WO2020238740A1 - 一种芳香族化合物的固体形式及其制备方法 - Google Patents

一种芳香族化合物的固体形式及其制备方法 Download PDF

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WO2020238740A1
WO2020238740A1 PCT/CN2020/091471 CN2020091471W WO2020238740A1 WO 2020238740 A1 WO2020238740 A1 WO 2020238740A1 CN 2020091471 W CN2020091471 W CN 2020091471W WO 2020238740 A1 WO2020238740 A1 WO 2020238740A1
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compound
formula
crystal
angles
diffraction
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PCT/CN2020/091471
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English (en)
French (fr)
Inventor
易仕东
王天明
吴转
李龙
杨成喜
宋智泉
龙冬
田强
宋宏梅
薛彤彤
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to US17/593,773 priority Critical patent/US20220220075A1/en
Priority to KR1020217030702A priority patent/KR20220012222A/ko
Priority to EP20815328.8A priority patent/EP3978476A4/en
Priority to CN202080024203.8A priority patent/CN113631542B/zh
Publication of WO2020238740A1 publication Critical patent/WO2020238740A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • 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

  • This application relates to (E)-2-(4-(3-(2-methoxyquinolin-3-yl)-3-oxo-1-propen-1-yl)-2,6-dimethyl (Phenoxy)-2-methylpropionic acid (hereinafter referred to as the "compound of formula (I)”) crystal or amorphous form and preparation method, pharmaceutical composition comprising it and its preparation for prevention or treatment Use in medicine for diseases or disorders such as non-alcoholic fatty liver disease (NAFLD).
  • NAFLD non-alcoholic fatty liver disease
  • Non-alcoholic fatty liver disease is a type of clinical pathological syndrome with liver histological changes similar to alcoholic liver disease, but without a history of excessive drinking, including simple fatty liver (SFL), non-alcoholic steatohepatitis (NASH) ) And related liver cirrhosis, in which NASH is an important intermediate stage of NAFLD progression.
  • SFL simple fatty liver
  • NASH non-alcoholic steatohepatitis
  • NASH non-alcoholic steatohepatitis
  • NASH non-alcoholic steatohepatitis
  • Non-alcoholic fatty liver disease is a new challenge in the contemporary medical field, and the development of drugs to treat non-alcoholic fatty liver-related diseases has important clinical significance. Therefore, there is an urgent need for effective and safe drugs to treat non-alcoholic fatty liver related diseases.
  • phenoxyacetic acid compounds with novel structures which have good performance as peroxisome proliferator-activated receptor (PPAR) agonists.
  • PPAR peroxisome proliferator-activated receptor
  • the pharmacokinetics and pharmacodynamic properties of in vivo and in vitro have the potential to prevent or treat diseases or disorders such as non-alcoholic fatty liver disease (NAFLD). Therefore, further research and development of such compounds and obtaining their crystalline or amorphous forms suitable for preparing pharmaceutical preparations are urgently needed in the field of medicine.
  • NAFLD non-alcoholic fatty liver disease
  • One aspect of the application provides the compound of formula (I) (E)-2-(4-(3-(2-methoxyquinolin-3-yl)-3-oxo-1-propene- 1-yl)-2,6-dimethylphenoxy)-2-methylpropionic acid crystals, especially crystals A, B, C, D, E and amorphous forms of the compound of formula (I).
  • Another aspect of the present application provides a method for preparing crystals A, B, C, D, E and amorphous forms of the compound of formula (I), which comprises combining any solid form of the compound of formula (I) with an inorganic acid or organic The acid reacts to precipitate a solid, and then the precipitated solid is separated and dried.
  • the solid precipitation method includes, but is not limited to, gas-solid infiltration method, anti-solvent crystallization method, room temperature suspension stirring method, high temperature suspension stirring method, gas-liquid infiltration method, room temperature slow volatilization method, slow cooling method, etc.
  • compositions which comprises the crystal of the compound of formula (I), especially the crystal A, B, C, D, E, amorphous form or any combination of the compound of formula (I), And one or more pharmaceutically acceptable carriers.
  • Another aspect of the present application provides a method for treating a disease or disorder associated with peroxisome proliferator activated receptor (PPAR) in an individual, which comprises administering to an individual in need thereof a therapeutically effective amount of the above formula (I)
  • PPAR peroxisome proliferator activated receptor
  • the crystals of the compound especially the crystals A, B, C, D, E and amorphous forms of the compound of formula (I), or any combination thereof.
  • crystals of the compound of formula (I) especially crystals A, B, C, D, E, and amorphous forms of the compound of formula (I) or any combination thereof, which are used to treat individual A disease or condition associated with peroxisome proliferator activated receptor (PPAR).
  • PPAR peroxisome proliferator activated receptor
  • Another aspect of the present application provides crystals of the compound of formula (I), especially crystals A, B, C, D, E, and amorphous forms of the compound of formula (I) or any combination thereof in preparation for treating an individual Use in diseases or disorders related to peroxisome proliferator activated receptor (PPAR).
  • PPAR peroxisome proliferator activated receptor
  • crystals of the compound of formula (I) of the present application have one or more of the following advantageous properties:
  • Excellent physical and chemical stability including but not limited to light stability, thermal stability, high humidity resistance, etc.
  • good light stability can ensure the reliability of the crystals during storage and transportation, thereby ensuring the safety of the preparation; so that the crystals do not need to be specially packaged to prevent the influence of light, thereby reducing costs; The crystals will not be degraded due to the influence of light, thereby improving the safety of the preparation and the effectiveness after long-term storage; and the patients taking the crystals will not worry about photosensitivity reaction of the preparation due to exposure to sunlight.
  • Good thermal stability enables the crystal to remain stable for a long time and is suitable for standard preparation production processes.
  • the good physical and chemical stability makes the crystals easy to prepare and more suitable for the preparation of formulations.
  • Figure 16 Amorphous XRPD pattern of the compound of formula (I).
  • solid form as used in the present application includes all solid forms of the compound of formula (I) and the salt of the compound of formula (I), such as crystalline form or amorphous form.
  • amorphous refers to any solid substance that has no order in three dimensions.
  • amorphous solids can be characterized by known techniques including XRPD crystallography, solid state nuclear magnetic resonance (ssNMR) spectroscopy, differential scanning calorimetry (DSC), or some combination of these techniques.
  • ssNMR solid state nuclear magnetic resonance
  • DSC differential scanning calorimetry
  • an amorphous solid produces a diffuse XRPD pattern, which usually includes one or two broad peaks (ie, a peak with a base width of about 5° 2 ⁇ or greater).
  • crystalline form or "crystalline” as used herein refers to any solid substance exhibiting a three-dimensional order, as opposed to an amorphous solid substance, which produces a characteristic XRPD pattern with well-defined peaks.
  • X-ray powder diffraction pattern refers to an experimentally observed diffraction pattern or a parameter derived from it.
  • the XRPD pattern is usually characterized by peak position (abscissa) and/or peak intensity (ordinate).
  • 2 ⁇ refers to a peak position expressed in degrees based on an experimental setting of an X-ray diffraction experiment, and is usually a unit of abscissa in a diffraction pattern. If the reflection is diffracted when the incident beam forms an angle ⁇ with a certain lattice plane, the experimental setup needs to record the reflected beam at an angle of 2 ⁇ . It should be understood that the specific 2 ⁇ value of the specific crystal form mentioned herein is intended to mean the 2 ⁇ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein.
  • thermogravimetric analysis (TGA) profile refers to a curve recorded by a thermogravimetric analyzer.
  • DSC differential scanning calorimetry
  • the term "substantially the same" for X-ray diffraction peak positions means that representative peak positions and intensity changes are taken into consideration. For example, those skilled in the art will understand that the peak position (2 ⁇ ) will show some variation, usually as much as 0.1-0.2 degrees, and the instrument used to measure diffraction will also show some variation. In addition, those skilled in the art will understand that the relative peak intensity will show changes between instruments and changes due to the degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be regarded as merely It is a qualitative measurement. Similarly, as used herein, "substantially the same” for the DSC profile and the TGA profile is also intended to cover the changes known to those skilled in the art related to these analysis techniques. .
  • good solvent means a solvent used to dissolve the (I) compound or (I) compound salt of the present application.
  • anti-solvent means a solvent for reducing the solubility of a substance to be crystallized in a good solvent.
  • anti-solvent crystallization method means a method of using a good solvent in combination with an anti-solvent, thereby reducing the solubility of the substance to be crystallized in the good solvent.
  • the anti-solvent crystallization method can be divided into anti-solvent addition method and anti-anti-solvent addition method.
  • the anti-solvent addition method is to dissolve the material to be crystallized in a good solvent, and then add an anti-solvent to it to crystallize, while the anti-solvent addition method is to dissolve the material to be crystallized in the good solvent, and then add the resulting solution The method of crystallizing into anti-solvent.
  • hydrocarbons means, for example, hydrocarbons having 1-10 carbon atoms, which include alkanes, halogenated alkanes, alkenes, alkynes, and aromatic hydrocarbons, including but not limited to methylene chloride , Trichloromethane (chloroform), n-hexane, n-heptane and toluene.
  • alcohols as used herein means, for example, alcohols having 1-10 carbon atoms, including but not limited to methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropanol) Alcohol), 1-butanol, 2-butanol and tert-butanol.
  • ethers means, for example, ethers having 2-6 carbon atoms, which include chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxanes). ), specifically including but not limited to diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, anisole and dimethoxyethane alkyl.
  • nitriles as used herein means, for example, nitriles having 2-6 carbon atoms, which include but are not limited to acetonitrile and propionitrile.
  • ketones as used herein means, for example, ketones having 2-6 carbon atoms, which include but are not limited to acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone.
  • esters as used herein means, for example, esters having 3-10 carbon atoms, which include, but are not limited to, ethyl acetate, propyl acetate, isopropyl acetate, ethyl isopropate, dicarbonate Methyl and butyl acetate.
  • organic acids as used herein means, for example, organic acids having 1-10 carbon atoms, which include, but are not limited to, formic acid and acetic acid.
  • sulfones as used herein means, for example, sulfones or sulfoxides having 2-10 carbon atoms, including but not limited to dimethylsulfoxide.
  • amides as used herein means, for example, amides having 1-10 carbon atoms, which include, but are not limited to, dimethylformamide or dimethylacetamide.
  • nitrogen heterocyclic ring means, for example, a nitrogen-containing heterocyclic ring having 3-10 carbon atoms and at least one nitrogen atom, which includes, but is not limited to, N-methylpyrrolidone.
  • the numerical range (such as “1-10") and its sub-ranges (such as “2-10", “2-6”, “3-10"), etc. cover the numerical range Any number of (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and is not limited to integers.
  • Solid lines (-) and wavy lines can be used in this article
  • Solid wedge Virtual wedge Depicts the chemical bonds of the compounds of this application.
  • the use of a solid line to depict the bond to an asymmetric atom is meant to indicate that all possible stereoisomers at that atom are included (e.g., specific enantiomers, racemic mixtures, etc.).
  • Use wavy lines to depict the bond to an asymmetric atom To show that the bond is a solid wedge Virtual wedge Any one of the keys.
  • the use of real or virtual wedges to depict bonds to asymmetric atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, use real and imaginary wedges to define relative stereochemistry, rather than absolute stereochemistry.
  • DSC spectra different types of equipment or different test conditions may give slightly different DSC spectra.
  • a Mettler Toledo DSC1 differential scanning calorimeter can be used to measure the DSC spectrum.
  • the term "substantially the same" for DSC spectra takes into account representative characteristic peak positions. For example, those skilled in the art will understand that the characteristic peak position will show some variation, usually as much as 5°C.
  • the heating rate of the DSC test has a greater impact on the DSC spectrum. At a faster heating rate, the thermal hysteresis effect of the instrument is obvious, and the high melting point solid crystal form is too late to recrystallize.
  • the DSC spectrum often only shows the melting endothermic peak of the low melting point crystal form.
  • the DSC spectrum shows two peaks: the melting endothermic peak of the low melting point crystal type and the melting endothermic peak of the high melting point crystal type; and only at a lower heating rate, the instrument thermal hysteresis effect is weak Below, three peaks appear: the melting peak of the low melting point crystal form-the exothermic peak of recrystallization-the melting endothermic peak of the high melting point crystal.
  • the skilled person will understand that the determination of the heating rate range corresponding to the above-mentioned different DSC maps will vary depending on the weight, shape, particle size and distribution of the test product (Reference: Giron D. Thermal analysis and calorimetric methods in the characterisation of polymorphs and solvates[J].Thermochimica Acta,1995,248:1-59.).
  • the solid form of the compound of formula (I), the salt of the compound of formula (I), or the crystal form thereof can be prepared by including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or under pressure or under reduced pressure Any other methods used for solids recovery.
  • the recovered solids can optionally be dried. "Drying" in this application is performed under reduced pressure (preferably vacuum) until the residual solvent content is reduced to the limit given in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines Within range.
  • the residual solvent content depends on the type of solvent, but does not exceed about 5000 ppm, or preferably about 4000 ppm, or more preferably about 3000 ppm.
  • the drying can be in a tray dryer, a vacuum oven, an air oven, a cone vacuum dryer, a rotary vacuum dryer, a fluidized bed dryer, a spin flash dryer, a rapid dryer, etc. get on.
  • the drying may be at a temperature of less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperature, under atmospheric pressure or reduced pressure ( It is preferable to carry out under vacuum) for any desired time (such as about 1, 2, 3, 5, 10, 15, 20, 24 hours or overnight) that can achieve the desired result, as long as the quality of the product does not deteriorate.
  • the drying can be performed any desired number of times until the desired product quality is achieved.
  • the dried product may optionally undergo a comminution operation to produce the desired particle size.
  • the product can be ground or micronized before or after drying. Techniques that can be used to reduce particle size include, but are not limited to, ball milling, roller milling, and hammer milling, and jet milling.
  • An object of this application is to provide crystal A of the compound of formula (I) as shown below:
  • the present application provides crystal A of the compound of formula (I).
  • the crystal A of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD patterns expressed in 2 ⁇ angles include 11.1 ⁇ 0.2°, 11.5 ⁇ 0.2°, 16.2 ⁇ 0.2°, 17.0 ⁇ 0.2°, 19.0 ⁇ 0.2 ° and a characteristic peak at a diffraction angle (2 ⁇ ) of 24.9 ⁇ 0.2°.
  • the crystal A of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD patterns expressed in 2 ⁇ angles include 7.3 ⁇ 0.2°, 11.1 ⁇ 0.2°, 11.5 ⁇ 0.2°, 16.0 ⁇ The characteristic peaks at diffraction angles (2 ⁇ ) of 0.2°, 16.2 ⁇ 0.2°, 16.9 ⁇ 0.2°, 19.0 ⁇ 0.2°, 20.9 ⁇ 0.2°, and 24.9 ⁇ 0.2°.
  • the crystal A of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes the values at 7.3 ⁇ 0.2°, 8.2 ⁇ 0.2°, 11.1 ⁇ 0.2°, 11.5 ⁇ 0.2°, 11.9 ⁇ 0.2°, 16.0 ⁇ 0.2°, 16.2 ⁇ 0.2°, 16.9 ⁇ 0.2°, 19.0 ⁇ 0.2°, 20.9 ⁇ 0.2°, 24.0 ⁇ 0.2° and 24.9 ⁇ 0.2° at the diffraction angle (2 ⁇ ) Characteristic peaks.
  • the crystal A of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes peaks at the following diffraction angles (2 ⁇ ):
  • the crystal A of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes peaks at the following diffraction angles (2 ⁇ ):
  • the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern of crystal A expressed at 2 ⁇ angles includes peaks at the following diffraction angles (2 ⁇ ):
  • the crystal A of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes the peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 1.
  • the crystal A of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD peak position expressed in 2 ⁇ angles is substantially the same as that shown in FIG. 1.
  • the XRPD pattern of crystal A of the compound of formula (I) is substantially the same as FIG. 1.
  • the DSC spectrum of the crystal A of the compound of formula (I) of the present application includes a characteristic peak at about 142 ⁇ 5°C (onset temperature). In some embodiments, the DSC spectrum of the crystal A of the compound of formula (I) has an endothermic peak in the range of about 130°C to 160°C. In some embodiments, the DSC spectrum of the crystal A of the compound of formula (I) includes characteristic peaks at substantially the same temperature as shown in FIG. 2. In some embodiments, the characteristic peak positions of the DSC spectrum of the crystal A of the compound of formula (I) are substantially the same as those shown in FIG. 2.
  • the TGA pattern of crystal A of the compound of formula (I) is substantially the same as FIG. 3.
  • the crystal A of the compound of formula (I) of the present application is a non-solvate. In some embodiments, the crystal A of the compound of formula (I) of the present application is an anhydrous crystal.
  • the present application provides crystal B of the compound of formula (I).
  • the crystal B of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD patterns expressed in 2 ⁇ angles include 7.5 ⁇ 0.2°, 10.8 ⁇ 0.2°, 12.4 ⁇ 0.2°, 14.7 ⁇ 0.2°, 18.2 ⁇ 0.2 ° and 25.3 ⁇ 0.2 ° diffraction angle (2 ⁇ ) characteristic peaks.
  • the crystal B of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes 7.5 ⁇ 0.2°, 10.8 ⁇ 0.2°, 12.4 ⁇ 0.2°, 14.7 ⁇ Diffraction angles of 0.2°, 14.8 ⁇ 0.2°, 15.0 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.1 ⁇ 0.2°, 18.2 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.2 ⁇ 0.2°, 23.4 ⁇ 0.2° and 25.3 ⁇ 0.2°
  • the crystal B of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes 7.5 ⁇ 0.2°, 10.8 ⁇ 0.2°, 12.4 ⁇ 0.2°, 14.7 ⁇ 0.2°, 14.8 ⁇ 0.2°, 15.0 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.1 ⁇ 0.2°, 18.2 ⁇ 0.2°, 19.2 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.2 ⁇ 0.2°, 23.4 ⁇ The characteristic peaks at diffraction angles (2 ⁇ ) of 0.2°, 25.3 ⁇ 0.2°, 28.5 ⁇ 0.2°, 30.3 ⁇ 0.2°, 33.8 ⁇ 0.2°, 35.8 ⁇ 0.2°, and 36.8 ⁇ 0.2°.
  • the crystal B of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes peaks at the following diffraction angles (2 ⁇ ):
  • the crystal B of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes peaks at the following diffraction angles (2 ⁇ ):
  • the crystal B of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes peaks at the following diffraction angles (2 ⁇ ):
  • the crystal B of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes the peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 4. In some embodiments, the crystal B of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD peak position expressed in 2 ⁇ angles is substantially the same as that shown in FIG. 4.
  • the DSC spectrum of the crystal B of the compound of formula (I) of the present application includes endothermic peaks at about 64 ⁇ 5°C and 142 ⁇ 5°C (initial temperature). In some embodiments, the DSC spectrum of the crystal B of the compound of formula (I) has an endothermic peak in the range of about 55°C to 80°C and the range of 130°C to 150°C. In some embodiments, the DSC spectrum of the crystal B of the compound of formula (I) includes characteristic peaks at substantially the same temperature as shown in FIG. 5. In some embodiments, the characteristic peak positions of the DSC spectrum of the crystal B of the compound of formula (I) are substantially the same as those shown in FIG. 5.
  • thermogravimetric analysis (TGA) pattern of the crystal B of the compound of formula (I) of the present application loses weight at about 60 ⁇ 10°C, and the weight loss percentage is 5-8%, preferably 6-7%, More preferably, it is 6.7%.
  • the TGA pattern of crystal B of the compound of formula (I) includes substantially the same weight loss temperature as shown in FIG. 6. In some embodiments, the TGA pattern of crystal B of the compound of formula (I) is substantially the same as FIG. 6.
  • the crystal B of the compound of formula (I) of the present application is an ether solvate, and the molar ratio of the compound of formula (I) to the solvent is 1:0.5.
  • the present application provides crystal C of the compound of formula (I).
  • the crystal C of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD patterns expressed in 2 ⁇ angles include 7.8 ⁇ 0.2°, 14.6 ⁇ 0.2°, 17.1 ⁇ 0.2°, 21.6 ⁇ 0.2° and 22.7 ⁇ 0.2 The characteristic peak at the diffraction angle (2 ⁇ ) of °.
  • the crystal C of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes 7.8 ⁇ 0.2°, 14.6 ⁇ 0.2°, 15.6 ⁇ 0.2°, 17.1 ⁇
  • the crystal C of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes the values at 7.8 ⁇ 0.2°, 9.6 ⁇ 0.2°, 10.8 ⁇ 0.2°, 12.7 ⁇ 0.2°, 13.1 ⁇ 0.2°, 14.6 ⁇ 0.2°, 15.6 ⁇ 0.2°, 17.1 ⁇ 0.2°, 18.6 ⁇ 0.2°, 20.4 ⁇ 0.2°, 20.6 ⁇ 0.2°, 21.1 ⁇ 0.2°, 21.6 ⁇ 0.2°, 22.3 ⁇ 0.2°, 22.7 ⁇ 0.2°, 23.6 ⁇ 0.2°, 27.2 ⁇ 0.2°, 27.8 ⁇ 0.2°, 28.7 ⁇ 0.2°, 29.3 ⁇ 0.2°, 29.6 ⁇ 0.2° and 31.3 ⁇ 0.2° diffraction angle (2 ⁇ ) Characteristic peaks.
  • the crystal C of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes peaks at the following diffraction angles (2 ⁇ ):
  • the crystal C of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes peaks at the following diffraction angles (2 ⁇ ):
  • the crystal C of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes peaks at the following diffraction angles (2 ⁇ ):
  • the crystal C of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes the peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 7. In some embodiments, the crystal C of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD peak position expressed in 2 ⁇ angles is substantially the same as that shown in FIG. 7.
  • the DSC spectrum of crystal C of the compound of formula (I) of the present application includes endothermic peaks at about 103 ⁇ 5°C and 141 ⁇ 5°C (onset temperature). In some embodiments, the DSC spectrum of the crystal C of the compound of formula (I) has an endothermic peak in the range of 130°C to 150°C in the range of about 80°C to 115°C. In some embodiments, the DSC spectrum of crystal C of the compound of formula (I) includes characteristic peaks at substantially the same temperature as shown in FIG. 8. In some embodiments, the characteristic peak positions of the DSC spectrum of the crystal C of the compound of formula (I) are substantially the same as those shown in FIG. 8.
  • thermogravimetric analysis (TGA) pattern of crystal C of the compound of formula (I) of the present application loses weight at about 80°C to 100°C, and the weight loss percentage is 7 to 11%, preferably 8 to 10% , More preferably 9.2%.
  • the TGA pattern of crystal C of the compound of formula (I) includes substantially the same weight loss temperature as shown in FIG. 9. In some embodiments, the TGA pattern of crystal C of the compound of formula (I) is substantially the same as FIG. 9.
  • the crystal C of the compound of formula (I) of the present application is an ethyl acetate solvate, and the molar ratio of the compound of formula (I) to the solvent is 1:0.5.
  • the present application provides crystal D of the compound of formula (I).
  • the crystal D of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD patterns expressed in 2 ⁇ angles include 10.8 ⁇ 0.2°, 14.6 ⁇ 0.2°, 14.7 ⁇ 0.2°, 20.3 ⁇ 0.2°, 21.4 ⁇ 0.2
  • the crystal D of the compound of formula (I) uses Cu-K ⁇ radiation
  • the XRPD patterns expressed in 2 ⁇ angles include 10.8 ⁇ 0.2°, 13.1 ⁇ 0.2°, 14.6 ⁇ 0.2°, 14.7 ⁇ 0.2°, 17.0 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.3 ⁇ 0.2°, 20.5 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.0 ⁇ 0.2°, 21.4 ⁇ 0.2°, 26.5 ⁇ 0.2°, and 31.2 ⁇ 0.2° diffraction angle
  • the crystal D of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD patterns expressed in 2 ⁇ angles include 7.6 ⁇ 0.2°, 10.8 ⁇ 0.2°, 13.1 ⁇ 0.2°, 14.6 ⁇ 0.2°, 14.7 ⁇ 0.2°, 15.4 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.0 ⁇ 0.2°, 19.9 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.3 ⁇ 0.2°, 20.5 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.0 ⁇ 0.2°, 21.4 ⁇ 0.2°, 22.5 ⁇ 0.2°, 23.3 ⁇ 0.2°, 23.5 ⁇ 0.2°, 26.5 ⁇ 0.2°, 30.2 ⁇ 0.2°, 31.2 ⁇ 0.2° and 32.1 ⁇ 0.2° diffraction angle (2 ⁇ ) Characteristic peaks.
  • the crystal D of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes peaks at the following diffraction angles (2 ⁇ ):
  • the crystal D of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes peaks at the following diffraction angles (2 ⁇ ):
  • the crystal D of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes peaks at the following diffraction angles (2 ⁇ ):
  • the crystal D of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes the peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 10. In some embodiments, the crystal D of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD peak position expressed in 2 ⁇ angles is substantially the same as that shown in FIG. 10.
  • the DSC spectrum of the crystal D of the compound of formula (I) of the present application includes characteristic peaks at about 84 ⁇ 5°C and 142 ⁇ 5°C (onset temperature).
  • the DSC spectrum of crystal B of the compound of formula (I) has an endothermic peak in the range of 130°C to 155°C in the range of about 75°C to 100°C.
  • the DSC spectrum of crystal D of the compound of formula (I) includes characteristic peaks at substantially the same temperature as shown in FIG. 11.
  • the characteristic peak positions of the DSC spectrum of the crystal D of the compound of formula (I) are substantially the same as those shown in FIG. 11.
  • thermogravimetric analysis (TGA) pattern of crystal D of the compound of formula (I) of the present application loses weight at about 70°C to 120°C, with a weight loss percentage of 8-12%, preferably 9-11% , More preferably 10.1%.
  • the TGA pattern of crystal D of the compound of formula (I) includes substantially the same weight loss temperature as shown in FIG. 12. In some embodiments, the TGA pattern of crystal D of the compound of formula (I) is substantially the same as FIG. 12.
  • the crystal D of the compound of formula (I) of the present application is an isopropyl acetate solvate, and the molar ratio of the compound of formula (I) to the solvent is 1:0.5.
  • the present application provides crystal E of the compound of formula (I).
  • the crystal E of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD patterns expressed in 2 ⁇ angles include 10.8 ⁇ 0.2°, 14.7 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.6 ⁇ 0.2°, 17.2 ⁇ 0.2 ° and a characteristic peak at a diffraction angle (2 ⁇ ) of 23.8 ⁇ 0.2°.
  • the crystal E of the compound of formula (I) uses Cu-K ⁇ radiation
  • the XRPD pattern expressed in 2 ⁇ angles includes the values at 10.8 ⁇ 0.2°, 13.1 ⁇ 0.2°, 14.7 ⁇ 0.2°, 15.0 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.6 ⁇ 0.2°, 17.2 ⁇ 0.2°, 19.2 ⁇ 0.2°, 22.7 ⁇ 0.2°, 23.5 ⁇ 0.2° and 23.8 ⁇ 0.2° diffraction angles (2 ⁇ ) Characteristic peaks.
  • the crystal E of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD patterns expressed in 2 ⁇ angles include 7.8 ⁇ 0.2°, 10.8 ⁇ 0.2°, 12.2 ⁇ 0.2°, 12.7 ⁇ 0.2°, 13.1 ⁇ 0.2°, 14.7 ⁇ 0.2°, 15.0 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.6 ⁇ 0.2°, 17.2 ⁇ 0.2°, 19.2 ⁇ 0.2°, 19.9 ⁇ 0.2°, 20.1 ⁇ 0.2°, 21.0 ⁇ 0.2°, 21.7 ⁇ 0.2°, 22.7 ⁇ 0.2°, 23.5 ⁇ 0.2°, 23.8 ⁇ 0.2°, 27.6 ⁇ 0.2°, 27.8 ⁇ 0.2°, 30.1 ⁇ 0.2° and 32.0 ⁇ 0.2° diffraction angle
  • the crystal E of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes peaks at the following diffraction angles (2 ⁇ ):
  • the crystal E of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes peaks at the following diffraction angles (2 ⁇ ):
  • the crystal E of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles includes peaks at the following diffraction angles (2 ⁇ ):
  • the crystal E of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angle includes the peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 13. In some embodiments, the crystal E of the compound of formula (I) uses Cu-K ⁇ radiation, and the XRPD peak position expressed in 2 ⁇ angles is substantially the same as that shown in FIG. 13.
  • the DSC spectrum of the crystal E of the compound of formula (I) of the present application includes characteristic peaks at about 81 ⁇ 5°C and 140 ⁇ 5°C (initial temperature).
  • the DSC spectrum of the crystal B of the compound of formula (I) has an endothermic peak in the range of 130°C to 155°C in the range of about 75°C to 110°C.
  • the DSC spectrum of crystal E of the compound of formula (I) includes characteristic peaks at substantially the same temperature as shown in FIG. 14.
  • the characteristic peak positions of the DSC spectrum of the crystal E of the compound of formula (I) are substantially the same as those shown in FIG. 14.
  • thermogravimetric analysis (TGA) pattern of crystal E of the compound of formula (I) of the present application loses weight at about 70°C to 120°C, and the weight loss percentage is 7 to 11%, preferably 8 to 10% , More preferably 8.8%.
  • the TGA pattern of crystal E of the compound of formula (I) includes substantially the same weight loss temperature as shown in FIG. 15. In some embodiments, the TGA pattern of crystal E of the compound of formula (I) is substantially the same as FIG. 15.
  • the crystal E of the compound of formula (I) of the present application is a dimethyl carbonate solvate, and the molar ratio of the compound of formula (I) to the solvent is 1:0.5.
  • the present application provides an amorphous form of the compound of formula (I), the amorphous form uses Cu-K ⁇ radiation, and the XRPD pattern expressed in 2 ⁇ angles does not have diffraction peaks.
  • the XRPD pattern of the amorphous form is substantially the same as FIG. 16.
  • a room temperature slow volatilization method is used to prepare crystals, which includes dissolving the compound of formula (I) in a solvent in a container to form a clear solution (if necessary, the solution can be filtered to obtain a clear solution, After filtering, add a solvent if necessary), seal the container (for example, use a sealing film), leave small holes or gaps at the seal, and place the clear solution to volatilize the solvent to obtain crystals.
  • the solvent includes but is not limited to alcohols, ethers or esters, such as methanol, ether, ethyl acetate, isopropyl acetate, or dimethyl carbonate , Or a mixed solvent formed by two or more of the above solvents.
  • the weight-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (1-50):1, preferably (1-30):1 .
  • a certain amount of the same type of solvent is further added.
  • the volume ratio of the additional solvent to the original solvent is 20:1 to 5.
  • the placing can be performed at room temperature.
  • the solvents and results used for preparing crystals by the room temperature slow volatilization method in this application are illustrated as follows:
  • a slow cooling method is used to prepare crystals.
  • the method includes adding a compound of formula (I) to a solvent, heating and stirring to dissolve it, and the resulting clear solution (the solution can be filtered to Obtain a clear solution) place, slowly lower the temperature to obtain crystals.
  • the solvent includes, but is not limited to, aromatic hydrocarbons or ethers, or a mixed solvent of the foregoing solvents, for example, toluene or isopropyl ether.
  • the cooling rate of the slow cooling is 0.1-0.5°C/min, preferably 0.1-0.3°C/min, more preferably 0.1°C/min.
  • the heating temperature is 50-90°C, preferably 60-80°C, such as 65°C, 70°C, or 75°C.
  • the temperature at the end of the cooling is room temperature or 0-10°C, such as 3°C, 5°C, or 7°C.
  • the weight-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (5-120):1, preferably (10-100):1.
  • the stirring time is 10-50 minutes; preferably 30 minutes.
  • the solvents and results used for preparing crystals by the slow cooling method in this application are illustrated as follows:
  • an anti-solvent addition method is used to prepare crystals.
  • the method includes, but is not limited to, dissolving the compound of formula (I) in a good solvent to form a clear solution (the solution may be filtered to obtain a clear solution if necessary).
  • the clear solution After the clear solution is obtained, it can be heated as needed), and then the anti-solvent is added to the clear solution, and stirred (the stirring can be at insulation, room temperature or cooling conditions (for example, cooling to 0-20 °C, preferably 0-10 °C, such as 0 °C, 5 °C or 10 °C) to precipitate crystals, or stand still (for example, placed at room temperature) (preferably while slowly volatilizing the solvent) to precipitate crystals.
  • the stirring can be at insulation, room temperature or cooling conditions (for example, cooling to 0-20 °C, preferably 0-10 °C, such as 0 °C, 5 °C or 10 °C) to precipitate crystals, or stand still (for example, placed at room temperature) (preferably while slowly volatilizing the solvent) to precipitate crystals.
  • the good solvent includes but is not limited to alcohols, ketones, nitriles or ethers (including cyclic ethers or chain ethers), such as methanol, ethanol, isopropanol, n-propanol, n-propanol, Butanol, acetone, methyl ethyl ketone, acetonitrile, or tetrahydrofuran, etc.
  • the anti-solvent includes, but is not limited to, inorganic solvents, such as water.
  • the volume ratio of the good solvent to the anti-solvent is 4:(1-5), preferably 4:3.
  • the weight of the compound of formula (I) to the good solvent is The volume ratio (mg/mL) is (120-80):1, preferably 100:1.
  • the solvent used in the preparation of crystals by the anti-solvent addition method and the results are illustrated as follows:
  • a room temperature suspension stirring method is used to prepare crystals, which includes, but is not limited to, adding a solid form (such as an amorphous form) of the compound of formula (I) to a solvent to obtain a suspension, and stirring at room temperature, Then separate crystals.
  • a solid form such as an amorphous form
  • the solvent includes, but is not limited to, inorganic solvents (such as water) and organic solvents (such as alkanes, ethers or aromatic hydrocarbons), such as water, n-hexane, n-heptane Alkane, cyclohexane, n-pentane, isopropyl ether, or toluene, or a mixed solvent of two or more selected from the above solvents.
  • the weight-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (10-50):1, preferably (20-40):1 .
  • the solvents and results used in the preparation of crystals by the room temperature suspension stirring method in this application are illustrated as follows:
  • an anti-solvent addition method is used to prepare the amorphous form.
  • the method includes, but is not limited to, dissolving the compound of formula (I) in a good solvent to form a clear solution, and then adding to the clear solution Anti-solvent to precipitate an amorphous form.
  • the good solvent includes, but is not limited to, esters and ethers, such as ethyl acetate, methyl tert-butyl ether, isopropyl ether, and the like.
  • the anti-solvent includes, but is not limited to, hydrocarbons, such as n-heptane.
  • the amorphous form is prepared by a reduced-pressure concentration method, which includes, but is not limited to, dissolving the compound of formula (I) in a good solvent to form a clear solution, and then concentrating the solvent under reduced pressure to precipitate Amorphous form.
  • the good solvent includes but is not limited to alcohols, such as methanol and the like.
  • the weight-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (10-50):1, preferably (20-40):1 .
  • the crystals A, B, C, D or E of the compound of formula (I) of the compound of formula (I) of the present application, or the amorphous form of the compound of formula (I), have obvious agonistic effects on PPAR ⁇ , and HepG2 cells and HEK293 cells have low toxicity, have no obvious inhibitory effect on hERG, and have no safety hazards leading to prolonged cardiac QT interval.
  • Another object of this application is to provide a pharmaceutical composition, which comprises:
  • Another object of the present application is to provide a method for treating peroxisome proliferator activated receptor (PPAR) related diseases such as non-alcoholic fatty liver disease (NAFLD) in an individual, which includes providing an individual in need Administration of a therapeutically effective amount of the compound of formula (I) of the present application, the crystal A, B, C, D or E of the compound of formula (I), or the amorphous form of the compound of formula (I), or any combination thereof .
  • PPAR peroxisome proliferator activated receptor
  • Another object of the present application is to provide crystals A, B, C, D, or E of the compound of formula (I) of the present application, or the amorphous form of the compound of formula (I), or any combination thereof, for use in therapy
  • Individuals have peroxisome proliferator activated receptor (PPAR) related diseases such as non-alcoholic fatty liver disease (NAFLD).
  • PPAR peroxisome proliferator activated receptor
  • Another object of this application is to provide the crystals A, B, C, D or E of the compound of formula (I) of the present application, or the amorphous form of the compound of formula (I), or any combination thereof in preparation for treatment
  • PPAR peroxisome proliferator activated receptor
  • NAFLD non-alcoholic fatty liver disease
  • the peroxisome proliferator activated receptor (PPAR) related diseases of non-alcoholic fatty liver disease (NAFLD) described in the present application include non-alcoholic fatty liver disease (NAFLD).
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle administered with a therapeutic agent, and which is suitable for contact within the scope of reasonable medical judgment Human and/or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • the pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present application include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, and minerals. Oil, sesame oil, etc.
  • water is an exemplary carrier. It is also possible to use physiological saline and aqueous glucose and glycerol solutions as liquid carriers, especially for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol etc.
  • the composition may also contain small amounts of wetting agents, emulsifiers or pH buffering agents as needed.
  • Oral preparations may contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • the pharmaceutical composition of the present application can act systemically and/or locally.
  • they can be administered by suitable routes, such as by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, transnasal, transmucosal, topical, It is administered in the form of ophthalmic preparations or by inhalation.
  • composition of the present application can be administered in a suitable dosage form.
  • the dosage form can be a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation, including but not limited to tablets, capsules, powders, granules, lozenges, hard candy, powders, sprays, creams, ointments , Suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, suspensions, elixirs, syrups.
  • the pharmaceutical composition described in the present application can be prepared by any method well known in the art, for example, by mixing, dissolving, granulating, sugar coating, milling, emulsifying, freeze-drying and other treatments.
  • terapéuticaally effective amount refers to the amount of a compound that will relieve one or more symptoms of the condition being treated to a certain extent after being administered.
  • the dosage regimen can be adjusted to provide the best desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgent need for the treatment situation. It should be noted that the dose value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It should be further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • the amount of the compound of the application administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the treatment of the compound, and the judgment of the prescribing physician.
  • the effective dose is about 0.0001 to about 50 mg per kg body weight per day, for example, about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, for example, about 0.7 mg/day to about 700 mg/day.
  • a dose level not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose can still be used without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
  • the content or amount of the compound of the present application in the pharmaceutical composition may be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2mg, 4mg, 10mg and 25mg etc.
  • treating means reversing, alleviating, inhibiting the progression of one or more symptoms of the disorder or condition to which such term is applied, or preventing such A disorder or condition or one or more symptoms of such a disorder or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as the diseases described herein.
  • “Non-human animals” in this application include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).
  • the detection range is from 3.5° to 40°, the step length is 0.013°, the dwell time is 50s, and the scan is performed once.
  • Test method thermal analysis method (Chinese Pharmacopoeia 2015 Edition Four General Rules 0661)
  • Test conditions heating rate 10°C/min, initial temperature 35.0°C
  • Sample preparation Weigh about 2-5 mg of the test sample, spread it flat in a 60 ⁇ l aluminum crucible with holes, and use an empty aluminum crucible as a reference.
  • Test method thermal analysis method (Chinese Pharmacopoeia 2015 Edition Four General Rules 0661)
  • Test conditions starting temperature 35.0°C, ending temperature 500.0°C, heating rate 10°C/min
  • the compound sample of formula (I) was prepared according to the method described in Example 5 in the International Patent Application No. PCT/CN2018/115615.
  • Example 6 Using a method similar to Example 6, the difference is that the water in Example 6 is replaced with n-hexane, n-heptane, cyclohexane, n-pentane, isopropyl ether, or toluene, and the result of XRPD detection of the obtained solid It is shown that the obtained product is the same as the crystal A obtained in Example 1.
  • the crystal A samples were given to male SD rats by intragastric (PO) to investigate the pharmacokinetic characteristics.
  • the dosage of administration was 5 mg/kg, and 0.5% MC (sodium methyl cellulose) was used as a solvent to prepare a suspension of crystal A.
  • whole blood was collected before PO administration (0h) and at 0.083, 0.17, 0.25, 0.5, 1, 2 , 4, 6, 8 and 24h after administration.
  • Whole blood was anticoagulated with EDTA.K 2 After centrifugation, a plasma sample was obtained and stored at -80°C for testing. In this experiment, there are three animals in each group in parallel.
  • Plasma samples were processed with precipitated protein and analyzed by LC-MS/MS. Using WinNonlin 6.3 software, the non-compartmental model was used to calculate the pharmacokinetic parameters. The results are shown in Table 1.
  • crystal A administered by PO at a dose of 5 mg/kg has a better exposure in rat plasma.
  • Purity test method use high performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition Four General Rules 0512).
  • Chromatographic column use phenyl bonded silica gel as filler
  • Mobile phase B Acetonitrile (containing 0.05% acetic acid);
  • the crystal form A was placed in a sealed and clean glass bottle, and then placed in a 60°C constant temperature drying oven, and samples were taken on the 11th day and the 30th day to detect the impurity content.
  • the purity is shown in Table 2:

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Abstract

本申请涉及式（I）的化合物的固体形式，制备所述固体形式的方法、包含所述固体形式的药物组合物，以及所述固体形式用于制备治疗或预防诸如非酒精性脂肪性肝病（NAFLD）的过氧化物酶体增殖物激活受体（PPAR）相关疾病的药物中的用途。

Description

一种芳香族化合物的固体形式及其制备方法
本申请是以CN申请号为201910448548.5，申请日为2019年5月24日的申请为基础，并主张其优先权，该CN申请的公开内容在此作为整体引入本申请中。
技术领域
本申请涉及(E)-2-(4-(3-(2-甲氧基喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(在下文中称作“式(I)的化合物”)的晶体或无定形形式和制备方法、包含其的药物组合物以及其在制备用于预防或治疗诸如非酒精性脂肪性肝病(NAFLD)等疾病或病症的药物中的用途。
背景技术
非酒精性脂肪性肝病(NAFLD)是一类肝组织学改变与酒精性肝病相似，但无过量饮酒史的临床病理综合征，包括单纯性脂肪肝(SFL)、非酒精性脂肪性肝炎(NASH)及其相关肝硬化，其中NASH是NAFLD进展的重要中间阶段。随着胰岛素抵抗及其相关的多元代谢综合征的高发，NAFLD/NASH的患病率逐渐升高。当前NASH已成为仅次于慢性病毒性肝炎、酒精性肝病的重要肝硬化前期病变之一，并为健康体检人群血清转氨酶异常的常见病因，NASH的有效防治可望阻止慢性肝病进展，减少肝硬化和肝病相关残疾和死亡的发生。非酒精性脂肪性肝病是当代医学领域的新挑战，治疗非酒精性脂肪肝相关疾病的药物开发具有重要的临床意义。因而迫切需要有效且安全的治疗非酒精性脂肪肝相关疾病的药物。
在申请人提交的第PCT/CN2018/115615号国际专利申请中，披露了结构新颖的苯氧基乙酸类化合物，该类化合物作为过氧化物酶体增殖物激活受体(PPAR)激动剂具有良好的体内外药代和药效性质，具有预防或治疗诸如非酒精性脂肪性肝病(NAFLD)等疾病或病症的潜力。因此，进一步研发该类化合物并获得其适用于制备药物制剂的晶体或无定形形式，在医药领域有迫切需求。
发明概述
本申请的一个方面提供如下所示的式(I)化合物(E)-2-(4-(3-(2-甲氧基喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸的晶体，特别是式(I)化合物的晶体A、B、C、D、E以及无定形形态。
Figure PCTCN2020091471-appb-000001
本申请的另一方面提供制备式(I)的化合物的晶体A、B、C、D、E以及无定形形态的方法，其包括使任意固体形式的式(I)的化合物与无机酸或有机酸反应，析出固体，随后将析出的固体分离并干燥。所述析出固体的方法包括但不限于气固渗透法、反溶剂结晶法、室温悬浮搅拌法、高温悬浮搅拌法、气液渗透法、室温缓慢挥发法、缓慢降温法等。
本申请的另一方面提供药物组合物，其包含上述式(I)化合物的晶体，特别是式(I)的化合物的晶体A、B、C、D、E、无定形形态或其任意组合，以及一种或多种药学上可接受的载体。
本申请的另一方面提供用于治疗个体的与过氧化物酶体增殖物激活受体(PPAR)相关的疾病或病症的方法，其包括向有此需要的个体给药治疗有效量的上述式(I)化合物的晶体，特别是式(I)化合物的晶体A、B、C、D、E以及无定形形态，或其任意组合。
本申请的另一方面提供上述式(I)的化合物的晶体，特别是式(I)化合物的晶体A、B、C、D、E以及无定形形态或其任意组合，其用于治疗个体的与过氧化物酶体增殖物激活受体(PPAR)相关的疾病或病症。
本申请的另一方面提供上述式(I)的化合物的晶体，特别是式(I)化合物的晶体A、B、C、D、E以及无定形形态或其任意组合在制备用于治疗个体的与过氧化物酶体增殖物激活受体(PPAR)相关的疾病或病症中的用途。
本申请的式(I)的化合物的晶体具有一种或多种以下有利性质：
i)高溶解度、高溶出率、低吸湿性、高流动性或明显改善的粘黏性。
ii)优良的物理化学稳定性，包括但不限于光稳定性、热稳定性、耐高湿性等。例如，良好的光稳定性可保证所述晶体在储存和运输时的可靠性，从而保证制剂的安全性；使得所述晶体不需要为防止受光照影响而采取特殊包装处理，从而降低了成本；使得所述晶体不会因光照影响产生降解，从而提高了制剂的安全性和长期贮藏后的有效性；并且使得服用所述晶体的患者不会担忧制剂因暴露于日光下而产生光敏反应。良好的热稳定性使得所述晶体能够保持长时间稳定，且适用于标准的制剂生产过程。良好的物理化学稳定性使所述晶体易于制备并且更适合用于制剂的制备。
iii)改善的代谢、提高的生物利用度、降低的毒性或提高的安全性。
iv)适合和便于大量制备，节约成本。
附图说明
图1：式(I)的化合物晶体A的XRPD图谱；
图2：式(I)的化合物晶体A的DSC图谱；
图3：式(I)的化合物晶体A的TGA图谱；
图4：式(I)的化合物晶体B的XRPD图谱；
图5：式(I)的化合物晶体B的DSC图谱；
图6：式(I)的化合物晶体B的TGA图谱；
图7：式(I)的化合物晶体C的XRPD图谱；
图8：式(I)的化合物晶体C的DSC图谱；
图9：式(I)的化合物晶体C的TGA图谱；
图10：式(I)的化合物晶体D的XRPD图谱；
图11：式(I)的化合物晶体D的DSC图谱；
图12：式(I)的化合物晶体D的TGA图谱；
图13：式(I)的化合物晶体E的XRPD图谱；
图14：式(I)的化合物晶体E的DSC图谱；
图15：式(I)的化合物晶体E的TGA图谱；
图16：式(I)的化合物无定形的XRPD图谱。
发明详述
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的 技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本申请。
如本文中所使用的术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
如本文中所使用的词语“约”是指本领域的普通技术人员认为在所述值的可接受的标准误差内，例如±0.05、±0.1、±0.2、±0.3、±1、±2或±3等。
本申请所使用的术语“固体形式”包括式(I)的化合物和式(I)的化合物的盐的所有固态形式，例如晶体形式或无定形形式。
如本文中所使用的术语“无定形”是指三维上无排序的任意固体物质。在一些情况中，无定形固体可通过已知技术表征，所述技术包括XRPD晶体学、固态核磁共振(ssNMR)波谱学、差示扫描量热(DSC)或这些技术的一些组合。如以下所说明，无定形固体产生弥散的XRPD图谱，其通常包括一个或两个宽峰(即具有约5°2θ或更大的基宽的峰)。
如本文中所使用的术语“晶型”或“晶体”是指呈现三维排序的任意固体物质，与无定形固体物质相反，其产生具有边界清楚的峰的特征性XRPD图谱。
如本文中所使用的术语“X射线粉末衍射图谱(XRPD图谱)”是指实验观察的衍射图或源于其的参数。XRPD图谱通常由峰位(横坐标)和/或峰强度(纵坐标)表征。
如本文中所使用的术语“2θ”是指基于X射线衍射实验的实验设置的以度数表示的峰位，并且通常是在衍射图谱中的横坐标单位。如果当入射束与某晶格面形成θ角时反射被衍射，则实验设置需要以2θ角记录反射束。应当理解，在本文中提到的特定晶体形式的特定2θ值意图表示使用本文所述的X射线衍射实验条件所测量的2θ值(以度数表示)。
如本文中所使用的术语“热重分析(TGA)图谱”是指由热重分析仪记录到的曲线。
如本文中所使用的术语“差示扫描量热(DSC)图谱”是指由差示扫描量热仪记录到的曲线。
如本文中所使用的，对于X射线衍射峰位的术语“基本上相同”意指将代表性峰位和强度变化考虑在内。例如，本领域技术人员会理解峰位(2θ)会显示一些变化，通常多达0.1-0.2度，并且用于测量衍射的仪器也会显示一些变化。另外，本领域技术人员会理解相对峰强度会显示仪器间的变化以及由于结晶性程度、择优取向、制备的样品表面以及本领域技术人员已知的其它因素的变化，并应将其看作仅为定性测量。相似地，如本文中所使用，对于DSC图谱和TGA图谱的“基本上相同”也意图涵盖本领域技术人员已知的与这些分析技术有关的变化。。
如本文中所使用的术语“良溶剂”意指用于溶解本申请的(I)化合物或者(I)化合物盐的溶剂。
如本文中所使用的术语“反溶剂”意指用于降低待结晶物在良溶剂中的溶解性的溶剂。
如本文中所使用的术语“反溶剂结晶法”意指将良溶剂与反溶剂结合使用，从而降低待结晶物在良溶剂中的溶解性的方法。按照溶剂的添加顺序，反溶剂结晶法可分为反溶剂添加法和反反溶剂添加法。反溶剂添加法是将待结晶物溶解于良溶剂中，然后向其中添加反溶剂从而析晶的方法，而反反溶剂添加法则是将待结晶物溶解于良溶剂中，然后将所得的溶液加入到反溶剂中从而析晶的方法。
如本文中所使用的术语“烃类”意指例如具有1-10个碳原子的烃，其包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类，包括但不限于二氯甲烷、三氯甲烷(氯仿)、正己烷、正庚烷和甲苯。
如本文中所使用的术语“醇类”意指例如具有1-10个碳原子的醇，其包括但不限于甲醇、乙醇、1-丙醇(正丙醇)、2-丙醇(异丙醇)、1-丁醇、2-丁醇和叔丁醇。
如本文中所使用的术语“醚类”意指例如具有2-6个碳原子的醚，其包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类)，具体包括但不限于乙醚、二异丙基 醚、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、二氧六环、环戊基甲醚、苯甲醚和二甲氧基乙烷。
如本文中所使用的术语“腈类”意指例如具有2-6个碳原子的腈，其包括但不限于乙腈和丙腈。
如本文中所使用的术语“酮类”意指例如具有2-6个碳原子的酮，其包括但不限于丙酮、丁酮、甲基乙基酮、甲基异丁基酮和二乙基酮。
如本文中所使用的术语“酯类”意指例如具有3-10个碳原子的酯，其包括但不限于乙酸乙酯、乙酸丙酯、乙酸异丙酯、异丙酸乙酯、碳酸二甲酯和乙酸丁酯。
如本文中所使用的术语“有机酸类”意指例如具有1-10个碳原子的有机酸，其包括但不限于甲酸和乙酸。
如本文中所使用的术语“砜类”意指例如具有2-10个碳原子的砜或亚砜，其包括但不限于二甲基亚砜。
如本文中所使用的术语“酰胺类”意指例如具有1-10个碳原子的酰胺，其包括但不限于二甲基甲酰胺或二甲基乙酰胺。
如本文中所使用的术语“氮杂环类”意指例如具有3-10个碳原子和至少一个氮原子的含氮杂环，其包括但不限于N-甲基吡咯烷酮。
如本文中所使用的数值范围(如“1-10个”)及其子范围(如“2-10个”、“2-6个”、“3-10个”)等涵盖所述数值范围中的任意个(例如1个、2个、3个、4个、5个、6个、7个、8个、9个或10个)，且不限于整数。
本文中可使用实线(-)、波浪线
Figure PCTCN2020091471-appb-000002
实楔形
Figure PCTCN2020091471-appb-000003
或虚楔形
Figure PCTCN2020091471-appb-000004
描绘本申请的化合物的化学键。使用实线以描绘键连至不对称原子的键欲表明，包括该原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用波浪线以描绘键连至不对称原子的键欲表明，该键为实楔形
Figure PCTCN2020091471-appb-000005
或虚楔形
Figure PCTCN2020091471-appb-000006
键中的任意一种。使用实或虚楔形以描绘键连至不对称原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。
应当理解用不同类型设备或用不同的测试条件可能会给出略有差异的DSC图谱。例如可以使用Mettler Toledo DSC1差示扫描量热仪测定DSC图谱。如本文中所使用的，对于DSC图谱的术语“基本上相同”会将代表性特征峰位考虑在内。例如，本领域技术人员会理解特征峰位会显示一些变化，通常多达5℃。对于存在多晶型的固体样品来说，DSC测试的升温速率对DSC图谱的影响较大。在较快的升温速率下，仪器热滞后效应明显，高熔点固体晶型来不及重结晶，因此，DSC图谱往往仅仅出现低熔点晶型的熔化吸热峰。在中等升温速率下，DSC图谱则显示两个峰：低熔点晶型熔化吸热峰和高熔点晶型熔化吸热峰；而只有在较低的升温速率下，仪器热滞后效应较弱的情况下，才会出现三个峰：低熔点晶型的熔化峰-重结晶放热峰-高熔点晶体的熔化吸热峰。本技术人员会理解，上述不同DSC图谱所对应的升温速率范围的确定，会因测试品的重量、形态、粒度大小及分布的不同而存在差异(参考文献:Giron D.Thermal analysis and calorimetric methods in the characterisation of polymorphs and solvates[J].Thermochimica Acta,1995,248:1-59.)。
可将制备的式(I)的化合物的固体形式、式(I)的化合物的盐或其晶体形式通过包括倾析、离心、蒸发、重力过滤、抽滤或者在加压下或在减压下的任何其它用于固体回收的技术在内的方法进行回收。可将回收的固体任选地进行干燥。本申请中的“干燥”是在减压(优选真空)下进行直到残留溶剂的含量降低至International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use(“ICH”)指南所给出的限度的范围内。残留溶剂含量取决于溶剂的类型，但不超过约5000ppm、或优选约4000ppm、或更优选约3000ppm。所述干燥可以在盘式干燥器、真空烘箱、空气烘箱、锥形真空干燥器(cone vacuum dryer)、旋转式真空干燥器、流化床干燥器、旋转闪蒸干燥 器、快速干燥器等中进行。所述干燥可以在低于约100℃、低于约80℃、低于约60℃、低于约50℃、低于约30℃的温度或任何其它合适的温度下，在大气压或减压(优选真空)下在能够实现期望的结果的任何期望的时间内(如约1、2、3、5、10、15、20、24小时或者过夜)进行，只要产物的品质不劣化。所述干燥可以进行任何期望的次数，直到实现所需的产物品质。干燥的产物可以任选地经历粉碎操作，以产生期望的粒度。可在产物的干燥前或干燥完成后进行研磨或微粉化。可用于减小粒度的技术包括但不限于球磨、辊磨和锤磨，以及喷射研磨(jet milling)。
式(I)的化合物的晶体、无定形形式及其制备方法
式(I)的化合物的晶体A
本申请的一个目的在于提供如下所示的式(I)的化合物的晶体A：
Figure PCTCN2020091471-appb-000007
根据本申请的一个实施方案，本申请提供式(I)的化合物的晶体A。所述式(I)的化合物的晶体A，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在11.1±0.2°、11.5±0.2°、16.2±0.2°、17.0±0.2°、19.0±0.2°和24.9±0.2°的衍射角(2θ)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体A，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在7.3±0.2°、11.1±0.2°、11.5±0.2°、16.0±0.2°、16.2±0.2°、16.9±0.2°、19.0±0.2°、20.9±0.2°和24.9±0.2°的衍射角(2θ)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体A，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在7.3±0.2°、8.2±0.2°、11.1±0.2°、11.5±0.2°、11.9±0.2°、16.0±0.2°、16.2±0.2°、16.9±0.2°、19.0±0.2°、20.9±0.2°、24.0±0.2°和24.9±0.2°的衍射角(2θ)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体A，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在以下衍射角(2θ)处的峰：
Figure PCTCN2020091471-appb-000008
Figure PCTCN2020091471-appb-000009
在部分实施方案中，所述式(I)的化合物的晶体A，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在以下衍射角(2θ)处的峰：
Figure PCTCN2020091471-appb-000010
Figure PCTCN2020091471-appb-000011
在部分实施方案中，所述式(I)的化合物，使用Cu-Kα辐射，以2θ角度表示的晶体A的XRPD图谱包括在以下衍射角(2θ)处的峰：
Figure PCTCN2020091471-appb-000012
Figure PCTCN2020091471-appb-000013
在部分实施方案中，所述式(I)的化合物的晶体A，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括与图1所示基本上相同的衍射角(2θ)处的峰。在部分实施方案中，所述式(I)的化合物的晶体A，使用Cu-Kα辐射，以2θ角度表示的XRPD峰位与图1所示基本上相同。在部分实施方案中，所述式(I)的化合物的晶体A的XRPD图谱与图1基本上相同。
在部分实施方案中，本申请的式(I)的化合物的晶体A的DSC图谱包括在约142±5℃(起始温度)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体A的DSC图谱在约130℃至160℃范围内具有吸热峰。在部分实施方案中，所述式(I)的化合物的晶体A的DSC图谱包括与图2所示基本上相同的温度处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体A的DSC图谱的特征峰位与图2所示基本上相同。
在部分实施方案中，所述式(I)的化合物的晶体A的TGA图谱与图3基本上相同。
在部分实施方案中，本申请的式(I)的化合物的晶体A为非溶剂合物。在部分实施方案中，本申请的式(I)的化合物的晶体A为无水晶型。
式(I)的化合物的晶体B
根据本申请的一个实施方案，本申请提供式(I)的化合物的晶体B。所述式(I)的化合物的晶体B，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在7.5±0.2°、10.8±0.2°、12.4±0.2°、14.7±0.2°、18.2±0.2°和25.3±0.2°的衍射角(2θ)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体B，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在7.5±0.2°、10.8±0.2°、12.4±0.2°、14.7±0.2°、14.8±0.2°、15.0±0.2°、16.4±0.2°、17.1±0.2°、18.2±0.2°、20.9±0.2°、21.2±0.2°、23.4±0.2°和25.3±0.2°的衍射角(2θ)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体B，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在7.5±0.2°、10.8±0.2°、12.4±0.2°、14.7±0.2°、14.8±0.2°、15.0±0.2°、16.4±0.2°、17.1±0.2°、18.2±0.2°、19.2±0.2°、20.1±0.2°、20.9±0.2°、21.2±0.2°、23.4±0.2°、25.3±0.2°、28.5±0.2°、30.3±0.2°、33.8±0.2°、35.8±0.2°和36.8±0.2°的衍射角(2θ)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体B，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在以下衍射角(2θ)处的峰：
Figure PCTCN2020091471-appb-000014
Figure PCTCN2020091471-appb-000015
在部分实施方案中，所述式(I)的化合物的晶体B，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在以下衍射角(2θ)处的峰：
Figure PCTCN2020091471-appb-000016
在部分实施方案中，所述式(I)的化合物的晶体B，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在以下衍射角(2θ)处的峰：
Figure PCTCN2020091471-appb-000017
Figure PCTCN2020091471-appb-000018
在部分实施方案中，所述式(I)的化合物的晶体B，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括与图4所示基本上相同的衍射角(2θ)处的峰。在部分实施方案中，所述式(I)的化合物的晶体B，使用Cu-Kα辐射，以2θ角度表示的XRPD峰位与图4所示基本上相同。
在部分实施方案中，本申请的式(I)的化合物的晶体B的DSC图谱包括在约64±5℃和142±5℃(起始温度)处的吸热峰。在部分实施方案中，所述式(I)的化合物的晶体B的DSC图谱在约55℃至80℃范围内130℃至150℃范围内具有吸热峰。在部分实施方案中，所述式(I)的化合物的晶体B的DSC图谱包括与图5所示基本上相同的温度处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体B的DSC图谱的特征峰位与图5所示基本上相同。
在部分实施方案中，本申请的式(I)的化合物的晶体B的热重分析(TGA)图谱在约60±10℃处失重，失重百分比为5～8％，优选为6～7％，进一步优选为6.7％。在部分实施方案中，所述式(I)的化合物的晶体B的TGA图谱包括与图6所示基本上相同的失重温度。在部分实施方案中，所述式(I)的化合物的晶体B的TGA图谱与图6基本上相同。
在部分实施方案中，本申请的式(I)的化合物的晶体B为乙醚溶剂合物，式(I)的化合物与溶剂的摩尔比为1:0.5。
式(I)的化合物的晶体C
根据本申请的一个实施方案，本申请提供式(I)的化合物的晶体C。所述式(I)的化合物的晶体C，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在7.8±0.2°、14.6±0.2°、17.1±0.2°、21.6±0.2°和22.7±0.2°的衍射角(2θ)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体C，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在7.8±0.2°、14.6±0.2°、15.6±0.2°、17.1±0.2°、20.4±0.2°、20.6±0.2°、21.6±0.2°、22.7±0.2°、29.3±0.2°、29.6±0.2°和31.3±0.2°的衍射角(2θ)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体C，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在7.8±0.2°、9.6±0.2°、10.8±0.2°、12.7±0.2°、13.1±0.2°、14.6±0.2°、15.6±0.2°、17.1±0.2°、18.6±0.2°、20.4±0.2°、20.6±0.2°、21.1±0.2°、21.6±0.2°、22.3±0.2°、22.7±0.2°、23.6±0.2°、27.2±0.2°、27.8±0.2°、28.7±0.2°、29.3±0.2°、29.6±0.2°和31.3±0.2°的衍射角(2θ)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体C，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在以下衍射角(2θ)处的峰：
Figure PCTCN2020091471-appb-000019
Figure PCTCN2020091471-appb-000020
在部分实施方案中，所述式(I)的化合物的晶体C，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在以下衍射角(2θ)处的峰：
Figure PCTCN2020091471-appb-000021
在部分实施方案中，所述式(I)的化合物的晶体C，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在以下衍射角(2θ)处的峰：
Figure PCTCN2020091471-appb-000022
Figure PCTCN2020091471-appb-000023
在部分实施方案中，所述式(I)的化合物的晶体C，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括与图7所示基本上相同的衍射角(2θ)处的峰。在部分实施方案中，所述式(I)的化合物的晶体C，使用Cu-Kα辐射，以2θ角度表示的XRPD峰位与图7所示基本上相同。
在部分实施方案中，本申请的式(I)的化合物的晶体C的DSC图谱包括在约103±5℃和141±5℃(起始温度)处的吸热峰。在部分实施方案中，所述式(I)的化合物的晶体C的DSC图谱在约80℃至115℃范围内130℃至150℃范围内具有吸热峰。在部分实施方案中，所述式(I)的化合物的晶体C的DSC图谱包括与图8所示基本上相同的温度处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体C的DSC图谱的特征峰位与图8所示基本上相同。
在部分实施方案中，本申请的式(I)的化合物的晶体C的热重分析(TGA)图谱在约80℃～100℃处失重，失重百分比为7～11％，优选为8～10％，进一步优选为9.2％。在部分实施方案中，所述式(I)的化合物的晶体C的TGA图谱包括与图9所示基本上相同的失重温度。在部分实施方案中，所述式(I)的化合物的晶体C的TGA图谱与图9基本上相同。
在部分实施方案中，本申请的式(I)的化合物的晶体C为乙酸乙酯溶剂合物，式(I)的化合物与溶剂的摩尔比为1:0.5。
式(I)的化合物的晶体D
根据本申请的一个实施方案，本申请提供式(I)的化合物的晶体D。所述式(I)的化合物的晶体D，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在10.8±0.2°、14.6±0.2°、14.7±0.2°、20.3±0.2°、21.4±0.2°、26.5±0.2°和31.2±0.2°的衍射角(2θ)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体D，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在10.8±0.2°、13.1±0.2°、14.6±0.2°、14.7±0.2°、17.0±0.2°、20.1±0.2°、20.3±0.2°、20.5±0.2°、20.7±0.2°、21.0±0.2°、21.4±0.2°、26.5±0.2°和31.2±0.2°的衍射角(2θ)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体D，使用Cu-Kα辐射，以2θ角度表 示的XRPD图谱包括在7.6±0.2°、10.8±0.2°、13.1±0.2°、14.6±0.2°、14.7±0.2°、15.4±0.2°、16.1±0.2°、17.0±0.2°、19.9±0.2°、20.1±0.2°、20.3±0.2°、20.5±0.2°、20.7±0.2°、21.0±0.2°、21.4±0.2°、22.5±0.2°、23.3±0.2°、23.5±0.2°、26.5±0.2°、30.2±0.2°、31.2±0.2°和32.1±0.2°的衍射角(2θ)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体D，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 2θ(°)±0.2° 2θ(°)±0.2°
7.65 20.30 26.47
10.76 20.50 27.48
13.12 20.73 28.03
14.56 20.98 30.20
14.68 21.36 31.16
15.39 22.48 32.06
16.15 23.25 32.85
16.96 23.52 34.76
19.50 24.69 35.20
19.86 25.27 37.35
20.10 26.02 -
在部分实施方案中，所述式(I)的化合物的晶体D，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在以下衍射角(2θ)处的峰：
Figure PCTCN2020091471-appb-000024
在部分实施方案中，所述式(I)的化合物的晶体D，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在以下衍射角(2θ)处的峰：
Figure PCTCN2020091471-appb-000025
Figure PCTCN2020091471-appb-000026
在部分实施方案中，所述式(I)的化合物的晶体D，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括与图10所示基本上相同的衍射角(2θ)处的峰。在部分实施方案中，所述式(I)的化合物的晶体D，使用Cu-Kα辐射，以2θ角度表示的XRPD峰位与图10所示基本上相同。
在部分实施方案中，本申请的式(I)的化合物的晶体D的DSC图谱包括在约84±5℃和142±5℃(起始温度)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体B的DSC图谱在约75℃至100℃范围内130℃至155℃范围内具有吸热峰。在部分实施方案中，所述式(I)的化合物的晶体D的DSC图谱包括与图11所示基本上相同的温度处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体D的DSC图谱的特征峰位与图11所示基本上相同。
在部分实施方案中，本申请的式(I)的化合物的晶体D的热重分析(TGA)图谱在约70℃～120℃处失重，失重百分比为8～12％，优选为9～11％，进一步优选为10.1％。在部分实施方案中，所述式(I)的化合物的晶体D的TGA图谱包括与图12所示基本上相同的失重温度。在部分实施方案中，所述式(I)的化合物的晶体D的TGA图谱与图12基本上相同。
在部分实施方案中，本申请的式(I)的化合物的晶体D为乙酸异丙酯溶剂合物，式(I)的化合物与溶剂的摩尔比为1:0.5。
式(I)的化合物的晶体E
根据本申请的一个实施方案，本申请提供式(I)的化合物的晶体E。所述式(I)的化合物的晶体E，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在10.8±0.2°、14.7±0.2°、15.8±0.2°、16.6±0.2°、17.2±0.2°和23.8±0.2°的衍射角(2θ)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体E，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在10.8±0.2°、13.1±0.2°、14.7±0.2°、15.0±0.2°、15.6±0.2°、15.8±0.2°、16.6±0.2°、17.2±0.2°、19.2±0.2°、22.7±0.2°、23.5±0.2°和23.8±0.2°的衍射角(2θ)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体E，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在7.8±0.2°、10.8±0.2°、12.2±0.2°、12.7±0.2°、13.1±0.2°、14.7±0.2°、15.0±0.2°、15.6±0.2°、15.8±0.2°、16.6±0.2°、17.2±0.2°、19.2±0.2°、19.9±0.2°、20.1±0.2°、21.0±0.2°、21.7±0.2°、22.7±0.2°、23.5±0.2°、23.8±0.2°、27.6±0.2°、27.8±0.2°、30.1±0.2°和32.0±0.2°的衍射角(2θ)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体E，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在以下衍射角(2θ)处的峰：
Figure PCTCN2020091471-appb-000027
在部分实施方案中，所述式(I)的化合物的晶体E，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在以下衍射角(2θ)处的峰：
Figure PCTCN2020091471-appb-000028
Figure PCTCN2020091471-appb-000029
在部分实施方案中，所述式(I)的化合物的晶体E，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在以下衍射角(2θ)处的峰：
Figure PCTCN2020091471-appb-000030
在部分实施方案中，所述式(I)的化合物的晶体E，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括与图13所示基本上相同的衍射角(2θ)处的峰。在部分实施方案中，所述式(I)的化合物的晶体E，使用Cu-Kα辐射，以2θ角度表示的XRPD峰位与图13所示基本上相同。
在部分实施方案中，本申请的式(I)的化合物的晶体E的DSC图谱包括在约81±5℃和140±5℃(起始温度)处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体B的DSC图谱在约75℃至110℃范围内130℃至155℃范围内具有吸热峰。在部分实施方案中，所述式(I)的化合物的晶体E的DSC图谱包括与图14所示基本上相同的温度处的特征峰。在部分实施方案中，所述式(I)的化合物的晶体E的DSC图谱的特征峰位与图14所示基本上相同。
在部分实施方案中，本申请的式(I)的化合物的晶体E的热重分析(TGA)图谱在约70℃ ～120℃处失重，失重百分比为7～11％，优选为8～10％，进一步优选为8.8％。在部分实施方案中，所述式(I)的化合物的晶体E的TGA图谱包括与图15所示基本上相同的失重温度。在部分实施方案中，所述式(I)的化合物的晶体E的TGA图谱与图15基本上相同。
在部分实施方案中，本申请的式(I)的化合物的晶体E为碳酸二甲酯溶剂合物，式(I)的化合物与溶剂的摩尔比为1:0.5。
式(I)的化合物的无定形形式
根据本申请的一个实施方案，本申请提供式(I)的化合物的无定形形式，所述无定形形式，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱不具有衍射峰。在部分实施方案中，所述无定形形式的XRPD图谱与图16基本相同。
根据本申请的一些实施方案，采用室温缓慢挥发法制备晶体，所述方法包括将式(I)的化合物在容器中的溶剂中溶解形成澄清溶液(视需要可将溶液进行过滤以得到澄清溶液，过滤后可视需要补加溶剂)，将容器密封(例如使用封口膜)，在封口处留小孔或缝隙，将所述澄清溶液放置，使溶剂挥发，得到晶体。在采用室温缓慢挥发法制备晶体的一些实施方案中，所述溶剂包括但不限于醇类、醚类或酯类，具体例如甲醇、乙醚、乙酸乙酯、乙酸异丙酯、或碳酸二甲酯，或者由上述溶剂中的两种或更多种形成的混合溶剂。在采用室温缓慢挥发法制备晶体的一些实施方案中，所述式(I)的化合物与溶剂的重量体积比(mg/mL)为(1-50):1，优选(1-30):1。在一些实施方案中，过滤得到澄清溶液后，进一步补加一定量的相同种类溶剂，优选地，补加溶剂与原溶剂的体积比为20:1～5。在一些实施方案中，所述放置可在室温下进行。
在本申请的一些实施方案中，对本申请采用室温缓慢挥发法制备晶体所使用的溶剂及结果举例说明如下：
溶剂 固体晶体
甲醇 晶体A
乙醚 晶体B
乙酸乙酯 晶体C
乙酸异丙酯 晶体D
碳酸二甲酯 晶体E
根据本申请的一些实施方案，采用缓慢降温法制备晶体，所述方法包括将式(I)的化合物加入至溶剂中，加热搅拌使其溶解，将所得澄清溶液(视需要可将溶液进行过滤以得到澄清溶液)放置，缓慢降温，得到晶体。在采用缓慢降温法制备晶体的一些实施方案中，所述溶剂包括但不限于芳烃类或醚类，或者上述溶剂的混合溶剂，具体例如甲苯、或异丙醚。在采用缓慢降温法制备晶体的一些实施方案中，所述缓慢降温的降温速度为0.1-0.5℃/分钟，优选0.1-0.3℃/分钟，更优选0.1℃/分钟。在一些实施方案中，加热温度为50-90℃，优选60-80℃，例如65℃、70℃、或75℃。在一些实施方案中，所述降温结束时的温度为室温或0-10℃，例如3℃、5℃或7℃。在采用缓慢降温法制备晶体的一些实施方案中，所述式(I)的化合物与溶剂的重量体积比(mg/mL)为(5-120):1，优选(10-100):1。在一些实施方案中，搅拌时间为10-50分钟；优选30分钟。
在本申请的一些实施方案中，对本申请采用缓慢降温法制备晶体所使用的溶剂及结果举例说明如下：
溶剂 固体晶体
甲苯 晶体A
异丙醚 晶体A
根据本申请的一些实施方案，采用反溶剂添加法制备晶体，所述方法包括但不限于将式(I)的化合物在良溶剂中溶解，形成澄清溶液(视需要可将溶液进行过滤以得到澄清溶液；得到澄清溶液后视需要可加热)，然后向所述澄清溶液中添加反溶剂，在搅拌(所述搅拌可在保温、室温或者降温条件(例如降温至0-20℃，优选0-10℃，例如0℃、5℃或10℃下进行)下析出晶体，或者静置(例如于室温下放置)(优选同时缓慢地挥发溶剂)从而析出晶体。在采用反溶剂添加法制备晶体的一些实施方案中，所述良溶剂包括但不限于醇类、酮类、腈类或醚类(包括环状醚类或链状醚类)，例如甲醇、乙醇、异丙醇、正丙醇、正丁醇、丙酮、丁酮、乙腈、或四氢呋喃等。在采用反溶剂添加法制备晶体的一些实施方案中，所述反溶剂包括但不限于无机溶剂，例如水。在采用反溶剂添加法制备晶体的一些实施方案中，所述良溶剂与反溶剂的体积比为4:(1-5)，优选为4:3。在一些实施方案中，所述式(I)的化合物与良溶剂的重量体积比(mg/mL)为(120-80):1，优选为100:1。
在本申请的一些实施方案中，对本申请采用反溶剂添加法制备晶体所使用的溶剂及结果举例说明如下：
Figure PCTCN2020091471-appb-000031
根据本申请的一些实施方案，采用室温悬浮搅拌法制备晶体，所述方法包括但不限于将式(I)的化合物的固体形式(例如无定形形式)加入溶剂中得到悬浮液，于室温搅拌，然后分离得到晶体。在采用室温悬浮搅拌法制备晶体的一些实施方案中，所述溶剂包括但不限于无机溶剂(例如水)以及有机溶剂(如烷烃类、醚类或芳烃类)，例如水、正己烷、正庚烷、环己烷、正戊烷、异丙醚、或甲苯，或者选自上述溶剂中的两种或更多种的混合溶剂。在采用室温悬浮搅拌法制备晶体的一些实施方案中，所述式(I)的化合物与溶剂的重量体积比(mg/mL)为(10-50):1，优选(20-40):1。
在本申请的一些实施方案中，对本申请采用室温悬浮搅拌法制备晶体所使用的溶剂及结果举例说明如下：
Figure PCTCN2020091471-appb-000032
根据本申请的一些实施方案，采用反溶剂添加法制备无定形形式，所述方法包括但不限于将式(I)的化合物在良溶剂中溶解，形成澄清溶液，然后向所述澄清溶液中添加反溶剂，从而析出无定形形式。在采用反溶剂添加法制备无定形形式的一些实施方案中，所述良溶剂包括但不限于酯类和醚类，例如乙酸乙酯、甲基叔丁醚、异丙醚等。在采用反溶剂添加法制备无定形形式的一些实施方案中，所述反溶剂包括但不限于烃类，例如正庚烷。
根据本申请的一些实施方案，采用减压浓缩法制备无定形形式，所述方法包括但不限于将式(I)的化合物在良溶剂中溶解，形成澄清溶液，然后减压浓缩溶剂，从而析出无定形形式。在采用减压浓缩法制备无定形形式的一些实施方案中，所述良溶剂包括但不限于醇类，例如甲醇等。在采用减压浓缩法制备晶体的一些实施方案中，所述式(I)的化合物与溶剂的重量体积比(mg/mL)为(10-50):1，优选(20-40):1。
PCT/CN2018/115615号国际专利申请的公开文本WO2019105234A1公开了本申请的式(I)的化合物的制备方法，例如实施例5，还公开了该化合物的治疗活性，参见药理学测试，包括试验例1-4。本申请将WO2019105234A1的全文引入作为参考。
本申请的式(I)的化合物的式(I)的化合物的晶体A、B、C、D或E、或者式(I)的化合物的无定形形式，对PPARδ具有明显的激动作用，并且对HepG2细胞和HEK293细胞的毒性低，对hERG无明显的抑制作用，无导致心脏QT间期延长的安全性隐患。
药物组合物和用途
本申请的另一目的在于提供一种药物组合物，其包含：
i)本申请的式(I)的化合物的固体形式，更特别是式(I)的化合物的晶体A、B、C、D或E、或者式(I)的化合物的无定形形式，或其任意组合；以及
ii)一种或多种药学上可接受的载体。
本申请的另一目的在于提供用于治疗个体的诸如非酒精性脂肪性肝病(NAFLD)的过氧化物酶体增殖物激活受体(PPAR)相关疾病的方法，其包括向有此需要的个体给药治疗有效量的本申请的式(I)的化合物的式(I)的化合物的晶体A、B、C、D或E、或者式(I)的化合物的无定形形式，或其任意组合。
本申请的另一目的在于提供本申请的式(I)的化合物的晶体A、B、C、D或E、或者式(I)的化合物的无定形形式，或其任意组合，其用于治疗个体的诸如非酒精性脂肪性肝病(NAFLD)的过氧化物酶体增殖物激活受体(PPAR)相关疾疾病。
本申请的另一目的在于提供本申请的式(I)的化合物的晶体A、B、C、D或E、或者式(I)的化合物的无定形形式，或其任意组合在制备用于治疗个体的诸如非酒精性脂肪性肝病(NAFLD)的过氧化物酶体增殖物激活受体(PPAR)相关疾病的药物中的用途。
根据本申请的一些实施方案，本申请所述的非酒精性脂肪性肝病(NAFLD)的过氧化物酶体增殖物激活受体(PPAR)相关疾病包括非酒精性脂肪性肝病(NAFLD)。
如本文中所使用的术语“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本申请的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润 剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。
本申请的药物组合物可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射、静脉内、动脉内、皮下、腹膜内、肌内或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
对于这些给药途径，可以适合的剂型给药本申请的组合物。
所述剂型可为固体制剂、半固体制剂、液体制剂或气态制剂，包括但不限于片剂、胶囊剂、散剂、颗粒剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、混悬剂、酏剂、糖浆剂。
本申请所述的药物组合物可以通过本领域熟知的任何方法来制备，例如通过混合、溶解、制粒、糖包衣、碾磨、乳化、冻干等处理来制备。
如本文中所使用的术语“治疗有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
所给药的本申请的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg，例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计为约0.007mg/日至约3500mg/日，例如约0.7mg/日至约700mg/日。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而在其它情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。
本申请的化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg，适合地是0.1-500mg，优选0.5-300mg，更优选1-150mg，特别优选1-50mg，例如1.5mg、2mg、4mg、10mg和25mg等。
除非另外说明，否则如本文中所使用，术语“治疗”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本申请中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
实施例
以下将结合实施例更详细地解释本申请，本申请的实施例仅用于说明本申请的技术方案，并非用于限定本申请的范围，本领域技术人员可进行一些非本质的改进和调整，仍属于本申请的保护范围。
实验所用的测试仪器信息和方法：
方法1、X射线粉末衍射(XRPD)
采用X`Pert3 Powder粉末衍射仪，该仪器采用Cu靶照射，Cu Kα1＝1.5406A，单色辐射，电压：40kV、电流：40mA激发，在室温下使用Absolute scan进行检测。检测范围 在3.5°至40°、步长为0.013°、停留时间为50s，扫描1次。
方法2、差示扫描量热分析(DSC)
设备信息：DSC2500(TA)
测试方法：热分析法(中国药典2015年版四部通则0661)
测试条件：升温速率10℃/min，起始温度35.0℃
样品制备：称取供试品约2～5mg，平铺于60μl带孔铝坩埚中，以空铝坩埚作为参比，
进样测定方法3、热重分析(TGA)
设备信息：Mettler-Toledo TGA
测试方法：热分析法(中国药典2015年版四部通则0661)
测试条件：起始温度35.0℃，终止温度500.0℃，升温速率10℃/min
实验所用的化合物样品的制备方法
式(I)的化合物样品按照PCT/CN2018/115615号国际专利申请中实施例5所记载的方法制备。
实施例6、7所使用的式(I)的化合物的无定形样品根据实施例12所记载的方法制备。
实施例1
称取50mg的式(I)的化合物样品在4mL甲醇中溶解澄清，通过室温挥发，除去溶剂；析出、收集固体。对固体进行XRPD检测，所得XRPD图谱如图1中所示。所得固体即为本申请式(I)的化合物的晶体A，对其进行差示扫描量热分析(DSC)，所得DSC图谱如图2所示，对其进行热重分析(TGA)，所得TGA图谱如图3所示。
实施例2.
称取200mg的式(I)的化合物样品在2.0mL甲苯中，搅拌加热至70℃溶澄清，保温搅拌30min；静置降温至室温，析出、收集固体。对所得固体进行XRPD检测，结果显示得到的产物与实施例1所得到的晶体A相同。
实施例3.
称取200mg的式(I)的化合物样品在17mL异丙醚中，搅拌加热至70℃溶澄清，保温搅拌30min；静置降温至室温，析出、收集固体。对所得固体进行XRPD检测，结果显示得到的产物与实施例1所得到的晶体A相同。
实施例4.
称取2.0g的式(I)的化合物样品，室温下加入20mL乙醇至刚好溶解澄清，加热至50℃，保温滴加水15mL，滴毕保温搅拌2h，然后搅拌降温至室温，保温搅拌16h，过滤，50℃真空干燥6h收集固体。对所得固体进行XRPD检测，结果显示得到的产物与实施例1所得到的晶体A相同。
实施例5.
称取式(I)的化合物样品50mg若干份，装入不同的玻璃瓶中；分别用下表中任意一种良溶剂溶解至澄清；缓慢向其中滴加水，至浑浊；加热，溶清后补加水，加热至溶清；降至室温后，静置析晶。
Figure PCTCN2020091471-appb-000033
Figure PCTCN2020091471-appb-000034
实施例6.
称取30mg的式(I)的化合物的无定形样品在1.0mL水中悬浮搅拌48h，过滤、收集固体。对所得固体进行XRPD检测，结果显示得到的产物与实施例1所得到的晶体A相同。
实施例7.
采用与实施例6相似的方法，区别在于将实施例6中的水分别替换为正己烷、正庚烷、环己烷、正戊烷、异丙醚、或甲苯，所得固体进行XRPD检测的结果显示得到的产物与实施例1所得到的晶体A相同。
实施例8.
称取50mg的式(I)的化合物样品在2.0mL乙醚中溶解澄清，过滤，收集滤液并补加300μL乙醚；室温挥发，析出固体，收集固体。对所得固体进行XRPD检测，结果如图4中所示。所得固体即为本申请式(I)的化合物的晶体B，对其进行差示扫描量热分析(DSC)，所得DSC图谱如图5所示，对其进行热重分析(TGA)，所得TGA图谱如图6所示。
实施例9.
称取50mg的式(I)的化合物样品在2.0mL乙酸乙酯中溶解澄清，过滤，收集滤液并补加300μL乙酸乙酯；室温挥发析出固体、收集固体。对所得固体进行XRPD检测，结果如图7中所示。所得固体即为本申请式(I)的化合物的晶体C，对其进行差示扫描量热分析(DSC)，所得DSC图谱如图8所示，对其进行热重分析(TGA)，所得TGA图谱如图9所示。
实施例10.
称取50mg的式(I)的化合物样品在2.0mL乙酸异丙酯中溶解澄清，过滤，收集滤液并补加300μL乙酸异丙酯；室温挥发析出固体、收集固体。对所得固体进行XRPD检测，结果如图10中所示。所得固体即为本申请式(I)的化合物的晶体D，对其进行差示扫描量热分析(DSC)，所得DSC图谱如图11所示，对其进行热重分析(TGA)，所得TGA图谱如图12所示。
实施例11.
称取50mg的式(I)的化合物样品在2.0mL碳酸二甲酯中溶解澄清，过滤，收集滤液并补加300μL碳酸二甲酯；室温挥发析出固体、收集固体。对所得固体进行XRPD检测，结果如图13中所示。所得固体即为本申请式(I)的化合物的晶型E，对其进行差示扫描量热分析(DSC)，所得DSC图谱如图14所示，对其进行热重分析(TGA)，所得TGA图谱如 图15所示。
实施例12.
称取200mg的式(I)的化合物样品在20ml甲醇中溶解澄清，减压浓缩，除去溶剂；析出、收集固体。对所得固体进行XRPD检测，所得XRPD图谱如图16中所示，为无定形。
实施例13.
称取30mg的式(I)的化合物的样品，室温下加入乙酸乙酯至溶解澄清，缓慢加入正庚烷，至大量固体析出，过滤、收集固体。对所得固体进行XRPD检测，其XRPD图谱不具有衍射峰，说明得到的产物为无定形。
实施例14.
称取30mg的式(I)的化合物的样品，室温下加入甲基叔丁基醚至溶解澄清，缓慢加入正庚烷，至大量固体析出，过滤、收集固体。对所得固体进行XRPD检测，其XRPD图谱不具有衍射峰，说明得到的产物为无定形。
实施例15.
称取30mg的式(I)的化合物的样品，室温下加入异丙醚至溶解澄清，缓慢加入正庚烷，至大量固体析出，过滤、收集固体。对所得固体进行XRPD检测，其XRPD图谱不具有衍射峰，说明得到的产物为无定形。
实验例1：大鼠药代动力学(PK)研究
通过灌胃(PO)分别给予雄性SD大鼠晶体A样品，考察药代动力学特点。给药剂量均为5mg/kg，利用0.5％MC(甲基纤维素钠)作为溶媒配置晶体A的混悬液。给药组在PO给药前(0h)以及给药后0.083、0.17、0.25、0.5、1、2、4、6、8和24h等时间点收集全血，全血采用EDTA.K 2抗凝，离心后得到血浆样品，保存于-80℃待测。本实验每组动物各平行三只。
血浆样品经沉淀蛋白处理后进行LC-MS/MS分析。应用WinNonlin 6.3软件，采用非房室模型计算药代动力学参数，结果见表1。
表1：通过PO给药的化合物晶体A在大鼠体内血液中的药代动力学参数
Figure PCTCN2020091471-appb-000035
如表1所示，通过以5mg/kg的剂量PO给予的晶体A在大鼠血浆中具有较好的暴露量。
实验例2稳定性试验
在本实验例中，采用高温、高湿试验对晶型A的化学稳定性进行了研究。
纯度测试方法：采用高效液相色谱法(中国药典2015年版四部通则0512)测定。
色谱柱：用苯基键合硅胶为填充剂；
流动相A：5mM乙酸铵(pH 4.0)；
流动相B：乙腈(其中含有0.05％乙酸)；
检测波长：230nm。
洗脱条件：梯度洗脱。
实验例2-1高温稳定性试验
将晶型A放置于密封洁净的玻璃瓶中，然后置于60℃恒温干燥箱中，分别于第11天和第30天取样检测杂质含量，纯度如表2所示：
表2：晶型A的高温稳定性数据
时间 纯度/％
0天 99.51
11天 99.53
30天 99.54
从表2中可以得出，晶型A在高温条件下纯度无明显变化。XRPD检测说明放置30天后晶型也未发生变化，说明晶型A具有耐高温性。
实验例2-2高湿稳定性试验
将式I化合物晶型A均摊至敞口培养皿中，厚度≤5mm，置于室温下(25±2℃)，相对湿度RH为92.5％的恒温培养箱中，分别于第11天和第30天取样检测杂质含量，纯度结果如表3所示：
表3：晶型A的高湿度稳定性数据
时间 纯度/％
0天 99.51
10天 99.53
30天 99.54
从表3中可以得出，晶型A在高湿条件下纯度无明显变化，XRPD检测说明放置30天后晶型也未发生变化，即具有耐高湿性。
上述具体实施方式对本申请作进一步的详细描述。但不应将此理解为本申请上述主题的范围仅限于所列的实施例，凡基于本申请内容所实施的技术方案均落入于本申请的范围。

Claims (16)

  1. 式(I)的化合物的晶体A：
    Figure PCTCN2020091471-appb-100001
    所述式(I)的化合物的晶体A，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在11.1±0.2°、11.5±0.2°、16.2±0.2°、17.0±0.2°、19.0±0.2°和24.9±0.2°的衍射角(2θ)处的特征峰；优选包括在7.3±0.2°、11.1±0.2°、11.5±0.2°、16.0±0.2°、16.2±0.2°、16.9±0.2°、19.0±0.2°、20.9±0.2°和24.9±0.2°的衍射角(2θ)处的特征峰；
    优选包括在7.3±0.2°、8.2±0.2°、11.1±0.2°、11.5±0.2°、11.9±0.2°、16.0±0.2°、16.2±0.2°、16.9±0.2°、19.0±0.2°、20.9±0.2°、24.0±0.2°和24.9±0.2°的衍射角(2θ)处的特征峰；
    优选所述式(I)的化合物的晶体A的XRPD图谱与图1基本上相同；
    优选所述式(I)的化合物的晶体A的DSC图谱在约130℃至160℃范围内具有吸热峰。
  2. 制备权利要求1的式(I)的化合物的晶体A的方法，所述方法选自反溶剂添加法、室温缓慢挥发法、室温悬浮搅拌法和缓慢降温法。
  3. 式(I)的化合物的晶体B：
    Figure PCTCN2020091471-appb-100002
    所述式(I)的化合物的晶体B，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在7.5±0.2°、10.8±0.2°、12.4±0.2°、14.7±0.2°、18.2±0.2°和25.3±0.2°的衍射角(2θ)处的特征峰；优选包括在7.5±0.2°、10.8±0.2°、12.4±0.2°、14.7±0.2°、14.8±0.2°、15.0±0.2°、16.4±0.2°、17.1±0.2°、18.2±0.2°、20.9±0.2°、21.2±0.2°、23.4±0.2°和25.3±0.2°的衍射角(2θ)处的特征峰；
    优选包括在7.5±0.2°、10.8±0.2°、12.4±0.2°、14.7±0.2°、14.8±0.2°、15.0±0.2°、16.4±0.2°、17.1±0.2°、18.2±0.2°、19.2±0.2°、20.1±0.2°、20.9±0.2°、21.2±0.2°、23.4±0.2°、25.3±0.2°、28.5±0.2°、30.3±0.2°、33.8±0.2°、35.8±0.2°和36.8±0.2°的衍射角(2θ)处的特征峰；
    优选所述式(I)的化合物的晶体B的XRPD图谱与图4基本上相同。
  4. 制备权利要求3的式(I)的化合物的晶体B的方法，所述方法为室温缓慢挥发法。
  5. 式(I)的化合物的晶体C：
    Figure PCTCN2020091471-appb-100003
    所述式(I)的化合物的晶体C，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在7.8±0.2°、14.6±0.2°、17.1±0.2°、21.6±0.2°和22.7±0.2°的衍射角(2θ)处的特征峰；优选包括在7.8±0.2°、14.6±0.2°、15.6±0.2°、17.1±0.2°、20.4±0.2°、20.6±0.2°、21.6±0.2°、22.7±0.2°、29.3±0.2°、29.6±0.2°和31.3±0.2°的衍射角(2θ)处的特征峰；
    优选包括在7.8±0.2°、9.6±0.2°、10.8±0.2°、12.7±0.2°、13.1±0.2°、14.6±0.2°、15.6±0.2°、17.1±0.2°、18.6±0.2°、20.4±0.2°、20.6±0.2°、21.1±0.2°、21.6±0.2°、22.3±0.2°、22.7±0.2°、23.6±0.2°、27.2±0.2°、27.8±0.2°、28.7±0.2°、29.3±0.2°、29.6±0.2°和31.3±0.2°的衍射角(2θ)处的特征峰；
    优选所述式(I)的化合物的晶体C的XRPD图谱与图7基本上相同。
  6. 制备权利要求5的式(I)的化合物的晶体C的方法，所述方法为室温缓慢挥发法。
  7. 式(I)的化合物的晶体D：
    Figure PCTCN2020091471-appb-100004
    所述式(I)的化合物的晶体D，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在10.8±0.2°、14.6±0.2°、14.7±0.2°、20.3±0.2°、21.4±0.2°、26.5±0.2°和31.2±0.2°的衍射角(2θ)处的特征峰；优选包括在10.8±0.2°、13.1±0.2°、14.6±0.2°、14.7±0.2°、17.0±0.2°、20.1±0.2°、20.3±0.2°、20.5±0.2°、20.7±0.2°、21.0±0.2°、21.4±0.2°、26.5±0.2°和31.2±0.2°的衍射角(2θ)处的特征峰；
    优选包括在7.6±0.2°、10.8±0.2°、13.1±0.2°、14.6±0.2°、14.7±0.2°、15.4±0.2°、16.1±0.2°、17.0±0.2°、19.9±0.2°、20.1±0.2°、20.3±0.2°、20.5±0.2°、20.7±0.2°、21.0±0.2°、21.4±0.2°、22.5±0.2°、23.3±0.2°、23.5±0.2°、26.5±0.2°、30.2±0.2°、31.2±0.2°和32.1±0.2°的衍射角(2θ)处的特征峰；
    优选所述式(I)的化合物的晶体D的XRPD图谱与图10基本上相同。
  8. 制备权利要求7的式(I)的化合物的晶体D的方法，所述方法为室温缓慢挥发法。
  9. 式(I)的化合物的晶体E：
    Figure PCTCN2020091471-appb-100005
    所述式(I)的化合物的晶体E，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱包括在10.8±0.2°、14.7±0.2°、15.8±0.2°、16.6±0.2°、17.2±0.2°和23.8±0.2°的衍射角(2θ)处的特征峰；优选包括在10.8±0.2°、13.1±0.2°、14.7±0.2°、15.0±0.2°、15.6±0.2°、15.8±0.2°、16.6±0.2°、17.2±0.2°、19.2±0.2°、22.7±0.2°、23.5±0.2°和23.8±0.2°的衍射角(2θ)处的特征峰；
    优选包括在7.8±0.2°、10.8±0.2°、12.2±0.2°、12.7±0.2°、13.1±0.2°、14.7±0.2°、15.0±0.2°、15.6±0.2°、15.8±0.2°、16.6±0.2°、17.2±0.2°、19.2±0.2°、19.9±0.2°、20.1±0.2°、21.0±0.2°、21.7±0.2°、22.7±0.2°、23.5±0.2°、23.8±0.2°、27.6±0.2°、27.8±0.2°、30.1±0.2°和32.0±0.2°的衍射角(2θ)处的特征峰；
    优选所述式(I)的化合物的晶体E的XRPD图谱与图13基本上相同。
  10. 制备权利要求9的式(I)的化合物的晶体E的方法，所述方法为室温缓慢挥发法。
  11. 式(I)的化合物的无定形形式：
    Figure PCTCN2020091471-appb-100006
    所述无定形形式，使用Cu-Kα辐射，以2θ角度表示的XRPD图谱不具有衍射峰。
  12. 制备权利要求11的式(I)的化合物的无定形形式的方法，所述方法选自反溶剂添加法和室温缓慢挥发法。
  13. 药物组合物，其包含权利要求1、3、5、7、9和11中任一项的式(I)的化合物的晶体A、B、C、D、E或无定形形式，以及一种或多种药学上可接受的载体。
  14. 权利要求1、3、5、7、9和11中任一项的式(I)的化合物的晶体A、B、C、D、E或无定形形式在制备用于预防或治疗诸如非酒精性脂肪性肝病(NAFLD)的过氧化物酶体增殖物激活受体(PPAR)相关疾病的药物中的用途。
  15. 治疗个体的诸如非酒精性脂肪性肝病(NAFLD)的过氧化物酶体增殖物激活受体(PPAR)相关疾病的方法，其包括向有此需要的个体给药治疗有效量的权利要求1、3、5、7、9和11中任一项的式(I)的化合物的晶体A、B、C、D或E、或者式(I)的化合物的无定形形式，或其任意组合，
    例如所述的非酒精性脂肪性肝病(NAFLD)的过氧化物酶体增殖物激活受体(PPAR)相关疾病包括非酒精性脂肪性肝病(NAFLD)。
  16. 权利要求1、3、5、7、9和11中任一项的式(I)的化合物的晶体A、B、C、D、E或无定形形式，其用于治疗个体的诸如非酒精性脂肪性肝病(NAFLD)的过氧化物酶体增殖物激活受体(PPAR)相关疾疾病，
    例如所述的非酒精性脂肪性肝病(NAFLD)的过氧化物酶体增殖物激活受体(PPAR)相关疾病包括非酒精性脂肪性肝病(NAFLD)。
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