Crystal form of thyroid hormone beta receptor modulator

Abstract

The invention relates to a polymorphic form of a compound capable of serving as a thyroid hormone beta receptor modulator, a preparation method and application of the polymorphic form and a pharmaceutical composition containing the polymorphic form. The polymorphic form is applied to preparation of drugs for treating various thyroid-related diseases.

Description

Technical Field

[0001] This application relates to the field of biomedicine, specifically to the polymorphs of compounds, their pharmaceutical compositions and uses. Background Art

[0002] Thyroid hormones are essential for normal human growth and development. Insufficient or excessive secretion can cause diseases. When thyroid function is insufficient, both physical and intellectual development are affected, leading to cretinism. In adults, hypothyroidism can cause myxedema. When thyroid function is hyperactive, symptoms such as nervousness, irritability, tremors, increased heart rate, and increased cardiac output occur. Thyroid hormones can promote material oxidation, increase oxygen consumption, and raise the basal metabolic rate, resulting in increased heat production.

[0003] 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 mainly has TRα1, and the liver mainly has TRβ1. The mRNA expression of TRβ2 is mostly limited to the pituitary gland and hypothalamus. TRα1, TRβ1, and TRβ2 can bind thyroid hormones and produce corresponding physiological effects. TRα2 does not bind thyroid hormones.

[0004] Making full use of the advantages of thyroid hormones in increasing the 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 by an overall increase in basal metabolic rate (BMR), along with a weight loss of about 15%; while hypothyroidism is often accompanied by a weight gain of 25-30%. When treating hypothyroidism with T3, most patients experience weight gain. In addition, thyroid hormones can also lower serum low-density lipoprotein (LDL) (Journal of Molecular and Celluar Cardiology 37(2004):1137-1146). Existing studies have shown that hyperthyroidism can significantly lower serum total cholesterol, mainly because thyroid hormones increase the expression of LDL receptors in the liver, thus promoting the process of cholesterol metabolism into bile acids; hypothyroidism is associated with hypercholesterolemia. Therefore, thyroid hormones may reduce the occurrence of atherosclerosis and other cardiovascular diseases.

[0005] When treating diseases with thyroid hormones, due to individual differences, side effects often occur at supra-physiological doses, including heart problems (mainly tachycardia), muscle weakness, and excessive weight loss, etc. Moreover, long-term use is also accompanied by bone loss. By modifying thyroid hormones to reduce the adverse effects brought by the thyroid hormone mimetics themselves and retain their beneficial effects, suitable drugs can be developed to treat corresponding diseases: obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver diseases (such as fatty liver, NASH, NAFLD, etc.), cardiovascular diseases (such as atherosclerosis, etc.), thyroid diseases (such as hypothyroidism, thyroid cancer, etc.), and other related diseases.

[0006] 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 with the structure of Formula I,

[0007]

[0008] This compound can be used to treat thyroid hormone-related diseases, such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver diseases (such as fatty liver, NASH, NAFLD, etc.), cardiovascular diseases (such as atherosclerosis, etc.), thyroid diseases (such as hypothyroidism, thyroid cancer, etc.). Summary of the Invention

[0009] One of the purposes of this 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 this application can be identified and distinguished from other crystal forms by means of conventional crystal form characterization methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), etc. By studying the properties of the crystal forms described in this application, it was unexpectedly found that the various crystal forms of this application have advantages such as good solubility, less hygroscopicity, and / or good stability, and are suitable as pharmaceutical crystal forms.

[0010] This application provides a crystal form M of the compound shown in Formula I,

[0011]

[0012] In certain embodiments, in the X-ray powder diffraction pattern obtained using Cu Kα radiation, the crystalline form M exhibits 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°.

[0013] In certain embodiments, in the X-ray powder diffraction pattern obtained using Cu Kα radiation, the crystalline form M exhibits 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°.

[0014] In certain embodiments, in the X-ray powder diffraction pattern obtained using Cu Kα radiation, the crystalline form M exhibits 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°.

[0015] In certain embodiments, the X-ray powder diffraction pattern of the crystalline form M is Figure 1 substantially the same.

[0016] In certain embodiments, the crystalline form M shows ( Figure 2 ) substantially no weight loss when heated to about 30°C - 180°C in a thermogravimetric analysis test.

[0017] In certain embodiments, the crystalline form M shows an endothermic peak at about 205 - 210°C in a differential scanning calorimetry test.

[0018] In certain specific embodiments, the DSC pattern of the crystalline form M is Figure 3 substantially the same.

[0019] The present application provides a crystalline form N of the compound represented by Formula I.

[0020] In certain embodiments, in the PXRD powder diffraction pattern expressed in terms of the diffraction angle 2θ obtained using CuKα radiation, the crystalline form N exhibits 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°.

[0021] In certain embodiments, in the PXRD powder diffraction pattern expressed in terms of the diffraction angle 2θ obtained using CuKα radiation, the crystalline form N exhibits 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°.

[0022] In certain embodiments, in the PXRD powder diffraction pattern expressed in terms of the diffraction angle 2θ obtained using CuKα radiation, the crystalline form N exhibits 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°.

[0023] In certain embodiments, the X-ray powder diffraction pattern of the crystalline form N is Figure 4 substantially the same.

[0024] In certain embodiments, the crystalline form N shows ( Figure 5 ) substantially no weight loss when heated to about 30°C - 180°C in a thermogravimetric analysis test.

[0025] In certain embodiments, the crystalline form N shows an endothermic peak at about 204 - 207°C in a differential scanning calorimetry test.

[0026] In certain specific embodiments, the DSC pattern of the crystalline form N is Figure 6 substantially the same.

[0027] The present application provides a hydrate crystalline form O of the compound shown in Formula I, and the water content of the hydrate crystalline form O is a hemihydrate.

[0028] Single crystals were obtained for the preparation of crystalline form O, and the crystal structure information was measured by single crystal X-ray diffraction. The crystallographic parameters of crystalline 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)°. The unit cell volume The number of molecules Z in the unit cell = 2, and the unit cell density ρ calc = 1.513 g / cm 3 .

[0029] In certain embodiments, in the PXRD powder diffraction pattern expressed in terms of the diffraction angle 2θ obtained using CuKα radiation, the crystalline form O exhibits 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°.

[0030] In certain embodiments, in the PXRD powder diffraction pattern expressed in terms of the diffraction angle 2θ obtained using CuKα radiation, the crystalline form O exhibits 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°.

[0031] In certain embodiments, in the PXRD powder diffraction pattern expressed in terms of the diffraction angle 2θ obtained using Cu - Kα radiation, the crystalline form O exhibits 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°.

[0032] In certain embodiments, the X - ray powder diffraction pattern of the crystalline form O is Figure 7 substantially the same.

[0033] In certain embodiments, the crystalline form O shows ( Figure 8 ) a weight loss of 2.14% in the range of 40 - 140°C in the thermogravimetric analysis test. Based on the weight loss temperature and the weight loss amount, it is speculated that the crystalline form O is a hemihydrate (the theoretical weight loss is 2.19%), which is consistent with the single - crystal results and the DSC results.

[0034] In certain embodiments, the polymorphic form O shows a broad endothermic peak in the range of 60 - 140 °C in differential scanning calorimetry test, which is a desolvation peak, and shows a sharp endothermic peak at 174 - 177 °C, which is a melting peak, indicating that the polymorphic form O is a solvate and is confirmed to be a hemihydrate according to the single crystal results.

[0035] In certain embodiments, the DSC pattern of the polymorphic form O is the same as Figure 9 substantially the same.

[0036] Another object of the present application is to provide a pharmaceutical composition comprising the above-mentioned polymorphs.

[0037] Another object of the present application is to provide the use of the above-mentioned polymorphs or pharmaceutical compositions in the preparation of a medicament for preventing or treating diseases related to the action of thyroid hormone β receptor agonists.

[0038] Another object of the present application is to provide the use of the above-mentioned polymorphs or pharmaceutical compositions in the preparation of a medicament for preventing or treating thyroid hormone-related diseases, such as obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, thyroid cancer, metabolic syndrome, cardiovascular diseases, coronary artery diseases, myocardial infarction, ventricular dysfunction, heart failure, fatty liver, liver cirrhosis, diabetes, steatohepatitis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, atherosclerosis, or hypothyroid diseases or disorders.

[0039] Those skilled in the art can easily insight into other aspects and advantages of the present application from the following detailed description. Only the exemplary embodiments of the present application are shown and described in the following detailed description. As those skilled in the art will recognize, the content of the present application enables those skilled in the art to make changes to the disclosed specific embodiments without departing from the spirit and scope of the invention involved in the present application. Accordingly, the description in the drawings and the specification of the present application is merely exemplary and not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 X-ray powder diffraction pattern of polymorphic form M

[0041] Figure 2 Thermogravimetric analysis graph of polymorphic form M

[0042] Figure 3 Differential scanning calorimetry analysis graph of polymorphic form M

[0043] Figure 4 X-ray powder diffraction pattern of polymorphic form N

[0044] Figure 5 Thermogravimetric analysis graph of polymorphic form N

[0045] Figure 6 Differential Scanning Calorimetry (DSC) Diagram of Crystal Form N

[0046] Figure 7 X-ray Powder Diffraction (XRPD) Pattern of Crystal Form O

[0047] Figure 8 Thermogravimetric Analysis (TGA) Diagram of Crystal Form O

[0048] Figure 9 Differential Scanning Calorimetry (DSC) Diagram of Crystal Form O

[0049] Figure 10 Schematic Diagram of the Molecular Asymmetric Unit of the Single Crystal Sample of Crystal Form O

[0050] Figure 11 X-ray Powder Diffraction (XRPD) Pattern of Crystal Form A

[0051] Figure 12 Differential Scanning Calorimetry (DSC) Diagram of Crystal Form A

[0052] Figure 13 X-ray Powder Diffraction (XRPD) Pattern of Amorphous Examples

[0053] The present invention will be further illustrated by specific examples below, but it is not intended to limit the protection scope of the present invention. Those skilled in the art can make improvements to the preparation method and the instruments used within the scope of the claims, and these improvements should also be regarded as within the protection scope of the present invention. Therefore, the protection scope of this invention patent shall be subject to the appended claims.

[0054] The explanations of the abbreviations used in the present invention are as follows:

[0055] XRPD: X-ray Powder Diffraction

[0056] DSC: Differential Scanning Calorimetry

[0057] TGA: Thermogravimetric Analysis

[0058] DVS: Dynamic Vapor Sorption

[0059] HPLC: High Performance Liquid Chromatography

[0060] RH: Relative Humidity

[0061] Instruments and Methods

[0062] 1. X-ray Powder Diffraction (XRPD)

[0063] 1.1 Detection Conditions

[0064] XRPD was measured by an Empyrean X-ray diffractometer at room temperature, using a copper target Cu Kα ray (I Kα1 :I Kα2= 0.5, λ1 = 1.540598, λ2 = 1.544426), and the specific instrument parameters are shown in Table 1.

[0065] Table 1 Instrument Parameters

[0066] Parameter Set value Parameter Set value Sample mode Transmission Scanning mode Continuous Voltage and current 45 kV, 40 mA Scanning range (2θ) 4-40° Scanning step size 0.01313° Scanning time per step 60s Divergence slit 1 / 2° Anti-scattering slit 1 / 2° Soller slit 0.04 rad Sample rotation speed 1 s / revolution

[0067] 2. Differential Scanning Calorimetry (DSC)

[0068] 2.1 Detection Conditions

[0069] DSC was measured using a Netzsch DSC 214 Nevio differential scanning calorimeter. The specific detection conditions are as follows: temperature range: 40°C - 250°C, heating rate: 10°C / min, aluminum crucible, gas atmosphere: N2, gas flow rate: 50 mL / min.

[0070] 3. Thermogravimetric Analysis (TGA)

[0071] 3.1 Detection Conditions

[0072] TGA was measured using a Mettler TGA 2 thermogravimetric analyzer. The specific detection conditions are as follows: temperature range: 30°C - 800°C, heating rate: 10°C / min, alumina crucible, gas atmosphere: N2, gas flow rate: 50 mL / min.

[0073] Unless otherwise specified in the examples, the room temperature is 20°C to 30°C.

[0074] Example 1

[0075] Weigh 500 mg of the compound of formula I into a reaction vessel, add 5 mL of n-heptane, slurry at 80°C for 2 hours, transfer to room temperature and let stand for 0.5 hour, filter, wash the filter cake with 2.5 mL of n-heptane, and dry the obtained solid at 80°C for 10 hours to obtain a yield of 92%.

[0076] It was confirmed to be crystalline form M by X-ray powder diffraction (XRPD). The X-ray powder diffraction data are shown in Table 2, and its diffraction pattern is as Figure 1 shown.

[0077] The crystalline form M in the thermogravimetric analysis test (TGA) is as Figure 2 shown. Figure 2 It shows that the crystalline form M has basically no weight loss when heated to about 30°C - 180°C.

[0078] The crystalline form M in the differential scanning calorimetry test (DSC) is as Figure 3 shown. Figure 3 It shows an endothermic peak at about 205 - 210°C.

[0079] Table 2 X-ray Powder Diffraction Data of Crystalline Form M

[0080]

[0081]

[0082] Example 2

[0083] Weigh 326 mg of the active pharmaceutical ingredient into a reaction vessel, add 1 mL of ethyl acetate, dissolve it clearly at 80 °C, dropwise add 10 mL of n-hexane, keep it warm for 10 min and then transfer it to room temperature for stirring. After 30 min, filter and dry. The obtained solid is confirmed to be crystal form N by X-ray powder diffraction (XRPD).

[0084] As detected by XRPD, the X-ray powder diffraction data of crystal form N are shown in Table 3, and its diffraction pattern is as Figure 4 shown.

[0085] The said crystal form N is as shown in the thermogravimetric analysis test (TGA). Figure 5 shown. Figure 5 It shows that there is basically no weight loss when crystal form M is heated to about 30 °C - 180 °C, indicating that crystal form N is polymorphic (non-solvate), which is consistent with the DSC result. There is a small amount of weight loss (about 1.21%) near 200 °C, and the decomposition temperature of crystal form N is 322.72 °C (extrapolated onset point).

[0086] The said crystal form N is as shown in the differential scanning calorimetry test (DSC). Figure 6 shown. Figure 6 It shows an endothermic peak at about 204 - 207 °C.

[0087] Table 3 X-ray powder diffraction data of crystal form N

[0088]

[0089]

[0090] Example 3

[0091] Weigh 1.000 g of the active pharmaceutical ingredient into a reaction vessel, add 5 mL of ethyl acetate and stir to dissolve, slowly add 50 mL of n-heptane, stir for crystal precipitation for 4 hours and then filter and dry. The obtained solid is confirmed to be crystal form O by X-ray powder diffraction (XRPD), and the yield is 73.0%.

[0092] As detected by XRPD, the X-ray powder diffraction data of crystal form O are shown in Table 4, and its diffraction pattern is as Figure 7 shown.

[0093] Table 4 X powder diffraction data of crystal form O

[0094]

[0095]

[0096] The crystalline form O is as shown in the thermogravimetric analysis test (TGA) Figure 8 as follows. Figure 8 It shows that the weight loss in the range of 40 - 140 °C is 2.14%. Based on the weight loss temperature and the weight loss amount, it is speculated that the crystalline form O is a hemihydrate (the theoretical weight loss is 2.19%), which is consistent with the single crystal results and the DSC results.

[0097] The crystalline form O is as shown in the differential scanning calorimetry test (DSC) Figure 9 as follows. Figure 9 It shows that there is a broad endothermic peak in the range of 60 - 140 °C, which is the desolvation peak, and a sharp endothermic peak is shown at 174 - 177 °C, which is the melting peak, indicating that the crystalline form O is a solvate and is confirmed to be a hemihydrate according to the single crystal results.

[0098] Single crystals of the crystalline form O were obtained. The crystal structure information was measured by single crystal X-ray diffraction. The single crystal data were collected using a CCDXcalibur Nova type X-ray instrument at room temperature (293.15 K), and multi-layer scanning was carried out using graphite monochromator Mo Kα radiation (λ = 0.71073). The Olex2 software was used for unit cell refinement and data processing, and ShelXT was used for crystal structure analysis and refinement.

[0099] The crystallographic parameters of the crystalline 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)°, the unit cell volume The number of molecules in the unit cell Z = 2, the unit cell density ρ calc = 1.513 g / cm 3 . The main crystallographic parameters are shown in Table 5.

[0100] Table 5 Main crystallographic parameters of the crystalline form O

[0101]

[0102]

[0103] The schematic diagram of the molecular asymmetric unit of the single crystal sample is as shown in Figure 10 the following. 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 molecule of the compound of formula I to the water molecule in the crystalline form O is 2:1, which is confirmed to be a hemihydrate.

[0104] Example 4

[0105] Weigh 50 mg of the compound of Formula I into a weighing bottle, add 2 mL of isopropyl acetate at room temperature, shake until dissolved clearly, seal it with a film, and let it stand at room temperature to slowly volatilize and crystallize to obtain a yellow solid, which is characterized as Crystal Form A after characterization.

[0106] After detection by XRPD, the X-ray powder diffraction data of Crystal Form A are shown in Table 6, and its diffraction pattern is as Figure 11 shown.

[0107] Table 6 X-ray powder diffraction data of Crystal Form A

[0108]

[0109]

[0110] The said Crystal Form A shows a weight loss of about 2.48% when heated to about 30 °C - 180 °C in thermogravimetric analysis (TGA).

[0111] The said Crystal Form A is as shown in differential scanning calorimetry (DSC) Figure 12 shown. Figure 12 It shows endothermic peaks at about 175.1 °C and 205.6 °C in differential scanning calorimetry for Crystal Form A.

[0112] Example 5:

[0113] The compound of Formula I is obtained according to the method described in Example 6 of WO2021244582A1, and it is characterized as amorphous by PXRD, and its diffraction pattern is as Figure 13 shown. The said amorphous shows a weight loss of about 7% when heated to about 30 °C - 180 °C in thermogravimetric analysis (TGA), and has endothermic peaks at about 120.7 °C and 206.1 °C in differential scanning calorimetry (DSC).

[0114] Example 6: Hygroscopicity test

[0115] The test method uses a dynamic vapor sorption instrument (DVS) to investigate hygroscopicity. The specific detection method is to weigh 20 - 50 mg of the sample to be tested and place it in the sample pan of the instrument, and change the environmental relative humidity according to the program, so as to measure the mass change during the water vapor adsorption and desorption processes. The program is set such that the relative humidity increases step by step from 10% RH to 98% RH in a gradient of 10%, and then decreases step by step from 98% RH to 10% RH in a gradient of 10%. The balance criterion is that the mass change rate is less than 0.002. The hygroscopicity research results of Crystal Forms M, N, O, A and amorphous are shown in Table 7.

[0116] Table 7 Hygroscopicity research results

[0117] Crystal form Moisture absorption weight gain Crystal form M 0.095％ Crystal form N 0.133％ Crystal form O 0.467％ Crystal form A 1.043％ Amorphous 2.335％

[0118] Example 7: Solubility Test

[0119] Test method: Weigh an excessive amount of the sample to be tested into a centrifuge tube, add 1 - 5 mL of media with pH values ranging from 1.0 to 8.0 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.

[0120] Table 8 Equilibrium Solubility Data

[0121]

[0122] Example 8:

[0123] According to the methods described in Examples 2 - 11 of CN117209480A, crystalline forms B, C, D, E, F, G, H, J, K, and L of the compound of formula I were obtained respectively. The obtained compounds were subjected to thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) tests to determine the types of crystalline forms. The results are shown in Table 9.

[0124] Table 9 TGA and DSC Test Results of Crystalline Forms B - L

[0125]

[0126]

[0127] Crystalline forms B, C, D, E, F, G, H, J, K, and L are all solvates of the compound of formula I, with problems such as solvent residue, complex quality control, and poor operability, and they do not have advantages in drug formation.

[0128] Example 9: Stability Test

[0129] Test method: Take the compounds of formula I in different crystalline forms and place them in clean containers. Place them under high humidity, high temperature, and light conditions for 30 days. Sampling is carried out on the 0th, 5th, 10th, and 30th days to detect their crystalline forms; place them under accelerated conditions for 30 days, and sampling is carried out on the 0th and 30th days to detect their crystalline forms. The results are shown in detail in Table 10.

[0130] Table 10 Crystalline Form Stability Study

[0131]

Claims

1. 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 the 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° in the X-ray powder diffraction pattern obtained using CuKα radiation. .16±0.2°, and 26.98±0.2° show characteristic peaks; more preferably, the crystalline form M shows 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°, 20.67°±0.2°, 22.94°±0.2°, 24.37°±0.2°, 26.98°±0.2°, and 27.37°±0.2° in the X-ray powder diffraction pattern obtained using CuKα radiation.

2. The crystal 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 that in FIG1 .

3. The crystal form M according to claim 1, characterized in that The crystal form M shows an endothermic peak at 205-210° C. in a differential scanning calorimetry test; preferably, the DSC spectrum of the crystal form M is substantially the same as that in FIG. 3 .

4. 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 the 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°, 14.67±0.2°, 15.20±0.2°, 15.81±0.2°, 18.96±0.2°, and 26.42±0.2° in the X-ray powder diffraction pattern obtained using CuKα radiation. .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.

5. The crystal 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 that in FIG. 4 .

6. The crystal form N according to claim 4, characterized in that: The crystal form N shows an endothermic peak at 204-207° C. in a differential scanning calorimetry test; preferably, the DSC spectrum of the crystal form N is substantially the same as that of FIG. 6 .

7. 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 the 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°, 26.57±0.2°. .2° shows characteristic peaks; more preferably, the crystalline form O shows 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° in the X-ray powder diffraction pattern obtained using CuKα radiation; more preferably, the crystallographic parameters of the crystalline form O are: triclinic system, P-1 space group, α=95.276(3)°, β=106.113(4)°, γ=109.816(4)°.

8. The crystal form O according to claim 7, characterized in that: The X-ray powder diffraction pattern of the crystalline form O is substantially the same as that in FIG. 7 .

9. A pharmaceutical composition, characterized in that Contains the crystal form as described in any one of claims 1 to 8.

10. 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, steatohepatitis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, atherosclerosis, or hypothyroidism.

Images