WO2020029912A1 - Disodium salt crystal form c of hcv inhibitor and preparation method therefor - Google Patents

Disodium salt crystal form c of hcv inhibitor and preparation method therefor Download PDF

Info

Publication number
WO2020029912A1
WO2020029912A1 PCT/CN2019/099229 CN2019099229W WO2020029912A1 WO 2020029912 A1 WO2020029912 A1 WO 2020029912A1 CN 2019099229 W CN2019099229 W CN 2019099229W WO 2020029912 A1 WO2020029912 A1 WO 2020029912A1
Authority
WO
WIPO (PCT)
Prior art keywords
salt
hexahydrate
solvent
hcv
formula
Prior art date
Application number
PCT/CN2019/099229
Other languages
French (fr)
Chinese (zh)
Inventor
谢洪明
方清洪
Original Assignee
广东东阳光药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广东东阳光药业有限公司 filed Critical 广东东阳光药业有限公司
Priority to CN201980046587.0A priority Critical patent/CN112513019B/en
Publication of WO2020029912A1 publication Critical patent/WO2020029912A1/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/695—Silicon compounds
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/10—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 two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Definitions

  • the invention belongs to the field of medicine, relates to HCV inhibitor disodium salt crystal form C and a preparation method thereof, and specifically relates to N- (6- (3- (tert-butyl) -5- (2,4-dioxo-3) Disodium salt crystal form C of 1,4-dihydropyrimidine-1 (2H) -yl) -6-fluoro-2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide and its preparation method; also relates to Its composition and use.
  • the salt of the compound has different properties compared to its free acid / base, however, these properties will have different meanings for the active pharmaceutical ingredient, which affects the development or use and storage of subsequent dosage forms.
  • N- (6- (3- (tert-butyl) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -6-fluoro-2-methoxy Phenyl) naphthalene-2-yl) methanesulfonamide (compound of formula (I)) is disclosed in the Chinese patent application CN20151036755.6, but its salts have not been studied in this patent application.
  • the specification discloses a salt of a compound of formula (I):
  • the salt is a sodium salt and the sodium salt shown is a disodium salt.
  • the disodium salt is a hexahydrate.
  • the hexahydrate is in Form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2 ⁇ angles: 4.72 ° ⁇ 0.2 °, 10.51 ° ⁇ 0.2 °, 13.20 ° ⁇ 0.2 °, 23.05 ° ⁇ 0.2 ° and 29.55 ° ⁇ 0.2 °.
  • the hexahydrate is in Form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2 ⁇ angles: 4.72 ° ⁇ 0.2 °, 10.51 ° ⁇ 0.2 °, 12.67 ° ⁇ 0.2 °, 13.20 ° ⁇ 0.2 °, 18.91 ° ⁇ 0.2 °, 21.12 ° ⁇ 0.2 °, 21.34 ° ⁇ 0.2 °, 23.05 ° ⁇ 0.2 °, and 29.55 ° ⁇ 0.2 °.
  • the hexahydrate is in Form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2 ⁇ angles: 4.72 ° ⁇ 0.2 °, 10.51 ° ⁇ 0.2 °, 12.67 ° ⁇ 0.2 °, 13.20 ° ⁇ 0.2 °, 15.13 ° ⁇ 0.2 °, 18.33 ° ⁇ 0.2 °, 18.51 ° ⁇ 0.2 °, 18.91 ° ⁇ 0.2 °, 21.12 ° ⁇ 0.2 °, 21.34 ° ⁇ 0.2 °, 21.93 ° ⁇ 0.2 °, 22.61 ° ⁇ 0.2 °, 23.05 ° ⁇ 0.2 °, 24.04 ° ⁇ 0.2 °, 24.74 ° ⁇ 0.2 °, 25.52 ° ⁇ 0.2 °, 29.55 ° ⁇ 0.2 °, 30.54 ° ⁇ 0.2 °, and 30.65 °
  • the hexahydrate is in Form C
  • the DSC includes endothermic peaks at 102.34 ° C ⁇ 3 ° C and 122.64 ° C ⁇ 3 ° C.
  • the hexahydrate is in Form C, and its TGA weight loss is 16.22 ⁇ 1.7%.
  • the hexahydrate is in Form C, and the X-ray powder diffraction pattern thereof is substantially as shown in FIG. 1.
  • the hexahydrate is in Form C, and the DSC spectrum thereof is substantially as shown in FIG. 2.
  • the hexahydrate is in Form C, and its TGA spectrum is substantially as shown in FIG. 3.
  • the hexahydrate is in Form C, and the single crystal structure of Form C has the following crystallographic parameters:
  • the present specification discloses a method for preparing a disodium salt crystal form C, comprising: reacting a compound represented by formula (I) with sodium hydroxide in a first solvent, and using the obtained sodium salt in a second solvent Medium beating to obtain the disodium salt crystal form C,
  • the first solvent is a hydrophilic organic solvent or a mixed solvent of a hydrophilic organic solvent and water
  • the second solvent has the same definition as the first solvent
  • the hydrophilic organic solvent is methanol, ethanol, isopropanol, or acetone.
  • the molar ratio of the compound represented by formula (I) and sodium hydroxide is 1: 1.5 or more; or the molar ratio of the compound represented by formula (I) and sodium hydroxide is 1: 1.5, 1 : 2, 1: 2.5, 1: 3, 1: 3.5, 1: 4, 1: 4.5, 1: 5, 1: 5.5, 1: 6, 1: 6.5, 1: 7, 1: 7.5, 1: 8 Or 1: 8.5.
  • the reaction is performed at 0-100 ° C; or the reaction is performed at 10-80 ° C; or the reaction is at 10 ° C, 20 ° C, 30 ° C, 40 ° C, It is performed at 50 ° C, 60 ° C, 70 ° C or 80 ° C.
  • the beating is performed at 0-100 ° C; or the beating is performed at 10-80 ° C; or the beating is performed at 10 ° C, 20 ° C, 30 ° C, 40 ° C, It is performed at 50 ° C, 60 ° C, 70 ° C or 80 ° C.
  • the present specification discloses a pharmaceutical composition comprising the sodium salt disclosed in the present specification or a sodium salt prepared according to the method disclosed in the present specification.
  • the pharmaceutical composition disclosed in this specification further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.
  • the pharmaceutical composition disclosed in the present specification further comprises other anti-HCV drugs.
  • the present specification discloses the use of a sodium salt disclosed in the present specification or a sodium salt prepared by the method disclosed in the present specification or a pharmaceutical composition disclosed in the present specification in the preparation of a medicament, wherein the medicament is used to inhibit HCV NS5B protein And / or for the prevention, management, treatment or alleviation of HCV infection or hepatitis C disease in a patient.
  • the present specification discloses a method of inhibiting HCV NS5B protein and / or for preventing, treating, treating or alleviating HCV infection or hepatitis C disease in a patient, comprising administering to the patient an effective amount of the sodium salt disclosed in the present specification Or the sodium salt prepared by the method disclosed in the specification or the pharmaceutical composition disclosed in the specification.
  • the present specification discloses a sodium salt disclosed in the present specification or a method disclosed in the present specification for inhibiting HCV NS5B protein and / or for preventing, treating, treating or alleviating HCV infection or hepatitis C disease in a patient.
  • Sodium salts or pharmaceutical compositions disclosed in this specification are disclosed in this specification.
  • Another aspect of the present invention relates to a method for preparing, isolating, and purifying a compound salt, solvate, and crystal form included in formula (I).
  • the term "subject" used in the present invention refers to an animal. Typically the animal is a mammal.
  • the test subject also refers to, for example, a primate (for example, human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like.
  • a primate for example, human, male or female
  • the subject is a primate.
  • the subject is a human.
  • patient refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to a human. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.
  • sodium salt refers to salts formed by combining sodium and acid ions.
  • the salt obtained by combining with only one sodium ion is a monosodium salt; the salt obtained by combining with two sodium ions is a disodium salt.
  • solvate refers to the association of one or more solvent molecules with a compound of the invention.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to an association formed by the solvent molecules being water.
  • hydrophilic organic solvent refers to an organic solvent that is miscible with water, has a large dielectric constant ( ⁇ is about 10-30), is soluble in water, and can induce Non-polar materials produce a certain dipole moment, which increases the solubility of the latter. Examples include, but are not limited to, methanol (CH 3 OH, MeOH), ethanol (CH 3 CH 2 OH, EtOH), isopropanol, and acetone.
  • volume ratio may also be represented by “V / V” or “v / v”, indicating the volume ratio of a substance.
  • the term "molar ratio” refers to the ratio of the amount of a substance.
  • treating refers to the continuous process of adding an appropriate amount of a suitable solvent to the target, stirring it, heating or not heating, and allowing the substance to dissolve and recrystallize in the solvent. Remove impurities from the surface or envelope of the target.
  • the second solvent has the same definition as the first solvent
  • the selection range of the second solvent is the same as the selection range of the first solvent, but the second solvent It is independent from the first solvent, that is, the specific selection may be the same or different.
  • a salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable means that the substance or composition employed must be chemically or toxicologically compatible with the other components making up the formulation and the mammal used for the treatment.
  • a person skilled in the art can specifically select a "pharmaceutically acceptable" substance or composition according to the other components employed and the subject to be treated, such as a human.
  • the desired salt can be prepared by a suitable method, for example, using an inorganic or organic base, such as ammonia (primary, secondary, tertiary), alkali metal hydroxide or alkaline earth.
  • Metal hydroxides, etc. include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary, and tertiary ammonia, and cyclic ammonia such as piperidine, morpholine, and piperazine Etc., and obtain inorganic salts from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the crystal form may be considered in the present invention to be characterized by graphical data "drawn" by a chart.
  • These data include, for example, X-ray single crystal diffraction patterns, X-ray powder diffraction patterns, Raman spectroscopy, Fourier transform-infrared spectroscopy, DSC curves, thermogravimetric analysis (TGA), and solid state NMR spectroscopy.
  • TGA thermogravimetric analysis
  • the skilled person will appreciate that small changes in the graphical representation of such data (such as peak relative intensity and peak position) can occur due to factors such as changes in instrument response and changes in sample concentration and purity, which are well known to the skilled person. Nevertheless, the technician can compare the graphic data in the figure in this paper with the graphic data generated for the unknown crystal form, and can confirm whether the two sets of graphic data represent the same crystal form.
  • the term "substantially pure” means that one crystalline form is substantially free of another crystalline form or forms, that is, the crystalline form is at least 60%, or at least 70%, or at least 80% pure. , Or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8% , Or at least 99.9%, or other crystal forms in the crystal form, the percentage of the other crystal forms in the total volume or weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or Less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
  • X-ray powder diffraction X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • X-ray powder diffraction pattern or "XRPD pattern” refers to a diffraction pattern experimentally observed or a parameter derived therefrom.
  • the peak X-ray diffraction pattern is characterized by the peak position (abscissa) and peak intensity (ordinate).
  • the relative peak height of the XRPD pattern depends on many factors related to sample preparation and instrument geometry, and the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compound of the present invention is characterized by an XRPD pattern having certain peak positions and has substantially the same characteristics as the XRPD pattern provided in the drawings of the present invention.
  • 2 ⁇ value refers to the peak position in degrees of the experimental device based on the X-ray diffraction experiment and is a common abscissa unit of the diffraction pattern.
  • the test setup requires that if the reflection is diffracted when the incident light beam forms an angle ⁇ ( ⁇ ) with a certain crystal plane, the reflected light beam is recorded at an angle 2 ⁇ (2 ⁇ ).
  • ⁇ angle
  • 2 ⁇ 2 ⁇
  • the specific 2 ⁇ values of the specific polymorphs mentioned herein are intended to refer to the 2 ⁇ values (in degrees) measured using the X-ray diffraction experimental conditions described herein.
  • a radiation source Cu, k ⁇ , 1.540598; 1.544426; K ⁇ 2 / K ⁇ 1 intensity ratio: 0.50).
  • the melting peak height of a differential scanning calorimetry (DSC) curve depends on many factors related to sample preparation and instrument geometry, and the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compound of the present invention is characterized by a DSC pattern having characteristic peak positions, having substantially the same properties as the DSC pattern provided in the drawings of the present invention. According to the condition of the instrument used in this test, the melting peak has an error tolerance of ⁇ 1 °, ⁇ 2 °, ⁇ 3 °, ⁇ 4 °, or ⁇ 5 °. In some embodiments, the melting peak has an error tolerance of ⁇ 3 ° C.
  • thermogravimetric analysis refers to a method of determining the weight loss and thermal degradation temperature of a material by the following steps: in a nitrogen or air environment, at a specified temperature change (in ° C / minute It is heated and the percentage of weight loss during the heating of the crystal is measured.
  • relative intensity refers to the ratio of the intensity of the other strong peak to the intensity of the first strong peak when the intensity of the first strong peak among all the diffraction peaks of the X-ray powder diffraction pattern (XRPD) is 100%.
  • peak refers to a feature that can be identified by those skilled in the art and does not belong to background noise.
  • this article provides a salt, its preparation method, composition, and use, as follows:
  • the specification discloses a salt of a compound of formula (I):
  • the salt is an alkali metal salt.
  • the alkali metal salts include sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium salts.
  • the salt is a sodium salt.
  • the sodium salt shown is a disodium salt.
  • the disodium salt is a hexahydrate.
  • the hexahydrate is in Form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2 ⁇ angles: 4.72 ° ⁇ 0.2 °, 10.51 ° ⁇ 0.2 °, 13.20 ° ⁇ 0.2 °, 23.05 ° ⁇ 0.2 ° and 29.55 ° ⁇ 0.2 °.
  • the hexahydrate is in Form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2 ⁇ angles: 4.72 ° ⁇ 0.2 °, 10.51 ° ⁇ 0.2 °, 12.67 ° ⁇ 0.2 °, 13.20 ° ⁇ 0.2 °, 18.91 ° ⁇ 0.2 °, 21.12 ° ⁇ 0.2 °, 21.34 ° ⁇ 0.2 °, 23.05 ° ⁇ 0.2 °, and 29.55 ° ⁇ 0.2 °.
  • the hexahydrate is in Form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2 ⁇ angles: 4.72 ° ⁇ 0.2 °, 10.51 ° ⁇ 0.2 °, 12.67 ° ⁇ 0.2 °, 13.20 ° ⁇ 0.2 °, 15.13 ° ⁇ 0.2 °, 18.33 ° ⁇ 0.2 °, 18.51 ° ⁇ 0.2 °, 18.91 ° ⁇ 0.2 °, 21.12 ° ⁇ 0.2 °, 21.34 ° ⁇ 0.2 °, 21.93 ° ⁇ 0.2 °, 22.61 ° ⁇ 0.2 °, 23.05 ° ⁇ 0.2 °, 24.04 ° ⁇ 0.2 °, 24.74 ° ⁇ 0.2 °, 25.52 ° ⁇ 0.2 °, 29.55 ° ⁇ 0.2 °, 30.54 ° ⁇ 0.2 °, and 30.65 °
  • the hexahydrate is in Form C
  • the DSC includes endothermic peaks at 102.34 ° C ⁇ 3 ° C and 122.64 ° C ⁇ 3 ° C.
  • the hexahydrate is in Form C, and its TGA weight loss is 16.22 ⁇ 1.7%.
  • the hexahydrate is in Form C, and the X-ray powder diffraction pattern thereof is substantially as shown in FIG. 1.
  • the hexahydrate is in Form C, and the DSC spectrum thereof is substantially as shown in FIG. 2.
  • the hexahydrate is in Form C, and its TGA spectrum is substantially as shown in FIG. 3.
  • the hexahydrate is in Form C, and the single crystal structure of Form C has the following crystallographic parameters:
  • the present specification discloses a method for preparing a disodium salt crystal form C, comprising: reacting a compound represented by formula (I) with sodium hydroxide in a first solvent, and using the obtained sodium salt in a second solvent Medium beating to obtain the disodium salt crystal form C,
  • the first solvent is a hydrophilic organic solvent or a mixed solvent of a hydrophilic organic solvent and water
  • the second solvent has the same definition as the first solvent
  • the first solvent is methanol, ethanol, isopropanol, or acetone.
  • the molar ratio of the compound represented by formula (I) and sodium hydroxide is 1: 1.5 or more; or the molar ratio of the compound represented by formula (I) and sodium hydroxide is 1: 1.5, 1 : 2, 1: 2.5, 1: 3, 1: 3.5, 1: 4, 1: 4.5, 1: 5, 1: 5.5, 1: 6, 1: 6.5, 1: 7, 1: 7.5, 1: 8 Or 1: 8.5.
  • the molar ratio of the compound represented by formula (I) to sodium hydroxide is greater than or equal to 1: 1.5.
  • the molar ratio of the compound represented by formula (I) to sodium hydroxide is 1: 1.5, 1: 2, 1: 2.5, 1: 3, 1: 3.5, 1: 4, 1: 4.5 , 1: 5, 1: 5.5, 1: 6, 1: 6.5, 1: 7, 1: 7.5, 1: 8, or 1: 8.5.
  • the reaction is performed at 0-100 ° C; or the reaction is performed at 10-80 ° C; or the reaction is at 10 ° C, 20 ° C, 30 ° C, 40 ° C, It is performed at 50 ° C, 60 ° C, 70 ° C or 80 ° C.
  • the reaction is performed at 0-100 ° C.
  • the reaction is performed at 10-80 ° C.
  • the reaction is performed at 10 ° C, 20 ° C, 30 ° C, 40 ° C, 50 ° C, 60 ° C, 70 ° C, or 80 ° C.
  • the second solvent is a hydrophilic organic solvent or a mixed solvent of a hydrophilic organic solvent and water.
  • the second solvent is methanol, ethanol, isopropanol, or acetone.
  • the beating is performed at 0-100 ° C; or the beating is performed at 10-80 ° C; or the beating is performed at 10 ° C, 20 ° C, 30 ° C, 40 ° C, It is performed at 50 ° C, 60 ° C, 70 ° C or 80 ° C.
  • the beating is performed at 0-100 ° C.
  • the beating is performed at 10-80 ° C.
  • the beating is performed at 10 ° C, 20 ° C, 30 ° C, 40 ° C, 50 ° C, 60 ° C, 70 ° C, or 80 ° C.
  • the present specification discloses a pharmaceutical composition comprising the sodium salt disclosed in the present specification or a sodium salt prepared according to the method disclosed in the present specification.
  • the pharmaceutical composition disclosed in this specification further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.
  • the pharmaceutical composition disclosed in the present specification further comprises other anti-HCV drugs.
  • the present specification discloses the use of a sodium salt disclosed in the present specification or a sodium salt prepared by the method disclosed in the present specification or a pharmaceutical composition disclosed in the present specification in the preparation of a medicament, wherein the medicament is used to inhibit HCV NS5B protein And / or for the prevention, management, treatment or alleviation of HCV infection or hepatitis C disease in a patient.
  • the present specification discloses a method of inhibiting HCV NS5B protein and / or for preventing, treating, treating or alleviating HCV infection or hepatitis C disease in a patient, comprising administering to the patient an effective amount of the sodium salt disclosed in the present specification Or the sodium salt prepared by the method disclosed in the specification or the pharmaceutical composition disclosed in the specification.
  • the present specification discloses a sodium salt disclosed in the present specification or a method disclosed in the present specification for inhibiting HCV NS5B protein and / or for preventing, treating, treating or alleviating HCV infection or hepatitis C disease in a patient.
  • Sodium salts or pharmaceutical compositions disclosed in this specification are disclosed in this specification.
  • compositions, formulations and administration of salts of the invention are provided.
  • the pharmaceutical composition comprises any one of the salts of the present invention.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.
  • the pharmaceutical composition can be used for treating hepatitis C virus (HCV) infection or hepatitis C disease, and in particular, it has a good inhibitory effect on HCV NS5B protein.
  • HCV hepatitis C virus
  • the pharmaceutical composition further comprises an anti-HCV drug.
  • the anti-HCV drugs are interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote the production of type 1 helper T cell responses, interference RNA, antisense RNA, imiquimod, muscle glycosides 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, Bavi infliximab (Bavituximab), Civacir TM, boceprevir (of boceprevir), telaprevir (of telaprevir), France Sofosbuvir, ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir (BI- 207127), dasabuvir (ABT-333), beclabuvir (BMS-791325), elbasvir (MK-8742), ombitasvir (ABT-267), necepre
  • the interferon is interferon ⁇ -2b, pegylated interferon ⁇ , interferon ⁇ -2a, pegylated interferon ⁇ -2a, complex ⁇ -interferon, interferon ⁇ or its combination.
  • the pharmaceutical composition further comprises at least one HCV inhibitor, the HCV inhibitor is used to inhibit at least one of the HCV replication process and the HCV viral protein function, wherein the HCV replication process is selected from the group consisting of HCV entry and shelling.
  • HCV viral protein is selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and internal ribosome entry points required for HCV virus replication (IRES) and inosine monophosphate dehydrogenase (IMPDH).
  • IFS HCV virus replication
  • IMPDH inosine monophosphate dehydrogenase
  • a therapeutically effective amount of a salt of the invention can be administered as a raw chemical, and can also be provided as an active ingredient of a pharmaceutical composition.
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, especially a salt of a compound of formula (I), and one or more pharmaceutically acceptable carriers, diluents or agents. Shape agent.
  • the carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to its recipient.
  • a method for preparing a pharmaceutical preparation comprises combining a compound of the present invention, especially a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable An acceptable carrier, diluent or excipient is mixed.
  • terapéuticaally effective amount refers to the total amount of each active ingredient sufficient to show a meaningful patient benefit, such as a reduction in viral load. When administered separately using a separate active ingredient, the term refers only to that ingredient. When used in combination, the term refers to the combined amount of active ingredients that, whether administered in combination, sequentially or simultaneously, causes a therapeutic effect.
  • pharmaceutically acceptable refers to compounds, raw materials, compositions and / or dosage forms which are within the scope of sound medical judgment and are suitable for contact with patient tissues without excessive toxicity or irritation , Allergies, or other problems and complications commensurate with a reasonable benefit / risk ratio, and effectively used for the intended purpose.
  • compositions may be in unit dosage form, each unit dose containing a predetermined amount of the active ingredient.
  • the dosage levels of the compounds of the present invention are between about 0.01 mg / kg (mg / kg) body weight / day and about 250 mg / kg body weight / day, preferably between about 0.05 mg / kg body weight / day and about 100 mg / kg body weight between days, monotherapy is often used to prevent or treat HCV-mediated diseases.
  • the pharmaceutical composition of the present invention may generally be administered at about 1 to about 5 times per day or as a continuous infusion. This type of administration can be used as a long-term or short-term therapy.
  • a preferred unit dosage form is a unit dosage form containing a daily or divided dose of the active ingredient described above or a suitable fraction thereof. Treatment can be initiated with small doses that are clearly below the optimal dose of the compound. Thereafter, the dose is increased in smaller increments until the best effect is achieved in this case. In general, it is most desirable to administer a compound at a concentration level that generally provides effective results in terms of antivirals without causing any harmful or toxic side effects.
  • compositions of the present invention comprises a combination of a compound of the present invention and one or more other therapeutic or prophylactic drugs
  • the dosage level of the compound and the additional drug is usually in a monotherapy regimen, accounting for About 10-150%, more preferably about 10-80% of the normal administered dose.
  • Pharmaceutical formulations are suitable for administration by any suitable route, such as by oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual, or transdermal), vaginal or parenteral (including subcutaneous, intradermal) , Intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route.
  • Such formulations may be prepared by any method known in the pharmaceutical arts, for example by mixing the active ingredient with a carrier or excipient. It is preferably administered orally or by injection.
  • compositions suitable for oral administration are provided in separate units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foam or foaming preparations (whip ); Or an oil-in-water emulsion or a water-in-oil emulsion.
  • the active pharmaceutical ingredient may be mixed with a pharmaceutically acceptable oral non-toxic inert carrier such as ethanol, glycerol, water, and the like.
  • a pharmaceutically acceptable oral non-toxic inert carrier such as ethanol, glycerol, water, and the like.
  • the powder is prepared by pulverizing the compound to a suitable fine size and mixing it with a similarly pulverized pharmaceutical carrier (such as starch or edible sugars such as mannitol). Flavoring agents, preservatives, dispersants and colorants may also be present.
  • Capsules are prepared by preparing a powdery mixture as described above and filling it into a shaped gelatin shell. Prior to the filling operation, glidants and lubricants (such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol) can be added to the powdery mixture. Disintegrating or solubilizing agents (such as agar, calcium carbonate, or sodium carbonate) that will improve the availability of the drug when the capsule is taken may also be added.
  • glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol
  • Disintegrating or solubilizing agents such as agar, calcium carbonate, or sodium carbonate
  • suitable binders include starch, gelatin, natural sugars (e.g. glucose or ⁇ -lactose), corn sweeteners, natural and synthetic gums (e.g. gum arabic, tragacanth or sodium alginate), carboxymethyl cellulose , Polyethylene glycol, etc.
  • Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like.
  • Disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • a tablet is made by making a powdery mixture, granulating or pre-pressing, adding a lubricant and a disintegrant, and pressing into tablets.
  • a suitably comminuted compound with a diluent or base as described above, optionally with a binder (e.g., carboxymethyl cellulose, alginate, gelatin, or polyvinylpyrrolidone), a dissolution inhibitor (e.g., paraffin),
  • An absorption accelerator (quaternary salt) and / or an absorbent such as bentonite, kaolin or dicalcium phosphate) are mixed to prepare a powdery mixture.
  • the powdery mixture can be granulated with a binder (for example, syrup, starch syrup, acadiamucilage, or a solution of a cellulose material or a polymeric material) and then sieved under pressure.
  • a binder for example, syrup, starch syrup, acadiamucilage, or a solution of a cellulose material or a polymeric material
  • An alternative method of granulation is to pass the powdery mixture through a tablet press, with the result that the poorly formed agglomerates are crushed and granulated.
  • the granules can be lubricated by adding stearic acid, stearates, talc or mineral oil to prevent sticking to the die of the tablet press.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be mixed with a free-flowing inert carrier and compressed into tablets without the need for granulation or pre-pressing steps.
  • Transparent or opaque protective coating materials consisting of shellac
  • Oral liquid preparations such as solutions, syrups and elixirs can be prepared in the form of dosage units so that a given amount contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution
  • elixirs can be prepared by using a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether
  • preservatives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners
  • flavoring additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners
  • dosage unit formulations for oral administration may be microencapsulated.
  • the formulations can also be formulated for delayed or sustained release, for example by coating or embedding in particulate materials such as polymers, waxes and the like.
  • the salts of the invention can also be administered in liposome delivery systems, such as small monolayer liposomes, large monolayer liposomes, and multilayer liposomes.
  • Liposomes can be composed of a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.
  • the salts of the present invention can also be delivered by using a monoclonal antibody as a separate carrier to which the compound molecule is coupled.
  • Compounds can also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylasparaginephenol or polyethylene oxide polylysine substituted with palmitoyl residues.
  • the compounds can be coupled with a class of biodegradable polymers, such as polylactic acid, poly ⁇ -caprolactone, polyhydroxybutyric acid, polyorthoesters, polymer Cross-linked or amphiphilic block copolymer of acetal, polydihydropyran, polycyanoacrylate and hydrogel.
  • biodegradable polymers such as polylactic acid, poly ⁇ -caprolactone, polyhydroxybutyric acid, polyorthoesters, polymer Cross-linked or amphiphilic block copolymer of acetal, polydihydropyran, polycyanoacrylate and hydrogel.
  • compositions suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions and aqueous and non-aqueous sterile suspensions.
  • Aqueous and non-aqueous sterile injectable solutions may contain antioxidants, buffers, and bacteriostatic agents.
  • Agents and solutes which render the formulation isotonic with the blood of the recipient, aqueous and non-aqueous sterile suspensions may include suspending and thickening agents.
  • the formulations can be provided in unit-dose or multi-dose containers, such as sealed Ankai and vials, and can be stored under freeze-dried (lyophilized) conditions by adding a sterile liquid carrier, such as water for injection, immediately before use.
  • the ready-to-use injection solutions and suspensions can be prepared from sterile powder injections, granules and tablets.
  • formulation also includes other ingredients commonly used in the art in relation to the type of formulation, for example, such formulations suitable for oral administration may include flavoring agents.
  • the present invention provides the use of the salt or the pharmaceutical composition of the present invention in the preparation of a medicament, which can be used to inhibit the HCV replication process and / or inhibit the HCV viral protein function.
  • the HCV replication process is selected from HCV entry, HCV husking, HCV translation, HCV replication, HCV assembly, or HCV release.
  • the HCV viral protein is selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and internal ribosome entry points (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV virus replication.
  • Any of the compounds or pharmaceutical compositions of the present invention can be used to treat hepatitis C virus (HCV) infection or hepatitis C disease, and in particular, it has a good inhibitory effect on HCV NS5B protein.
  • the treatment method comprising the administration of the salt or the pharmaceutical composition of the present invention further comprises administering other HCV drugs to the patient, whereby the salt of the present invention can be combined with other anti-HCV drugs, wherein the anti-HCV drugs are Interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote the production of type 1 helper T cell responses, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenation Enzyme inhibitors, amantadine, rimantadine, Bavituximab, CivacirTM, boceprevir, telaprevir, sofosbuvir, redipa Ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir (BI-207127), dasabuvir (ABT-333) , Beclabuvir (BMS-791325), elbasvir
  • It also includes a method for treating the administration of a salt or a pharmaceutical composition of the present invention, and further includes administration of other anti-HCV drugs, wherein other anti-HCV drugs can be administered in combination with a salt of the present invention or a pharmaceutical composition thereof.
  • the composition is provided as a single dosage form or as separate salts or pharmaceutical compositions as part of a multiple dosage form.
  • Other anti-HCV drugs may be administered at the same time or not at the same time as the salt of the invention. In the latter case, administration can be staggered, such as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.
  • an “effective amount” or “effective dose” of a salt or pharmaceutically acceptable composition of the present invention refers to an effective amount that treats or reduces the severity of one or more of the conditions mentioned in the present invention.
  • the salts and compositions can be used in any amount and route of administration to effectively treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on race, age, general condition of the patient, severity of infection, special factors, mode of administration, and so on.
  • the salt or composition can be administered in combination with one or more other therapeutic agents, as discussed herein.
  • the solvent used in the method for preparing the salt according to the present invention is not particularly limited, and any solvent that can dissolve the starting materials to a certain extent without affecting its properties is included in the present invention.
  • many similar modifications, equivalent replacements, or different ratios of the solvents, solvent combinations, and solvent combinations described in the present invention are regarded as the scope of the present invention.
  • the present invention gives preferred solvents for each reaction step.
  • the preparation experiment of the salt according to the present invention will be described in detail in the Examples section.
  • the present invention provides an activity test experiment (such as a pharmacokinetic experiment) of the salt. It can be known from the experimental results that the salt of the present invention has good biological properties and is suitable for pharmaceutical use.
  • Crystalline forms can be prepared by a variety of methods including, but not limited to, for example, crystallization or recrystallization from a suitable solvent mixture; sublimation; solid-state conversion from another phase; crystallization from a supercritical fluid; and spraying.
  • Techniques for crystalline crystallization or recrystallization of a solvent mixture include, but are not limited to, for example, solvent evaporation; lowering the temperature of the solvent mixture; crystal seeding of a supersaturated solvent mixture of the compound and / or its salt; freezing of the solvent mixture Dry; and add antisolvent (antisolvent) to the solvent mixture.
  • Crystalline forms, including polymorphs can be prepared using high yield crystallization techniques.
  • Drug crystals including polymorphs
  • preparation methods preparation methods, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S.R.Byrn, R.R.Pfeiffer, and J.G.Stowell, Second Edition, SSCI, West Lafayette, Indiana (1999).
  • the solvent is generally selected based on one or more factors including, but not limited to, the solubility of the compound, the crystallization technology used, and the vapor pressure of the solvent.
  • a combination of solvents is available.
  • the compound can be solubilized in a first solvent to obtain a solution, and then an anti-solvent is added to reduce the solubility of the compound in the solution, and precipitate a crystal formation.
  • Antisolvents are solvents in which the compound has low solubility.
  • Seed crystals can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of specific polymorphs, and / or to control the grain size distribution of the crystalline product. Therefore, the calculation of the amount of seed required depends on the size of the available seeds and the desired size of the average product particles, such as "Programmed Cooling Batches Crystallizers", JWMullin and J. Nyvlt, Chemical Engineering, Science, 1971, 26, 369-377 Described. Seeds of small size are generally required to effectively control crystal growth in the batch. By sieving, grinding, or micronizing large crystals, or by microcrystallization of a solution, small-sized seeds can be produced. In crystal grinding or micronization, care should be taken to avoid changing the crystallinity from the desired crystal form (ie, to become amorphous or other polymorph).
  • the cooled crystalline mixture can be filtered under vacuum and the isolated solid product is washed with a suitable solvent (eg, a cold recrystallization solvent). After washing, the product can be dried under a nitrogen purge to obtain the desired crystalline form.
  • a suitable solvent eg, a cold recrystallization solvent
  • the product can be dried under a nitrogen purge to obtain the desired crystalline form.
  • Products can be analyzed by suitable spectroscopy or analytical techniques, including but not limited to, for example, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and dynamic moisture adsorption analysis (DVS), To ensure that the crystalline form of the compound has been formed.
  • the resulting crystalline form can be formed in an amount of greater than about 70% by weight based on the weight of the compound originally used during the crystallization process, and preferably greater than about 90% by weight of the isolated yield.
  • the product may optionally be deblocked by co-milling or through a screen.
  • the radiation source used is (Cu, k ⁇ , 1.540598; 1.544426; K ⁇ 2 / K ⁇ 1 intensity ratio: 0.50), where the voltage is set at 45KV, the current is set at 40mA, and the beam divergence of the X-ray, that is, the effective size of the X-ray constraint on the sample, is 10mm, using ⁇ - ⁇ In continuous scanning mode, an effective 2 ⁇ range of 3 ° to 40 ° is obtained.
  • DSC Differential Scanning Calorimetry
  • Thermogravimetric Analysis TGA measurements exposure apparatus model Q500 with TA Instruments TM.
  • the sample (approximately 10 mg to 30 mg) was put into a platinum skin crucible which had been peeled in advance.
  • the instrument accurately weighs the sample and records it to a thousandth of a milligram by the instrument.
  • the balance was purged with nitrogen at 40 mL / min, and the sample was purged with nitrogen at 60 mL / min.
  • Data were collected between room temperature and 300 °C with a heating rate of 10 °C / min, and the data was analyzed and displayed by TA Universal Analysis.
  • Dynamic Moisture Adsorption Experiment Take 15-30mg sample into the sample tray, suspend the sample tray in the dynamic moisture adsorber, and after the parameters are balanced, start the adsorption-desorption process. Under the conditions, the humidity range is 5% as a stage, from 0% to 95% and then reduced to 0%, to monitor the moisture absorption and weight gain of the sample during the change of humidity.
  • the crystal form of the salt according to the present invention can be prepared by a conventional preparation method.
  • Figure 1 shows an XRPD pattern of Form C described in this description
  • FIG. 2 shows a DSC chart of Form C described in this description
  • FIG. 3 shows a TGA diagram of Form C described in this description
  • FIG. 4 is a diagram showing a single crystal structure of Form C described in this description.
  • Method 1 90mg NaOH was dissolved in 36mL EtOH at 60 ° C, and N- (6- (3- (tert-butyl) -5- (2,4-dioxo-3,4-dihydropyrimidine-1 ( 2H) -yl) -6-fluoro-2-methoxyphenyl) naphthalene-2-yl) methanesulfonamide (formula (I)) 450 mg, stirred overnight, the solid obtained after filtration was added with 16 mL of acetone, and 10 was added dropwise It was dripped with water, stirred at 30 ° C for 3-4 hours, and filtered to obtain 340 mg of Form C.
  • Method 2 60mg NaOH is dissolved in 24mL EtOH at 60 ° C, and N- (6- (3- (tert-butyl) -5- (2,4-dioxo-3,4-dihydropyrimidine-1 ( 300 mg of 2H) -yl) -6-fluoro-2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide (formula (I)), stirred overnight, and the solid obtained after filtration was left under 92.5% humidity After 24 hours, 9 mL of acetone was added, 6 drops of water were added dropwise, and the mixture was stirred at room temperature for 5 hours. 168 mg of Form C was obtained by filtration.
  • the unit cell parameters of Form C single crystal structure are as follows:
  • Beagle dogs were used to conduct in vivo pharmacokinetic tests of the compound of formula (I) and its disodium salt form C, and the oral absorption of the compound of formula (I) and its disodium salt form C was initially studied. Take 8-12kg Beagle dogs, 3 in each group.
  • the method of administration is oral capsules, the dose is 5mg / kg, based on free acid.
  • WinNonLin 6.3 software non-compartment model method was used to calculate the pharmacokinetic parameters. Note: SD indicates individual differences.
  • the disodium salt crystal form C of the present invention has a smaller Tmax than the free acid compound, which indicates that the disodium salt crystal form C of the present invention has a faster onset of action; further, the disodium salt crystal form C has a more effective High in vivo exposure; further, individual differences in disodium salt form C are smaller.

Abstract

The present invention relates to the field of medicine, and relates to a disodium salt crystal form C of an HCV inhibitor and a preparation method therefor, specifically relating to a disodium salt crystal form C of N-(6-(3-(tert-butyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-6-fluoro-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide and a preparation method therefor; the present invention also relates to a composition and use thereof.

Description

HCV抑制剂二钠盐晶型C及其制备方法HCV inhibitor disodium salt crystal form C and preparation method thereof 发明领域Field of invention
本发明属于药物领域，涉及HCV抑制剂二钠盐晶型C及其制备方法，具体的涉及N-(6-(3-(叔丁基)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-6-氟-2-甲氧基苯基)萘-2-基)甲磺酰胺的二钠盐晶型C及其制备方法；还涉及其组合物和用途。The invention belongs to the field of medicine, relates to HCV inhibitor disodium salt crystal form C and a preparation method thereof, and specifically relates to N- (6- (3- (tert-butyl) -5- (2,4-dioxo-3) Disodium salt crystal form C of 1,4-dihydropyrimidine-1 (2H) -yl) -6-fluoro-2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide and its preparation method; also relates to Its composition and use.
发明背景Background of the invention
化合物的盐与其游离酸/碱相比具有不同的性质，然而这些性质对于药物活性成分来说将具有不同的意义，其影响着后续剂型的开发或使用、储存。N-(6-(3-(叔丁基)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-6-氟-2-甲氧基苯基)萘-2-基)甲磺酰胺(式(I)化合物)公开在中国专利申请CN20151036755.6上，但该专利申请中并未对其盐进行研究。The salt of the compound has different properties compared to its free acid / base, however, these properties will have different meanings for the active pharmaceutical ingredient, which affects the development or use and storage of subsequent dosage forms. N- (6- (3- (tert-butyl) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -6-fluoro-2-methoxy Phenyl) naphthalene-2-yl) methanesulfonamide (compound of formula (I)) is disclosed in the Chinese patent application CN20151036755.6, but its salts have not been studied in this patent application.
Figure PCTCN2019099229-appb-000001
Figure PCTCN2019099229-appb-000001
发明内容Summary of the invention
本说明书公开了对N-(6-(3-(叔丁基)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-6-氟-2-甲氧基苯基)萘-2-基)甲磺酰胺(式(I)化合物)盐的研究，特别是二钠盐，取得了不可预料的技术效果。This specification discloses p-N- (6- (3- (tert-butyl) -5- (2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) -6-fluoro- Studies on 2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide (compounds of formula (I)) salts, especially disodium salts, have achieved unexpected technical effects.
一方面，本说明书公开了一种式(I)所示化合物的盐：In one aspect, the specification discloses a salt of a compound of formula (I):
Figure PCTCN2019099229-appb-000002
Figure PCTCN2019099229-appb-000002
在一些实施例中，所述盐为钠盐，所示钠盐为二钠盐。In some embodiments, the salt is a sodium salt and the sodium salt shown is a disodium salt.
在另一些实施例中，所述二钠盐为六水合物。In other examples, the disodium salt is a hexahydrate.
在另一些实施例中，所述六水合物为晶型C，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：4.72°±0.2°、10.51°±0.2°、13.20°±0.2°、23.05°±0.2°和29.55°±0.2°。In other examples, the hexahydrate is in Form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.72 ° ± 0.2 °, 10.51 ° ± 0.2 °, 13.20 ° ± 0.2 °, 23.05 ° ± 0.2 ° and 29.55 ° ± 0.2 °.
在另一些实施例中，所述六水合物为晶型C，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：4.72°±0.2°、10.51°±0.2°、12.67°±0.2°、13.20°±0.2°、18.91°±0.2°、21.12°±0.2°、21.34°±0.2°、23.05°±0.2°和29.55°±0.2°。In other examples, the hexahydrate is in Form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.72 ° ± 0.2 °, 10.51 ° ± 0.2 °, 12.67 ° ± 0.2 °, 13.20 ° ± 0.2 °, 18.91 ° ± 0.2 °, 21.12 ° ± 0.2 °, 21.34 ° ± 0.2 °, 23.05 ° ± 0.2 °, and 29.55 ° ± 0.2 °.
在另一些实施例中，所述六水合物为晶型C，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：4.72°±0.2°、10.51°±0.2°、12.67°±0.2°、13.20°±0.2°、15.13°±0.2°、18.33°±0.2°、18.51°±0.2°、18.91°±0.2°、21.12°±0.2°、21.34°±0.2°、21.93°±0.2°、22.61°±0.2°、23.05°±0.2°、24.04°±0.2°、24.74°±0.2°、25.52°±0.2°、29.55°±0.2°、30.54°±0.2°和30.65°±0.2°。In other examples, the hexahydrate is in Form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.72 ° ± 0.2 °, 10.51 ° ± 0.2 °, 12.67 ° ± 0.2 °, 13.20 ° ± 0.2 °, 15.13 ° ± 0.2 °, 18.33 ° ± 0.2 °, 18.51 ° ± 0.2 °, 18.91 ° ± 0.2 °, 21.12 ° ± 0.2 °, 21.34 ° ± 0.2 °, 21.93 ° ± 0.2 °, 22.61 ° ± 0.2 °, 23.05 ° ± 0.2 °, 24.04 ° ± 0.2 °, 24.74 ° ± 0.2 °, 25.52 ° ± 0.2 °, 29.55 ° ± 0.2 °, 30.54 ° ± 0.2 °, and 30.65 ° ± 0.2 °.
在另一些实施例中，所述六水合物为晶型C，其DSC包含102.34℃±3℃和122.64℃±3℃的吸热峰In other examples, the hexahydrate is in Form C, and the DSC includes endothermic peaks at 102.34 ° C ± 3 ° C and 122.64 ° C ± 3 ° C.
在另一些实施例中，所述六水合物为晶型C，其TGA重量损失为16.22±1.7％。In other examples, the hexahydrate is in Form C, and its TGA weight loss is 16.22 ± 1.7%.
在另一些实施例中，所述六水合物为晶型C，其X射线粉末衍射图谱基本上如图1所示。In other examples, the hexahydrate is in Form C, and the X-ray powder diffraction pattern thereof is substantially as shown in FIG. 1.
在另一些实施例中，所述六水合物为晶型C，其DSC图谱基本上如图2所示。In other examples, the hexahydrate is in Form C, and the DSC spectrum thereof is substantially as shown in FIG. 2.
在另一些实施例中，所述六水合物为晶型C，其TGA图谱基本上如图3所示。In other examples, the hexahydrate is in Form C, and its TGA spectrum is substantially as shown in FIG. 3.
在另一些实施例中，所述六水合物为晶型C，晶型C的单晶结构具有如下的晶体学参数：In other embodiments, the hexahydrate is in Form C, and the single crystal structure of Form C has the following crystallographic parameters:
Figure PCTCN2019099229-appb-000003
Figure PCTCN2019099229-appb-000003
另一方面，本说明书公开了一种二钠盐晶型C的制备方法，包括：式(I)所示的化合物与氢氧化钠在第一溶剂中反应，将得到的钠盐在第二溶剂中打浆，得到所述的二钠盐晶型C，On the other hand, the present specification discloses a method for preparing a disodium salt crystal form C, comprising: reacting a compound represented by formula (I) with sodium hydroxide in a first solvent, and using the obtained sodium salt in a second solvent Medium beating to obtain the disodium salt crystal form C,
Figure PCTCN2019099229-appb-000004
Figure PCTCN2019099229-appb-000004
在一些实施例中，所述第一溶剂为亲水性有机溶剂或亲水性有机溶剂与水的混合溶剂，所述第二溶剂具有所述第一溶剂相同的定义。In some embodiments, the first solvent is a hydrophilic organic solvent or a mixed solvent of a hydrophilic organic solvent and water, and the second solvent has the same definition as the first solvent.
在另一些实施例中，所述亲水性有机溶剂为甲醇、乙醇、异丙醇或丙酮。In other examples, the hydrophilic organic solvent is methanol, ethanol, isopropanol, or acetone.
在另一些实施例中，式(I)所示的化合物与氢氧化钠的摩尔比大于等于1:1.5；或式(I)所示的化合物与氢氧化钠的摩尔比为1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5、1:5、1:5.5、1:6、1:6.5、1:7、1:7.5、1:8或1:8.5。In other embodiments, the molar ratio of the compound represented by formula (I) and sodium hydroxide is 1: 1.5 or more; or the molar ratio of the compound represented by formula (I) and sodium hydroxide is 1: 1.5, 1 : 2, 1: 2.5, 1: 3, 1: 3.5, 1: 4, 1: 4.5, 1: 5, 1: 5.5, 1: 6, 1: 6.5, 1: 7, 1: 7.5, 1: 8 Or 1: 8.5.
在另一些实施例中，所述反应是在0-100℃下进行；或所述反应是在10-80℃下进行；或所述反应是在10℃、20℃、30℃、40℃、50℃、60℃、70℃或80℃下进行。In other examples, the reaction is performed at 0-100 ° C; or the reaction is performed at 10-80 ° C; or the reaction is at 10 ° C, 20 ° C, 30 ° C, 40 ° C, It is performed at 50 ° C, 60 ° C, 70 ° C or 80 ° C.
在另一些实施例中，所述打浆是在0-100℃下进行；或所述打浆是在10-80℃下进行；或所述打浆是在10℃、20℃、30℃、40℃、50℃、60℃、70℃或80℃下进行。In other examples, the beating is performed at 0-100 ° C; or the beating is performed at 10-80 ° C; or the beating is performed at 10 ° C, 20 ° C, 30 ° C, 40 ° C, It is performed at 50 ° C, 60 ° C, 70 ° C or 80 ° C.
另一方面，本说明书公开了一种药物组合物，包含本说明书公开的钠盐或根据本说明书公开的方法制备的钠盐。In another aspect, the present specification discloses a pharmaceutical composition comprising the sodium salt disclosed in the present specification or a sodium salt prepared according to the method disclosed in the present specification.
在另一些实施例中，本说明书公开的药物组合物进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。In other embodiments, the pharmaceutical composition disclosed in this specification further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.
在另一些实施例中，本说明书公开的药物组合物进一步包含其他的抗HCV的药物。In other embodiments, the pharmaceutical composition disclosed in the present specification further comprises other anti-HCV drugs.
另一方面，本说明书公开了本说明书公开的钠盐或本说明书公开的方法制备的钠盐或本说明书公开的药物组合物在制备药物中的用途，其中，所述药物用于抑制HCV NS5B蛋白和/或用于预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病。In another aspect, the present specification discloses the use of a sodium salt disclosed in the present specification or a sodium salt prepared by the method disclosed in the present specification or a pharmaceutical composition disclosed in the present specification in the preparation of a medicament, wherein the medicament is used to inhibit HCV NS5B protein And / or for the prevention, management, treatment or alleviation of HCV infection or hepatitis C disease in a patient.
另一方面，本说明书公开了一种抑制HCV NS5B蛋白和/或用于预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病的方法，包括给予患者有效量的本说明书公开的钠盐或本说明书公开的方法制备的钠盐或本说明书公开的药物组合物。In another aspect, the present specification discloses a method of inhibiting HCV NS5B protein and / or for preventing, treating, treating or alleviating HCV infection or hepatitis C disease in a patient, comprising administering to the patient an effective amount of the sodium salt disclosed in the present specification Or the sodium salt prepared by the method disclosed in the specification or the pharmaceutical composition disclosed in the specification.
另一方面，本说明书公开了用于抑制HCV NS5B蛋白和/或用于预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病的本说明书公开的钠盐或本说明书公开的方法制备的钠盐或本说明书公开的药物组合 物。In another aspect, the present specification discloses a sodium salt disclosed in the present specification or a method disclosed in the present specification for inhibiting HCV NS5B protein and / or for preventing, treating, treating or alleviating HCV infection or hepatitis C disease in a patient. Sodium salts or pharmaceutical compositions disclosed in this specification.
本发明另一方面涉及式(I)所包含的化合物盐、溶剂化物、晶型的制备、分离和纯化的方法。Another aspect of the present invention relates to a method for preparing, isolating, and purifying a compound salt, solvate, and crystal form included in formula (I).
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他的方面的内容将在下面作更加具体完整的描述。The foregoing has outlined, but is not limited to, certain aspects of the invention. The content of these and other aspects will be described in more detail below.
本发明的详细说明书Detailed description of the invention
定义和一般术语Definitions and general terms
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are all included within the scope of the invention as defined by the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The invention is in no way limited to the methods and materials described herein. In the case where one or more of the incorporated documents, patents and similar materials are different or inconsistent with this application (including but not limited to the defined terms, term applications, described technologies, etc.), Application shall prevail.
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。It should be further recognized that certain features of the invention have been described in multiple independent embodiments for clarity, but may also be provided in combination in a single embodiment. Conversely, various features of the invention have been described in a single embodiment for simplicity, but may also be provided separately or in any suitable subcombination.
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考＂Organic Chemistry＂,Thomas Sorrell,University Science Books,Sausalito:1999,和＂March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。Unless otherwise stated, the following definitions used herein shall apply. For the purposes of the present invention, the chemical element is in accordance with the CAS version of the Periodic Table of the Elements, in accordance with the Handbook of Chemistry and Physics, 75th edition, 1994. In addition, the general principles of organic chemistry can be described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007 , The entire contents of which are incorporated herein by reference.
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。Unless otherwise stated or there is a clear conflict in context, the articles "a," "an," and "said" as used herein are intended to include "at least one" or "one or more". Thus, as used herein, these articles refer to the articles of one or more (ie, at least one) objects. For example, "a component" means one or more components, that is, more than one component may be considered for adoption or use in an embodiment of the described embodiment.
本发明所使用的术语“受试对象”是指动物。典型地所述动物是哺乳动物。受试对象，例如也指灵长类动物(例如人类，男性或女性)、牛、绵羊、山羊、马、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中，所述受试对象是灵长类动物。在其他实施方案中，所述受试对象是人。The term "subject" used in the present invention refers to an animal. Typically the animal is a mammal. The test subject also refers to, for example, a primate (for example, human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.
如本文所使用的，术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。As used herein, the term "comprising" is an open-ended expression that includes what is specified in the invention, but does not exclude other aspects.
如本文所使用的，术语“钠盐”是指钠离子和酸根离子化合而成的盐类。只与一个钠离子化合得到的盐为单钠盐；与两个钠离子化合得到的盐为二钠盐。As used herein, the term "sodium salt" refers to salts formed by combining sodium and acid ions. The salt obtained by combining with only one sodium ion is a monosodium salt; the salt obtained by combining with two sodium ions is a disodium salt.
如本文所使用的，术语“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。如本文所使用的，术语“亲水性有机溶剂”是指与水能混溶的有机溶剂，其具有较大的介电常数(ε约为10～30)，能溶于水，又能诱导非极性物质产生一定的偶极矩，而使后者的溶解度增加。例如但不限于，甲醇(CH 3OH，MeOH)、乙醇(CH 3CH 2OH，EtOH)、异丙醇、丙酮。 As used herein, the term "solvate" refers to the association of one or more solvent molecules with a compound of the invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed by the solvent molecules being water. As used herein, the term "hydrophilic organic solvent" refers to an organic solvent that is miscible with water, has a large dielectric constant (ε is about 10-30), is soluble in water, and can induce Non-polar materials produce a certain dipole moment, which increases the solubility of the latter. Examples include, but are not limited to, methanol (CH 3 OH, MeOH), ethanol (CH 3 CH 2 OH, EtOH), isopropanol, and acetone.
如本文所使用的，术语“体积比”也可用“V/V”或“v/v”表示，表示物质的体积比率。As used herein, the term "volume ratio" may also be represented by "V / V" or "v / v", indicating the volume ratio of a substance.
如本文所使用的，术语“摩尔比”是指物质的量的比。As used herein, the term "molar ratio" refers to the ratio of the amount of a substance.
如本文所使用的，术语“打浆”是指向目标物中加入适量合适的溶剂，进行搅拌，可加热，可不加热，让物质在溶剂中进行溶解并再析晶的连续过程，最后通过过滤，达到去除目标物表层或包裹的杂质。As used herein, the term "beating" refers to the continuous process of adding an appropriate amount of a suitable solvent to the target, stirring it, heating or not heating, and allowing the substance to dissolve and recrystallize in the solvent. Remove impurities from the surface or envelope of the target.
如本文所使用的，“所述第二溶剂具有所述第一溶剂相同的定义”表示所述的第二溶剂的选择范围与所述的第一溶剂的选择范围相同，但所述第二溶剂和所述第一溶剂各自独立，即具体选择可以相同也可以不同。As used herein, "the second solvent has the same definition as the first solvent" means that the selection range of the second solvent is the same as the selection range of the first solvent, but the second solvent It is independent from the first solvent, that is, the specific selection may be the same or different.
如本文所使用的，盐是药学上可接受的盐。术语“药学上可接受的”的含义是，所采用的物质或组合物必须是适合化学或毒理上与组成制剂的其他组分和用于治疗的哺乳动物匹配的。本领域技术人员可以根据所采用其他组分和所用于治疗的对象例如人，来具体选择“药学上可以接受的”的物质或组合物。As used herein, a salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition employed must be chemically or toxicologically compatible with the other components making up the formulation and the mammal used for the treatment. A person skilled in the art can specifically select a "pharmaceutically acceptable" substance or composition according to the other components employed and the subject to be treated, such as a human.
如果本发明的化合物是酸性的，则想得到的盐可以通过合适的方法制备得到，如，使用无机碱或有机碱，如氨(伯氨、仲氨、叔氨)，碱金属氢氧化物或碱土金属氢氧化物，等等。合适的盐包括，但并不限于，从氨基酸得到的有机盐，如甘氨酸和精氨酸，氨，如伯氨、仲氨和叔氨，和环状氨，如哌啶、吗啉和哌嗪等，和从钠、钙、钾、镁、锰、铁、铜、锌、铝和锂得到无机盐。If the compound of the present invention is acidic, the desired salt can be prepared by a suitable method, for example, using an inorganic or organic base, such as ammonia (primary, secondary, tertiary), alkali metal hydroxide or alkaline earth. Metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary, and tertiary ammonia, and cyclic ammonia such as piperidine, morpholine, and piperazine Etc., and obtain inorganic salts from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
晶型在本发明中可认为是由图表“描绘”的图形数据表征。这些数据包括，例如X-射线单晶衍射图谱、X-射线粉末衍射图谱、拉曼光谱、傅立叶变换-红外光谱、DSC曲线、热重分析(TGA)和固态NMR光谱。技术人员将理解，这类数据的图形表示可发生小的变化(例如峰相对强度和峰位置)，原因是诸如仪器响应变化和样品浓度及纯度变化的因素，这对于技术人员是公知的。尽管如此，技术人员能够比较本文图中的图形数据和对未知晶形产生的图形数据，并可确认两组图形数据是否表征相同的晶形。The crystal form may be considered in the present invention to be characterized by graphical data "drawn" by a chart. These data include, for example, X-ray single crystal diffraction patterns, X-ray powder diffraction patterns, Raman spectroscopy, Fourier transform-infrared spectroscopy, DSC curves, thermogravimetric analysis (TGA), and solid state NMR spectroscopy. The skilled person will appreciate that small changes in the graphical representation of such data (such as peak relative intensity and peak position) can occur due to factors such as changes in instrument response and changes in sample concentration and purity, which are well known to the skilled person. Nevertheless, the technician can compare the graphic data in the figure in this paper with the graphic data generated for the unknown crystal form, and can confirm whether the two sets of graphic data represent the same crystal form.
如本文所使用的，术语“基本上纯的”是指一种晶型基本上不含另外一种或多种晶型，即晶型的纯度至少60％，或至少70％，或至少80％，或至少85％，或至少90％，或至少93％，或至少95％，或至少98％，或至少99％，或至少99.5％，或至少99.6％，或至少99.7％，或至少99.8％，或至少99.9％，或晶型中含有其它晶型，所述其它晶型在晶型的总体积或总重量中的百分比少于20％，或少于10％，或少于5％，或少于3％，或少于1％，或少于0.5％，或少于0.1％，或少于0.01％。As used herein, the term "substantially pure" means that one crystalline form is substantially free of another crystalline form or forms, that is, the crystalline form is at least 60%, or at least 70%, or at least 80% pure. , Or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8% , Or at least 99.9%, or other crystal forms in the crystal form, the percentage of the other crystal forms in the total volume or weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or Less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
X-射线粉末衍射(XRPD)、差式扫描量热曲线(DSC)或热重分析曲线(TGA)“实质上相同”“基本上如”是指X-射线粉末衍射图、差式扫描量热曲线(DSC)或热重分析曲线(TGA)至少有50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰显示在图中。X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), or thermogravimetric analysis (TGA) "substantially the same" "essentially" refers to the X-ray powder diffraction pattern, differential scanning calorimetry At least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks of the curve (DSC) or thermogravimetric analysis (TGA) are shown in In the figure.
术语“X-射线粉末衍射图谱”或“XRPD图谱”是指实验观测到的衍射图或源自其的参数。通过峰位置(横坐标)及峰强度(纵坐标)表征粉末X-射线衍射图谱。XRPD图谱的相对峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施方案中，本发明的结晶化合物的特征在于具有某些峰位置的XRPD图，具有与本发明附图中提供的XRPD图实质上相同的特征。根据本试验所用仪器状况，衍射峰存在±0.1°、±0.2°、±0.3°、±0.4°或±0.5°的误差容限；在一些实施方案中衍射峰存在±0.2°的误差容限。The term "X-ray powder diffraction pattern" or "XRPD pattern" refers to a diffraction pattern experimentally observed or a parameter derived therefrom. The peak X-ray diffraction pattern is characterized by the peak position (abscissa) and peak intensity (ordinate). The relative peak height of the XRPD pattern depends on many factors related to sample preparation and instrument geometry, and the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compound of the present invention is characterized by an XRPD pattern having certain peak positions and has substantially the same characteristics as the XRPD pattern provided in the drawings of the present invention. Depending on the instrument used in this test, there is an error tolerance of ± 0.1 °, ± 0.2 °, ± 0.3 °, ± 0.4 °, or ± 0.5 ° for the diffraction peaks; in some embodiments there is an error tolerance of ± 0.2 ° for the diffraction peaks.
术语“2θ数值”或“2θ”是指基于X-射线衍射实验的实验装置的以度计的峰位置且是衍射图谱的常见横坐标单位。所述试验设置要求如果在入射光束与某一晶面形成角θ(θ)时反射被衍射，则以角2θ(2θ)记录反射的光束。应理解，本文所提及具体多晶型的具体2θ数值意欲指使用本文所述的X-射线衍射实验条件测量的2θ数值(以度计)。举例而言，如本文所述，使用辐射源(Cu，kα，
Figure PCTCN2019099229-appb-000005
1.540598；
Figure PCTCN2019099229-appb-000006
1.544426；Kα2/Kα1强度比例：0.50)。 The term "2θ value" or "2θ" refers to the peak position in degrees of the experimental device based on the X-ray diffraction experiment and is a common abscissa unit of the diffraction pattern. The test setup requires that if the reflection is diffracted when the incident light beam forms an angle θ (θ) with a certain crystal plane, the reflected light beam is recorded at an angle 2θ (2θ). It should be understood that the specific 2θ values of the specific polymorphs mentioned herein are intended to refer to the 2θ values (in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, a radiation source (Cu, kα,
Figure PCTCN2019099229-appb-000005
1.540598;
Figure PCTCN2019099229-appb-000006
1.544426; Kα2 / Kα1 intensity ratio: 0.50).
差示扫描量热(DSC)曲线的熔融峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施方案中，本发明的结晶化合物的特征在于具有特征峰位置的DSC图，具有与本发明附图中提供的DSC图实质上相同的性质。根据本试验所用仪器状况，熔融峰存在±1°、±2°、±3°、±4°或±5°的误差容限。在一些实施方案中熔融峰存在±3℃的误差容限。The melting peak height of a differential scanning calorimetry (DSC) curve depends on many factors related to sample preparation and instrument geometry, and the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compound of the present invention is characterized by a DSC pattern having characteristic peak positions, having substantially the same properties as the DSC pattern provided in the drawings of the present invention. According to the condition of the instrument used in this test, the melting peak has an error tolerance of ± 1 °, ± 2 °, ± 3 °, ± 4 °, or ± 5 °. In some embodiments, the melting peak has an error tolerance of ± 3 ° C.
如本文所使用的，术语“TGA”或热重分析指的是通过以下步骤来测定材料的重量损失和热降解温度 的方法：在氮气或空气环境中，以指定的温度变化(以℃/分钟计)对其进行加热并测量在晶体的加热过程中重量损失的百分数。As used herein, the term "TGA" or thermogravimetric analysis refers to a method of determining the weight loss and thermal degradation temperature of a material by the following steps: in a nitrogen or air environment, at a specified temperature change (in ° C / minute It is heated and the percentage of weight loss during the heating of the crystal is measured.
术语“相对强度”是指X-射线粉末衍射图(XRPD)的所有衍射峰中第一强峰的强度为100％时，其它峰的强度与第一强峰的强度的比值。The term "relative intensity" refers to the ratio of the intensity of the other strong peak to the intensity of the first strong peak when the intensity of the first strong peak among all the diffraction peaks of the X-ray powder diffraction pattern (XRPD) is 100%.
当提及谱图或/和出现在图中的数据时，“峰”指本领域技术人员能够识别的不会归属于背景噪音的一个特征。When referring to a spectrum or / and the data appearing in the graph, "peak" refers to a feature that can be identified by those skilled in the art and does not belong to background noise.
在本发明的上下文中，当使用或者无论是否使用“大约”或“约”等字眼时，表示每一个数字的数值有可能会出现1％、2％、3％、4％、5％、6％、7％、8％、9％、10％、15％或20％等差异。In the context of the present invention, when the words "about" or "about" are used or not, the numerical value of each digit may appear 1%, 2%, 3%, 4%, 5%, 6 %, 7%, 8%, 9%, 10%, 15%, or 20%.
详细的，本文提供了一种盐、其制备方法、组合物、用途，如下：In detail, this article provides a salt, its preparation method, composition, and use, as follows:
一方面，本说明书公开了一种式(I)所示化合物的盐：In one aspect, the specification discloses a salt of a compound of formula (I):
Figure PCTCN2019099229-appb-000007
Figure PCTCN2019099229-appb-000007
在一些实施例中，所述盐为碱金属盐。In some embodiments, the salt is an alkali metal salt.
在另一些实施例中，所述碱金属盐包括钠盐、钙盐、钾盐、镁盐、锰盐、铁盐、铜盐、锌盐、铝盐和锂盐。In other examples, the alkali metal salts include sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium salts.
在一些实施例中，所述盐为钠盐。In some embodiments, the salt is a sodium salt.
在另一些实施例中，所示钠盐为二钠盐。In other examples, the sodium salt shown is a disodium salt.
在另一些实施例中，所述二钠盐为六水合物。In other examples, the disodium salt is a hexahydrate.
在另一些实施例中，所述六水合物为晶型C，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：4.72°±0.2°、10.51°±0.2°、13.20°±0.2°、23.05°±0.2°和29.55°±0.2°。In other examples, the hexahydrate is in Form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.72 ° ± 0.2 °, 10.51 ° ± 0.2 °, 13.20 ° ± 0.2 °, 23.05 ° ± 0.2 ° and 29.55 ° ± 0.2 °.
在另一些实施例中，所述六水合物为晶型C，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：4.72°±0.2°、10.51°±0.2°、12.67°±0.2°、13.20°±0.2°、18.91°±0.2°、21.12°±0.2°、21.34°±0.2°、23.05°±0.2°和29.55°±0.2°。In other examples, the hexahydrate is in Form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.72 ° ± 0.2 °, 10.51 ° ± 0.2 °, 12.67 ° ± 0.2 °, 13.20 ° ± 0.2 °, 18.91 ° ± 0.2 °, 21.12 ° ± 0.2 °, 21.34 ° ± 0.2 °, 23.05 ° ± 0.2 °, and 29.55 ° ± 0.2 °.
在另一些实施例中，所述六水合物为晶型C，其X射线粉末衍射图谱在下列2θ角处具有衍射峰： 4.72°±0.2°、10.51°±0.2°、12.67°±0.2°、13.20°±0.2°、15.13°±0.2°、18.33°±0.2°、18.51°±0.2°、18.91°±0.2°、21.12°±0.2°、21.34°±0.2°、21.93°±0.2°、22.61°±0.2°、23.05°±0.2°、24.04°±0.2°、24.74°±0.2°、25.52°±0.2°、29.55°±0.2°、30.54°±0.2°和30.65°±0.2°。In other examples, the hexahydrate is in Form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.72 ° ± 0.2 °, 10.51 ° ± 0.2 °, 12.67 ° ± 0.2 °, 13.20 ° ± 0.2 °, 15.13 ° ± 0.2 °, 18.33 ° ± 0.2 °, 18.51 ° ± 0.2 °, 18.91 ° ± 0.2 °, 21.12 ° ± 0.2 °, 21.34 ° ± 0.2 °, 21.93 ° ± 0.2 °, 22.61 ° ± 0.2 °, 23.05 ° ± 0.2 °, 24.04 ° ± 0.2 °, 24.74 ° ± 0.2 °, 25.52 ° ± 0.2 °, 29.55 ° ± 0.2 °, 30.54 ° ± 0.2 °, and 30.65 ° ± 0.2 °.
在另一些实施例中，所述六水合物为晶型C，其DSC包含102.34℃±3℃和122.64℃±3℃的吸热峰In other examples, the hexahydrate is in Form C, and the DSC includes endothermic peaks at 102.34 ° C ± 3 ° C and 122.64 ° C ± 3 ° C.
在另一些实施例中，所述六水合物为晶型C，其TGA重量损失为16.22±1.7％。In other examples, the hexahydrate is in Form C, and its TGA weight loss is 16.22 ± 1.7%.
在另一些实施例中，所述六水合物为晶型C，其X射线粉末衍射图谱基本上如图1所示。In other examples, the hexahydrate is in Form C, and the X-ray powder diffraction pattern thereof is substantially as shown in FIG. 1.
在另一些实施例中，所述六水合物为晶型C，其DSC图谱基本上如图2所示。In other examples, the hexahydrate is in Form C, and the DSC spectrum thereof is substantially as shown in FIG. 2.
在另一些实施例中，所述六水合物为晶型C，其TGA图谱基本上如图3所示。In other examples, the hexahydrate is in Form C, and its TGA spectrum is substantially as shown in FIG. 3.
在另一些实施例中，所述六水合物为晶型C，晶型C的单晶结构具有如下的晶体学参数：In other embodiments, the hexahydrate is in Form C, and the single crystal structure of Form C has the following crystallographic parameters:
Figure PCTCN2019099229-appb-000008
Figure PCTCN2019099229-appb-000008
另一方面，本说明书公开了一种二钠盐晶型C的制备方法，包括：式(I)所示的化合物与氢氧化钠在第一溶剂中反应，将得到的钠盐在第二溶剂中打浆，得到所述的二钠盐晶型C，On the other hand, the present specification discloses a method for preparing a disodium salt crystal form C, comprising: reacting a compound represented by formula (I) with sodium hydroxide in a first solvent, and using the obtained sodium salt in a second solvent Medium beating to obtain the disodium salt crystal form C,
Figure PCTCN2019099229-appb-000009
Figure PCTCN2019099229-appb-000009
在一些实施例中，所述第一溶剂为亲水性有机溶剂或亲水性有机溶剂与水的混合溶剂，所述第二溶剂具有所述第一溶剂相同的定义。In some embodiments, the first solvent is a hydrophilic organic solvent or a mixed solvent of a hydrophilic organic solvent and water, and the second solvent has the same definition as the first solvent.
在另一些实施例中，所述第一溶剂为甲醇、乙醇、异丙醇或丙酮。In other examples, the first solvent is methanol, ethanol, isopropanol, or acetone.
在另一些实施例中，式(I)所示的化合物与氢氧化钠的摩尔比大于等于1:1.5；或式(I)所示的化合物与氢氧化钠的摩尔比为1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5、1:5、1:5.5、1:6、1:6.5、1:7、1:7.5、1:8或1:8.5。In other embodiments, the molar ratio of the compound represented by formula (I) and sodium hydroxide is 1: 1.5 or more; or the molar ratio of the compound represented by formula (I) and sodium hydroxide is 1: 1.5, 1 : 2, 1: 2.5, 1: 3, 1: 3.5, 1: 4, 1: 4.5, 1: 5, 1: 5.5, 1: 6, 1: 6.5, 1: 7, 1: 7.5, 1: 8 Or 1: 8.5.
在另一些实施例中，式(I)所示的化合物与氢氧化钠的摩尔比大于等于1:1.5。In other embodiments, the molar ratio of the compound represented by formula (I) to sodium hydroxide is greater than or equal to 1: 1.5.
在另一些实施例中，式(I)所示的化合物与氢氧化钠的摩尔比为1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5、1:5、1:5.5、1:6、1:6.5、1:7、1:7.5、1:8或1:8.5。In other embodiments, the molar ratio of the compound represented by formula (I) to sodium hydroxide is 1: 1.5, 1: 2, 1: 2.5, 1: 3, 1: 3.5, 1: 4, 1: 4.5 , 1: 5, 1: 5.5, 1: 6, 1: 6.5, 1: 7, 1: 7.5, 1: 8, or 1: 8.5.
在另一些实施例中，所述反应是在0-100℃下进行；或所述反应是在10-80℃下进行；或所述反应是在10℃、20℃、30℃、40℃、50℃、60℃、70℃或80℃下进行。In other examples, the reaction is performed at 0-100 ° C; or the reaction is performed at 10-80 ° C; or the reaction is at 10 ° C, 20 ° C, 30 ° C, 40 ° C, It is performed at 50 ° C, 60 ° C, 70 ° C or 80 ° C.
在另一些实施例中，所述反应是在0-100℃下进行。In other examples, the reaction is performed at 0-100 ° C.
在另一些实施例中，所述反应是在10-80℃下进行。In other examples, the reaction is performed at 10-80 ° C.
在另一些实施例中，所述反应是在10℃、20℃、30℃、40℃、50℃、60℃、70℃或80℃下进行。In other examples, the reaction is performed at 10 ° C, 20 ° C, 30 ° C, 40 ° C, 50 ° C, 60 ° C, 70 ° C, or 80 ° C.
在另一些实施例中，所述第二溶剂为亲水性有机溶剂或亲水性有机溶剂与水的混合溶剂。In other embodiments, the second solvent is a hydrophilic organic solvent or a mixed solvent of a hydrophilic organic solvent and water.
在另一些实施例中，所述第二溶剂为甲醇、乙醇、异丙醇或丙酮。In other examples, the second solvent is methanol, ethanol, isopropanol, or acetone.
在另一些实施例中，所述打浆是在0-100℃下进行；或所述打浆是在10-80℃下进行；或所述打浆是在10℃、20℃、30℃、40℃、50℃、60℃、70℃或80℃下进行。In other examples, the beating is performed at 0-100 ° C; or the beating is performed at 10-80 ° C; or the beating is performed at 10 ° C, 20 ° C, 30 ° C, 40 ° C, It is performed at 50 ° C, 60 ° C, 70 ° C or 80 ° C.
在另一些实施例中，所述打浆是在0-100℃下进行。In other examples, the beating is performed at 0-100 ° C.
在另一些实施例中，所述打浆是在10-80℃下进行。In other examples, the beating is performed at 10-80 ° C.
在另一些实施例中，所述打浆是在10℃、20℃、30℃、40℃、50℃、60℃、70℃或80℃下进行。In other examples, the beating is performed at 10 ° C, 20 ° C, 30 ° C, 40 ° C, 50 ° C, 60 ° C, 70 ° C, or 80 ° C.
另一方面，本说明书公开了一种药物组合物，包含本说明书公开的钠盐或根据本说明书公开的方法制备的钠盐。In another aspect, the present specification discloses a pharmaceutical composition comprising the sodium salt disclosed in the present specification or a sodium salt prepared according to the method disclosed in the present specification.
在另一些实施例中，本说明书公开的药物组合物进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。In other embodiments, the pharmaceutical composition disclosed in this specification further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.
在另一些实施例中，本说明书公开的药物组合物进一步包含其他的抗HCV的药物。In other embodiments, the pharmaceutical composition disclosed in the present specification further comprises other anti-HCV drugs.
另一方面，本说明书公开了本说明书公开的钠盐或本说明书公开的方法制备的钠盐或本说明书公开的药物组合物在制备药物中的用途，其中，所述药物用于抑制HCV NS5B蛋白和/或用于预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病。In another aspect, the present specification discloses the use of a sodium salt disclosed in the present specification or a sodium salt prepared by the method disclosed in the present specification or a pharmaceutical composition disclosed in the present specification in the preparation of a medicament, wherein the medicament is used to inhibit HCV NS5B protein And / or for the prevention, management, treatment or alleviation of HCV infection or hepatitis C disease in a patient.
另一方面，本说明书公开了一种抑制HCV NS5B蛋白和/或用于预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病的方法，包括给予患者有效量的本说明书公开的钠盐或本说明书公开的方法制备的钠盐或本说明书公开的药物组合物。In another aspect, the present specification discloses a method of inhibiting HCV NS5B protein and / or for preventing, treating, treating or alleviating HCV infection or hepatitis C disease in a patient, comprising administering to the patient an effective amount of the sodium salt disclosed in the present specification Or the sodium salt prepared by the method disclosed in the specification or the pharmaceutical composition disclosed in the specification.
另一方面，本说明书公开了用于抑制HCV NS5B蛋白和/或用于预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病的本说明书公开的钠盐或本说明书公开的方法制备的钠盐或本说明书公开的药物组合物。In another aspect, the present specification discloses a sodium salt disclosed in the present specification or a method disclosed in the present specification for inhibiting HCV NS5B protein and / or for preventing, treating, treating or alleviating HCV infection or hepatitis C disease in a patient. Sodium salts or pharmaceutical compositions disclosed in this specification.
本发明盐的组合物，制剂和给药Compositions, formulations and administration of salts of the invention
所述药物组合物包含任何一种本发明的盐。该药物组合物还可以进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。所述药物组合物可以用于治疗丙型肝炎病毒(HCV)感染或丙型肝炎疾病，特别地，其对HCV NS5B蛋白有很好的抑制作用。The pharmaceutical composition comprises any one of the salts of the present invention. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof. The pharmaceutical composition can be used for treating hepatitis C virus (HCV) infection or hepatitis C disease, and in particular, it has a good inhibitory effect on HCV NS5B protein.
所述药物组合物进一步包含抗HCV的药物。其中所述抗HCV的药物为干扰素、利巴韦林、白介素2、白介素6、白介素12、促进产生1型辅助性T细胞应答的化合物、干扰RNA、反义RNA、咪喹莫德、肌苷5’-单磷酸脱氢酶抑制剂、金刚烷胺、金刚乙胺、巴维昔单抗(Bavituximab)、Civacir TM、波普瑞韦(boceprevir)、替拉瑞韦(telaprevir)、索非布韦(sofosbuvir)、雷迪帕韦(ledipasvir)、达卡他韦(daclatasvir)、丹诺普韦(danoprevir)、西鲁瑞韦(ciluprevir)、那拉匹韦(narlaprevir)、deleobuvir(BI-207127)、dasabuvir(ABT-333)、beclabuvir(BMS-791325)、elbasvir(MK-8742)、ombitasvir(ABT-267)、neceprevir(ACH-2684)、tegobuvir(GS-9190)、grazoprevir(MK-5172)、sovaprevir(ACH-1625)、samatasvir(IDX-719)、setrobuvir、veruprevir(ABT-450)、埃罗替尼(erlotinib)、simeprevir(TMC-435)、asunaprevir(BMS-650032)、vaniprevir(MK-7009)、faldaprevir(BI-2013335)、VX-135、CIGB-230、TG-2349、ABT-530、ABT-493、IDX-21437、GS-9669、JHJ-56914845、vedroprevir(GS-9451)、BZF-961、GS-9256、ANA975、EDP239、PPI-668、GS-5816、MK-8325、GSK-2336805、PPI-461、ACH-1095、VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、EP-013420、VBY-376、TMC-649128、R-7128、PSI-7977、INX-189、IDX-184、IDX102、R1479、UNX-08189、PSI-6130、PSI-938、PSI-879、HCV-796、HCV-371、VCH-916、VCH-222、ANA-598、MK-3281、ABT-072、PF-00868554、BI-207127、A-837093、JKT-109、Gl-59728、GL-60667、AZD-2795、TMC-647055或其组合。其中，所述干扰素为干扰素α-2b、聚乙二醇化的干扰 素α、干扰素α-2a、聚乙二醇化的干扰素α-2a、复合α-干扰素、干扰素γ或其组合。所述药物组合物，进一步包含至少一种HCV抑制剂，所述HCV抑制剂用于抑制HCV复制过程和抑制HCV病毒蛋白功能的至少之一，其中所述HCV复制过程选自HCV进入、脱壳、翻译、复制、组装、释放的HCV的完整病毒周期；所述的HCV病毒蛋白选自金属蛋白酶、NS2、NS3、NS4A、NS4B、NS5A、NS5B；以及HCV病毒复制所需要的内部核糖体进入点(IRES)和肌苷单磷酸脱氢酶(IMPDH)。 The pharmaceutical composition further comprises an anti-HCV drug. The anti-HCV drugs are interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote the production of type 1 helper T cell responses, interference RNA, antisense RNA, imiquimod, muscle glycosides 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, Bavi infliximab (Bavituximab), Civacir TM, boceprevir (of boceprevir), telaprevir (of telaprevir), Sophia Sofosbuvir, ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir (BI- 207127), dasabuvir (ABT-333), beclabuvir (BMS-791325), elbasvir (MK-8742), ombitasvir (ABT-267), neceprevir (ACH-2684), tegobuvir (GS-9190), grazoprevir (MK-5172 ), Sovaprevir (ACH-1625), samatasvir (IDX-719), setrobuvir, veruprevir (ABT-450), erlotinib (slot), simeprevir (TMC-435), asunaprevir (BMS-650032), vaniprevir (MK -7009), faldaprevir (BI-2013335), VX-135, CIGB-230, TG-2349, ABT-530, ABT-493, IDX-21437, GS-9669, JHJ-56914845, vedroprevir (GS-9451), BZF-961, GS-9256, ANA975, EDP239, PPI-668, GS-5816, MK-8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX- 184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-072 PF-00868554, BI-207127, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055, or a combination thereof. Wherein, the interferon is interferon α-2b, pegylated interferon α, interferon α-2a, pegylated interferon α-2a, complex α-interferon, interferon γ or its combination. The pharmaceutical composition further comprises at least one HCV inhibitor, the HCV inhibitor is used to inhibit at least one of the HCV replication process and the HCV viral protein function, wherein the HCV replication process is selected from the group consisting of HCV entry and shelling. , Translation, replication, assembly, release of the complete viral cycle of HCV; the HCV viral protein is selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and internal ribosome entry points required for HCV virus replication (IRES) and inosine monophosphate dehydrogenase (IMPDH).
当可用于治疗时，治疗有效量的本发明的盐，尤其是式(I)化合物的盐可作为未加工的化学药品给予，还可作为药物组合物的活性成分提供。因此，本发明内容还提供药物组合物，该药物组合物包括治疗有效量的本发明化合物，尤其是式(I)化合物的盐和一种或多种药学上可接受的载体、稀释剂或赋形剂。从与制剂其他成分相容以及对其接受者无害的意义上来讲，载体、稀释剂或赋形剂必须是可接受的。根据本发明内容的另一方面，还提供用于制备药物制剂的方法，该方法包括将本发明化合物，尤其是式(I)化合物或其药学上可接受的盐与一种或多种药学上可接受的载体、稀释剂或赋形剂混匀。When available for treatment, a therapeutically effective amount of a salt of the invention, especially a salt of a compound of formula (I), can be administered as a raw chemical, and can also be provided as an active ingredient of a pharmaceutical composition. Accordingly, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, especially a salt of a compound of formula (I), and one or more pharmaceutically acceptable carriers, diluents or agents. Shape agent. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to its recipient. According to another aspect of the present invention, there is also provided a method for preparing a pharmaceutical preparation, which method comprises combining a compound of the present invention, especially a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable An acceptable carrier, diluent or excipient is mixed.
本文所使用的术语“治疗有效量”是指足以显示出有意义的患者益处(例如病毒负荷减少)的各活性组分的总量。当使用单独的活性成分单独给药时，该术语仅指该成分。当组合应用时，该术语则是指不论组合，依次或同时给药时，都引起治疗效果的活性成分的组合量。本发明所使用的术语“药学上可接受的”是指这样的化合物、原料、组合物和/或剂型，它们在合理医学判断的范围内，适用于与患者组织接触而无过度毒性、刺激性、变态反应或与合理的利益/风险比相对称的其他问题和并发症，并有效用于既定用途。The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to show a meaningful patient benefit, such as a reduction in viral load. When administered separately using a separate active ingredient, the term refers only to that ingredient. When used in combination, the term refers to the combined amount of active ingredients that, whether administered in combination, sequentially or simultaneously, causes a therapeutic effect. The term "pharmaceutically acceptable" as used in the present invention refers to compounds, raw materials, compositions and / or dosage forms which are within the scope of sound medical judgment and are suitable for contact with patient tissues without excessive toxicity or irritation , Allergies, or other problems and complications commensurate with a reasonable benefit / risk ratio, and effectively used for the intended purpose.
药物制剂可呈单位剂型，每个单位剂量含有预定量的活性成分。本发明内容的化合物的剂量水平介于约0.01毫克/千克(mg/kg)体重/天和约250毫克/千克体重/天之间，优选介于约0.05mg/kg体重/天和约100mg/kg体重/天之间，常常以单一疗法用于预防或治疗HCV介导的疾病。通常可按每天约1至约5次或者作为连续输注给予本发明内容的药物组合物。这类给药法可用作长期或短期疗法。与载体材料混合以制备单一剂型的活性成分的量将根据待治疗的疾病、疾病的严重程度、给药时间、给药途径、所用化合物的排泄速率、治疗时间和患者年龄、性别、体重和情况而改变。优选的单位剂型是含有本文上述活性成分的日剂量或分剂量或其适宜分数的单位剂型。可用显然低于化合物最佳剂量的小剂量开始治疗。此后，以较小的增量来加大剂量直到在这种情况下达到最佳效果。一般而言，最理想地给予化合物的浓度水平是通常可在抗病毒方面提供有效结果而又不至于引起任何有害或有毒的副作用。Pharmaceutical preparations may be in unit dosage form, each unit dose containing a predetermined amount of the active ingredient. The dosage levels of the compounds of the present invention are between about 0.01 mg / kg (mg / kg) body weight / day and about 250 mg / kg body weight / day, preferably between about 0.05 mg / kg body weight / day and about 100 mg / kg body weight Between days, monotherapy is often used to prevent or treat HCV-mediated diseases. The pharmaceutical composition of the present invention may generally be administered at about 1 to about 5 times per day or as a continuous infusion. This type of administration can be used as a long-term or short-term therapy. The amount of active ingredient mixed with the carrier material to produce a single dosage form will depend on the disease to be treated, the severity of the disease, the time of administration, the route of administration, the excretion rate of the compound used, the time of treatment and the age, sex, weight and condition of the patient And change. A preferred unit dosage form is a unit dosage form containing a daily or divided dose of the active ingredient described above or a suitable fraction thereof. Treatment can be initiated with small doses that are clearly below the optimal dose of the compound. Thereafter, the dose is increased in smaller increments until the best effect is achieved in this case. In general, it is most desirable to administer a compound at a concentration level that generally provides effective results in terms of antivirals without causing any harmful or toxic side effects.
当本发明内容的组合物包含本发明内容的化合物和一种或多种其他治疗药物或预防药物的组合时，化合物和另外的药物的剂量水平通常在单一疗法方案中，占正常给药剂量的约10-150％，更优选 占正常给药剂量的约10-80％。药物制剂适于通过任何合适的途径给药，例如通过口服(包括口腔或舌下)、直肠、鼻、局部(包括口腔、舌下或经皮)、阴道或胃肠外(包括皮下、皮内、肌内、关节内、滑膜内、胸骨内、鞘内、病灶内、静脉内或者真皮下注射或输注)途径。可按药剂学领域的任何已知方法制备这类制剂，例如通过将活性成分与载体或赋形剂混合。优选口服给药或注射给药。When a composition of the present invention comprises a combination of a compound of the present invention and one or more other therapeutic or prophylactic drugs, the dosage level of the compound and the additional drug is usually in a monotherapy regimen, accounting for About 10-150%, more preferably about 10-80% of the normal administered dose. Pharmaceutical formulations are suitable for administration by any suitable route, such as by oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual, or transdermal), vaginal or parenteral (including subcutaneous, intradermal) , Intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route. Such formulations may be prepared by any method known in the pharmaceutical arts, for example by mixing the active ingredient with a carrier or excipient. It is preferably administered orally or by injection.
适于口服给药的药物制剂按独立的单位提供，例如胶囊剂或片剂；散剂或颗粒剂；水性或非水性液体中的溶液剂或混悬剂；可食用泡沫制剂或起泡制剂(whip)；或水包油乳液剂或油包水乳液剂。Pharmaceutical preparations suitable for oral administration are provided in separate units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foam or foaming preparations (whip ); Or an oil-in-water emulsion or a water-in-oil emulsion.
举例来说，对于以片剂或胶囊剂形式的口服给药，活性药物组分可与药学上可接受的口服无毒惰性载体(例如乙醇、甘油、水等)相混合。通过将化合物粉碎成合适的微细尺寸，并与被同样粉碎的药用载体(例如淀粉或甘露醇等可食用的糖类)混匀来制备散剂。还可存在矫味剂、防腐剂、分散剂和着色剂。For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient may be mixed with a pharmaceutically acceptable oral non-toxic inert carrier such as ethanol, glycerol, water, and the like. The powder is prepared by pulverizing the compound to a suitable fine size and mixing it with a similarly pulverized pharmaceutical carrier (such as starch or edible sugars such as mannitol). Flavoring agents, preservatives, dispersants and colorants may also be present.
通过制备如上所述的粉状混合物，并装填到成形的明胶壳内，来制备胶囊剂。在装填操作之前，可将助流剂和润滑剂(例如胶态二氧化硅、滑石粉、硬脂酸镁、硬脂酸钙或固态聚乙二醇)加到粉状混合物中。还可加入当服下胶囊剂时将改进药物可利用性的崩解剂或增溶剂(例如琼脂、碳酸钙或碳酸钠)。Capsules are prepared by preparing a powdery mixture as described above and filling it into a shaped gelatin shell. Prior to the filling operation, glidants and lubricants (such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol) can be added to the powdery mixture. Disintegrating or solubilizing agents (such as agar, calcium carbonate, or sodium carbonate) that will improve the availability of the drug when the capsule is taken may also be added.
此外需要或必需时，也可将合适的粘合剂、润滑剂、崩解剂和着色剂掺到混合物中。合适的粘合剂包括淀粉、明胶、天然糖(例如葡萄糖或β-乳糖)、玉米甜味剂、天然和合成树胶(例如阿拉伯树胶、西黄蓍胶或藻酸钠)、羧甲基纤维素、聚乙二醇等。用于这些剂型的润滑剂包括油酸钠、氯化钠等。崩解剂包括但并不限于淀粉、甲基纤维素、琼脂、皂土、黄原胶等。例如，通过制成粉状混合物，制粒或预压片，加入润滑剂和崩解剂，压制成片，从而制成片剂。将适当粉碎的化合物与如上述所述的稀释剂或基料、任选与粘合剂(例如羧甲基纤维素、藻酸盐、明胶或聚乙烯吡咯烷酮)、溶解阻止剂(例如石蜡)、吸收加速剂(季盐)和/或吸收剂(例如皂土、高岭土或磷酸二钙)混合，来制备粉状混合物。可用粘合剂(例如糖浆、淀粉浆、阿拉伯胶浆(acadiamucilage)或纤维素材料或聚合材料溶液)润湿后加压过筛，将粉状混合物制粒。制粒的一个替代方法是，可将粉状混合物通过压片机，结果是将形成不佳的团块再击碎制成颗粒。可通过加入硬脂酸、硬脂酸盐，滑石粉或矿物油使颗粒润滑以防止粘到压片机的冲模上。然后将经润滑的混合物压制成片。本发明内容的化合物还可与自由流动的惰性载体混合，无需通过制粒或预压片步骤便可压制成片。可提供透明或不透明的由虫胶密封衣、糖衣或聚合材料衣和蜡质抛光衣(polish coating of wax)组成的保护性包衣材料。可将染料加到这些包衣材料中以区分不同的单位剂量。In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (e.g. glucose or β-lactose), corn sweeteners, natural and synthetic gums (e.g. gum arabic, tragacanth or sodium alginate), carboxymethyl cellulose , Polyethylene glycol, etc. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. For example, a tablet is made by making a powdery mixture, granulating or pre-pressing, adding a lubricant and a disintegrant, and pressing into tablets. Combining a suitably comminuted compound with a diluent or base as described above, optionally with a binder (e.g., carboxymethyl cellulose, alginate, gelatin, or polyvinylpyrrolidone), a dissolution inhibitor (e.g., paraffin), An absorption accelerator (quaternary salt) and / or an absorbent (such as bentonite, kaolin or dicalcium phosphate) are mixed to prepare a powdery mixture. The powdery mixture can be granulated with a binder (for example, syrup, starch syrup, acadiamucilage, or a solution of a cellulose material or a polymeric material) and then sieved under pressure. An alternative method of granulation is to pass the powdery mixture through a tablet press, with the result that the poorly formed agglomerates are crushed and granulated. The granules can be lubricated by adding stearic acid, stearates, talc or mineral oil to prevent sticking to the die of the tablet press. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be mixed with a free-flowing inert carrier and compressed into tablets without the need for granulation or pre-pressing steps. Transparent or opaque protective coating materials consisting of shellac, sugar or polymeric coatings and wax coatings of wax are available. Dyes can be added to these coating materials to distinguish different unit doses.
口服液体制剂例如溶液剂、糖浆剂和酏剂可以剂量单位形式制备，从而给定量含有预定量的化 合物。糖浆剂可通过将化合物溶于适当调味的水溶液中来制备，而酏剂可通过使用无毒溶媒来制备。还可加入增溶剂和乳化剂(例如乙氧基化异硬脂醇和聚氧乙烯山梨醇醚)、防腐剂、矫味添加剂(例如薄荷油或天然甜味剂或糖精或其他人造甜味剂)等。Oral liquid preparations such as solutions, syrups and elixirs can be prepared in the form of dosage units so that a given amount contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, and elixirs can be prepared by using a non-toxic vehicle. Solubilizers and emulsifiers (such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether), preservatives, flavoring additives (such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners) can also be added Wait.
如果适当的话，可将用于口服给药的剂量单位制剂微胶囊化。也可将制剂制成延时或持续释放，例如通过包衣或包埋在聚合物、蜡等微粒材料中。If appropriate, dosage unit formulations for oral administration may be microencapsulated. The formulations can also be formulated for delayed or sustained release, for example by coating or embedding in particulate materials such as polymers, waxes and the like.
本发明的盐，尤其是式(I)化合物的盐还可以脂质体递药系统给予，例如小单层脂质体、大单层脂质体和多层脂质体。脂质体可由多种磷脂(例如胆固醇、十八烷基胺或磷脂酰胆碱)构成。The salts of the invention, especially the compounds of formula (I), can also be administered in liposome delivery systems, such as small monolayer liposomes, large monolayer liposomes, and multilayer liposomes. Liposomes can be composed of a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.
本发明的盐，尤其是式(I)化合物的盐也可通过使用单克隆抗体作为单独的载体(化合物分子与之偶联)递药。化合物也可与作为可靶向药物载体的可溶性聚合物偶联。这类聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺苯酚、聚羟乙基天冬酰胺苯酚或被棕榈酰残基取代的聚氧化乙烯聚赖氨酸。此外，化合物可与一类生物可降解的聚合物偶联，用于达到药物的控释，这类聚合物例如聚乳酸、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联共聚物或两亲性嵌段共聚物。The salts of the present invention, especially the compounds of formula (I), can also be delivered by using a monoclonal antibody as a separate carrier to which the compound molecule is coupled. Compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylasparaginephenol or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the compounds can be coupled with a class of biodegradable polymers, such as polylactic acid, polyε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polymer Cross-linked or amphiphilic block copolymer of acetal, polydihydropyran, polycyanoacrylate and hydrogel.
适于胃肠外给药的药物制剂包括水性和非水性无菌注射溶液剂及水性和非水性无菌混悬剂，水性和非水性无菌注射溶液剂可含有抗氧化剂、缓冲剂、抑菌剂和使所述制剂与待接受者血液等渗的溶质，水性和非水性无菌混悬剂可包括悬浮剂和增稠剂。制剂可以单位剂量或多剂量容器提供，例如密封的安凯和小瓶，并可保存在冷冻干燥(冻干)条件下，只需在临用前加入无菌液体载体，例如注射用水。临用时配置的注射溶液剂和混悬剂可由无菌粉针剂、颗粒剂和片剂制备。Pharmaceutical formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions and aqueous and non-aqueous sterile suspensions. Aqueous and non-aqueous sterile injectable solutions may contain antioxidants, buffers, and bacteriostatic agents. Agents and solutes which render the formulation isotonic with the blood of the recipient, aqueous and non-aqueous sterile suspensions may include suspending and thickening agents. The formulations can be provided in unit-dose or multi-dose containers, such as sealed Ankai and vials, and can be stored under freeze-dried (lyophilized) conditions by adding a sterile liquid carrier, such as water for injection, immediately before use. The ready-to-use injection solutions and suspensions can be prepared from sterile powder injections, granules and tablets.
应当了解的是，除了以上特别提到的成分以外，制剂还包括与所述制剂类型有关的本领域常用的其它成分，例如适于口服给药的这类制剂可包括矫味剂。It should be understood that, in addition to the ingredients specifically mentioned above, the formulation also includes other ingredients commonly used in the art in relation to the type of formulation, for example, such formulations suitable for oral administration may include flavoring agents.
本发明盐和药物组合物的用途Uses of the salts and pharmaceutical compositions of the invention
在本发明提供了本发明的盐或药物组合物在制备药物中的用途，所述药物可以用于抑制HCV复制过程和/或抑制HCV病毒蛋白功能。所述HCV复制过程选自HCV进入、HCV脱壳、HCV翻译、HCV复制、HCV组装或HCV释放。所述的HCV病毒蛋白选自金属蛋白酶、NS2、NS3、NS4A、NS4B、NS5A、NS5B；以及HCV病毒复制所需要的内部核糖体进入点(IRES)和肌苷单磷酸脱氢酶(IMPDH)。本发明所述任一化合物或药物组合物可以用于治疗丙型肝炎病毒(HCV)感染或丙型肝炎疾病，特别地，其对HCV NS5B蛋白有很好的抑制作用。The present invention provides the use of the salt or the pharmaceutical composition of the present invention in the preparation of a medicament, which can be used to inhibit the HCV replication process and / or inhibit the HCV viral protein function. The HCV replication process is selected from HCV entry, HCV husking, HCV translation, HCV replication, HCV assembly, or HCV release. The HCV viral protein is selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and internal ribosome entry points (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV virus replication. Any of the compounds or pharmaceutical compositions of the present invention can be used to treat hepatitis C virus (HCV) infection or hepatitis C disease, and in particular, it has a good inhibitory effect on HCV NS5B protein.
包含本发明盐或药物组合物给药的治疗方法，进一步包括对患者给药其他HCV药物，由此，可 以将本发明的盐与其他抗HCV药物进行联合治疗，其中所述抗HCV的药物为干扰素、利巴韦林、白介素2、白介素6、白介素12、促进产生1型辅助性T细胞应答的化合物、干扰RNA、反义RNA、咪喹莫德、肌苷5’-单磷酸脱氢酶抑制剂、金刚烷胺、金刚乙胺、巴维昔单抗(Bavituximab)、CivacirTM、波普瑞韦(boceprevir)、替拉瑞韦(telaprevir)、索非布韦(sofosbuvir)、雷迪帕韦(ledipasvir)、达卡他韦(daclatasvir)、丹诺普韦(danoprevir)、西鲁瑞韦(ciluprevir)、那拉匹韦(narlaprevir)、deleobuvir(BI-207127)、dasabuvir(ABT-333)、beclabuvir(BMS-791325)、elbasvir(MK-8742)、ombitasvir(ABT-267)、neceprevir(ACH-2684)、tegobuvir(GS-9190)、grazoprevir(MK-5172)、sovaprevir(ACH-1625)、samatasvir(IDX-719)、setrobuvir、veruprevir(ABT-450)、埃罗替尼(erlotinib)、simeprevir(TMC-435)、asunaprevir(BMS-650032)、vaniprevir(MK-7009)、faldaprevir(BI-2013335)、VX-135、CIGB-230、TG-2349、ABT-530、ABT-493、IDX-21437、GS-9669、JHJ-56914845、vedroprevir(GS-9451)、BZF-961、GS-9256、ANA975、EDP239、PPI-668、GS-5816、MK-8325、GSK-2336805、PPI-461、ACH-1095、VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、EP-013420、VBY-376、TMC-649128、R-7128、PSI-7977、INX-189、IDX-184、IDX102、R1479、UNX-08189、PSI-6130、PSI-938、PSI-879、HCV-796、HCV-371、VCH-916、VCH-222、ANA-598、MK-3281、ABT-072、PF-00868554、BI-207127、A-837093、JKT-109、Gl-59728、GL-60667、AZD-2795、TMC-647055或其组合。The treatment method comprising the administration of the salt or the pharmaceutical composition of the present invention further comprises administering other HCV drugs to the patient, whereby the salt of the present invention can be combined with other anti-HCV drugs, wherein the anti-HCV drugs are Interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote the production of type 1 helper T cell responses, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenation Enzyme inhibitors, amantadine, rimantadine, Bavituximab, CivacirTM, boceprevir, telaprevir, sofosbuvir, redipa Ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir (BI-207127), dasabuvir (ABT-333) , Beclabuvir (BMS-791325), elbasvir (MK-8742), ombitasvir (ABT-267), neceprevir (ACH-2684), tegobuvir (GS-9190), grazoprevir (MK-5172), sovaprevir (ACH-1625), samatasvir (IDX-719), setrobuvir, veruprevir (ABT-450), erlotinib, simeprevir (TMC-435), asunaprevir (BMS-650032), vaniprevir (MK-7009), faldaprevir (BI-2013335), VX-135, CIGB-230, TG-2349, ABT-530, ABT-493, IDX-21437 , GS-9669, JHJ-56914845, vedroprevir (GS-9451), BZF-961, GS-9256, ANA975, EDP239, PPI-668, GS-5816, MK-8325, GSK-2336805, PPI-461, ACH- 1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, VCH-222, ANA- 598, MK-3281, ABT-072, PF-00868554, BI-207127, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055, or a combination thereof.
并且包含本发明盐或药物组合物给药的治疗方法，进一步包含其他抗HCV药物的给药，其中，其他抗HCV药物可以和本发明盐或其药物组合物联合给药，本发明盐或药物组合物作为单个剂型，或分开的盐或药物组合物作为多剂型的一部分。其他抗HCV药物可以与本发明盐同时给药或不同时给药。后者的情况，给药可以错开进行如6小时、12小时、1天、2天、3天、1周、2周、3周、1个月或2个月进行。It also includes a method for treating the administration of a salt or a pharmaceutical composition of the present invention, and further includes administration of other anti-HCV drugs, wherein other anti-HCV drugs can be administered in combination with a salt of the present invention or a pharmaceutical composition thereof. The composition is provided as a single dosage form or as separate salts or pharmaceutical compositions as part of a multiple dosage form. Other anti-HCV drugs may be administered at the same time or not at the same time as the salt of the invention. In the latter case, administration can be staggered, such as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.
本发明的盐或药学上可接受的组合物的“有效量”或“有效剂量”是指处理或减轻一个或多个本发明所提到病症的严重度的有效量。根据本发明的方法，盐和组合物可以是任何给药量和任何给药途径来有效地用于处理或减轻疾病的严重程度。必需的准确的量将根据患者的情况而改变，这取决于种族，年龄，患者的一般条件，感染的严重程度、特殊的因素、给药方式，等等。盐或组合物可以和一个或多个其他治疗剂联合给药，如本发明所讨论的。An "effective amount" or "effective dose" of a salt or pharmaceutically acceptable composition of the present invention refers to an effective amount that treats or reduces the severity of one or more of the conditions mentioned in the present invention. According to the methods of the present invention, the salts and compositions can be used in any amount and route of administration to effectively treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on race, age, general condition of the patient, severity of infection, special factors, mode of administration, and so on. The salt or composition can be administered in combination with one or more other therapeutic agents, as discussed herein.
盐的一般制备方法General preparation method of salt
本发明所述的盐的制备方法中所使用的溶剂没有特别限制，任何在程度上能溶解起始原料并且不影响其性质的溶剂均包含在本发明中。另外，本领域的许多类似改动，等同替换，或等同于本发明所描述的溶剂，溶剂组合，及溶剂组合的不同比例，均视为本发明的包含范围。本发明给出了各反应步骤所使用的较 佳的溶剂。The solvent used in the method for preparing the salt according to the present invention is not particularly limited, and any solvent that can dissolve the starting materials to a certain extent without affecting its properties is included in the present invention. In addition, many similar modifications, equivalent replacements, or different ratios of the solvents, solvent combinations, and solvent combinations described in the present invention are regarded as the scope of the present invention. The present invention gives preferred solvents for each reaction step.
本发明所述的盐的制备实验将在实施例部分进行了详细描述。同时，本发明提供了所述盐的活性测试实验(如药代动力学实验)等。由实验结果可知，本发明所述的盐具有较好生物学性质，适合制药用途。The preparation experiment of the salt according to the present invention will be described in detail in the Examples section. At the same time, the present invention provides an activity test experiment (such as a pharmacokinetic experiment) of the salt. It can be known from the experimental results that the salt of the present invention has good biological properties and is suitable for pharmaceutical use.
结晶型的一般制备方法Crystalline general preparation method
结晶型可通过多种方法制备，包括但不限于例如从适合的溶剂混合物结晶或重结晶；升华；从另一相固态转化；从超临界流体结晶；和喷雾。用于溶剂混合物的结晶型的结晶或重结晶的技术包括但不限于例如溶剂蒸发；降低溶剂混合物的温度；化合物和/或其盐的过饱和溶剂混合物的引晶(crystal seeding)；溶剂混合物冷冻干燥；和抗溶剂(反溶剂)加到溶剂混合物。可用高产量结晶技术制备结晶型，包括多晶型体。Crystalline forms can be prepared by a variety of methods including, but not limited to, for example, crystallization or recrystallization from a suitable solvent mixture; sublimation; solid-state conversion from another phase; crystallization from a supercritical fluid; and spraying. Techniques for crystalline crystallization or recrystallization of a solvent mixture include, but are not limited to, for example, solvent evaporation; lowering the temperature of the solvent mixture; crystal seeding of a supersaturated solvent mixture of the compound and / or its salt; freezing of the solvent mixture Dry; and add antisolvent (antisolvent) to the solvent mixture. Crystalline forms, including polymorphs, can be prepared using high yield crystallization techniques.
药物的晶体(包括多晶型体)、制备方法和药物晶体的表征讨论于Solid-State Chemistry of Drugs,S.R.Byrn,R.R.Pfeiffer和J.G.Stowell,第二版,SSCI,West Lafayette,Indiana(1999)。Drug crystals (including polymorphs), preparation methods, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S.R.Byrn, R.R.Pfeiffer, and J.G.Stowell, Second Edition, SSCI, West Lafayette, Indiana (1999).
在其中利用溶剂的结晶技术中，溶剂一般根据一个或多个因素选择，所述因素包括但不限于例如化合物的溶解度、所用的结晶技术和溶剂的蒸气压。可利用溶剂的组合。例如，可使化合物在第一溶剂中增溶以得到溶液，然后加入抗溶剂以减小溶液中化合物的溶解度，并沉淀晶体形成物。抗溶剂为其中化合物具有低溶解度的溶剂。In the crystallization technology in which the solvent is utilized, the solvent is generally selected based on one or more factors including, but not limited to, the solubility of the compound, the crystallization technology used, and the vapor pressure of the solvent. A combination of solvents is available. For example, the compound can be solubilized in a first solvent to obtain a solution, and then an anti-solvent is added to reduce the solubility of the compound in the solution, and precipitate a crystal formation. Antisolvents are solvents in which the compound has low solubility.
可将晶种加到任何结晶混合物以促进结晶。可用引晶控制特定多晶型体的生长，和/或控制结晶产物的晶粒尺寸分布。因此，所需晶种的量的计算取决于可用晶种的尺寸和平均产物颗粒的期望尺寸，如“Programmed Cooling Batch Crystallizers”，J.W.Mullin和J.Nyvlt,Chemical Engineering Science,1971,26,369-377所述。一般需要小尺寸的晶种，以有效控制批料中的晶体生长。通过大晶体过筛、研磨或微粉化，或者通过溶液微晶化，可产生小尺寸的晶种。在晶体研磨或微粉化中，应注意避免结晶性从期望的结晶型改变(即，变成非晶型或其它多晶型)。Seed crystals can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of specific polymorphs, and / or to control the grain size distribution of the crystalline product. Therefore, the calculation of the amount of seed required depends on the size of the available seeds and the desired size of the average product particles, such as "Programmed Cooling Batches Crystallizers", JWMullin and J. Nyvlt, Chemical Engineering, Science, 1971, 26, 369-377 Described. Seeds of small size are generally required to effectively control crystal growth in the batch. By sieving, grinding, or micronizing large crystals, or by microcrystallization of a solution, small-sized seeds can be produced. In crystal grinding or micronization, care should be taken to avoid changing the crystallinity from the desired crystal form (ie, to become amorphous or other polymorph).
可在真空下过滤经冷却的结晶混合物，经分离的固体产物用适合溶剂(例如，冷的重结晶溶剂)洗涤。洗涤后，产物可在氮吹扫下干燥以得到所需的结晶型。产物可通过适合的光谱或分析技术分析，包括但不限于例如差示扫描量热法(DSC)、X-射线粉末衍射(XRPD)、热重分析(TGA)和动态水分吸附分析(DVS)，以保证化合物的结晶型已经形成。所得的结晶型可按基于结晶过程中初始使用化合物重量的大于约70％重量的分离产率的量生成，优选大于约90％重量分离产率。可任选通过共研磨或通过网筛使产物去块。The cooled crystalline mixture can be filtered under vacuum and the isolated solid product is washed with a suitable solvent (eg, a cold recrystallization solvent). After washing, the product can be dried under a nitrogen purge to obtain the desired crystalline form. Products can be analyzed by suitable spectroscopy or analytical techniques, including but not limited to, for example, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and dynamic moisture adsorption analysis (DVS), To ensure that the crystalline form of the compound has been formed. The resulting crystalline form can be formed in an amount of greater than about 70% by weight based on the weight of the compound originally used during the crystallization process, and preferably greater than about 90% by weight of the isolated yield. The product may optionally be deblocked by co-milling or through a screen.
X-射线粉末衍射(XRPD)研究：在装配有自动化3*15零背景样品架的透射反射样品台的荷兰PANalytical Empyrean X-射线衍射仪上收集X-射线粉末衍射(XRPD)图案。所用辐射源为(Cu，kα，
Figure PCTCN2019099229-appb-000010
Figure PCTCN2019099229-appb-000011
1.540598；
Figure PCTCN2019099229-appb-000012
1.544426；Kα2/Kα1强度比例：0.50)，其中电压设定在45KV，电流设定在40mA，X-射线的束发散度，即样品上X-射线约束的有效尺寸，为10mm，采用θ-θ连续扫描模式，得到3°～40°的有效2θ范围。取适量样品在环境条件下(约18℃～32℃)于零背景样品架圆形凹槽处，用洁净的载玻片轻压，得到一个平整的平面，并将零背景样品架固定。将样品(通常为1～2mg)以0.0168°的扫描步长在3～40°2θ±0.2°范围内扫描。用于数据收集的软件为Data Collector，数据用Data Viewer和HighScore Plus分析和展示。 X-Ray Powder Diffraction (XRPD) Study: X-ray powder diffraction (XRPD) patterns were collected on a PANalytical Empyrean X-ray diffractometer equipped with a transflective sample stage equipped with an automated 3 * 15 zero background sample holder. The radiation source used is (Cu, kα,
Figure PCTCN2019099229-appb-000010
Figure PCTCN2019099229-appb-000011
1.540598;
Figure PCTCN2019099229-appb-000012
1.544426; Kα2 / Kα1 intensity ratio: 0.50), where the voltage is set at 45KV, the current is set at 40mA, and the beam divergence of the X-ray, that is, the effective size of the X-ray constraint on the sample, is 10mm, using θ-θ In continuous scanning mode, an effective 2θ range of 3 ° to 40 ° is obtained. Take an appropriate amount of sample at the circular groove of the zero background sample holder under ambient conditions (approximately 18 ° C to 32 ° C), press gently with a clean glass slide to obtain a flat surface, and fix the zero background sample holder. The sample (usually 1 to 2 mg) was scanned at a scanning step of 0.0168 ° in a range of 3 to 40 ° 2θ ± 0.2 °. The software used for data collection is Data Collector, and the data is analyzed and displayed with Data Viewer and HighScore Plus.
差示扫描量热法(DSC)分析：DSC测量在TA Instruments TM型号Q2000中用密封盘装置进行。将样品(约2～6mg)在铝盘中称量，用Tzero压盖，精密记录到百分之一毫克，并将样品转移至仪器中进行测量。仪器用氮气以50mL/min吹扫。在室温到300℃之间以10℃/min的加热速率收集数据。以吸热峰向下进行绘图,数据用TA Universal Analysis分析和展示。 Differential Scanning Calorimetry (DSC) Analysis: DSC measurements were performed in a TA Instruments ™ model Q2000 using a sealed disc device. The sample (about 2 to 6 mg) was weighed in an aluminum pan, capped with Tzero, accurately recorded to one hundredth of a milligram, and the sample was transferred to the instrument for measurement. The instrument was purged with nitrogen at 50 mL / min. Data were collected between room temperature and 300 ° C at a heating rate of 10 ° C / min. The endothermic peak was plotted downward, and the data was analyzed and displayed by TA Universal Analysis.
热重分析(TGA)：TGA测量在TA Instruments TM型号Q500中用敞口装置进行。将样品(约10mg～30mg)放入预先去皮的铂坩埚。仪器精密称量样品的重量，并由仪器记录到千分之一毫克。天平用氮气以40mL/min吹扫，样品用氮气以60mL/min吹扫。在室温到300℃之间以10℃/min的加热速率收集数据,数据用TA Universal Analysis分析和展示。 Thermogravimetric Analysis (TGA): TGA measurements exposure apparatus model Q500 with TA Instruments TM. The sample (approximately 10 mg to 30 mg) was put into a platinum skin crucible which had been peeled in advance. The instrument accurately weighs the sample and records it to a thousandth of a milligram by the instrument. The balance was purged with nitrogen at 40 mL / min, and the sample was purged with nitrogen at 60 mL / min. Data were collected between room temperature and 300 ℃ with a heating rate of 10 ℃ / min, and the data was analyzed and displayed by TA Universal Analysis.
动态水分吸附实验(DVS)：取15-30mg样品置于样品盘中，将样品盘悬挂于动态水分吸附仪内，待各参数平衡后，开始进行吸附-脱附过程，在温度为25℃的条件下，湿度范围以5％为一个阶段，由0％升至95％后再降至0％，监测湿度变化过程中样品的吸湿增重量。Dynamic Moisture Adsorption Experiment (DVS): Take 15-30mg sample into the sample tray, suspend the sample tray in the dynamic moisture adsorber, and after the parameters are balanced, start the adsorption-desorption process. Under the conditions, the humidity range is 5% as a stage, from 0% to 95% and then reduced to 0%, to monitor the moisture absorption and weight gain of the sample during the change of humidity.
本发明所述的盐的晶型可以通过常规的制备方法制备得到。The crystal form of the salt according to the present invention can be prepared by a conventional preparation method.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1显示的是本说明所述的晶型C的XRPD图；Figure 1 shows an XRPD pattern of Form C described in this description;
图2显示的是本说明所述的晶型C的DSC图；FIG. 2 shows a DSC chart of Form C described in this description;
图3显示的是本说明所述的晶型C的TGA图；FIG. 3 shows a TGA diagram of Form C described in this description;
图4显示的是本说明所述的晶型C的单晶结构图。FIG. 4 is a diagram showing a single crystal structure of Form C described in this description.
具体实施方式detailed description
下面通过实施例的方式进一步说明本发明，并不因此将本发明限制在所述的实施例范围之中。The present invention is further described below by way of examples, and therefore the present invention is not limited to the scope of the examples.
实施例：Example:
化合物N-(6-(3-(叔丁基)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-6-氟-2-甲氧基苯基)萘-2-基) 甲磺酰胺(式(I))的具体合成方法参照专利CN 20151036755.1中实施例的合成方法，具体的可参照实施例2，并且将其中的内容整体并入本发明中。Compound N- (6- (3- (tert-butyl) -5- (2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) -6-fluoro-2-methoxy Phenylphenyl) naphthalene-2-yl) methanesulfonamide (formula (I)) for the specific synthesis method, refer to the synthesis method of the embodiment of the patent CN20151036755.1, specific reference can be made to Example 2, and the content is incorporated in its entirety In the present invention.
实施例1：N-(6-(3-(叔丁基)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-6-氟-2-甲氧基苯基)萘-2-基)甲磺酰胺二钠盐晶型C的制备Example 1: N- (6- (3- (tert-butyl) -5- (2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) -6-fluoro-2 -Methoxyphenyl) naphthalen-2-yl) methanesulfonamide disodium salt Form C
1、晶型C的制备1. Preparation of Form C
方法1：90mg NaOH在60℃溶于36mL EtOH中，加入N-(6-(3-(叔丁基)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-6-氟-2-甲氧基苯基)萘-2-基)甲磺酰胺(式(I))450mg，搅拌过夜，过滤后得到的固体加入16mL丙酮，滴加10滴水，30℃搅拌3-4h，过滤可得340mg晶型C。Method 1: 90mg NaOH was dissolved in 36mL EtOH at 60 ° C, and N- (6- (3- (tert-butyl) -5- (2,4-dioxo-3,4-dihydropyrimidine-1 ( 2H) -yl) -6-fluoro-2-methoxyphenyl) naphthalene-2-yl) methanesulfonamide (formula (I)) 450 mg, stirred overnight, the solid obtained after filtration was added with 16 mL of acetone, and 10 was added dropwise It was dripped with water, stirred at 30 ° C for 3-4 hours, and filtered to obtain 340 mg of Form C.
方法2：60mg NaOH在60℃溶于24mL EtOH中，加入N-(6-(3-(叔丁基)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-6-氟-2-甲氧基苯基)萘-2-基)甲磺酰胺(式(I))300mg，搅拌过夜，过滤后得到的固体在92.5％湿度条件下放置24h后，加入9mL丙酮中，滴加6滴水，室温搅拌5h，过滤可得168mg晶型C。Method 2: 60mg NaOH is dissolved in 24mL EtOH at 60 ° C, and N- (6- (3- (tert-butyl) -5- (2,4-dioxo-3,4-dihydropyrimidine-1 ( 300 mg of 2H) -yl) -6-fluoro-2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide (formula (I)), stirred overnight, and the solid obtained after filtration was left under 92.5% humidity After 24 hours, 9 mL of acetone was added, 6 drops of water were added dropwise, and the mixture was stirred at room temperature for 5 hours. 168 mg of Form C was obtained by filtration.
方法3：360mg的N-(6-(3-(叔丁基)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-6-氟-2-甲氧基苯基)萘-2-基)甲磺酰胺(式(I))溶于120mL甲醇中，加入60mg氢氧化钠，60℃搅拌3h后停止反应，旋干甲醇得到的固体加入16mL丙酮，滴加10滴水，30℃搅拌3-4h，过滤可得340mg晶型C。Method 3: 360 mg of N- (6- (3- (tert-butyl) -5- (2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) -6-fluoro- 2-methoxyphenyl) naphthalen-2-yl) methanesulfonamide (formula (I)) was dissolved in 120 mL of methanol, 60 mg of sodium hydroxide was added, and the reaction was stopped after stirring at 60 ° C for 3 h. The solid obtained by spinning the methanol was added 16mL of acetone, 10 drops of water were added dropwise, and the mixture was stirred at 30 ° C for 3-4h. Filtration yielded 340mg of Form C.
2、晶型C的鉴定2. Identification of Form C
(1)通过Empyrean X射线粉末衍射(XRPD)分析，晶型C的X-射线粉末衍射图如图1所示，可存在±0.2°的误差容限。(1) According to Empyrean X-ray powder diffraction (XRPD) analysis, the X-ray powder diffraction pattern of Form C is shown in Figure 1, and an error tolerance of ± 0.2 ° may exist.
(2)通过TA Q2000差示扫描量热(DSC)分析，晶型C的差示扫描量热曲线如图2所示，其包含102.34℃和122.64℃的吸热峰，存在±3℃的误差容限。(2) Through TA2000 differential scanning calorimetry (DSC) analysis, the differential scanning calorimetry curve of Form C is shown in Figure 2, which includes endothermic peaks at 102.34 ° C and 122.64 ° C, with an error of ± 3 ° C. Tolerance.
(3)通过TGA在TA InstrumentsTM型号Q500中分析，晶型C的TGA如图3所示，重量损失为16.22±1.7％。(3) Analysis by TGA in TA InstrumentsTM Model Q500, the TGA of Form C is shown in Figure 3, and the weight loss is 16.22 ± 1.7%.
实施例2：晶型C单晶培养Example 2: Form C single crystal culture
取200mg N-(6-(3-(叔丁基)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-6-氟-2-甲氧基苯基)萘-2-基)甲磺酰胺(式(I))二钠盐溶于2mL水中，加热至50℃溶解后，滴加3mL丙酮，搅拌5分钟后停止加热和搅拌，静置降温。3-4天后得到长条状晶体。Take 200 mg of N- (6- (3- (tert-butyl) -5- (2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -yl) -6-fluoro-2-methyl Disodium salt of oxyphenyl) naphthalene-2-yl) methanesulfonamide (formula (I)) was dissolved in 2 mL of water, and after heating to 50 ° C to dissolve, 3 mL of acetone was added dropwise. After stirring for 5 minutes, heating and stirring were stopped, Set to cool down. After 3-4 days, long crystals were obtained.
晶型C单晶结构晶胞参数如下：The unit cell parameters of Form C single crystal structure are as follows:
Figure PCTCN2019099229-appb-000013
Figure PCTCN2019099229-appb-000013
通过对单晶的模拟XRD确定，为晶型C，同时确定晶型C的六水合物在晶格中。It is determined by simulation XRD of the single crystal that it is the form C, and it is also determined that the hexahydrate of the form C is in the crystal lattice.
实施例3：药代动力学实验Example 3: Pharmacokinetic Experiment
采用比格犬进行式(I)化合物及其二钠盐晶型C的体内药代动力学试验，初步研究式(I)化合物及其二钠盐晶型C的口服吸收情况。取8-12kg Beagle犬，各组3只，给药方式为胶囊口服，剂量为5mg/kg，以游离酸计。根据样品浓度建立合适范围的标准曲线，使用AB SCIEX API4000型LC-MS/MS，在MRM模式下测定血浆样品中待测物浓度。根据药物浓度-时间曲线，采用WinNonLin 6.3软件非房室模型法计算药动学参数。注：SD表示个体差异。Beagle dogs were used to conduct in vivo pharmacokinetic tests of the compound of formula (I) and its disodium salt form C, and the oral absorption of the compound of formula (I) and its disodium salt form C was initially studied. Take 8-12kg Beagle dogs, 3 in each group. The method of administration is oral capsules, the dose is 5mg / kg, based on free acid. Establish a standard curve of a suitable range according to the sample concentration, and use the AB SCIEX API4000 LC-MS / MS to determine the concentration of the analyte in the plasma sample in the MRM mode. According to the drug concentration-time curve, WinNonLin 6.3 software non-compartment model method was used to calculate the pharmacokinetic parameters. Note: SD indicates individual differences.
式(I)化合物及其二钠盐晶型C对比实验结果如表4-1和表4-2：The comparative experimental results of the compound of formula (I) and its disodium salt form C are shown in Table 4-1 and Table 4-2:
表4-1：Table 4-1:
化合物Compound T max±SD(h) T max ± SD (h)
式(I)化合物Compound of formula (I) 11.3±1111.3 ± 11
式(I)化合物二钠盐晶型CForm C of a disodium salt of a compound of formula (I) 3±2.63 ± 2.6
表4-2：Table 4-2:
化合物Compound AUC last±SD(ng.h/ml) AUC last ± SD (ng.h / ml )
式(I)化合物Compound of formula (I) 18300±1300018300 ± 13000
式(I)化合物二钠盐晶型CForm C of a disodium salt of a compound of formula (I) 14700±530014700 ± 5300
结论：本发明所述的二钠盐晶型C具有比游离酸化合物更小的Tmax，说明本发明所述的二钠盐晶型C起效快；进一步的，二钠盐晶型C具有更高的体内暴露量；进一步的，二钠盐晶型C的个体差异更小。Conclusion: The disodium salt crystal form C of the present invention has a smaller Tmax than the free acid compound, which indicates that the disodium salt crystal form C of the present invention has a faster onset of action; further, the disodium salt crystal form C has a more effective High in vivo exposure; further, individual differences in disodium salt form C are smaller.
出于清楚和理解的目的，前面公开的已通过说明和实施例在一些细节上作了描述。本发明已参考不同的具体及优选的实施方案和技术作了描述。然而，应了解，在保持在本发明精神和范围之内的同时，可进行许多变化和修改。在权利要求范围内可实施变化和修改对于本领域技术人员而言是显而易见的。因此，应了解，以上描述旨在说明性的，不为限制性的。因此，本发明的范围不应参考以上描述而确定，而应参 考权利要求连同这些权利要求的等价的完全范围而确定。For clarity and understanding, the foregoing disclosure has been described in some detail through illustrations and examples. The invention has been described with reference to different specific and preferred embodiments and techniques. It should be understood, however, that many variations and modifications may be made while remaining within the spirit and scope of the invention. It will be apparent to those skilled in the art that changes and modifications can be implemented within the scope of the claims. Therefore, it should be understood that the above description is intended to be illustrative, and not restrictive. Therefore, the scope of the invention should not be determined with reference to the above description, but should be determined with reference to the claims, along with the full scope of equivalents of these claims.

Claims (20)

  1. 一种式(I)所示化合物的盐：A salt of a compound of formula (I):
    Figure PCTCN2019099229-appb-100001
    所述盐为六水合物。
    Figure PCTCN2019099229-appb-100001
    The salt is a hexahydrate.
  2. 根据权利要求1所述的盐，其中，所述六水合物为晶型C，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：4.72°±0.2°、10.51°±0.2°、13.20°±0.2°、23.05°±0.2°和29.55°±0.2°。The salt according to claim 1, wherein the hexahydrate is in Form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.72 ° ± 0.2 °, 10.51 ° ± 0.2 °, 13.20 ° ± 0.2 °, 23.05 ° ± 0.2 °, and 29.55 ° ± 0.2 °.
  3. 根据权利要求1所述的盐，其中，所述六水合物为晶型C，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：4.72°±0.2°、10.51°±0.2°、12.67°±0.2°、13.20°±0.2°、18.91°±0.2°、21.12°±0.2°、21.34°±0.2°、23.05°±0.2°和29.55°±0.2°。The salt according to claim 1, wherein the hexahydrate is in Form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.72 ° ± 0.2 °, 10.51 ° ± 0.2 °, 12.67 ° ± 0.2 °, 13.20 ° ± 0.2 °, 18.91 ° ± 0.2 °, 21.12 ° ± 0.2 °, 21.34 ° ± 0.2 °, 23.05 ° ± 0.2 °, and 29.55 ° ± 0.2 °.
  4. 根据权利要求1所述的盐，其中，所述六水合物为晶型C，其X射线粉末衍射图谱在下列2θ角处具有衍射峰：4.72°±0.2°、10.51°±0.2°、12.67°±0.2°、13.20°±0.2°、15.13°±0.2°、18.33°±0.2°、18.51°±0.2°、18.91°±0.2°、21.12°±0.2°、21.34°±0.2°、21.93°±0.2°、22.61°±0.2°、23.05°±0.2°、24.04°±0.2°、24.74°±0.2°、25.52°±0.2°、29.55°±0.2°、30.54°±0.2°和30.65°±0.2°。The salt according to claim 1, wherein the hexahydrate is in Form C, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.72 ° ± 0.2 °, 10.51 ° ± 0.2 °, 12.67 ° ± 0.2 °, 13.20 ° ± 0.2 °, 15.13 ° ± 0.2 °, 18.33 ° ± 0.2 °, 18.51 ° ± 0.2 °, 18.91 ° ± 0.2 °, 21.12 ° ± 0.2 °, 21.34 ° ± 0.2 °, 21.93 ° ± 0.2 °, 22.61 ° ± 0.2 °, 23.05 ° ± 0.2 °, 24.04 ° ± 0.2 °, 24.74 ° ± 0.2 °, 25.52 ° ± 0.2 °, 29.55 ° ± 0.2 °, 30.54 ° ± 0.2 °, and 30.65 ° ± 0.2 °.
  5. 根据权利要求1-4任一项所述的盐，其中，所述六水合物为晶型C，其DSC包含102.34℃±3℃和122.64℃±3℃的吸热峰。The salt according to any one of claims 1 to 4, wherein the hexahydrate is in Form C, and DSC thereof includes endothermic peaks at 102.34 ° C ± 3 ° C and 122.64 ° C ± 3 ° C.
  6. 根据权利要求1-4任一项所述的盐，其中，所述六水合物为晶型C，其TGA重量损失为16.22±1.7％。The salt according to any one of claims 1 to 4, wherein the hexahydrate is in Form C and its TGA weight loss is 16.22 ± 1.7%.
  7. 根据权利要求1-4任一项所述的盐，其中，所述六水合物为晶型C，其X射线粉末衍射图谱基本上如图1所示。The salt according to any one of claims 1 to 4, wherein the hexahydrate is in Form C, and the X-ray powder diffraction pattern thereof is substantially as shown in Fig. 1.
  8. 根据权利要求1-4任一项所述的盐，其中，所述六水合物为晶型C，其DSC图谱基本上如图2所示。The salt according to any one of claims 1-4, wherein the hexahydrate is a crystalline form C, and a DSC spectrum thereof is substantially as shown in FIG. 2.
  9. 根据权利要求1-4任一项所述的盐，其中，所述六水合物为晶型C，其TGA图谱基本上如图3所示。The salt according to any one of claims 1 to 4, wherein the hexahydrate is in Form C and its TGA spectrum is substantially as shown in FIG.
  10. 根据权利要求1-4任一项所述的盐，其中，所述六水合物为晶型C，晶型C的单晶结构具有如下的晶体学参数：The salt according to any one of claims 1-4, wherein the hexahydrate is a crystalline form C, and the single crystal structure of the crystalline form C has the following crystallographic parameters:
    Figure PCTCN2019099229-appb-100002
    Figure PCTCN2019099229-appb-100002
    Figure PCTCN2019099229-appb-100003
    Figure PCTCN2019099229-appb-100003
  11. 一种制备权利要求1-10任一项所述二钠盐晶型C的方法，包括：式(I)所示的化合物与氢氧化钠在第一溶剂中反应，将得到的钠盐在第二溶剂中打浆，得到所述的二钠盐晶型C，A method for preparing the disodium salt crystal form C according to any one of claims 1 to 10, comprising: reacting a compound represented by formula (I) with sodium hydroxide in a first solvent, and Beating in two solvents to obtain the disodium salt crystal form C,
    Figure PCTCN2019099229-appb-100004
    Figure PCTCN2019099229-appb-100004
  12. 根据权利要求11所述的制备方法，其中，所述第一溶剂为亲水性有机溶剂或亲水性有机溶剂与水的混合溶剂，所述第二溶剂具有所述第一溶剂相同的定义。The method according to claim 11, wherein the first solvent is a hydrophilic organic solvent or a mixed solvent of a hydrophilic organic solvent and water, and the second solvent has the same definition as the first solvent.
  13. 根据权利要求12所述的制备方法，其中，所述第一溶剂为甲醇、乙醇、异丙醇或丙酮。The method according to claim 12, wherein the first solvent is methanol, ethanol, isopropanol, or acetone.
  14. 根据权利要求11所述的制备方法，其中，式(I)所示的化合物与氢氧化钠的摩尔比大于等于1:1.5；或式(I)所示的化合物与氢氧化钠的摩尔比为1:1.5、1:2、1:2.5、1:3、1:3.5、1:4、1:4.5、1:5、1:5.5、1:6、1:6.5、1:7、1:7.5、1:8或1:8.5。The method according to claim 11, wherein the molar ratio of the compound represented by the formula (I) and sodium hydroxide is 1: 1.5 or more; or the molar ratio of the compound represented by the formula (I) and sodium hydroxide is 1: 1.5, 1: 2, 1: 2.5, 1: 3, 1: 3.5, 1: 4, 1: 4.5, 1: 5, 1: 5.5, 1: 6, 1: 6.5, 1: 7, 1: 7.5, 1: 8 or 1: 8.5.
  15. 根据权利要求11所述的制备方法，其中，所述反应是在0-100℃下进行；或所述反应是在10-80℃下进行；或所述反应是在10℃、20℃、30℃、40℃、50℃、60℃、70℃或80℃下进行。The preparation method according to claim 11, wherein the reaction is performed at 0-100 ° C; or the reaction is performed at 10-80 ° C; or the reaction is performed at 10 ° C, 20 ° C, 30 ° C It is carried out at 40 ° C, 40 ° C, 50 ° C, 60 ° C, 70 ° C or 80 ° C.
  16. 根据权利要求11所述的制备方法，其中，所述打浆是在0-100℃下进行；或所述打浆是在10-80℃下进行；或所述打浆是在10℃、20℃、30℃、40℃、50℃、60℃、70℃或80℃下进行。The preparation method according to claim 11, wherein the beating is performed at 0-100 ° C; or the beating is performed at 10-80 ° C; or the beating is at 10 ° C, 20 ° C, 30 ° C It is carried out at 40 ° C, 40 ° C, 50 ° C, 60 ° C, 70 ° C or 80 ° C.
  17. 一种药物组合物，包含权利要求1-10中任一项所述的钠盐或根据权利要求11-16方法制备的钠盐。A pharmaceutical composition comprising the sodium salt according to any one of claims 1-10 or the sodium salt prepared according to the method according to claims 11-16.
  18. 根据权利要求17所述的药物组合物，进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。The pharmaceutical composition according to claim 17, further comprising a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.
  19. 根据权利要求17或18所述的药物组合物，进一步包含其他的抗HCV的药物。The pharmaceutical composition according to claim 17 or 18, further comprising another anti-HCV drug.
  20. 权利要求1-10中任一项所述的钠盐或权利要求11-16方法制备的钠盐或权利要求17-19中任一项所述的药物组合物在制备药物中的用途，其中，所述药物用于抑制HCV NS5B蛋白和/或用于预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病。Use of the sodium salt according to any one of claims 1 to 10 or the sodium salt prepared by the method according to claims 11 to 16 or the pharmaceutical composition according to any one of claims 17 to 19 in the preparation of a medicament, wherein: The medicament is used for inhibiting HCV NS5B protein and / or for preventing, treating, treating or reducing HCV infection or hepatitis C disease in a patient.
PCT/CN2019/099229 2018-08-10 2019-08-05 Disodium salt crystal form c of hcv inhibitor and preparation method therefor WO2020029912A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201980046587.0A CN112513019B (en) 2018-08-10 2019-08-05 HCV inhibitor disodium salt crystal form C and preparation method thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810908122 2018-08-10
CN201810908122.9 2018-08-10

Publications (1)

Publication Number Publication Date
WO2020029912A1 true WO2020029912A1 (en) 2020-02-13

Family

ID=69413407

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/CN2019/099229 WO2020029912A1 (en) 2018-08-10 2019-08-05 Disodium salt crystal form c of hcv inhibitor and preparation method therefor
PCT/CN2019/099199 WO2020029903A1 (en) 2018-08-10 2019-08-05 Salt of hcv inhibitor and preparation method therefor

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/099199 WO2020029903A1 (en) 2018-08-10 2019-08-05 Salt of hcv inhibitor and preparation method therefor

Country Status (2)

Country Link
CN (2) CN112513019B (en)
WO (2) WO2020029912A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016105547A1 (en) * 2014-12-24 2016-06-30 Concert Pharmaceuticals, Inc. Deuterated dasabuvir
CN106065009A (en) * 2014-06-28 2016-11-02 广东东阳光药业有限公司 As the compound of hepatitis c inhibitor and the application in medicine thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106065009A (en) * 2014-06-28 2016-11-02 广东东阳光药业有限公司 As the compound of hepatitis c inhibitor and the application in medicine thereof
WO2016105547A1 (en) * 2014-12-24 2016-06-30 Concert Pharmaceuticals, Inc. Deuterated dasabuvir

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHEN, F. ET. AL.: "Research and development of Pharmaceutical salts", PROGRESS IN PHARMACEUTICAL SCIENCES, vol. 36, no. 4, 25 April 2012 (2012-04-25), pages 151 - 157, ISSN: 1001-5094 *

Also Published As

Publication number Publication date
CN112424172A (en) 2021-02-26
WO2020029903A1 (en) 2020-02-13
CN112424172B (en) 2022-08-12
CN112513019B (en) 2022-09-27
CN112513019A (en) 2021-03-16

Similar Documents

Publication Publication Date Title
US20210017163A1 (en) Hydrochloride salt form for ezh2 inhibition
AU2017304779B2 (en) Salts of 2, 6-dimethylpyrimidone derivatives and uses thereof
US10323035B2 (en) Co-crystal of a CDK inhibitor and an MEK inhibitor and process of preparation thereof
TW202233625A (en) Fgfr inhibitors and methods of making and using the same
KR102531772B1 (en) Crystalline targeting CDK4/6 kinase inhibitors
CN108822126B (en) Thienopyran formyl piperazine compound and medical application thereof
TWI815820B (en) Solid forms of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-n-benzylacetamide
WO2021047528A1 (en) Maleate of nicotinyl alcohol ether derivative, crystal form thereof, and application thereof
WO2021121146A1 (en) Crystal form a of aminopyrimidine mesylate compound, preparation method therefor, and application thereof
CN115385894A (en) With pyridine acyl piperidine 5-HT 1F Compositions and methods relating to agonists
JP6178799B2 (en) Aprepitant L-proline solvate-composition and co-crystal
WO2020029912A1 (en) Disodium salt crystal form c of hcv inhibitor and preparation method therefor
TW201922690A (en) Inhibitors of cyclic-AMP response element-binding protein
CN108586485B (en) 1- (4-hydroxyiminothieno [2,3-b ] thiopyranoformyl) piperazine compound and application thereof
WO2023093861A1 (en) Mono-p-toluenesulfonate of axl kinase inhibitor and crystal form thereof
WO2021143819A1 (en) Crystal form of polycyclic anaplastic lymphoma kinase inhibitor
US11179376B2 (en) Salts of pyrazolo[1,5-a]pyridine derivative and use thereof
CN110117287B (en) Salts as hepatitis c virus inhibitors
CN108822127B (en) 4-hydroxyiminothieno [2,3-b ] thiopyran-2-carboxamides and their use
US20220204502A1 (en) Crystal polymorphism of pi3k inhibitor and method for preparing same
CN108822125B (en) 1- (thieno [2,3-b ] thiopyranoformyl) -4-aliphatic alkyl piperazine compound and medical application thereof
US20210332056A1 (en) Crystal of pyrazolo[3,4-d]pyrimidine
WO2024035830A1 (en) Solid forms of a cdk inhibitor
JP2022532186A (en) Amorphous PI3K inhibitor and pharmaceutical composition containing it
WO2021247845A1 (en) Quinazoline-derived hck inhibitors for use in the treatment of myd88 mutated diseases

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19848141

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19848141

Country of ref document: EP

Kind code of ref document: A1