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WO2025011259A1 - Crystal form of resmetirom, and preparation method therefor and use thereof - Google Patents

Crystal form of resmetirom, and preparation method therefor and use thereof Download PDF

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Publication number
WO2025011259A1
WO2025011259A1 PCT/CN2024/099109 CN2024099109W WO2025011259A1 WO 2025011259 A1 WO2025011259 A1 WO 2025011259A1 CN 2024099109 W CN2024099109 W CN 2024099109W WO 2025011259 A1 WO2025011259 A1 WO 2025011259A1
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Prior art keywords
crystalline form
present
compound
csvii
preparation
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French (fr)
Chinese (zh)
Inventor
张雨星
张婧
孟丽苹
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Crystal Pharmaceutical Suzhou Co Ltd
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Crystal Pharmaceutical Suzhou Co Ltd
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Publication of WO2025011259A1 publication Critical patent/WO2025011259A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of crystal chemistry, and in particular to a crystal form of resmetirole and a preparation method and use thereof.
  • Heterozygous familial hypercholesterolemia is the most serious of the lipid metabolism diseases and can lead to various life-threatening cardiovascular complications.
  • Nonalcoholic steatohepatitis is a serious liver disease with fatty degeneration accompanied by inflammation and hepatocellular damage.
  • Resmetirom a thyroid hormone receptor THR- ⁇ selective agonist, can stimulate liver mitochondrial biogenesis in MASH individuals by reducing low-density lipoprotein cholesterol, triglycerides, and liver fat levels, thereby improving the symptoms of MASH and HeFH. Resmetirom has been approved in the United States for the treatment of MASH.
  • Resmetiro 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 (hereinafter referred to as "Compound I”), and its structural formula is as follows:
  • a crystal is a solid in which the molecules of a compound are arranged in a three-dimensional orderly manner in a microscopic structure to form a crystal lattice.
  • Polymorphism refers to the phenomenon that a compound exists in multiple crystal forms.
  • a compound may exist in one or more crystal forms, but its existence and characteristics cannot be specifically predicted.
  • APIs of different crystal forms have different physical and chemical properties, which may lead to different dissolution and absorption of the drug in the body, thereby affecting the clinical efficacy of the drug to a certain extent.
  • the crystal form is crucial to the product performance. Therefore, polymorphism is an important part of drug research and drug quality control.
  • US9266861B2 discloses hydrates, anhydrous crystalline form I, methyl isobutyl ketone solvates, and dimethylacetamide solvates of compound I.
  • WO2020010068A1 discloses various salt forms of compound I, such as free state, calcium salt, magnesium salt, sodium salt, potassium salt, and ethanolamine salt, including various free state solvate forms and multiple desolvate forms.
  • WO2022086894A1, WO2022171200A1, and CN115124515A disclose multiple crystalline forms of compound I, mainly solvates and cocrystals.
  • Crystalline Form I is a known solid form of Compound I with relatively good properties.
  • the inventors of the present application repeated the preparation method disclosed in US9266861B2 to obtain Crystalline Form I, and characterized the properties of Crystalline Form I. The results showed that Crystalline Form I has low solubility.
  • the inventors of the present application unexpectedly discovered that Crystalline Form CSVII of Compound I provided by the present invention is It has high solubility and good physical and chemical stability, solves the problems existing in the prior art, and is of great significance to the development of drugs containing compound I.
  • the present invention provides a new crystal form of Compound I and a preparation method thereof, as well as a pharmaceutical composition comprising the crystal form.
  • the present invention provides a crystalline form CSVII of Compound I (hereinafter referred to as "crystalline form CSVII").
  • the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at one, two, or three of the diffraction angles 2 ⁇ of 6.5° ⁇ 0.2°, 7.7° ⁇ 0.2°, and 23.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at diffraction angles 2 ⁇ of 6.5° ⁇ 0.2°, 7.7° ⁇ 0.2°, and 23.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at one or two of the diffraction angles 2 ⁇ of 12.2° ⁇ 0.2° and 19.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at diffraction angles 2 ⁇ of 12.2° ⁇ 0.2° and 19.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at one, or two, or three, or four, or five, or six, or seven, or eight, or nine of the diffraction angles 2 ⁇ of 6.5° ⁇ 0.2°, 7.7° ⁇ 0.2°, 23.4° ⁇ 0.2°, 19.7° ⁇ 0.2°, 24.2° ⁇ 0.2°, 22.7° ⁇ 0.2°, 25.4° ⁇ 0.2°, 12.2° ⁇ 0.2°, or 21.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSVII is substantially as shown in FIG. 1 .
  • Form CSVII is an anhydrate.
  • Form CSVII has a weight loss of about 0.5% upon heating to 100°C.
  • the present invention also provides a method for preparing the crystalline form CSVII, which comprises: placing the solid of compound I in methyl tert-butyl ether and stirring, separating the solid, and heating the obtained solid to obtain the crystalline form CSVII.
  • the heating end point temperature is 100°C-170°C, more preferably 140°C.
  • the crystal form CSVII of the present invention is used to prepare other crystal forms or salts or co-crystals of compound I.
  • the present invention provides a pharmaceutical composition, which comprises an effective therapeutic amount of crystalline form CSVII and pharmaceutically acceptable excipients.
  • the present invention provides the use of the crystalline form CSVII in the preparation of THR- ⁇ selective agonist pharmaceutical preparations.
  • the present invention provides the use of the crystalline form CSVII in the preparation of pharmaceutical preparations for treating MASH and HeFH.
  • Figure 1 is the XRPD diagram of Form CSVII
  • Figure 2 is a TGA diagram of crystalline form CSVII
  • Figure 3 is a DSC graph of Form CSVII
  • Figure 4 is a comparison of the solubility of Form CSVII and Form I
  • FIG5 is a comparison of XRPD images of Form CSVII before and after storage under different conditions (from top to bottom: before storage, 6 months at 25°C/60% RH, 6 months at 40°C/75%, and 3 months at 60°C/75%)
  • Figure 6 is the XRPD image of Type K65
  • Figure 7 is the XRPD image of Type K65
  • Figure 8 is the XRPD pattern of Type K65 desolvate
  • the X-ray powder diffraction pattern of the present invention was collected on a Bruker D8ADVANCE X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction of the present invention are as follows:
  • the TGA graph of the present invention was collected on TA Q500.
  • the method parameters of the TGA of the present invention are as follows:
  • the DSC graphs described in the present invention were collected on a METTLER TOLEDO DSC 3.
  • the method parameters of the DSC described in the present invention are as follows:
  • the solubility detection method of the present invention is shown in Table 1.
  • the "stirring” is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring speed is preferably 300-900 rpm, and the mechanical stirring speed is preferably 100-300 rpm.
  • the “separation” is accomplished by conventional methods in the art, such as centrifugation or filtration.
  • the “centrifugation” operation is: placing the sample to be separated in a centrifuge tube and centrifuging at a rate of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube.
  • the "drying” is accomplished by conventional methods in the art, such as vacuum drying, forced air drying or natural air drying.
  • the drying temperature can be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C.
  • the drying time can be 2-48 hours, or overnight.
  • the drying is carried out in a fume hood, forced air oven or vacuum oven.
  • room temperature is not a specific temperature value, but refers to the temperature range of 10-30°C.
  • the “characteristic peak” refers to a representative diffraction peak used to identify crystals.
  • the peak position can usually have an error of ⁇ 0.2°.
  • crystals or “crystal forms” can be characterized by X-ray powder diffraction.
  • X-ray powder diffraction pattern is affected by the conditions of the instrument, the preparation of the sample and the purity of the sample.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with the change of experimental conditions, so the diffraction peak intensity cannot be used as the only or decisive factor in determining the crystal form.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal, and the diffraction peak intensity shown in the present invention is illustrative rather than for absolute comparison. Therefore, those skilled in the art will understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern that is the same or similar to the characteristic peaks in these patterns falls within the scope of the present invention.
  • the X-ray powder diffraction pattern of an unknown crystal form is compared with that of the unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.
  • the crystalline form CSVII of the present invention is pure, substantially without any other crystalline form mixed.
  • substantially without when used to refer to a new crystalline form means that this crystalline form contains less than 20% (by weight) of other crystalline forms, particularly less than 10% (by weight) of other crystalline forms, more less than 5% (by weight) of other crystalline forms, and more less than 1% (by weight) of other crystalline forms.
  • the compound I and/or its salt as a raw material includes but is not limited to solid form (crystalline or amorphous), oily, liquid form and solution.
  • the compound I as a raw material is in solid form.
  • the compound I and/or its salt used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2020010068A1.
  • the crystalline form CSVII of the present invention was subjected to TGA, DSC and 1 H NMR tests, and its TGA graph is shown in FIG2 .
  • TGA TGA graph
  • DSC DSC graph
  • FIG3 DSC graph
  • FaSSIF is a simulated intestinal fluid in the fasting state, and the solubility tested in FaSSIF is closer to the solubility in the human body environment.
  • Compound I is a drug with poor water solubility.
  • the crystalline form CSVII provided by the present invention has higher solubility, which is beneficial to improving the absorption of the drug in the human body and improving the bioavailability; in addition, higher solubility can reduce the dosage of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.
  • Example 4 After the Type K65 obtained in Example 4 was placed at room temperature for about 5 hours, it was tested and the obtained solid was the desolvate of Type K65 described in the present invention. Its XRPD data is shown in Table 7, and the XRPD diagram is shown in Figure 8.

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Abstract

The present invention relates to a new crystal form of Resmetirom and a preparation method therefor, a pharmaceutical composition containing the crystal form, and a use of the crystal form in preparation of a THR-β selective agonist pharmaceutical formulation and a pharmaceutical formulation for treating MASH and HeFH.

Description

瑞司美替罗的晶型及其制备方法和用途Crystal form of resmetirol, preparation method and use thereof 技术领域Technical Field

本发明涉及晶体化学领域。具体而言，涉及瑞司美替罗的晶型及其制备方法和用途。The present invention relates to the field of crystal chemistry, and in particular to a crystal form of resmetirole and a preparation method and use thereof.

背景技术Background Art

杂合性家族性高胆固醇血症(HeFH)是脂质代谢疾病中最严重的一种，可导致各种危及生命的心血管疾病并发症。非酒精性脂肪性肝炎(MASH)是一种严重的肝脏疾病，伴随有炎症及肝细胞损伤的脂肪变性现象。瑞司美替罗(Resmetirom)作为一种甲状腺激素受体THR-β选择性激动剂，可通过降低低密度脂蛋白胆固醇、甘油三酯、肝脏脂肪水平，刺激MASH个体中肝脏线粒体生物合成，进而改善MASH和HeFH的症状。瑞司美替罗已在美国获批，用于治疗MASH。Heterozygous familial hypercholesterolemia (HeFH) is the most serious of the lipid metabolism diseases and can lead to various life-threatening cardiovascular complications. Nonalcoholic steatohepatitis (MASH) is a serious liver disease with fatty degeneration accompanied by inflammation and hepatocellular damage. Resmetirom, a thyroid hormone receptor THR-β selective agonist, can stimulate liver mitochondrial biogenesis in MASH individuals by reducing low-density lipoprotein cholesterol, triglycerides, and liver fat levels, thereby improving the symptoms of MASH and HeFH. Resmetirom has been approved in the United States for the treatment of MASH.

瑞司美替罗的化学名称为2-(3,5-二氯-4-((5-异丙基-6-氧代-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧代-2,3,4,5-四氢-1,2,4-三嗪-6-甲腈(以下称为“化合物I”)，其结构式如下：
The chemical name of Resmetiro 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 (hereinafter referred to as "Compound I"), and its structural formula is as follows:

晶体是化合物分子在微观结构中三维有序排列而形成晶格的固体。多晶型是指一种化合物存在多种晶体形式的现象。化合物可能以一种或多种晶型存在，但是无法具体预期其存在与特性。不同晶型的原料药有不同的理化性质，可能导致药物在体内有不同的溶出、吸收，进而在一定程度上影响药物的临床疗效。特别是一些难溶性口服固体或半固体制剂，晶型对产品性能至关重要。因此，多晶型是药物研究和药物质量控制的重要内容。A crystal is a solid in which the molecules of a compound are arranged in a three-dimensional orderly manner in a microscopic structure to form a crystal lattice. Polymorphism refers to the phenomenon that a compound exists in multiple crystal forms. A compound may exist in one or more crystal forms, but its existence and characteristics cannot be specifically predicted. APIs of different crystal forms have different physical and chemical properties, which may lead to different dissolution and absorption of the drug in the body, thereby affecting the clinical efficacy of the drug to a certain extent. In particular, for some poorly soluble oral solid or semi-solid preparations, the crystal form is crucial to the product performance. Therefore, polymorphism is an important part of drug research and drug quality control.

US9266861B2中公开了化合物I的水合物、无水晶型I、甲基异丁酮溶剂合物、二甲基乙酰胺溶剂合物。WO2020010068A1公开化合物I的游离态、钙盐、镁盐、钠盐、钾盐、乙醇胺盐等多种盐形态晶型，其中包含多种游离态溶剂合物晶型和多个脱溶剂合物晶型。WO2022086894A1、WO2022171200A1与CN115124515A公开了多个化合物I的晶型，主要为溶剂合物和共晶。US9266861B2 discloses hydrates, anhydrous crystalline form I, methyl isobutyl ketone solvates, and dimethylacetamide solvates of compound I. WO2020010068A1 discloses various salt forms of compound I, such as free state, calcium salt, magnesium salt, sodium salt, potassium salt, and ethanolamine salt, including various free state solvate forms and multiple desolvate forms. WO2022086894A1, WO2022171200A1, and CN115124515A disclose multiple crystalline forms of compound I, mainly solvates and cocrystals.

晶型I是已知的性质相对较好的化合物I固体形态。本申请发明人重复US9266861B2公开的制备方法得到晶型I，对晶型I的性质进行表征，结果显示晶型I的溶解度低。本申请的发明人意外发现了本发明提供的化合物I晶型CSVII， 其溶解度大、物理化学稳定性好，解决了现有技术存在的问题，对含化合物I的药物开发具有非常重要的意义。Crystalline Form I is a known solid form of Compound I with relatively good properties. The inventors of the present application repeated the preparation method disclosed in US9266861B2 to obtain Crystalline Form I, and characterized the properties of Crystalline Form I. The results showed that Crystalline Form I has low solubility. The inventors of the present application unexpectedly discovered that Crystalline Form CSVII of Compound I provided by the present invention is It has high solubility and good physical and chemical stability, solves the problems existing in the prior art, and is of great significance to the development of drugs containing compound I.

发明内容Summary of the invention

本发明提供化合物I的新晶型及其制备方法以及包含该晶型的药物组合物。The present invention provides a new crystal form of Compound I and a preparation method thereof, as well as a pharmaceutical composition comprising the crystal form.

根据本发明的目的，本发明提供化合物I的晶型CSVII(以下称作“晶型CSVII”)。According to the purpose of the present invention, the present invention provides a crystalline form CSVII of Compound I (hereinafter referred to as "crystalline form CSVII").

一方面，使用Cu-Kα辐射，所述晶型CSVII的X射线粉末衍射图在衍射角2θ值为6.5°±0.2°、7.7°±0.2°、23.4°±0.2°中的1处、或2处、或3处有特征峰。优选地，所述晶型CSVII的X射线粉末衍射图在衍射角2θ为6.5°±0.2°、7.7°±0.2°、23.4°±0.2°处有特征峰。On the one hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at one, two, or three of the diffraction angles 2θ of 6.5°±0.2°, 7.7°±0.2°, and 23.4°±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at diffraction angles 2θ of 6.5°±0.2°, 7.7°±0.2°, and 23.4°±0.2°.

进一步地，使用Cu-Kα辐射，所述晶型CSVII的X射线粉末衍射图在衍射角2θ值为12.2°±0.2°、19.7°±0.2°中的1处、或2处有特征峰。优选地，所述晶型CSVII的X射线粉末衍射图在衍射角2θ为12.2°±0.2°、19.7°±0.2°处有特征峰。Further, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at one or two of the diffraction angles 2θ of 12.2°±0.2° and 19.7°±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at diffraction angles 2θ of 12.2°±0.2° and 19.7°±0.2°.

另一方面，使用Cu-Kα辐射，所述晶型CSVII的X射线粉末衍射图在衍射角2θ值为6.5°±0.2°、7.7°±0.2°、23.4°±0.2°、19.7°±0.2°、24.2°±0.2°、22.7°±0.2°、25.4°±0.2°、12.2°±0.2°、21.1°±0.2°中的1处、或2处、或3处、或4处、或5处、或6处、或7处、或8处、或9处有特征峰。On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVII has characteristic peaks at one, or two, or three, or four, or five, or six, or seven, or eight, or nine of the diffraction angles 2θ of 6.5°±0.2°, 7.7°±0.2°, 23.4°±0.2°, 19.7°±0.2°, 24.2°±0.2°, 22.7°±0.2°, 25.4°±0.2°, 12.2°±0.2°, or 21.1°±0.2°.

非限制性地，使用Cu-Kα辐射，所述晶型CSVII的X射线粉末衍射图基本如图1所示。Without limitation, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSVII is substantially as shown in FIG. 1 .

非限制性地，晶型CSVII为无水物。Without limitation, Form CSVII is an anhydrate.

非限制性地，将晶型CSVII加热至100℃有约0.5％失重。Without limitation, Form CSVII has a weight loss of about 0.5% upon heating to 100°C.

根据本发明的目的，本发明还提供所述晶型CSVII的制备方法，所述制备方法包括：将化合物I固体置于甲基叔丁基醚中搅拌，分离固体，将所得固体加热得到晶型CSVII。According to the purpose of the present invention, the present invention also provides a method for preparing the crystalline form CSVII, which comprises: placing the solid of compound I in methyl tert-butyl ether and stirring, separating the solid, and heating the obtained solid to obtain the crystalline form CSVII.

进一步地，所述加热终点温度为100℃-170℃，更优选140℃。Furthermore, the heating end point temperature is 100°C-170°C, more preferably 140°C.

根据本发明的目的，本发明晶型CSVII用于制备化合物I其他晶型或盐或共晶的用途。According to the purpose of the present invention, the crystal form CSVII of the present invention is used to prepare other crystal forms or salts or co-crystals of compound I.

根据本发明的目的，本发明提供一种药物组合物，所述药物组合物包含有效治疗量的晶型CSVII及药学上可接受的辅料。According to the purpose of the present invention, the present invention provides a pharmaceutical composition, which comprises an effective therapeutic amount of crystalline form CSVII and pharmaceutically acceptable excipients.

根据本发明的目的，本发明提供的晶型CSVII在制备THR-β选择性激动剂药物制剂中的用途。According to the purpose of the present invention, the present invention provides the use of the crystalline form CSVII in the preparation of THR-β selective agonist pharmaceutical preparations.

根据本发明的目的，本发明提供的晶型CSVII在制备治疗MASH和HeFH药物制剂中的用途。According to the purpose of the present invention, the present invention provides the use of the crystalline form CSVII in the preparation of pharmaceutical preparations for treating MASH and HeFH.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1为晶型CSVII的XRPD图Figure 1 is the XRPD diagram of Form CSVII

图2为晶型CSVII的TGA图 Figure 2 is a TGA diagram of crystalline form CSVII

图3为晶型CSVII的DSC图Figure 3 is a DSC graph of Form CSVII

图4为晶型CSVII与晶型I的溶解度对比图Figure 4 is a comparison of the solubility of Form CSVII and Form I

图5为晶型CSVII在不同条件下放置前后的XRPD对比图(从上至下依次为：放置前，在25℃/60％RH放置6个月，在40℃/75％放置6个月，在60℃/75％放置3个月)FIG5 is a comparison of XRPD images of Form CSVII before and after storage under different conditions (from top to bottom: before storage, 6 months at 25°C/60% RH, 6 months at 40°C/75%, and 3 months at 60°C/75%)

图6为晶型Type K65的XRPD图Figure 6 is the XRPD image of Type K65

图7为晶型Type K65的XRPD图Figure 7 is the XRPD image of Type K65

图8为Type K65去溶剂化物的XRPD图Figure 8 is the XRPD pattern of Type K65 desolvate

具体实施方式DETAILED DESCRIPTION

结合以下实施例对本发明做详细说明，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。The present invention is described in detail with reference to the following examples, which describe in detail the preparation and use of the crystalline forms of the present invention. It will be apparent to those skilled in the art that many changes in both materials and methods may be made without departing from the scope of the present invention.

本发明中所用到的缩写的解释如下：The abbreviations used in the present invention are explained as follows:

XRPD：X射线粉末衍射XRPD: X-ray powder diffraction

TGA：热重分析TGA: Thermogravimetric analysis

DSC：差示扫描量热分析DSC: Differential Scanning Calorimetry

HPLC：高效液相色谱HPLC: High Performance Liquid Chromatography

1H NMR：液态核磁氢谱 1 H NMR: liquid hydrogen nuclear magnetic spectrum

RH：相对湿度RH: Relative humidity

采集数据所用的仪器及方法：Instruments and methods used to collect data:

本发明所述的X射线粉末衍射图在Bruker D8ADVANCE X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：The X-ray powder diffraction pattern of the present invention was collected on a Bruker D8ADVANCE X-ray powder diffractometer. The method parameters of the X-ray powder diffraction of the present invention are as follows:

X射线光源：Cu,KαX-ray source: Cu, Kα

Kα1：1.54060；Kα2：1.54439Kα1 ：1.54060；Kα2 :1.54439

Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50

电压：40kVVoltage: 40kV

电流：40mACurrent: 40mA

扫描范围：自4.0至40.0度Scanning range: from 4.0 to 40.0 degrees

本发明所述的TGA图在TA Q500上采集。本发明所述的TGA的方法参数如下：The TGA graph of the present invention was collected on TA Q500. The method parameters of the TGA of the present invention are as follows:

扫描速率：10℃/minScan rate: 10℃/min

保护气体：N2 Protective gas: N2

本发明所述的DSC图在METTLER TOLEDO DSC 3上采集。本发明所述的DSC的方法参数如下：The DSC graphs described in the present invention were collected on a METTLER TOLEDO DSC 3. The method parameters of the DSC described in the present invention are as follows:

扫描速率：10℃/minScan rate: 10℃/min

保护气体：N2 Protective gas: N2

1H NMR数据采自于Bruker Avance IIDMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲基亚砜溶解，配成2-10mg/mL的溶液。 1 H NMR data were collected on a Bruker Avance IIDMX 400M HZ nuclear magnetic resonance spectrometer. 1-5 mg of sample was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a 2-10 mg/mL solution.

本发明的溶解度检测方法如表1所示。The solubility detection method of the present invention is shown in Table 1.

表1
Table 1

本发明中，所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50-1800转/分钟，其中，磁力搅拌速度优选300-900转/分钟，机械搅拌速度优选100-300转/分钟。In the present invention, the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring speed is preferably 300-900 rpm, and the mechanical stirring speed is preferably 100-300 rpm.

所述“分离”，采用本领域的常规方法完成，例如离心或过滤。“离心”的操作为：将欲分离的样品置于离心管中，以10000转/分的速率进行离心，至固体全部沉至离心管底部。The "separation" is accomplished by conventional methods in the art, such as centrifugation or filtration. The "centrifugation" operation is: placing the sample to be separated in a centrifuge tube and centrifuging at a rate of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube.

所述“干燥”，采用本领域的常规方法完成，例如真空干燥，鼓风干燥或自然晾干。干燥温度可以是室温或更高，优选室温到约60℃，或者到50℃，或者到40℃。干燥时间可以为2-48小时，或者过夜。干燥在通风橱、鼓风烘箱或真空烘箱里进行。The "drying" is accomplished by conventional methods in the art, such as vacuum drying, forced air drying or natural air drying. The drying temperature can be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C. The drying time can be 2-48 hours, or overnight. The drying is carried out in a fume hood, forced air oven or vacuum oven.

所述“室温”不是特定的温度值，是指10-30℃温度范围。The "room temperature" is not a specific temperature value, but refers to the temperature range of 10-30°C.

所述“特征峰”是指用于甄别晶体的有代表性的衍射峰，使用Cu-Kα辐射测试时，峰位置通常可以有±0.2°的误差。The “characteristic peak” refers to a representative diffraction peak used to identify crystals. When Cu-Kα radiation is used for testing, the peak position can usually have an error of ±0.2°.

本发明中，“晶体”或“晶型”可以用X射线粉末衍射表征。本领域技术人员能够理解，X射线粉末衍射图受仪器的条件、样品的准备和样品纯度的影响而有所改变。X射线粉末衍射图中衍射峰的相对强度也可能随着实验条件的变化而变化，所以衍射峰强度不能作为判定晶型的唯一或决定性因素。事实上，X射线粉末衍射图中衍射峰的相对强度与晶体的择优取向有关，本发明所示的衍射峰强度为说明性而非用于绝对比较。因而，本领域技术人员可以理解的是，本发明所保护晶型的X射线粉末衍射图不必和这里所指的实施例中的X射线粉末衍射图完全一致，任何具有和这些图谱中的特征峰相同或相似的X射线粉末衍射图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的X射线粉末衍射 图和一个未知晶型的X射线粉末衍射图相比较，以证实这两组图反映的是相同还是不同的晶型。In the present invention, "crystals" or "crystal forms" can be characterized by X-ray powder diffraction. Those skilled in the art will understand that the X-ray powder diffraction pattern is affected by the conditions of the instrument, the preparation of the sample and the purity of the sample. The relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with the change of experimental conditions, so the diffraction peak intensity cannot be used as the only or decisive factor in determining the crystal form. In fact, the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal, and the diffraction peak intensity shown in the present invention is illustrative rather than for absolute comparison. Therefore, those skilled in the art will understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern that is the same or similar to the characteristic peaks in these patterns falls within the scope of the present invention. Those skilled in the art will be able to compare the X-ray powder diffraction patterns listed in the present invention to the X-ray powder diffraction patterns listed in the present invention. The X-ray powder diffraction pattern of an unknown crystal form is compared with that of the unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.

在一些实施方案中，本发明的晶型CSVII是纯的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。In some embodiments, the crystalline form CSVII of the present invention is pure, substantially without any other crystalline form mixed. In the present invention, "substantially without" when used to refer to a new crystalline form means that this crystalline form contains less than 20% (by weight) of other crystalline forms, particularly less than 10% (by weight) of other crystalline forms, more less than 5% (by weight) of other crystalline forms, and more less than 1% (by weight) of other crystalline forms.

本发明中术语“约”，当用来指可测量的数值时，例如质量、时间、温度等，意味着可围绕具体数值有一定的浮动的范围，该范围可以为±10％、±5％、±1％、±0.5％、或±0.1％。The term "about" in the present invention, when used to refer to a measurable value, such as mass, time, temperature, etc., means that there is a certain floating range around the specific value, which can be ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.

除非特殊说明，以下实施例均在室温条件下操作。Unless otherwise specified, the following examples were all operated at room temperature.

根据本发明，作为原料的所述化合物I和/或其盐包括但不限于固体形式(结晶或无定形)、油状、液体形式和溶液。优选地，作为原料的化合物I为固体形式。According to the present invention, the compound I and/or its salt as a raw material includes but is not limited to solid form (crystalline or amorphous), oily, liquid form and solution. Preferably, the compound I as a raw material is in solid form.

以下实施例中所使用的化合物I和/或其盐可根据现有技术制备得到，例如根据WO2020010068A1文献所记载的方法制备获得。The compound I and/or its salt used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2020010068A1.

实施例1：晶型CSVII的制备方法Example 1: Preparation method of crystalline form CSVII

称取527.6mg化合物I固体至玻璃瓶中，加入15mL甲基叔丁基醚，室温搅拌1天后，抽滤分离固体，25℃真空干燥0.5小时后得到干燥固体。取部分干燥固体在氮气保护下以10℃/min加热至140℃并保温60分钟，冷却至室温得到晶型CSVII，将所得固体在研钵中研磨1分钟仍为晶型CSVII，其XRPD图如图1，XRPD数据如表2所示。527.6 mg of Compound I solid was weighed into a glass bottle, 15 mL of methyl tert-butyl ether was added, and after stirring at room temperature for 1 day, the solid was separated by suction filtration, and dried under vacuum at 25°C for 0.5 hour to obtain a dry solid. A portion of the dry solid was heated to 140°C at 10°C/min under nitrogen protection and kept warm for 60 minutes, and cooled to room temperature to obtain Form CSVII. The obtained solid was ground in a mortar for 1 minute to still obtain Form CSVII, and its XRPD pattern is shown in Figure 1, and the XRPD data are shown in Table 2.

将本发明的晶型CSVII进行TGA，DSC和1H NMR测试，其TGA图如图2所示，将其加热至100℃时，具有约0.5％的质量损失；其DSC图如图3所示，其在264℃附近存在一个放热峰，在333℃附近存在一个吸热峰；核磁数据为：1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),7.79(s,2H),7.44(d,J＝0.7Hz,1H),3.13–2.97(m,1H),1.19(d,J＝6.9Hz,6H)，其中一个活泼氢未出峰。The crystalline form CSVII of the present invention was subjected to TGA, DSC and 1 H NMR tests, and its TGA graph is shown in FIG2 . When it is heated to 100° C., it has a mass loss of about 0.5%; its DSC graph is shown in FIG3 , which has an exothermic peak near 264° C. and an endothermic peak near 333° C.; the nuclear magnetic resonance data are: 1 H NMR (400 MHz, DMSO-d6) δ12.24 (s, 1H), 7.79 (s, 2H), 7.44 (d, J＝0.7 Hz, 1H), 3.13–2.97 (m, 1H), 1.19 (d, J＝6.9 Hz, 6H), in which one active hydrogen peak did not appear.

表2

Table 2

实施例2：晶型CSVII的动态溶解度Example 2: Dynamic Solubility of Form CSVII

进行药物溶解度测试以预测药物体内性能的时候，很重要的一点是尽可能的模拟体内条件。FaSSIF是禁食状态模拟肠液，在FaSSIF中测试的溶解度与人体环境中的溶解度更加接近。取适量本发明的晶型CSVII及现有技术晶型I分别分散在FaSSIF中配制成悬浊液，平衡5分钟、15分钟和30分钟后过滤得到饱和溶液，使用高效液相色谱法测试饱和溶液中样品的浓度(mg/mL)，结果如表3和图4所示。结果表明晶型CSVII在FaSSIF中具有更高的溶解度。When conducting a drug solubility test to predict the in vivo performance of a drug, it is very important to simulate the in vivo conditions as much as possible. FaSSIF is a simulated intestinal fluid in the fasting state, and the solubility tested in FaSSIF is closer to the solubility in the human body environment. Take an appropriate amount of the crystal form CSVII of the present invention and the crystal form I of the prior art and disperse them in FaSSIF to prepare a suspension, and filter to obtain a saturated solution after balancing for 5 minutes, 15 minutes and 30 minutes. The concentration (mg/mL) of the sample in the saturated solution is tested by high performance liquid chromatography, and the results are shown in Table 3 and Figure 4. The results show that the crystal form CSVII has a higher solubility in FaSSIF.

表3
Table 3

化合物I是水溶性差的药物。本发明提供的晶型CSVII有更高的溶解度，有利于提高药物在人体内的吸收，提高生物利用度；另外，更高的溶解度能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。Compound I is a drug with poor water solubility. The crystalline form CSVII provided by the present invention has higher solubility, which is beneficial to improving the absorption of the drug in the human body and improving the bioavailability; in addition, higher solubility can reduce the dosage of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.

实施例3：晶型CSVII的稳定性Example 3: Stability of Form CSVII

取适量本发明制备得到的晶型CSVII，分别放置在25℃/60％RH、40℃/75％RH、60℃/75％RH条件下，采用HPLC和XRPD测定纯度与晶型。结果如表4所示，XRPD对比图如图5所示。结果表明，晶型CSVII在25℃/60％RH和40℃/75％RH条件下至少可稳定6个月，60℃/75％RH条件下放置至少可稳定3个月，可见晶型CSVII在长期条件、加速条件和更严苛的条件下均可保持良好的稳定性。Take an appropriate amount of the crystalline form CSVII prepared by the present invention, place it under 25°C/60%RH, 40°C/75%RH, and 60°C/75%RH conditions, and use HPLC and XRPD to determine the purity and crystal form. The results are shown in Table 4, and the XRPD comparison chart is shown in Figure 5. The results show that the crystalline form CSVII is stable for at least 6 months under 25°C/60%RH and 40°C/75%RH conditions, and is stable for at least 3 months under 60°C/75%RH conditions. It can be seen that the crystalline form CSVII can maintain good stability under long-term conditions, accelerated conditions, and more stringent conditions.

表4
Table 4

包装条件：密封(加干燥剂)Packaging conditions: Sealed (with desiccant)

季节差异、不同地区气候差异和环境因素等带来的高温和高湿条件会影响原料药和制剂的储存、运输、生产。因此，原料药和制剂在加速条件及更严苛的条件下的稳定性对于药物至关重要。晶型CSVII原料药在苛刻的条件下具有良好 的稳定性，有利于避免药物储存过程中因转晶或纯度下降对药物质量产生影响。High temperature and high humidity conditions caused by seasonal differences, climate differences in different regions, and environmental factors can affect the storage, transportation, and production of APIs and preparations. Therefore, the stability of APIs and preparations under accelerated conditions and more stringent conditions is crucial for drugs. The stability of the drug is beneficial to avoid the impact on drug quality due to crystal transformation or purity reduction during drug storage.

实施例4：晶型Type K65的制备方法Example 4: Preparation method of crystal form Type K65

称取51.2mg化合物I固体于小瓶中，加入1.0mL乙腈和甲醇的混合溶剂(体积比为7:1)，室温下悬浮搅拌过夜，离心后得到固体。经检测，所得固体为本发明所述晶型Type K65，其XRPD数据如表5所示，XRPD图如6所示。Weigh 51.2 mg of Compound I solid into a vial, add 1.0 mL of a mixed solvent of acetonitrile and methanol (volume ratio of 7:1), suspend and stir overnight at room temperature, and obtain a solid after centrifugation. After testing, the obtained solid is the crystal form Type K65 of the present invention, and its XRPD data is shown in Table 5 and the XRPD diagram is shown in Figure 6.

表5
Table 5

实施例5：晶型Type K65的制备方法Example 5: Preparation method of crystal form Type K65

称取10.1mg化合物I固体于小瓶中，加入0.2mL乙腈，室温下超声约1分钟，离心后得到固体。经检测，所得固体为本发明所述晶型Type K65，其XRPD数据如表6所示，XRPD图如图7所示。Weigh 10.1 mg of Compound I solid into a vial, add 0.2 mL of acetonitrile, sonicate at room temperature for about 1 minute, and centrifuge to obtain a solid. After testing, the obtained solid is the crystal form Type K65 of the present invention, and its XRPD data is shown in Table 6, and the XRPD diagram is shown in Figure 7.

表6
Table 6

实施例6：Type K65去溶剂化物的制备方法Example 6: Preparation of Type K65 desolvate

将实施例4得到的Type K65于室温环境下放置约5h后，经检测，所得固体为本发明所述Type K65去溶剂化物，其XRPD数据如表7所示，XRPD图如图8所示。After the Type K65 obtained in Example 4 was placed at room temperature for about 5 hours, it was tested and the obtained solid was the desolvate of Type K65 described in the present invention. Its XRPD data is shown in Table 7, and the XRPD diagram is shown in Figure 8.

表7

Table 7

上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。 The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims (7)

一种化合物I的晶型，其特征在于使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为6.5°±0.2°、7.7°±0.2°、23.4°±0.2°处具有特征峰，
A crystalline form of compound I, characterized in that using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 6.5°±0.2°, 7.7°±0.2°, and 23.4°±0.2°,
根据权利要求1所述的晶型，其特征在于使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为19.7°±0.2°、12.2°±0.2°中的至少一处具有特征峰。The crystalline form according to claim 1 is characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has a characteristic peak at at least one of the 2θ values of 19.7°±0.2° and 12.2°±0.2°. 根据权利要求1所述的晶型，其特征在于使用Cu-Kα辐射，其X射线粉末衍射图基本如图1所示。The crystalline form according to claim 1 is characterized in that Cu-Kα radiation is used, and its X-ray powder diffraction pattern is substantially as shown in Figure 1. 权利要求1所述的晶型的制备方法，其特征在于，所述方法包括：将化合物I固体置于甲基叔丁基醚中搅拌，分离固体，加热得到。The method for preparing the crystalline form according to claim 1 is characterized in that the method comprises: placing the solid of Compound I in methyl tert-butyl ether and stirring, separating the solid, and heating to obtain. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1所述的化合物I的晶型及药学上可接受的辅料。A pharmaceutical composition comprising an effective therapeutic amount of the crystalline form of Compound I according to claim 1 and a pharmaceutically acceptable excipient. 权利要求1中所述的化合物I的晶型在制备THR-β选择性激动剂药物中的用途。Use of the crystalline form of Compound I described in claim 1 in the preparation of THR-β selective agonist drugs. 权利要求1中所述的化合物I的晶型在制备治疗MASH和HeFH药物中的用途。 Use of the crystalline form of Compound I described in claim 1 in the preparation of drugs for treating MASH and HeFH.
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