 10.15°±0.2°, 11.38°±0.2°, 12.11±0.2°, 14.04°±0.2°, 14.67°±0.2°, 15.59±0.2°, 19.16±0.2°, and 26.98±0.2°; more preferably, the crystalline form M has characteristic peaks at diffraction angles 2θ of 6.58±0.2°, 10.15°±0.2°, 11.38 Characteristic peaks are shown at 14.04°±0.2°, 14.67°±0.2°, 15.59±0.2°, 19.16±0.2°, 20.67°±0.2°, 22.94°±0.2°, 24.37°±0.2°, 26.98°±0.2°, and 27.37°±0.2°. The crystalline form M according to claim 1, characterized in that the X-ray powder diffraction pattern of the crystalline form M is substantially the same as Figure 1. The crystalline form M according to claim 1, characterized in that the crystalline form M shows an endothermic peak at 205-210° C. in a differential scanning calorimetry test; preferably, the DSC spectrum of the crystalline form M is substantially the same as FIG. 3. A crystalline form N of 2-(3,5-dichloro-4-((5-hydroxy-4-isopropylpyrimidin-2-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, characterized in that, in an X-ray powder diffraction pattern obtained using CuKα radiation, characteristic peaks are shown at diffraction angles 2θ of 6.28±0.2°, 10.21°±0.2°, 12.29±0.2°, 15.81±0.2°, 18.96±0.2°, and 26.42±0.2°; preferably, the crystalline form N has characteristic peaks at diffraction angles 2θ of 6.28±0.2°, 10.21°±0.2°, 12.29±0.2°, 14.16±0.2°, and 26.42±0.2° in an X-ray powder diffraction pattern obtained using CuKα radiation. °, 14.67±0.2°, 15.20±0.2°, 15.81±0.2°, 18.96±0.2°, and 26.42±0.2° show characteristic peaks; more preferably, the crystalline form N shows characteristic peaks at diffraction angles 2θ of 6.28±0.2°, 10.21°±0.2°, 12.29±0.2°, 14.16±0.2°, 14.67±0.2°, 15.20±0.2°, 15.81±0.2°, 18.96±0.2°, 19.85°±0.2°, 20.63°±0.2°, 23.01°±0.2°, 26.42°±0.2°, and 28.54°±0.2° in the X-ray powder diffraction pattern obtained using CuKα radiation. The crystalline form N according to claim 4, characterized in that the X-ray powder diffraction pattern of the crystalline form N is substantially the same as Figure 4. The crystalline form N according to claim 4, characterized in that the crystalline form N shows an endothermic peak at 204-207° C. in a differential scanning calorimetry test; preferably, the DSC spectrum of the crystalline form N is substantially the same as FIG. 6 . A crystalline form O of 2-(3,5-dichloro-4-((5-hydroxy-4-isopropylpyrimidin-2-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, characterized in that, in an X-ray powder diffraction pattern obtained using CuKα radiation, characteristic peaks are shown at diffraction angles 2θ of 8.14±0.2°, 8.68°±0.2°, 9.11±0.2°, 14.01±0.2°, 24.11±0.2°, and 26.57±0.2°; preferably, the crystalline form O has characteristic peaks at diffraction angles 2θ of 8.14±0.2°, 8.68°±0.2°, 9.11±0.2°, 11.82±0.2°, 12.21±0.2°, 13. 34±0.2°, 14.01±0.2°, 24.11±0.2°, and 26.57±0.2°; more preferably, the crystalline form O has characteristic peaks at diffraction angles 2θ of 8.14±0.2°, 8.68±0.2°, 9.11±0.2°, 11.82±0.2°, 12.21 ±0.2°, 13.34±0.2°, 14.01±0.2°, 16.20°±0.2°, 20.30°±0.2°, 20.75°±0.2°, 21.12°±0.2°, 24.11°±0.2°, and 26.57±0.2° show characteristic peaks; more preferably, the crystallographic parameters of the crystal form O are: triclinic system, P-1 space group, α=95.276(3)°, β=106.113(4)°, γ=109.816(4)°. The crystal form O according to claim 7, characterized in that the X-ray powder diffraction pattern of the crystal form O is substantially the same as Figure 7. A pharmaceutical composition, characterized in that it contains the crystal form according to any one of claims 1 to 8. Use of the crystal form according to any one of claims 1 to 8 and the pharmaceutical composition according to claim 9 in the preparation of a drug for preventing or treating a disease related to the action of a thyroid hormone beta receptor agonist; preferably, the disease related to the action of a thyroid hormone beta receptor agonist is obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, thyroid cancer, metabolic syndrome, cardiovascular disease, coronary artery disease, myocardial infarction, ventricular dysfunction, heart failure, fatty liver, cirrhosis, diabetes, fatty hepatitis, non-alcoholic fatty hepatitis, non-alcoholic fatty liver disease, atherosclerosis, or hypothyroidism.