WO2020224208A1 - 吡啶酮衍生物的晶型及制备方法和应用 - Google Patents

吡啶酮衍生物的晶型及制备方法和应用 Download PDF

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WO2020224208A1
WO2020224208A1 PCT/CN2019/115641 CN2019115641W WO2020224208A1 WO 2020224208 A1 WO2020224208 A1 WO 2020224208A1 CN 2019115641 W CN2019115641 W CN 2019115641W WO 2020224208 A1 WO2020224208 A1 WO 2020224208A1
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compound
formula
crystal
crystal form
type
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PCT/CN2019/115641
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English (en)
French (fr)
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邵庆
甘立斌
陈力
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江西彩石医药科技有限公司
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Priority to CN201980005140.9A priority Critical patent/CN111670191B/zh
Priority to CA3139343A priority patent/CA3139343A1/en
Priority to SG11202112354SA priority patent/SG11202112354SA/en
Priority to EP19928278.1A priority patent/EP3967697A4/en
Priority to US17/595,013 priority patent/US20230144122A1/en
Priority to AU2019444375A priority patent/AU2019444375B2/en
Publication of WO2020224208A1 publication Critical patent/WO2020224208A1/zh
Priority to ZA2021/08765A priority patent/ZA202108765B/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems
    • 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 belongs to the field of medicinal chemistry, and specifically relates to the crystal form of a pyridone derivative with influenza virus inhibitory effect, and its preparation method and application.
  • Influenza viruses are highly contagious and easily cause acute respiratory infections, affecting 5%-20% of adults and 20%-30% of children every year. In special groups, such as those over 65 years of age or those suffering from chronic underlying diseases, influenza viruses can easily cause serious complications such as the respiratory system or the cardiovascular system, causing hundreds of thousands of deaths worldwide each year.
  • Neuraminidase inhibitors oseltamivir and zanamivir can inhibit the spread of the virus, but must be taken within 48 hours after infection.
  • influenza viruses are prone to antigenic variation.
  • the Spanish influenza in 1918 was caused by the H1N1 subtype
  • the Asian influenza in 1957 was caused by the H2N2 subtype
  • the Hong Kong influenza in 1968 was caused by the H3N2 subtype
  • the influenza from 2007 to 2008 was caused by Caused by the H5N1 subtype.
  • Influenza viruses are RNA viruses, and their genetic material is single-stranded negative-strand RNA.
  • RNA polymerase is composed of PA, PB1 and PB2 three subunits, and is responsible for the transcription and replication of viral RNA in the infected cell nucleus.
  • the transcription of influenza virus RNA has a special "cap” mechanism.
  • the PB2 subunit is responsible for recognizing and binding the "cap structure" of the host cell mRNA precursor, and the PA subunit is responsible for editing the host cell mRNA precursor, forming primers, and initiating the transcription process. .
  • the PB1 subunit is responsible for the synthesis of viral mRNA.
  • the cap-dependent endonuclease action of the PA subunit is necessary for the life process of the virus, and has a specificity that the host cell does not possess, and is suitable for developing new anti-influenza drugs as a new target.
  • the crystal structure of the active ingredient of the drug often causes differences in various physical and chemical properties of the drug, such as solubility, dissolution rate, melting point, density, hardness, etc., which directly affect the prescription preparation process, storage method, and in vivo pharmacokinetics of the drug.
  • the kinetic performance in turn affects the bioavailability, clinical efficacy and safety of the drug. Therefore, it is very important to study the polymorphism of drugs in depth and to find crystal forms with good properties.
  • the problem to be solved by this application is to provide a novel pyridone derivative, which has high bioavailability and can be transformed into a compound with strong inhibitory activity against influenza virus type A and influenza virus type B after being taken by humans.
  • This application also provides a variety of crystals of novel pyridone derivatives or solvates thereof, and these crystals meet the requirements of medicine in terms of stability, hygroscopicity, solubility and the like.
  • This application also provides the preparation methods of the above-mentioned crystals and their applications in the preparation of anti-influenza virus drugs.
  • one aspect of the present application provides a crystal of a compound of formula (1) or a solvate thereof:
  • the present application provides a type A crystal form of the compound of formula (1), and its X-ray powder diffraction pattern (the radiation source used is Cu-K ⁇ , the same below) at a 2 ⁇ angle of 3.10° ⁇ 0.2 °, 8.74° ⁇ 0.2°, 15.44° ⁇ 0.2°, 21.91° ⁇ 0.2°, there are characteristic peaks.
  • the X-ray powder diffraction pattern of the Form A crystal form of the compound of formula (1) may also be in the 2 ⁇ angles of 13.08° ⁇ 0.2°, 26.35° ⁇ 0.2° and 30.83° ⁇ 0.2° One or more of them have characteristic peaks.
  • thermogravimetric analysis of the type A crystal form of the compound of formula (1) shows that it starts to lose weight when heated to 26.8 ⁇ 2°C, and loses weight when heated to 150 ⁇ 2°C. 0.2%.
  • the type A crystal form of the compound of formula (1) shows an endothermic peak in the spectrum determined by differential scanning calorimetry, indicating that the melting point onset temperature of the type A crystal form is 230.5 ⁇ 2°C, with an endothermic peak at 232 ⁇ 2°C.
  • the type A crystal form of the compound of formula (1) is an amorphous form.
  • the present application provides the B crystal form of the compound of formula (1), and its X-ray powder diffraction pattern at 2 ⁇ angles is 8.42° ⁇ 0.2°, 14.27° ⁇ 0.2°, 16.04° ⁇ There are characteristic peaks at 0.2° and 25.41° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the B crystal form of the compound of formula (1) may also be at one or two of the 2 ⁇ angles of 10.75° ⁇ 0.2°, 16.87° ⁇ 0.2° With characteristic peaks.
  • the X-ray powder diffraction pattern of the type B crystal form of the compound of formula (1) is also 18.21° ⁇ 0.2°, 18.78° ⁇ 0.2°, 19.26° ⁇ 0.2°, 2 ⁇ angles, One of 19.60° ⁇ 0.2°, 20.40° ⁇ 0.2°, 21.39° ⁇ 0.2°, 21.66° ⁇ 0.2°, 23.38° ⁇ 0.2°, 27.32° ⁇ 0.2°, 29.17° ⁇ 0.2° and 34.08° ⁇ 0.2° There are characteristic peaks at one or more places.
  • thermogravimetric analysis of the type B crystal form of the compound of formula (1) shows that it starts to lose weight when heated to 22.6 ⁇ 2°C, and loses weight when heated to 150 ⁇ 2°C 2.2 ⁇ 0.2%.
  • the type B crystal form of the compound of formula (1) has two endothermic peaks in the spectrum determined by differential scanning calorimetry, and the onset temperatures of the two endothermic peaks are respectively 208.5.5 ⁇ 2°C, 233.8 ⁇ 2°C, with endothermic peaks at 213.5 ⁇ 2°C and 235.1 ⁇ 2°C respectively.
  • the type B crystal form of the compound of formula (1) is an anhydrous crystal form.
  • the present application provides the type C crystal form of the compound of formula (1), and its X-ray powder diffraction pattern at 2 ⁇ angles is 7.73° ⁇ 0.2°, 17.13° ⁇ 0.2°, 20.08° ⁇ 0.2 There are characteristic peaks at °, 21.74° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form C crystal form of the compound of formula (1) is also 13.13° ⁇ 0.2°, 13.65° ⁇ 0.2°, 20.98° ⁇ 0.2° and 23.22 at 2 ⁇ angles. There are characteristic peaks at one or more of ° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the type C crystal form of the compound of formula (1) may also be 12.51° ⁇ 0.2°, 14.76° ⁇ 0.2°, 15.21° ⁇ 0.2°, 2 ⁇ angles, One or more of 18.39° ⁇ 0.2° and 24.13° ⁇ 0.2° has characteristic peaks.
  • thermogravimetric analysis of the type C crystal form of the compound of formula (1) shows that it starts to lose weight when heated to 25.9 ⁇ 2°C, and loses weight when heated to 150 ⁇ 2°C 12.1 ⁇ 0.2%.
  • the type C crystal form of the compound of formula (1) has two endothermic peaks in the spectrum determined by differential scanning calorimetry, and the onset temperatures of the two endothermic peaks are respectively 86.8 ⁇ 2°C, 233.9 ⁇ 2°C, and endothermic peaks at 94.9 ⁇ 2°C and 234.8 ⁇ 2°C, respectively.
  • the type C crystal form of the compound of formula (1) is a tetrahydrofuran solvate of the compound of formula (1).
  • the present application provides the D crystal form of the compound of formula (1), and its X-ray powder diffraction pattern at 2 ⁇ angles is 7.94° ⁇ 0.2°, 22.16° ⁇ 0.2°, 28.03° ⁇ 0.2 ° has a characteristic peak.
  • the X-ray powder diffraction pattern of the D crystal form of the compound of formula (1) may also be 15.09° ⁇ 0.2°, 15.50° ⁇ 0.2°, 19.63° ⁇ 0.2°, 2 ⁇ angles, One or more of 23.56° ⁇ 0.2° and 25.86° ⁇ 0.2° have characteristic peaks.
  • the spectra determined by thermogravimetric analysis of the type D crystal form of the compound of formula (1) show that it starts to lose weight when heated to 23.5 ⁇ 2°C, and loses weight when heated to 150 ⁇ 2°C 7.5 ⁇ 0.2%.
  • the pattern D crystal form of the compound of formula (1) measured by differential scanning calorimetry shows two endothermic peaks, and the onset temperatures of the two endothermic peaks are respectively 113.2 ⁇ 2°C, 230.6 ⁇ 2°C, and endothermic peaks at 140.4 ⁇ 2°C and 232.4 ⁇ 2°C, respectively.
  • the D crystal form of the compound of formula (1) is an N-methylpyrrolidone solvate of the compound of formula (1).
  • the present application provides the E-type crystal form of the compound of formula (1), and its X-ray powder diffraction pattern at 2 ⁇ angles is 8.01° ⁇ 0.2°, 8.78° ⁇ 0.2°, 26.33° ⁇ 0.2 ° has a characteristic peak.
  • the X-ray powder diffraction pattern of the E-type crystal form of the compound of formula (1) is also at 2 ⁇ angles of 4.44° ⁇ 0.2°, 17.56° ⁇ 0.2°, 21.95° ⁇ 0.2°, 22.25 There are characteristic peaks at one or more of ° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the E-type crystal form of the compound of formula (1) is also at a 2 ⁇ angle of 5.87° ⁇ 0.2°, 19.64° ⁇ 0.2°, 28.15° ⁇ 0.2°, 29.07
  • ° ⁇ 0.2° and 30.86° ⁇ 0.2° have characteristic peaks.
  • the present application provides the F crystal form of the compound of formula (1), and its X-ray powder diffraction pattern at 2 ⁇ angles is 5.77° ⁇ 0.2°, 8.69° ⁇ 0.2°, 17.48° ⁇ 0.2 °, 22.84° ⁇ 0.2°, there are characteristic peaks.
  • the X-ray powder diffraction pattern of the F-type crystal form of the compound of formula (1) also has a 2 ⁇ angle of 11.61° ⁇ 0.2°, 19.47° ⁇ 0.2° in one or two places. Characteristic peaks.
  • the X-ray powder diffraction pattern of the F crystal form of the compound of formula (1) is also 11.98° ⁇ 0.2°, 13.84° ⁇ 0.2°, 14.30° ⁇ 0.2°, 18.33 One or more of ° ⁇ 0.2° and 18.95° ⁇ 0.2° have characteristic peaks.
  • the spectra determined by thermogravimetric analysis of the F crystal form of the compound of formula (1) show that it starts to lose weight when heated to 29.6 ⁇ 2°C, and loses weight when heated to 150 ⁇ 2°C 1.2 ⁇ 0.2%.
  • the F-type crystal form of the compound of formula (1) shows an endothermic peak in the spectrum determined by differential scanning calorimetry, and the onset temperature of the endothermic peak is 231.1 ⁇ 2°C , Has an endothermic peak at 234.5 ⁇ 2°C.
  • the F crystal form of the compound of formula (1) is an anhydrous crystal form.
  • the X-ray powder diffraction pattern of the F crystal form of the compound of formula (1) is basically the same as that of FIG. 14, FIG. 19 or FIG. 20.
  • the unit cell of the single crystal contains 8 molecules.
  • the unit cell volume of the single crystal is According to a specific aspect of the present application, the unit cell volume of the single crystal is
  • the calculated density of the single crystal is 1.480 ⁇ 0.1 g/cm 3 . According to a specific aspect of the present application, the calculated density of the single crystal is 1.480 g/cm 3 .
  • the method for preparing the single crystal includes: dissolving the compound of formula (1) in an alcohol solvent, filtering, and the filtrate evaporating the solvent at room temperature to precipitate crystals, collecting the resulting crystals by filtration and drying at room temperature Dry, made.
  • the alcohol solvent includes methanol, ethanol, and the like.
  • this application also provides a technical solution: this application provides a method for preparing the above-mentioned Form A crystal form of the compound of formula (1), and the method includes:
  • ester solvents for example, isopropyl acetate, ethyl acetate, etc.
  • alcohol solvents for example, methanol, ethanol, isopropanol, etc.
  • ketone solvents for example, It can be dissolved in a mixed system of one or more of acetone, butanone, etc., and then mixed with a hydrocarbon solvent (for example, n-heptane, etc.), crystallized, filtered, and dried to obtain A of the compound of formula (1) Crystal form; or
  • this application also provides a technical solution: this application provides a method for preparing the above-mentioned type B crystal form of the compound of formula (1), and the method includes:
  • the compound of formula (1) is added to an alcohol solvent (for example, methanol, etc.) or a ketone solvent (for example, acetone, etc.) or its mixed system to dissolve, and then mixed with water, crystallized, and filtered to obtain a solid. The obtained solid is dried to obtain the type B crystal form of the compound of formula (1); or
  • an alcohol solvent for example, methanol, etc.
  • a ketone solvent for example, acetone, etc.
  • This application also provides a method for preparing the type C crystal form of the compound of formula (1): adding the compound of formula (1) to a mixed system of tetrahydrofuran and hydrocarbon solvents to form a turbid liquid, and at a first set temperature After stirring, filter and take the supernatant, the obtained supernatant was cooled from the first set temperature to the second set temperature at a rate of 0.1 ⁇ 0.05°C/min and kept at the second set temperature at a constant temperature, and the precipitated Solid, the obtained solid is dried to obtain the type C crystal form of the compound of formula (1), the first set temperature is 45-55°C, and the second set temperature is 0-10°C.
  • This application also provides a method for preparing the type D crystal form of the compound of formula (1): adding the compound of formula (1) to a mixed system of N-methylpyrrolidone and water to form a turbid liquid, and the resulting turbid liquid Stir at 45-55°C, filter to obtain a solid, and dry the obtained solid to obtain the D crystal form of the compound of formula (1).
  • This application also provides a method for preparing the E crystal form of the compound of formula (1): the method includes: dissolving the compound of formula (1) in N,N-dimethylacetamide, in water or The solid is obtained by gas-liquid diffusion in the atmosphere of alcohol solvent, and the E crystal form of the compound of formula (1) is obtained by filtration.
  • This application also provides a method for preparing the F crystal form of the compound of formula (1), the method comprising: adding the compound of formula (1) to an ester solvent, an alcohol solvent or a mixed system thereof to form turbidity The liquid is stirred at 0-10°C, filtered to obtain a solid, and the obtained solid is dried to obtain the F crystal form of the compound of formula (1).
  • the ester solvent may be ethyl acetate.
  • the alcohol solvent may be methanol and/or ethanol.
  • the stirring time is 2-4h.
  • the turbid liquid before the turbid liquid is placed at 0-10 °C for stirring, the turbid liquid is heated to 30-60 °C, and at this temperature It is stirred for 5 minutes or more, preferably for 30 minutes or more, specifically, for example, 1-1.5 hours.
  • the crystal form F product prepared in this way has better particle size uniformity.
  • the application also provides a pharmaceutical composition, which contains one or more of the above-mentioned crystals in combination and a pharmaceutically acceptable carrier.
  • the application further provides the application of the crystal in the preparation of anti-influenza virus drugs.
  • Solvate of the compound of formula (1) refers to a substance formed by the interaction of a compound of formula (1) with a solvent through hydrogen bonds, salt bonds, and the like.
  • Any form of the compound of formula (1) includes any forms of the compound of formula (1) such as amorphous, crystal, and solvate.
  • “Isomers” refer to compounds that have the same molecular formula but differ in the bonding properties or bonding sequence of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called “stereoisomers”. Stereoisomers that are not mirror images of each other are called “diastereomers”, and stereoisomers that are physical and mirror images of each other without being superimposable are called “enantiomers”. When the compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, there may be a pair of enantiomers.
  • Enantiomers can be characterized by the absolute configuration of their asymmetric centers and described by Cahn-Ingold-Prelog's R and S sequence rules, or according to where the molecule rotates the plane of polarized light and is designated as right-handed or left-handed (ie, They are described as (+) or (-) isomers respectively).
  • the methods for determining the absolute configuration of chiral compounds mainly include single crystal X-ray diffraction, nuclear magnetic resonance and circular dichroism.
  • “Pharmaceutically acceptable carrier” refers to a carrier used for the administration of a therapeutic agent, and includes various excipients and diluents. The term refers to such pharmaceutical carriers: they are not essential active ingredients themselves, and they do not have excessive toxicity after administration. Suitable carriers are well known to those of ordinary skill in the art. A full discussion of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences (Mack Pub. Co., N.J. 1991). Pharmaceutically acceptable carriers in the composition may include liquids such as water, saline, glycerol and ethanol. In addition, auxiliary substances such as disintegrants, wetting agents, emulsifiers, and pH buffer substances may also be present in these carriers.
  • the X-ray powder diffraction pattern is characteristic for a specific crystal form.
  • the relative position of the peaks ie 2 ⁇
  • the relative intensity of the spectrum will change due to the superior orientation effect caused by the difference in crystal conditions, particle size and other measurement conditions, especially the low intensity peak (intensity less than 20%) may not exist in some cases, diffraction
  • the relative intensity of the peak is not characteristic for the determination of the crystal form.
  • the relative intensity of the diffraction peak in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensity shown in this article is illustrative and not for absolute comparison.
  • those skilled in the art are usually allowed to select several characteristic peaks to define the crystal form, and the selection of characteristic peaks can be comprehensively considered based on a certain purpose, and is not strictly limited. For example, those skilled in the art are more inclined to select relatively high intensity peaks, relatively low angle peaks, and characteristic peaks with relatively complete peak shapes, as well as selecting characteristic peaks that are sufficiently distinguishable from other crystals, so that the characteristic peaks can be distinguished. , The meaning of identification and identification. Therefore, it cannot be concluded that a different crystal form is formed or exceeds the originally requested crystal form range just because the combination of the selected characteristic peaks is changed.
  • DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or crystal melting.
  • the error of thermal transition temperature and melting point is typically within about 5°C.
  • the DSC peak or melting point is ⁇ 5°C.
  • the DSC peak or melting point may vary in a larger range.
  • the melting temperature is related to the heating rate.
  • This application provides a novel pyridone derivative, which has high bioavailability and can be converted into a compound with strong inhibitory activity against influenza virus type A and influenza virus type B after being taken in humans, and can be used alone in clinical treatment or In combination with other anti-influenza drugs such as neuraminidase inhibitors, nucleoside drugs, and PB2 inhibitors, it can quickly cure influenza patients in clinical practice.
  • anti-influenza drugs such as neuraminidase inhibitors, nucleoside drugs, and PB2 inhibitors
  • These compounds are active, pharmacokinetic properties (such as bioavailability) and At least one aspect of cytotoxicity is superior to existing pyridone derivatives.
  • the crystal of the compound of formula (1) or its solvate provided in this application meets the requirements of medicinal use in terms of stability, moisture absorption, solubility, storage, etc., and is suitable for application in the preparation of influenza drugs.
  • Figure 1 is an XRPD spectrum of the Form A crystal form of the compound of formula (1) prepared in Example 3;
  • Figure 2 is a TGA spectrum of the Form A crystal form of the compound of formula (1) prepared in Example 3;
  • Fig. 3 is a DSC chart of the Form A crystal form of the compound of formula (1) prepared in Example 3;
  • Example 4 is an XRPD spectrum of the B crystal form of the compound of formula (1) prepared in Example 4;
  • Figure 5 is a TGA spectrum of the B-type crystal form of the compound of formula (1) prepared in Example 4.
  • Fig. 6 is a DSC chart of the type B crystal form of the compound of formula (1) prepared in Example 4.
  • Fig. 7 is an XRPD spectrum of the type C crystal form of the compound of formula (1) prepared in Example 5;
  • Fig. 8 is a TGA spectrum of the type C crystal form of the compound of formula (1) prepared in Example 5;
  • Figure 9 is a DSC chart of the type C crystal form of the compound of formula (1) prepared in Example 5;
  • Fig. 12 is a DSC chart of the type D crystal form of the compound of formula (1) prepared in Example 6;
  • Figure 13 is an XRPD spectrum of the E crystal form of the compound of formula (1) prepared in Example 7;
  • Figure 16 is a DSC chart of the F crystal form of the compound of formula (1) prepared in Example 8.
  • FIG. 17 is an X-ray single crystal diffraction spectrum of the F type crystal form of the compound of formula (1) prepared in Example 8;
  • Figure 19 is an XRPD spectrum of the F crystal form of the compound of formula (1) prepared in Example 11;
  • Figure 20 is an XRPD spectrum of the F crystal form of the compound of formula (1) prepared in Example 11 after jet pulverization.
  • room temperature refers to the natural environmental temperature that can be reached without additional heating or cooling, and the corresponding specific temperature may be between 10-30°C.
  • test equipment and conditions used in the experiment are as follows:
  • Temperature range room temperature to set end temperature
  • formula (9) dissolve compound (1.0g, 7.8mmol) in 10mL of anhydrous tetrahydrofuran, and slowly add 2.5M n-butyllithium solution (3.1 mL, 7.8mmol). After dripping, continue to stir and react at this temperature for 2 hours. Then allyl chloroformate (0.94 g, 7.8 mmol) was added dropwise. After dripping, the reaction was continued to stir for 2 hours. TLC monitored that the raw materials were basically reacted. The reaction solution was poured into saturated ammonium chloride solution for quenching, and extracted with ethyl acetate (15 mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and evaporated to dryness to obtain 1.65 g of oil.
  • the compound of formula (1) is a prodrug of the compound of formula (2), which is converted into an active drug (compound of formula (2)) in the body to exert its pharmacological effects.
  • an active drug compound of formula (2)
  • Table a For the activity data and toxicity data of the compound of formula (2), see Table a.
  • Test method for in vitro biological activity study MDCK cells were seeded into a 384-well cell culture plate at a density of 2,000 cells per well, and then placed in a 37°C, 5% CO 2 incubator overnight. On the next day, the compound of formula (2) was diluted and added to the cell wells (3 times dilution, 8 test concentration points), and the influenza virus A/PR/8/34 (H1N1) strain was then added to each well with 2 *TCID90 is added to the cell culture wells, the final concentration of DMSO in the medium is 0.5%. The cell plate was placed in a 37°C, 5% CO 2 incubator for 5 days. After 5 days of culture, the cell viability was detected using the cell viability test kit CCK8. GraphPad Prism software was used for the raw data to perform nonlinear fitting analysis on the inhibition rate and cytotoxicity of the compound to obtain the EC 50 value (see Table a for the results).
  • Cytotoxicity research method the cytotoxicity test and antiviral activity test of the compound of formula (2) are performed in parallel, except that no virus is added, other experimental conditions are consistent with the antiviral activity test. After 5 days of culture, the cell viability was detected using the cell viability test kit CCK8. The raw data was used to calculate the compound cytotoxicity (CC 50 ) (see Table a for the results).
  • SD rats were given a single oral administration of 3.0 mg ⁇ kg -1 of the compound of formula (1) by gavage, and then measured at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 h before and after administration The concentration of the compound of formula (2) in the plasma of SD rats. See Table c for the results.
  • mice Female BALB/c mice were inoculated with influenza A virus (H1N1, A/WSN/33) by nasal drip to establish an IAV mouse infection model.
  • the body weight and survival status of the animals were monitored every day.
  • some animals were killed and lung tissues were collected for virus titer detection, and the remaining mice were used for survival rate monitoring.
  • the anti-influenza virus efficacy of the test compound in vivo is determined by the lung tissue virus titer, the change of mouse body weight and the survival rate.
  • Lung tissue virus titer On the 5th day after virus infection, the average virus titer in the lung tissue of mice in the vehicle group reached 7.20 Log10 (number of plaques per gram of lung tissue), and the virus in the lung tissue of the oseltamivir phosphate group The average titer is 3.74 Log 10 (number of plaques per gram of lung tissue).
  • mice in the vehicle group began to show significant weight loss on the third day after infection, and then continued to decline or even died; the mice in the oseltamivir phosphate group and the compound group of formula (1) maintained their weight during the experiment Stable, no significant decline, the mice are in good health.
  • mice in the vehicle group were found dead on the 7th day after infection. By the 10th day, all the mice died or were euthanized due to weight loss to the humane endpoint. The survival rate was 0%; Oseltamivir phosphate The mice in the compound group of the formula (1) maintained health during the experiment, and all the animals survived to the predetermined experimental end point, with a survival rate of 100%, showing an excellent anti-influenza drug effect in vivo.
  • Method 1 Weigh 15 mg of the compound of formula (1) and completely dissolve it with 1 ml of isopropyl acetate. To the clear solution, 4 ml of n-heptane was slowly added while stirring, and a solid was precipitated. After stirring for 1 hour, it was filtered, and the solid was dried at 50° C. for 4 hours by blowing air to obtain 13.6 mg with a yield of 90.7% and an HPLC purity of 99.3%.
  • Method 2 Weigh 15 mg of the compound of formula (1) and completely dissolve it with 1 ml of ethyl acetate. 4 ml of n-heptane was added to a 20 ml vial, the ethyl acetate solution of the compound was slowly added to the n-heptane, adding dropwise while stirring, a solid precipitated. After stirring for 1 hour, it was filtered, and the solid was dried at 50°C with air for 4 hours to obtain 14.0 mg with a yield of 93.3% and an HPLC purity of 99.1%.
  • Method 3 Weigh 15 mg of the compound of formula (1), completely dissolve it with 1 ml of acetone, and then slowly volatilize at room temperature, collect the obtained solid, and dry it at 50° C. for 4 hours.
  • Method 4 Weigh 15 mg of the compound of formula (1) and add 0.5 ml of methyl tert-butyl ether. The resulting turbid liquid is placed at room temperature and magnetically stirred for 3 days. The resulting solid is collected by centrifugation and air-dried at 50°C for 4 hours.
  • Method 5 Weigh 15 mg of the compound of formula (1), add 0.5 ml of water, and place the resulting turbid liquid at 50°C with magnetic stirring for 3 days, collect the resulting solid by centrifugation, and dry it with air at 50°C for 4 hours.
  • Method 6 Weigh 15 mg of the compound of formula (1), add 0.1 ml of toluene and 0.4 ml of methyl tert-butyl ether, and place the resulting turbid liquid at 50°C and stir for about 2 hours, then place the sample in a biochemical incubator , The temperature rises and falls at a rate of 0.1°C/min, and the temperature rises and falls for three cycles at 50-5°C. The sample was finally stirred at 5°C, and the resulting solid was collected by centrifugation, and dried at 50°C with air blowing for 4 hours.
  • the XRPD test was performed on the solid obtained in Method 1.
  • the spectrum is shown in Figure 1.
  • There are characteristic peaks at diffraction angles 2 ⁇ 3.10, 8.74, 13.08, 15.44, 21.91, 26.35, 30.83 degrees, and the 2 ⁇ error range is ⁇ 0.2 degrees.
  • the x-ray powder diffraction data are shown in Table 1.
  • Method 1 Weigh 15 mg of the compound of formula (1) and completely dissolve it with 1 ml methanol. 4 ml of water was slowly added to the clear solution while stirring, and a solid precipitated out. After stirring for 1 hour, it was filtered, and the solid was dried at 50° C. for 4 hours with air blowing to obtain 14.1 mg with a yield of 94% and an HPLC purity of 99.2%.
  • Method 2 Weigh 15 mg of the compound of formula (1) and completely dissolve it with 1 ml of acetone. 4 ml of water was added to a 20 ml vial, and the acetone solution of the compound was slowly added to the water, adding dropwise while stirring, and a solid was precipitated. After stirring for 1 hour, it was filtered, and the solid was dried at 50° C. for 4 hours with air blowing to obtain 13.8 mg. The yield was 92% and the HPLC purity was 99.2%.
  • Method 3 Weigh 15 mg of the compound of formula (1), completely dissolve it with 1 ml of chloroform, then slowly volatilize at room temperature, collect the obtained solid, and dry it at 50° C. for 4 hours.
  • Method 4 Weigh 15 mg of the compound of formula (1), add 0.5 ml of toluene, place the resulting turbid liquid at room temperature and magnetically stir for 3 days, collect the resulting solid by centrifugation, and dry it at 50° C. for 4 hours.
  • Method 5 Weigh 15 mg of the compound of formula (1), add 0.5 ml of 2-methyltetrahydrofuran, and place the resulting turbid liquid at 50° C. and stir for 2 hours, and then filter the supernatant. The obtained supernatant was cooled from 50°C to 5°C at a rate of 0.1°C/min and kept constant at 5°C. The precipitated solid was collected and dried at 50°C with blowing air for 4 hours.
  • the XRPD test was performed on the solid obtained by method 1.
  • the x-ray powder diffraction data are shown in Table 2.
  • the XRPD test was performed on the solid obtained by the above method.
  • the x-ray powder diffraction data are shown in Table 3.
  • the XRPD test was performed on the solid obtained by the above method.
  • the spectrum is shown in Figure 10.
  • There are characteristic peaks at diffraction angles 2 ⁇ 7.94, 15.09, 15.50, 19.63, 22.16, 23.56, 25.86, 28.03 degrees, and the 2 ⁇ error range is ⁇ 0.2 degree.
  • the x-ray powder diffraction data are shown in Table 4.
  • Method 1 Weigh 33 grams of the compound of formula (1), add 40 ml of methanol, stir at 0-10°C for 3 hours and then filter. The solid was dried by blowing air at 50°C for 8 hours to obtain 31.88 g of white solid with a yield of 96.6% and an HPLC purity of 99.4%.
  • Method 2 Weigh 33 grams of the compound of formula (1), add 40 ml of ethanol, stir at 0-10°C for 3 hours and then filter. The solid was dried by blowing air at 50°C for 8 hours to obtain 30.76 g of white solid with a yield of 93.2% and an HPLC purity of 99.5%.
  • Method 3 Weigh 33 grams of the compound of formula (1), add 40 ml of ethyl acetate, stir at 0-10°C for 3 hours and then filter. The solid was dried by blowing air at 50°C for 8 hours to obtain 31.24 g of white solid with a yield of 94.7% and a purity of 99.5% by HPLC.
  • the F type crystal of the compound of formula (1) can be prepared by the following method: dissolving the compound of formula (1) in methanol, filtering, and the filtrate slowly volatilizes methanol at room temperature to precipitate crystals, and collect the obtained crystals by filtration and store at room temperature. Dry and prepare.
  • the obtained single crystal was subjected to single crystal X-ray diffraction data collection and the single crystal structure was analyzed. See Table 7 for single crystal structure data of the compound of formula (1).
  • the single crystal structure analysis determined the absolute configuration of the chiral center of the compound of formula (1). As shown in Fig. 17, according to the R and S order rules of Cahn-Ingold-Prelog, the chirality of C 15 is R and the chirality of C 16 is S.
  • the F crystal form samples of the compound of formula (1) were placed at 60° C. for 30 days, 25° C./92.5% RH for 30 days, and exposed to light for 15 days.
  • the physical and chemical stability of the samples were tested by XRPD and HPLC. The results show that under the various stability test conditions, the F crystal form samples of the compound of formula (1) did not undergo a crystal form transformation and HPLC purity decreased, indicating that it has good physical and chemical stability under the test conditions (Table 8).
  • Example 10 Evaluation of the wettability of crystal form
  • the moisture absorption of the F crystal form of the compound of formula (1) was measured by the dynamic moisture adsorption test (DVS) at 25°C. The results showed that the moisture absorption weight gain of the sample under the condition of 25°C/80%RH was 0.10% ( Figure 18), indicating that the sample has almost no hygroscopicity. At the same time, the XRPD results showed that the F crystal form of the compound of formula (1) did not change before and after the DVS test.
  • the stability and hygroscopicity of other crystal forms have also been studied, and the results show that they all meet the requirements for medicinal use.
  • the F crystal form of the compound of formula (1) is the most stable and has the best hygroscopicity.
  • Example 11 Scale-up production of crystalline form F of the compound of formula (1)
  • ⁇ 60°C is refluxing, add 480mL acetone and then dissolve it, 40 ⁇ 50°C reduce pressure to dry, add 730mL methanol, heat to 50 ⁇ 60°C and stir for 1h, then cool to 0 ⁇ 10°C to crystallize 1h, filter The cake was rinsed with 310 mL of cold methanol and dried at 50° C. for 8 hours to obtain 237.18 g of the compound of formula (1).

Abstract

提供了(((R)-12'-((S)-7,8-二氟-6,11-二氢二苯并[b,e]噻庚英-11-基)-6',8'-二氧代-6',8',12',12a'四氢-1'H-,4'H-螺[环丙烷-1,3'-[1,4]恶嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪]-7'-基)氧基)甲基碳酸甲酯即式(1)化合物或其溶剂合物的结晶及其制备方法，结晶包括A型晶型、B型晶型、C型晶型、D型晶型、E型晶型、F型晶型以及单晶。式(1)化合物或其溶剂合物的结晶可以单独用于临床治疗或和其他抗流感药物例如神经氨酸酶抑制剂、核苷类药物、PB2抑制剂联合用药，在临床上可能快速治愈流感病人，与现有的吡啶酮衍生物相比，不仅具有非常好的活性，而且具有好的生物利用度。同时，这些晶体的稳定性、引湿性以及存储性等符合药用要求。

Description

吡啶酮衍生物的晶型及制备方法和应用 技术领域
本申请属于医药化学领域，具体涉及具有流感病毒抑制作用的吡啶酮衍生物的晶型以及它的制备方法和应用。
背景技术
流感病毒传染性强，容易引起急性呼吸道感染，每年影响5％-20％的成人和20％-30％的儿童。在特殊群体中，如65岁以上老人或者患有慢性基础疾病者，流感病毒容易引起严重的呼吸系统或心血管系统等并发症，在世界范围内每年导致数十万人死亡。
神经氨酸酶抑制剂奥司他韦和扎那米韦可以抑制病毒的传播，但是必须在感染后48小时内服用。另外流感病毒容易发生抗原变异，例如1918年的西班牙流感由H1N1亚型引起，1957年的亚洲流感由H2N2亚型引起，1968年的香港流感由H3N2亚型引起，2007年到2008年的流感由H5N1亚型引起。对于新型流感病毒大流行和现有药物产生耐药性的担心，临床上迫切需要全新机理的抗流感药物。
流感病毒是RNA病毒，其遗传物质是单股负链RNA。在流感病毒的生命周期中，病毒反义RNA的转录和复制是一个重要的步骤。RNA聚合酶由PA、PB1和PB2三个亚基组成，在感染的细胞核内负责病毒RNA的转录和复制。流感病毒RNA的转录具有特殊的“夺帽”机制，PB2亚基负责识别和结合宿主细胞mRNA前体的“帽子结构”，PA亚基负责宿主细胞mRNA前体的剪辑，形成引物，启动转录过程。PB1亚基负责病毒mRNA的合成。其中PA亚基的帽依赖性内切酶作用，是病毒生命过程所必须的，且具有宿主细胞所不具备的特异性，适合作为全新的靶位开发新型的抗流感药物。
此外，药物活性成分的晶型结构往往会引起该药物各种理化性质的差异，如溶解度、溶出速率、熔点、密度、硬度等，这些差异直接影响药物的处方制剂工艺、储存方法、体内药代动力学表现，进而影响到药物的生物利用度、临床疗效和安全性。因此深入研究药物的多晶型现象并找到具备良好性质的晶型具有十分重要的意义。
发明内容
本申请所要解决的问题是：提供一种新型吡啶酮衍生物，该化合物生物利用度高，在人体服用后可转化为对流感病毒A型和流感病毒B型有极强的抑制活性的化合物。
本申请同时还提供了新型吡啶酮衍生物或其溶剂合物的多种结晶，该些结晶在稳定性、引湿性、溶解性等方面符合药用的要求。
本申请同时还提供了上述多种结晶的制备方法以及它们在制备抗流感病毒药物中的应用。
为解决上述问题，本申请一方面提供一种式(1)化合物或其溶剂合物的结晶：
Figure PCTCN2019115641-appb-000001
式(1)化合物的中文名称为：
(((R)-12'-((S)-7,8-二氟-6,11-二氢二苯并[b,e]噻庚英-11-基)-6',8'-二氧代-6',8',12',12a'四氢-1'H-,4'H-螺[环丙烷-1,3'-[1,4]恶嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪]-7'-基)氧基)甲基碳酸甲酯；
式(1)化合物的英文名称为：
(((R)-12'-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-6',8'-dioxo-6',8',12',12a'-tetrahydro-1'H,4'H-s piro[cyclopropane-1,3'-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin]-7'-yl)oxy)methyl methyl carbonate。
根据本申请的一些优选方面，本申请提供了式(1)化合物的A型晶型，其X-射线粉末衍射图(使用辐射源为 Cu-Kα，下同)在2θ角为3.10°±0.2°、8.74°±0.2°、15.44°±0.2°、21.91°±0.2°处有特征峰。在一些具体实施方式中，所述式(1)化合物的A型晶型的X-射线粉末衍射图还可能在2θ角为13.08°±0.2°、26.35°±0.2°和30.83°±0.2°中的一处或多处具有特征峰。
根据本申请的一些具体方面，所述式(1)化合物的A型晶型以热重分析法测定的图谱中显示加热到26.8±2℃时开始失重，加热至150±2℃时失重1.8±0.2％。
根据本申请的一些具体方面，所述式(1)化合物的A型晶型以差示扫描量热法测定的图谱中显示有一个吸热峰，显示A型晶型的熔点起始温度为230.5±2℃，在232±2℃时具有吸热峰。
根据本申请的一个具体且优选的方面，所述式(1)化合物的A型晶型为无水晶型。
根据本申请的另一些优选方面，本申请提供了式(1)化合物的B型晶型，其X-射线粉末衍射图在2θ角为8.42°±0.2°、14.27°±0.2°、16.04°±0.2°和25.41°±0.2°处有特征峰。在一些具体实施方式中，所述式(1)化合物的B型晶型的X-射线粉末衍射图还可能在2θ角为10.75°±0.2°、16.87°±0.2°中的一处或两处具有特征峰。
根据本申请的一个具体方面，所述式(1)化合物的B型晶型的X-射线粉末衍射图还在2θ角为18.21°±0.2°、18.78°±0.2°、19.26°±0.2°、19.60°±0.2°、20.40°±0.2°、21.39°±0.2°、21.66°±0.2°、23.38°±0.2°、27.32°±0.2°、29.17°±0.2°和34.08°±0.2°中的一处或多处具有特征峰。
根据本申请的一些具体方面，所述式(1)化合物的B型晶型以热重分析法测定的图谱中显示在被加热到22.6±2℃时开始失重，加热至150±2℃时失重2.2±0.2％。
根据本申请的一些具体方面，所述式(1)化合物的B型晶型以差示扫描量热法测定的图谱中显示有两个吸热峰，两个吸热峰的起始温度分别为208.5.5±2℃、233.8±2℃，在213.5±2℃、235.1±2℃时分别具有吸热峰。
根据本申请的一个具体方面，所述式(1)化合物的B型晶型为无水晶型。
根据本申请的一些优选方面，本申请提供了式(1)化合物的C型晶型，其X-射线粉末衍射图在2θ角为7.73°±0.2°、17.13°±0.2°、20.08°±0.2°、21.74°±0.2°处有特征峰。在一些具体实施方式中，所述式(1)化合物的C型晶型的X-射线粉末衍射图还在2θ角为13.13°±0.2°、13.65°±0.2°、20.98°±0.2°和23.22°±0.2°中的一处或多处具有特征峰。
在一些具体实施方式中，所述式(1)化合物的C型晶型的X-射线粉末衍射图还可能在2θ角为12.51°±0.2°、14.76°±0.2°、15.21°±0.2°、18.39°±0.2°和24.13°±0.2°中的一处或多处具有特征峰。
根据本申请的一些具体方面，所述式(1)化合物的C型晶型以热重分析法测定的图谱中显示在被加热到25.9±2℃时开始失重，加热至150±2℃时失重12.1±0.2％。
根据本申请的一些具体方面，所述式(1)化合物的C型晶型以差示扫描量热法测定的图谱中显示有两个吸热峰，两个吸热峰的起始温度分别为86.8±2℃、233.9±2℃，在94.9±2℃、234.8±2℃时分别具有吸热峰。
根据本申请的一个具体方面，所述式(1)化合物的C型晶型为式(1)化合物的四氢呋喃溶剂合物。
根据本申请的一些优选方面，本申请提供了式(1)化合物的D型晶型，其X-射线粉末衍射图在2θ角为7.94°±0.2°、22.16°±0.2°、28.03°±0.2°处有特征峰。在一些具体实施方式中，所述式(1)化合物的D型晶型的X-射线粉末衍射图还可能在2θ角为15.09°±0.2°、15.50°±0.2°、19.63°±0.2°、23.56°±0.2°、25.86°±0.2°中的一处或多处具有特征峰。
根据本申请的一些具体方面，所述式(1)化合物的D型晶型以热重分析法测定的图谱中显示在被加热到23.5±2℃时开始失重，加热至150±2℃时失重7.5±0.2％。
根据本申请的一些具体方面，所述式(1)化合物的D型晶型以差示扫描量热法测定的图谱中显示有两个吸热峰，两个吸热峰的起始温度分别为113.2±2℃、230.6±2℃，在140.4±2℃、232.4±2℃时分别具有吸热峰。
根据本申请的一个具体方面，所述式(1)化合物的D型晶型为式(1)化合物的N-甲基吡咯烷酮溶剂合物。
根据本申请的一些优选方面，本申请提供了式(1)化合物的E型晶型，其X-射线粉末衍射图在2θ角为8.01°±0.2°、8.78°±0.2°、26.33°±0.2°处有特征峰。
在一些具体实施方式中，所述式(1)化合物的E型晶型的X-射线粉末衍射图还在2θ角为4.44°±0.2°、17.56°±0.2°、21.95°±0.2°、22.25°±0.2°中的一处或多处具有特征峰。
在一些具体实施方式中，所述式(1)化合物的E型晶型的X-射线粉末衍射图还在2θ角为5.87°±0.2°、19.64°±0.2°、28.15°±0.2°、29.07°±0.2°、30.86°±0.2°中的一处或多处具有特征峰。
根据本申请的一些优选方面，本申请提供了式(1)化合物的F型晶型，其X-射线粉末衍射图在2θ角为5.77°±0.2°、 8.69°±0.2°、17.48°±0.2°、22.84°±0.2°处有特征峰。
在一些具体实施方式中，所述式(1)化合物的F型晶型的X-射线粉末衍射图还在2θ角为11.61°±0.2°、19.47°±0.2°中的一处或两处具有特征峰。
在一些具体实施方式中，所述式(1)化合物的F型晶型的X-射线粉末衍射图还在2θ角为11.98°±0.2°、13.84°±0.2°、14.30°±0.2°、18.33°±0.2°、18.95°±0.2°中的一处或多处具有特征峰。
根据本申请的一些具体方面，所述式(1)化合物的F型晶型以热重分析法测定的图谱中显示在被加热到29.6±2℃时开始失重，加热至150±2℃时失重1.2±0.2％。
根据本申请的一些具体方面，所述式(1)化合物的F型晶型以差示扫描量热法测定的图谱中显示有一个吸热峰，吸热峰的起始温度为231.1±2℃，在234.5±2℃时具有吸热峰。
根据本申请的一个具体方面，所述式(1)化合物的F型晶型为无水晶型。
根据本申请的一个具体方面，所述式(1)化合物的F型晶型，其X-射线粉末衍射图与图14、图19或图20基本一致。
根据本申请的一些优选方面，本申请还提供了式(1)化合物单晶形式的结晶，其属于斜方晶系，空间群P2 12 12 1，单位晶胞参数为：
Figure PCTCN2019115641-appb-000002
α＝90°±0.2°，β＝90°±0.2°，γ＝90°±0.2°。
根据本申请的一些优选方面，所述单位晶胞参数为：
Figure PCTCN2019115641-appb-000003
α＝89.9-90.1°，β＝89.9-90.1°，γ＝89.9-90.1°。
根据本申请的一些具体且优选的方面，所述单位晶胞参数为：
Figure PCTCN2019115641-appb-000004
Figure PCTCN2019115641-appb-000005
α＝89.95-90.05°，β＝89.95-90.05°，γ＝89.95-90.05°。
在一个具体实施方式中，所述的单位晶胞参数中：
Figure PCTCN2019115641-appb-000006
α＝β＝γ＝90°。
根据本申请的一个具体方面，所述单晶的单位晶胞包含8个分子。
根据本申请的一些具体且优选的方面，所述单晶的单位晶胞体积为
Figure PCTCN2019115641-appb-000007
根据本申请的一个具体方面，所述单晶的单位晶胞体积为
Figure PCTCN2019115641-appb-000008
根据本申请的一些具体且优选的方面，所述单晶的计算密度为1.480±0.1g/cm 3。根据本申请的一个具体方面，所述单晶的计算密度为1.480g/cm 3。
根据本申请的一些优选方面，所述单晶的制备方法包括：将式(1)化合物溶解于醇类溶剂中，过滤，滤液在室温下挥发溶剂，析出晶体，过滤收集所得晶体并于室温晾干，制得。根据本申请的一些具体方面，所述醇类溶剂包括甲醇、乙醇等。
本申请同时又提供了一种技术方案：本申请提供了上述所述的式(1)化合物的A型晶型的制备方法，所述方法包括：
1)将式(1)化合物加入到酯类溶剂(例如可以是乙酸异丙酯、乙酸乙酯等)、醇类溶剂(例如可以是甲醇、乙醇、异丙醇等)和酮类溶剂(例如可以是丙酮、丁酮等)中的一种或多种的混合体系中溶解，再与烃类溶剂(例如可以是正庚烷等)混合，结晶，过滤，干燥，得到式(1)化合物的A型晶型；或
2)将式(1)化合物加入到酮类溶剂(例如可以是丙酮等)中，室温挥发，得固体，对所得固体进行干燥，得到式(1)化合物的A型晶型；或
3)将式(1)化合物加入到醚类溶剂(例如可以是甲基叔丁基醚等)中，室温下搅拌，过滤得固体，对所得固体进行干燥，得到式(1)化合物的A型晶型；或
3)将式(1)化合物加入到水中，在45-55℃下搅拌，过滤得固体，对所得固体进行干燥，得到式(1)化合物的A型晶型；或
4)将式(1)化合物加入烃类溶剂(例如可以是甲苯等)和醚类溶剂(例如可以是甲基叔丁基醚等)的混合溶剂中，在设定温度下搅拌1～3h，然后以0.1±0.05℃/min的速率进行升温或降温，使体系的温度在所述设定温度至5℃之间循环多次，最终置于3-7℃下搅拌，过滤得到固体，对所得固体进行干燥，得到式(1)化合物的A型晶型，所述设定温度为45～55℃。
本申请同时又提供了一种技术方案：本申请提供了上述所述的式(1)化合物的B型晶型的制备方法，所述方法包括：
1)将式(1)化合物加入到醇类溶剂(例如可以是甲醇等)或酮类溶剂(例如可以是丙酮等)或其混合体系中 溶解，再与水混合，结晶，过滤得固体，对所得固体进行干燥，得到式(1)化合物的B型晶型；或
2)将式(1)化合物加入到卤代烃类溶剂(例如可以是氯仿等)中，室温挥发，得固体，对所得固体进行干燥，得到式(1)化合物的B型晶型；或
3)将式(1)化合物加入到烃类溶剂(例如可以是甲苯等)中，溶解室温下搅拌，过滤得固体，对所得固体进行干燥，得到式(1)化合物的B型晶型；或
4)将式(1)化合物加入到2-甲基四氢呋喃中，置于第一设定温度下搅拌，过滤取上清液，将所得上清液以0.1±0.05℃/min的速率从所述第一设定温度降温至第二设定温度后并在第二设定温度保持恒温，收集析出的固体，对所得固体进行干燥，得到式(1)化合物的B型晶型，所述第一设定温度为45～55℃，所述第二设定温度为0～10℃。
本申请还提供一种所述的式(1)化合物的C型晶型的制备方法：将式(1)化合物加入到四氢呋喃和烃类溶剂的混合体系中形成浑浊液，在第一设定温度下搅拌，过滤取上清液，将所得上清液以0.1±0.05℃/min的速率从第一设定温度降温至第二设定温度后并在第二设定温度保持恒温，收集析出的固体，对所得固体进行干燥，得到式(1)化合物的C型晶型，所述第一设定温度为45～55℃，所述第二设定温度为0～10℃。
本申请还提供一种所述的式(1)化合物的D型晶型的制备方法：将式(1)化合物加入到N-甲基吡咯烷酮和水的混合体系中形成浑浊液，将所得浑浊液置于45-55℃下搅拌，过滤得固体，对所得固体进行干燥，得到式(1)化合物的D型晶型。
本申请还提供一种所述的式(1)化合物的E型晶型的制备方法：所述方法包括：将式(1)化合物溶解在N,N-二甲基乙酰胺中，在水或醇类溶剂的氛围中通过气液扩散得到固体，过滤得式(1)化合物的E型晶型。
本申请还提供一种所述的式(1)化合物的F型晶型的制备方法，所述方法包括：将式(1)化合物加入到酯类溶剂、醇类溶剂或其混合体系中形成浑浊液，在0-10℃搅拌，过滤得固体，对所得固体进行干燥，得到式(1)化合物的F型晶型。
根据本申请的一些具体且优选的方面，所述酯类溶剂可以为乙酸乙酯。
根据本申请的一些具体且优选的方面，所述醇类溶剂可以为甲醇和/或乙醇。
根据本申请的一些具体且优选的方面，所述搅拌的时间为2-4h。
在一些优选实施方式中(例如大规模制备晶型F的生产中)，在将所述浑浊液置于0-10℃进行搅拌之前，先将浑浊液加热至30-60℃，并在该温度下搅拌5分钟以上，优选搅拌30分钟以上，具体例如1-1.5小时。这样制备的晶型F产品的粒径均一性更好。
本申请还提供一种药物组合物，其含有上述所述的结晶中的一种或多种的组合及药学上可接受的载体。
本申请还进一步提供所述的结晶在用于制备抗流感病毒药物中的应用。
为了帮助理解本申请公开的各种实施方案，提供以下说明：
“式(1)化合物的溶剂合物”，是式(1)化合物与溶剂通过氢键、盐键等相互作用而形成的物质。
“任意形态的式(1)化合物”，包含式(1)化合物的无定型、晶型、溶剂合物等任意存在的形式。
“异构体”是指具有相同分子式但是在其原子的键合性质或键合顺序或其原子空间排列方面有区别的化合物。在其原子空间排列方面不同的异构体被称作“立体异构体”。彼此为非镜像的立体异构体被称作“非对映异构体”，彼此互为实物与镜像而不可重叠的立体异构体被称作“对映异构体”。当化合物具有不对称中心时，例如，如果碳原子与四个不同基团键合时，可能存在一对对映体。对映体可以其不对称中心的绝对构型为特征并且通过Cahn-Ingold-Prelog的R和S顺序规则进行描述，或根据其中分子使偏振光平面旋转并被指定为右旋或左旋(即，分别为(+)或(-)异构体)的方式进行描述。手性化合物绝对构型的测定方法，主要有单晶X-射线衍射法、核磁共振法和圆二色谱法。
“药学上可接受的载体”指用于治疗剂给药的载体，包括各种赋形剂和稀释剂。该术语指这样一些药剂载体：它们本身并不是必要的活性成分，且施用后没有过分的毒性。合适的载体是本领域普通技术人员所熟知的。在Remington's Pharmaceutical Sciences(Mack Pub.Co.，N.J.1991)中可找到关于药学上可接受的赋形剂的充分讨论。在组合物中药学上可接受的载体可包括液体，如水、盐水、甘油和乙醇。另外，这些载体中还可存在辅助性的物质，如崩解剂、润湿剂、乳化剂、pH缓冲物质等。
X-射线粉末衍射图谱对于特定的晶型具有特征性。判断是否与已知晶型相同时，应该注意的是峰的相对位置(即2θ)而不是它们的相对强度。这是由于谱图的相对强度会因为晶体条件、粒径和其它测定条件的差异 产生的优势取向效果而变化，特别是低强度峰值(强度小于20％)在某些情况下可能不存在，衍射峰的相对强度对晶型的确定并非是特征性的，事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，本领域知道，用X射线衍射测定化合物的结晶时，由于测定的仪器或测定的条件等的影响，同一个晶型的2θ值可存在一定的测量误差，约为±0.2°。因此，在确定每种结晶结构时，应该将此误差考虑在内。在XRD图谱中通常用2θ角或晶面距d值表示峰位置，两者之间具有简单的换算关系：d＝λ/2sinθ，其中d代表晶面间距d值，λ代表入射X射线的波长，θ为衍射角。还应特别指出的是，在混合物的鉴定中，由于含量下降等因素会造成部分衍射线缺失。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本申请所指晶型的X射线衍射图不必和这里所指的例子中的X射线衍射图完全一致，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°(或更大误差)且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本申请的范畴之内。本领域技术人员能够将本申请所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
在具体X线晶体衍射图谱的基础上，通常允许本领域技术人员选取几个特征峰来对晶型进行定义，而特征峰的选择是基于一定的目的可以进行综合考量的，并无严格限制，例如，本领域技术人员更倾向于选择相对强度较高的峰、相对低角度的峰和峰形较为完整的特征峰，以及选择足以与其他晶体区别的特征峰等，以使得特征峰具有被区分、识别和鉴定的意义。因此，不能仅因为所选择的特征峰的组合发生改变而断定构成了不同的晶型或超出了原有请求的晶型范围。
DSC测定当晶体由于其晶体结构发生变化或晶体熔融而吸收或释放热时的转变温度。对于同种化合物的同种晶型，在连续的分析中，热转变温度和熔点误差典型的在约5℃之内。当我们说一个化合物具有一给定的DSC峰或熔点时，这是指该DSC峰或熔点±5℃。需要指出的是对于混合物而言，其DSC峰或熔点可能会在更大的范围内变动。此外，由于在物质熔化的过程中伴有分解，因此熔化温度与升温速率相关。
需要说明的是，本申请中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本申请精神和原则的基础上围绕具体数值有所浮动。
由于以上技术方案的实施，本申请与现有技术相比存在如下优势：
本申请提供了新型吡啶酮衍生物，该化合物生物利用度高，在人体服用后可转化为对流感病毒A型和流感病毒B型有极强的抑制活性的化合物，可以单独用于临床治疗或和其他抗流感药物例如神经氨酸酶抑制剂、核苷类药物、PB2抑制剂联合用药，在临床上可快速治愈流感病人，这些化合物在活性、药代动力学特性(如生物利用度)以及细胞毒性等中的至少一个方面优于现有的吡啶酮衍生物。同时本申请提供的式(1)化合物或其溶剂合物的结晶在稳定性、引湿性、溶解性、存储性等方面符合药用的要求，适于在制备治疗流感药物中的应用。
附图说明
图1为实施例3制得式(1)化合物的A型晶型的XRPD谱图；
图2为实施例3制得式(1)化合物的A型晶型的TGA谱图；
图3为实施例3制得式(1)化合物的A型晶型的DSC谱图；
图4为实施例4制得式(1)化合物的B型晶型的XRPD谱图；
图5为实施例4制得式(1)化合物的B型晶型的TGA谱图；
图6为实施例4制得式(1)化合物的B型晶型的DSC谱图；
图7为实施例5制得式(1)化合物的C型晶型的XRPD谱图；
图8为实施例5制得式(1)化合物的C型晶型的TGA谱图；
图9为实施例5制得式(1)化合物的C型晶型的DSC谱图；
图10为实施例6制得式(1)化合物的D型晶型的XRPD谱图；
图11为实施例6制得式(1)化合物的D型晶型的TGA谱图；
图12为实施例6制得式(1)化合物的D型晶型的DSC谱图；
图13为实施例7制得式(1)化合物的E型晶型的XRPD谱图；
图14为实施例8制得式(1)化合物的F型晶型的XRPD谱图；
图15为实施例8制得式(1)化合物的F型晶型的TGA谱图；
图16为实施例8制得式(1)化合物的F型晶型的DSC谱图；
图17为实施例8制得式(1)化合物的F型晶型的单晶的X射线单晶衍射谱图；
图18为实施例10制得式(1)化合物的F型晶型的动态水分吸附谱图；
图19为实施例11制得式(1)化合物的F型晶型的XRPD谱图；
图20为实施例11制得式(1)化合物的F型晶型经过气流粉碎后测得的XRPD谱图。
具体实施方式
本申请所述“室温”，是指无需另外进行加热或冷却即达成的自然环境温度，对应的具体温度可能在10-30℃之间。本申请中，实验所用的测试仪器和条件如下：
1.单晶X-射线衍射
仪器型号：Bruker D8 Venture单晶衍射仪
光源：Mo靶
X射线：
Figure PCTCN2019115641-appb-000009
探测器：CMOS面探测器
分辨率：
Figure PCTCN2019115641-appb-000010
电流电压：50kV，1.4A
2.X-射线粉末衍射(XRPD)
仪器型号：PANalytical X'Pert3 Power
X射线：Cu，Kα，Kα1
Figure PCTCN2019115641-appb-000011
1.540598；Kα2
Figure PCTCN2019115641-appb-000012
1.544426
X射线光管设定：45kV，40mA
发散狭缝：1/8°
扫描模式：continuous
扫描范围(2θ)：3°-40°
扫描步长(2θ)：0.0263°
3.差示扫描量热(DSC)
仪器型号：TA Q2000/2500型差示扫描量热仪
升温速率：10℃/min
温度范围：25℃至设置终点温度
保护气体：氮气
4.热重分析(TGA)
仪器型号：TA Q5000/5500型热重分析仪
升温速率：10℃/min
温度范围：室温至设置终点温度
保护气体：氮气
5.动态水分吸附(DVS)
仪器型号：SMS DVS Intrinsic型水分吸附分析仪
温度：25℃
RH范围：0％RH-95％RH
保护气体：氮气
下面结合具体实施例，对本申请做进一步的说明：
实施例1式(1)化合物的制备
路线如下：
Figure PCTCN2019115641-appb-000013
式(10)化合物的制备：式(11)化合物(388mg，1mmol)溶于3mL二氯甲烷，加入1mL三氟乙酸，室温搅拌3小时。TLC显示反应完全，加3N氢氧化钠溶液调至pH＝9-10。二氯甲烷萃取，有机相合并，饱和食盐水洗，干燥后浓缩得270mg固体，直接用于下一步。
式(8)化合物的制备：式(9)将化合物(1.0g,7.8mmol)溶于10mL无水四氢呋喃中,-78℃条件下，氮气保护下缓慢滴加2.5M正丁基锂溶液(3.1mL,7.8mmol)。滴完后在此温度继续搅拌反应2小时。然后滴加氯甲酸烯丙酯(0.94g,7.8mmol)。滴毕继续搅拌反应2h，TLC监测原料基本反应完毕，将反应液倒入饱和氯化铵溶液中淬灭，乙酸乙酯(15mL×3)萃取。合并有机相,无水硫酸钠干燥，浓缩蒸干得1.65g油状物。
式(7)化合物的制备：将式(8)化合物(1.65g,7.8mmol)溶于15mL无水四氢呋喃中，氮气保护，于-78℃缓慢滴加1M二异丁基氢化铝溶液(11.7mL,11.7mmol)。滴完后在此温度继续搅拌反应2小时。TLC监测原料基本反应完毕,将反应液倒入饱和酒石酸钾钠溶液中淬灭,乙酸乙酯(20mL×3)萃取。合并有机相,无水硫酸钠干燥,浓缩蒸干得1.57g油状物。
式(6)化合物的制备：将式(7)化合物(1.57g,7.4mmol)溶于15mL甲醇，加入对甲苯磺酸一水合物(140mg，0.74mmol)，于室温搅拌过夜。TLC监测原料基本反应完毕，加入饱和碳酸氢钠溶液调至中性，浓缩。剩余物经柱层析分离得0.86g黄色油状物。
式(5)化合物的制备：式(10)化合物(270mg，0.94mmol)和式(6)化合物(255mg，1.13mmol)溶于5mL乙腈。氮气保护，在-20℃下滴加1M四氯化锡的二氯甲烷溶液(1.4mL,1.41mmol)。滴完后在此温度搅拌3小时。加入饱和碳酸氢钠溶液，搅拌30min，分液，水相用二氯甲烷萃取。有机相合并，饱和食盐水洗，干燥后浓缩得428mg粗产品。
式(4)化合物的制备：式(5)化合物(428mg，0.89mmol)溶于5mL四氢呋喃，加入四(三苯基膦)钯(104mg，0.09mmol)和吗啉(774mg,8.9mmol)，于室温反应2小时。点板反应结束。浓缩，剩余物柱层析得到216mg产品。
式(3)化合物的制备：式(4)化合物(216mg,0.61mmol)和式(12)化合物(242mg,0.92mmol)在3mL T3P 的乙酸乙酯溶液中于100℃密闭反应3小时。冷却，加饱和NaHCO 3稀释，然后乙酸乙酯萃取。有机相合并，干燥后浓缩，柱层析分离得200mg粗品，然后手性柱分离得到40mg产品。
式(2)化合物的制备：式(3)化合物(40mg，0.067mmol)和氯化锂(20mg,0.48mmol)在1mL DMA中于100℃反应3小时。反应完全后加10mL水稀释，用2N盐酸调pH至3-4。过滤，固体抽干得25mg产品。 1HNMR(400MHz,CDCl 3)δ:7.05-7.15(m,5H),6.85(m,1H),6.70(d,1H,J＝7.6Hz),5.78(d,1H,J＝7.6Hz),5.3(m,2H),4.69(d,1H,J＝6.8Hz),4.17(d,1H,J＝14Hz),4.09(d,1H,J＝14Hz),3.90(m,1H),3.69(m,1H),3.44(d,1H,J＝15.2Hz),0.95(m,1H),0.74(m,3H)；ESI-MS m/z(M+H) +510.1。
式(1)化合物的制备：式(2)化合物(40mg,0.08mmol)，氯甲基甲基碳酸酯(25mg，0.2mmol)，碳酸钾(28mg,0.2mmol)和碘化钾(3mg，0.02mmol)在1mL N,N-二甲基乙酰胺中于60℃反应5小时。点板反应完全，加水淬灭反应，然后用1N稀盐酸调pH至3-4。固体过滤后干燥，柱层析得35mg产品，即为式(1)化合物，该固体经分析为无定形，用作后续实施例中制备各种晶型的起始原料。 1HNMR(400MHz,DMSO-d6)δ:7.40-7.42(m，2H),7.25(d，1H,J＝7.6Hz),7.15(m,1H),7.10(m,1H),7.00(d，1H,J＝7.2Hz),6.84(t,1H,J＝7.6Hz),5.75(m,4H),5.43(d,1H,J＝16.4Hz),4.57(dd,1H,J＝3.2,9.6Hz),3.96-4.03(m,3H),3.73(s,3H),3.51(t,1H,J＝10.0Hz),3.41(s,1H),0.75(t,2H,J＝8.4Hz),0.50(m,2H)；ESI-MS m/z(M+H) +598.1。
实施例2式(1)化合物的药效实验
2.1、体外生物活性研究和细胞毒性研究
实际用药中，式(1)化合物为式(2)化合物的前药，其在体内转化为活性药物(式(2)化合物)而发挥药效，式(2)化合物的活性数据以及毒性数据参见表a。
体外生物活性研究的试验方法：将MDCK细胞以2,000细胞每孔的密度种入384孔细胞培养板中，随后置于37℃，5％CO 2培养箱中培养过夜。第二天，将式(2)化合物稀释后分别加入到细胞孔内(3倍倍比稀释，8个测试浓度点)，流感病毒A/PR/8/34(H1N1)株随后以每孔2*TCID90加入细胞培养孔中，培养基中DMSO终浓度为0.5％。细胞板置于37℃，5％CO 2培养箱中培养5天。培养5天后使用细胞活力检测试剂盒CCK8检测细胞活性。原始数据用GraphPad Prism软件对化合物的抑制率和细胞毒性进行非线性拟合分析，得到EC 50值(结果参见表a)。
细胞毒性研究的研究方法：式(2)化合物的细胞毒性测定和抗病毒活性测定平行进行，除了不加病毒，其它的实验条件和抗病毒活性实验一致。培养5天后使用细胞活力检测试剂盒CCK8检测细胞活性。原始数据用于化合物细胞毒性(CC 50)计算(结果参见表a)。
表a.化合物对于流感病毒A/PR/8/34(H1N1)的抑制活性以及毒性
Figure PCTCN2019115641-appb-000014
结果表明，根据本申请的化合物相比对照化合物，具有更优秀的抑制H1N1的活性，并且同时具有很低的细胞毒性。
2.2、大鼠PK研究
静脉注射:准确称量式(2)化合物供试品约2mg，加入适量DMA，涡旋振荡使固体物质完全溶解；再加入适量体积的30％solutol HS-15水溶液，涡旋振荡后再加入saline，使得DMA:30％solutol HS-15:saline＝20:20:60(v/v/v)，涡旋振荡使液体混合均匀，并过滤，得浓度为0.05mg·mL -1的给药制剂。SD大鼠单次静脉注射给予0.25mg·kg -1的式(2)化合物静注给药制剂。分别于给药前及给药后0.083、0.25、0.5、1、2、4、8、12和24h，由颈静脉采血0.20mL，置于EDTA-K 2抗凝管中。立即准确吸取150μL全血，加到已加入450μL乙腈的试管中蛋白沉淀，涡旋振荡，置于湿冰上。保存在-90～-60℃冰箱，用于生物样品分析。利用LC-MS/MS分析方法，测定S-D大鼠血浆中对应化合物的浓度。采用Pharsight Phoenix 7.0中的非房室模型计算相应的药代动力学参数。结果参见表b。
灌胃给药：准确称量式(1)化合物供试品4mg，加入适量PEG400，涡旋振荡使固体物质溶解；再加入适量体积的30％solutol HS-15水溶液和saline，使得PEG400:30％solutol HS15(w/v):Saline＝2:2:6(v/v/v)，漩涡振荡，得浓度为0.3mg·mL -1的给药制剂。SD大鼠单次灌胃给予3.0mg·kg -1的式(1)化合物口服给药制剂，然后于给药前及给药后0.25、0.5、1、2、4、8、12和24h测定S-D大鼠血浆中对应式(2)化合物的浓度。结果参见表c。
表b.式(2)化合物的PK参数(静脉注射)
Figure PCTCN2019115641-appb-000015
表c.式(1)化合物的PK参数(灌胃)
Figure PCTCN2019115641-appb-000016
以上结果表明本申请的式(1)化合物体内清除率低，具有较长的半衰期，生物利用度高，在体内有较高的吸收。
2.3、小鼠药效
雌性BALB/c小鼠通过滴鼻方式接种甲型流感病毒(H1N1,A/WSN/33)建立IAV小鼠感染模型。每天2次口服溶媒、式(1)化合物(15mpk)或磷酸奥司他韦(15mpk)。试验期间每天监测动物体重及存活状态，并在第5天处死部分动物取肺组织用于病毒滴度检测，剩余小鼠用于存活率监测。通过肺组织病毒滴度，小鼠体重变化及存活率确定测试化合物的体内抗流感病毒药效。
肺组织病毒滴度：病毒感染后第5天，溶媒组小鼠肺组织中病毒滴度平均值达7.20Log10(每克肺组织空斑数)，磷酸奥司他韦组小鼠肺组织中病毒滴度平均值为3.74Log 10(每克肺组织空斑数)。与溶媒组相比，磷酸奥司他韦显著抑制了病毒在小鼠体内的复制，病毒的滴度平均值降低3.46Log10(每克肺组织空斑数)，结果具有非常显著性统计学差异(p<0.01)，显示出预期的药效；感染小鼠经受试式(1)化合物治疗后，第5天小鼠肺组织中病毒滴度平均值为3.28Log 10(每克肺组织空斑数)，与溶媒组相比，受试化合物显著抑制了病毒在小鼠体内的复制，病毒滴度平均值降低3.92Log10(每克肺组织空斑数)，结果具有极其显著性统计学差异(p<0.001)，并优于对照化合物磷酸奥司他韦(表d)。
表d.肺组织病毒滴度
Figure PCTCN2019115641-appb-000017
Figure PCTCN2019115641-appb-000018
**P<0.01表示具有非常显著性差异，***，P<0.001表示具有极其显著性差异
体重变化及结果分析：溶媒组小鼠在感染后第3天开始出现显著的体重下降，随后持续下降甚至死亡；磷酸奥司他韦组和式(1)化合物组小鼠在实验过程中体重维持稳定，未见明显下降，小鼠健康状况良好。
生存率及结果分析：溶媒组小鼠在感染后在第7天发现死亡，至第10天小鼠全部死亡或因体重下降至人道终点而被安乐死，存活率为0％；磷酸奥司他韦和式(1)化合物组小鼠在实验过程中维持健康，所有动物均存活至预定实验终点，存活率为100％，显示了极佳的体内抗流感药效。
实施例3：式(1)化合物的A型晶型的制备
方法1：称取式(1)化合物15毫克，用1毫升乙酸异丙酯完全溶解。向该澄清溶液中边搅拌边缓慢加入4毫升正庚烷，有固体析出。搅拌1小时后过滤，固体在50℃鼓风干燥4h，得13.6毫克，收率90.7％，HPLC纯度99.3％。
方法2：称取式(1)化合物15毫克，用1毫升乙酸乙酯完全溶解。在20毫升小瓶中加入4毫升正庚烷，将化合物的乙酸乙酯溶液缓慢加入到正庚烷中，边搅拌边滴加，有固体析出。搅拌1小时后过滤，固体在50℃鼓风干燥4h，得14.0毫克，收率93.3％，HPLC纯度99.1％。
方法3：称取式(1)化合物15毫克，用1毫升丙酮完全溶解，然后在室温缓慢挥发，收集所得固体，于50℃鼓风干燥4h。
方法4：称取式(1)化合物15毫克，加入0.5毫升甲基叔丁基醚，得到的浑浊液置于室温下磁力搅拌3天，离心收集所得固体，于50℃鼓风干燥4h。
方法5：称取式(1)化合物15毫克，加入0.5毫升水，得到的浑浊液置于50℃下磁力搅拌3天，离心收集所得固体，于50℃鼓风干燥4h。
方法6：称取式(1)化合物15毫克，加入0.1毫升甲苯和0.4毫升甲基叔丁基醚，得到的浑浊液置于50℃下搅拌约2小时后，将样品放置在生化培养箱中，以0.1℃/分钟的速率升降温，并进行50-5℃三次循环升降温测试。样品最终被置于5℃搅拌，离心收集所得固体，于50℃鼓风干燥4h。
对方法1得到的固体进行XRPD测试，谱图如图1所示，在衍射角2θ＝3.10、8.74、13.08、15.44、21.91、26.35、30.83度处有特征峰，2θ误差范围为±0.2度。其x-射线粉末衍射数据如表1所示。
TGA(图2)和DSC结果(图3)显示样品加热至150℃时有1.8％的失重，且在232.0℃(峰值)有一个吸热峰，式(1)化合物A型晶型为无水晶型。
表1：式(1)化合物的A型晶型的XRPD图谱详情
Figure PCTCN2019115641-appb-000019
对其它方法得到的固体分别进行了XRPD测试，测试谱图均与图1基本一致，表明所得固体为式(1)化合物的A 型晶型。
实施例4：式(1)化合物的B型晶型的制备
方法1：称取式(1)化合物15毫克，用1毫升甲醇完全溶解。向该澄清溶液中边搅拌边缓慢加入4毫升水，有固体析出。搅拌1小时后过滤，固体在50℃鼓风干燥4h，得14.1毫克，收率94％，HPLC纯度99.2％。
方法2：称取式(1)化合物15毫克，用1毫升丙酮完全溶解。在20毫升小瓶中加入4毫升水，将化合物的丙酮溶液缓慢加入到水中，边搅拌边滴加，有固体析出。搅拌1小时后过滤，固体在50℃鼓风干燥4h，得13.8毫克，收率92％，HPLC纯度99.2％。
方法3：称取式(1)化合物15毫克，用1毫升氯仿完全溶解，然后在室温缓慢挥发，收集所得固体，于50℃鼓风干燥4h。
方法4：称取式(1)化合物15毫克，加入0.5毫升甲苯，得到的浑浊液置于室温下磁力搅拌3天，离心收集所得固体，于50℃鼓风干燥4h。
方法5：称取式(1)化合物15毫克，加入0.5毫升2-甲基四氢呋喃，得到的浑浊液置于50℃下搅拌2小时后，过滤取上清液。将所得上清液以0.1℃/分钟从50℃降温至5℃后并在5℃保持恒温。收集析出的固体，于50℃鼓风干燥4h。
对方法1得到的固体进行XRPD测试，谱图如图4所示，在衍射角2θ＝8.42、10.75、14.27、16.04、16.87、19.60、20.40、21.39、21.66、23.38、25.41、27.32、29.17、34.08度处有特征峰，2θ误差范围为±0.2度。其x-射线粉末衍射数据如表2所示。
TGA(图5)和DSC结果(图6)显示样品加热至150℃时有2.2％的失重，且在213.5℃和231.5℃(峰值)有2个吸热峰，式(1)化合物的B型晶型为无水晶型。
表2：式(1)化合物的B型晶型的XRPD图谱详情
Figure PCTCN2019115641-appb-000020
对其它方法得到的固体分别进行了XRPD测试，测试谱图均与图4基本一致，表明所得固体为式(1)化合物的B型晶型。
实施例5：式(1)化合物的C型晶型的制备
方法：称取式(1)化合物15毫克，加入0.25毫升四氢呋喃和0.25毫升正庚烷，得到的浑浊液置于50℃下搅拌2小时后，过滤取上清液。将所得上清液以0.1℃/分钟从50℃降温至5℃后并在5℃保持恒温。收集析出的固体，于50℃鼓风干燥4h。
对上述方法得到的固体进行XRPD测试，谱图如图7所示，在衍射角2θ＝7.73、12.51、13.13、13.65、14.76、15.21、17.13、18.39、20.08、20.98、21.74、23.22、24.13度处有特征峰，2θ误差范围为±0.2度。其x-射线粉末衍射数据如表3所示。
TGA(图8)和DSC(图9)结果显示样品加热至150℃时有12.1％的失重，且在94.9℃和234.8℃(峰值)有2个吸热峰，式(1)化合物的C型晶型为THF溶剂合物。
表3：式(1)化合物的C型晶型的XRPD图谱详情
Figure PCTCN2019115641-appb-000021
实施例6：式(1)化合物的D型晶型的制备
方法：称取式(1)化合物15毫克，加入0.05毫升N-甲基吡咯烷酮和0.45毫升水，得到的浑浊液置于50℃下搅拌3天后，离心收集固体，并于50℃鼓风干燥4h。
对上述方法得到的固体进行XRPD测试，谱图如图10所示，在衍射角2θ＝7.94、15.09、15.50、19.63、22.16、23.56、25.86、28.03度处有特征峰，2θ误差范围为±0.2度。其x-射线粉末衍射数据如表4所示。
TGA(图11)和DSC(图12)结果显示样品加热至150℃时有7.5％的失重，且在140.4℃和232.4℃(峰值)有2个吸热峰，式(1)化合物的D型晶型为N-甲基吡咯烷酮溶剂合物。
表4：式(1)化合物的D型晶型的XRPD图谱详情
Figure PCTCN2019115641-appb-000022
Figure PCTCN2019115641-appb-000023
实施例7：式(1)化合物的E型晶型的制备
方法：称取式(1)化合物15毫克，加入0.5毫升N,N-二甲基乙酰胺溶解，将装有此溶液的3mL小瓶敞口置于装有4mL水的20mL小瓶中，密封20mL小瓶并于室温下静置7天，得到14.3毫克白色固体，收率95.2％，HPLC纯度99.2％
对上述方法得到的固体进行XRPD测试，谱图如图13所示，在衍射角2θ＝4.44、5.87、8.01、8.78、17.56、19.64、21.95、22.25、26.33、28.15、29.07、30.86度处有特征峰，2θ误差范围为±0.2度。其x-射线粉末衍射数据如表5所示。
表5：式(1)化合物的E型晶型的XRPD图谱详情
Figure PCTCN2019115641-appb-000024
实施例8：式(1)化合物的F型晶型的制备
方法1：称取式(1)化合物33克，加入40毫升甲醇，在0-10℃搅拌3h后过滤。固体在50℃鼓风干燥8h，得31.88克白色固体，收率96.6％，HPLC纯度99.4％。
方法2：称取式(1)化合物33克，加入40毫升乙醇，在0-10℃搅拌3h后过滤。固体在50℃鼓风干燥8h，得30.76克白色固体，收率93.2％，HPLC纯度99.5％。
方法3：称取式(1)化合物33克，加入40毫升乙酸乙酯，在0-10℃搅拌3h后过滤。固体在50℃鼓风干燥8h，得31.24克白色固体，收率94.7％，HPLC纯度99.5％。
对方法1所得固体进行XRPD测试，谱图如图14所示，在衍射角2θ＝5.77、8.69、11.61、11.98、13.84、14.30、17.48、18.33、18.95、19.47、22.84度处有特征峰，2θ误差范围为±0.2度。其x-射线粉末衍射数据如表6所示。
TGA(图15)和DSC(图16)结果显示样品加热至150℃时有1.2％的失重，且在234.5℃(峰值)有1个吸热峰，式(1)化合物的F型晶型为无水晶型。
表6：式(1)化合物的F型晶型的XRPD图谱详情
Figure PCTCN2019115641-appb-000025
Figure PCTCN2019115641-appb-000026
对其它方法得到的固体分别进行了XRPD测试，测试谱图均与图14基本一致，表明所得固体为式(1)化合物的F型晶型。
可通过如下方法制备式(1)化合物的F型晶型的单晶：将式(1)化合物溶解于甲醇中，过滤，滤液在室温下缓慢挥发甲醇，析出晶体，过滤收集所得晶体并于室温晾干，制得。
对所得单晶进行单晶X-射线衍射数据收集并解析其单晶结构。式(1)化合物的单晶结构数据参见表7。单晶结构解析确定了式(1)化合物手性中心的绝对构型。如图17示，根据Cahn-Ingold-Prelog的R和S顺序规则，C 15的手性是R，C 16的手性是S。
表7：式(1)化合物的F型晶型的单晶结构数据
Figure PCTCN2019115641-appb-000027
实施例9：晶型固态稳定性评估
将式(1)化合物的F型晶型样品分别在60℃放置30天，25℃/92.5％RH放置30天，以及接受光照考察15天。通过XRPD和HPLC检测样品的物理和化学稳定性。结果表明在各稳定性测试条件下，式(1)化合物的F型晶型样品均未发生晶型转变和HPLC纯度降低，表明其在测试条件下具有良好的物理化学稳定性(表8)。
表8：式(1)化合物的F型晶型的固态稳定性
条件 纯度(面积％) 纯度/起始(％) 晶型变化 外观性状
起始 98.6 - 否 白色粉末
60℃/30天 98.7 100.1 否 白色粉末
25℃/92.5％RH/30天 99.0 100.4 否 白色粉末
光照*/15天 98.5 99.9 否 白色粉末
*白光：4500Lux,紫外光：90μw/cm 2
实施例10：晶型引湿性评估
通过25℃下的动态水分吸附试验(DVS)测量了式(1)化合物的F型晶型样品的引湿性，结果显示在25℃/80％RH条件下样品的吸湿增重为0.10％(图18)，表明样品几乎无引湿性。同时，XRPD结果显示式(1)化合物的F型晶型在DVS测试前后晶型未发生转变。
对其他晶型的稳定性和引湿性也进行了研究，结果表明，它们均符合药用要求，其中以式(1)化合物的F晶型最为稳定，引湿性最好。
实施例11：式(1)化合物的晶型F的放大生产
2L三口瓶中，往1215mL的N,N-二甲基乙酰胺中加入243.31g的式(2)化合物、89.90g氯甲基碳酸二甲酯，133.20g碳酸钾以及79.19g碘化钾，加热至45～55℃反应5h。HPLC监控反应完全。趁热过滤，固体用1215mL的N,N-二甲基乙酰胺漂洗，滤液合并，冷却并保持在0～10℃。然后滴入240mL的1N盐酸溶液调节pH至1～2，再滴加4860mL水，搅拌0.5h后过滤，滤饼用1L水漂洗，抽滤至干，得式(1)化合物粗品。该粗品用3600mL二氯甲烷溶解，分出水层，水层用480mL二氯甲烷萃取，有机层合并，用1200mL水洗涤，40～50℃减压浓缩干，加入1215mL丙酮及500mL甲醇，加热至50～60℃呈回流，补加480mL丙酮后溶清，40～50℃减压浓缩干，加入730mL甲醇，加热至50～60℃搅拌1h，后降温至0～10℃析晶1h，过滤，滤饼用310mL冷甲醇漂洗，50℃鼓风干燥8h得237.18g式(1)化合物。经XRPD检测为F晶型，谱图如图19所示，在衍射角2θ＝5.77±0.2、8.69±0.2、11.61±0.2、11.98±0.2、13.84±0.2、14.30±0.2、17.48±0.2、18.33±0.2、18.95±0.2、19.47±0.2、22.84±0.2度处有特征峰，表明所制备的式(1)化合物为F晶型。衍射峰的相对强度如表9所示。
表9：放大生产所得F型晶型的XRPD图谱详情
Figure PCTCN2019115641-appb-000028
另外，取224.90g上述式(1)化合物经气流粉碎(进料压力0.4～0.5MPa，粉碎压力0.18～0.22MPa)后得到212.00g样品，粒径为D90≤10um。粉碎后的样品经XRPD检测，如图20所示，X射线衍射数据见表10。结果表明晶型在粉碎前后未发生变化，表明粉碎过程不会对F晶型发生影响，晶型F具有良好的机械稳定性。
表10：粉碎后的XRPD图谱详情
Figure PCTCN2019115641-appb-000029
Figure PCTCN2019115641-appb-000030
以上实施例的说明只是用于帮助理解本申请的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本申请原理的前提下，还可以对本申请进行若干改进和修饰，这些改进和修饰也落入本申请权利要求的保护范围内。

Claims (40)

  1. 一种式(1)化合物或其溶剂合物的结晶：
    Figure PCTCN2019115641-appb-100001
  2. 如权利要求1所述的结晶，其特征在于，所述结晶为式(1)化合物的A型晶型，其X-射线粉末衍射图在2θ角为3.10°±0.2°、8.74°±0.2°、15.44°±0.2°、21.91°±0.2°处有特征峰。
  3. 如权利要求2所述的结晶，其特征在于，所述式(1)化合物的A型晶型的X-射线粉末衍射图还在2θ角为13.08°±0.2°、26.35°±0.2°和30.83°±0.2°中的一处或多处具有特征峰。
  4. 如权利要求2或3所述的结晶，其特征在于，所述式(1)化合物的A型晶型以热重分析法测定的图谱中显示在被加热至150±2℃时失重1.8±0.2％；和/或，所述式(1)化合物的A型晶型以差示扫描量热法测定的图谱中显示有一个吸热峰，显示A型晶型的熔点起始温度为230.5±2℃。
  5. 如权利要求2或3所述的结晶，其特征在于，所述式(1)化合物的A型晶型为无水晶型。
  6. 如权利要求1所述的结晶，其特征在于，所述结晶为式(1)化合物的B型晶型，其X-射线粉末衍射图在2θ角为8.42°±0.2°、14.27°±0.2°、16.04°±0.2°和25.41°±0.2°处有特征峰。
  7. 如权利要求6所述的结晶，其特征在于，所述式(1)化合物的B型晶型的X-射线粉末衍射图还在2θ角为10.75°±0.2°、16.87°±0.2°中的一处或两处具有特征峰。
  8. 如权利要求6或7所述的结晶，其特征在于，所述式(1)化合物的B型晶型的X-射线粉末衍射图还在2θ角为18.21°±0.2°、18.78°±0.2°、19.26°±0.2°、19.60°±0.2°、20.40°±0.2°、21.39°±0.2°、21.66°±0.2°、23.38°±0.2°、27.32°±0.2°、29.17°±0.2°和34.08°±0.2°中的一处或多处具有特征峰。
  9. 如权利要求6或7所述的结晶，其特征在于，所述式(1)化合物的B型晶型以热重分析法测定的图谱中显示在被加热到150±2℃时失重2.2±0.2％；和/或，所述式(1)化合物的B型晶型以差示扫描量热法测定的图谱中显示有两个吸热峰，两个吸热峰的起始温度分别为208.5.5±2℃、233.8±2℃。
  10. 如权利要求6或7所述的结晶，其特征在于，所述式(1)化合物的B型晶型为无水晶型。
  11. 如权利要求1所述的结晶，其特征在于，所述结晶为式(1)化合物的C型晶型，其X-射线粉末衍射图在2θ角为7.73°±0.2°、17.13°±0.2°、20.08°±0.2°、21.74°±0.2°处有特征峰。
  12. 如权利要求11所述的结晶，其特征在于，所述式(1)化合物的C型晶型的X-射线粉末衍射图还在2θ角为13.13°±0.2°、13.65°±0.2°、20.98°±0.2°和23.22°±0.2°中的一处或多处具有特征峰。
  13. 如权利要求11或12所述的结晶，其特征在于，所述式(1)化合物的C型晶型的X-射线粉末衍射图还在2θ角为12.51°±0.2°、14.76°±0.2°、15.21°±0.2°、18.39°±0.2°和24.13°±0.2°中的一处或多处具有特征峰。
  14. 如权利要求11或12所述的结晶，其特征在于，所述式(1)化合物的C型晶型以热重分析法测定的图谱中显示在被加热到150±2℃时失重12.05±0.2％；和/或，所述式(1)化合物的C型晶型以差示扫描量热法测定的图谱中显示有两个吸热峰，两个吸热峰的起始温度分别为86.8±2℃、233.9±2℃。
  15. 如权利要求11或12所述的结晶，其特征在于，所述式(1)化合物的C型晶型为式(1)化合物的四氢呋喃溶剂合物。
  16. 如权利要求1所述的结晶，其特征在于，所述结晶为式(1)化合物的D型晶型，其X-射线粉末衍射图在2θ角为7.94°±0.2°、22.16°±0.2°、28.03°±0.2°处有特征峰。
  17. 如权利要求16所述的结晶，其特征在于，所述式(1)化合物的D型晶型的X-射线粉末衍射图还在2θ角为15.09°±0.2°、15.50°±0.2°、19.63°±0.2°、23.56°±0.2°和25.86°±0.2°中的一处或多处具有特征峰。
  18. 如权利要求16或17所述的结晶，其特征在于，所述式(1)化合物的D型晶型以热重分析法测定的图谱中显示在被加热到150±2℃时失重7.5±0.2％；和/或，所述式(1)化合物的D型晶型以差示扫描量热法测定的图谱中显示有两个吸热峰，两个吸热峰的起始温度分别为113.2±2℃、230.6±2℃。
  19. 如权利要求16或17所述的结晶，其特征在于，所述式(1)化合物的D型晶型为式(1)化合物的N-甲基吡咯烷酮溶剂合物。
  20. 如权利要求1所述的结晶，其特征在于，所述结晶为式(1)化合物的E型晶型，其X-射线粉末衍射图在2θ角为8.01°±0.2°、8.78°±0.2°、26.33°±0.2°处有特征峰。
  21. 如权利要求20所述的结晶，其特征在于，所述式(1)化合物的E型晶型的X-射线粉末衍射图还在2θ角为4.44°±0.2°、17.56°±0.2°、21.95°±0.2°、22.25°±0.2°中的一处或多处具有特征峰。
  22. 如权利要求20或21所述的结晶，其特征在于，所述式(1)化合物的E型晶型的X-射线粉末衍射图还在2θ角为5.87°±0.2°、19.64°±0.2°、28.15°±0.2°、29.07°±0.2°、30.86°±0.2°中的一处或多处具有特征峰。
  23. 如权利要求1所述的结晶，其特征在于，所述结晶为式(1)化合物的F型晶型，其X-射线粉末衍射图在2θ角为5.77°±0.2°、8.69°±0.2°、17.48°±0.2°、22.84°±0.2°处有特征峰。
  24. 如权利要求23所述的结晶，其特征在于，所述式(1)化合物的F型晶型的X-射线粉末衍射图还在2θ角为11.61°±0.2°、19.47°±0.2°中的一处或两处具有特征峰。
  25. 如权利要求23或24所述的结晶，其特征在于，所述式(1)化合物的F型晶型的X-射线粉末衍射图还在2θ角为11.98°±0.2°、13.84°±0.2°、14.30°±0.2°、18.33°±0.2°、18.95°±0.2°中的一处或多处具有特征峰。
  26. 如权利要求23或24所述的结晶，其特征在于，所述式(1)化合物的F型晶型以热重分析法测定的图谱中显示在被加热到150±2℃时失重1.16±0.2％；和/或，所述式(1)化合物的F型晶型以差示扫描量热法测定的图谱中显示有一个吸热峰，吸热峰的起始温度为231.1±2℃。
  27. 如权利要求23或24所述的结晶，其特征在于，所述式(1)化合物的F型晶型为无水晶型。
  28. 根据权利要求1或23所述的结晶，其特征在于，所述结晶为单晶形式，所述单晶属于斜方晶系，空间群P2 12 12 1，单位晶胞参数为：
    Figure PCTCN2019115641-appb-100002
    α＝90°±0.2°，β＝90°±0.2°，γ＝90°±0.2°。
  29. 根据权利要求28所述的结晶，其特征在于，所述单位晶胞参数为：
    Figure PCTCN2019115641-appb-100003
    Figure PCTCN2019115641-appb-100004
    α＝89.9-90.1°，β＝89.9-90.1°，γ＝89.9-90.1°。
  30. 根据权利要求28或29所述的结晶，其特征在于，所述单晶的制备方法包括：将式(1)化合物溶解于醇类溶剂中，过滤，滤液在室温下挥发溶剂，析出晶体，过滤收集所得晶体并于室温晾干，制得。
  31. 一种权利要求1-5中任一项权利要求所述的结晶的制备方法，其特征在于，所述方法包括：
    1)将式(1)化合物加入到酯类溶剂、醇类溶剂和酮类溶剂中的一种或多种的混合体系中溶解，再与烃类溶剂混合，结晶，过滤，干燥，得到式(1)化合物的A型晶型；或
    2)将式(1)化合物加入到酮类溶剂中，室温挥发，得固体，对所得固体进行干燥，得到式(1)化合物的A型晶型；或
    3)将式(1)化合物加入到醚类溶剂中，室温下搅拌，过滤得固体，对所得固体进行干燥，得到式(1)化合物的A型晶型；或
    4)将式(1)化合物加入到水中，在45-55℃下搅拌，过滤得固体，对所得固体进行干燥，得到式(1)化合物的A型晶型；或
    5)将式(1)化合物加入烃类溶剂和醚类溶剂的混合溶剂中，在设定温度下搅拌1～3h，然后以0.1±0.05℃/min的速率进行升温或降温，使体系的温度在所述设定温度至5℃之间循环多次，最终置于3-7℃下搅拌，过滤得到固体，对所得固体进行干燥，得到式(1)化合物的A型晶型，所述设定温度为45～55℃。
  32. 一种权利要求1、6-10中任一项权利要求所述的结晶的制备方法，其特征在于，所述方法包括：
    1)将式(1)化合物加入到醇类溶剂或酮类溶剂或其混合体系中溶解，再与水混合，结晶，过滤得固体，对所得固体进行干燥，得到式(1)化合物的B型晶型；或
    2)将式(1)化合物加入到卤代烃类溶剂中，室温挥发，得固体，对所得固体进行干燥，得到式(1)化合物的B型晶型；或
    3)将式(1)化合物加入到烃类溶剂中溶解，室温下搅拌，过滤得固体，对所得固体进行干燥，得到式(1)化合物的B型晶型；或
    4)将式(1)化合物加入到2-甲基四氢呋喃中，置于第一设定温度下搅拌，过滤取上清液，将所得上清液以0.1±0.05℃/min的速率从所述第一设定温度降温至第二设定温度后并在第二设定温度保持恒温，收集析出的 固体，对所得固体进行干燥，得到式(1)化合物的B型晶型，所述第一设定温度为45～55℃，所述第二设定温度为0～10℃。
  33. 一种权利要求1、11-15中任一项权利要求所述的结晶的制备方法，其特征在于，所述方法包括：将式(1)化合物加入到四氢呋喃和烃类溶剂的混合体系中形成浑浊液，在第一设定温度下搅拌，过滤取上清液，将所得上清液以0.1±0.05℃/min的速率从第一设定温度降温至第二设定温度后并在第二设定温度保持恒温，收集析出的固体，对所得固体进行干燥，得到式(1)化合物的C型晶型，所述第一设定温度为45～55℃，所述第二设定温度为0～10℃。
  34. 一种权利要求1、16-19中任一项权利要求所述的结晶的制备方法，其特征在于，所述方法包括：将式(1)化合物加入到N-甲基吡咯烷酮和水的混合体系中形成浑浊液，将所得浑浊液置于45-55℃下搅拌，过滤得固体，对所得固体进行干燥，得到式(1)化合物的D型晶型。
  35. 一种权利要求1、20-22中任一项权利要求所述的结晶的制备方法，其特征在于，所述方法包括：将式(1)化合物溶解在N,N-二甲基乙酰胺中，在水或醇类溶剂的氛围中通过气液扩散得到固体，过滤得式(1)化合物的E型晶型。
  36. 一种权利要求1、23-27中任一项权利要求所述的结晶的制备方法，其特征在于，所述方法包括：将式(1)化合物加入到酯类溶剂、醇类溶剂或其混合体系中形成浑浊液，在0-10℃搅拌，过滤得固体，对所得固体进行干燥，得到式(1)化合物的F型晶型。
  37. 根据权利要求36所述的制备方法，其特征在于，所述酯类溶剂为乙酸乙酯；和/或，所述醇类溶剂为甲醇和/或乙醇；和/或，所述搅拌的时间为2-4h。
  38. 根据权利要求36或37所述的制备的方法，其特征在于：在将所述浑浊液置于0-10℃进行搅拌之前，先将浑浊液加热至30-60℃，并在该温度下搅拌5分钟以上。
  39. 一种药物组合物，其含有如权利要求1-30中任一项权利要求所述的结晶及药学上可接受的载体。
  40. 权利要求1-30中任一项权利要求所述的结晶在用于制备抗流感病毒药物中的应用。
PCT/CN2019/115641 2019-05-08 2019-11-05 吡啶酮衍生物的晶型及制备方法和应用 WO2020224208A1 (zh)

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US17/595,013 US20230144122A1 (en) 2019-05-08 2019-11-05 Pyridone derivative crystal form and preparation method and application therefor
AU2019444375A AU2019444375B2 (en) 2019-05-08 2019-11-05 Crystal form of pyridone derivative, and preparation method and use thereof
ZA2021/08765A ZA202108765B (en) 2019-05-08 2021-11-08 Pyridone derivative crystal form and preparation method and application therefor

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