WO2019218883A1 - 一种二氢嘧啶类化合物的固体形式及其制备方法和用途 - Google Patents

一种二氢嘧啶类化合物的固体形式及其制备方法和用途 Download PDF

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WO2019218883A1
WO2019218883A1 PCT/CN2019/085641 CN2019085641W WO2019218883A1 WO 2019218883 A1 WO2019218883 A1 WO 2019218883A1 CN 2019085641 W CN2019085641 W CN 2019085641W WO 2019218883 A1 WO2019218883 A1 WO 2019218883A1
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crystal
solvent
compound
formula
suitable solvent
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PCT/CN2019/085641
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English (en)
French (fr)
Inventor
王天明
杨成喜
蔡家强
刘伟
张保磊
田强
宋帅
胡昊
韩维彪
李友强
陈兴
王利春
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 JP2020549786A priority Critical patent/JP2021523880A/ja
Priority to CN201980019631.9A priority patent/CN111868057B/zh
Priority to KR1020207026739A priority patent/KR20210008829A/ko
Priority to EP19804104.8A priority patent/EP3766880B1/en
Priority to US16/981,430 priority patent/US11434235B2/en
Publication of WO2019218883A1 publication Critical patent/WO2019218883A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—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
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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
    • 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
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

  • the present invention relates to (E)-3-((R)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazole-2) a solid form of -3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)acrylic acid (hereinafter referred to as "the compound of formula (I)”), the solid form is prepared , a pharmaceutical composition comprising the solid form, and the solid form for preventing or treating, including but not limited to, viral hepatitis A, hepatitis B virus, hepatitis C virus, influenza, herpes And use in viral diseases of acquired immunodeficiency syndrome (AIDS).
  • AIDS acquired immunodeficiency syndrome
  • Hepatitis B virus is a common hepadnavirus-like viral pathogen. Such viruses can cause diseases such as acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis and liver cancer.
  • Drugs for the treatment of hepatitis B include interferons and nucleoside analogs (such as lamivudine and adefovir dipivoxil).
  • interferon inhibits the replication of hepatitis B virus by reacting with cell surface receptors to produce antiviral proteins.
  • nucleoside analogs act primarily by inhibiting the replication of viral polymerase (reverse transcriptase). The disadvantage of this type of drug is that long-term use can easily cause virus mutation and produce drug resistance.
  • hepatitis B can also be treated with non-nucleoside analogs.
  • heteroaryldihydropyrimidines Boy 41-4109
  • dihydropyrimidines induce misassembly of core proteins, resulting in unstable capsid proteins that accelerate the degradation of core proteins (Biochem. Pharmacol., 2003, 66, 2273-2279).
  • the heteroaryl dihydropyrimidine compound HAP1 (Proc. Natl. Acad. Sci., 2005, 102, 8138-8143) discovered by Zlotnick et al.
  • the recently developed compound of formula (I) not only exhibits high antiviral activity, but also has no cardiotoxicity and good pharmacokinetic properties, which in turn contributes to the improvement of the efficacy against viral diseases:
  • the present invention provides a solid form of the compound of formula (I), the chemical name of the compound of formula (I): (E)-3-((R)-4-(((R)-6-(2-chloro-4-) Fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)acrylic acid:
  • One aspect of the invention provides crystal A of a compound of formula (I) having an X-ray powder diffraction (XRPD) pattern comprised at 8.7 ⁇ 0.2 °, 17.5 ⁇ 0.2 °, 19.3 ⁇ 0.2 °, 20.3 ⁇ 0.2 ° And a characteristic peak at a diffraction angle (2 ⁇ ) of 21.4 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • Another aspect of the invention provides a method of making the crystal A or amorphous material of the invention.
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline A and/or amorphous of the invention, together with one or more pharmaceutically acceptable carriers or one or more additional therapeutic agents.
  • Another aspect of the invention provides a pharmaceutical formulation comprising crystalline A and/or amorphous of the invention, together with one or more pharmaceutically acceptable carriers.
  • Another aspect of the present invention provides the use of the crystal A and/or amorphous material of the present invention, the pharmaceutical composition of the present invention and/or the pharmaceutical preparation of the present invention for the preparation of a medicament for preventing or treating a viral disease.
  • Another aspect of the present invention provides the crystal A and/or amorphous material of the present invention, the pharmaceutical composition of the present invention and/or the pharmaceutical preparation of the present invention for use in the prevention or treatment of a viral disease.
  • Another aspect of the invention provides a method of preventing or treating a viral disease comprising administering to an individual in need thereof an effective amount of a crystalline A and/or amorphous material of the invention, a pharmaceutical composition of the invention and/or the present invention The pharmaceutical preparation of the invention.
  • solid form includes all solid forms of the compounds of formula (I), such as crystalline or amorphous forms.
  • amorphous refers to any solid material that is not ordered in three dimensions.
  • amorphous solids can be characterized by known techniques, including XRPD crystal diffraction analysis, solid state nuclear magnetic resonance (ssNMR) spectroscopy, differential scanning calorimetry (DSC), or some combination of these techniques. As explained below, the XRPD pattern produced by the amorphous solid has no distinct diffraction characteristic peaks.
  • crystal form or “crystal” as used herein refers to any solid material that exhibits a three-dimensional order, as opposed to an amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.
  • X-ray powder diffraction pattern refers to an experimentally observed diffraction pattern or parameters, data or values derived therefrom.
  • the XRPD pattern is usually characterized by a peak position (abscissa) and/or a peak intensity (ordinate).
  • 2 ⁇ refers to a peak position expressed in degrees (°) set in an X-ray diffraction experiment, and is usually an abscissa unit in a diffraction pattern. If the reflection is diffracted when the incident beam forms an angle ⁇ with a certain lattice plane, the experimental setup requires that the reflected beam be recorded at a 2 ⁇ angle. It will be understood that the particular 2 theta value of a particular crystal form referred to herein is intended to mean a 2 theta value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein.
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TGA) map refers to a curve recorded by a thermogravimetric analyzer.
  • the term "substantially the same” means taking into account representative peak position and/or intensity variations. For example, for X-ray diffraction peaks, those skilled in the art will appreciate that the peak position (2 theta) will show some variation, typically as much as 0.1-0.2 degrees, and the instrument used to measure the diffraction will also cause some variation. Additionally, those skilled in the art will appreciate that the relative peak intensities may vary due to differences between the instruments and the degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art.
  • the invention provides crystal A of a compound of formula (I), characterized in that the X-ray powder diffraction pattern of said crystal A is at a diffraction angle of 8.7 ⁇ 0.2 °, 17.5 ⁇ 0.2 °, 19.3 ⁇ Characteristic peaks at 0.2°, 20.3 ⁇ 0.2°, and 21.4 ⁇ 0.2°,
  • the XRPD pattern of the crystal A of the compound of formula (I) is comprised at 8.7 ⁇ 0.2 °, 16.0 ⁇ 0.2 °, 17.5 ⁇ 0.2 °, 17.8 ⁇ 0.2 °, 19.3 ⁇ 0.2 °, 20.3 ⁇ 0.2. Characteristic peaks at diffraction angles (2 ⁇ ) of °, 21.4 ⁇ 0.2 °, 22.3 ⁇ 0.2 °, and 23.1 ⁇ 0.2 °.
  • the XRPD pattern of crystal A of the compound of formula (I) is comprised at 8.7 ⁇ 0.2 °, 10.8 ⁇ 0.2 °, 15.8 ⁇ 0.2 °, 16.0 ⁇ 0.2 °, 17.5 ⁇ 0.2 °, 17.8 ⁇ Diffraction angle (2 ⁇ ) at 0.2°, 19.3 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.3 ⁇ 0.2°, 21.1 ⁇ 0.2°, 21.4 ⁇ 0.2°, 22.3 ⁇ 0.2°, 23.1 ⁇ 0.2°, and 27.0 ⁇ 0.2° Characteristic peaks.
  • the XRPD pattern of crystal A of the compound of formula (I) comprises a characteristic peak at the following diffraction angle (2 ⁇ ), wherein the 2 ⁇ value has an error range of ⁇ 0.2°:
  • the XRPD pattern of crystal A of the compound of formula (I) comprises a peak at substantially the same diffraction angle (2 theta) as shown in FIG.
  • the XRPD pattern of crystal A of the compound of formula (I) is shown in Figure 1.
  • the differential scanning calorimetry (DSC) pattern of crystal A of the compound of formula (I) exhibits an endothermic peak at 173 ⁇ 2 °C.
  • the DSC spectrum of the crystal A is as shown in FIG.
  • thermogravimetric analysis (TGA) pattern of crystal A of the compound of formula (I) begins to decompose at 190 ⁇ 2 °C.
  • the TGA profile of Crystal A is shown in Figure 3.
  • Another aspect of the invention provides a process for the preparation of crystal A of a compound of formula (I) above, which process includes, but is not limited to, slow volatilization, suspension agitation, permeation or recrystallization.
  • the solvent used in the method is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, dimethyl carbonate , tetrahydrofuran, dichloromethane, chloroform, methyl tert-butyl ether, acetonitrile, anisole, toluene, diethyl ether, water, diisopropyl ether, n-hexane, n-heptane, cyclohexane, petroleum ether.
  • the crystal A is prepared by a slow volatilization process comprising the steps of: dissolving the compound of formula (I) in a first suitable solvent, then allowing to stand at room temperature, volatilizing, removing Solvent, collecting solids to obtain crystal A;
  • the first suitable solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, dimethyl carbonate, One or more of tetrahydrofuran, dichloromethane, chloroform, methyl tert-butyl ether, acetonitrile, anisole, toluene, diethyl ether; the solvent is used in such a manner that the compound of formula (I) is dissolved. .
  • the mass to volume ratio (mg/ml) of the compound of formula (I) to the first suitable solvent is from 100:1 to 10:1.
  • the first suitable solvent is a mixed solvent of the A solvent and the B solvent, wherein the A solvent is selected from the group consisting of acetone, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, dichloromethane, water, and methyl t-butyl ether.
  • a solvent is selected from the group consisting of acetone, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, dichloromethane, water, and methyl t-butyl ether.
  • B solvent is selected from one or more of methanol, acetone, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, dichloromethane;
  • the volume ratio of the A solvent to the B solvent is 1:2-2:1; preferably, the volume ratio of the A solvent to the B solvent is 1:1;
  • the A solvent or the B solvent is used in an amount to completely dissolve the compound of the formula (I).
  • the crystal A is prepared by a slow volatilization process comprising the steps of: dissolving the compound of formula (I) in solvent A, then adding B solvent, and then allowing to stand at room temperature. , volatilize, remove the solvent, collect the solid to obtain crystal A;
  • the A solvent is selected from the group consisting of methanol, acetone, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, dichloromethane, water, methyl tert-butyl ether
  • B solvent is selected from one or more of methanol, acetone, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, dichloromethane, water;
  • the volume ratio of the A solvent to the B solvent is 1:2 to 2:1; preferably, the volume ratio of the A solvent to the B solvent is 1:1.
  • the crystal A is prepared by a recrystallization method, the method comprising the steps of: heating and stirring the compound of the formula (I) in a second suitable solvent; and slowly cooling to room temperature. Filtration, collecting solids to obtain crystal A;
  • the second suitable solvent is selected from the group consisting of isopropanol, acetonitrile, toluene, n-propanol; preferably, the mass to volume ratio (g/ml) of the compound of the formula (I) to the solvent is 1: (5) -10);
  • the second suitable solvent is diethyl ether
  • the mass to volume ratio (g/ml) of the compound of the formula (I) to diethyl ether is 1:60.
  • the crystal A is prepared by a suspension stirring method, which comprises the steps of dispersing, suspending, or suspending the compound of the formula (I) or its amorphous substance in a third suitable solvent at room temperature or Suspended and stirred under high temperature conditions, collecting solids to obtain crystal A;
  • the third suitable solvent is selected from the group consisting of: ethanol, n-propanol, n-butanol, diethyl ether, diisopropyl ether, acetonitrile, toluene, n-hexane, n-heptane, cyclohexane, methyl tert-butyl ether, One or more of water and petroleum ether; preferably, the third suitable solvent is used in an amount such that the solute is suspended therein (the mass to volume ratio of the solute to the solvent (mg/ml) is preferably 150:1 to 10:1); Preferably, the high temperature condition is 60 °C.
  • the crystal A is prepared by an infiltration method, the method comprising the steps of: loading the compound of the formula (I) into a container A, and placing it in a container containing an appropriate amount of a fourth suitable solvent. In B, the container B is sealed, allowed to stand at room temperature, and the solid is collected to obtain crystal A;
  • the fourth suitable solvent is selected from one or more of methanol, ethanol, isopropyl acetate, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether, toluene; preferably, the static Set the time to not less than 8 days.
  • Another aspect of the invention provides an amorphous form of a compound of formula (I), the XRPD pattern of the amorphous material having no sharp sharp peaks.
  • the XRPD pattern of the amorphous material is shown in Figure 4.
  • Another aspect of the invention provides a process for the preparation of an amorphous form of a compound of formula (I), which comprises the steps of: clarifying a compound of formula (I) in a fifth suitable solvent, followed by steaming under reduced pressure Obtaining the amorphous substance;
  • the fifth suitable solvent is selected from one or more of dichloromethane and chloroform;
  • the water bath temperature is 40-50 ° C; more preferably 45 ° C.
  • the compound of formula (I) of the invention may form a corresponding salt of a compound of formula (I) with an organic or inorganic acid, including but not limited to: fumarate, citrate, tartrate, phosphate, Maleate, succinate, sulphate, sulphate, hydrochloride, carbonate, phosphate, hydrobromide, nitrate, malate, glycolate, sulphate, lactic acid Salt, gentisate, methanesulfonate, camphorsulfonate, besylate, p-toluenesulfonate, ethanedisulfonate, naphthalene disulfonate, hippurate, nicotinate, grass Acid salt, malonate, L-arginine salt, lysine salt;
  • an organic or inorganic acid including but not limited to: fumarate, citrate, tartrate, phosphate, Maleate, succinate, sulphate, sulphate, hydrochloride,
  • the molar ratio of the compound of the formula (I) to the organic or inorganic acid is preferably 1:1 or 2:1 or 3:1.
  • the compounds of formula (I) of the invention may form the corresponding salts of the compounds of formula (I) with an organic or inorganic base.
  • the salt of the compound of the formula (I) with an inorganic base includes, but is not limited to, an ammonium salt, a magnesium salt, a potassium salt, a sodium salt, a calcium salt, a lithium salt or the like;
  • the organic base is selected from the group consisting of: meglumine, benzylamine, betaine, dimethylethanolamine, diethylaminoethanol, tromethamine, diethanolamine, ethylenediamine, imidazole, piperazine, tromethamine , triethylamine, choline, etc.;
  • the molar ratio of the compound of the formula (I) to the organic or inorganic base is preferably 1:1 or 2:1 or 3:1.
  • compositions and methods of treatment are provided.
  • a further aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystal A and/or an amorphous form of a compound of formula (I) of the invention, and one or more pharmaceutically acceptable carriers or one or A variety of other therapeutic agents.
  • the "other therapeutic agent” means a pharmacologically active substance other than the crystal A and/or the amorphous substance of the compound of the formula (I) of the present invention, for example, capable of synergistic therapeutic action with the compound of the formula (I).
  • Other antiviral agents are pharmacologically active substance other than the crystal A and/or the amorphous substance of the compound of the formula (I) of the present invention, for example, capable of synergistic therapeutic action with the compound of the formula (I).
  • a further aspect of the invention provides a pharmaceutical formulation comprising crystal A and/or amorphous form of a compound of formula (I) of the invention, together with one or more pharmaceutically acceptable carriers.
  • the "pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or others within the scope of sound medical judgment. Animal tissue without excessive toxicity, irritation, allergic reactions or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • the pharmaceutical preparations of the invention may act systemically and/or locally.
  • they may be administered in a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, It is administered in the form of an ophthalmic preparation or by inhalation.
  • the formulations of the invention may be administered in a suitable dosage form.
  • the dosage form may be a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation, including but not limited to a tablet, a capsule, a powder, a granule, a lozenge, a hard candy, a powder, a spray, a cream, an ointment. , suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, suspensions, elixirs, syrups.
  • the pharmaceutical preparations of the present invention can be prepared by any method well known in the art, for example, by mixing, dissolving, granulating, sugar coating, milling, emulsifying, lyophilizing, and the like.
  • the amount or amount of the compound of the present invention in the pharmaceutical preparation may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, and the like.
  • a further aspect of the invention provides crystal A and/or amorphous of a compound of formula (I), a pharmaceutical composition of the invention and/or a pharmaceutical formulation of the invention in the manufacture of a medicament for the prevention or treatment of a viral disease Uses; preferably, the viral diseases include, but are not limited to, viral hepatitis A, hepatitis B virus, hepatitis C virus, influenza, herpes, and acquired immunodeficiency syndrome (AIDS).
  • the viral diseases include, but are not limited to, viral hepatitis A, hepatitis B virus, hepatitis C virus, influenza, herpes, and acquired immunodeficiency syndrome (AIDS).
  • a further aspect of the invention provides a method of preventing or treating a viral disease, the method comprising administering to an individual in need thereof an effective amount of crystal A of the compound of formula (I) of the invention, an amorphous substance, the invention Pharmaceutical composition and/or pharmaceutical preparation of the invention.
  • the viral disease includes, but is not limited to, viral hepatitis A, hepatitis B virus, hepatitis C virus, influenza, herpes, and acquired immunodeficiency syndrome (AIDS).
  • a further aspect of the invention provides crystal A and/or amorphous of a compound of formula (I), a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention for use in the prevention or treatment of a viral disease.
  • the viral disease includes, but is not limited to, viral hepatitis A, hepatitis B virus, hepatitis C virus, influenza, herpes, and acquired immunodeficiency syndrome (AIDS).
  • the crystal of the compound of the formula (I) provided by the present invention not only has an excellent effect in preventing or treating a viral disease, but also exhibits good chemical stability, physical stability, and pharmacokinetic properties.
  • the crystalline form of the compound of the formula (I) of the present invention has excellent solubility, low hygroscopicity and the like, and thus is more advantageous for sufficient dissolution at the time of administration and formulation, and maintaining sufficient biological activity.
  • it has good high temperature resistance, high humidity resistance, fluidity, is more suitable and convenient for mass production and is used to form preparations, and can maintain reliability during transportation and storage, thus effectively ensuring the quality and safety of medicines.
  • Figure 1 XRPD pattern of crystal A of the compound of formula (I).
  • Figure 4 XRPD pattern of the amorphous form of the compound of formula (I).
  • Figure 6 XRPD comparison of crystal A of the compound of formula (I) after standing at 60 ° C for 0 days and 7 days.
  • Figure 7 XRPD pattern of the compound of formula (I) prepared in Example 1.
  • the X ⁇ Pert3 Powder powder diffractometer was used, which was irradiated with a Cu target and detected at room temperature using an Absolute scan.
  • the detection range is from 3.5° to 40°
  • the step size is 0.013°
  • the residence time is 50 s
  • the scanning is performed once.
  • the differential scanning calorimetry (DSC) test instrument is: DSC1 (METTLER TOLEDO).
  • thermogravimetric analysis (TGA) test instrument is: METTLER TOLEDO.
  • Both DSC and TGA instruments have a heating rate of 10 K/min.
  • the dynamic moisture adsorption instrument (DVS) experimental conditions are as follows:
  • Detection was performed at 25 ° C in cycle-DMDT mode using DVS Intrinsic (SMS).
  • SMS DVS Intrinsic
  • the crude product was purified by preparative liquid chromatography to give 205 mg of Compound of formula (I).
  • the obtained sample was subjected to XRPD analysis, and the XRPD pattern is shown in Fig. 7, which indicates that the obtained solid is an amorphous substance of the compound of the formula (I).
  • the obtained sample was subjected to DSC measurement, and the DSC spectrum was as shown in Fig. 2, and the peak of the endothermic peak appeared at 173.18 ° C;
  • the obtained sample was subjected to TGA measurement, and the obtained TGA pattern was as shown in Fig. 3, and decomposition started at about 190 °C.
  • Example 2 The same preparation method as in Example 2, in which the methanol in Example 2 was replaced with the solvent and the amount in Table 2 below, crystal A of the compound of the formula (I) was prepared, and the obtained sample was subjected to XRPD detection to show the obtained product. The same as the crystal A obtained in Example 2.
  • the compound of the formula (I) prepared in Example 1 was dissolved in a solvent A to prepare a solution of the compound of the formula (I) in an amount of 30 mg/ml, and then mixed with an equal volume of the solvent B of the solvent A (A solvent).
  • the type and volume of the B solvent were as shown in Table 3, and the mixture was allowed to stand at room temperature, volatilized, solvent removed, and crystallized to collect a solid. XRPD detection showed that the obtained crystal was the same as that of the crystal A of Example 2.
  • Solvent Ratio (solute: solvent) N-propanol 0.5g/4.0ml Acetonitrile 0.5g/4.0ml Ether 0.5g/30.0ml Isopropanol 0.5g/4.0ml Toluene 0.5g/4.0ml
  • Example 2 50 mg of the compound of the formula (I) prepared in Example 1 was weighed, and 0.5 ml of a solvent (solvent type and addition ratio as shown in Table 5) was added thereto to be dispersed, suspended, and then sealed and stirred at room temperature for 72 hours, filtered, and a solid was collected. XRPD detection showed that the obtained crystal was the same as the crystal A of Example 2.
  • a solvent solvent type and addition ratio as shown in Table 5
  • Solvent Ratio (solute: solvent) Ethanol 50mg/0.5ml N-propanol 50mg/0.5ml N-butanol 50mg/0.5ml Hexane 50mg/2.0ml N-heptane 50mg/2.0ml Cyclohexane 50mg/2.0ml Acetonitrile 50mg/0.5ml Ether 50mg/1.0ml Methyl tert-butyl ether 50mg/0.5ml Isopropyl ether 50mg/1.0ml Toluene 50mg/0.5ml water 50mg/2.0ml Petroleum ether 50mg/2.0ml
  • Solvent Ratio (solute: solvent) Hexane 0.2g/4.0ml Cyclohexane 0.2g/4.0ml N-heptane 0.2g/4.0ml Isopropyl ether 0.2g/4.0ml Petroleum ether 0.2g/4.0ml water 0.2g/4.0ml
  • a crystal A sample of the compound of the formula (I) was placed at room temperature, and XRPD was separately sampled on the fifth and fifteenth days.
  • a crystal A sample of the compound of the formula (I) was placed under vacuum at 60 ° C, and XRPD was separately sampled on the second, fifth, and seventh days.
  • the test results showed that the XRPD test results showed that the crystals were the same as in Example 2 after being placed at 60 ° C for seven days under vacuum conditions, and the crystal A did not change (the XRPD pattern of crystal A after being placed at 60 ° C for 7 days and the comparison chart at 0 days are as shown in the figure. 6)).
  • the crystal A sample of the compound of the formula (I) was uniformly ground in a mortar, and XRPD was sampled and detected after grinding for 2 min and 5 min, respectively.
  • the crystal A sample of the compound of the formula (I) was examined for its wettability by a dynamic moisture adsorber (DVS): its wettability was measured at 25 ° C, 10% step humidity in the range of 0% - 90% - 0%.
  • DVS dynamic moisture adsorber
  • the DVS detection spectrum is shown in Figure 5.
  • the results show that the sample has a wet weight gain of 0.28% under 80% humidity.
  • the wet weight gain is in the range of 0.2%-2%. , belonging to "slightly wettability".
  • Intravenous administration for the preparation of the test sample taking the sample of Example 5 (crystal preparation solvent is isopropanol), dissolved in 5% DMSO + 5% Solutol (HS15) + 90% physiological saline, as a test solution for intravenous administration;
  • Oral administration for test preparation Take the sample of Example 5 (crystal preparation solvent is isopropanol), and prepare a suspension by using 97.5% of 0.5% methylcellulose (MC) + 2.5% Solutol (HS15). It is administered as a test sample by intragastric administration.
  • crystal preparation solvent is isopropanol
  • T max data is the median (range).
  • Example 5 crystal preparation solvent is isopropanol
  • Example 5 crystal preparation solvent is isopropanol
  • a total volume of 2.5% polyethylene glycol-15 hydroxystearate in a mortar.
  • the acid ester (HS15) was evenly ground, and the mortar was cleaned with 0.5% methylcellulose solution (MC) while grinding to no visible residue, and transferred to a calibrated container, and then treated with 0.5% methylcellulose solution.
  • the mixture was stirred with a magnetic stirrer to prepare a suspension, which was used as a test sample.
  • a single dose toxicity test of SD rats was set up in four groups, a vehicle control group and a low, medium and high dose group of the crystal A of the compound of the formula (I), each group of 10 rats, half male and half female. After continuous oral administration for 14 days. During the observation period, the animals were found to be in good condition, and there was no significant change in body weight and food intake. Hematology and blood biochemical indicators were normal, and no abnormalities were observed in gross anatomy. At the end of the experiment, under the conditions of this test, SD rats were well tolerated against crystal A of the compound of formula (I), and no abnormality was observed within 14 days after administration.
  • Beagle dogs were administered in a single dose toxicity test, which consisted of a vehicle control group and a low- and high-dose group of crystal A of the compound of formula (I), with 4 rats in each group, half male and half female. Dogs in each group were observed continuously for 14 days after oral administration. During the observation period, the animals were found to be in good condition, no significant changes in body weight, normal hematology and blood biochemical indicators, no obvious abnormalities in II lead electrocardiogram, respiratory rate and blood pressure, and no abnormalities in gross anatomy.
  • Test solvent methanol, acetonitrile, ethanol, isopropanol, 0.1 mol/L hydrochloric acid aqueous solution, 0.1 mol/L sodium hydroxide aqueous solution.
  • Example 5 crystal preparation solvent is isopropanol
  • Test results The crystal A sample was dissolved in methanol, acetonitrile, ethanol, slightly soluble in isopropanol, and slightly dissolved in a 0.1 mol/L aqueous hydrochloric acid solution and a 0.1 mol/L sodium hydroxide aqueous solution.
  • the log P value of the crystal A sample prepared in Example 5 was measured using a Sirius T3 physicochemical constant meter.
  • the inspection method is Sirius logP test (pH-metric medium logP), and the pH-metric medium logP measurement mode is selected, and the titration sequence is low to high pH.

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Abstract

本申请公开了(E)-3-((R)-4-(((R)-6-(2-氯-4-氟苯基)-5-(甲氧羰基)-2-(噻唑-2-基)-3，6-二氢嘧啶-4-基)甲基)吗啉-2-基)丙烯酸的固体形式，其制备方法、包含其的药物组合物及其在制备用于预防或治疗病毒性疾病药物中的用途。

Description

一种二氢嘧啶类化合物的固体形式及其制备方法和用途 发明领域
本发明涉及(E)-3-((R)-4-(((R)-6-(2-氯-4-氟苯基)-5-(甲氧羰基)-2-(噻唑-2-基)-3，6-二氢嘧啶-4-基)甲基)吗啉-2-基)丙烯酸(在下文中称作“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预防或治疗包括但不限于甲型病毒性肝炎、乙型病毒性肝炎、丙型病毒性肝炎、流行性感冒、疱疹和获得性免疫缺陷综合征(AIDS)的病毒性疾病中的用途。
发明背景
乙型肝炎病毒(HBV)是一种常见的嗜肝性DNA病毒性病原体。这类病毒可以引起急性肝炎、慢性肝炎、肝纤维化、肝硬化和肝癌等疾病。
治疗乙肝的药物包括干扰素和核苷类似物(如拉米夫定和阿德福韦酯)。其中，干扰素通过与细胞表面受体作用使细胞产生抗病毒蛋白，从而抑制乙肝病毒的复制。它的缺点是有效应答率较低，并且需长期注射给药。核苷类似物主要通过抑制病毒多聚酶(逆转录酶)的复制来发挥作用。该类药物的缺点是长期服用易使病毒变异而产生耐药性。
此外，乙型病毒性肝炎还可以使用非核苷类似物进行治疗。Deres等人研究发现杂芳基二氢嘧啶类化合物(Bay41-4109)可以通过抑制病毒衣壳蛋白装配进而阻止HBV病毒复制(Science，2003，299，893-896)。其具体作用机制是二氢嘧啶类化合物诱导核心蛋白错误装配，从而形成不稳定的衣壳蛋白，加速核心蛋白的降解(Biochem.Pharmacol.，2003，66，2273-2279)。Zlotnick等人发现的杂芳基二氢嘧啶类化合物HAP1(Proc.Natl.Acad.Sci.，2005，102，8138-8143)以及广东东阳光药业有限公司报道的杂芳基二氢嘧啶类化合物(GLS4)(Antimicrob.Agents Chemother.，2013，57，5344-5354；WO2015078391，US2016206616以及WO2015144093)也具有抗HBV活性。
虽然上述化合物均不同程度地表现出了抗病毒活性，但它们的活性还不能达到令人满意的程度，并且一些化合物还表现出明显的毒性作用(例如GLS4表现出明显的hERG心脏毒性)。
近期研发获得的式(I)的化合物不仅表现出了高抗病毒性，且无心脏毒性、具有良好的药物代谢动力学性质，进而有利于改善对于病毒性疾病的疗效：
Figure PCTCN2019085641-appb-000001
同一药物的不同晶型，其稳定性以及生物利用度等方面可能会存在明显差异，从而影响药物的疗效。因此，发现并获得一种化合物的稳定晶型，使其更利于药物加工和在药物组合物中使用，并为固体药物的疗效研究提供更多的定性定量信息具有非常重要的意义，也是药物开发过程的迫切需求。
发明概述
本发明提供式(I)化合物的固体形式，式(I)化合物的化学名为：(E)-3-((R)-4-(((R)-6-(2-氯-4-氟苯基)-5-(甲氧羰基)-2-(噻唑-2-基)-3，6-二氢嘧啶-4-基)甲基)吗啉-2-基)丙烯酸：
Figure PCTCN2019085641-appb-000002
本发明一方面提供式(I)的化合物的晶体A，所述晶体A的X-射线粉末衍射(XRPD)图谱包括在8.7±0.2°、17.5±0.2°、19.3±0.2°、20.3±0.2°和21.4±0.2°的衍射角(2θ)处的特征峰。
本发明的另一方面提供制备本发明的晶体A或无定形物的方法。
本发明的另一方面提供药物组合物，其包含本发明的晶体A和/或无定形物，以及一种或多种药学上可接受的载体或者一种或多种其他治疗剂。
本发明的另一方面提供药物制剂，其包含本发明的晶体A和/或无定形物，以及一种或多种药学上可接受的载体。
本发明的另一方面提供本发明的晶体A和/或无定形物、本发明的药物组合物和/或本发明的药物制剂在制备用于预防或治疗病毒性疾病的药物中的用途。
本发明的另一方面提供本发明的晶体A和/或无定形物、本发明的药物组合物和/或本发明的药物制剂，其用于预防或治疗病毒性疾病。
本发明的另一方面提供预防或治疗病毒性疾病的方法，其包括向需要其的个体给药有效量的本发明的晶体A和/或无定形物、本发明的药物组合物和/或本发明的药物制剂。
发明详细描述
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发明。
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，尽管其它未列举的元素或方法步骤不一定存在(即，这些术语也涵盖术语“基本上由……组成”和“由……组成”)。
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、±0.5、±1、±2或±3等。
如本文中所使用的术语“固体形式”包括式(I)的化合物的所有固态形式，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晶体衍射分析、固态核磁共振(ssNMR)波谱分析、差示扫描量热(DSC)或这些技术的一些组合。如以下所说明，无定形固体产生的XRPD图谱无明显的衍射特征峰。
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、数据或值。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射线衍射实验中设置的以度数(°)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“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，术语“基本上相同”意指将代表性峰位和/或强度变化考虑在内。例如，对于X射线衍射峰，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导致一些变化。另外，本领域技术人员会理解相对峰强度会因仪器间的差异以及结晶性程度、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而出现变化。
晶体和制备方法
在一些实施方案中，本发明提供式(I)的化合物的晶体A，其特征在于，所述晶体A的X-射线粉末衍射图谱在衍射角为8.7±0.2°、17.5±0.2°、19.3±0.2°、20.3±0.2°和21.4±0.2°处有特征峰，
Figure PCTCN2019085641-appb-000003
在优选实施方案中，所述式(I)的化合物的晶体A的XRPD图谱包括在8.7±0.2°、16.0±0.2°、17.5±0.2°、17.8±0.2°、19.3±0.2°、20.3±0.2°、21.4±0.2°、22.3±0.2°和23.1±0.2°的衍射角(2θ)处的特征峰。
在更优选实施方案中，所述式(I)的化合物的晶体A的XRPD图谱包括在8.7±0.2°、10.8±0.2°、15.8±0.2°、16.0±0.2°、17.5±0.2°、17.8±0.2°、19.3±0.2°、19.5±0.2°、20.3±0.2°、21.1±0.2°、21.4±0.2°、22.3±0.2°、23.1±0.2°和27.0±0.2°的衍射角(2θ)处的特征峰。
在特别优选实施方案中，所述式(I)的化合物的晶体A的XRPD图谱包括在以下衍射角(2θ)处的特征峰，其中2θ值的误差范围为±0.2°：
Figure PCTCN2019085641-appb-000004
Figure PCTCN2019085641-appb-000005
在更优选的实施方案中，所述式(I)的化合物的晶体A的XRPD图谱包括与图1所示基本上相同的衍射角(2θ)处的峰。在最优选的实施方案中，所述式(I)的化合物的晶体A的XRPD图谱如图1所示。
在部分实施方案中，所述式(I)的化合物的晶体A的差示扫描量热分析(DSC)图谱在173±2℃处出现吸热峰。
在更优选的实施方案中，所述晶体A的DSC图谱如图2所示。
在部分实施方案中，所述式(I)的化合物的晶体A的热重分析(TGA)图谱在190±2℃开始分解。
在优选的实施方案中，所述晶体A的TGA图谱如图3所示。
本发明的另一方面提供制备上述式(I)化合物的晶体A的方法，所述方法包括但不限于缓慢挥发法、悬浮搅拌法、渗透法或重结晶法。
其中，所述方法中采用的溶剂选自：甲醇、乙醇、正丙醇、异丙醇、正丁醇、丙酮、丁酮、乙酸乙酯、乙酸丁酯、乙酸异丙酯、碳酸二甲酯、四氢呋喃、二氯甲烷、三氯甲烷、甲基叔丁基醚、乙腈、苯甲醚、甲苯、乙醚、水、异丙醚、正己烷、正庚烷、环己烷、石油醚。
在本发明的一些实施方案中，采用缓慢挥发法制备晶体A，所述方法包括以下步骤：将式(I)的化合物在第1适当溶剂中溶清，然后在室温下静置，挥发，除去溶剂，收集固体，得到晶体A；
其中，所述第1适当溶剂选自：甲醇、乙醇、正丙醇、异丙醇、正丁醇、丙酮、丁酮、乙酸乙酯、乙酸丁酯、乙酸异丙酯、碳酸二甲酯、四氢呋喃、二氯甲烷、三氯甲烷、甲基叔丁醚、乙腈、苯甲醚、甲苯、乙醚中的一种或多种；所述溶剂的用量为使式(I)的化合物溶清即可。
优选地，所述式(I)的化合物与第1适当溶剂的质量体积比(mg/ml)为100∶1至10∶1。
或者，所述第1适当溶剂为A溶剂和B溶剂的混合溶剂，其中A溶剂选自：丙酮、四氢呋喃、乙酸乙酯、乙腈、甲苯、二氯甲烷、水、甲基叔丁基醚中的一种或多种；B溶剂选自甲醇、丙酮、四氢呋喃、乙酸乙酯、乙腈、甲苯、二氯甲烷中的一种或多种；
优选地，所述A溶剂与B溶剂的体积比为1∶2-2∶1；优选地，所述A溶剂与B溶剂的体积比为1∶1；
优选地，所述A溶剂或B溶剂的用量为使式(I)的化合物完全溶解即可。
在本发明的一些实施方案中，采用缓慢挥发法制备晶体A，所述方法包括以下步骤：将式(I)的化合物在A溶剂中溶清，然后加入B溶剂混合，然后在室温下静置，挥发，除去溶剂，收集固体，得到晶体A；优选地，所述A溶剂选自：甲醇、丙酮、四氢呋喃、乙酸乙酯、乙腈、甲苯、二氯甲烷、水、甲基叔丁基醚中的一种或多种；B溶剂选自甲醇、丙酮、四氢呋喃、乙酸乙酯、乙腈、甲苯、二氯甲烷、水中的一种或多种；
优选地，所述A溶剂与B溶剂的体积比为1∶2-2∶1；优选的，所述A溶剂与B溶剂的体积比为1∶1。
在本发明的另一些实施方案中，采用重结晶法制备晶体A，所述方法包括以下步骤：将式(I)的化合物在第2适当溶剂中加热搅拌、溶清；再缓慢冷至室温，过滤，收集固体，得到晶体A；
优选地，所述第2适当溶剂选自异丙醇、乙腈、甲苯、正丙醇；优选地，所述式(I)的化合物与溶剂的质量体积比(g/ml)为1∶(5-10)；
或者，所述第2适当溶剂为乙醚，所述式(I)的化合物与乙醚的质量体积比(g/ml)为1∶60。
在本发明的另一些实施方案中，采用悬浮搅拌法制备晶体A，所述方法包括以下步骤：将式(I)的化合物或其无定形物用第3适当溶剂分散、悬浮后，在室温或者高温条件下悬浮搅拌，收集固体，得到晶体A；
优选地，所述第3适当溶剂选自：乙醇、正丙醇、正丁醇、乙醚、异丙醚、乙腈、甲苯、正己烷、正庚烷、环己烷、甲基叔丁基醚、水、石油醚中的一种或多种；优选地，所述第3适当溶剂的用量为使溶质在其中悬浮即可(溶质与溶剂的质量体积比(mg/ml)优选为150∶1至10∶1)；优选地，所述高温条件为60℃。
在本发明的又一些实施方案中，采用渗透法制备晶体A，所述方法包括以下步骤：将式(I)的化合物装入容器A中，敞口放置在装有适量第4适当溶剂的容器B中，密封容器B，室温静置，收集固体，得到晶体A；
优选地，所述第4适当溶剂选自：甲醇、乙醇、乙酸异丙酯、正己烷、乙腈、乙醚、甲基叔丁基醚、甲苯中的一种或多种；优选地，所述静置时间不少于8天。
本发明的另一个方面提供式(I)的化合物的无定形物，所述无定形物的XRPD图谱无明显的尖锐衍射峰。
在优选的实施方案中，所述无定形物的XRPD图谱如图4所示。
本发明的另一方面提供制备式(I)的化合物的无定形物的方法，所述方法包括以下步骤：将式(I)的化合物在第5适当溶剂中溶解澄清，再通过减压旋蒸，得到所述无定形物；
优选地，所述第5适当溶剂选自二氯甲烷、氯仿中的一种或多种；
优选地，所述水浴温度为40-50℃；更优选45℃。
又一方面，本发明的式(I)化合物可以与有机酸或无机酸形成相应的式(I)化合物的盐，包括但不限于：富马酸盐、柠檬酸盐、酒石酸盐、磷酸盐、马来酸盐、琥珀酸盐、已二酸盐、硫酸盐、盐酸盐、碳酸盐、磷酸盐、氢溴酸盐、硝酸盐、苹果酸盐、乙醇酸盐、黏酸盐、乳酸盐、龙胆酸盐、甲磺酸盐、樟脑磺酸盐、苯磺酸盐、对甲苯磺酸盐、乙二磺酸盐、萘二磺酸盐、马尿酸盐、烟酸盐、草酸盐、丙二酸盐、L-精氨酸盐、赖氨酸盐；
其中，式(I)化合物与有机酸或无机酸的摩尔比优选为1∶1或2∶1或3∶1。
另一方面，本发明的式(I)化合物可以与有机碱或无机碱形成相应的式(I)化合物的盐。
优选地，所述式(I)化合物与无机碱形成的盐包括但不限于铵盐、镁盐、钾盐、钠盐、钙盐、锂盐等；
或者，所述有机碱选自：葡甲胺、苄胺、甜菜碱、二甲基乙醇胺、二乙氨基乙醇、氨丁三醇、二乙醇胺、乙二胺、咪唑、哌嗪、氨丁三醇，三乙胺、胆碱等；
其中，式(I)化合物与有机碱或无机碱的摩尔比优选为1∶1或2∶1或3∶1。
药物组合物和治疗方法
本发明的再一方面提供一种药物组合物，其包含本发明的式(I)的化合物的晶体A和/或无定形 物，以及一种或多种药学上可接受的载体或者一种或多种其他治疗剂。
所述“其它治疗剂”是指除本发明的式(I)的化合物晶体A和/或无定形物以外其他具有药理活性的物质，例如能够与式(I)的化合物起到协同治疗作用的其它抗病毒剂。
本发明的又一方面提供一种药物制剂，其包含本发明的式(I)的化合物的晶体A和/或无定形物，以及一种或多种药学上可接受的载体。
所述“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。
本发明的药物制剂可以系统地作用和/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发明的制剂。
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。
本发明所述的药物制剂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。
本发明的化合物在药物制剂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等。
本发明的又一方面提供式(I)的化合物的晶体A和/或无定形物、本发明的药物组合物和/或本发明的药物制剂在制备用于预防或治疗病毒性疾病的药物中的用途；优选地，所述病毒性疾病包括但不限于甲型病毒性肝炎、乙型病毒性肝炎、丙型病毒性肝炎、流行性感冒、疱疹和获得性免疫缺陷综合征(AIDS)。
本发明的又一方面提供一种预防或治疗病毒性疾病的方法，所述方法包括向需要其的个体给药有效量的本发明式(I)的化合物的晶体A、无定形物、本发明的药物组合物和/或本发明的药物制剂。优选地，所述病毒性疾病包括但不限于甲型病毒性肝炎、乙型病毒性肝炎、丙型病毒性肝炎、流行性感冒、疱疹和获得性免疫缺陷综合征(AIDS)。
本发明的又一方面提供式(I)的化合物的晶体A和/或无定形物、本发明的药物组合物或者本发明的药物制剂，其用于预防或治疗病毒性疾病。优选地，所述病毒性疾病包括但不限于甲型病毒性肝炎、乙型病毒性肝炎、丙型病毒性肝炎、流行性感冒、疱疹和获得性免疫缺陷综合征(AIDS)。
本发明提供的式(I)化合物的晶体，不仅在预防或治疗病毒性疾病中具有优异的效果，还表现出良好的化学稳定性、物理稳定性以及药物代谢动力学性质。例如，本发明的式(I)的化合物的晶体形式具有优良的溶解性、低吸湿性等，因而更有利于给药和配制时的充分溶解，保持足够的生物活性。同时，具有良好的耐高温性、耐高湿性、流动性，更适合和便于大量制造和用于形成制剂，还能够保持在运输和储存过程中的可靠性，从而有效保证了药品的质量和安全性；而且，还具有良好的光稳定性，不需要为防止受光照影响而采取的特殊包装处理，从而降低成本。也不会因光照影响产生降解，提高了药品的安全性和长期贮藏后的有效性。
附图说明
图1：式(I)的化合物的晶体A的XRPD图谱。
图2：式(I)的化合物的晶体A的DSC图谱。
图3：式(I)的化合物的晶体A的TGA图谱。
图4：式(I)的化合物的无定形物的XRPD图谱。
图5：式(I)的化合物的晶体A的DVS图谱。
图6：式(I)的化合物的晶体A在60℃放置0天与7天后的XRPD对比图谱。
图7：实施例1制备得到的式(I)化合物的XRPD图谱。
实施例
以下通过实施例对本发明做进一步阐述，本发明的实施例仅用于说明本发明的技术方案，并非用于限定本发明的范围，本领域技术人员可进行一些非本质的改进和调整，仍属于本发明的保护范围。
实验所用的测试仪器信息和方法：
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，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。
差示扫描量热法(DSC)测试仪器为：DSC1(METTLER TOLEDO)。
热重分析(TGA)测试仪器为：METTLER TOLEDO。
DSC和TGA仪器的加热速度均为10K/min。
动态水分吸附仪(DVS)实验条件如下：
采用DVS Intrinsic(SMS)，在25℃，cycle-DMDT模式下进行检测。
实施例1 (E)-3-((R)-4-(((R)-6-(2-氯-4-氟苯基)-5-(甲氧羰基)-2-(噻唑-2-基)-3，6-二氢嘧啶-4-基)甲基)吗啉-2-基)丙烯酸(式(I)的化合物)的制备
Figure PCTCN2019085641-appb-000006
在室温下，将(R)-6-(溴甲基)-4-(2-氯-4-氟苯基)-2-(噻唑-2-基)-1，4-二氢嘧啶-5-羧酸甲酯(400mg，0.90mmol)和(R，E)-3-(吗啉-2-基)丙烯酸三氟乙酸盐(488mg，1.80mmol)在二氯甲烷(10mL)中溶解，然后加入N，N-二异丙基乙胺(696mg，5.40mmol)，在室温下反应过夜。将反应液浓缩得粗品。粗品经制备液相色谱法纯化，得式(I)的化合物205mg。对所得样品进行XRPD分析，XRPD图谱如图7所示，其表明所得的固体为式(I)的化合物的无定形物。
其结构表征如下：
1H NMR(400MHz，DMSO-d 6)δ12.44(s，1H)，9.68(s，1H)，7.98(dd，J＝27.6，3.1Hz，2H)，7.48-7.36(m，2H)，7.18(td，J＝8.5，2.6Hz，1H)，6.73(dd，J＝15.8，4.1Hz，1H)，6.04(s，1H)，5.93(dd，J＝15.8，1.6Hz，1H)，4.23(d，J＝9.3Hz，1H)，4.01-3.90(m，3H)，3.68(t，J＝10.2Hz，1H)，3.52(s，3H)，2.94(d，J＝11.0Hz，1H)，2.82(d，J＝11.1Hz，1H)，2.41(dd，J＝11.0，8.6Hz，1H)，2.08(t，J＝10.7Hz，1H)。ESI-MS(m/z)：521.1[M+H] +。
实施例2 式(I)的化合物的晶体A的制备
称取30mg实施例1制备得到的式(I)的化合物，在0.9ml甲醇中溶清，然后在室温下静置，挥发、除去溶剂，析晶，收集固体，对所得样品进行XRPD检测，XRPD图谱如图1所示，相关数据如表1所示，即为式(I)的化合物的晶体A。
表1
Figure PCTCN2019085641-appb-000007
Figure PCTCN2019085641-appb-000008
对所得样品进行DSC测定，DSC图谱如图2所示，吸热峰的峰值出现在173.18℃处；
对所得样品进行TGA测定，所得TGA图谱如图3所示，在约190℃处开始分解。
实施例3 式(I)的化合物的晶体A的制备
按照与实施例2相同的制备方法，其中将实施例2中的甲醇替换为下表2中的溶剂以及用量，制备式(I)的化合物的晶体A，对所得样品进行XRPD检测显示得到的产物与实施例2得到的晶体A相同。
表2
Figure PCTCN2019085641-appb-000009
Figure PCTCN2019085641-appb-000010
实施例4 式(I)的化合物的晶体A的制备
将实施例1制备得到的式(I)的化合物溶解在A溶剂中，制成式(I)的化合物含量为30mg/ml的溶液，然后加入与A溶剂等体积量的B溶剂混合(A溶剂与B溶剂种类及体积比如表3所示)，在室温下静置，挥发、除去溶剂，析晶，收集固体，XRPD检测显示得到的晶体与实施例2的晶体A相同。
表3
Figure PCTCN2019085641-appb-000011
实施例5 式(I)的化合物的晶体A的制备
称取500mg实施例1制备得到的式(I)化合物，向其中加入一定量的溶剂(溶剂种类及加入比例参见表4)加热搅拌，溶清，然后缓慢降至室温、过滤，收集固体，XRPD检测显示得到的晶体与实施例2的晶体A相同。
表4
溶剂 比例(溶质∶溶剂)
正丙醇 0.5g/4.0ml
乙腈 0.5g/4.0ml
乙醚 0.5g/30.0ml
异丙醇 0.5g/4.0ml
甲苯 0.5g/4.0ml
实施例6 式(I)化合物的无定形物悬浮转晶
称取50mg实施例1制备得到的式(I)化合物，再向其中加入0.5ml的溶剂(溶剂种类及加入比例参见表5)分散、悬浮，然后在室温下密封搅拌72h，过滤，收集固体，XRPD检测显示得到的晶体与实施例2的晶体A相同。
表5
溶剂 比例(溶质∶溶剂)
乙醇 50mg/0.5ml
正丙醇 50mg/0.5ml
正丁醇 50mg/0.5ml
正己烷 50mg/2.0ml
正庚烷 50mg/2.0ml
环己烷 50mg/2.0ml
乙腈 50mg/0.5ml
乙醚 50mg/1.0ml
甲基叔丁基醚 50mg/0.5ml
异丙醚 50mg/1.0ml
甲苯 50mg/0.5ml
水 50mg/2.0ml
石油醚 50mg/2.0ml
实施例7 式(I)的化合物的晶体A的制备
称取200mg实施例1制备得到的式(I)化合物样品，向其中加入4ml的溶剂(溶剂种类及加入比例参见表6)分散、悬浮，然后在60℃下加热搅拌8h，过滤，收集固体，XRPD检测显示得到的晶体与实施例2的晶体A相同。
表6
溶剂 比例(溶质∶溶剂)
正己烷 0.2g/4.0ml
环己烷 0.2g/4.0ml
正庚烷 0.2g/4.0ml
异丙醚 0.2g/4.0ml
石油醚 0.2g/4.0ml
水 0.2g/4.0ml
实施例8 式(I)的化合物悬浮转晶
称取150mg实施例1制备得到的式(I)化合物样品，向其中加入适量溶剂(溶剂种类及加入比例参见表7)分散、悬浮，然后在室温下密封、搅拌72h，过滤，收集固体，XRPD检测显示得到的晶体与实施例2的晶体A相同。
表7
Figure PCTCN2019085641-appb-000012
Figure PCTCN2019085641-appb-000013
实施例9 式(I)的化合物的晶体A的制备
称取30mg实施例1制备得到的式(I)的化合物样品，装入西林瓶中，敞口放置在装有适量溶剂(溶剂种类及用量参见表8)的50ml烧杯中，密封、室温静置约8天，收集固体，XRPD检测显示得到的晶体与实施例2的晶体A相同。
表8
溶剂 体积(ml)
甲醇 6ml
乙醇 6ml
乙酸异丙酯 6ml
正己烷 6ml
乙腈 6ml
乙醚 12ml
甲基叔丁基醚 12ml
甲苯 6ml
实施例10 式(I)的化合物的无定形物的制备
称取3g实施例1制备得到的式(I)的化合物样品，加入50ml溶剂(溶剂种类及加入比例参见表9)溶清，过滤，然后在45℃水浴中通过旋蒸仪减压旋干，得到固体，对所得样品进行XRPD分析，XRPD图谱如图4所示，即为式(I)的化合物的无定形物。
表9
溶剂 比例(溶质∶溶剂)
二氯甲烷 3g/50ml
氯仿 3g/50ml
实验例
实验例1 晶体A在室温条件下的稳定性考察
将式(I)的化合物的晶体A样品置于室温条件下放置，并在第五天、第十五天分别取样检测XRPD。
检测结果：XRPD检测结果显示于室温条件下放置十五天后晶体与实施例2相同，晶体A未发生转变。
实验例2 晶体A在高温条件下的稳定性考察
将式(I)的化合物的晶体A样品于60℃、真空条件下放置，并在第二天、第五天、第七天分别取样检测XRPD。
检测结果：XRPD检测结果显示于60℃、真空条件下放置七天后晶体与实施例2相同，晶体A均未发生转变(晶体A在60℃放置7天后的XRPD图谱与0天时的对比图谱如图6所示)。
实验例3 晶体A在研磨条件下的稳定性考察
将式(I)的化合物的晶体A样品在研钵中匀速研磨，分别在研磨2min、5min后取样检测XRPD。
检测结果：XRPD检测结果显示在研磨5min后晶体与实施例2相同，晶体A未发生转变。
实验例4 晶体A的DVS考察
将式(I)的化合物的晶体A样品通过动态水分吸附仪(DVS)检测其引湿性：在25℃、10％的阶梯湿度在0％-90％-0％范围内测定其引湿性。
DVS检测图谱如图5所示，结果显示：样品在80％的湿度条件下，引湿增重为0.28％，根据《中国药典》2015版规定，引湿增重在0.2％-2％范围内，属于“略有引湿性”。
实验例5 晶体A在大鼠体内的药物代谢动力学试验
1、待测样品
静脉给药供试品配制：取实施例5(晶体制备溶剂为异丙醇)样品，采用5％DMSO+5％Solutol(HS15)+90％生理盐水溶解，作为静脉给药供试品溶液；
灌胃给药供试品配制：取实施例5(晶体制备溶剂为异丙醇)样品，采用97.5％的0.5％甲基纤维素(MC)+2.5％Solutol(HS15)配制成混悬液，作为灌胃给药供试品。
2、试验方法及结果
取12只SD大鼠随机分为A、B两组，每组6只，雌雄各半，A组分别单次静脉给药供试品药物；B组分别灌胃给药供试品药物，给药剂量均为3mg/kg。静脉和灌胃给药采血时间点为给药前及给药后0.083、0.25、0.5、1.0、2.0、4.0、6.0、8.0、10和24h。根据血药浓度计算药代动学参数，结果见表10。从表10中数据可以看出，晶体A在大鼠体内绝对生物利用度为62.4％(以AUC 0-∞计算)，其在大鼠体内口服吸收良好。
表10 大鼠单次给予晶体A后的药动学参数(n＝6，雌雄各半)
Figure PCTCN2019085641-appb-000014
备注：T max数据为中位数(范围)。
实验例6 式(I)所示化合物晶体A安全性实验
供试品配制：称取所需量的实施例5(晶体制备溶剂为异丙醇)制备得到的晶体A样品，于研钵中，加入总体积2.5％的聚乙二醇-15羟基硬脂酸酯(HS15)研磨均匀，再用0.5％甲基纤维素溶液(MC)边研磨边清洗研钵至无可见残留，并转移至已标定的容器中，再用0.5％甲基纤维素溶液定容，用磁力搅拌器搅拌均匀制成混悬液，作为供试品。
1.SD大鼠单次给药毒性
SD大鼠单次给药毒性试验设4个组，分别为溶媒对照组以及式(I)所示化合物晶体A的低、中、高剂量组，每组10只大鼠，雌雄各半。经口灌胃给药后连续观察14天。观察期内发现动物状况良好，体重、摄食量未见明显变化，血液学、血液生化指标正常，大体解剖观察也未见异常情况。试验结束时，在本试验条件下，可见SD大鼠对式(I)所示化合物晶体A的耐受性较好，给药后14天内未见异常。
2.Beagle犬单次给药毒性
Beagle犬单次给药毒性试验设3个组，分别为溶媒对照组及式(I)所示化合物晶体A的低、高剂量组，每组4只，雌雄各半。各组犬经口灌胃给药后连续观察14天。观察期内发现动物状况良好，体重未见明显变化，血液学、血液生化指标正常，II导联心电图、呼吸频率及血压未见明显异常，大体解剖观察也未见异常情况。
试验结果表明Beagle犬对式(I)所示化合物晶体A单次给药耐受性较好，给药后14天内未见异常。
实验例7 晶体A的溶解性测定
测试溶剂：甲醇、乙腈、乙醇、异丙醇、0.1mol/L盐酸水溶液、0.1mol/L氢氧化钠水溶液。
操作方法：按照中国药典2015年版四部凡例第十五(2)项进行考察。称取适量实施例5(晶体制备溶剂为异丙醇)制备得到的晶体A样品，将其加入25±2℃一定容量的溶剂中，每隔5分钟强力振摇30秒钟；观察30分钟内的溶解情况，如无目视可见的溶质颗粒时，即视为完全溶解。
试验结果：晶体A样品在甲醇、乙腈、乙醇中溶解，在异丙醇中微溶，在0.1mol/L的盐酸水溶液和0.1mol/L氢氧化钠水溶液中略溶。
实验例8 晶体A的logP值测定
使用Sirius T3理化常数测定仪，测定实施例5(晶体制备溶剂为异丙醇)制备的晶体A样品的logP值。检查方法为Sirius logP测试(pH-metric medium logP)，选择pH-metric medium logP测定模式，滴定顺序为低至高pH。
测定结果：本产品的logP值为2.4～2.6。说明本发明晶体A具有优异的透膜性，有利于体内ADME过程以及受体亲和力。
本申请公开的式(I)的化合物的固体形式及其制备方法，本领域技术人员可通过借鉴本文内容，适当改变原料、工艺参数等环节实现。本申请的方法与产品已通过较佳实施例进行了描述，相关技术人员明显能在不脱离本申请内容、精神和范围内对本文所述的方法和产品进行改动或适当变更与组合，来实现本申请技术。特别需要指出的是，所有相类似的替换和改动对本领域技术人员来说是显而易见的，他们都被视为包括在本申请精神、范围和内容中。

Claims (18)

  1. 式(I)的化合物的晶体A，其特征在于，所述晶体A的X-射线粉末衍射图谱在衍射角为8.7±0.2°、17.5±0.2°、19.3±0.2°、20.3±0.2°和21.4±0.2°处有特征峰，
    Figure PCTCN2019085641-appb-100001
  2. 根据权利要求1所述的晶体A，其特征在于，所述晶体A的X-射线粉末衍射图谱在衍射角为8.7±0.2°、16.0±0.2°、17.5±0.2°、17.8±0.2°、19.3±0.2°、20.3±0.2°、21.4±0.2°、22.3±0.2°和23.1±0.2°处有特征峰；优选地，所述晶体A的X-射线粉末衍射图谱如图1所示。
  3. 根据权利要求1或2所述的晶体A，其特征在于，所述式(I)的化合物的晶体A的DSC图谱的吸热峰的峰值出现在173±2℃处；优选地，所述晶体A的DSC图谱如图2所示。
  4. 根据权利要求1或2所述的晶体A，其特征在于，所述式(I)的化合物的晶体A的TGA图谱在190±2℃开始分解；优选地，所述晶体A的TGA图谱如图3所示。
  5. 一种制备权利要求1-4任一项所述的式(I)的化合物的晶体A的方法，其特征在于，所述方法为缓慢挥发法、悬浮搅拌法、渗透法或重结晶法。
  6. 根据权利要求5所述的制备晶体A的方法，其特征在于，所述缓慢挥发法包括以下步骤：将式(I)的化合物在第1适当溶剂中溶清，然后在室温下静置，挥发，除去溶剂，收集固体，得到晶体A。
  7. 根据权利要求6所述的制备晶体A的方法，其特征在于，所述第1适当溶剂选自：甲醇、乙醇、正丙醇、异丙醇、正丁醇、丙酮、丁酮、乙酸乙酯、乙酸丁酯、乙酸异丙酯、碳酸二甲酯、四氢呋喃、二氯甲烷、三氯甲烷、甲基叔丁基醚、乙腈、苯甲醚、甲苯、乙醚中的一种或多种；所述第1适当溶剂的用量为使式(I)的化合物溶清即可。
  8. 根据权利要求6所述的制备晶体A的方法，其特征在于，所述第1适当溶剂为A溶剂和B溶剂的混合溶剂，其中所述A溶剂选自：丙酮、四氢呋喃、乙酸乙酯、乙腈、甲苯、二氯甲烷、水、甲基叔丁基醚中的一种或多种；B溶剂选自甲醇、丙酮、四氢呋喃、乙酸乙酯、乙腈、甲苯、二氯甲烷中的一种或多种；
    优选地，所述A溶剂与B溶剂的体积比为1∶2-2∶1；优选地，所述A溶剂与B溶剂的体积比为1∶1。
  9. 根据权利要求5所述的制备晶体A的方法，其特征在于，所述重结晶法包括以下步骤：将式(I)的化合物在第2适当溶剂中加热搅拌、溶清；再缓慢冷至室温，过滤，收集固体，得到晶体A；
    优选地，所述第2适当溶剂选自异丙醇、乙腈、甲苯、正丙醇；优选地，所述式(I)的化合物与第2适当溶剂的质量体积比(g/ml)为1∶(5-10)；
    或者，所述第2适当溶剂为乙醚，所述式(I)的化合物与乙醚的质量体积比(g/ml)为1∶60。
  10. 根据权利要求5所述的制备晶体A的方法，其特征在于，所述悬浮搅拌法包括以下步骤：将式(I)的化合物或其无定形物用第3适当溶剂分散、悬浮后，在室温或者高温条件下悬浮搅拌，收集固体，得到晶体A；
    优选地，所述第3适当溶剂选自：乙醇、正丙醇、正丁醇、乙醚、异丙醚、乙腈、甲苯、正己烷、正庚烷、环己烷、甲基叔丁基醚、水、石油醚中的一种或多种；优选地，所述第3适当溶剂的用量为使溶质在其中悬浮即可；优选地，所述高温条件为60℃。
  11. 根据权利要求5所述的制备晶体A的方法，其特征在于，所述渗透法包括以下步骤：将式(I)的化合物装入容器A中，敞口放置在装有适量第4适当溶剂的容器B中，密封容器B，室温静置，收集固体，得到晶体A；
    优选地，所述第4适当溶剂选自：甲醇、乙醇、乙酸异丙酯、正己烷、乙腈、乙醚、甲基叔丁基醚、甲苯中的一种或多种；优选地，所述静置时间不少于8天。
  12. 根据权利要求5所述的制备晶体A的方法，其特征在于，所述缓慢挥发法包括以下步骤：将式(I)的化合物在A溶剂中溶清，然后加入B溶剂混合，然后在室温下静置，挥发，除去溶剂，收集固体，得到晶体A；优选地，所述A溶剂选自：甲醇、丙酮、四氢呋喃、乙酸乙酯、乙腈、甲苯、二氯甲烷、水、甲基叔丁基醚中的一种或多种；B溶剂选自甲醇、丙酮、四氢呋喃、乙酸乙酯、乙腈、甲苯、二氯甲烷、水中的一种或多种；
    优选的，所述A溶剂与B溶剂的体积比为1∶2-2∶1；优选地，所述A溶剂与B溶剂的体积比为1∶1。
  13. 一种制备式(I)化合物的无定形物的方法，其特征在于，所述方法包括以下步骤：将式(I)的化合物在第5适当溶剂中溶解澄清，再通过减压旋蒸，得到所述无定形物；
    优选地，所述第5适当溶剂选自二氯甲烷、氯仿中的一种或多种；优选地，所述水浴温度为40-50℃；更优选45℃。
  14. 一种药物组合物，包含权利要求1-4中任意一项所述的晶体A和/或根据权利要求13的方法制备的无定形物，以及一种或多种药学上可接受的载体或者一种或多种其他治疗剂。
  15. 一种药物制剂，包含权利要求1-4中任意一项所述的晶体A和/或根据权利要求13的方法制备的无定形物，以及一种或多种药学上可接受的载体。
  16. 权利要求1-4中任意一项所述的晶体A、根据权利要求13的方法制备的无定形物、权利要求14所述的药物组合物或者权利要求15所述的药物制剂在制备用于预防或治疗病毒性疾病的药物中的用途，优选地，所述的病毒性疾病为甲型病毒性肝炎、乙型病毒性肝炎、丙型病毒性肝炎、流行性感冒、疱疹或获得性免疫缺陷综合征(AIDS)。
  17. 一种预防或治疗病毒性疾病的方法，包括向需要其的个体给药有效量的权利要求1-4中任意一项所述的晶体A、根据权利要求13的方法制备的无定形物、权利要求14所述的药物组合物或者权利要求15所述的药物制剂；优选地，所述的病毒性疾病为甲型病毒性肝炎、乙型病毒性肝炎、丙型病毒性肝炎、流行性感冒、疱疹或获得性免疫缺陷综合征(AIDS)。
  18. 权利要求1-4中任意一项所述的晶体A、根据权利要求13的方法制备的无定形物、权利要求14所述的药物组合物或者权利要求15所述的药物制剂，其用于预防或治疗病毒性疾病，优选地，所述的病毒性疾病为甲型病毒性肝炎、乙型病毒性肝炎、丙型病毒性肝炎、流行性感冒、疱疹或获得性免疫缺陷综合征(AIDS)。
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