Crystal form of thyroid hormone receptor stimulant as well as preparation method and application of crystal form

Abstract

The invention aims to provide a crystal form of a thyroid hormone receptor agonist, a preparation method, a pharmaceutical composition and application of the crystal form in preparation of a TRbeta selective agonist medicine. Compared with the prior art, the crystal form provided by the invention has one or more improved properties, and is of great significance to further development of the medicine.

Description

Technical Field

[0001] The present invention relates to the field of chemical medicine, and in particular to a crystal form of a thyroid hormone receptor agonist, a preparation method and use thereof. Background Art

[0002] Thyroid hormones are necessary for normal growth and development of the human body, and their insufficient or excessive secretion can cause disease. 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.

[0003] Studies have shown that TRβ1 plays an important role in regulating TRH (thyrotropin-releasing hormone) and regulating the behavior of thyroid hormones in the liver. Therefore, scientists are committed to developing thyroid hormone receptor agonists that are selective and / or tissue-selective for thyroid hormone receptor β. Such thyroid hormone receptor agonists are expected to regulate serum low-density lipoprotein (LDL), triglycerides, liver fat levels, etc. through the stimulatory effect on thyroid hormone receptors, and thus be used to prevent or treat obesity, hyperlipidemia, hypercholesterolemia, metabolic diseases of diabetes and other disorders and diseases (such as fatty liver and NASH, etc.).

[0004] Resmetirom (MGL3196) is a class of pyridazinone thyroid hormone analogs developed by Madrigal Pharmaceuticals with high TRβ selectivity. On March 14, 2024, the U.S. FDA accelerated the approval of Resmetirom (trade name: Rezdiffra) in combination with diet and exercise to treat adult patients with non-cirrhotic non-alcoholic steatohepatitis (NASH) / metabolic dysfunction-associated steatohepatitis (MASH) with moderate to severe liver fibrosis (stages F2 to F3), becoming the world's first marketed NASH / MASH treatment drug. The chemical name of Resmetirom is: 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, and the structural formula is as follows:

[0005]

[0006] Drug polymorphism refers to the different lattice arrangements formed by the orderly arrangement of chemical drug molecules in the microstructure, which is generally manifested as different forms of drug raw materials in the solid state. A drug can exist in multiple crystal forms. Different crystal forms of the same drug may show different physical or chemical properties. The study of drug polymorphism can discover the drug's dominant crystal form that is conducive to the drug's effect. Summary of the invention

[0007] One object of the present invention is to provide a new crystal form of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound, named as crystal form K1.

[0008] In some embodiments, the crystal form K1 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 4.8°±0.2°, 10.7°±0.2°, 11.2°±0.2°, 17.1°±0.2°, and 24.1°±0.2°.

[0009] In some embodiments, the crystal form K1 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 4.8°±0.2°, 8.1°±0.2°, 9.7°±0.2°, 10.7°±0.2°, 11.2°±0.2°, 13.6°±0.2°, 17.1°±0.2°, and 24.1°±0.2°.

[0010] In some embodiments, the present invention provides a crystalline form K1, characterized in that its X-ray powder diffraction pattern is as follows Figure 1 shown.

[0011] Another object of the present invention is to provide a new crystalline form of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound, named as crystalline form K2.

[0012] In some embodiments, the crystal form K2 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.3°±0.2°, 10.2°±0.2°, 15.4°±0.2°, 21.4°±0.2°, and 25.2°±0.2°.

[0013] In some embodiments, the crystal form K2 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.8°±0.2°, 8.3°±0.2°, 10.2°±0.2°, 11.1°±0.2°, 14.3°±0.2°, 15.4°±0.2°, 17.5°±0.2°, 21.4°±0.2°, and 25.2°±0.2°.

[0014] In some embodiments, the present invention provides a crystalline form K2, characterized in that its X-ray powder diffraction pattern is as follows Figure 4 shown.

[0015] In some embodiments, the crystal form K3 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.2°±0.2°, 6.4°±0.2°, 7.7°±0.2°, 11.8°±0.2°, and 19.6°±0.2°.

[0016] In some embodiments, the crystal form K3 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.2°±0.2°, 6.4°±0.2°, 7.7°±0.2°, 11.8°±0.2°, 19.6°±0.2°, 20.9°±0.2°, 23.4°±0.2°, and 24.0°±0.2°.

[0017] In some embodiments, the present invention provides a crystalline form K3, characterized in that its X-ray powder diffraction pattern is as follows Figure 7 shown.

[0018] In some embodiments, the present invention provides a method for preparing form K3, which is characterized by comprising: adding an alcohol solvent to a 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound, slurrying, filtering, then adding methyl tert-butyl ether, slurrying, filtering, and drying to obtain the product.

[0019] In some specific embodiments, in the preparation method, the alcohol solvent is an alcohol with a carbon number below C12, such as methanol, ethanol, isopropanol, n-butanol, etc., preferably ethanol.

[0020] In some specific embodiments, in the preparation method, the 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound can be any form of the compound, including salt form, polymorphic form, cocrystal, amorphous form, etc. In some more specific embodiments, in the preparation method, the 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound adopts the form I.

[0021] Another object of the present invention is to provide a new crystal form of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound, named as crystal form K4.

[0022] In some embodiments, the crystal form K4 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.9°±0.2°, 8.1°±0.2°, 10.5°±0.2°, 11.7°±0.2°, and 24.6°±0.2°.

[0023] In some embodiments, the crystal form K4 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.9°±0.2°, 8.1°±0.2°, 10.5°±0.2°, 11.7°±0.2°, 16.3±0.2°, 18.6±0.2°, 22.5±0.2°, and 24.6°±0.2°.

[0024] In some embodiments, the present invention provides a crystalline form K4, characterized in that its X-ray powder diffraction pattern is as follows Fig.10 shown.

[0025] Another object of the present invention is to provide a new crystal form of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound, named as Crystal Form K5.

[0026] In some embodiments, the crystal form K5 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.5°±0.2°, 8.7°±0.2°, 11.0°±0.2°, 16.5°±0.2°, and 22.5°±0.2°.

[0027] In some embodiments, the crystal form K5 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.5°±0.2°, 8.7°±0.2°, 10.6±0.2°, 11.0°±0.2°, 14.9±0.2°, 16.5°±0.2°, 22.5°±0.2°, and 21.2°±0.2°.

[0028] In some embodiments, the present invention provides a crystalline form K5, characterized in that its X-ray powder diffraction pattern is as follows Fig.13 shown.

[0029] Another object of the present invention is to provide a new crystal form of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound, named as crystal form K6.

[0030] In some embodiments, the crystal form K6 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.1°±0.2°, 6.4°±0.2°, 7.9±0.2°, 10.0°±0.2°, and 24.0±0.2°.

[0031] In some embodiments, the crystal form K6 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.1°±0.2°, 6.4°±0.2°, 7.9±0.2°, 10.0°±0.2°, 14.5°±0.2°, 18.0°±0.2°, 20.2°±0.2°, and 24.0±0.2°.

[0032] In some embodiments, the present invention provides a crystalline form K6, characterized in that its X-ray powder diffraction pattern is as follows Fig.16 shown.

[0033] Another object of the present invention is to provide a new crystal form of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound, named as Crystal Form K7.

[0034] In some embodiments, the crystal form K7 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.8°±0.2°, 10.3°±0.2°, 11.6±0.2°, 20.1°±0.2°, and 24.3±0.2°.

[0035] In some embodiments, the crystal form K7 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.8°±0.2°, 10.3°±0.2°, 11.2°±0.2°, 11.6±0.2°, 18.9°±0.2°, 20.1°±0.2°, 24.3±0.2°, and 27.6±0.2°.

[0036] In some embodiments, the present invention provides a crystalline form K7, characterized in that its X-ray powder diffraction pattern is as follows Fig.19 shown.

[0037] Another object of the present invention is to provide a new crystal form of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound, named as Crystal Form K8.

[0038] In some embodiments, the crystal form K8 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.6°±0.2°, 7.7°±0.2°, 8.3°±0.2°, 10.1±0.2°, and 19.6°±0.2°.

[0039] In some embodiments, the crystal form K8 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.6°±0.2°, 7.7°±0.2°, 8.3°±0.2°, 10.1±0.2°, 18.1°±0.2°, 19.6°±0.2°, 23.3±0.2°, and 24.8±0.2°.

[0040] In some embodiments, the present invention provides a crystalline form K8, characterized in that its X-ray powder diffraction pattern is as follows Fig. 22 shown.

[0041] Another object of the present invention is to provide a new crystal form of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound, named as Crystal Form K9.

[0042] In some embodiments, the crystalline form K9 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.9°±0.2°, 7.9°±0.2°, 13.8°±0.2°, 14.3±0.2°, and 21.1°±0.2°.

[0043] In some embodiments, the crystalline form K9 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.9°±0.2°, 7.9°±0.2°, 13.8°±0.2°, 14.3±0.2°, 21.1°±0.2°, 20.4°±0.2°, 20.7±0.2°, and 23.8±0.2°.

[0044] In some embodiments, the present invention provides a crystalline form K9, characterized in that its X-ray powder diffraction pattern is as follows Fig.25 shown.

[0045] Another object of the present invention is to provide a new crystal form of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound, named as crystal form K10.

[0046] In some embodiments, the crystal form K10 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.7°±0.2°, 8.7°±0.2°, 11.1°±0.2°, 14.3±0.2°, and 23.0°±0.2°.

[0047] In some embodiments, the crystalline form K10 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.7°±0.2°, 8.7°±0.2°, 11.1°±0.2°, 14.3±0.2°, 23.0°±0.2°, 12.0°±0.2°, 18.0°±0.2°, and 21.5±0.2°.

[0048] In some embodiments, the present invention provides a crystalline form K10, characterized in that its X-ray powder diffraction pattern is as follows Fig.28 shown.

[0049] Another object of the present invention is to provide a new crystal form of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound, named as crystal form K11.

[0050] In some embodiments, the crystal form K11 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.2°±0.2°, 10.9°±0.2°, 11.6°±0.2°, 22.0±0.2°, and 24.0°±0.2°.

[0051] In some embodiments, the crystal form K11 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.2°±0.2°, 10.9°±0.2°, 11.6°±0.2°, 12.8°±0.2°, 19.9°±0.2°, 20.9±0.2°, 22.0±0.2°, and 24.0°±0.2°.

[0052] In some embodiments, the present invention provides a crystalline form K11, characterized in that its X-ray powder diffraction pattern is as follows Fig.31 shown.

[0053] Another object of the present invention is to provide a new crystal form of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound, named as crystal form K12.

[0054] In some embodiments, the crystal form K12 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.3°±0.2°, 8.6°±0.2°, 10.2°±0.2°, 14.2±0.2°, and 18.2°±0.2°.

[0055] In some embodiments, the crystal form K12 provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.3°±0.2°, 8.6°±0.2°, 10.2°±0.2°, 12.2°±0.2°, 14.2±0.2°, 15.6°±0.2°, 18.2°±0.2°, and 23.0±0.2°.

[0056] In some embodiments, the present invention provides a crystalline form K12, characterized in that its X-ray powder diffraction pattern is as follows Fig.33 shown.

[0057] In some embodiments, the present invention provides a pharmaceutical composition comprising any crystalline form of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile described in the present invention, and a pharmaceutically acceptable excipient.

[0058] In some embodiments, the present invention provides the use of any crystalline form of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile described in the present invention in the preparation of TRβ selective agonist drugs.

[0059] In some embodiments, the present invention provides the use of any crystalline form of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile described in the present invention in the preparation of drugs for hypercholesterolemia, non-alcoholic fatty hepatitis, hyperlipidemia, diabetes, obesity, and fatty liver. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 is the X-ray powder diffraction pattern of the crystal form K1 according to Example 1 of the present invention;

[0061] Figure 2 is a DSC graph of the crystal form K1 according to Example 1 of the present invention;

[0062] Figure 3 is a TGA diagram of the crystal form K1 according to Example 1 of the present invention;

[0063] Figure 4 is the X-ray powder diffraction pattern of the crystal form K2 according to Example 2 of the present invention;

[0064] Figure 5 is a DSC graph of the crystal form K2 according to Example 2 of the present invention;

[0065] Figure 6 is a TGA diagram of the crystal form K2 according to Example 2 of the present invention;

[0066] Figure 7 is the X-ray powder diffraction pattern of the crystal form K3 according to Example 3 of the present invention;

[0067] Figure 8 is a DSC graph of the crystal form K3 according to Example 3 of the present invention;

[0068] Fig. 9 is a TGA diagram of the crystal form K3 according to Example 3 of the present invention;

[0069] Fig.10 is the X-ray powder diffraction pattern of the crystal form K4 according to Example 4 of the present invention;

[0070] Fig.11 is a DSC graph of the crystal form K4 according to Example 4 of the present invention;

[0071] Fig.12 is a TGA diagram of the crystal form K4 according to Example 4 of the present invention;

[0072] Fig.13 is the X-ray powder diffraction pattern of the crystal form K5 according to Example 5 of the present invention;

[0073] Fig.14 is a DSC graph of the crystal form K5 according to Example 5 of the present invention;

[0074] Fig.15 is a TGA graph of the crystal form K5 according to Example 5 of the present invention;

[0075] Fig.16 is the X-ray powder diffraction pattern of the crystal form K6 according to Example 6 of the present invention;

[0076] Fig.17 is a DSC graph of the crystal form K6 according to Example 6 of the present invention;

[0077] Fig.18 is a TGA diagram of the crystal form K6 according to Example 6 of the present invention;

[0078] Fig.19 is the X-ray powder diffraction pattern of the crystal form K7 according to Example 7 of the present invention;

[0079] Fig. 20 is a DSC graph of the crystal form K7 according to Example 7 of the present invention;

[0080] Fig.21 is a TGA diagram of the crystal form K7 according to Example 7 of the present invention;

[0081] Fig. 22 is the X-ray powder diffraction pattern of the crystal form K8 according to Example 8 of the present invention;

[0082] Fig.23 is a DSC graph of the crystal form K8 according to Example 8 of the present invention;

[0083] Fig.24 is a TGA diagram of the crystal form K8 according to Example 8 of the present invention;

[0084] Fig.25 is the X-ray powder diffraction pattern of the crystal form K9 according to Example 9 of the present invention;

[0085] Fig.26 is a DSC graph of the crystal form K9 according to Example 9 of the present invention;

[0086] Fig. 27 is a TGA diagram of the crystal form K9 according to Example 9 of the present invention;

[0087] Fig.28 is the X-ray powder diffraction pattern of the crystal form K10 according to Example 10 of the present invention;

[0088] Fig.29 is a DSC graph of the crystal form K10 according to Example 10 of the present invention;

[0089] Fig.30 is a TGA graph of the crystal form K10 according to Example 10 of the present invention;

[0090] Fig.31 is the X-ray powder diffraction pattern of the crystal form K11 according to Example 11 of the present invention;

[0091] Fig.32 is a DSC graph of the crystal form K11 according to Example 11 of the present invention;

[0092] Fig.33 is the X-ray powder diffraction pattern of the crystal form K12 according to Example 12 of the present invention;

[0093] Fig.34 is a DSC graph of the crystal form K12 according to Example 12 of the present invention;

[0094] Fig.35 This is the TGA chart of the crystal form K12 according to Example 12 of the present invention. DETAILED DESCRIPTION

[0095] The present invention is further described in detail by the following examples, which are not intended to limit the protection scope of the present invention.

[0096] Testing instruments and methods:

[0097] X-ray powder diffraction (XRPD) test method: instrument model: Empyrean, diffraction line: CuK (45KV, 50mA), scanning time: 30s, scanning range: 3°-30° (2θ), Soller slit: 0.04rad.

[0098] Differential scanning calorimetry (DSC) test method: instrument model: DSC214Nevio; heating rate: 10°C / min, temperature range: 40°C-400°C, atmosphere: N2.

[0099] Thermogravimetric analyzer (TGA) test method: instrument model: Mettler TGA2; heating rate: 10°C / min, temperature range: 30°C-500°C, atmosphere: N2.

[0100] The 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound can be obtained by commercial purchase or self-production, for example, by referring to the method described in the prior art patent WO2007009913A1.

[0101] The crystalline form I of [3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound is the crystalline form I prepared with reference to the prior art patent CN201810077707.0.

[0102] Example 1 Preparation of Form K1

[0103] Weigh 0.50 g of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound sample (hereinafter referred to as compound sample), slowly add 8.5 mL of ethylene glycol dimethyl ether thereto, heat and dissolve until the solution is clear, cool naturally to room temperature, transfer to an ice bath, add Form I as a seed crystal, add 15 mL of n-heptane dropwise, stir for 3 h, filter, and dry naturally to obtain the product.

[0104] Its XRPD powder diffraction spectrum, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are as follows: Figure 1 , 2 , 3. The DSC spectrum shows that the crystal form K1 has an endothermic peak when heated to around 333.4°C. The TGA spectrum shows that the crystal form K1 has no obvious weight loss at 30°C-180°C. The XRPD data are shown in Table 1.

[0105] Table 1

[0106]

[0107]

[0108] Example 2 Preparation of Form K2

[0109] Method 1: Weigh 0.50 g of compound sample, slowly add 8.0 mL of ethylene glycol dimethyl ether, heat and dissolve until the solution is clear, take another 15 mL of n-heptane, add 15 mL of ethylene glycol dimethyl ether solution dropwise into the n-heptane system, stir for 3 hours, filter, and dry at 80°C for 4 to 5 hours.

[0110] Method 2: Weigh 0.50 g of compound sample, add 3 mL of THF, heat and dissolve until the solution is clear, take another 15 mL of n-heptane, slowly add the THF solution dropwise into the n-heptane system, stir for 2 h, filter, and dry naturally.

[0111] Its XRPD powder diffraction spectrum, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are as follows: Figure 4 , 5 , 6. The DSC spectrum shows that the crystal form K2 has an exothermic peak near 136.1°C when heated, and endothermic peaks near 177.6°C and 330.2°C. The TGA spectrum shows that the crystal form K2 has a weight loss of 12.65% before 180°C. The XRPD data are shown in Table 2.

[0112] Table 2

[0113]

[0114] Example 3 Preparation of Compound Crystalline Form K3

[0115] Weigh 3.00 g of Form I sample, add 30 mL of anhydrous ethanol, slurry at room temperature, and filter; add 30 mL of MTBE to the filtered solid, slurry at room temperature, filter, and dry in vacuum at 120°C to obtain.

[0116] Its XRPD powder diffraction spectrum, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are as follows: Figure 7 , 8 , 9. The DSC spectrum shows that the crystal form K3 has an exothermic peak near 207.2°C and an endothermic peak near 332.3°C when heated. The TGA spectrum shows that the crystal form K3 has no obvious weight loss at 30°C-180°C. The XRPD data are shown in Table 3.

[0117] Table 3

[0118]

[0119] Example 4 Preparation of Compound Crystalline Form K4

[0120] Weigh 100 mg of the compound sample, add 4 mL of dichloromethane, slurry at 35° C., filter, and dry naturally.

[0121] Its XRPD powder diffraction spectrum, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are as follows: Fig.10 , 11, 12. The DSC spectrum shows that the crystal form K4 has endothermic peaks when heated to 105.9°C and 334.2°C. The TGA spectrum shows that the crystal form K4 has a weight loss of 2.66% before 180°C. The XRPD data are shown in Table 4.

[0122] Table 4

[0123]

[0124]

[0125] Example 5 Preparation of Compound Crystalline Form K5

[0126] Weigh 100 mg of the compound sample, add 1 mL of N,N-dimethylformamide (DMF) thereto, dissolve at room temperature, and evaporate slowly to obtain a solid.

[0127] Its XRPD powder diffraction spectrum, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are as follows: Fig.13 , 14 , 15. The DSC spectrum shows that the crystal form K5 has endothermic peaks when heated to 156.0°C and 333.3°C. The TGA spectrum shows that the crystal form K5 has a weight loss of 14.24% before 180°C. The XRPD data are shown in Table 5.

[0128] Table 5

[0129]

[0130]

[0131] Example 6 Preparation of Compound Crystalline Form K6

[0132] Weigh 100 mg of the compound sample, add 4 mL of methyl tert-butyl ether (MTBE) thereto, slurry at 53° C., filter, and dry naturally.

[0133] Its XRPD powder diffraction spectrum, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are as follows: Fig.16 , 17 , 18. The DSC spectrum shows that the crystal form K6 has endothermic peaks near 131.0°C and 333.2°C, and an exothermic peak near 214.9°C when heated. The TGA spectrum shows that the crystal form K6 has a weight loss of 8.64% before 230°C. The XRPD data are shown in Table 6.

[0134] Table 6

[0135]

[0136]

[0137] Example 7 Preparation of Compound Crystalline Form K7

[0138] Weigh 100 mg of the compound sample, add 4 mL of methyl tert-butyl ether (MTBE) thereto, slurry at 75° C., filter, and dry naturally.

[0139] Its XRPD powder diffraction spectrum, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are as follows: Fig.19 , 20 , 21. The DSC spectrum shows that the crystal form K7 has endothermic peaks when heated to 107.6°C and 333.8°C. The TGA spectrum shows that the crystal form K7 has a weight loss of 13.95% before 180°C. The XRPD data are shown in Table 7.

[0140] Table 7

[0141]

[0142]

[0143] Example 8 Preparation of Compound Crystalline Form K8

[0144] Weigh 100 mg of the compound sample, add 4 mL of acetonitrile, slurry at 75° C., filter, and dry naturally.

[0145] Its XRPD powder diffraction spectrum, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are as follows: Fig. 22 , 23 , 24. The DSC spectrum shows that the crystal form K8 has endothermic peaks near 153.0°C and 335.4°C, and an exothermic peak near 186.3°C. The TGA spectrum shows that the crystal form K8 has a weight loss of 4.32% at 100°C-180°C. The XRPD data are shown in Table 8.

[0146] Table 8

[0147]

[0148]

[0149] Example 9 Preparation of Compound Crystalline Form K9

[0150] Weigh 500 mg of the compound sample, add 10 mL of isopropanol, heat to reflux, the system cannot be dissolved, then add 5 mL of butanone to the system to dissolve, cool and crystallize, add 10 mL of isopropanol and Form I seeds, filter, and dry naturally.

[0151] Its XRPD powder diffraction spectrum, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are as follows: Fig.25 , 26 , 27. The DSC spectrum shows that the crystal form K9 has endothermic peaks when heated to 106.3°C and 333.4°C. The TGA spectrum shows that the crystal form K9 has a weight loss of 11.63% before 180°C. The XRPD data are shown in Table 9.

[0152] Table 9

[0153]

[0154]

[0155] Example 10 Preparation of Compound Crystalline Form K10

[0156] Weigh 100 mg of the compound sample, add 1 mL of ethylene glycol dimethyl ether, dissolve at room temperature, and evaporate slowly to obtain a solid.

[0157] Its XRPD powder diffraction spectrum, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are as follows: Fig.28 , 29 , 30. The DSC spectrum shows that the crystal form K10 has endothermic peaks when heated to 68.2°C and 332.8°C. The TGA spectrum shows that the crystal form K10 has a weight loss of 15.18% before 150°C. The XRPD data are shown in Table 10.

[0158] Table 10

[0159]

[0160]

[0161]

[0162] Example 11 Preparation of Compound Crystalline Form K11

[0163] Weigh 150 mg of the compound sample, add 4 mL of butanone, dissolve at 75°C, then add 2 mL of n-butanol and slowly evaporate to obtain a solid.

[0164] Its XRPD powder diffraction spectrum and differential scanning calorimetry (DSC) spectrum are as follows: Fig.31 , 32 The DSC spectrum shows that the crystal form K11 has endothermic peaks near 105.2°C and 334.7°C when heated. The XRPD data are shown in Table 11.

[0165] Table 11

[0166]

[0167]

[0168] Example 12 Preparation of Compound Crystalline Form K12

[0169] Weigh 0.50 g of compound sample, add 8.5 mL of ethylene glycol dimethyl ether, heat to dissolve, cool naturally to room temperature, transfer to an ice bath, add crystal form K1 seed crystals, add 15 mL of n-heptane dropwise, stir for 0.5 h, filter, and dry naturally.

[0170] Its XRPD powder diffraction spectrum, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are as follows: Fig.33 , 34 , 35. The DSC spectrum shows that the crystal form K12 has endothermic peaks when heated to 180.0°C and 325.4°C. The TGA spectrum shows that the crystal form K12 has a weight loss of 17.07% before 200°C. The XRPD data are shown in Table 12.

[0171] Table 12

[0172]

[0173]

[0174] Example 13 Solubility Experiment

[0175] The solubility of Resmetirom forms K2 and K3 prepared by the present invention and the form I prepared according to CN201810077707.0 was investigated in water and different pH buffers (dissolution media are shown in Table 13), and the results are shown in Table 14. The results show that the solubility of form K2 is better than that of form I.

[0176] Table 13 Dissolution media

[0177] pH Dissolution medium 1.0 Hydrochloric acid solution 4.5 Acetate buffer 6.8 Phosphate buffered saline

[0178] Table 14

[0179]

[0180] Example 14 Stability Study

[0181] Investigation of influencing factors: The Resmetirom crystal forms K2 and K3 prepared by the present invention and the crystal form I prepared with reference to CN201810077707.0 were placed under high temperature (60°C, placed in a weighing bottle with an opening), high humidity (25°C, 92.5%, placed in a weighing bottle with an opening) and light (5000lx±500lx, placed in a weighing bottle with an opening) for 0, 5, 10, and 30 days, and whether crystal transformation occurred was investigated by XPRD detection, and the results are shown in Table 15. The results show that the new crystal forms K2 and K3 have good stability and are stable for at least 30 days without crystal transformation under high temperature (60°C, placed in a weighing bottle with an opening), high humidity (25°C, 92.5%, placed in a weighing bottle with an opening) and light (5000lx±500lx, placed in a weighing bottle with an opening).

[0182] Table 16

[0183]

[0184] Grinding stability: The Resmetirom forms K2 and K3 prepared by the present invention and the form I prepared according to CN201810077707.0 were ground in an agate mortar at room temperature for 1 minute, 3 minutes, 5 minutes and 10 minutes, and XPRD detection was used to investigate whether crystal transformation occurred. The results are shown in Table 16.

[0185] Table 16

[0186]

[0187]

Claims

1. A crystalline form K1 of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 4.8°±0.2°, 10.7°±0.2°, 11.2°±0.2°, 17.1°±0.2°, and 24.1°±0.2°.

2. The crystal form K1 according to claim 1, characterized in that Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 4.8°±0.2°, 8.1°±0.2°, 9.7°±0.2°, 10.7°±0.2°, 11.2°±0.2°, 13.6°±0.2°, 17.1°±0.2°, and 24.1°±0.2°.

3. The crystal form K1 according to claim 1, characterized in that Its X-ray powder diffraction pattern is basically consistent with that in FIG1 .

4. A crystalline form K2 of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 8.3°±0.2°, 10.2°±0.2°, 15.4°±0.2°, 21.4°±0.2°, and 25.2°±0.2°.

5. The crystal form K2 according to claim 4, characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.8°±0.2°, 8.3°±0.2°, 10.2°±0.2°, 11.1°±0.2°, 14.3°±0.2°, 15.4°±0.2°, 17.5°±0.2°, 21.4°±0.2°, and 25.2°±0.2°.

6. The crystal form K2 according to claim 4, characterized in that: Its X-ray powder diffraction pattern is basically consistent with that in FIG4 .

7. A crystalline form K3 of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.2°±0.2°, 6.4°±0.2°, 7.7°±0.2°, 11.8°±0.2°, and 19.6°±0.2°.

8. The crystal form K3 according to claim 7, characterized in that: Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 5.2°±0.2°, 6.4°±0.2°, 7.7°±0.2°, 11.8°±0.2°, 19.6°±0.2°, 20.9°±0.2°, 23.4°±0.2°, and 24.0°±0.2°.

9. The crystal form K3 according to claim 7, characterized in that: Its X-ray powder diffraction pattern is basically consistent with that in FIG7 .

10. A method for preparing the crystal form K3 according to any one of claims 7 to 9, characterized in that The method comprises adding an alcohol solvent to a 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound, beating the mixture, filtering the mixture, and then adding methyl tert-butyl ether, beating the mixture, filtering the mixture, and drying the mixture; preferably, the alcohol solvent is methanol, ethanol, isopropanol, or n-butanol.

11. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the crystal form according to any one of claims 1 to 9, and a pharmaceutically acceptable excipient.

12. Use of the crystal form according to any one of claims 1 to 9, the crystal form prepared by the method according to claim 10, or the pharmaceutical composition according to claim 11 in the preparation of a TRβ selective agonist drug.

13. Use of the crystal form according to any one of claims 1 to 9, the crystal form prepared according to the method of claim 10, or the pharmaceutical composition according to claim 11 in the preparation of a drug for treating hypercholesterolemia, non-alcoholic steatohepatitis, hyperlipidemia, diabetes, obesity, and fatty liver.

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