WO2018137670A1 - 一种病毒蛋白抑制剂药物vx-787的晶型及其制备方法和用途 - Google Patents

一种病毒蛋白抑制剂药物vx-787的晶型及其制备方法和用途 Download PDF

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WO2018137670A1
WO2018137670A1 PCT/CN2018/074050 CN2018074050W WO2018137670A1 WO 2018137670 A1 WO2018137670 A1 WO 2018137670A1 CN 2018074050 W CN2018074050 W CN 2018074050W WO 2018137670 A1 WO2018137670 A1 WO 2018137670A1
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hydrochloride salt
crystal form
compound
formula
hydrochloride
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PCT/CN2018/074050
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English (en)
French (fr)
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陈敏华
张炎锋
陈列
杨朝惠
夏楠
张晓宇
黄春香
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苏州科睿思制药有限公司
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Priority to CN201880005106.7A priority Critical patent/CN110177779A/zh
Priority to JP2019539983A priority patent/JP2020505391A/ja
Priority to US16/480,470 priority patent/US10815232B2/en
Publication of WO2018137670A1 publication Critical patent/WO2018137670A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the field of pharmaceutical crystal technology. Specifically, it relates to a crystal form of a viral protein inhibitor drug VX-787, a preparation method thereof and use thereof.
  • Influenza A virus is a common influenza virus, which is highly pathogenic to humans and has caused worldwide pandemics.
  • the subtype of influenza A virus is called "bird flu".
  • Avian flu is an acute infectious disease caused by avian influenza virus.
  • the virus gene can infect humans after mutation.
  • the symptoms after infection are mainly high fever and cough. , drooling, myalgia, etc., most of them are accompanied by severe pneumonia. In severe cases, heart, kidney and other organ failures lead to death, and the mortality rate is very high.
  • VX-787 or JNJ-872, is a viral protein inhibitor originally developed by Vertex and later licensed to Janssen for joint development. The compound is currently in clinical stage for the treatment of influenza A. Preliminary clinical evaluations show that the VX-787 is very promising. Phase I studies have demonstrated that VX-787 is well tolerated. A completed phase IIa study showed that VX-787 showed a statistically significant improvement in the virology and clinical evaluation of influenza virus infection.
  • VX-787 is (2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl) Amino)bicyclo[2.2.2]octane-2-carboxylic acid having the structural formula shown in formula (I):
  • Solid chemical drugs have different crystal forms, which can cause differences in solubility, stability, fluidity, etc., thereby affecting the safety and effectiveness of pharmaceutical products containing the compound (see K. Knapman, Modern Drug Discovery, 3, 53-54, 57, 2000.), resulting in differences in clinical efficacy.
  • New crystalline forms of pharmaceutically active ingredients (including anhydrates, hydrates, solvates, etc.) have been found to produce more processing advantages or to provide materials with better physicochemical properties, such as better bioavailability, storage stability, and ease of use. Processed, easy to purify or as an intermediate crystal form that facilitates conversion to other crystal forms.
  • New crystalline forms of certain pharmaceutically useful compounds can also help improve the performance of the drug. It expands the formulation of raw materials that can be used in the formulation, such as improved dissolution, improved shelf life, easier processing, and the like.
  • Patent CN105849100A discloses hemihydrate crystal form A, trihydrate crystal form F and crystal form D of the hydrochloride salt of the compound of formula (I), which needs to be prepared under a water activity of 0.05-0.85; The product obtained by dehydration of Form A; Form F needs to be prepared under the condition that the water activity is equal to or greater than 0.9, and the environmental requirements during storage are too high, which is unfavorable for storage, and the crystal form A is disclosed in the text. More preferred form.
  • patent CN105849100A discloses Form A and Form B in free form of the compound of the formula (I), and it is disclosed in the text that the hydrated form B of the free base compound (I) is the same crystal as the form A of the free base compound (I). Type, but its preparation method is more complicated.
  • the present invention provides a hydrochloride salt form CS1 of a compound of formula (I), a hydrochloride salt form CS2, a hydrochloride form CS3, a hydrochloride form CS4, and a compound of formula (I) form CS3, formula (I)
  • the compound crystal form CS9 has a simple preparation method and has advantages in stability, mechanical stability, moisture absorption, solubility, purification, etc., and provides a new and better choice for preparation of a pharmaceutical preparation containing the compound of the formula (I). It is very important for drug development.
  • the present invention provides a novel crystal form of the hydrochloride salt of the compound of the formula (I), a preparation method and use thereof.
  • the X-ray powder diffraction of the hydrochloride crystal form has characteristic peaks at diffraction angle 2 ⁇ values of 7.1 ° ⁇ 0.2 °, 27.0 ° ⁇ 0.2 °, and 15.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the hydrochloride salt crystal form has one or two or three points in the diffraction angle 2 ⁇ value of 25.8° ⁇ 0.2°, 14.7° ⁇ 0.2°, and 23.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the hydrochloride salt form has characteristic peaks in the diffraction angle 2 ⁇ values of 25.8° ⁇ 0.2°, 14.7° ⁇ 0.2°, and 23.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the hydrochloride salt crystal form has one or two or three places in the diffraction angle 2 ⁇ value of 17.5° ⁇ 0.2°, 13.5 ⁇ 0.2°, and 28.7° ⁇ 0.2°. Characteristic peaks; preferably, the X-ray powder diffraction of the hydrochloride crystal form has characteristic peaks at diffraction angle 2 ⁇ values of 17.5° ⁇ 0.2°, 13.5° ⁇ 0.2°, and 28.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the hydrochloride salt form has a diffraction angle 2 ⁇ values of 7.1° ⁇ 0.2°, 27.0° ⁇ 0.2°, 15.7° ⁇ 0.2°, 25.8° ⁇ 0.2°, 14.7° ⁇ 0.2°, 23.9° ⁇ 0.2°, 17.5° ⁇ 0.2°, 13.5° ⁇ 0.2°, 28.7° ⁇ 0.2°, 6.7° ⁇ 0.2°, 7.6° ⁇ 0.2°, 9.8° ⁇ 0.2°, 10.7° There are characteristic peaks at ⁇ 0.2°, 18.6° ⁇ 0.2° and 21.6° ⁇ 0.2°.
  • the crystal form of the hydrochloride is isomorphous.
  • the hydrochloride salt crystal form is crystalline form CS3.
  • the X-ray powder diffraction pattern of the hydrochloride salt form CS3 is as shown in FIG.
  • the hydrochloride salt form CS3 provided by the present invention when subjected to differential scanning calorimetry, is heated to a temperature near 54 ° C to start the first endothermic peak.
  • An exothermic peak began to appear near 200 ° C, and its DSC chart is shown in Figure 2.
  • the hydrochloride salt form CS3 provided by the present invention when subjected to thermogravimetric analysis, has a mass loss of about 4.8% when heated to 120 ° C, and continues to be heated until At 230 ° C, there is a 7.5% mass loss, and its TGA is shown in Figure 3.
  • hydrochloride salt form CS3 is a hydrate.
  • the present invention also provides a process for the preparation of the crystalline form CS3 of the hydrochloride salt of the compound of the formula (I), characterized in that the method comprises: placing the crystalline form CS1 of the hydrochloride salt of the compound of the formula (I) in The inert atmosphere was heated to 100 to 200 ° C for 5 to 20 minutes, and transferred to a room temperature environment to obtain a hydrochloride crystal form CS3.
  • the rate of temperature rise is 1 to 20 ° C / min, preferably 10 ° C / min; the inert atmosphere is preferably nitrogen; and the temperature of the temperature rise is preferably 150 ° C.
  • hydrochloride salt form CS3 of the present invention has the following beneficial properties:
  • the hydrochloride salt form CS3 of the present invention is higher than the patent CN105849100A crystal form A at 6 hours, 4 hours and 24 hours, and is 6 to 51 times higher.
  • the hydrochloride salt form CS3 has a high solubility, and while ensuring the efficacy of the drug, the dosage of the drug is lowered, thereby reducing the side effects of the drug and improving the safety of the drug.
  • the increase in the solubility of the hydrochloride salt form CS3 helps to improve the dissolution rate and reduce the difficulty in the development of the formulation process.
  • the hydrochloride salt form CS3 of the present invention can be stable for at least 2 weeks under the conditions of 25 ° C / 60% RH, 40 ° C / 75% RH, 60 ° C / 75% RH, preferably, can be stabilized for 1 month, preferably, It can be stable for 7 months, and the crystal form and purity are not changed.
  • the better stability of the hydrochloride crystal form CS3 can reduce the risk of drug dissolution rate and bio-profit change due to the change of crystal form, which is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.
  • the better stability of the hydrochloride crystal form CS3 makes it more controllable in the crystallization process, preparation process and storage process, and it is not easy to appear mixed crystal, which is of great value for realizing industrial production.
  • hydrochloride salt crystal form is crystalline form CS1.
  • the X-ray powder diffraction pattern of the hydrochloride salt form CS1 is as shown in FIG.
  • the hydrochloride salt form CS1 provided by the present invention when subjected to differential scanning calorimetry, is heated to a temperature near 40 ° C to start the first endothermic peak.
  • a second endothermic peak begins to appear near 202 ° C and its DSC pattern is shown in Figure 5.
  • the hydrochloride salt form CS1 provided by the present invention when subjected to thermogravimetric analysis, has a mass loss of about 11.2% when heated to 160 ° C, and continues to be heated until At 220 ° C, there is a 6.7% mass loss, and its TGA is shown in Figure 6.
  • hydrochloride salt form CS1 is an acetic acid solvate.
  • the present invention also provides a process for the preparation of the crystalline form CS1 of the hydrochloride salt of the compound of the formula (I), characterized in that the process comprises:
  • the molar ratio of the compound of the formula (I) and hydrochloric acid in the method 1) is from 5/1 to 1/5; and the stirring temperature is preferably 25 °C.
  • stirring temperature in the method 2) is preferably 25 °C.
  • hydrochloride salt form CS1 of the present invention has the following beneficial properties:
  • the hydrochloride salt form CS1 of the present invention can be stabilized for at least one month under the conditions of 25 ° C / 60% RH and 40 ° C / 75% RH, the crystal form remains unchanged, and the purity remains substantially unchanged.
  • the better stability of the hydrochloride crystal form CS1 can reduce the risk of drug dissolution rate and bio-profit change due to the change of crystal form, which is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.
  • the better stability of the hydrochloride crystal form CS1 makes it more controllable in the crystallization process, preparation process and storage process, and it is not easy to appear mixed crystal, which is of great value to industrial production.
  • the crystal form of the hydrochloride salt form CS1 did not change before and after the grinding.
  • the hydrochloride salt form CS1 has good mechanical stability, so that its crystalline drug has low requirements on crystallization equipment, requires no special post-treatment conditions, and is more stable in the formulation process, which can reduce the development cost of the drug and improve the quality of the drug.
  • Another object of the present invention is to provide a crystalline form CS2 of the hydrochloride salt of the compound of formula (I).
  • the X-ray powder diffraction of the hydrochloride salt form CS2 has characteristic peaks at diffraction angle 2 ⁇ values of 25.0° ⁇ 0.2°, 22.2° ⁇ 0.2°, and 17.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the hydrochloride salt form CS2 has one or two or three places in the diffraction angle 2 ⁇ value of 25.9° ⁇ 0.2°, 16.1° ⁇ 0.2°, and 8.0° ⁇ 0.2°. Characteristic peak; Preferably, the X-ray powder diffraction of the hydrochloride salt form CS2 has characteristic peaks in the diffraction angle 2 ⁇ values of 25.9° ⁇ 0.2°, 16.1° ⁇ 0.2°, and 8.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the hydrochloride salt form CS2 is at one or two or three places in the diffraction angle 2 ⁇ value of 29.2° ⁇ 0.2°, 15.1° ⁇ 0.2°, and 21.1° ⁇ 0.2°. There is a characteristic peak; preferably, the X-ray powder diffraction of the hydrochloride salt form CS2 has characteristic peaks in the diffraction angle 2 ⁇ values of 29.2° ⁇ 0.2°, 15.1° ⁇ 0.2°, and 21.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the hydrochloride salt form CS2 has a diffraction angle 2 ⁇ of 25.0° ⁇ 0.2°, 22.2° ⁇ 0.2°, 17.0° ⁇ 0.2°, 25.9° ⁇ 0.2°. Characteristic peaks at 16.1 ° ⁇ 0.2 °, 8.0 ° ⁇ 0.2 °, 29.2 ° ⁇ 0.2 °, 15.1 ° ⁇ 0.2 °, and 21.1 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the hydrochloride salt form CS2 is as shown in FIG.
  • the hydrochloride salt form CS2 provided by the present invention when subjected to differential scanning calorimetry, is heated to a temperature near 51 ° C to start the first endothermic peak.
  • a second endothermic peak began to appear near 196 ° C and its DSC pattern is shown in Figure 8.
  • the hydrochloride salt form CS2 provided by the present invention when subjected to thermogravimetric analysis, has a mass loss of about 9.4% when heated to 140 ° C, and continues to be heated until At 230 ° C, there is a mass loss of 16.7%, and its TGA is as shown in FIG.
  • the present invention also provides a process for the preparation of the crystalline form CS2 of the hydrochloride salt of the compound of the formula (I), which comprises adding a compound of the formula (I) to a chloroform solvent at 5 to 30 ° C. Stir for 10 to 100 minutes, add a certain amount of hydrochloric acid, and stir for another 6 to 48 hours.
  • the solid obtained by filtration and drying is the crystalline form CS2.
  • the stirring temperature is preferably 25 ° C; the molar ratio of the compound of the formula (I) to hydrochloric acid is from 5/1 to 1/5, preferably 1/1.
  • Another object of the invention is to provide the crystalline form CS4 of the hydrochloride salt of the compound of formula (I).
  • the X-ray powder diffraction of the hydrochloride salt form CS4 has a diffraction angle 2 ⁇ values of 8.0° ⁇ 0.2°, 4.7° ⁇ 0.2°, 20.6° ⁇ 0.2°, and 11.6° ⁇ 0.2°. Characteristic peaks.
  • the X-ray powder diffraction of the hydrochloride salt crystal form CS4 has one or two or three places in the diffraction angle 2 ⁇ value of 16.4° ⁇ 0.2°, 17.1 ⁇ °°, and 12.7° ⁇ 0.2°. Characteristic peaks; preferably, the X-ray powder diffraction of the hydrochloride salt crystal form CS4 has characteristic peaks in diffraction angle 2 ⁇ values of 16.4° ⁇ 0.2°, 17.1° ⁇ 0.2°, and 12.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the hydrochloride salt form CS4 is at a diffraction angle 2 ⁇ of 8.0° ⁇ 0.2°, 4.7° ⁇ 0.2°, 20.6° ⁇ 0.2°, 11.6° ⁇ 0.2°. There are characteristic peaks at 16.4 ° ⁇ 0.2 °, 17.1 ° ⁇ 0.2 °, and 12.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the hydrochloride salt form CS4 is as shown in FIG.
  • the hydrochloride salt form CS4 provided by the present invention when subjected to differential scanning calorimetry, is heated to about 48 ° C to start the first endothermic peak.
  • An exothermic peak began to appear near 186 ° C, and its DSC chart is shown in FIG.
  • the hydrochloride salt form CS4 provided by the present invention when subjected to thermogravimetric analysis, has a mass loss of about 9.6% when heated to 120 ° C, and continues to be heated until At 230 ° C, there is a 4.8% mass loss, and its TGA is shown in Figure 12.
  • the present invention also provides a process for the preparation of the crystalline form CS4 of the hydrochloride salt of the compound of the formula (I), which comprises adding a hydrochloride salt of the compound of the formula (I) to a mixed system of an alcohol and water. The mixture is stirred at 5 to 30 ° C for 1 to 7 days, and the solid obtained by filtration and drying is the crystalline form CS4.
  • the volume ratio of the alcohol solvent to water is from 19/1 to 1/19, preferably 3/1; and the stirring temperature is preferably 25 °C.
  • the alcohol solvent is preferably isopropyl alcohol.
  • hydrochloride salt form CS4 of the present invention has the following beneficial properties:
  • the hydrochloride salt form CS4 is placed at 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity, 60 ° C / 75% relative humidity, at least stable for 2 weeks, preferably at least stable for 1 month, Preferably, it is stable for at least 6 months.
  • the better stability of the hydrochloride salt form CS4 can reduce the risk of drug dissolution rate and bio-profit change due to the change of crystal form, which is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.
  • the better stability of the hydrochloride salt form CS4 makes it more controllable in the crystallization process, preparation process and storage process, and it is not easy to appear mixed crystal, which is of great value to industrial production.
  • the saturated solution prepared in water, the solubility of the present hydrochloride salt form CS4 is higher than that of CN105849100A crystal form A, which is 38 to 283 times higher.
  • the hydrochloride salt form CS4 has a high solubility, which can reduce the dosage of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.
  • the increase in the solubility of the hydrochloride salt form CS4 helps to improve the dissolution rate and reduces the difficulty in the development of the formulation process.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of the hydrochloride salt form CS1 of the present invention, a hydrochloride salt form CS3, a hydrochloride form CS4, or Any combination, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides the use of the hydrochloride salt form CS1, the hydrochloride form CS3, the hydrochloride form CS4 of the compound of the formula (I), or any mixture thereof, for the preparation of a pharmaceutical preparation for a viral protein inhibitor.
  • the present invention provides the use of the hydrochloride salt form CS1, the hydrochloride form CS3, the hydrochloride form CS4 of the compound of the formula (I), or any mixture thereof, for the preparation of a pharmaceutical preparation for the treatment of influenza A.
  • Another object of the invention is to provide the crystalline form CS9 of the compound of formula (I).
  • the X-ray powder diffraction of the crystalline form CS9 has characteristic peaks at diffraction angle 2 ⁇ values of 16.4° ⁇ 0.2°, 7.7° ⁇ 0.2°, and 8.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS9 has one or more of the diffraction angle 2 ⁇ values of 5.4° ⁇ 0.2°, 18.4° ⁇ 0.2°, 19.7° ⁇ 0.2°, and 12.6° ⁇ 0.2°. Characteristic peak; preferably, the X-ray powder diffraction of the crystal form CS9 has characteristic peaks at diffraction angle 2 ⁇ values of 5.4° ⁇ 0.2°, 18.4° ⁇ 0.2°, 19.7° ⁇ 0.2°, and 12.6° ⁇ 0.2°. .
  • the X-ray powder diffraction of the crystalline form CS9 has a diffraction angle 2 ⁇ value of 16.4° ⁇ 0.2°, 7.7° ⁇ 0.2°, 8.6° ⁇ 0.2°, 5.4° ⁇ 0.2°, 18.4°. Characteristic peaks at ⁇ 0.2°, 19.7° ⁇ 0.2°, and 12.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS9 is as shown in FIG.
  • the crystal form CS9 provided by the present invention when subjected to differential scanning calorimetry, is heated to a temperature near 119 ° C to start an endothermic peak, and is heated to near 191 ° C. An exothermic peak began to appear, and another endothermic peak began to appear near 278 ° C.
  • the DSC chart is shown in FIG.
  • the crystalline form CS9 provided by the present invention has a mass loss of about 10.1% when heated to 167 ° C when subjected to thermogravimetric analysis, and its TGA is as shown in FIG. 21 Shown.
  • the present invention also provides a process for the preparation of the crystalline form CS9 of the compound of the formula (I), characterized in that the method comprises:
  • the solid of the compound of the formula (I) is placed in a mixed solvent of an alcohol and toluene, stirred at room temperature, and the solid is separated and dried to obtain a crystal form CS9.
  • the alcohol solvent comprises methanol.
  • Another object of the invention is to provide a crystalline form CS3 of a compound of formula (I).
  • the X-ray powder diffraction of the crystalline form CS3 has characteristic peaks at diffraction angle 2 ⁇ values of 6.4° ⁇ 0.2°, 15.0° ⁇ 0.2°, and 8.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS3 has a characteristic peak at one or two of the diffraction angle 2 ⁇ values of 13.1° ⁇ 0.2° and 8.1° ⁇ 0.2°; preferably, the crystal form CS3
  • the X-ray powder diffraction has characteristic peaks at diffraction angle 2 ⁇ values of 13.1° ⁇ 0.2° and 8.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 has characteristic peaks at one or two or three of the diffraction angle 2 ⁇ values of 7.2° ⁇ 0.2°, 16.3° ⁇ 0.2°, and 10.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 has characteristic peaks at diffraction angle 2 ⁇ values of 7.2° ⁇ 0.2°, 16.3° ⁇ 0.2°, and 10.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 has a diffraction angle 2 ⁇ of 6.4° ⁇ 0.2°, 15.0° ⁇ 0.2°, 8.7° ⁇ 0.2°, 13.1° ⁇ 0.2°, 8.1°. There are characteristic peaks at ⁇ 0.2°, 7.2° ⁇ 0.2°, 16.3° ⁇ 0.2°, and 10.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS3 is as shown in FIG.
  • the crystal form CS3 provided by the present invention when subjected to differential scanning calorimetry, is heated to a temperature near 178 ° C to start an exothermic peak, starting at around 276 ° C. An endothermic peak appears and its DSC pattern is shown in Figure 23.
  • the crystalline form CS3 provided by the present invention has a mass loss of about 5.5% when heated to 197 ° C when subjected to thermogravimetric analysis, and its TGA is as shown in FIG. Shown.
  • the present invention also provides a process for the preparation of the crystalline form CS3 of the compound of the formula (I), characterized in that the method comprises:
  • the solid of the compound of the formula (I) is placed in a mixed solvent of an ether and a halogenated hydrocarbon, stirred at a temperature of 50 ° C, and the solid is separated and dried to obtain a crystal form CS3.
  • the ether solvent is tetrahydrofuran; and the halogenated hydrocarbon solvent is dichloromethane.
  • the crystalline form CS3 of the compound of the formula (I) of the present invention has the following beneficial properties:
  • the solubility of the compound crystal form CS3 is higher than that of the CN105849100A free form crystal form A, which is 4 to 11 times higher in FeSSIF and 6 to 16 times higher in FaSSIF.
  • the high dynamic solubility can ensure the disintegration and absorption of the crystalline form CS3 of the compound of formula (I) in the stomach and intestine of the human body, improve the drug effect, and increase the blood concentration in the living body, thereby effectively improving the bioavailability of the drug. degree.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of the crystalline form CS3 of the compound of the formula (I) provided by the present invention, and at least one pharmaceutically acceptable carrier, diluted Agent or excipient.
  • the present invention provides the use of the crystalline form CS3 of the compound of the formula (I) for the preparation of a pharmaceutical preparation for a viral protein inhibitor.
  • the present invention provides the use of the crystalline form CS3 of the compound of formula (I) for the preparation of a pharmaceutical preparation for the treatment of influenza A.
  • room temperature as used in the present invention generally means a temperature range of 10 ° C to 30 ° C.
  • isomorphic isomorphism refers to a phenomenon in which the chemical compositions are similar or similar, and under the same thermodynamic conditions, the formed crystals have the same structure, which is also called heterogeneous crystal.
  • crystal or “crystal form” refers to the characterization by the X-ray diffraction pattern shown.
  • Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • the hydrochloride salt form CS1 of the present invention is pure, single, and substantially free of any other crystal form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • Example 1 is an X-ray powder diffraction pattern of a hydrochloride salt crystal form CS3 obtained according to Example 10 of the present invention.
  • Example 2 is a DSC chart of the hydrochloride salt form CS3 obtained according to Example 10 of the present invention.
  • Figure 3 is a TGA diagram of the hydrochloride salt form CS3 obtained according to Example 10 of the present invention.
  • Example 4 is an X-ray powder diffraction pattern of the hydrochloride salt form CS1 obtained according to Example 1 of the present invention.
  • Figure 5 is a DSC chart of the hydrochloride salt form CS1 obtained according to Example 1 of the present invention.
  • Figure 6 is a TGA diagram of the hydrochloride salt form CS1 obtained according to Example 1 of the present invention.
  • Figure 7 is an X-ray powder diffraction pattern of the hydrochloride salt form CS2 obtained according to Example 9 of the present invention.
  • Figure 8 is a DSC chart of the hydrochloride salt form CS2 obtained according to Example 9 of the present invention.
  • Figure 9 is a TGA diagram of the hydrochloride salt form CS2 obtained according to Example 9 of the present invention.
  • Figure 10 is an X-ray powder diffraction pattern of the hydrochloride salt form CS4 obtained according to Example 13 of the present invention.
  • Figure 11 is a DSC chart of the hydrochloride salt form CS4 obtained according to Example 13 of the present invention.
  • Figure 12 is a TGA diagram of the hydrochloride salt form CS4 obtained according to Example 13 of the present invention.
  • Figure 13 is a 1 H NMR chart of the hydrochloride salt form CS3
  • Figure 14 is a 1 H NMR chart of the hydrochloride salt form CS1
  • Figure 15 is a 1 H NMR chart of the hydrochloride salt form CS2
  • Figure 16 is a 1 H NMR chart of the hydrochloride salt form CS4
  • Figure 17 is an X-ray powder diffraction pattern of the hydrochloride salt form CS1 obtained according to Example 6 of the present invention.
  • Figure 18 is an X-ray powder diffraction pattern of the hydrochloride salt form CS4 obtained according to Example 14 of the present invention.
  • Figure 19 is an X-ray powder diffraction pattern of the crystalline form CS9 obtained according to Example 18 of the present invention.
  • Figure 20 is a DSC chart of the crystalline form CS9 obtained according to Example 18 of the present invention.
  • Figure 21 is a TGA diagram of a crystalline form CS9 obtained according to Example 18 of the present invention.
  • Figure 22 is an X-ray powder diffraction pattern of the crystalline form CS3 obtained according to Example 19 of the present invention.
  • Figure 23 is a DSC diagram of a crystalline form CS3 obtained according to Example 19 of the present invention.
  • Figure 24 is a TGA diagram of a crystalline form CS3 obtained according to Example 19 of the present invention.
  • Figure 25 is a comparison of XRPD before and after the salt crystal form CS1 (the figure above is before grinding, the figure below is after grinding)
  • the X-ray powder diffraction pattern of the present invention was collected on a Bruker D2 Phaser X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential thermal analysis (DSC) data was taken from the TA Instruments Q2000 DSC, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually, 1 to 10 mg of the sample is placed in an aluminum crucible (unless otherwise specified), and the sample is raised from room temperature to a set temperature under the protection of dry N2 at a heating rate of 10 ° C/min, while TA software records The heat change of the sample during the heating process. In the present application, the melting point is reported as the starting temperature.
  • Thermogravimetric analysis (TGA) data was taken from the TA Instruments Q500TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually, 5 to 15 mg of the sample is placed in a platinum crucible, and the sample is raised from room temperature to a set temperature by a stepwise high-resolution detection method at a heating rate of 10 ° C/min under the protection of 50 mL/min dry N 2 . At the same time, the TA software records the change in weight of the sample during the heating process. The water content of the crystalline form of the present invention is calculated based on the TGA weight loss estimation. As is known to those skilled in the art, TGA weight loss is a reference for the water content of the crystalline form, but does not absolutely represent the number of molecules of the crystalline form.
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • H NMR data (1 HNMR) collected from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
  • Example Raw material quality (mg) Acetic acid volume (mL) Concentrated hydrochloric acid volume (mL) Sample mark 1 500.3 9.0 0.1 Sample 1 2 10.2 0.5 0.002 Sample 2 3 20.1 0.5 0.004 Sample 3 4 99.8 2.0 0.02 Sample 4 5 499.9 8.0 0.108 Sample 5
  • Samples 1 to 5 were all hydrochloride salt crystal form CS1 by XRPD detection.
  • Sample 1 was selected for test characterization, and its X-ray powder diffraction data is shown in Figure 4 and Table 2. Its DSC is shown in Figure 5. It has two endothermic peaks, and the first endothermic peak begins to appear near 40 °C; a second endothermic peak begins to appear near 202 °C. Its TGA, as shown in Figure 6, was heated to 160 ° C with a mass loss gradient of about 11.2%, from which it was calculated to contain about 1 mole of acetic acid per mole of VX-787 hydrochloride salt form CS1. When heating was continued to 220 ° C, there was a mass loss of about 6.7%.
  • CS1 hydrochloride polymorph has a singlet peak at 1.91, corresponding to acetic acid (CH 3 COOH) methyl hydrogen molecule chemical shift, NMR data according to the calculated molar ratio of acetic acid to the API molecules is 1: 1, 1 H NMR is shown in Figure 14.
  • VX-787 hydrochloride solid was weighed into a 5 mL glass vial, and about 1 mL of acetic acid solvent was added thereto, stirred at room temperature (about 25 ° C) for 1 day, centrifuged, and vacuum dried at room temperature.
  • the solid obtained in this example was a crystalline form CS1, and its X-ray powder diffraction data is shown in FIG. 17 and Table 3.
  • the hydrochloride salt form CS1 prepared by the present invention was allowed to stand under the conditions of 25 ° C / 60% relative humidity (RH) and 40 ° C / 75% relative humidity (RH) for 1 month, and the XRPD was measured before and after standing. The results are shown in Table 4.
  • the results show that the crystalline form CS1 is kept at 25 ° C / 60% RH and 40 ° C / 75% RH for at least 1 month, the crystal form remains unchanged, the purity remains basically unchanged, and the purity is maintained above 98%.
  • the crystal form CS1 provided by the invention has good stability.
  • the hydrochloride salt form CS2 has a singlet peak at 8.32, corresponding to the hydrogen chemical shift of chloroform (CHCl 3 ). According to the nuclear magnetic data, the molar ratio of chloroform to the compound of formula (I) is 0.75:1, and the NMR is attached. Figure 15 shows.
  • the DSC of this crystal form is shown in Figure 8, which has two endothermic peaks, and the first endothermic peak begins to appear near 51 ° C.
  • the endothermic peak is the loss of chloroform near this temperature ( 1 H NMR data shows compound Chloroform was present, as shown in Figure 15; a second endothermic peak began to appear near 196 °C.
  • each mole of VX-787 hydrochloride salt form CS2 contained about 0.75 moles of chloroform.
  • VX-787 hydrochloride salt form CS1 Weigh about 10 mg of VX-787 hydrochloride salt form CS1, heat it by TGA, raise it from room temperature (about 25 ° C) to 150 ° C at 10 ° C / min under nitrogen protection, and then equilibrate at 150 ° C. 10 minutes, transfer to room temperature environment.
  • the solid obtained in this example was the hydrochloride salt form CS3, and the X-ray powder diffraction data thereof is shown in FIG. 1 and Table 6.
  • the DSC of this crystal form is shown in Fig. 2, in which there is an endothermic peak and an exothermic peak, respectively, an endothermic peak begins to appear near 54 ° C, and an exothermic peak begins to appear near 200 ° C.
  • TGA of this crystalline form is shown in Figure 3, which has a mass loss gradient of about 4.8% when heated to 120 ° C; and a mass loss of about 7.5% when heated to 230 ° C.
  • solubility of the hydrochloride salt crystal form CS3 of the present invention is higher than that of the CN105849100A hydrochloride salt form A after 4 hours and 2 hours after standing in water. 6-51 times.
  • hydrochloride salt form CS3 of the present invention is allowed to stand for at least 7 months at 25 ° C / 60% RH, at least 1 month at 40 ° C / 75% RH, and at least 60 ° C / 75% RH. After 2 weeks of storage, the crystal form and purity did not change, and the purity was above 98%. It can be seen that the hydrochloride salt form CS3 has good stability.
  • VX-787 hydrochloride crystal form CS3 was obtained by adding 0.4 mL of a mixed solvent of isopropyl alcohol and water in a volume ratio of 3::1, and stir at room temperature (about 25 ° C). After 30 minutes, 10.5 mg of VX-787 hydrochloride crystal form A (CN105849100A) was further added, and stirring was continued at room temperature for 1 week, centrifugation, and vacuum drying at room temperature. Upon examination, the solid obtained in this example was the hydrochloride salt form CS4, and the X-ray powder diffraction data thereof is shown in Fig. 10 and Table 9.
  • the DSC of the crystal form is shown in Fig. 11, in which there is an endothermic peak and an exothermic peak, respectively, and an endothermic peak starts to appear near 48 ° C, and the endothermic peak is caused by water loss near the temperature; An exothermic peak began to appear near °C.
  • the TGA of this crystalline form had a mass loss gradient of about 9.6% when heated to 120 °C; it had a mass loss of about 4.8% when heated to 230 °C.
  • the results show that the crystalline form CS4 is placed at 25 ° C / 60% RH for at least 2 weeks, at 40 ° C / 75% RH for at least 1 month, at 60 ° C / 75% RH for at least 2 weeks, crystal retention The same, the purity remained basically the same, both higher than 98%.
  • the crystal form CS4 provided by the invention has good stability.
  • the CN105849100A hydrochloride salt form A prepared by the same raw materials and the hydrochloride salt form form CS4 of the present invention were measured by HPLC, and the product purity was calculated.
  • the HPLC purity test results show that the hydrochloride salt form CS4 of the present invention has a remarkable purification effect.
  • CN105849100A The purity of the hydrochloride salt crystal form A is 97.91%, and the purity of the hydrochloride salt crystal form CS4 of the present invention is 99.70%. The purity of the present invention is higher than the purity of the CN105849100A hydrochloride salt form A.
  • Example 17 Dynamic dissolution of the hydrochloride salt form A in the hydrochloride salt form CS4 and CN105849100A Degree comparison
  • the hydrochloride salt form CS4 of the present invention and CN105849100A crystal form A are prepared into a saturated solution with pure water, and the sample in the saturated solution is determined by high performance liquid chromatography (HPLC) after 1 hour, 4 hours and 24 hours. The content.
  • HPLC high performance liquid chromatography
  • the solubility data of the hydrochloride salt form CS4 and CN105849100A crystal form A of the present invention are shown in Table 12.
  • solubility of the hydrochloride salt form CS4 of the present invention is higher than that of the CN105849100A hydrochloride salt form A after 4 hours and 2 hours after standing in water. 38 to 283 times.
  • VX-787 solid 308.3 mg was added to a 20 mL glass vial, 10 mL of a methanol and toluene mixed solvent in a volume ratio of 1:3 was added, and the mixture was stirred at room temperature for 72 hours, and the solid was centrifuged, and dried at room temperature under vacuum.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 13. Its XRPD diagram is shown in Figure 19, its DSC diagram is shown in Figure 20, and its TGA diagram is shown in Figure 21.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 14.
  • the obtained sample was examined as Form CS3, its XRPD pattern is shown in Figure 22, its DSC chart is shown in Figure 23, and its TGA pattern is shown in Figure 24.
  • the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 1 hour, 4 hours, and 24 hours. The solubility results are shown in Table 16.

Abstract

一种病毒蛋白抑制剂药物VX-787的盐酸盐晶型与游离形式晶型及其制备方法和用途，所述式(I)化合物的晶型包括盐酸盐晶型CS1、盐酸盐晶型CS2、盐酸盐晶型CS3、盐酸盐晶型CS4和晶型CS3、晶型CS9。

Description

一种病毒蛋白抑制剂药物VX-787的晶型及其制备方法和用途 技术领域
本发明涉及药物晶体技术领域。具体而言，涉及一种病毒蛋白抑制剂药物VX-787的晶型及其制备方法和用途。
背景技术
甲型流感病毒为常见流感病毒，对人类致病性高，曾多次引起世界性大流行。甲型流感病毒的亚型则被人们称为“禽流感”，禽流感是由禽流感病毒引起的一种急性传染病，病毒基因变异后能够感染人类，感染后的症状主要表现为高热、咳嗽、流涕、肌痛等，多数伴有严重的肺炎，严重者心、肾等多种脏器衰竭导致死亡，病死率很高。
VX-787，或JNJ-872，是一种病毒蛋白抑制剂，最初是由Vertex研发，后授权给杨森公司共同开发。该化合物目前处于临床阶段，用于治疗甲型流感。初步的临床评估显示VX-787非常有前景。I期研究证明VX-787具有良好的耐受性。已完成的IIa期研究表明，VX-787在流感病毒感染的病毒学和临床评测方面表现出了统计学意义的显著改善。VX-787的化学名称为(2S，3S)-3-((2-(5-氟-1H-吡咯并[2，3-b]吡啶-3-基)-5-氟嘧啶-4基)氨基)二环[2.2.2]辛烷-2-羧酸，其结构式如式(I)所示：
Figure PCTCN2018074050-appb-000001
固体化学药物晶型不同，可造成其溶解度、稳定性、流动性等不同，从而影响含有该化合物的药物产品的安全性和有效性(参见K.Knapman,Modern Drug Discovery,3,53-54,57,2000.)，从而导致临床药效的差异。发现药物活性成分新的晶型(包括无水物、水合物、溶剂化物等)可能会产生更具加工优势 或提供具有更好理化特性的物质，比如更好的生物利用度、储存稳定、易加工处理、易提纯或作为促进转化为其他晶型的中间体晶型。某些药学上有用的化合物的新晶型也可以帮助改善药物的性能。它扩大了制剂学上可选用的原料型态，例如改善溶出度、改善储藏期限、更容易加工等。
专利CN105849100A公开了式(I)化合物盐酸盐的半水合物晶型A、三水合物晶型F和晶型D，晶型A需要在0.05-0.85的水活度条件下制备；晶型D为晶型A脱水得到的产物；晶型F需要在水活度为等于或大于0.9的条件下制备，在储存过程中对环境的要求太高，不利于储存，且文本中披露晶型A为较优选形式。同时，专利CN105849100A公开了式(I)化合物游离形式的晶型A和晶型B，文本中披露，游离碱化合物(I)的水化形式B与游离碱化合物(I)的形式A为相同晶型，但其制备方法较复杂。
因此，本领域仍需要***全面的开发式(I)化合物不同的晶型和盐型，从而实现其药物学上的发展并释放其潜能，并促进该活性药物成分的更好的配方的制备。本发明提供式(I)化合物的盐酸盐晶型CS1、盐酸盐晶型CS2、盐酸盐晶型CS3、盐酸盐晶型CS4和式(I)化合物晶型CS3、式(I)化合物晶型CS9，其制备方法简单，在稳定性、机械稳定性、引湿性、溶解度、提纯作用等方面存在优势，为含式(I)化合物的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。
发明内容
为解决上述问题，本发明提供式(I)化合物盐酸盐的新晶型及其制备方法和用途。
本发明的一个目的，是提供式(I)化合物盐酸盐的晶型。
使用Cu-Kα辐射，所述盐酸盐晶型的X射线粉末衍射在衍射角2θ值为7.1°±0.2°、27.0°±0.2°、15.7°±0.2°处有特征峰。
进一步的，所述盐酸盐晶型的X射线粉末衍射在衍射角2θ值为25.8°±0.2°、14.7°±0.2°、23.9°±0.2°中的一处或两处或三处有特征峰；优选的，所述盐酸盐晶型的X射线粉末衍射在衍射角2θ值为25.8°±0.2°、14.7°±0.2°、23.9°±0.2°中均有特征峰。
更进一步的，所述盐酸盐晶型的X射线粉末衍射在衍射角2θ值为 17.5°±0.2°、13.5°±0.2°、28.7°±0.2°中的一处或两处或三处有特征峰；优选的，所述盐酸盐晶型的X射线粉末衍射在衍射角2θ值为17.5°±0.2°、13.5°±0.2°、28.7°±0.2°中均有特征峰。
在一个优选的实施方案中，所述盐酸盐晶型的X射线粉末衍射在衍射角2θ值为7.1°±0.2°、27.0°±0.2°、15.7°±0.2°、25.8°±0.2°、14.7°±0.2°、23.9°±0.2°、17.5°±0.2°、13.5°±0.2°、28.7°±0.2°、6.7°±0.2°、7.6°±0.2°、9.8°±0.2°、10.7°±0.2°、18.6°±0.2°与21.6°±0.2°处有特征峰。
进一步的，所述盐酸盐的晶型是类质同晶。
一方面，所述盐酸盐晶型为晶型CS3。
非限制性地，在本发明的一个具体实施方案中，盐酸盐晶型CS3的X射线粉末衍射谱图如附图1所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的盐酸盐晶型CS3，当进行差示扫描量热分析时，加热至54℃附近开始出现第一个吸热峰，在200℃附近开始出现一个放热峰，其DSC图如附图2所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的盐酸盐晶型CS3，当进行热重分析时，加热至120℃时，具有约4.8％的质量损失，继续加热至230℃时，具有7.5％的质量损失，其TGA如附图3所示。
非限制性地，所述盐酸盐晶型CS3为水合物。
根据本发明的目的，本发明还提供式(I)化合物盐酸盐的晶型CS3的制备方法，其特征在于，所述方法包含：将式(I)化合物盐酸盐的晶型CS1放置在惰性气氛升温至100～200℃，并保持5～20分钟，转移至室温环境，所得固体即为盐酸盐晶型CS3。
进一步的，所述升温的速率为1～20℃/分钟，优选10℃/分钟；所述惰性气氛优选氮气；所述升温的温度优选150℃。
本发明盐酸盐晶型CS3具有以下有益性质：
1)溶解度高。在水中配制成的饱和溶液，本发明的盐酸盐晶型CS3在1小时、4小时和24小时时，均比专利CN105849100A晶型A高，高出6～51倍。盐酸盐晶型CS3溶解度较高，在保证药物疗效的同时，降低药品的给药剂量，从而降低药品的副作用并提高药品的安全性。同时，盐酸盐晶型CS3溶解度的提高有助于提升溶出度，降低了制剂工艺开发的难度。
2)稳定性好。本发明盐酸盐晶型CS3在25℃/60％RH、40℃/75％RH、60℃/75％RH条件下，至少可以稳定2周，优选地，可以稳定1个月，优选地，可以稳定7个月，晶型和纯度都不发生改变。盐酸盐晶型CS3较好的稳定性能够减少药物由于晶型变化而导致药物溶出速率及生物利度改变的风险，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。同时，盐酸盐晶型CS3较好的稳定性使其在结晶工艺、制剂工艺和储存过程中更加可控，不易出现混晶，对实现工业化生产具有较大价值。
另一方面，所述盐酸盐晶型为晶型CS1。
非限制性地，在本发明的一个具体实施方案中，盐酸盐晶型CS1的X射线粉末衍射谱图如附图4所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的盐酸盐晶型CS1，当进行差示扫描量热分析时，加热至40℃附近开始出现第一个吸热峰，在202℃附近开始出现第二个吸热峰，其DSC图如附图5所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的盐酸盐晶型CS1，当进行热重分析时，加热至160℃时，具有约11.2％的质量损失，继续加热至220℃时，具有6.7％的质量损失，其TGA如附图6所示。
非限制地，所述盐酸盐晶型CS1为醋酸溶剂合物。
根据本发明的目的，本发明还提供式(I)化合物盐酸盐的晶型CS1的制备方法，其特征在于，所述方法包含：
1)将式(I)化合物加入醋酸中，在5～30℃条件下搅拌10～100分钟，加入一定量的盐酸，再搅拌6～48小时，过滤干燥得到固体；或
2)将式(I)化合物盐酸盐加入醋酸中，在一定5～30℃条件下搅拌6～48小时，过滤干燥得到固体，所得固体为盐酸盐晶型CS1。
进一步的，方法1)中所述式(I)化合物和盐酸的投料摩尔比为5/1～1/5；所述搅拌温度优选25℃。
进一步的，方法2)中所述搅拌温度优选25℃。
本发明盐酸盐晶型CS1具有以下有益性质：
1)稳定性好。本发明盐酸盐晶型CS1在25℃/60％RH和40℃/75％RH条件下，至少可以稳定1个月，晶型保持不变，纯度基本保持不变。盐酸盐晶型CS1较好的稳定性能够减少药物由于晶型变化而导致药物溶出速率及生物利度改变的 风险，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。同时，盐酸盐晶型CS1较好的稳定性使其在结晶工艺、制剂工艺和储存过程中更加可控，不易出现混晶，对工业化生产具有较大价值。
2)机械稳定性好。研磨前后盐酸盐晶型CS1晶型未发生变化。盐酸盐晶型CS1具有较好的机械稳定性，使其晶型药物对结晶设备要求低，无需特别的后处理条件，在制剂过程中更加稳定，可降低药物的开发成本并提升药物质量。
本发明的另一个目的，是提供式(I)化合物盐酸盐的晶型CS2。
使用Cu-Kα辐射，所述盐酸盐晶型CS2的X射线粉末衍射在衍射角2θ值为25.0°±0.2°、22.2°±0.2°、17.0°±0.2°处有特征峰。
进一步的，所述盐酸盐晶型CS2的X射线粉末衍射在衍射角2θ值为25.9°±0.2°、16.1°±0.2°、8.0°±0.2°中的一处或两处或三处有特征峰；优选的，所述盐酸盐晶型CS2的X射线粉末衍射在衍射角2θ值为25.9°±0.2°、16.1°±0.2°、8.0°±0.2°中均有特征峰。
更进一步的，所述盐酸盐晶型CS2的X射线粉末衍射在衍射角2θ值为29.2°±0.2°、15.1°±0.2°、21.1°±0.2°中的一处或两处或三处有特征峰；优选的，所述盐酸盐晶型CS2的X射线粉末衍射在衍射角2θ值为29.2°±0.2°、15.1°±0.2°、21.1°±0.2°中均有特征峰。
在一个优选的实施方案中，所述盐酸盐晶型CS2的X射线粉末衍射在衍射角2θ值为25.0°±0.2°、22.2°±0.2°、17.0°±0.2°、25.9°±0.2°、16.1°±0.2°、8.0°±0.2°、29.2°±0.2°、15.1°±0.2°、21.1°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，盐酸盐晶型CS2的X射线粉末衍射谱图如附图7所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的盐酸盐晶型CS2，当进行差示扫描量热分析时，加热至51℃附近开始出现第一个吸热峰，在196℃附近开始出现第二个吸热峰，其DSC图如附图8所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的盐酸盐晶型CS2，当进行热重分析时，加热至140℃时，具有约9.4％的质量损失，继续加热至230℃时，具有16.7％的质量损失，其TGA如附图9所示。
根据本发明的目的，本发明还提供式(I)化合物盐酸盐的晶型CS2的制备方法，所述方法包含：将式(I)化合物加入到氯仿溶剂中，在5～30℃条件下搅拌 10～100分钟，加入一定量的盐酸，再搅拌6～48小时，过滤干燥得到的固体即为晶型CS2。
进一步地，所述搅拌温度优选25℃；所述式(I)化合物和盐酸的摩尔比介于5/1～1/5，优选1/1。
本发明的另一个目的，是提供式(I)化合物盐酸盐的晶型CS4。
使用Cu-Kα辐射，所述盐酸盐晶型CS4的X射线粉末衍射在衍射角2θ值为8.0°±0.2°、4.7°±0.2°、20.6°±0.2°、11.6°±0.2°处有特征峰。
进一步的，所述盐酸盐晶型CS4的X射线粉末衍射在衍射角2θ值为16.4°±0.2°、17.1°±0.2°、12.7°±0.2°中的一处或两处或三处有特征峰；优选的，所述盐酸盐晶型CS4的X射线粉末衍射在衍射角2θ值为16.4°±0.2°、17.1°±0.2°、12.7°±0.2°中均有特征峰。
在一个优选的实施方案中，所述盐酸盐晶型CS4的X射线粉末衍射在衍射角2θ值为8.0°±0.2°、4.7°±0.2°、20.6°±0.2°、11.6°±0.2°、16.4°±0.2°、17.1°±0.2°、12.7°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，盐酸盐晶型CS4的X射线粉末衍射谱图如附图10所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的盐酸盐晶型CS4，当进行差示扫描量热分析时，加热至48℃附近开始出现第一个吸热峰，在186℃附近开始出现一个放热峰，其DSC图如附图11所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的盐酸盐晶型CS4，当进行热重分析时，加热至120℃时，具有约9.6％的质量损失，继续加热至230℃时，具有4.8％的质量损失，其TGA如附图12所示。
根据本发明的目的，本法明还提供式(I)化合物盐酸盐的晶型CS4的制备方法，所述方法包含：将式(I)化合物盐酸盐加入醇类和水的混合体系中，在5～30℃条件下，搅拌1～7天，过滤干燥得到的固体即为晶型CS4。
进一步地，所述醇类溶剂和水的体积比介于19/1～1/19，优选3/1；所述搅拌温度优选25℃。
更进一步地，所述醇类溶剂优选异丙醇。
本发明盐酸盐晶型CS4具有以下有益性质：
1)稳定性好。盐酸盐晶型CS4在25℃/60％相对湿度、40℃/75％相对湿度、 为60℃/75％相对湿度下放置，至少可以稳定2周，优选的至少可稳定放置1个月，优选的至少可稳定放置6个月。盐酸盐晶型CS4较好的稳定性能够减少药物由于晶型变化而导致药物溶出速率及生物利度改变的风险，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。同时，盐酸盐晶型CS4较好的稳定性使其在结晶工艺、制剂工艺和储存过程中更加可控，不易出现混晶，对工业化生产具有较大价值。
2)提纯效果好。CN105849100A盐酸盐晶型A的纯度为97.91％，本发明盐酸盐晶型CS4的纯度为99.70％，晶型CS4纯度较高。药物的纯度对于保证药物的疗效和安全性，防止药物不良反应的发生具有重要意义；同时，药物纯度越高，收率越稳定，更易于工业化生产。
3)溶解度高。在水中配制成的饱和溶液，本发盐酸盐晶型CS4的溶解度比CN105849100A晶型A高，高出38～283倍。盐酸盐晶型CS4溶解度较高，可降低给药剂量，从而降低药品的副作用并提高药品的安全性。同时，盐酸盐晶型CS4溶解度的提高有助于提高溶出度，降低了制剂工艺开发的难度。
此外，本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的本发明盐酸盐晶型CS1、盐酸盐晶型CS3、盐酸盐晶型CS4，或它们的任意混合，以及至少一种药学上可接受的载体、稀释剂或赋形剂。
进一步的，本发明提供式(I)化合物盐酸盐晶型CS1、盐酸盐晶型CS3、盐酸盐晶型CS4，或它们的任意混合在制备病毒蛋白抑制剂药物制剂中的用途。
更进一步的，本发明提供式(I)化合物盐酸盐晶型CS1、盐酸盐晶型CS3、盐酸盐晶型CS4，或它们的任意混合在制备治疗甲型流感药物制剂中的用途。
本发明的另一个目的，是提供式(I)化合物的晶型CS9。
使用Cu-Kα辐射，所述晶型CS9的X射线粉末衍射在衍射角2θ值为16.4°±0.2°、7.7°±0.2°、8.6°±0.2°处有特征峰
进一步的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为5.4°±0.2°、18.4°±0.2°、19.7°±0.2°、12.6°±0.2°中的一处或多处有特征峰；优选的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为5.4°±0.2°、18.4°±0.2°、19.7°±0.2°、12.6°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS9的X射线粉末衍射在衍射角2θ值为16.4°±0.2°、7.7°±0.2°、8.6°±0.2°、5.4°±0.2°、18.4°±0.2°、19.7°±0.2°、12.6°±0.2° 处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS9的X射线粉末衍射谱图如附图19所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS9，当进行差示扫描量热分析时，加热至119℃附近开始出现一个吸热峰，加热至191℃附近开始出现一个放热峰，在278℃附近开始出现另一个吸热峰，其DSC图如附图20所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS9，当进行热重分析时，加热至167℃时，具有约10.1％的质量损失，其TGA如附图21所示。
根据本发明的目的，本发明还提供式(I)化合物晶型CS9的制备方法，其特征在于，所述方法包含：
将式(I)化合物的固体置于醇类和甲苯的混合溶剂中，于室温下搅拌，分离取固体，干燥即可得到晶型CS9。
优选地，所述醇类溶剂包括甲醇。
本发明的另一个目的，是提供式(I)化合物的晶型CS3。
使用Cu-Kα辐射，所述晶型CS3的X射线粉末衍射在衍射角2θ值为6.4°±0.2°、15.0°±0.2°、8.7°±0.2°处有特征峰。
进一步的，所述晶型CS3的X射线粉末衍射在衍射角2θ值为13.1°±0.2°、8.1°±0.2°、中的一处或两处有特征峰；优选的，所述晶型CS3的X射线粉末衍射在衍射角2θ值为13.1°±0.2°、8.1°±0.2°处均有特征峰。
更进一步的，所述晶型CS3的X射线粉末衍射在衍射角2θ值为7.2°±0.2°、16.3°±0.2°、10.4°±0.2°中的一处或两处或三处有特征峰；优选的，所述晶型CS3的X射线粉末衍射在衍射角2θ值为7.2°±0.2°、16.3°±0.2°、10.4°±0.2°处均有特征峰。
在一个优选的实施方案中，所述晶型CS3的X射线粉末衍射在衍射角2θ值为6.4°±0.2°、15.0°±0.2°、8.7°±0.2°、13.1°±0.2°、8.1°±0.2°、7.2°±0.2°、16.3°±0.2°、10.4°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS3的X射线粉末衍射谱图如附图22所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS3，当进行差示扫描量热分析时，加热至178℃附近开始出现一个放热峰，在276℃附近开始出现一个吸热峰，其DSC图如附图23所示。
非限制性地，在本发明的一个具体实施方案中，本发明提供的晶型CS3，当进行热重分析时，加热至197℃时，具有约5.5％的质量损失，其TGA如附图24所示。
根据本发明的目的，本发明还提供式(I)化合物晶型CS3的制备方法，其特征在于，所述方法包含：
将式(I)化合物的固体置于醚类和卤代烃类的混合溶剂中，在50℃温度下搅拌，分离取固体，干燥即可得到晶型CS3。
优选地，所述醚类溶剂为四氢呋喃；所述卤代烃溶剂为二氯甲烷。
本发明式(I)化合物晶型CS3具有以下有益性质：
1)稳定性好。在25℃/60％相对湿度(RH)和40℃/75％相对湿度条件下，至少可以稳定5个月，且晶型和纯度未发生变化。式(I)化合物晶型CS3较好的稳定性能够减少药物由于晶型变化而导致药物溶出速率及生物利度改变的风险，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。同时，式(I)化合物晶型CS3较好的稳定性使其在结晶工艺、制剂工艺和储存过程中更加可控，不易出现混晶，对实现工业化生产具有较大价值。
2)溶解度高。在pH＝5.0FeSSIF(进食状态下人工肠液)和pH＝6.5FaSSIF(空腹状态下人工肠液)配制的饱和溶液中，1个小时，4个小时和24个小时时，本发明的式(I)化合物晶型CS3的溶解度均高于CN105849100A游离形式晶型A，在FeSSIF中，高出4～11倍，在FaSSIF中，高出6～16倍。较高的动态溶解度可保证式(I)化合物晶型CS3在人体胃、肠中的崩解与吸收，改善用药效果，提高其在生物体内的血药浓度，从而有效提高了该药物的生物利用度。
此外，本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的本发明提供的式(I)化合物晶型CS3，以及至少一种药学上可接受的载体、稀释剂或赋形剂。
进一步的，本发明提供式(I)化合物晶型CS3，在制备病毒蛋白抑制剂药物制剂中的用途。
更进一步的，本发明提供式(I)化合物晶型CS3，在制备治疗甲型流感药物 制剂中的用途。
本发明所述的“室温”，通常是指10℃～30℃温度范围。
所述“类质同晶”是指化学组成相似或相近，在相同的热力学条件下，形成的晶体具有相同的结构的现象，也称作异质同晶。
本发明中，“晶体”或“晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线衍射图不必和这里所指的例子中的X射线衍射图完全一致。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
在一些实施方案中，本发明的盐酸盐晶型CS1、盐酸盐晶型CS2、盐酸盐晶型CS3、盐酸盐晶型CS4和式(I)化合物晶型CS3、式(I)化合物晶型CS9是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
附图说明
图1为根据本发明实施例10所得盐酸盐晶型CS3的X射线粉末衍射图
图2为根据本发明实施例10所得盐酸盐晶型CS3的DSC图
图3为根据本发明实施例10所得盐酸盐晶型CS3的TGA图
图4为根据本发明实施例1所得盐酸盐晶型CS1的X射线粉末衍射图
图5为根据本发明实施例1所得盐酸盐晶型CS1的DSC图
图6为根据本发明实施例1所得盐酸盐晶型CS1的TGA图
图7为根据本发明实施例9所得盐酸盐晶型CS2的X射线粉末衍射图
图8为根据本发明实施例9所得盐酸盐晶型CS2的DSC图
图9为根据本发明实施例9所得盐酸盐晶型CS2的TGA图
图10为根据本发明实施例13所得盐酸盐晶型CS4的X射线粉末衍射图
图11为根据本发明实施例13所得盐酸盐晶型CS4的DSC图
图12为根据本发明实施例13所得盐酸盐晶型CS4的TGA图
图13为盐酸盐晶型CS3的 1H NMR图
图14为盐酸盐晶型CS1的 1H NMR图
图15为盐酸盐晶型CS2的 1H NMR图
图16为盐酸盐晶型CS4的 1H NMR图
图17为根据本发明实施例6所得盐酸盐晶型CS1的X射线粉末衍射图
图18为根据本发明实施例14所得盐酸盐晶型CS4的X射线粉末衍射图
图19为根据本发明实施例18所得晶型CS9的X射线粉末衍射图
图20为根据本发明实施例18所得晶型CS9的DSC图
图21为根据本发明实施例18所得晶型CS9的TGA图
图22为根据本发明实施例19所得晶型CS3的X射线粉末衍射图
图23为根据本发明实施例19所得晶型CS3的DSC图
图24为根据本发明实施例19所得晶型CS3的TGA图
图25为盐酸盐晶型CS1研磨前后XRPD对比图(上图为研磨前，下图为研磨后)
具体实施方式
本发明进一步参考以下实施例限定，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
采集数据所用的仪器及方法：
本发明所述的X射线粉末衍射图在Bruker D2Phaser X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu,Kα
Figure PCTCN2018074050-appb-000002
1.54060；
Figure PCTCN2018074050-appb-000003
1.54439
Kα2/Kα1强度比例：0.50
电压：30仟伏特(kV)
电流：10毫安培(mA)
扫描范围：自3.0至40.0度
差热分析(DSC)数据采自于TA Instruments Q2000DSC，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。通常取1～10mg的样品放置于加盖(除非特别说明)的铝坩埚内，以10℃/min的升温速度在干燥N2的保护下将样品从室温升至设定温度，同时TA软件记录样品在升温过程中的热量变化。在本申请中，熔点是按起始温度来报告的。
热重分析(TGA)数据采自于TA Instruments Q500TGA，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。通常取5～15mg的样品放置于白金坩埚内，采用分段高分辨检测的方式，以10℃/min的升温速度在50mL/min干燥N2的保护下将样品从室温升至设定温度，同时TA软件记录样品在升温过程中的重量变化。本发明晶型的含水量是根据TGA失重推测算出，如本领域技术人员所知，TGA失重是晶型含水量的参考，但并不能绝对代表晶型所含水分子数。
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N 2,200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
核磁共振氢谱数据( 1HNMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配成2-10mg/mL 的溶液。
除非特殊说明，以下实施例均在室温条件下操作。
以下实施例中所使用的式(I)化合物和/或其盐可根据现有技术制备得到，例如根据CN105849100A文献所记载的方法制备获得。
实施例1～5盐酸盐晶型CS1的制备方法
称取一定质量的VX-787固体，加入一定体积的醋酸溶剂中，在室温下搅拌30～60分钟，再加入一定量的浓度约为12mol/L的浓盐酸溶液，继续在室温下搅拌1～2天，离心，室温下真空干燥得到固体。表1中实施例所得到的固体标记为样品1～5。
表1
实施例 原料质量(mg) 醋酸体积(mL) 浓盐酸体积(mL) 样品标记
1 500.3 9.0 0.1 样品1
2 10.2 0.5 0.002 样品2
3 20.1 0.5 0.004 样品3
4 99.8 2.0 0.02 样品4
5 499.9 8.0 0.108 样品5
经XRPD检测，样品1～5均为盐酸盐晶型CS1。
其中选取样品1测试表征，其X射线粉末衍射数据如图4，表2所示。其DSC如图5所示，其有两个吸热峰，在40℃附近开始出现第一个吸热峰；在202℃附近开始出现第二个吸热峰。其TGA如附图6所示，将其加热至160℃时，具有约11.2％的质量损失梯度，据此计算，每摩尔VX-787盐酸盐晶型CS1含有约1摩尔的醋酸。继续加热至220℃时，具有约6.7％的质量损失。
盐酸盐晶型CS1在1.91处有一个单重峰，对应于醋酸(CH 3COOH)分子的甲基氢化学位移，根据核磁数据，计算醋酸分子与API的摩尔比为1：1，其 1H NMR如附图14所示。其数据如下：{ 1H NMR(400MHz,DMSO)δ8.88(s,1H),8.53–8.43(m,2H),8.41(m,1H),4.89(m,1H),2.99(d,J＝6.2Hz,1H),2.08(d,J＝5.9Hz,1H),1.98(d,J＝8.6Hz,1H),1.91(s,3H),1.86–1.61(m,4H),1.48(dd,J＝54.1,17.6Hz,4H),1.23(s,1H).}。
表2
2θ值 d间隔 强度％
6.69 13.20 43.73
7.06 12.52 100.00
7.58 11.67 24.03
9.76 9.06 13.63
10.70 8.2 13.63
11.11 7.96 2.39
12.18 7.27 3.85
12.60 7.03 7.59
13.46 6.58 15.57
14.29 6.20 14.58
14.62 6.06 38.38
15.73 5.64 36.30
16.53 5.36 6.29
17.44 5.08 20.34
18.18 4.88 6.53
18.53 4.79 13.11
18.73 4.74 9.94
19.02 4.67 11.49
19.53 4.55 8.30
19.96 4.45 2.90
20.48 4.34 9.95
21.12 4.21 11.97
21.62 4.11 15.43
22.52 3.95 2.44
23.14 3.84 6.61
23.91 3.72 20.03
24.77 3.59 12.02
25.71 3.47 16.15
26.03 3.42 6.73
26.41 3.37 8.07
26.99 3.30 28.01
27.67 3.22 8.39
28.65 3.12 16.41
28.91 3.09 9.81
30.07 2.97 6.88
30.38 2.94 15.03
31.44 2.85 6.39
32.22 2.78 1.89
32.80 2.73 4.30
33.39 2.68 1.14
34.30 2.61 4.78
34.90 2.57 5.42
38.39 2.34 2.63
实施例6盐酸盐晶型CS1的制备方法
称取149.6mg的VX-787盐酸盐固体于5mL的玻璃瓶中，加入约1mL的醋酸溶剂，在室温下(约25℃)搅拌1天，离心，室温下真空干燥。经检测，本实施例得到的固体为晶型CS1，其X射线粉末衍射数据如图17，表3所示。
表3
2θ值 d间隔 强度％
6.66 13.28 100.00
7.06 1.51 66.67
7.54 11.72 28.12
7.83 11.29 4.43
9.72 9.10 17.9
10.64 8.32 30.64
12.09 7.32 4.90
12.57 7.04 5.62
13.37 6.62 26.59
14.28 6.20 25.71
14.65 6.05 49.57
15.74 5.63 30.45
16.51 5.37 3.42
17.15 5.17 22.26
17.47 5.08 18.88
18.09 4.90 9.42
18.45 4.81 28.53
18.73 4.74 12.40
19.04 4.66 12.30
19.46 4.56 9.93
20.51 4.33 9.38
21.06 4.22 17.31
21.42 4.15 9.11
21.67 4.10 8.96
21.94 4.05 6.25
22.64 3.93 3.15
23.13 3.85 8.17
23.60 3.77 16.12
23.88 3.73 33.15
24.65 3.61 25.85
25.32 3.52 10.73
25.63 3.48 20.02
25.97 3.43 6.13
26.32 3.39 11.29
26.90 3.31 32.36
27.61 3.23 9.20
27.98 3.19 8.69
28.56 3.13 14.24
29.97 2.98 7.47
30.31 2.95 23.75
30.67 2.92 10.95
31.17 2.87 2.44
31.48 2.84 2.88
32.10 2.79 3.13
32.82 2.73 4.96
33.72 2.66 3.71
34.19 2.62 9.14
34.93 2.57 6.22
35.41 2.53 1.74
实施例7盐酸盐晶型CS1的稳定性
将本发明制备得到的盐酸盐晶型CS1在25℃/60％相对湿度(RH)、40℃/75％相对湿度(RH)的条件下放置1个月，分别测定放置前后其XRPD，实验结果见表4。
表4
起始晶型 放置条件 放置时间 晶型变化
盐酸盐晶型CS1 25℃/60％RH 1个月 晶型保持不变
盐酸盐晶型CS1 40℃/75％RH 1个月 晶型保持不变
结果表明，晶型CS1在25℃/60％RH和40℃/75％RH条件下放置至少1个月，晶型保持不变，纯度基本保持不变，纯度均保持在98％以上。本发明所提供晶型CS1具有良好的稳定性。
实施例8盐酸盐晶型CS1的机械稳定性
取本发明的盐酸盐晶型CS1约10mg，置于玛瑙研钵中研磨约2min后，测试XRPD结果如图25所示，结果表明研磨前后盐酸盐晶型CS1晶型未发生变化。
实施例9盐酸盐晶型CS2的制备方法
称取99.7mg的VX-787固体于5mL的玻璃瓶中，加入约1.5mL的氯仿溶剂， 在室温下(约25℃)搅拌30分钟，再加入0.02mL浓度约为12mol/L的浓盐酸，继续在室温下搅拌12小时，离心，室温下真空干燥。经检测，本实施例得到的固体为盐酸盐晶型CS2，其X射线粉末衍射数据如图7，表5所示。
盐酸盐晶型CS2在8.32处有一个单重峰，对应于氯仿(CHCl 3)的氢化学位移，根据核磁数据，氯仿与式(I)化合物的摩尔比为0.75：1，其NMR如附图15所示。其数据如下：{ 1H NMR(400MHz,DMSO)δ8.77(s,1H),8.46(dd,J＝9.5,3.1Hz,2H),8.40(m,1H),8.32(s,0.75H),4.88(m,1H),2.98(d,J＝6.3Hz,1H),2.06(d,1H),1.97(d,1H),1.72(dd,J＝41.6,7.4Hz,4H),1.47(dd,J＝54.7,17.4Hz,4H),1.23(s,1H).}。
表5
2θ值 d间隔 强度％
6.36 13.90 30.63
8.02 11.02 57.90
9.45 9.36 8.50
10.72 8.26 8.65
13.05 6.79 6.96
15.11 5.86 41.67
15.65 5.66 34.01
16.15 5.49 60.14
16.95 5.23 86.59
17.41 5.10 19.79
17.89 4.96 34.10
18.75 4.73 26.63
19.22 4.62 29.22
19.91 4.46 8.36
20.74 4.28 35.37
21.10 4.21 38.89
21.61 4.11 18.53
22.25 4.00 94.29
24.05 3.70 37.37
24.59 3.62 24.42
24.95 3.57 100.00
25.94 3.43 83.09
26.33 3.38 19.56
26.84 3.32 23.69
29.19 3.06 55.34
30.17 2.96 25.13
31.37 2.85 18.64
31.67 2.83 25.95
33.59 2.67 26.86
34.26 2.62 8.68
34.88 2.57 7.90
35.55 2.53 7.31
37.38 2.41 11.90
38.42 2.34 3.56
该晶型的DSC如图8所示，其有两个吸热峰，在51℃附近开始出现第一个吸热峰，该吸热峰是在该温度附近失去氯仿( 1H NMR数据显示化合物中存在氯仿，如图15所示)所致；在196℃附近开始出现第二个吸热峰。
该晶型的TGA如附图9所示，将其加热至140℃时，具有约9.4％的质量损失，继续加热至230℃时，具有约16.7％的质量损失。据此推算，每摩尔VX-787盐酸盐晶型CS2含有约0.75摩尔的氯仿。
实施例10盐酸盐晶型CS3的制备方法
称取约10mg的VX-787盐酸盐晶型CS1，通过TGA进行加热，在氮气保护下，以10℃/分钟从室温(约为25℃)升高到150℃，然后在150℃下平衡10分钟，转移至室温环境。经检测，本实施例得到的固体为盐酸盐晶型CS3，其X射线粉末衍射数据如图1，表6所示。
表6
2θ值 d间隔 强度％
6.76 13.07 50.90
7.07 12.50 100.00
7.64 11.58 29.97
7.83 11.29 15.37
9.77 9.05 8.27
10.73 8.24 4.81
11.15 7.94 13.40
12.22 7.24 15.73
12.59 7.03 20.09
13.13 6.74 5.94
13.53 6.55 39.07
14.41 6.15 44.54
14.67 6.04 46.31
15.71 5.64 62.63
16.55 5.36 21.64
17.45 5.08 40.72
18.26 4.86 27.27
18.61 4.77 37.66
19.05 4.66 22.61
19.59 4.53 19.55
19.93 4.45 12.83
20.46 4.34 14.55
21.18 4.20 29.16
21.60 4.11 35.08
22.11 4.02 7.43
23.20 3.83 11.50
23.91 3.72 41.92
24.88 3.58 29.78
25.78 3.46 50.74
26.51 3.36 31.79
27.03 3.30 68.58
27.73 3.22 28.20
28.19 3.17 19.89
28.67 3.11 38.80
30.43 2.94 26.16
30.82 2.90 12.66
31.32 2.86 11.71
32.35 2.77 5.90
32.83 2.73 9.26
34.46 2.60 8.43
35.44 2.53 5.41
盐酸盐晶型CS3的 1H NMR如附图13所示。其数据如下：{ 1H NMR(400MHz,DMSO)δ8.75(s,1H),8.46(dd,J＝9.4,2.8Hz,2H),8.40(m,1H),4.87(m,1H),2.97(d,J＝6.7Hz,1H),2.09–2.02(m,1H),1.98(d,J＝8.6Hz,1H),1.91(s,0.17H),1.72(dd,J＝41.1,9.0Hz,4H),1.47(dd,J＝55.8,16.5Hz,4H),1.23(s,1H).}。
该晶型的DSC如图2所示，其中分别有一个吸热峰和一个放热峰，在54℃附近开始出现吸热峰，在200℃附近开始出现放热峰。
该晶型的TGA如附图3所示，将其加热至120℃时，具有约4.8％的质量损失梯度；继续加热至230℃时，具有约7.5％的质量损失。
实施例11盐酸盐晶型CS3和CN105849100A中的盐酸盐晶型A的动态溶解 度比较
精密称取本发明制备得到的盐酸盐的晶型CS3和CN105849100A中的盐酸盐晶型A原料各12mg，分别置于小瓶中，各加入1.2mL水进行混合。在旋转器 上以30转/分钟的速率旋转，并分别于1小时、4小时和24小时取样，在使用0.45μm聚四氟乙烯(PTFE)过滤器离心分离后，收集滤液进行HPLC分析。实验结果如下表7。
表7
Figure PCTCN2018074050-appb-000004
通过上述对比结果可以看出，在水中放置1个小时后，4个小时后和24个小时后，本发明的盐酸盐晶型CS3的溶解度均高于CN105849100A盐酸盐晶型A，高出6-51倍。
实施例12盐酸盐晶型CS3的稳定性
取本发明的盐酸盐晶型CS3三份样品敞口放置于25℃/60％相对湿度，40℃/75％相对湿度条件下1个月，60℃/75％相对湿度条件下2周，放置前后采用HPLC和XRPD法测定晶型与纯度的变化。实验结果如下表8。
表8
起始晶型 放置条件 放置时间 晶型变化
盐酸盐晶型CS3 25℃/60％RH 7个月 晶型保持不变
盐酸盐晶型CS3 40℃/75％RH 1个月 晶型保持不变
盐酸盐晶型CS3 60℃/75％RH 2周 晶型保持不变
结果表明，本发明的盐酸盐晶型CS3在25℃/60％RH条件下至少放置7个月，40℃/75％RH条件下至少放置1个月，60℃/75％RH条件下至少放置2周，晶型和纯度都没有发生改变，纯度均在98％以上。可见，盐酸盐晶型CS3稳定性好。
实施例13盐酸盐晶型CS4的制备方法
称取9.7mg的VX-787盐酸盐晶型CS3于1.5mL的玻璃瓶中，加入0.4mL体积比为3：：1的异丙醇和水的混合溶剂，在室温下(约25℃)搅拌30分钟，再加入10.5mg的VX-787盐酸盐晶型晶型A(CN105849100A)，继续在室温下搅拌1周，离心，室温下真空干燥。经检测，本实施例得到的固体为盐酸盐晶型CS4， 其X射线粉末衍射数据如图10，表9所示。
表9
2θ值 d间隔 强度％
4.73 18.69 22.98
5.67 15.60 6.74
8.04 10.99 100.00
8.73 10.13 5.00
9.71 9.11 2.70
10.21 8.66 1.05
11.57 7.65 7.25
12.19 7.26 5.52
12.70 6.97 5.64
13.87 6.39 4.69
14.65 6.05 4.46
16.39 5.41 6.27
17.14 5.17 5.69
18.33 4.84 5.73
19.05 4.66 5.03
20.57 4.32 8.49
21.40 4.15 5.32
22.68 3.92 3.21
24.27 3.67 4.28
25.87 3.44 7.31
26.32 3.39 10.66
27.15 3.28 5.80
28.00 3.19 6.62
29.55 3.02 3.87
30.70 2.91 3.13
33.29 2.69 3.30
34.69 2.59 1.40
35.42 2.53 1.38
盐酸盐晶型CS4的液态核磁氢谱中没有发现溶剂峰的存在，其 1H NMR如附图16所示。其数据如下：{ 1H NMR(400MHz,DMSO)δ8.75(s,1H),8.51–8.43(m,2H),8.40(m,1H),4.87(m,1H),2.97(d,J＝6.4Hz,1H),2.06(m,1H),1.97(m,1H),1.72(dd,J＝41.7,7.4Hz,4H),1.47(dd,J＝55.6,16.2Hz,4H),1.23(s,1H).}。结果表明盐酸盐晶型CS4中不存在除水以外的其他溶剂。
该晶型的DSC如图11所示，其中分别有一个吸热峰和一个放热峰，在48℃附近开始出现吸热峰，该吸热峰是在该温度附近失水所致；在186℃附近开始 出现放热峰。
该晶型的TGA如附图12所示，将其加热至120℃时，具有约9.6％的质量损失梯度；继续加热至230℃时，具有约4.8％的质量损失。
实施例14盐酸盐晶型CS4的制备方法
称取200mg的VX-787盐酸盐的固体于20mL的玻璃瓶中，加入约8mL体积比为3：1的异丙醇和水的混合溶剂中，在室温下(约25℃)搅拌5天，离心分离得到固体。经检测，本实施例得到的固体为晶型CS4，其X射线粉末衍射数据如图18，表10所示。
表10
2θ值 d间隔 强度％
4.76 18.56 13.64
8.03 11.01 100.00
8.17 10.82 62.73
8.69 10.18 3.62
10.26 8.62 3.85
11.66 7.59 3.98
12.29 7.20 3.47
12.69 6.98 6.02
12.80 6.92 4.64
13.85 6.40 4.42
14.68 6.03 1.78
15.48 5.72 0.54
16.38 5.41 4.14
17.17 5.16 2.26
17.84 4.97 1.77
19.04 4.66 2.38
20.55 4.32 4.20
21.53 4.13 3.13
22.78 3.90 0.94
24.33 3.66 2.63
25.08 3.55 1.27
25.89 3.44 1.92
27.01 3.30 0.65
28.13 3.17 2.31
29.64 3.01 1.68
30.75 2.91 1.54
31.84 2.81 1.01
33.30 2.69 1.01
35.54 2.53 0.32
实施例15盐酸盐晶型CS4稳定性
取本发明的盐酸盐晶型CS4三份样品敞口放置于25℃/60％相对湿度2周，40℃/75％相对湿度条件下放置1个月，60℃/75％相对湿度条件下放置2周，采用HPLC和XRPD法测定放置前后晶型与纯度的变化。实验结果如表11所示。
表11
起始晶型 放置条件 放置时间 晶型变化
盐酸盐晶型CS4 25℃/60％RH 2周 晶型保持不变
盐酸盐晶型CS4 40℃/75％RH 1个月 晶型保持不变
盐酸盐晶型CS4 60℃/75％RH 2周 晶型保持不变
结果表明，晶型CS4在25℃/60％RH条件下放置至少2周，40℃/75％RH条件下放置至少1个月，60℃/75％RH条件下放置至少2周，晶型保持不变，纯度基本保持不变，均高于98％。本发明所提供晶型CS4具有良好的稳定性。
实施例16盐酸盐晶型CS4的提纯效果
采用HPLC测定采用相同原料制备得到的CN105849100A盐酸盐晶型A与本发明盐酸盐晶型CS4，并计算产品纯度。
HPLC纯度测试结果显示，本发明盐酸盐晶型CS4具有显著的提纯效果。CN105849100A盐酸盐晶型A的纯度为97.91％，本发明盐酸盐晶型CS4的纯度为99.70％，本发明纯度高于CN105849100A盐酸盐晶型A的纯度。
实施例17盐酸盐晶型CS4和CN105849100A中的盐酸盐晶型A的动态溶解 度比较
将本发明的盐酸盐晶型CS4以及CN105849100A晶型A用纯水配制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。本发明的盐酸盐晶型CS4以及CN105849100A晶型A的溶解度数据如表12所示。
表12
Figure PCTCN2018074050-appb-000005
Figure PCTCN2018074050-appb-000006
通过上述对比结果可以看出，在水中放置1个小时后，4个小时后和24个小时后，本发明的盐酸盐晶型CS4的溶解度均高于CN105849100A盐酸盐晶型A，高出38～283倍。
实施例18式(I)化合物晶型CS9的制备方法
将308.3mg的VX-787固体加入20mL玻璃瓶，加入10mL体积比为1：3的甲醇和甲苯混合溶剂，室温下搅拌72小时，离心取固体，室温真空干燥即可得到。
本实施例得到的晶型的X射线粉末衍射数据如表13所示。其XRPD图如图19，其DSC图如图20，其TGA图如图21。
表13
2θ值 d间隔 相对强度％
5.37 16.44 28.12
7.68 11.50 100.00
8.59 10.29 86.39
9.56 9.25 33.86
10.32 8.57 22.49
11.25 7.86 12.22
12.62 7.02 33.81
13.01 6.80 28.67
13.81 6.41 15.99
14.32 6.19 22.48
15.13 5.85 15.47
16.39 5.41 96.82
17.09 5.19 56.02
18.43 4.81 43.41
18.84 4.71 35.25
19.74 4.50 39.15
20.19 4.40 36.34
21.28 4.17 16.60
23.04 3.86 20.36
24.04 3.70 11.10
25.32 3.52 17.74
31.93 2.80 5.66
实施例19式(I)化合物晶型CS3的制备方法
取29.0mg晶型CS9固体于1.5mL玻璃瓶中，加入1mL体积比为1：4的四氢呋喃和二氯甲烷的混合溶剂，50℃温度下搅拌72小时，离心取出固体，室温真空干燥即可得到。
本实施例得到的晶型的X射线粉末衍射数据如表14所示。所得样品经检测为晶型CS3，其XRPD图如图22，其DSC图如图23，其TGA图如图24。
表14
2θ值 d间隔 相对强度％
3.52 25.08 12.23
6.44 13.73 100.00
7.20 12.28 20.93
8.09 10.93 24.66
8.70 10.17 33.42
9.13 9.68 7.77
10.38 8.52 14.10
11.79 7.50 3.33
12.73 6.95 9.09
13.11 6.75 28.18
13.97 6.34 8.79
14.55 6.09 18.06
15.03 5.89 36.08
15.43 5.74 20.73
16.31 5.44 19.27
16.80 5.28 27.50
17.63 5.03 12.27
18.36 4.83 14.03
19.08 4.65 12.05
19.93 4.46 10.73
21.00 4.23 15.63
21.86 4.07 12.40
22.61 3.93 10.64
23.77 3.74 7.36
24.45 3.64 12.23
25.07 3.55 17.31
26.41 3.38 6.55
27.15 3.28 8.58
29.47 3.03 4.75
30.25 2.95 5.35
31.70 2.82 3.96
33.08 2.71 1.97
实施例20式(I)化合物晶型CS3的稳定性
取本发明的式(I)化合物晶型CS3两份样品(起始纯度为99.24％)分别敞口放置于25℃/60％相对湿度(RH)和40℃/75％相对湿度5个月，放置前后采用HPLC和XRPD法测定晶型与纯度的变化。实验结果如下表15。
表15
起始晶型 放置条件 放置时间 晶型变化 纯度变化
CS3 25℃/60％RH 5个月 晶型保持不变 99.28％
CS3 40℃/75％RH 5个月 晶型保持不变 99.26％
结果表明，本发明的式(I)化合物晶型CS3在25℃/60％RH和40℃/75％RH条件下放置5个月后，晶型和纯度都没有发生明显改变。说明本发明的式(I)化合物晶型CS3具有良好的稳定性。
实施例22式(I)化合物晶型CS3和CN105849100A游离形式晶型A的动态 溶解度对比
将本发明的式(I)化合物晶型CS3以及CN105849100A游离形式晶型A分别用pH＝5.0FeSSIF(进食状态下人工肠液)和pH＝6.5FaSSIF(空腹状态下人工肠液)配制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。溶解度结果如表16所示。
表16
Figure PCTCN2018074050-appb-000007
结果表明，在FaSSIF以及FeSSIF中放置1个小时后，4个小时后和24个小时后，本发明式(I)化合物晶型CS3的溶解度均高于CN105849100A游离形式晶型A，在FeSSIF中，高出4～11倍，在FaSSIF中，高出6～16倍。
上述实施例只为说明本发明的技术构思及特点，其目的在于让；熟悉此项 技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (20)

  1. 一种式(I)化合物的盐酸盐晶型，其特征在于，其X射线粉末衍射图在2θ值为7.1°±0.2°、27.0°±0.2°、15.7°±0.2°处具有特征峰。
    Figure PCTCN2018074050-appb-100001
  2. 根据权利要求1所述的盐酸盐晶型，其特征还在于，其X射线粉末衍射图在2θ值为25.8°±0.2°、14.7°±0.2°、23.9°±0.2°中的一处或两处或三处具有特征峰。
  3. 根据权利要求1或2所述的盐酸盐晶型，其特征还在于，其X射线粉末衍射图在2θ值为17.5°±0.2°、13.5°±0.2°、28.7°±0.2°中的一处或两处或三处具有特征峰。
  4. 根据权利要求1所述的盐酸盐的晶型，其特征在于，所述盐酸盐的晶型是盐酸盐水合物晶型CS3或盐酸盐醋酸溶剂合物晶型CS1。
  5. 一种权利要求4所述的盐酸盐水合物晶型CS3，其特征在于，其制备方法包含:将式(I)化合物盐酸盐晶型CS1放置在惰性气氛升温至100～200℃，并保持5～20分钟，转移至室温环境，所得固体即为盐酸盐晶型CS3。
  6. 一种权利要求4所述的盐酸盐醋酸溶剂合物晶型CS1，其特征在于，其制备方法包含：
    1)将式(I)化合物加入醋酸中，在5～30℃条件下搅拌10～100分钟，加入一定量的盐酸，再搅拌6～48小时，过滤干燥得到固体；所述式(I)化合物和盐酸的投料摩尔比为5/1～1/5；或
    2)将式(I)化合物盐酸盐加入醋酸中，在一定5～30℃条件下搅拌6～48小时，过滤干燥得到固体，所得固体为盐酸盐晶型CS1。
  7. 一种式(I)化合物的盐酸盐晶型CS4，其特征在于，其X射线粉末衍射图在2θ值为8.0°±0.2°、4.7°±0.2°、20.6°±0.2°、11.6°±0.2°处具有特征峰。
  8. 根据权利要求7所述的盐酸盐晶型，其特征还在于，其X射线粉末衍射图在2θ值为16.4°±0.2°、17.1°±0.2°、12.7°±0.2°中的一处或两处或三处具有特征峰。
  9. 一种权利要求7所述的盐酸盐晶型CS4，其特征在于，其制备方法包含：将式(I)化合物盐酸盐加入醇类和水的混合体系中，在5～30℃条件下搅拌1～7天，过滤干燥得到的固体即为盐酸盐晶型CS4；所述醇类与水的体积比介于19/1～1/19。
  10. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1所述的盐酸盐晶型、权利要求7所述的盐酸盐晶型CS4、或几种晶型的任意混合及药学上可接受的载体、稀释剂或赋形剂。
  11. 权利要求1所述的式(I)化合物的盐酸盐晶型、权利要求7所述的盐酸盐晶型CS4、或几种晶型的任意混合在生产用于制备病毒蛋白抑制剂药物制剂中的用途。
  12. 权利要求1所述的式(I)化合物的盐酸盐晶型、权利要求7所述的盐酸盐晶型CS4或几种晶型的任意混合在生产用于制备治疗甲型流感药物制剂中的用途。
  13. 一种式(I)化合物的晶型CS3，其特征在于，其X射线粉末衍射图在2θ值为6.4°±0.2°、15.0°±0.2°、8.7°±0.2°处具有特征峰。
  14. 根据权利要求13所述的晶型CS3，其特征还在于，其X射线粉末衍射图在2θ值为13.1°±0.2°、8.1°±0.2°中的一处或两处具有特征峰。
  15. 根据权利要求13所述的晶型CS3，其特征还在于，其X射线粉末衍射图在2θ值为7.2°±0.2°、16.3°±0.2°、10.4°±0.2°中的一处或两处或三处具有特征峰。
  16. 一种权利要求13所述的晶型CS3，其特征在于，其制备方法包含：将式(I)化合物的固体置于醚类和卤代烃类的混合溶剂中，在50℃温度下搅拌，分离取固体，干燥即可得到晶型CS3。
  17. 根据权利要求16所述的制备方法，其特征在于，所述醚类溶剂为四氢呋喃；所述卤代烃溶剂为二氯甲烷。
  18. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求13所述的晶型CS3及药学上可接受的载体、稀释剂或赋形剂。
  19. 权利要求13所述的晶型CS3在生产用于制备病毒蛋白抑制剂药物制剂中的用途。
  20. 权利要求13所述的晶型CS3在生产用于制备治疗甲型流感药物制剂中的用途。
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