WO2022194073A1 - 一种1，2，4-三嗪-3，5-二酮类化合物的盐型、晶型及其制备方法 - Google Patents

一种1，2，4-三嗪-3，5-二酮类化合物的盐型、晶型及其制备方法 Download PDF

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WO2022194073A1
WO2022194073A1 PCT/CN2022/080571 CN2022080571W WO2022194073A1 WO 2022194073 A1 WO2022194073 A1 WO 2022194073A1 CN 2022080571 W CN2022080571 W CN 2022080571W WO 2022194073 A1 WO2022194073 A1 WO 2022194073A1
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compound
salt
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present
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吕贺军
王朋
叶文武
纪海霞
刘军锋
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昆药集团股份有限公司
上海昆恒医药科技有限公司
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    • 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
    • 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
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
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    • 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
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    • 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
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    • 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
    • C07D237/18—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D403/10—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 carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a salt form, a crystal form and a preparation method of a 1,2,4-triazine-3,5-dione compound.
  • Thyroid hormones play a key role in normal growth and development of the body and in maintaining metabolic balance (Physiological Reviews 2001, 81(3), 1097-1126.). Thyroid hormones are produced by the thyroid gland and secreted into the circulatory system (hypothalamic/pituitary/thyroid system) in two different forms, T4 and T3, with T4 being the predominant form secreted by the thyroid gland and T3 the physiologically more active form. T4 is converted to T3 by tissue-specific deiodinase, which is present in all tissues, but mainly in liver and kidney tissues.
  • THR thyroid hormone receptor
  • THR belongs to the nuclear receptor superfamily, which forms heterodimers with retinoid receptors that act as ligand-induced transcription factors.
  • THR has a ligand-binding domain, a DNA-binding domain, and an amino-terminal domain, and regulates gene expression through interactions with DNA-responsive elements and with various nuclear co-activators and co-repressors.
  • THR is encoded by the expression ⁇ and ⁇ of different genes located on human chromosomes 17 and 3. Different protein isoforms are generated by selective splicing of the primary transcript.
  • THR ⁇ 1 and THR ⁇ 2 are differentially expressed from promoters, and the two isoforms differ only at the amino terminus.
  • THR ⁇ 1 and THR ⁇ 2 result from differential splicing of pre-mRNAs, mainly at the carboxy terminus.
  • THR ⁇ 1, THR ⁇ 1 and THR ⁇ 2 can bind thyroid hormones. Studies have shown that thyroid hormone receptor subtypes can differ in their contribution to specific physiological responses.
  • THR ⁇ 1 plays an important role in the regulation of thyroid stimulating hormone and thyroid hormone in the liver, and THR ⁇ 2 plays a major role in the regulation of thyroid stimulating hormone.
  • THR ⁇ which is involved in lipid metabolism
  • Thyroid hormones are metabolized in target organs and excreted mainly in bile, and their physiological roles in mammals are mainly manifested in growth and differentiation and maintenance of life functions, such as heart rate, blood cholesterol and triglyceride concentrations, and systemic metabolism Control and regulation of speed and weight etc. From a pathophysiological point of view, tachycardia, arrhythmia, heart failure, as well as fatigue, shortness of breath, sarcopenia, and osteoporosis are observed in hyperthyroidism such as Graves disease (Physiol. Rev. 2001, 81, 1097; J. Steroid. Biochem. Mol. Biol. 2001, 76, 31.).
  • thyroid hormone itself is limited by the adverse side effects associated with hyperthyroidism, especially cardiovascular toxicity.
  • a thyroid hormone analog that may be used in the treatment of disease-responsive diseases such as metabolic diseases including obesity, hyperlipidemia, hyperlipidemia, and Cholesterolemia, diabetes and other conditions such as hepatic steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease and the like.
  • diseases including obesity, hyperlipidemia, hyperlipidemia, and Cholesterolemia
  • diabetes and other conditions such as hepatic steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease and the like.
  • NASH non-alcoholic steatohepatitis
  • Thyroid hormone analogs different in structure from the compounds of the present invention discloses a pyridazinone derivative, especially Example 8 (compound 31, namely MGL-3196), as a THR ⁇ selective and liver tissue selective Thyroid hormone analogs have achieved good results and may be used to treat a variety of diseases, but MGL-3196 still has problems such as insufficient activity and fast metabolism in the body.
  • a pyridazinone compound shown in formula I is provided as a thyroid hormone inhibitor, namely 2-(3,5-dichloro-4-((5-isopropyl-6-oxyl-1, 6-Dihydropyridin-3-yl)oxy)phenyl)-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione, further providing a salt of this compound Form, crystal form and preparation method thereof.
  • the compound of formula I has poor free base solubility and poor free base crystallinity, which brings great challenges to druggability.
  • the active compound can be crystallized to form a pharmaceutically acceptable stable compound with good fluidity, or it can be improved by selecting an appropriate salt form.
  • the selection of an appropriate salt for a particular active substance to exhibit a stable crystalline state is not always straightforward, since different compounds form salts with the same salt-forming agent with very different properties.
  • the object of the present invention is to provide the compound of formula I in the form of crystal forms and salts that meet the above requirements for solubility, handling and stability; it is further surprisingly found that the addition salt formed by the compound is compared with the free compound of formula I. Has better pharmacokinetic properties in mice.
  • One aspect of the present invention provides a crystalline form A of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 12.30 ⁇ 0.20, 14.02 ⁇ 0.20, 24.66 ⁇ 0.20, 25.22 ⁇ 0.20, 28.58 ⁇ 0.20 ,
  • the X-ray powder diffraction pattern of the compound of formula (I), Form A has characteristic diffraction peaks at the following 2 ⁇ angles: 12.30 ⁇ 0.20, 14.02 ⁇ 0.20, 17.02 ⁇ 0.20, 20.18 ⁇ 0.20, 23.52 ⁇ 0.20, 24.66 ⁇ 0.20, 25.22 ⁇ 0.20, 25.86 ⁇ 0.20, 28.30 ⁇ 0.20, 28.58 ⁇ 0.20.
  • the X-ray powder diffraction pattern of the compound of formula (I), Form A has characteristic diffraction peaks at the following 2 ⁇ angles: 12.30 ⁇ 0.20, 14.02 ⁇ 0.20, 17.02 ⁇ 0.20, 18.86 ⁇ 0.20, 20.18 ⁇ 0.20, 22.36 ⁇ 0.20, 23.52 ⁇ 0.20, 23.72 ⁇ 0.20, 24.66 ⁇ 0.20, 25.22 ⁇ 0.20, 25.86 ⁇ 0.20, 28.30 ⁇ 0.20, 28.58 ⁇ 0.20, 29.74 ⁇ 0.20, 32.86 ⁇ 0.20.
  • the 2 ⁇ angle represented by the X-ray powder diffraction pattern is due to errors in equipment detection.
  • ⁇ 0.20 is used to indicate the deviation
  • ⁇ 0.10 is used to indicate the deviation
  • ⁇ 0.05 is used to indicate the deviation
  • ⁇ 0.02 is further used to indicate the deviation.
  • the crystalline form A of the compound of formula (I) above has substantially the same XRPD pattern as FIG. 1 .
  • the compound of the above formula (I) in crystal form A has a maximum endothermic peak at 308.85 ° C; in some embodiments of the present invention, the above formula (I) )
  • the DSC spectrum of the compound crystal form A is shown in FIG. 2 .
  • the above formula (I) compound crystal form A has a thermogravimetric analysis curve of 0.0494% weight loss at 120°C and 0.5069% weight loss at 250°C.
  • the TGA spectrum of the crystalline form A of the compound of formula (I) above is shown in FIG. 3 .
  • the preparation method of above-mentioned crystal form A weigh the compound of formula (I) into a reaction flask, add an appropriate amount of glacial acetic acid, and heat to a clear state; then slowly cool down to room temperature, and a large amount of white solid is precipitated The solid is placed in a reaction flask, an appropriate amount of anhydrous ethanol is added, heated to obtain a suspension; slowly cooled to room temperature, and the crystal form A of the compound of formula (I) is obtained after the solid is separated.
  • Another aspect of the present invention also provides a pharmaceutically acceptable salt of the compound of formula (I), the pharmaceutically acceptable salt is selected from: sodium salt, potassium salt, L-arginine salt, choline salt, meglumine salt, diethylamine salt and L-lysine salt, preferably sodium salt, choline salt and L-lysine salt, more preferably sodium salt and choline salt.
  • the present invention further provides the sodium salt of the compound of formula (I) as shown in formula (II), and the molar ratio of the compound of formula (I) to the cation or anion of the salt is 1:1,
  • the present invention provides the sodium salt of the compound of formula (I), the crystalline form of formula (II) in one of the embodiments, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 10.48 ⁇ 0.20, 19.14 ⁇ 0.20, 22.30 ⁇ 0.20, 23.60 ⁇ 0.20, 26.92 ⁇ 0.20; further the crystalline form of the sodium salt of the compound of formula (I) of the present invention provided in one of the embodiments of formula (II), its X-ray powder diffraction pattern has characteristic diffraction at the following 2 ⁇ angles Peaks 10.48 ⁇ 0.20, 11.28 ⁇ 0.20, 17.26 ⁇ 0.20, 19.14 ⁇ 0.20, 22.30 ⁇ 0.20, 23.60 ⁇ 0.20, 25.26 ⁇ 0.20, 26.92 ⁇ 0.20, 28.28 ⁇ 0.20, 28.66 ⁇ 0.20.
  • the X-ray powder diffraction pattern of the crystalline form of the sodium salt of the compound of formula (I) above, formula (II), is substantially the same as the XRPD pattern of FIG. 4 .
  • the crystalline form of the above-mentioned sodium salt of the compound of formula (I) of formula (II) has a peak of a maximum exothermic peak at 326.25°C in its differential scanning calorimetry curve.
  • the DSC spectrum of the crystalline form of the sodium salt of the compound of formula (I) above, formula (II) is shown in FIG. 5 .
  • the above-mentioned crystalline form of the sodium salt of the compound of formula (I) of formula (II) has a thermogravimetric analysis curve of 0.6243% weight loss at 120°C.
  • the TGA spectrum of the above crystal form is shown in FIG. 6 .
  • the above-mentioned preparation method of the sodium salt of the compound of formula (I), formula (II) put the compound of formula (I) into a reaction flask, add it to an organic solvent, and stir to suspend at room temperature. Then the alkaline salt solution of Na is slowly added dropwise to the reaction solution in a molar ratio of 1:1-1.5, and magnetically stirred at room temperature to separate out a solid and collect the solid to obtain the sodium salt of the compound of formula (I), formula (II).
  • the present invention further provides the L-lysine salt of the compound of formula (I) as shown in formula (III), and the molar ratio of the compound of formula (I) to the cation or anion of the salt is 1:1,
  • the present invention provides the L-lysine salt of the compound of formula (I) in one embodiment of the crystal form of formula (III), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.86 ⁇ 0.20, 16.32 ⁇ 0.20, 22.62 ⁇ 0.20, 25.00 ⁇ 0.20, 25.80 ⁇ 0.20; further, the crystal form of the L-lysine salt formula (III) of the compound of the present invention (I) is provided in one of the embodiments, and its X-ray powder diffraction pattern is in the following There are characteristic diffraction peaks at 2 ⁇ angle: 6.71 ⁇ 0.20, 8.86 ⁇ 0.20, 10.98 ⁇ 0.20, 13.82 ⁇ 0.20, 16.32 ⁇ 0.20, 18.92 ⁇ 0.20, 20.72, 22.62 ⁇ 0.20, 25.00 ⁇ 0.20, 25.80 ⁇ 0.20.
  • the X-ray powder diffraction pattern of the crystalline form of the L-lysine salt of the compound of the above formula (I) of the formula (III) is substantially the same as the XRPD pattern of FIG. 7 .
  • the crystalline form of the L-lysine salt of the compound of the above formula (I), the crystalline form of the formula (III), the differential scanning calorimetry curve has a maximum endothermic peak at 244.18 ° C, in There is an exothermic peak at 252.63°C.
  • the DSC spectrum of the above-mentioned crystal form is shown in FIG. 8 .
  • the crystalline form of the L-lysine salt of the compound of formula (I) of formula (III) has a thermogravimetric analysis curve of 0.5199% weight loss at 120°C.
  • the TGA spectrum of the above crystal form is shown in FIG. 9 .
  • the preparation method of the L-lysine salt formula (III) of the above-mentioned compound of formula (I) put the compound of formula (I) into a reaction flask, add it to an organic solvent, and stir at room temperature to form a suspension state. Then, the aqueous solution of L-Lysine (L-Lysine) was slowly added dropwise to the reaction solution in a molar ratio of 1:1-1.5, magnetically stirred at room temperature, and a solid was precipitated to collect the solid to obtain the L-Lysine of the compound of formula (I). Amino acid salt of formula (III).
  • the present invention further provides the choline salt of the compound of formula (I) as shown in formula (IV), the ratio of the cation or anion of the compound of formula (I) to the salt can be 1:1,
  • the present invention provides the crystalline form of the choline salt of the compound of formula (I) in one of the embodiments of formula (IV), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 15.46 ⁇ 0.20, 19.02 ⁇ 0.20, 19.60 ⁇ 0.20, 21.68 ⁇ 0.20, 23.64 ⁇ 0.20; further the crystalline form of the choline salt formula (IV) of the compound of formula (I) of the present invention provided in one of the embodiments has an X-ray powder diffraction pattern at the following 2 ⁇ angles.
  • Characteristic diffraction peaks 7.78 ⁇ 0.20, 15.46 ⁇ 0.20 ⁇ 0.20, 18.00 ⁇ 0.20, 19.02 ⁇ 0.20, 19.60 ⁇ 0.20, 21.68 ⁇ 0.20, 23.64 ⁇ 0.20, 24.02 ⁇ 0.20, 25.76 ⁇ 0.20, 29.16 ⁇ 0.20.
  • the X-ray powder diffraction pattern of the crystalline form of the choline salt of formula (IV) of the compound of formula (I) above is substantially the same as the XRPD pattern of FIG. 10 .
  • the crystalline form of the choline salt formula (IV) of the compound of formula (I) above has a peak of a maximum endothermic peak at 202.26°C in its differential scanning calorimetry curve.
  • the DSC spectra of the above crystal forms are shown in FIG. 11 .
  • the crystalline form of the choline salt formula (IV) of the compound of formula (I) above has a thermogravimetric analysis curve of 0.0128% weight loss at 120°C.
  • the TGA spectrum of the above crystal form is shown in FIG. 12 .
  • the above-mentioned preparation method of the choline salt of the compound of formula (I) of formula (IV) adding the compound of formula (I) to a reaction flask, adding it to an organic solvent, and stirring at room temperature to form a suspended state. Then, the aqueous choline (Choline) solution was slowly added dropwise to the reaction solution in a molar ratio of 1:1-1.5, magnetically stirred at room temperature, and a solid was precipitated to collect the solid to obtain the choline salt formula (IV) of the compound of formula (I).
  • the use of the salts of the compounds of formula (I) and their crystalline forms provided above in the present invention in therapy and or in the preparation of medicines is to treat diseases associated with thyroid hormone receptors.
  • the present invention provides the above-mentioned pharmaceutical composition of the salt of the compound of formula (I) and its crystalline form.
  • the present invention provides a method of treatment comprising administering to a patient in need of a salt of a compound of formula (I) provided above, and crystalline forms thereof, an effective amount of a compound of formula (I) provided above Salts and their crystalline forms.
  • the beneficial effects of the present invention are as follows: it has been surprisingly found that the free base crystal form has better stability and crystal form stability, which is helpful for preparing the corresponding pharmaceutical dosage form; the addition salt of the compound of formula (I) Compared with the free base, it has better pharmacokinetic properties in mice, and the best one is the choline salt.
  • Fig. 1 is the XRPD spectrum of the Cu-K ⁇ radiation of compound crystal form A of formula (I);
  • Fig. 2 is the DSC spectrogram of formula (I) compound crystal form A;
  • Fig. 3 is the TGA spectrogram of formula (I) compound crystal form A
  • Fig. 4 is the XRPD spectrum of the Cu-K ⁇ radiation of the sodium salt formula (II) crystal form of the compound of formula (I);
  • Fig. 5 is the DSC spectrogram of the sodium salt formula (II) crystal form of the compound of formula (I);
  • Fig. 6 is the TGA spectrum of the sodium salt formula (II) crystal form of the compound of formula (I);
  • Fig. 7 is the XRPD spectrum of the Cu-K ⁇ radiation of the L-lysine salt formula (III) crystal form of the compound of formula (I);
  • Fig. 8 is the DSC spectrogram of the L-lysine salt formula (III) crystal form of the compound of formula (I);
  • Fig. 9 is the TGA spectrum of the L-lysine salt formula (III) crystal form of the compound of formula (I);
  • Fig. 10 is the Cu-K ⁇ radiation XRPD spectrum of the choline salt formula (IV) crystal form of the compound of formula (I);
  • Figure 11 is the DSC spectrum of the choline salt formula (IV) crystal form of the compound of formula (I);
  • Figure 12 is the TGA spectrum of the choline salt formula (IV) crystal form of the compound of formula (I);
  • Figure 13 shows the H-NMR results of the L-lysine salt of the compound of formula (I), formula (III).
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
  • the equipment is Shimadzu XRD-6000, and the sample is scanned according to the following parameters:
  • the radiation source is Cu ⁇ K ⁇ target
  • the minimum operating voltage and current of the light pipe are 40kV and 30mA, respectively.
  • the 2-Theta value of the sample scan range is from 5° to 50° or (2° to 50°).
  • the scanning speed is 5deg/min.
  • the sample is dispersed in a medium (silicone oil), the sample is observed using a 10X eyepiece, a 10X objective, and the image is recorded with a camera computer system.
  • a medium silicone oil
  • Methyl 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-carboxylate 1c 200 mg, 0.43 mmol was dissolved in 20 mL of tetrahydrofuran, and sodium borohydride (82 mg) was added at room temperature , 2.15 mmol), then methanol was slowly added dropwise.
  • Methyl 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-(hydroxymethyl) base)-1,2,4-triazine-3,5(2H,4H)-dione 1d (100 mg, 0.23 mmol) was dissolved in 20 mL of dichloromethane, DAST (5 drops) was added under ice bath, and the reaction solution React at this temperature for 30 minutes.
  • reaction solution was added to 20 mL of ice water, extracted with dichloromethane (20 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative chromatography to give 2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridin-3-yl)oxy)phenyl )-(fluoromethyl)-1,2,4-triazine-3,5(2H,4H)-dione (formula I) (45 mg), yield: 45%.
  • the corresponding cation or anion salts are used to complete the preparation of L-arginine, meglumine, and diethylamine salts.
  • the agonist binds to THR ⁇ -LBD/RXR ⁇ and causes a conformational change of THR ⁇ -LBD, thereby increasing the recruitment capacity of the heterodimer to the SRC2-2 co-activating peptide.
  • the resulting decreased distance between the d2-labeled SRC2-2 co-activating peptide and the Eu-anti-GST antibody increased the THR-FRET signal.
  • the agonistic ability of a compound can be assessed based on the effect of different concentrations of the compound on THR[beta] activity.
  • a 100X reference compound or compound was prepared in DMSO and diluted 1:3 in equal proportions.
  • a 100X serial dilution of the reference compound or compound was diluted 4X with 1X reaction buffer and added to the assay plate.
  • a mixed solution of 4X THR ⁇ -LBD, 4X RXR ⁇ was prepared with 1X reaction buffer and added to the experimental plate.
  • a mixed solution of 2X biotin-SRC2-2, 2X Eu-anti-GST, 2X streptavidin-d2 was prepared with 1X reaction buffer and added to the assay plate.
  • the 665nm and 615nm fluorescence signal values were read on an EnVision 2104 plate reader and the Ratio 665nm/615nm was calculated.
  • Compound 1 is T3; Compound 2 is Example 8 (Compound 31) of WO2007009913; Compound 3 is the corresponding compound of Example 4 of WO2020239076Al.
  • test substance and the positive control substance, verapamil were respectively dissolved in DMSO to 10 mM as a stock solution, and the above-mentioned 10 mM stock solution was diluted with a 70% acetonitrile aqueous solution to a concentration of 0.25 mM.
  • the NADPH regeneration system was formulated with final concentrations of 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-PDH and 3.3 mM magnesium chloride.
  • the stop solution was an acetonitrile solution containing tolbutamide and propranolol (both internal standards).
  • the mixed system was incubated with gentle shaking in a water bath at 37°C, and at 5, 10, 30, and 60 min, 100 ⁇ L of the incubation solution was taken into each well of a new 96-well plate containing 400 ⁇ L of stop solution, mixed well, and the protein was precipitated (4000 ⁇ g, centrifuged at 4°C for 15 minutes).
  • mice Using mice as test animals, the drug concentrations in plasma at different times after the mice were administered the compounds of formula (I) to formula (IV) by gavage were tested.
  • the pharmacokinetic behavior of the compound of the present invention in mice was studied, and its drug metabolism characteristics were evaluated.
  • Each group of examples selected 9 healthy adult male ICR mice of similar body weight, and the oral administration dose was 15.0 mg/kg (or equivalently 15.0 mg/kg), and the single administration was performed before administration and 1 hour after administration. ,2h,4h,6h,8h,12h,24h,48h to collect whole blood.
  • An LC/MS/MS method was established to determine the concentration of unchanged drug in plasma samples.
  • the main pharmacokinetic parameters were calculated using the WinNonlin 6.3NCA model, as shown in Table 8 below.
  • mice 9 healthy adult male ICR mice were equally divided into 3 groups, with 3 mice in each group, Shanghai Sipple-Bike Laboratory Animal Co., Ltd., animal certificate number: SCXK (Shanghai) 2018-0006 2018 0006 010467.
  • Drug configuration Precisely weigh a certain amount of compounds of formula (I)-formula (IV), place them in a 15ml sample tube, add 5uL of Tween 80 to wet, and then add 2% hydroxypropyl cellulose (Klucel LF) solution 4 mL, sonicated and vortexed to obtain a homogeneous suspension. Prepare freshly before use.
  • ICR mice were fasted overnight and then intragastrically administered at a dose of 15.0 mg/kg (or equivalently 15.0 mg/kg).
  • the sodium salt formula (II), L-lysine salt formula (III) and choline salt formula (IV) of the compound of the present invention have good pharmacokinetic absorption and have obvious pharmacokinetic advantages.
  • Some compounds of the present invention unexpectedly show higher Cmax values and exposures, and longer half-lives than compounds of formula (I) at the same dose and formulation. All the above PK results show that the compounds provided by the present invention have good PK properties and can be used as therapeutic drugs for metabolism-related diseases.

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Abstract

本发明公开了一种1，2，4-三嗪-3，5-二酮类(式I)化合物的盐型、晶型及其制备方法，其在治疗和或药物制备中的用途，所述的用途是治疗与甲状腺激素受体相关的疾病。

Description

一种1，2，4-三嗪-3，5-二酮类化合物的盐型、晶型及其制备方法
本申请要求于2021年03月15日提交中国专利局、申请号为202110274432.1、发明名称为“一种1，2，4-三嗪-3，5-二酮类化合物的盐型、晶型及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及一种1，2，4-三嗪-3，5-二酮类化合物的盐型、晶型及其制备方法。
背景技术
甲状腺激素在机体正常生长和发育以及维持代谢平衡中起到关键作用(Physiological Reviews 2001,81(3),1097-1126.)。甲状腺激素由甲状腺产生且以T4和T3两种不同形式分泌到循环系统(下丘脑/垂体/甲状腺系统)中，其中T4是甲状腺分泌的主要形式，而T3是生理上更活跃的形式。T4通过组织特异性脱碘酶被转化为T3，组织特异性脱碘酶存在于所有组织中，但主要存在于肝肾组织。
甲状腺激素的生理活性主要由甲状腺激素受体(THR)介导(Endocrine Reviews 1993,14,348-399.)。THR属于核受体超家族，它与担当配体-诱导的转录因子的类维生素A受体形成杂二聚体。THR具有配体结合结构域，DNA结合结构域和氨基末端结构域，并通过与DNA响应要素以及与各种核共-活化剂和共-阻遏剂的相互作用而调节基因表达。THR由位于人类染色体17和3上的不同基因表达α和β编码而来，通过对初级转录物进行选择性剪切后产生不同的蛋白亚型，每个基因产生两个亚型，即THRα1、THRα2、THRβ1、THRβ2。THRβ1和THRβ2由启动子差异表达得到，这两个亚型仅在氨基末端存在差异。THRα1和THRα2由前体mRNA的差异剪接而来，主要在羧基末端存在差异。THRα1、THRβ1和THRβ2可以结合甲状腺激素。研究表明，甲状腺激素受体亚型在特殊生理响应的贡献方面可以不同。THRβ1在肝脏中的调节促甲状腺激素和甲状腺激素方面起重要作用，THRβ2在调节甲状腺刺激激素方面起主 要作用。研究表明，THR的两种亚型α和β在肝脏中并存，其中与脂代谢有关的THRβ占70-80％，在心脏中，THRα与心跳增加和心输出量增加有关(Endocrinology 2001,142,544；J.Biol.Chem.1992,267,11794.)。
甲状腺激素在靶器官中新陈代谢并主要在胆汁中排泄，其在哺乳动物中的生理作用主要表现在生长和分化以及维持生命机能方面，如心率、血液中的胆固醇和甘油三酯浓度、以及全身代谢速度和体重等的控制和调节。从病理生理学角度，在甲状腺机能亢进症如Graves病中观察到心动过速、心律不齐、心脏衰竭，以及疲劳感、呼吸急促、骨骼肌减少和骨质酥松症等(Physiol.Rev.2001,81,1097；J.Steroid.Biochem.Mol.Biol.2001,76,31.)。
甲状腺激素本身的治疗用途受到与甲状腺机能亢进、特别是心血管毒性有关的不利副作用的限制。一种甲状腺激素类似物，如果可以避免甲状腺机能亢进和甲状腺功能减退的不良效果，同时保持甲状腺激素的有益效果，则可能应用于响应疾病的治疗，如代谢类疾病包括肥胖、高血脂症、高胆固醇血症、糖尿病和其它病症如肝脏脂肪变性和非酒精性脂肪性肝炎(NASH)、动脉粥样硬化、心血管疾病、甲状腺功能减退、甲状腺癌、甲状腺疾病等。
与本发明化合物结构不同的甲状腺激素类似物WO2007009913公开了一种哒嗪酮衍生物，尤其是其中的实施例8(化合物31，即MGL-3196)，作为具有THRβ选择性和肝脏组织选择性的甲状腺激素类似物，取得了良好的效果，可能用于治疗多种疾病，但MGL-3196仍存在活性不足，体内代谢快等问题。
Figure PCTCN2022080571-appb-000001
根据本发明提供的一种如式I所示哒嗪酮化合物作为甲状腺激素抑制剂，即2-(3,5-二氯-4-((5-异丙基-6-氧基-1,6-二氢吡啶-3-基)氧基)苯基)-(氟甲基)-1,2,4-三嗪-3,5(2H,4H)-二酮，进一步提供该化合物的盐型、晶型及其制备方法。但是式I化合物游离碱溶解度较差、游离碱的结晶度较差，为成药性带 来巨大的挑战。例如，结晶度差导致制剂处方工艺中流动性差难以制剂成型或者化学稳定性差等，溶解度低导致药物的生物利用度降低。作为公知的是作为活性化合物可通过结晶形成可药用稳定、流动性佳的晶型化合物，或者选择其适当盐的形式得以改善。然而为具体活性物质能否呈现稳定的晶态，选择适当的盐并不总是简单易行，因为不同的化合物与相同的成盐剂形成的盐的性质有很大不同。因此本发明目的提供式I化合物晶型及盐的形式，满足上述溶解度、处理性和稳定性的要求；进一步令人惊讶的发现，该化合物部分形成的加成盐与游离的式I化合物相比具有更好的小鼠体内药代动力学性质。
Figure PCTCN2022080571-appb-000002
发明内容
本发明一方面提供式(I)化合物的晶型A，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.30±0.20、14.02±0.20、24.66±0.20、25.22±0.20、28.58±0.20，
Figure PCTCN2022080571-appb-000003
在本发明的一些方案中，上述式(I)化合物晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.30±0.20、14.02±0.20、17.02±0.20、20.18±0.20、23.52±0.20、24.66±0.20、25.22±0.20、25.86±0.20、28.30±0.20、28.58±0.20。
在本发明的一些方案中，上述式(I)化合物晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.30±0.20、14.02±0.20、17.02±0.20、18.86±0.20、20.18±0.20、22.36±0.20、23.52±0.20、23.72±0.20、24.66±0.20、25.22±0.20、25.86±0.20、28.30±0.20、28.58±0.20、29.74±0.20、32.86±0.20。 本发明中X射线粉末衍射图谱所表述的2θ角由于设备检测存在误差等原因，通常采用±0.20表示偏差，进一步采用±0.10表示偏差，更进一步采用±0.05表示偏差，更进一步采用±0.02表示偏差，以上表述方式均代表本发明所要表述的X射线粉末衍射图谱2θ角具体数字，不改变本发明的本意，以下X射线粉末衍射图谱2θ角描述均以此意。
在本发明的一些方案中，上述式(I)化合物晶型A，具有与图1本质上相同的XRPD图谱。
本发明的一些方案中，上述式(I)化合物晶型A的XRPD图谱解析数据如表1所示：
表1.A晶型的XRPD图谱解析数据
Figure PCTCN2022080571-appb-000004
在本发明的一些方案中，上述式(I)化合物晶型A，其差示扫描量热曲 线在308.85℃处有一个最大吸热峰的峰值；在本发明的一些方案中，上述式(I)化合物晶型A的DSC图谱如图2所示。
在本发明的一些方案中，上述式(I)化合物晶型A，其热重分析曲线在120℃时失重达0.0494％，在250℃时失重为0.5069％。在本发明的一些方案中，上述式(I)化合物晶型A的TGA图谱如图3所示。
在本发明的一些方案中，上述晶型A的制备方法：称取式(I)化合物至反应瓶中，加入适量的冰醋酸，加热至澄清状态；然后缓慢降温至室温，有大量白色固体析出；该固体放置于反应瓶中，加入适量无水乙醇，加热至得到一个悬浊液；缓慢冷却至室温，固体分离后得到式(I)化合物晶型A。
本发明另一方面还提供了式(I)化合物的药学可接受的盐，所述药学可接受的盐选自：钠盐、钾盐、L-精氨酸盐、胆碱盐、葡甲胺盐、二乙胺盐和L-赖氨酸盐，优选钠盐、胆碱盐和L-赖氨酸盐，更优选钠盐和胆碱盐。
本发明进一步提供式(I)化合物的钠盐如式(II)所示,式(I)化合物对该盐的阳离子或阴离子的摩尔比例为1:1，
Figure PCTCN2022080571-appb-000005
本发明提供式(I)化合物的钠盐式(II)在其中一个实施例中的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.48±0.20、19.14±0.20、22.30±0.20、23.60±0.20、26.92±0.20；进一步本发明式(I)化合物的钠盐式(II)其中一个实施例中提供的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰10.48±0.20、11.28±0.20、17.26±0.20、19.14±0.20、22.30±0.20、23.60±0.20、25.26±0.20、26.92±0.20、28.28±0.20、28.66±0.20。
在本发明的一些方案中，上述式(I)化合物的钠盐式(II)的晶型，其X射线粉末衍射图谱，与图4本质上相同的XRPD图谱。
本发明的一些方案中，上述式(I)化合物的钠盐式(II)的晶型XRPD图谱解析数据如表2所示：
表2.式(I)化合物的钠盐式(II)的晶型的XRPD图谱解析数据
Figure PCTCN2022080571-appb-000006
在本发明的一些方案中，上述式(I)化合物的钠盐式(II)的晶型，其差示扫描量热曲线在326.25℃处有一个最大放热峰的峰值。在本发明的一些方案中，上述式(I)化合物的钠盐式(II)晶型的DSC图谱如图5所示。
在本发明的一些方案中，上述式(I)化合物的钠盐式(II)的晶型，其热重分析曲线在120℃时失重达0.6243％。在本发明的一些方案中，上述晶型的TGA图谱如图6所示。
在本发明的一些方案中，上述式(I)化合物的钠盐式(II)制备方法：将式(I)化合物至反应瓶中，加入有机溶剂中，室温下搅拌成混悬状态。然后将Na的碱盐水溶液按摩尔比1:1-1.5缓慢滴加到反应液中，在室温下磁力搅拌，析出固体收集固体，得到式(I)化合物的钠盐式(II)。
本发明进一步提供式(I)化合物的L-赖氨酸盐如式(III)所示,式(I)化合物对该盐的阳离子或阴离子的摩尔比例为1:1，
Figure PCTCN2022080571-appb-000007
本发明提供式(I)化合物的L-赖氨酸盐式(III)其中一个实施例中的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.86±0.20、16.32±0.20、22.62±0.20、25.00±0.20、25.80±0.20；进一步本发明(I)化合物的L-赖氨酸盐式(III)其中一个实施例中提供的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:6.71±0.20、8.86±0.20、10.98±0.20、13.82±0.20、16.32±0.20、18.92±0.20、20.72、22.62±0.20、25.00±0.20、25.80±0.20。
在本发明的一些方案中，上述式(I)化合物的L-赖氨酸盐式(III)的晶型，其X射线粉末衍射图谱，与图7本质上相同的XRPD图谱。
本发明的一些方案中，上述式(I)化合物的L-赖氨酸盐式(III)晶型的XRPD图谱解析数据如表3所示：
表3.式(I)化合物的L-赖氨酸盐式(III)化合物晶型的XRPD图谱解析数据
Figure PCTCN2022080571-appb-000008
在本发明的一些方案中，上述式(I)化合物的L-赖氨酸盐式(III)的晶型，其差示扫描量热曲线在244.18℃处有一个最大吸热峰的峰值，在252.63℃处有一个放热峰的峰值。在本发明的一些方案中，上述晶型的DSC图谱如图8所示。
在本发明的一些方案中，上述式(I)化合物的L-赖氨酸盐式(III)的晶型，其热重分析曲线在120℃时失重达0.5199％。在本发明的一些方案中，上述晶型的TGA图谱如图9所示。
在本发明的一些方案中，上述式(I)化合物的L-赖氨酸盐式(III)制备方法：将式(I)化合物至反应瓶中，加入有机溶剂中，室温下搅拌成混悬状态。然后将L-赖氨酸(L-Lysine)水溶液按摩尔比1:1-1.5缓慢滴加到反应液中，在室温下磁力搅拌，析出固体收集固体，得到式(I)化合物的L-赖氨酸盐式(III)。
本发明进一步提供式(I)化合物的胆碱盐如式(IV)所示,式(I)化合物对该盐的阳离子或阴离子的比例可为1:1，
Figure PCTCN2022080571-appb-000009
本发明提供式(I)化合物的胆碱盐式(IV)其中一个实施例中的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：15.46±0.20、19.02±0.20、19.60±0.20、21.68±0.20、23.64±0.20；进一步本发明式(I)化合物的的胆碱盐式(IV)其中一个实施例中提供的晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:7.78±0.20、15.46±0.20±0.20、18.00±0.20、19.02±0.20、19.60±0.20、21.68±0.20、23.64±0.20、24.02±0.20、25.76±0.20、29.16±0.20。
在本发明的一些方案中，上述式(I)化合物的胆碱盐式(IV)的晶型其X射线粉末衍射图谱，与图10本质上相同的XRPD图谱。
本发明的一些方案中，上述式(I)化合物的胆碱盐式(IV)的晶型的XRPD图谱解析数据如表4所示：
表4.式(I)化合物的胆碱盐式(IV)晶型的XRPD图谱解析数据
Figure PCTCN2022080571-appb-000010
Figure PCTCN2022080571-appb-000011
在本发明的一些方案中，上述式(I)化合物的胆碱盐式(IV)的晶型，其差示扫描量热曲线在202.26℃处有一个最大吸热峰的峰值。在本发明的一些方案中，上述晶型的DSC图谱如图11所示。
在本发明的一些方案中，上述式(I)化合物的胆碱盐式(IV)的晶型，其热重分析曲线在120℃时失重达0.0128％。在本发明的一些方案中，上述晶型的TGA图谱如图12所示。
在本发明的一些方案中，上述式(I)化合物的胆碱盐式(IV)制备方法：将式(I)化合物至反应瓶中，加入有机溶剂中，室温下搅拌成混悬状态。然后将胆碱(Choline)水溶液按摩尔比1:1-1.5缓慢滴加到反应液中，在室温下磁力搅拌，析出固体收集固体，得到式(I)化合物的胆碱盐式(IV)。
在一个实施方案中，本发明上述所提供的式(I)化合物的盐及其晶型在治疗和或药物制备中的用途，所述的用途是治疗与甲状腺激素受体相关的疾病。
在一个实施方案中，本发明上述所提供的式(I)化合物的盐及其晶型的药物组合物。
在一个实施方案中，本发明提供了治疗方法，该方法包括向需要上述所提供的式(I)化合物的盐及其晶型的患者给药有效量的上述所提供的式(I)化合物的盐及其晶型。
本发明有益效果如下：已经令人惊讶的发现，游离碱晶型具有更好的稳定性、晶型稳定性，有助于制成药物相应的制剂剂型；该式(I)化合物的加成盐与 游离碱相比具有更好的小鼠体内药代动力学性质，其中最优的为胆碱盐。
附图说明
图1为式(I)化合物晶型A的Cu-Kα辐射的XRPD谱图；
图2为式(I)化合物晶型A的DSC谱图；
图3为式(I)化合物晶型A的TGA谱图；
图4为式(I)化合物的钠盐式(II)晶型的Cu-Kα辐射的XRPD谱图；
图5为式(I)化合物的钠盐式(II)晶型的DSC谱图；
图6为式(I)化合物的钠盐式(II)晶型的TGA谱图；
图7为式(I)化合物的L-赖氨酸盐式(III)晶型的Cu-Kα辐射的XRPD谱图；
图8为式(I)化合物的L-赖氨酸盐式(III)晶型的DSC谱图；
图9为式(I)化合物的L-赖氨酸盐式(III)晶型的TGA谱图；
图10为式(I)化合物的胆碱盐式(IV)晶型的Cu-Kα辐射的XRPD谱图；
图11为式(I)化合物的胆碱盐式(IV)晶型的DSC谱图；
图12为式(I)化合物的胆碱盐式(IV)晶型的TGA谱图；
图13为式(I)化合物的L-赖氨酸盐式(III)的H-NMR结果。
具体实施方式
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须 适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022080571-appb-000012
软件命名，市售化合物采用供应商目录名称,式(I)化合物游离碱描述均表示式(I)化合物本身未成任何阳离子或者阴离子的盐。
实验试剂
试剂 级别 生产厂家 批号
水 Purified SUNDIA N/A
甲醇(MeOH) AR 润捷化学 20200618JN
乙醇(EtOH) AR 润捷化学 20200720JN
异丙醇(IPA) AR 润捷化学 20170101
丙酮(Acetone) AR 润捷化学 20200612JN
乙腈(ACN) HPLC FULLTIME 6308BW07
丁酮(MEK) AR 润捷化学 20190210
乙酸乙酯(EA) AR 润捷化学 20190410JN
甲基叔丁基醚(MTBE) GC 阿拉丁 B1913007
四氢呋喃(THF) HPLC 阿拉丁 D2021037
甲苯 AR 润捷化学 20181110JN
正庚烷 AR GENERAL-REAGENT P1521685
二氯甲烷(DCM) AR 润捷化学 20190501JN
环己烷 AR 润捷化学 20191010JN
2-甲基四氢呋喃 AR GENERAL-REAGENT P1459120
二甲亚砜(DMSO) HPLC HiPure Chem 16190326
氢氧化钠(NaOH) AR 润捷化学 20201026JN
氢氧化钾(KOH) AR 润捷化学 20170901JN
氢氧化镁 试剂级 Damas-beta P1430920
氢氧化钙 AR 阿拉丁 12024035
L-精氨酸 BR 阿拉丁 KYFEM04
L-赖氨酸 BR 阿拉丁 G2027041
胆碱 N/A TGI AWYHH-ET
二乙胺 GC 阿拉丁 K1704009
N-甲基-D-葡糖胺 试剂级 阿拉丁 F1928087
无水氯化镁 N/A lnnochem KYFFT14
无水氯化钙 AR 润捷化学 20181010
甲醇镁 试剂级 阿拉丁 G1925082
实验设备
设备名称 生产厂家 型号
分析天平 赛特里斯 CP225D
X-射线粉末衍射仪(XRPD) 日本岛津 XRD-6000
差示扫描量热仪(DSC) 梅特勒 DSC3
热重分析仪(TGA) 铂金埃尔默 Pyris 1TGA
动态水分吸附仪(DVS) SMS DVS intrinsic
偏振光显微镜(PLM) 上海长方光学仪器有限公司 XPV-203E
磁力搅拌器 上海司乐仪器有限公司 B13-3
超声波清洗仪 上海科导 SK8300BT
高速离心机 可成仪器 H4-20K
氮气吹干仪 N/A ND100-2
试验仪器参数
X-射线粉末衍射(XRPD)
设备为Shimadzu XRD-6000，按以下参数扫描样品：
射线源为Cu～Kα靶
Figure PCTCN2022080571-appb-000013
光管的最小操作电压与电流分别为40kV和30mA，
样品扫描范围的2-Theta值从5°到50°或者(2°到50°)。扫描速度为5deg/min。
热重分析(TGA)
称取大约5mg样品于坩埚中，氮气保护，从30℃升温至400℃，升温速率为20℃/min，400℃保持1min。
差示扫描量热仪(DSC)
称取大约1～5mg粉末样品放置在一个封闭的铝坩埚中，坩埚盖上扎一针孔。氮气保护，从30℃升温到350℃进行差示热量扫描，350℃保持1min。升温速率为20℃/min。
偏光显微镜(PLM)
样品分散在介质中(硅油)，使用10X目镜、10X物镜观察样品，用照相机计算机系统记录图像。
下面结合说明书附图对本发明实施例作进一步详细描述,但具体的实施方式并不是对本发明的内容所做的限制。
实施例1
2-(3,5-二氯-4-((5-异丙基-6-氧基-1,6-二氢吡啶-3-基)氧基)苯基)-(氟甲基)-1,2,4-三嗪-3,5(2H,4H)-二酮(式I)化合物的制备
Figure PCTCN2022080571-appb-000014
第一步
2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-羧酸1b
将2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2，4-三嗪-6-氰1a(300mg，0.69mmol,合成方法见WO2014043706A1)溶于10mL冰醋酸中，加入浓盐酸(2mL)，加热至120℃反应5小时。反应完毕后反应液冷却至室温，加入20mL水稀释搅拌并过滤，烘干后得到2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2，4-三嗪-6-羧酸1b(260mg，淡黄色固体)，产率：84％。
1H NMR(400MHz,DMSO-d 6)δ12.71(s,1H),12.21(s,1H),7.82(s,2H),7.45(s,1H),3.21(m,1H),1.19(d,J＝6.4Hz,6H)。MS m/z(ESI)：453.8[M+1] +。
第二步
甲基2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-羧酸酯1c
将2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2，4-三嗪-6-羧酸1b(200mg，0.44mmol)溶于20mL甲醇中，冰浴下缓慢加入氯化亚砜(2mL)，将反应液加热至100℃反应5小时。反应完毕后，将反应液减压浓缩，残留固体用石油醚：乙酸乙酯(10:1)打浆过滤，烘干后得到甲基2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-羧酸酯1c(200mg，淡黄色固体)，产率：97％。MS m/z(ESI)：466.2[M-1] -。
第三步
2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧基)苯基)-(羟甲基)-1,2,4-三嗪-3,5(2H,4H)-二酮1d
将甲基2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧基)苯基)-3,5-二氧-2,3,4,5-四氢-1,2,4-三嗪-6-羧酸酯1c(200mg，0.43mmol)溶于20mL四氢呋喃中，室温下加入硼氢化钠(82mg，2.15mmol)，然后缓慢滴加甲醇。反应完毕后，加入20mL水并用3M稀盐酸调到pH＝6,用乙酸乙酯(30mL×3)萃取，合并有机相，用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析法(洗脱剂：石油醚：乙酸乙酯＝5:1～0:1)纯化，得到2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧基)苯基)-(羟甲基)-1,2,4三嗪-3,5(2H,4H)-二酮1d(150mg，白色固体)，产率：79％。
1H NMR(400MHz,DMSO-d 6)δ12.49(s,1H),12.25(s,1H),7.86(s,2H),7.45(s,1H),5.33(t,J＝6.4Hz,1H),4.40(d,J＝6.0Hz,2H),3.21(m,1H),1.19(d,J＝6.4Hz,6H)。MS m/z(ESI)：438.2[M-1] -。
第四步
2-(3,5-二氯-4-((5-异丙基-6-氧基-1,6-二氢吡啶-3-基)氧基)苯基)-(氟甲基)-1,2,4-三嗪-3,5(2H,4H)-二酮(式I)化合物
将甲基2-(3,5-二氯-4-((5-异丙基-6-氧-1,6-二氢哒嗪-3-基)氧基)苯基)-(羟甲基)-1,2,4-三嗪-3,5(2H,4H)-二酮1d(100mg，0.23mmol)溶于20mL二氯甲烷中，冰浴下加入DAST(5滴)，反应液在该温度反应30分钟。反应完毕后，将反应液加入20mL冰水中,用二氯甲烷(20mL×3)萃取，合并有机相，用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用制备色谱纯化，得到2-(3,5-二氯-4-((5-异丙基-6-氧基-1,6-二氢吡啶-3-基)氧基)苯基)-(氟甲基)-1,2,4-三嗪-3,5(2H,4H)-二酮(式I)(45mg)，产率：45％。 1H NMR(400MHz,DMSO-d 6)δ12.48(s,1H),12.21(s,1H),7.81(s,2H),7.43(s,1H),5.29(d,J＝48.0Hz,1H),3.21(m,1H),1.19(d,J＝6.4Hz,6H)。 19F NMR(400MHz,DMSO-d 6)δ-219.9ppm。MS m/z(ESI)：442.2[M+1] +。
实施例2
式(I)化合物晶型A的制备
称使用实施例1中方法获得的7.0g的式(I)化合物游离碱至250mL烧瓶中，加入150mL的冰醋酸，加热至120℃至澄清状态。然后缓慢降温至室温，该过程持续约2h，有大量白色固体析出。固体分离后在50℃条件下减压真空干燥约2h，得到白色固体。该固体放置于250mL烧瓶中，加入50mL无水乙醇，加热至90℃保持1h，得到一个悬浊液。缓慢冷却至室温，固体分离后在50℃条件下减压真空干燥约2h，得到式(I)化合物晶型A。
本实施例中其获得的晶型A的Cu-Kα辐射的XRPD谱图、DSC谱图、TGA谱图分别如图1、2、3所示。
实施例3
式(I)化合物的钠盐式(II)的制备
称使用实施例1中方法获得的 502.95mg的式(I)化合物至40mL小瓶中，加入8mL的异丙醇，室温下搅拌成混悬状态。然后将NaOH水溶液(2N水溶液)按摩尔比1:1.05(600μL)缓慢滴加到反应液中，大致溶清，部分粘壁，约0.5h大量析出，最后将样品在室温下磁力搅拌过夜(约20h)，采用离心法(12000rpm,离心5min)收集固体，50℃条件下减压真空干燥过夜约20h， 得到式(I)化合物的钠盐式(II)。
该实施例式(I)化合物的钠盐式(II)所获得晶型的Cu-Kα辐射的XRPD谱图、DSC谱图、TGA谱图分别如图4、5、6所示。
实施例4
式(I)化合物的L-赖氨酸盐式(III)的制备
称使用实施例1中方法获得的509.65mg的式(I)化合物至40mL小瓶中，加入10mL的异丙醇，室温下搅拌成混悬状态。然后将L-赖氨酸(L-Lysine)水溶液(2N in water)按摩尔比1:1.05(607μL)缓慢滴加到反应液中，呈乳状，最后将样品在室温下磁力搅拌过夜(约20h)，采用离心法(12000rpm,离心5min)收集固体；50℃条件下减压真空干燥过夜约20h，得到式(I)化合物的L-赖氨酸盐式(III)。
该实施例式(I)化合物的L-赖氨酸盐式(III)获得晶型的Cu-Kα辐射的XRPD谱图、DSC谱图、TGA谱图分别如图7、8、9所示。
实施例5
式(I)化合物的胆碱盐式(IV)的制备
称使用实施例1中方法获得的501.02mg的式(I)化合物至40mL小瓶中，加入10mL的异丙醇，室温下搅拌成混悬状态。然后将胆碱(Choline)水溶液(48％in water)按摩尔比1:1.05(302μL)缓慢滴加到反应液中，澄清，最后将样品在室温下磁力搅拌过夜析出(约20h)，采用离心法(12000rpm,离心5min)收集固体；50℃条件下减压真空干燥过夜约20h，得到式(IV)化合物晶型。
该实施例式(I)化合物的胆碱盐获得晶型的Cu-Kα辐射的XRPD谱图、DSC谱图、TGA谱图分别如图10、11、12所示。
实施例6
式(I)化合物的镁盐的制备
称使用实施例1中方法获得的50.0mg的式(I)化合物至10mL小瓶中， 加入2mL的丙酮，室温下搅拌成混悬状态。然后将氯化镁水溶液按摩尔比1:1.05缓慢滴加到反应液中，得到一个混悬液。该混悬液在室温下磁力搅拌过夜(约20h)，采用离心法(12000rpm,离心5min)收集固体；50℃条件下减压真空干燥过夜约20h，得到固体。经XRPD谱图分析，没有形成相应理想的盐。
实施例7
式(I)化合物的钙盐的制备
称使用实施例1中方法获得的50.0mg的式(I)化合物至10mL小瓶中，加入2mL的丙酮，室温下搅拌成混悬状态。然后将氯化钙水溶液按摩尔比1:1.05缓慢滴加到反应液中，得到一个混悬液。该混悬液在室温下磁力搅拌过夜(约20h)，采用离心法(12000rpm,离心5min)收集固体；50℃条件下减压真空干燥过夜约20h，得到固体。经XRPD谱图分析，没有形成相应理想的盐。
实施例8
按照实施例2-7同样类似的方法，采用相应的阳离子或者阴离子盐完成制备L-精氨酸、葡甲胺、二乙胺盐的制备。
实施例9 THRβ结合实验
实验方法：化合物对THRβ的激动作用的活体外分析是采用时间分辨荧光共振能量转移共激活肽的招募实验进行的。该实验采用Eu-anti-GST抗体,biotin-SRC2-2共激活肽,streptavidin-d2,RXRα和带GST标签的THRβ-LBD。Eu-anti-GST抗体通过结合到GST标签来间接标记THRβ-LBD。Streptavidin-d2通过结合到biotin标签来间接标记SRC2-2共激活肽。在RXRα存在时，THRβ-LBD可以与其形成异质二聚体THRβ-LBD/RXRα。激动剂与THRβ-LBD/RXRα结合并导致THRβ-LBD构象的变化，从而增加了异质二聚体对SRC2-2共激活肽的招募能力。同时，由此引起的d2-labeled SRC2-2共激活肽和Eu-anti-GST抗体的距离减小，增加了THR-FRET信号。根据不同浓 度的化合物对THRβ活性的影响，可以评估化合物的激动能力。
详细程序如下。
用DMSO制备100X参比化合物或化合物，并进行1:3等比稀释。
用1X反应缓冲液将100X梯度稀释参比化合物或化合物稀释为4X，并加入实验板中。
用1X反应缓冲液制备4X THRβ-LBD,4X RXRα的混合溶液，并加入实验板中。
用1X反应缓冲液制备2X biotin-SRC2-2,2X Eu-anti-GST,2X streptavidin-d2的混合溶液，并加入实验板中。
1000rpm离心1min并在室温及避光条件下孵育4小时。
在EnVision 2104板读取器上读取665nm和 615nm荧光信号值，并计算Ratio 665nm/615nm。
实验结果：见表5
表5：THRβ结合实验测试结果
实施例编号 EC50(nM) Emax(％)
式I化合物 5 92.76
*对照化合物1 0.6 97.3
*对照化合物2 204 105.4
*对照化合物3 663 125
*对照化合物1为T3；对照化合物2为WO2007009913实施例8(化合物31)；*对照化合物3为WO2020239076Al实施例4相应化合物。
实施例10 THRα结合实验
实验方法：化合物对THRα的激动作用的活体外分析采用实施例9中THRβ结合实验的类似方法，区别是用THRα代替THRβ。
实验结果：见表6
表6：THRα结合实验测试结果
实施例编号 EC50(nM) Emax(％)
式I化合物 190 106.6
*对照化合物1 0.2 91.4
*对照化合物2 2690 111.4
*对照化合物1为T3，对照化合物2为WO2007009913实施例8(化合物 31)。
实施例11
体外肝微粒体稳定性实验
实验方法：
(一)溶液配制
将受试物与阳性对照物维拉帕米分别用DMSO溶解至10mM作为储备液，将上述10mM的储备液用70％乙腈水溶液稀释至0.25mM浓度。
配制最终含有浓度分别为6.5mM NADP，16.5mM G-6-P，3U/mL G-6-PDH和3.3mM氯化镁的NADPH再生系统。
终止液为含有甲苯磺丁脲和普萘洛尔(均为内标)的乙腈溶液。
磷酸盐缓冲液为100mM含3.3mM MgCl 2的K 3PO 4(pH＝7.4)缓冲液。
肝微粒体孵育体系在100mM磷酸盐缓冲液中，包含0.2mg/mL肝微粒体蛋白和1μM受试物/阳性对照
(二)孵育过程
从孵育体系中取80μL混合液，加入400μL终止液沉淀蛋白，涡旋后加入20μL NADPH再生系统作为0min样品点。
在剩余520μL蛋白药物混合液中加入NADPH再生系统130μL，混匀，开始孵育。最终孵育体系为650μL，包含0.2mg/mL肝微粒体蛋白、1μM受试物/阳性对照、1.3mM NADP,3.3mM G-6-P,0.6U/mL G-6-PDH。
混合体系在37℃水浴中缓慢振摇孵育，分别在5，10，30，60min，各取100μL孵育液到每孔装有400μL终止液的新96孔板中，混匀，沉淀蛋白(4000×g，4℃条件下离心15分钟)。
取上清液100μL，按照1:2的比例用水稀释后用LC-MS/MS方法进行样品分析。
实验结果：见表7.
表7：体外肝微粒体稳定性实验结果
Figure PCTCN2022080571-appb-000015
Figure PCTCN2022080571-appb-000016
实施例12
药代动力学评价：
以小鼠为受试动物，测试了小鼠灌胃给予式(I)-式(IV)化合物后不同时刻血浆中药物浓度。研究本发明化合物在小鼠体内药物代谢动力学行为，评价其药物代谢特征。每组实施例选用9只体重相近的健康成年雄性ICR小鼠，口服给予剂量为15.0mg/kg(或等效为15.0mg/kg)，单次给药，分别于给药前及给药1h,2h,4h,6h,8h,12h,24h,48h采集全血。建立LC/MS/MS法测定血浆样品中的原形药物浓度。采用WinNonlin 6.3NCA模型计算主要药动学参数，具体见下表8。
实验方法：
实验药品:上述实施例获得的式(I)化合物、式(I)化合物的钠盐式(II)、式(I)化合物的L-赖氨酸盐式(III)和式(I)化合物的胆碱盐式(IV)。
实验动物：健康成年雄性ICR小鼠9只，平均分成3组，每组3只，上海西普尔-必凯实验动物有限公司，动物合格证号：SCXK(沪)2018-0006 2018 0006 010467。
药物配置：分别精密称取一定量式(I)-式(IV)化合物，置于15ml样品管中，加入吐温80 5uL使润湿，再加入2％羟丙基纤维素(Klucel LF)溶液4mL，超声并涡旋混匀，获得均匀的混悬液。临用前新鲜配制。
给药：ICR小鼠禁食过夜后灌胃给药，给药剂量为15.0mg/kg(或等效为15.0mg/kg)。
操作：小鼠灌胃给药式(I)-式(IV)化合物，于给药前及给药后1h,2h,4h,6h,8h,12h,24h,48h采集全血，经肝素钠抗凝后于4℃离心5min分离血浆，于-80℃保存待测，给药后4小时进食。
测定不同浓度药物灌胃给药后小鼠血浆中待测化合物的含量:分别取式(I)-式(IV)化合物给药后各时刻待测小鼠血浆12.5uL，两两混合，加入内标溶液100uL，甲醇125uL，涡旋混合2min，4℃13000rpm离心10min，取上清液用于LC-MS/MS分析。
药代动力学参数结果见表8。
表8:小鼠药物代谢数据
Figure PCTCN2022080571-appb-000017
结论:本发明(式I)化合物的钠盐式(II)、L-赖氨酸盐式(III)和胆碱盐式(IV)化合物药代吸收良好，具有明显的药代动力学优势。同式(I)化合物相比，在同等剂量和制剂情况下，本发明的有些化合物出乎意料的显示了更高的Cmax值和暴露量，以及更长的半衰期。所有以上PK结果表明，本发明提供的化合物有良好的PK性质可以作为代谢相关疾病的治疗药物。
显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。

Claims (18)

  1. 一种式(I)化合物的晶型A，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.30±0.20、14.02±0.20、24.66±0.20、25.22±0.20、28.58±0.20，
    Figure PCTCN2022080571-appb-100001
  2. 根据权利要求1所述的晶型A，其特征在于其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.30±0.20、14.02±0.20、17.02±0.20、20.18±0.20、23.52±0.20、24.66±0.20、25.22±0.20、25.86±0.20、28.30±0.20、28.58±0.20。
  3. 根据权利要求2所述的晶型A，具有与图1本质上相同的XRPD图谱。
  4. 根据权利要求1所述的晶型A，其特征在于其DSC图谱如图2所示。
  5. 一种式(I)化合物药学可接受的盐，其特征在于所述药学可接受的盐选自：钠盐、钾盐、L-精氨酸盐、胆碱盐、葡甲胺盐、二乙胺盐和L-赖氨酸盐，
    Figure PCTCN2022080571-appb-100002
  6. 根据权利要求5所述的盐，其特征在于式(I)化合物的钠盐如式(II)所示,式(I)化合物对该盐的阳离子或阴离子的摩尔比例为1:1，
    Figure PCTCN2022080571-appb-100003
  7. 根据权利要求6所述的盐，其特征在于式(I)化合物的钠盐式(II)的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.48±0.20、19.14± 0.20、22.30±0.20、23.60±0.20、26.92±0.20。
  8. 根据权利要求7所述的盐，其特征在于式(I)化合物的钠盐式(II)的X射线粉末衍射图谱，具有与图4本质上相同的XRPD图谱。
  9. 根据权利要求6所述的盐，其特征在于式(I)化合物的钠盐式(II)的DSC图谱如图5所示。
  10. 根据权利要求5所述的盐，其特征在于式(I)化合物的L-赖氨酸盐如式(III)所示,式(I)化合物对该盐的阳离子或阴离子的摩尔比例为1:1，
    Figure PCTCN2022080571-appb-100004
  11. 根据权利要求10所述的盐，其特征在于式(I)化合物的L-赖氨酸盐式(III)的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.86±0.20、16.32±0.20、22.62±0.20、25.00±0.20、25.80±0.20。
  12. 根据权利要求11所述的盐，其特征在于式(I)化合物的L-赖氨酸盐式(III)的X射线粉末衍射图谱，具有与图7本质上相同的XRPD图谱。
  13. 根据权利要求10所述的盐，其特征在于式(I)化合物的L-赖氨酸盐式(III)的DSC图谱如图8所示。
  14. 根据权利要求5所述的盐，其特征在于式(I)化合物的胆碱盐如式(IV)所示,式(I)化合物对该盐的阳离子或阴离子的比例可为1:1，
    Figure PCTCN2022080571-appb-100005
  15. 根据权利要求14所述的盐，其特征在于本发明提供式(I)化合物的胆碱盐式(IV)的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：15.46±0.20、19.02±0.20、19.60±0.20、21.68±0.20、23.64±0.20。
  16. 根据权利要求15所述的盐，其特征在于式(I)化合物的胆碱盐式(IV)的X射线粉末衍射图谱，具有与图10本质上相同的XRPD图谱。
  17. 根据权利要求14所述的盐，其特征在于式(I)化合物的胆碱盐式(IV)的DSC图谱如图11所示。
  18. 根据权利要求1-17任意的盐及其晶型在治疗和或制备药物中的用途，所述的用途是治疗与甲状腺激素受体相关的疾病。
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