WO2020228745A1 - Forme cristalline du composé tétrahydroisoxazolo[4,3-c]pyridine contre le vhb - Google Patents

Forme cristalline du composé tétrahydroisoxazolo[4,3-c]pyridine contre le vhb Download PDF

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WO2020228745A1
WO2020228745A1 PCT/CN2020/090059 CN2020090059W WO2020228745A1 WO 2020228745 A1 WO2020228745 A1 WO 2020228745A1 CN 2020090059 W CN2020090059 W CN 2020090059W WO 2020228745 A1 WO2020228745 A1 WO 2020228745A1
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crystal form
compound
formula
following
angles
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PCT/CN2020/090059
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Chinese (zh)
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吴立方
孙飞
杜金华
丁照中
徐宏江
杨玲
张喜全
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正大天晴药业集团股份有限公司
南京明德新药研发有限公司
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Priority to CN202080031672.2A priority Critical patent/CN113825758B/zh
Publication of WO2020228745A1 publication Critical patent/WO2020228745A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • 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
    • 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
    • C07D498/02—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 two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • This application relates to a new crystal form of tetrahydroisoxazolo[4,3-c]pyridine compound against HBV, and specifically to the crystal form of the compound of formula (I), its hydrate and the crystal form of its hydrate The form also includes the application of the crystal form in the preparation of anti-HBV drugs.
  • cccDNA a stable covalently closed circular DNA, namely cccDNA, is formed in the nucleus of the host's liver cells, which serves as a template for HBV to continuously replicate.
  • All subgenomic RNA (sgRNA) and pregenomic RNA (pgRNA) are formed by cccDNA transcription. After exiting the nucleus, sgRNA is translated into X protein and three other envelope proteins, and pgRNA is translated into core protein and viral polymerase. pgRNA and core protein self-assemble under the action of polymerase to form RNA that wraps the nucleocapsid.
  • nucleocapsid In the nucleocapsid, pgRNA is reverse transcribed into negative-strand DNA, and the positive strand of DNA is further synthesized from this, forming rcDNA.
  • the rcDNA wrapped by nucleocapsid re-uncoated into the nucleus to further amplify the cccDNA; on the other hand, it recombines with the envelope protein and releases the cell through the endoplasmic reticulum to form a new HBV.
  • the synthesis of nucleocapsid is a key step in the HBV genome replication process. The synthesis of viral DNA can only occur specifically inside the nucleocapsid.
  • nucleocapsid The assembly of nucleocapsid is an evolutionary constraint process that limits the diversity of HBV, and it is very sensitive to even subtle molecular interference.
  • targets that act on the synthesis and degradation of nucleocapsid are extremely promising.
  • Some anti-HBV virus compounds related to nucleocapsid have been reported.
  • Several related compounds such as NVR 3-778 (WO 2015109130A1), JNJ-56136379, and GLS-4JHS are in the clinical research stage.
  • this application provides a hydrate of the compound of formula (I), the structure of which is shown in formula (I-1),
  • x is 0.8 to 1.2.
  • x of the hydrate is 0.9 to 1.1, preferably 1.0.
  • x is 0.8 to 1.2.
  • x of the crystal form is 0.9 to 1.1, preferably 1.0.
  • the present application provides the crystalline form A of the compound of formula (I-1), and its Cu K ⁇ radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.54 ⁇ 0.20°, 12.35 ⁇ 0.20°, 19.31 ⁇ 0.20°, 24.50 ⁇ 0.20° and 28.01 ⁇ 0.20°,
  • x is 0.8 to 1.2.
  • x of the crystal form A is 0.9 to 1.1, preferably 1.0.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 8.54 ⁇ 0.20°, 12.35 ⁇ 0.20°, 15.27 ⁇ 0.20°, 19.31 ⁇ 0.20° , 22.78 ⁇ 0.20°, 24.50 ⁇ 0.20°, 28.01 ⁇ 0.20° and 29.43 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 8.54 ⁇ 0.20°, 12.35 ⁇ 0.20°, 13.43 ⁇ 0.20°, 15.27 ⁇ 0.20° , 16.57 ⁇ 0.20°, 17.83 ⁇ 0.20°, 19.31 ⁇ 0.20°, 22.78 ⁇ 0.20°, 24.50 ⁇ 0.20°, 28.01 ⁇ 0.20° and 29.43 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 8.54 ⁇ 0.20°, 12.35 ⁇ 0.20°, 12.68 ⁇ 0.20°, 13.43 ⁇ 0.20° , 15.27 ⁇ 0.20°, 16.57 ⁇ 0.20°, 17.83 ⁇ 0.20°, 19.31 ⁇ 0.20°, 19.79 ⁇ 0.20°, 20.93 ⁇ 0.20°, 22.05 ⁇ 0.20°, 22.78 ⁇ 0.20°, 24.50 ⁇ 0.20°, 25.41 ⁇ 0.20° , 25.74 ⁇ 0.20°, 27.56 ⁇ 0.20°, 28.01 ⁇ 0.20°, 29.07 ⁇ 0.20°, 29.43 ⁇ 0.20°, 30.17 ⁇ 0.20°, 31.53 ⁇ 0.20°, 32.27 ⁇ 0.20°, 33.77 ⁇ 0.20° and 35.88 ⁇ 0.20° .
  • the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form A has endothermic peaks at 89.41°C and 131.81°C.
  • thermogravimetric analysis (TGA) curve of the above crystal form A has a weight loss of 4.229% at 78.45 ⁇ 3°C. According to the results of TGA, the above-mentioned crystal form A is a water-containing crystal form.
  • the TGA pattern of the above-mentioned crystal form A is shown in FIG. 3.
  • the above-mentioned crystal form A is prepared in a mixed solvent of ethanol and water.
  • the present application provides a method for preparing crystal form A, the method comprising the following steps:
  • the compound of the above formula (I) is added to the solvent, and then the solid is separated.
  • the solvent is a mixed solvent of ethanol and water.
  • the compound of formula (I) in the preparation method of the above-mentioned crystal form A, after the compound of formula (I) is added to the solvent, it can be selectively heated, and the heating temperature is selected from 30 to 60°C; in some embodiments, the heating temperature It is 40°C. In some specific embodiments, the heating is performed under stirring or shaking conditions for 60 hours.
  • the method of separating the solid is selected from centrifugation or filtration.
  • this application also provides the crystalline form C of the compound of formula (I-1), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 10.53 ⁇ 0.20°, 13.36 ⁇ 0.20°, 19.39 ⁇ 0.20 ° and 21.08 ⁇ 0.20°,
  • x is 0.8 to 1.2.
  • x of the crystal form C is 0.9 to 1.1, preferably 1.0.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 9.53 ⁇ 0.20°, 10.53 ⁇ 0.20°, 13.36 ⁇ 0.20°, 19.39 ⁇ 0.20°, 21.09 ⁇ 0.20 °, 21.58 ⁇ 0.20°, 22.08 ⁇ 0.20° and 28.96 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 9.53 ⁇ 0.20°, 10.53 ⁇ 0.20°, 13.36 ⁇ 0.20°, 17.06 ⁇ 0.20°, 19.39 ⁇ 0.20 °, 21.09 ⁇ 0.20°, 21.58 ⁇ 0.20°, 22.08 ⁇ 0.20°, 23.65 ⁇ 0.20°, 28.53 ⁇ 0.20°, 28.96 ⁇ 0.20° and 30.51 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 9.53 ⁇ 0.20°, 10.53 ⁇ 0.20°, 13.36 ⁇ 0.20°, 17.06 ⁇ 0.20°, 18.80 ⁇ 0.20 ° ⁇ 19.39 ⁇ 0.20° ⁇ 19.69 ⁇ 0.20 ⁇ 21.09 ⁇ 0.20° ⁇ 21.58 ⁇ 0.20° ⁇ 22.08 ⁇ 0.20° ⁇ 23.65 ⁇ 0.20° ⁇ 24.26 ⁇ 0.20° ⁇ 25.90 ⁇ 0.20° ⁇ 26.85 ⁇ 0.20° ⁇ 28.53 ⁇ 0.20° , 28.96 ⁇ 0.20°, 29.91 ⁇ 0.20°, 30.51 ⁇ 0.20°, 31.82 ⁇ 0.200°, 34.52 ⁇ 0.20°, 34.93 ⁇ 0.20°, 37.30 ⁇ 0.20° and 38.17 ⁇ 0.20°.
  • the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form C has an endothermic peak at 134.93°C.
  • thermogravimetric analysis curve of the above-mentioned crystal form C has a weight loss of 4.741% at 132.15 ⁇ 3°C.
  • the TGA pattern of the above-mentioned crystal form C is shown in FIG. 6.
  • the above-mentioned crystal form C is prepared in a mixed solvent of acetone and water.
  • this application provides a method for preparing the above-mentioned crystal form C, the method comprising the following steps: adding a compound of formula (I) to a solvent, and then depositing a solid.
  • the above-mentioned preparation method of Type C wherein the solvent is a mixed solvent of acetone and water.
  • the compound of formula (I) in the preparation method of the above-mentioned crystal form C, after the compound of formula (I) is added to the solvent, it can be selectively heated under reflux and stirred. In some specific embodiments, the heating and stirring are cooled to room temperature.
  • the solid in the preparation method of the above crystal form C, after the solid is precipitated, the solid can be separated by centrifugation or filtration.
  • this application also provides the crystalline form B of the compound of formula (I) above, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.91 ⁇ 0.20°, 11.80 ⁇ 0.20°, 15.46 ⁇ 0.20° and 16.15 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystalline form B has characteristic diffraction peaks at the following 2 ⁇ angles: 8.91 ⁇ 0.20°, 11.80 ⁇ 0.20°, 15.46 ⁇ 0.20°, 16.15 ⁇ 0.20°, 17.63 ⁇ 0.20 °, 24.72 ⁇ 0.20° and 26.39 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystalline form B has characteristic diffraction peaks at the following 2 ⁇ angles: 8.91 ⁇ 0.20°, 11.80 ⁇ 0.20°, 15.46 ⁇ 0.20°, 16.15 ⁇ 0.20°, 17.63 ⁇ 0.20 °, 19.28 ⁇ 0.20°, 23.46 ⁇ 0.20°, 24.72 ⁇ 0.20°, 25.94 ⁇ 0.20°, and 26.39 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 8.91 ⁇ 0.20°, 11.80 ⁇ 0.20°, 13.83 ⁇ 0.20°, 15.46 ⁇ 0.20°, 16.15 ⁇ 0.20 ° ⁇ 16.49 ⁇ 0.20° ⁇ 17.63 ⁇ 0.20° ⁇ 19.28 ⁇ 0.20° ⁇ 20.53 ⁇ 0.20° ⁇ 22.66 ⁇ 0.20° ⁇ 23.46 ⁇ 0.20° ⁇ 24.72 ⁇ 0.20° ⁇ 25.94 ⁇ 0.20° ⁇ 26.39 ⁇ 0.20° ⁇ 26.95 ⁇ 0.20 °, 27.99 ⁇ 0.20°, 29.35 ⁇ 0.20°, 30.32 ⁇ 0.20°, 30.99 ⁇ 0.20°, 31.20 ⁇ 0.20°, 34.54 ⁇ 0.20°, 36.10 ⁇ 0.20°, 38.13 ⁇ 0.20°, 38.83 ⁇ 0.20° and 39.47 ⁇ 0.20 °.
  • the XRPD pattern of the above crystal form B is shown in FIG. 8.
  • the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form B has an endothermic peak at 178.62°C.
  • the above-mentioned crystalline form B is prepared in ethyl acetate.
  • the present application provides a method for preparing the above-mentioned crystal form B, the method comprising the following steps: adding the compound of formula (I) to a solvent, and then separating the solid.
  • the solvent is ethyl acetate.
  • the compound of formula (I) in the preparation method of the above-mentioned crystal form B, after the compound of formula (I) is added to the solvent, it can be selectively heated, and the heating temperature is selected from 30 to 60°C; in some embodiments, the heating temperature It is 40°C. In some specific embodiments, the heating is performed under stirring or shaking conditions for 60 hours.
  • the method of separating the solid is selected from centrifugation or filtration.
  • the preparation method of the above-mentioned crystal form A, crystal form B, and crystal form C further includes drying the separated solid, for example, drying in a vacuum drying oven.
  • the present application provides a crystal form composition comprising the above-mentioned crystal form A, crystal form B, and crystal form C, wherein the crystal form A, crystal form B, and crystal form C account for the weight of the crystal form composition 50% or more, preferably 80% or more, more preferably 90% or more, most preferably 95% or more.
  • the application provides a pharmaceutical composition, which contains a therapeutically effective amount of the crystal form A, crystal form B, crystal form C, or crystal form composition thereof.
  • the pharmaceutical composition of the present application may or may not contain pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the present application may further include one or more other therapeutic agents.
  • this application also provides the application of the above-mentioned crystal form A, crystal form B, crystal form C, crystal form composition, or pharmaceutical composition thereof in the preparation of anti-hepatitis B drugs.
  • this application also provides the application of the above-mentioned crystal form A, crystal form B, crystal form C, crystal form composition thereof, or pharmaceutical composition thereof in the prevention or treatment of hepatitis B.
  • this application also provides a method for the treatment or prevention of hepatitis B, comprising administering a therapeutically effective amount of the above-mentioned crystal form A, crystal form B, and crystal form C to a mammal in need of such treatment or prevention, preferably a human. , Its crystal composition, or its pharmaceutical composition.
  • this application also provides the above-mentioned crystal form A, crystal form B, crystal form C, crystal form composition thereof, or pharmaceutical composition thereof for treating or preventing hepatitis B.
  • the preparation process of the crystal form of the present application is simple, and the crystal form is stable and less affected by heat, humidity, and light, which is convenient for preparation.
  • the crystal form of the present application has good pharmacokinetic properties and is suitable for use as drugs.
  • the pharmacokinetic properties can be measured in preclinical animal experiments such as SD rats and beagle dogs, or in Measured in clinical human trials.
  • the position of the peak or the relative intensity of the peak may be different due to factors such as the measuring instrument and the measuring method/condition.
  • the measurement error of the 2 ⁇ value may be ⁇ 0.2°. Therefore, when determining each crystal type, this error should be taken into consideration, and the error also belongs to the scope of this application.
  • the position of the endothermic peak of DSC may be different due to factors such as measuring instrument, measuring method/condition and so on.
  • there may be an error in the position of the endothermic peak which can be ⁇ 5°C. Therefore, when determining each crystal type, this error should be taken into consideration, and the error also belongs to the scope of this application.
  • the location of the TGA weight loss temperature may be different due to factors such as the measuring instrument, measuring method/condition and other factors.
  • the measuring instrument measuring method/condition and other factors.
  • there may be an error in the position of the weight loss temperature which can be ⁇ 5°C. Therefore, when determining each crystal type, this error should be taken into consideration, and the error also belongs to the scope of this application.
  • the "pharmaceutically acceptable excipients” refer to inert substances that are administered together with the active ingredients to facilitate the administration of the active ingredients, including but not limited to those acceptable for use in humans or animals approved by the State Food and Drug Administration. (Such as livestock) any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer Agent, isotonic agent, solvent or emulsifier.
  • auxiliary materials include calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • compositions of this application can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, Gels, microspheres and aerosols, etc.
  • Typical routes of administration of the pharmaceutical composition of the present application include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, and peritoneal administration. Intramuscular, subcutaneous, and intravenous administration.
  • the preferred route of administration is oral administration.
  • TFA trifluoroacetic acid
  • Boc 2 O stands for di-tert-butyl dicarbonate
  • Boc stands for tert-butoxycarbonyl, which is a protecting group for amino groups
  • LCMS stands for liquid mass chromatography
  • HPLC represents liquid chromatography
  • QD represents once a day
  • BID represents twice a day.
  • Test method Approximately 10-20mg sample is used for XRPD detection.
  • Light tube voltage 40kV
  • light tube current 40mA
  • Test method Take a sample (0.5 ⁇ 1mg) and place it in a DSC aluminum pan for testing. Under the condition of 50mL/min N 2 and at a heating rate of 10°C/min, heat the sample from room temperature (25°C) to 300°C or 350 °C.
  • Test method Take a sample (2 ⁇ 5mg) and place it in a TGA platinum pot for testing. Under the condition of 25mL/min N 2 and at a heating rate of 10°C/min, heat the sample from room temperature (25°C) to 300°C, 350 °C or 20% weight loss.
  • Test conditions Approximately 10-15 mg of sample is used for DVS detection.
  • the analysis method is as follows:
  • Figure 1 is an XRPD spectrum of the crystal form A of the compound of formula (I-1).
  • Figure 2 is a DSC chart of the crystal form A of the compound of formula (I-1).
  • Figure 3 is a TGA spectrum of the crystal form A of the compound of formula (I-1).
  • Figure 4 is an XRPD spectrum of the crystal form C of the compound of formula (I-1).
  • Figure 5 is a DSC spectrum of the crystal form C of the compound of formula (I-1).
  • Figure 6 is a TGA spectrum of the crystal form C of the compound of formula (I-1).
  • Figure 7 is a DVS spectrum of the crystal form C of the compound of formula (I-1).
  • Figure 8 is an XRPD spectrum of the crystalline form B of the compound of formula (I).
  • Figure 9 is a DSC spectrum of the crystal form B of the compound of formula (I).
  • Figure 10 is a DVS spectrum of the crystal form B of the compound of formula (I).
  • Phenyl chloroformate (58.54 g, 373.90 mmol, 46.83 ml) was slowly added dropwise to dissolve 3-cyano-4-fluoroaniline (46.23 g, 339.91 mmol) and pyridine (29.58 g, 373.90 mmol) at 0 degrees Celsius. Mol, 30.18 mL) in dichloromethane (300 mL). After the reaction mixture was stirred at 25 degrees Celsius for 3 hours, it was quenched by adding 250 ml of water, and a white precipitate precipitated. After filtering the precipitate, it was dried under reduced pressure to obtain Intermediate A-1.
  • Mobile phase A 0.1% TFA aqueous solution.
  • Assay (%) indicates the relative content of the main peak; TRS: total impurity content; RH: relative humidity.
  • HBV DNA inhibition rate% (1-sample HBV DNA copy number/DMSO control HBV DNA copy number) ⁇ 100%
  • the HepG2.2.15EC 50 value of the compound of formula (I) is shown in Table 6 below.
  • This experiment aims to evaluate the pharmacokinetic behavior of the compound of formula (I) after a single intravenous injection or intragastric administration in mice.
  • the compound is formulated as a clear solution of 0.5 mg/mL, and the solvent: 5% DMSO/5% dodecyl hydroxystearate (solutol)/90% water; for intragastric administration, the compound is formulated as 2 mg/mL
  • the concentration of the compound in plasma was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • the retention time of the compound and the internal standard (diclofenac), chromatogram acquisition and chromatogram integration are processed by the software Analyst (Applied Biosystems), and the data statistics are processed by the software Watson LIMS (Thermo Fisher Scientific) or Analyst (Applied Biosystems).
  • the unit of the analyte concentration in the sample is ng/mL, with 3 significant digits reserved, and all values expressed as percentages (such as% deviation and% coefficient of variation, etc.) are kept to one decimal place.
  • Each calibration curve contains at least 6 concentration levels.
  • the preparation of calibration standards requires stock solutions from different sources from the quality control samples.
  • the standard should be rejected in regression analysis.
  • the rejected calibration standards should be less than 25%, and each calibration curve contains at least 6 calibration standards that meet the acceptance criteria. If the lower limit of quantification and upper limit of quantification need to be rejected, the upper and lower limit of quantification of the analysis batch will be increased and decreased accordingly.
  • the non-compartmental model of WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to process the plasma concentration, and the linear logarithmic ladder method was used to calculate the pharmacokinetic parameters.
  • the pharmacokinetic parameters to be calculated include but are not limited to (data allowed) T 1/2 , Vdss, CL, AUC 0-24h in the intravenous injection group; C max , T max , AUC 0-24h , and oral gavage group Bioavailability (F%).
  • mice The pharmacokinetic parameters of the compound of formula (I) in mice are shown in Table 7 below.
  • the purpose of this study is to detect the inhibitory effect of compounds (compounds of formula (I)) on HBV in mice through a mouse model of high-pressure tail vein injection.
  • This experiment uses female BABL/c mice, 6-7 weeks old.
  • the HBV plasmid DNA was extracted with pAAV2-HBV 1.3mer and Qiagen EndoFree Plasmid Giga kit at a concentration of 1000ng/ ⁇ L. Dilute with normal saline before use and store at 4°C until use.
  • Dosing schedule dose/dosing method/frequency/total duration
  • 1 Solvent control group 10mL/Kg, gavage, once a day, from day 1 to day 7 * 2

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Abstract

L'invention concerne une nouvelle forme cristalline d'un composé tétrahydroisoxazolo[4,3-c]pyridine contre le VHB, et en particulier, l'invention concerne une forme cristalline d'un composé de formule (I), un hydrate de celui-ci, une forme cristalline de l'hydrate de celui-ci, et l'utilisation de la forme cristalline dans la préparation d'un médicament anti-VHB.
PCT/CN2020/090059 2019-05-14 2020-05-13 Forme cristalline du composé tétrahydroisoxazolo[4,3-c]pyridine contre le vhb WO2020228745A1 (fr)

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CN107207515A (zh) * 2015-01-16 2017-09-26 豪夫迈·罗氏有限公司 用于治疗感染性疾病的吡嗪化合物
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WO2019096241A1 (fr) * 2017-11-16 2019-05-23 正大天晴药业集团股份有限公司 Composés de tétrahydroisoxazolo[4,3-c]pyridine anti-vhb
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