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WO2024032751A1 - Crystal form of substituted 2-hydro-pyrazole derivative and method for preparing same - Google Patents

Crystal form of substituted 2-hydro-pyrazole derivative and method for preparing same Download PDF

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Publication number
WO2024032751A1
WO2024032751A1 PCT/CN2023/112459 CN2023112459W WO2024032751A1 WO 2024032751 A1 WO2024032751 A1 WO 2024032751A1 CN 2023112459 W CN2023112459 W CN 2023112459W WO 2024032751 A1 WO2024032751 A1 WO 2024032751A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
crystalline
present disclosure
crystal
Prior art date
Application number
PCT/CN2023/112459
Other languages
French (fr)
Chinese (zh)
Inventor
黄体聪
刘飞
朱善良
刘彦龙
蔡垚
石赟蓉
吴小磊
杨博源
董平
李晓娜
Original Assignee
正大天晴药业集团股份有限公司
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Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN202380056281.XA priority Critical patent/CN119731164A/en
Publication of WO2024032751A1 publication Critical patent/WO2024032751A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D401/14—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 three or more hetero rings

Definitions

  • the present disclosure relates to a crystal form of a substituted 2-hydro-pyrazole derivative and a preparation method thereof, and also includes the use of the crystal form in preparing drugs for treating breast cancer and other cancers.
  • CDKs cyclin-dependent kinases
  • cyclins combine to promote the progression of the cell cycle, the transcription of genetic information and the normal division and proliferation of cells.
  • CDK4/6 is a key regulator of the cell cycle and can trigger the transition of the cell cycle from the growth phase (G1 phase) to the DNA replication phase (S1 phase).
  • G1 phase growth phase
  • S1 phase DNA replication phase
  • Rb retinoblastoma protein
  • the tumor suppressor protein Rb Once the tumor suppressor protein Rb is phosphorylated, it can release its tightly bound transcription factor E2F in the unphosphorylated state. E2F activates further transcription to promote the cell cycle through the restriction point (R point) and progress from the G1 phase to the S phase. Entered the cell proliferation cycle. Therefore, inhibiting CDK4/6 so that it cannot form the Cyclin D-CDK4/6 complex can block the progression of the cell cycle from the G1 phase to the S phase, thereby achieving the purpose of inhibiting tumor proliferation.
  • ER+ estrogen receptor-positive breast cancer
  • overactivity of CDK4/6 a key downstream target of ER signaling, is very frequent.
  • Preclinical data indicate that dual inhibition of CDK4/6 and estrogen receptor (ER) signaling is synergistic and can inhibit the growth of G1-phase estrogen receptor-positive (ER+) breast cancer (BC) cells.
  • WO2018045993A1 discloses a crystal form of a substituted 2-hydro-pyrazole derivative, whose structure is shown as the compound of formula (I), and also discloses the B crystal form of the compound of formula (I)
  • the present disclosure provides crystallization of a compound of formula (I),
  • the crystallization of the compound of formula (I) described in the present disclosure may be in an unsolvated form or in a solvated form, such as a hydrate.
  • the present disclosure provides crystalline A of the compound of formula (I), whose X-ray powder diffraction pattern using Cu K ⁇ radiation includes 3, 4, 5, 6, 7, 8 selected from the following 2 ⁇ angles , 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 diffraction peaks: 6.92 ⁇ 0.20°, 10.47 ⁇ 0.20°, 11.41 ⁇ 0.20°, 13.36 ⁇ 0.20°, 13.87 ⁇ 0.20°, 15.53 ⁇ 0.20°, 16.22 ⁇ 0.20°, 17.25 ⁇ 0.20°, 18.21 ⁇ 0.20°, 19.02 ⁇ 0.20°, 20.87 ⁇ 0.20°, 21.10 ⁇ 0.20°, 23.52 ⁇ 0.20°, 24.09 ⁇ 0.20°, 25.24 ⁇ 0.20°, 26.21 ⁇ 0.20°, 26.61 ⁇ 0.20° and 27.91 ⁇ 0.20°.
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation, including 3, 4, 5, 6, 7, 8, 9, 10 or 11 diffraction peaks: 6.92 ⁇ 0.20°, 10.47 ⁇ 0.20°, 11.41 ⁇ 0.20°, 13.87 ⁇ 0.20°, 17.25 ⁇ 0.20°, 18.21 ⁇ 0.20°, 19.02 ⁇ 0.20°, 23.52 ⁇ 0.20°, 24.09 ⁇ 0.20°, 25.24 ⁇ 0.20° and 26.61 ⁇ 0.20°.
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation, including 3, 4, 5, 6, 7 or 8 diffraction peaks: 6.92 ⁇ 0.20°, 10.47 ⁇ 0.20°, 11.41 ⁇ 0.20°, 13.87 ⁇ 0.20°, 17.25 ⁇ 0.20°, 18.21 ⁇ 0.20°, 19.02 ⁇ 0.20° and 24.09 ⁇ 0.20°.
  • the present disclosure provides crystalline A of the compound of formula (I), whose X-ray powder diffraction pattern using Cu K ⁇ radiation has diffraction peaks at the following 2 ⁇ angles: 6.92 ⁇ 0.20°, 10.47 ⁇ 0.20°, and 11.41 ⁇ 0.20°. .
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation at the following 2 ⁇ angles: 6.92 ⁇ 0.20°, 10.47 ⁇ 0.20°, 11.41 ⁇ 0.20° and 19.02 ⁇ 0.20°.
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation at the following 2 ⁇ angles: 6.92 ⁇ 0.20°, 10.47 ⁇ 0.20°, 11.41 ⁇ 0.20°, 17.25 ⁇ 0.20°, 19.02 ⁇ 0.20° and 24.09 ⁇ 0.20°.
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation at the following 2 ⁇ angles: 6.92 ⁇ 0.20°, 10.47 ⁇ 0.20°, 11.41 ⁇ 0.20°, 13.87 ⁇ 0.20°, 17.25 ⁇ 0.20°, 18.21 ⁇ 0.20°, 19.02 ⁇ 0.20° and 24.09 ⁇ 0.20°.
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation at the following 2 ⁇ angles: 6.92 ⁇ 0.20°, 10.47 ⁇ 0.20°, 11.41 ⁇ 0.20°, 13.87 ⁇ 0.20°, 17.25 ⁇ 0.20°, 18.21 ⁇ 0.20°, 19.02 ⁇ 0.20°, 23.52 ⁇ 0.20°, 24.09 ⁇ 0.20°, 25.24 ⁇ 0.20° and 26.61 ⁇ 0.20°.
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation.
  • the spectrum has diffraction peaks at the following 2 ⁇ angles: 6.92 ⁇ 0.20°, 10.47 ⁇ 0.20°, 11.41 ⁇ 0.20°, 13.36 ⁇ 0.20°, 13.87 ⁇ 0.20°, 15.53 ⁇ 0.20°, 16.22 ⁇ 0.20°, 17.25 ⁇ 0.20°, 18.21 ⁇ 0.20°, 19.02 ⁇ 0.20°, 20.87 ⁇ 0.20°, 21.10 ⁇ 0.20°, 23.52 ⁇ 0.20°, 24.09 ⁇ 0.20°, 25.24 ⁇ 0.20°, 26.21 ⁇ 0.20°, 26.61 ⁇ 0.20° and 27.91 ⁇ 0.20°.
  • the XRPD pattern of crystalline A of the compound of formula (I) using CuK ⁇ radiation is shown in Figure 1 .
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation, including 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 diffraction peaks: 6.92 ⁇ 0.20°, 10.45 ⁇ 0.20°, 11.40 ⁇ 0.20°, 13.35 ⁇ 0.20°, 13.88 ⁇ 0.20 °, 15.52 ⁇ 0.20°, 16.21 ⁇ 0.20°, 17.24 ⁇ 0.20°, 18.18 ⁇ 0.20°, 19.01 ⁇ 0.20°, 20.77 ⁇ 0.20°, 21.09 ⁇ 0.20°, 23.63 ⁇ 0.20°, 24.07 ⁇ 0.20°, 25.19 ⁇ 0.20 °, 26.19 ⁇ 0.20°, 26.60 ⁇ 0.20° and 27.89 ⁇ 0.20°.
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation, including 3, 4, 5, 6, 7, 8, 9, 10 or 11 diffraction peaks: 6.92 ⁇ 0.20°, 10.45 ⁇ 0.20°, 11.40 ⁇ 0.20°, 13.88 ⁇ 0.20°, 17.24 ⁇ 0.20°, 18.18 ⁇ 0.20°, 19.01 ⁇ 0.20°, 23.63 ⁇ 0.20°, 24.07 ⁇ 0.20°, 25.19 ⁇ 0.20° and 26.60 ⁇ 0.20°.
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation, including 3, 4, 5, 6, 7 or 8 diffraction peaks: 6.92 ⁇ 0.20°, 10.45 ⁇ 0.20°, 11.40 ⁇ 0.20°, 13.88 ⁇ 0.20°, 17.24 ⁇ 0.20°, 18.18 ⁇ 0.20°, 19.01 ⁇ 0.20° and 24.07 ⁇ 0.20°.
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation at the following 2 ⁇ angles: 6.92 ⁇ 0.20°, 10.45 ⁇ 0.20° and 11.40 ⁇ 0.20°.
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation at the following 2 ⁇ angles: 6.92 ⁇ 0.20°, 10.45 ⁇ 0.20°, 11.40 ⁇ 0.20° and 19.01 ⁇ 0.20°.
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation at the following 2 ⁇ angles: 6.92 ⁇ 0.20°, 10.45 ⁇ 0.20°, 11.40 ⁇ 0.20°, 17.24 ⁇ 0.20°, 19.01 ⁇ 0.20° and 24.07 ⁇ 0.20°.
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation at the following 2 ⁇ angles: 6.92 ⁇ 0.20°, 10.45 ⁇ 0.20°, 11.40 ⁇ 0.20°, 13.88 ⁇ 0.20°, 17.24 ⁇ 0.20°, 18.18 ⁇ 0.20°, 19.01 ⁇ 0.20° and 24.07 ⁇ 0.20°.
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation at the following 2 ⁇ angles: 6.92 ⁇ 0.20°, 10.45 ⁇ 0.20°, 11.40 ⁇ 0.20°, 13.88 ⁇ 0.20°, 17.24 ⁇ 0.20°, 18.18 ⁇ 0.20°, 19.01 ⁇ 0.20°, 23.63 ⁇ 0.20°, 24.07 ⁇ 0.20°, 25.19 ⁇ 0.20° and 26.60 ⁇ 0.20°.
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation at the following 2 ⁇ angles: 6.92 ⁇ 0.20°, 10.45 ⁇ 0.20°, 11.40 ⁇ 0.20°, 13.35 ⁇ 0.20°, 13.88 ⁇ 0.20°, 15.52 ⁇ 0.20°, 16.21 ⁇ 0.20°, 17.24 ⁇ 0.20°, 18.18 ⁇ 0.20°, 19.01 ⁇ 0.20°, 20.77 ⁇ 0.20°, 21.09 ⁇ 0.20°, 23.63 ⁇ 0.20°, 24.07 ⁇ 0.20°, 25.19 ⁇ 0.20°, 26.19 ⁇ 0.20°, 26.60 ⁇ 0.20° and 27.89 ⁇ 0.20°.
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation at the following 2 ⁇ angles: 6.92 ⁇ 0.20°, 9.09 ⁇ 0.20°, 10.45 ⁇ 0.20°, 11.40 ⁇ 0.20°, 13.35 ⁇ 0.20°, 13.88 ⁇ 0.20°, 14.78 ⁇ 0.20°, 15.52 ⁇ 0.20°, 16.00 ⁇ 0.20°, 16.21 ⁇ 0.20°, 17.24 ⁇ 0.20°, 18.18 ⁇ 0.20°, 19.01 ⁇ 0.20°, 19.66 ⁇ 0.20°, 20.77 ⁇ 0.20°, 21.09 ⁇ 0.20°, 21.55 ⁇ 0.20°, 22.22 ⁇ 0.20°, 22.55 ⁇ 0.20°, 23.63 ⁇ 0.20°, 24.07 ⁇ 0.20°, 25.19 ⁇ 0.20°, 26.19 ⁇ 0.20°, 26.60 ⁇ 0.20°, 27.21 ⁇ 0.20°, 27.89 ⁇ 0.20°, 28.74 ⁇ 0.20°, 29.55 ⁇ 0.20°,
  • the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu K ⁇ radiation at the following 2 ⁇ angles: 6.92, 9.09, 10.45, 11.40, 13.35, 13.88, 14.78, 15.52, 16.00, 16.21, 17.24, 18.18, 19.01, 19.66, 20.77, 21.09, 21.55, 22.22, 22.55, 23.63, 24.07, 25.19, 26.19, 26.60, 27.21, 27. 89, 28.74, 29.55, 29.88, 30.38, 31.36 and 31.85.
  • the XRPD spectrum analysis data of crystalline A of the compound of formula (I) using Cu K ⁇ radiation is as shown in Table 1.
  • the differential scanning calorimetry curve of crystalline A of the compound of formula (I) has endothermic peaks at 213.2 ⁇ 5.0°C and 228.5 ⁇ 5.0°C, respectively.
  • the DSC pattern of crystalline A of the compound of formula (I) is as shown in Figure 3.
  • the present disclosure also provides a method for preparing crystal A of the compound of formula (I), including the step of precipitating the compound of formula (I) from an organic solvent.
  • the method for preparing crystal A of the compound of formula (I) is selected from a mixed solvent of methanol and dichloromethane.
  • the volume ratio of methanol and dichloromethane is 1:5.
  • the preparation method of crystal A of the compound of formula (I) includes: (a) stirring the compound of formula (I), ethanol, water and hydrochloric acid together; (b) adding sodium hydroxide The aqueous solution is heated and stirred for a period of time, then lowered to room temperature and filtered to obtain crystal A of the compound of formula (I).
  • the temperature increase in step (b) is to increase the temperature to 70-80°C.
  • the starting compound of formula (I) in the preparation method of crystal A of the compound of formula (I), can be in any form, such as crystal, amorphous, hydrate, solvate, crude product, etc.
  • the present disclosure also provides a crystalline composition comprising crystalline A of the compound of formula (I), wherein the crystalline A of the compound of formula (I) accounts for more than 50% by weight of the crystalline composition, preferably more than 75%, more preferably More than 90%, preferably more than 95%.
  • the crystalline A of the compound of formula (I) accounts for more than 96%, or more than 97% by weight of the crystalline composition. , or more than 98%, or more than 99%.
  • Each of the crystalline compositions may also contain small amounts of other crystalline or non-crystalline forms of the compound of formula (I).
  • the remainder of the crystalline composition except Crystalline A of the compound of Formula (I) is the compound of Formula (I) Amorphous Form A.
  • the content of the compound of Formula (I) in the crystalline composition may be more than 95%, or 99% % or more, or 99.9% or more, or 99.99% or more.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of crystalline A of the compound of formula (I), or a crystalline composition thereof; the pharmaceutical composition may comprise at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the present application may further comprise a one or more other therapeutic agents.
  • the pharmaceutical composition comprising Crystalline A of a compound of Formula (I) is a solid pharmaceutical composition.
  • the excipients in the solid pharmaceutical composition comprising Crystalline A of the compound of Formula (I) include at least one of a diluent, a binder, a disintegrant and a lubricant.
  • the excipients in the solid pharmaceutical composition comprising Crystalline A of the compound of Formula (I) include at least one of a filler, a glidant and a lubricant.
  • excipients in the solid pharmaceutical composition comprising Crystalline A of the compound of Formula (I) include fillers, glidants and lubricants.
  • the filler is selected from starch, pregelatinized starch, sucrose, lactose (eg, lactose monohydrate), fructose, maltose, trehalose, pullulan, polydextrose, paste Essence, maltodextrin, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cellulose acetate, ethyl cellulose, mannitol, sorbitol, erythritol, isomalt, lactitol, maltitol, polyethylene glycol Diol, xylitol, sorbitol, calcium carbonate, calcium phosphate, anhydrous calcium hydrogen phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate, sodium chloride or any two or more of them A mixture; preferably, the filler is selected from mannitol, microcrystalline cellulose, pregelatinized starch, low-substituted hydroxypropyl
  • the glidant is selected from silica, colloidal silica, magnesium trisilicate, starch, powdered cellulose, micronized silica gel or talc, or any two thereof and The above mixture; preferably, the glidant is selected from silica, colloidal silica, micronized silica gel or talc powder; further preferably, the glidant is selected from colloidal silica or talc powder; In a specific embodiment of the present application, the glidant is selected from colloidal silica.
  • the lubricant is selected from the group consisting of stearic acid, calcium stearate, sodium stearate, zinc stearate, magnesium stearate, glyceryl monostearate, glyceryl behenate Ester, glyceryl dibehenate, glyceryl tribehenate, palmitoylstearoylglyceride, leucine, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, Sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate or talc; preferably, the lubricant is selected from magnesium stearate, glyceryl behenate, sodium lauryl sulfate or stearyl fumarate. Sodium Malate; In a specific embodiment of the present application, the lubricant is selected from magnesium stearate.
  • the crystalline A of the compound of formula (I) accounts for 10 to 90 wt% of the total weight of the solid pharmaceutical composition; preferably 20 to 85 wt%, 25 to 80 wt%, 25 to 75 wt%, 30 to 75wt%, 40 ⁇ 75wt%, 45 ⁇ 75wt%, 45 ⁇ 65wt%, 45 ⁇ 55wt% or 50-55wt%; more preferably 50wt%, 51wt%, 52wt%, 53wt%, 54wt% or 55wt%.
  • the crystalline A of the compound of formula (I) accounts for 50 wt% of the total weight of the solid pharmaceutical composition.
  • the filler accounts for 10-98wt% of the total weight of the solid pharmaceutical composition; preferably 20-98wt%, 25-80wt%, 25-75wt%, 30-75wt%, 40-75wt %, 45-75wt%, 45-65wt%, 45-55wt% or 45-50wt%; more preferably 45wt%, 45.5wt%, 46wt%, 46.5wt%, 46wt%, 47.5wt%, 48wt%, 48.5wt %, 49wt%, 49.5wt% or 50wt%.
  • the filler is selected from a mixture of mannitol and anhydrous calcium hydrogen phosphate, and the weight ratio of the mannitol and anhydrous calcium hydrogen phosphate is 1:0.5 ⁇ 2; preferably 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1: 1.8, 1:1.9 or 1:2.0.
  • the filler is selected from a mixture of mannitol and anhydrous calcium hydrogen phosphate, and the mannitol and anhydrous calcium hydrogen phosphate account for 47.5 wt% of the total weight of the solid pharmaceutical composition.
  • the weight ratio of alcohol and anhydrous calcium hydrogen phosphate is 1:1.0.
  • the glidant accounts for 0.5 to 5wt% of the total weight of the solid pharmaceutical composition; preferably 0.8wt%, 1.0wt%, 1.2wt%, 1.5wt%, 2.0wt%, 2.2wt %, 2.5wt%, 2.8wt%, 3.0wt%, 3.2wt%, 3.5wt%, 3.8wt%, 4.0wt%, 4.2wt%, 4.5wt% or 4.8wt%; in a specific embodiment of the present disclosure , the glidant accounts for 1.0 wt% of the total weight of the solid pharmaceutical composition.
  • the lubricant accounts for 0.5 to 5wt% of the total weight of the solid pharmaceutical composition; preferably 0.8wt%, 1.0wt%, 1.2wt%, 1.5wt%, 2.0wt%, 2.2wt% , 2.5wt%, 2.8wt%, 3.0wt%, 3.2wt%, 3.5wt%, 3.8wt%, 4.0wt%, 4.2wt%, 4.5wt% or 4.8wt%; in a specific embodiment of the present disclosure , the lubricant accounts for 1.5wt% of the total weight of the solid pharmaceutical composition.
  • a solid pharmaceutical composition of crystalline A of the compound of formula (I) comprises: crystalline A of the compound of formula (I); mannitol and anhydrous calcium hydrogen phosphate; colloidal silicon dioxide; magnesium stearate .
  • the solid pharmaceutical composition of crystalline A of the compound of formula (I) includes: 10 to 90 wt% of crystalline A of the compound of formula (I); 10 to 98 wt% of mannitol and anhydrous calcium hydrogen phosphate ; 0.5-5wt% colloidal silica; 0.5-5wt% magnesium stearate.
  • the solid pharmaceutical composition of crystalline A of the compound of formula (I) includes: 50 to 55 wt% of crystalline A of the compound of formula (I); 45 to 50 wt% of mannitol and anhydrous calcium hydrogen phosphate ; 1.0wt% colloidal silica; 1.2wt% magnesium stearate.
  • crystalline A of the compound of formula (I) is used as the active ingredient, mannitol and anhydrous calcium hydrogen phosphate are used as fillers, and colloidal silicon dioxide As glidant, magnesium stearate acts as lubricant.
  • a solid pharmaceutical composition of crystalline A of the compound of formula (I) comprises: crystalline A of the compound of formula (I); microcrystalline cellulose and lactose monohydrate; colloidal silicon dioxide; stearic acid magnesium.
  • the crystalline A of the compound of formula (I) serves as the active ingredient, microcrystalline cellulose and lactose monohydrate as fillers, colloidal silica as glidant, and magnesium stearate as lubricant.
  • the solid pharmaceutical composition of the present disclosure can be formed into a variety of preparation forms suitable for oral administration to humans, including, for example, tablets, pills, capsules, powders or granules, and the like.
  • the solid pharmaceutical composition is in the form of a capsule.
  • the solid pharmaceutical composition preparation form of crystalline A of the compound of formula (I) is a capsule, and the capsule shell of the capsule is selected from the group consisting of plant capsule shells or gelatin capsule shells.
  • the plant capsule shell Selected from hypromellose hollow capsules.
  • the solid pharmaceutical composition formulation of Crystalline A of the compound of Formula (I) is a capsule containing 50 mg of Crystalline A of the compound of Formula (I) per unit.
  • the formulation is a capsule containing 60 mg of Crystalline A of a compound of Formula (I) per unit.
  • the solid pharmaceutical composition of the crystal A of the compound of formula (I) per unit preparation includes 50 mg of crystal A of the compound of formula (I), 23.75 mg of mannitol, and 23.75 mg of anhydrous calcium hydrogen phosphate. mg, colloidal silica 1mg, magnesium stearate 1.5mg.
  • the solid pharmaceutical composition of the crystalline A of the compound of formula (I) per unit preparation includes 60 mg of crystalline A of the compound of formula (I), 28.5 mg of mannitol, and 28.5 mg of anhydrous calcium hydrogen phosphate. mg, colloidal silica 1.2mg, magnesium stearate 1.8mg.
  • the present disclosure provides crystal A of the compound of formula (I), a crystal composition of crystal A of the compound of formula (I), or a solid pharmaceutical composition of crystal A of the compound of formula (I) prepared for use in the treatment of Or use in drugs to prevent diseases related to selective CDK4/6 inhibition, including breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer and acute myeloid leukemia cancer.
  • the present disclosure provides crystal A of the compound of formula (I), a crystal composition of crystal A of the compound of formula (I), or a solid pharmaceutical composition of crystal A of the compound of formula (I) for treatment or prevention.
  • diseases related to selective CDK4/6 inhibition including breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer and acute myeloid leukemia cancer.
  • the present disclosure provides a method for treating or preventing diseases related to selective CDK4/6 inhibition, which comprises administering to a mammal in need thereof a therapeutically effective amount of Crystal A, Formula (I) of the compound of Formula (I) A crystalline composition of crystalline A of the compound or a solid pharmaceutical composition of crystalline A of the compound of formula (I),
  • the selective CDK4/6 inhibition-related diseases include breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer and Acute myeloid leukemia cancer.
  • the present disclosure provides crystal A of the compound of formula (I), a crystal composition of crystal A of the compound of formula (I), or said formula (I) for treating or preventing diseases related to selective CDK4/6 inhibition.
  • a solid pharmaceutical composition of a crystalline compound A, said selective CDK4/6 inhibition-related diseases include breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer and acute myeloid leukemia cancer.
  • the mammal is a human.
  • the present disclosure provides a method for preparing a solid pharmaceutical composition of crystalline A of the compound of formula (I), comprising the following steps:
  • the filler in the preparation method of the solid pharmaceutical composition of crystalline A of the compound of formula (I), is as described above, for example, the filler is mannitol and anhydrous calcium hydrogen phosphate. mixture, or a mixture of microcrystalline cellulose and lactose monohydrate.
  • the glidant in the preparation method of the solid pharmaceutical composition of crystalline A of the compound of formula (I), is as described above, for example, the glidant is colloidal silica.
  • the internal lubricant and the external lubricant in the preparation method of the solid pharmaceutical composition of crystalline A of the compound of formula (I) are the same, and the lubricant is as described above, such as The lubricant is magnesium stearate.
  • the X-ray powder diffraction spectra of the samples were measured under the following conditions: Instrument: Bruker D8advance X-ray diffractometer.
  • the position of the peak or the relative intensity of the peak may vary due to factors such as the measuring instrument and the measuring method/conditions.
  • the position of the peaks there may be errors in the position of the peaks, and the error in determining the 2 ⁇ value is ⁇ 0.2. Therefore, this error should be taken into account when determining each crystallization, and it is within the scope of this application.
  • the position of the endothermic peak of DSC may differ due to factors such as measuring instruments, measuring methods/conditions, etc.
  • there may be an error in the position of the endothermic peak which may be ⁇ 5°C. Therefore, this error should be taken into account when determining each crystallization, and it is within the scope of this application.
  • Crystalline A of the compound of formula (I) disclosed in the present disclosure has good solubility, shows good stability under conditions such as high humidity, high temperature, light, jet pulverization and high-pressure grinding, and also shows good stability under long-term test conditions. sex. Crystalline A of the compound of formula (I) and its pharmaceutical composition disclosed in the present disclosure have excellent performance in pharmaceutical activity, pharmacokinetics, bioavailability, hygroscopicity, stability, melting point, solubility, preparation dissolution, excipient compatibility, It has advantages in purity and ease of preparation to meet the needs of drug production, storage, transportation and preparation. For example, crystal A of the compound of formula (I) has better water solubility than crystal B of the compound of formula (I), shows better dissolution in preparation, and also shows better pharmacokinetics. Dynamic properties.
  • mammals include humans and domestic animals, such as laboratory mammals and household pets (such as cats, dogs, pigs, sheep, cattle, sheep, goats, horses, rabbits), and non-domesticated mammals, such as wild mammals.
  • composition refers to the formulation of a compound of the present disclosure with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal, such as a human. Such media include all pharmaceutically acceptable carriers for their use. Pharmaceutical compositions facilitate the administration of compounds to an organism.
  • terapéuticaally effective amount refers to a non-toxic amount of a drug or agent sufficient to achieve the desired effect.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • treating means administering a compound or formulation of the present disclosure to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means the administration of a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with said disease, and includes: preventing a disease or disease state from occurring in a mammal, particularly when Such mammals are susceptible to the disease state but have not yet been diagnosed as having the disease state.
  • pharmaceutically acceptable carriers refer to those carriers that are administered together with the active ingredients, have no obvious irritating effect on the organism, and do not impair the biological activity and performance of the active compound.
  • pharmaceutically acceptable carriers refer to those carriers that are administered together with the active ingredients, have no obvious irritating effect on the organism, and do not impair the biological activity and performance of the active compound.
  • Remington The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • each parameter value (including 2 ⁇ value, reaction condition) is deemed to be modified by the term "about" to reflect the measurement error of each value, such as ⁇ relative to a given value. 5% error.
  • Figures 1 and 2 are XRPD spectra of crystal A of the compound of formula (I).
  • Figure 3 is the DSC spectrum of crystal A of the compound of formula (I).
  • Figure 4 is a comparison chart of the dissolution rates of crystal A capsules of compound of formula (I) and crystal B capsules of compound of formula (I).
  • SD rats weighing 180-220g, were randomly divided into 2 groups after adapting for 3-5 days, with 4 rats in each group.
  • Compound A of formula I and crystal form B of compound of formula I were administered by gavage at a dose of 12 mg/kg.
  • the rats were fasted for 12 hours before administration and were given food 4 hours after administration. They had free access to water before, before, and during the experiment.
  • the collection time points after administration are 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 24h, 30h, and 48h.
  • About 0.3mL of blood was collected from the orbital venous plexus and placed in centrifuge tubes containing EDTA-K2. Store at 4°C, centrifuge at 4°C, 4000rpm, 10min within 1 hour, and store at -20°C for testing.
  • LC-MS/MS Liquid chromatography-tandem mass spectrometry

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Abstract

The present disclosure relates to a crystal form of a substituted 2-hydro-pyrazole derivative (I) and a method for preparing same, and further comprises use of the crystal form in preparing drugs for treating breast cancer and other cancers.

Description

一种取代的2-氢-吡唑衍生物的晶型及其制备方法Crystal form of a substituted 2-hydro-pyrazole derivative and preparation method thereof

相关申请的交叉引用Cross-references to related applications

本公开要求于2022年08月12日向中华人民共和国国家知识产权局提交的第202210971553.6号中国发明专利申请的权益和优先权，在此将其全部内容以援引的方式整体并入本文中。This disclosure claims the rights and priority of Chinese invention patent application No. 202210971553.6 submitted to the State Intellectual Property Office of the People's Republic of China on August 12, 2022, the entire content of which is hereby incorporated by reference in its entirety.

技术领域Technical field

本公开涉及一种取代的2-氢-吡唑衍生物的晶型及其制备方法，还包括所述晶型在制备治疗乳腺癌与其他癌症药物中的应用。The present disclosure relates to a crystal form of a substituted 2-hydro-pyrazole derivative and a preparation method thereof, and also includes the use of the crystal form in preparing drugs for treating breast cancer and other cancers.

背景技术Background technique

细胞周期的调控主要受一系列丝氨酸/苏氨酸激酶的影响，这类丝氨酸/苏氨酸激酶又被称作细胞周期蛋白依赖性激酶(CDK)，他们通过与其相对应的调节亚基周期素(cyclins)相结合，推动细胞周期的进行、遗传信息的转录和细胞的正常分裂增殖。CDK4/6是细胞周期的关键调节因子，能够触发细胞周期从生长期(G1期)向DNA复制期(S1期)转变。在细胞增殖过程中，细胞周期素D(Cyclin D)与CDK4/6形成的复合物能够磷酸化视网膜母细胞瘤蛋白(Rb)。肿瘤抑制蛋白Rb一旦发生磷酸化，可释放其在未被磷酸化的状态下紧密结合的转录因子E2F，E2F激活进一步转录推动细胞周期通过限制点(R点)并从G1期进展到S期，进入了细胞增殖的周期。因此，抑制CDK4/6使之无法形成Cyclin D-CDK4/6复合物，就能够阻滞细胞周期自G1期向S期的进程，从而达到抑制肿瘤增殖的目的。在雌激素受体阳性(ER+)乳腺癌(BC)中，CDK4/6的过度活跃非常频繁，而CDK4/6是ER信号的关键下游靶标。临床前数据表明，CDK4/6和雌激素受体(ER)信号双重抑制具有协同作用，并能够抑制G1期雌激素受体阳性(ER+)乳腺癌(BC)细胞的生长。The regulation of the cell cycle is mainly affected by a series of serine/threonine kinases. These serine/threonine kinases are also called cyclin-dependent kinases (CDKs). They regulate the cell cycle through the corresponding regulatory subunit cyclin. (cyclins) combine to promote the progression of the cell cycle, the transcription of genetic information and the normal division and proliferation of cells. CDK4/6 is a key regulator of the cell cycle and can trigger the transition of the cell cycle from the growth phase (G1 phase) to the DNA replication phase (S1 phase). During cell proliferation, the complex formed by cyclin D and CDK4/6 can phosphorylate retinoblastoma protein (Rb). Once the tumor suppressor protein Rb is phosphorylated, it can release its tightly bound transcription factor E2F in the unphosphorylated state. E2F activates further transcription to promote the cell cycle through the restriction point (R point) and progress from the G1 phase to the S phase. Entered the cell proliferation cycle. Therefore, inhibiting CDK4/6 so that it cannot form the Cyclin D-CDK4/6 complex can block the progression of the cell cycle from the G1 phase to the S phase, thereby achieving the purpose of inhibiting tumor proliferation. In estrogen receptor-positive (ER+) breast cancer (BC), overactivity of CDK4/6, a key downstream target of ER signaling, is very frequent. Preclinical data indicate that dual inhibition of CDK4/6 and estrogen receptor (ER) signaling is synergistic and can inhibit the growth of G1-phase estrogen receptor-positive (ER+) breast cancer (BC) cells.

WO2018045993A1公开了一种取代的2-氢-吡唑衍生物的晶型，其结构如式(I)化合物所示，并公开了式(I)化合物的B晶型
WO2018045993A1 discloses a crystal form of a substituted 2-hydro-pyrazole derivative, whose structure is shown as the compound of formula (I), and also discloses the B crystal form of the compound of formula (I)

发明内容Contents of the invention

一方面，本公开提供式(I)化合物的结晶，
In one aspect, the present disclosure provides crystallization of a compound of formula (I),

本公开所述式(I)化合物的结晶可以是非溶剂合物形式，也可以是溶剂合物形式，例如水合物。The crystallization of the compound of formula (I) described in the present disclosure may be in an unsolvated form or in a solvated form, such as a hydrate.

另一方面，本公开提供了式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱中，包含选自下述2θ角处的3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个衍射峰：6.92±0.20°、10.47±0.20°、11.41±0.20°、13.36±0.20°、13.87±0.20°、15.53±0.20°、16.22±0.20°、17.25±0.20°、18.21±0.20°、19.02±0.20°、20.87±0.20°、21.10±0.20°、23.52±0.20°、24.09±0.20°、25.24±0.20°、26.21±0.20°、26.61±0.20°和27.91±0.20°。On the other hand, the present disclosure provides crystalline A of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation includes 3, 4, 5, 6, 7, 8 selected from the following 2θ angles , 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 diffraction peaks: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 13.36±0.20°, 13.87±0.20°, 15.53 ±0.20°, 16.22±0.20°, 17.25±0.20°, 18.21±0.20°, 19.02±0.20°, 20.87±0.20°, 21.10±0.20°, 23.52±0.20°, 24.09±0.20°, 25.24±0.20°, 26.21 ±0.20°, 26.61±0.20° and 27.91±0.20°.

在本公开的一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱中，包含选自下述2θ角处的3、4、5、6、7、8、9、10或11个衍射峰：6.92±0.20°、10.47±0.20°、11.41±0.20°、13.87±0.20°、17.25±0.20°、18.21±0.20°、19.02±0.20°、23.52±0.20°、24.09±0.20°、25.24±0.20°和26.61±0.20°。In some embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation, including 3, 4, 5, 6, 7, 8, 9, 10 or 11 diffraction peaks: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 13.87±0.20°, 17.25±0.20°, 18.21±0.20°, 19.02±0.20°, 23.52± 0.20°, 24.09±0.20°, 25.24±0.20° and 26.61±0.20°.

在本公开的一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱中，包含选自下述2θ角处的3、4、5、6、7或8个衍射峰：6.92±0.20°、10.47±0.20°、11.41±0.20°、13.87±0.20°、17.25±0.20°、18.21±0.20°、19.02±0.20°和24.09±0.20°。In some embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation, including 3, 4, 5, 6, 7 or 8 diffraction peaks: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 13.87±0.20°, 17.25±0.20°, 18.21±0.20°, 19.02±0.20° and 24.09±0.20°.

另一方面，本公开提供式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92±0.20°、10.47±0.20°和11.41±0.20°。In another aspect, the present disclosure provides crystalline A of the compound of formula (I), whose X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, and 11.41±0.20°. .

在本公开的一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92±0.20°、10.47±0.20°、11.41±0.20°和19.02±0.20°。In some embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, 11.41±0.20° and 19.02±0.20°.

在本公开的一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92±0.20°、10.47±0.20°、11.41±0.20°、17.25±0.20°、19.02±0.20°和24.09±0.20°。In some embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 17.25±0.20°, 19.02±0.20° and 24.09±0.20°.

在本公开的一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92±0.20°、10.47±0.20°、11.41±0.20°、13.87±0.20°、17.25±0.20°、18.21±0.20°、19.02±0.20°和24.09±0.20°。In some embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 13.87±0.20°, 17.25±0.20°, 18.21±0.20°, 19.02±0.20° and 24.09±0.20°.

在本公开的一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92±0.20°、10.47±0.20°、11.41±0.20°、13.87±0.20°、17.25±0.20°、18.21±0.20°、19.02±0.20°、23.52±0.20°、24.09±0.20°、25.24±0.20°和26.61±0.20°。In some embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 13.87±0.20°, 17.25±0.20°, 18.21±0.20°, 19.02±0.20°, 23.52±0.20°, 24.09±0.20°, 25.24±0.20° and 26.61±0.20°.

在本公开的一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图 谱在下列2θ角处具有衍射峰：6.92±0.20°、10.47±0.20°、11.41±0.20°、13.36±0.20°、13.87±0.20°、15.53±0.20°、16.22±0.20°、17.25±0.20°、18.21±0.20°、19.02±0.20°、20.87±0.20°、21.10±0.20°、23.52±0.20°、24.09±0.20°、25.24±0.20°、26.21±0.20°、26.61±0.20°和27.91±0.20°。In some embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation. The spectrum has diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 13.36±0.20°, 13.87±0.20°, 15.53±0.20°, 16.22±0.20°, 17.25±0.20°, 18.21±0.20°, 19.02±0.20°, 20.87±0.20°, 21.10±0.20°, 23.52±0.20°, 24.09±0.20°, 25.24±0.20°, 26.21±0.20°, 26.61±0.20° and 27.91±0.20°.

在本公开的一些实施方案中，所述式(I)化合物的结晶A，其使用CuKα辐射的XRPD图谱如图1所示。In some embodiments of the present disclosure, the XRPD pattern of crystalline A of the compound of formula (I) using CuKα radiation is shown in Figure 1 .

在本公开另一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱中，包含选自下述2θ角处的3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个衍射峰：6.92±0.20°、10.45±0.20°、11.40±0.20°、13.35±0.20°、13.88±0.20°、15.52±0.20°、16.21±0.20°、17.24±0.20°、18.18±0.20°、19.01±0.20°、20.77±0.20°、21.09±0.20°、23.63±0.20°、24.07±0.20°、25.19±0.20°、26.19±0.20°、26.60±0.20°和27.89±0.20°。In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation, including 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 diffraction peaks: 6.92±0.20°, 10.45±0.20°, 11.40±0.20°, 13.35±0.20°, 13.88±0.20 °, 15.52±0.20°, 16.21±0.20°, 17.24±0.20°, 18.18±0.20°, 19.01±0.20°, 20.77±0.20°, 21.09±0.20°, 23.63±0.20°, 24.07±0.20°, 25.19±0.20 °, 26.19±0.20°, 26.60±0.20° and 27.89±0.20°.

在本公开另一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱中，包含选自下述2θ角处的3、4、5、6、7、8、9、10或11个衍射峰：6.92±0.20°、10.45±0.20°、11.40±0.20°、13.88±0.20°、17.24±0.20°、18.18±0.20°、19.01±0.20°、23.63±0.20°、24.07±0.20°、25.19±0.20°和26.60±0.20°。In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation, including 3, 4, 5, 6, 7, 8, 9, 10 or 11 diffraction peaks: 6.92±0.20°, 10.45±0.20°, 11.40±0.20°, 13.88±0.20°, 17.24±0.20°, 18.18±0.20°, 19.01±0.20°, 23.63± 0.20°, 24.07±0.20°, 25.19±0.20° and 26.60±0.20°.

在本公开另一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱中，包含选自下述2θ角处的3、4、5、6、7或8个衍射峰：6.92±0.20°、10.45±0.20°、11.40±0.20°、13.88±0.20°、17.24±0.20°、18.18±0.20°、19.01±0.20°和24.07±0.20°。In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation, including 3, 4, 5, 6, 7 or 8 diffraction peaks: 6.92±0.20°, 10.45±0.20°, 11.40±0.20°, 13.88±0.20°, 17.24±0.20°, 18.18±0.20°, 19.01±0.20° and 24.07±0.20°.

在本公开另一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92±0.20°、10.45±0.20°和11.40±0.20°。In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation at the following 2θ angles: 6.92±0.20°, 10.45±0.20° and 11.40±0.20°.

在本公开另一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92±0.20°、10.45±0.20°、11.40±0.20°和19.01±0.20°。In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation at the following 2θ angles: 6.92±0.20°, 10.45±0.20°, 11.40±0.20° and 19.01±0.20°.

在本公开另一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92±0.20°、10.45±0.20°、11.40±0.20°、17.24±0.20°、19.01±0.20°和24.07±0.20°。In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation at the following 2θ angles: 6.92±0.20°, 10.45±0.20°, 11.40±0.20°, 17.24±0.20°, 19.01±0.20° and 24.07±0.20°.

在本公开另一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92±0.20°、10.45±0.20°、11.40±0.20°、13.88±0.20°、17.24±0.20°、18.18±0.20°、19.01±0.20°和24.07±0.20°。In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation at the following 2θ angles: 6.92±0.20°, 10.45±0.20°, 11.40±0.20°, 13.88±0.20°, 17.24±0.20°, 18.18±0.20°, 19.01±0.20° and 24.07±0.20°.

在本公开另一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92±0.20°、10.45±0.20°、11.40±0.20°、13.88±0.20°、17.24±0.20°、18.18±0.20°、19.01±0.20°、23.63±0.20°、24.07±0.20°、25.19±0.20°和26.60±0.20°。In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation at the following 2θ angles: 6.92±0.20°, 10.45±0.20°, 11.40±0.20°, 13.88±0.20°, 17.24±0.20°, 18.18±0.20°, 19.01±0.20°, 23.63±0.20°, 24.07±0.20°, 25.19±0.20° and 26.60±0.20°.

在本公开另一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92±0.20°、10.45±0.20°、11.40±0.20°、13.35±0.20°、13.88±0.20°、15.52±0.20°、 16.21±0.20°、17.24±0.20°、18.18±0.20°、19.01±0.20°、20.77±0.20°、21.09±0.20°、23.63±0.20°、24.07±0.20°、25.19±0.20°、26.19±0.20°、26.60±0.20°和27.89±0.20°。In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation at the following 2θ angles: 6.92±0.20°, 10.45±0.20°, 11.40±0.20°, 13.35±0.20°, 13.88±0.20°, 15.52±0.20°, 16.21±0.20°, 17.24±0.20°, 18.18±0.20°, 19.01±0.20°, 20.77±0.20°, 21.09±0.20°, 23.63±0.20°, 24.07±0.20°, 25.19±0.20°, 26.19±0.20°, 26.60±0.20° and 27.89±0.20°.

在本公开另一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92±0.20°、9.09±0.20°、10.45±0.20°、11.40±0.20°、13.35±0.20°、13.88±0.20°、14.78±0.20°、15.52±0.20°、16.00±0.20°、16.21±0.20°、17.24±0.20°、18.18±0.20°、19.01±0.20°、19.66±0.20°、20.77±0.20°、21.09±0.20°、21.55±0.20°、22.22±0.20°、22.55±0.20°、23.63±0.20°、24.07±0.20°、25.19±0.20°、26.19±0.20°、26.60±0.20°、27.21±0.20°、27.89±0.20°、28.74±0.20°、29.55±0.20°、29.88±0.20°、30.38±0.20°、31.36±0.20°和31.85±0.20°。In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation at the following 2θ angles: 6.92±0.20°, 9.09±0.20°, 10.45±0.20°, 11.40±0.20°, 13.35±0.20°, 13.88±0.20°, 14.78±0.20°, 15.52±0.20°, 16.00±0.20°, 16.21±0.20°, 17.24±0.20°, 18.18±0.20°, 19.01±0.20°, 19.66±0.20°, 20.77±0.20°, 21.09±0.20°, 21.55±0.20°, 22.22±0.20°, 22.55±0.20°, 23.63±0.20°, 24.07±0.20°, 25.19±0.20°, 26.19±0.20°, 26.60±0.20°, 27.21±0.20°, 27.89±0.20°, 28.74±0.20°, 29.55±0.20°, 29.88±0.20°, 30.38±0.20°, 31.36±0.20° and 31.85±0.20°.

在本公开另一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92、9.09、10.45、11.40、13.35、13.88、14.78、15.52、16.00、16.21、17.24、18.18、19.01、19.66、20.77、21.09、21.55、22.22、22.55、23.63、24.07、25.19、26.19、26.60、27.21、27.89、28.74、29.55、29.88、30.38、31.36和31.85。In other embodiments of the present disclosure, the crystalline A of the compound of formula (I) has an X-ray powder diffraction pattern using Cu Kα radiation at the following 2θ angles: 6.92, 9.09, 10.45, 11.40, 13.35, 13.88, 14.78, 15.52, 16.00, 16.21, 17.24, 18.18, 19.01, 19.66, 20.77, 21.09, 21.55, 22.22, 22.55, 23.63, 24.07, 25.19, 26.19, 26.60, 27.21, 27. 89, 28.74, 29.55, 29.88, 30.38, 31.36 and 31.85.

在本公开另一些实施方案中，所述式(I)化合物的结晶A，其使用CuKα辐射的XRPD图谱如图2所示。In other embodiments of the present disclosure, the XRPD pattern of crystalline A of the compound of formula (I) using CuKα radiation is shown in Figure 2.

在本公开的另一些实施方案中，所述式(I)化合物的结晶A，其使用Cu Kα辐射的XRPD图谱解析数据如表1所示。In other embodiments of the present disclosure, the XRPD spectrum analysis data of crystalline A of the compound of formula (I) using Cu Kα radiation is as shown in Table 1.

表1：式(I)化合物的结晶A的XRPD图谱解析数据

Table 1: XRPD spectrum analysis data of crystal A of the compound of formula (I)

在本公开的一些实施方案中，所述式(I)化合物的结晶A，其差示扫描量热曲线分别在213.2±5.0℃和228.5±5.0℃处具有吸热峰的峰值。In some embodiments of the present disclosure, the differential scanning calorimetry curve of crystalline A of the compound of formula (I) has endothermic peaks at 213.2±5.0°C and 228.5±5.0°C, respectively.

在本公开的一些实施方案中，所述式(I)化合物的结晶A，其DSC图谱如图3所示。In some embodiments of the present disclosure, the DSC pattern of crystalline A of the compound of formula (I) is as shown in Figure 3.

另一方面，本公开还提供了所述式(I)化合物的结晶A的制备方法，包括：将式(I)化合物从有机溶剂中析出的步骤。On the other hand, the present disclosure also provides a method for preparing crystal A of the compound of formula (I), including the step of precipitating the compound of formula (I) from an organic solvent.

在本公开的一些实施方案中，所述式(I)化合物的结晶A的制备方法，所述有机溶剂选自甲醇和二氯甲烷的混合溶剂。In some embodiments of the present disclosure, the method for preparing crystal A of the compound of formula (I), the organic solvent is selected from a mixed solvent of methanol and dichloromethane.

在本公开的一些实施方案中，所述式(I)化合物的结晶A的制备方法，甲醇和二氯甲烷的体积比为1：5。In some embodiments of the present disclosure, in the preparation method of crystalline A of the compound of formula (I), the volume ratio of methanol and dichloromethane is 1:5.

在本公开另一些实施方案中，所述式(I)化合物的结晶A的制备方法，包括：(a)将式(I)化合物、乙醇、水和盐酸一起搅拌；(b)加入氢氧化钠的水溶液，升温搅拌一段时间，然后降至室温过滤，得到式(I)化合物的结晶A。In other embodiments of the present disclosure, the preparation method of crystal A of the compound of formula (I) includes: (a) stirring the compound of formula (I), ethanol, water and hydrochloric acid together; (b) adding sodium hydroxide The aqueous solution is heated and stirred for a period of time, then lowered to room temperature and filtered to obtain crystal A of the compound of formula (I).

在本公开的一些实施方案中，所述式(I)化合物的结晶A的制备方法，步骤(b)所述升温为升温至70～80℃。In some embodiments of the present disclosure, in the preparation method of crystal A of the compound of formula (I), the temperature increase in step (b) is to increase the temperature to 70-80°C.

本公开中，所述式(I)化合物的结晶A的制备方法中，起始物式(I)化合物可以是任何形态，例如结晶、无定型物、水合物、溶剂合物，粗品等。In the present disclosure, in the preparation method of crystal A of the compound of formula (I), the starting compound of formula (I) can be in any form, such as crystal, amorphous, hydrate, solvate, crude product, etc.

本公开还提供了包含式(I)化合物的结晶A的结晶组合物，其中式(I)化合物的结晶A占所述结晶组合物重量的50％以上，较好是75％以上，更好是90％以上，最好是95％以上。在本公开的另一些实施方案中，述包含式(I)化合物的结晶A的结晶组合物中，式(I)化合物的结晶A占所述结晶组合物重量的96％以上，或者97％以上，或者98％以上，或者99％以上。所述各结晶组合物中，还可能含有少量的式(I)化合物的其他结晶或非结晶形式。The present disclosure also provides a crystalline composition comprising crystalline A of the compound of formula (I), wherein the crystalline A of the compound of formula (I) accounts for more than 50% by weight of the crystalline composition, preferably more than 75%, more preferably More than 90%, preferably more than 95%. In other embodiments of the present disclosure, in the crystalline composition comprising crystalline A of the compound of formula (I), the crystalline A of the compound of formula (I) accounts for more than 96%, or more than 97% by weight of the crystalline composition. , or more than 98%, or more than 99%. Each of the crystalline compositions may also contain small amounts of other crystalline or non-crystalline forms of the compound of formula (I).

在本公开的一些实施方案中，所述包含式(I)化合物的结晶A的结晶组合物中，所述结晶组合物除式(I)化合物的结晶A以外的其余部分为式(I)化合物的非结晶A形式。In some embodiments of the present disclosure, in the crystalline composition comprising Crystalline A of the compound of Formula (I), the remainder of the crystalline composition except Crystalline A of the compound of Formula (I) is the compound of Formula (I) Amorphous Form A.

在本公开的一些实施方案中，所述包含式(I)化合物的结晶A的结晶组合物中，所述式(I)化合物占所述结晶组合物的含量可以是95％以上，或者是99％以上，或者是99.9％以上，或者是99.99％以上。In some embodiments of the present disclosure, in the crystalline composition of Crystalline A comprising the compound of Formula (I), the content of the compound of Formula (I) in the crystalline composition may be more than 95%, or 99% % or more, or 99.9% or more, or 99.99% or more.

另一方面，本公开提供一种药物组合物，其包含治疗有效量的式(I)化合物的结晶A，或其结晶组合物；所述药物组合物可以包含至少一种药学上可接受的辅料。此外，本申请的药物组合物可进一步包括一 种或多种其它治疗剂。On the other hand, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline A of the compound of formula (I), or a crystalline composition thereof; the pharmaceutical composition may comprise at least one pharmaceutically acceptable excipient. . In addition, the pharmaceutical composition of the present application may further comprise a one or more other therapeutic agents.

在本公开的一些实施方案中，所述包含式(I)化合物的结晶A的药物组合物为固体药物组合物。In some embodiments of the present disclosure, the pharmaceutical composition comprising Crystalline A of a compound of Formula (I) is a solid pharmaceutical composition.

在本公开的一些实施方案中，所述包含式(I)化合物的结晶A的固体药物组合物中的辅料包括稀释剂、粘合剂、崩解剂和润滑剂中的至少一种。In some embodiments of the present disclosure, the excipients in the solid pharmaceutical composition comprising Crystalline A of the compound of Formula (I) include at least one of a diluent, a binder, a disintegrant and a lubricant.

在本公开的一些实施方案中，所述包含式(I)化合物的结晶A的固体药物组合物中的辅料包括填充剂、助流剂和润滑剂中的至少一种。In some embodiments of the present disclosure, the excipients in the solid pharmaceutical composition comprising Crystalline A of the compound of Formula (I) include at least one of a filler, a glidant and a lubricant.

在本公开的一些实施方案中，所述包含式(I)化合物的结晶A的固体药物组合物中的辅料包括填充剂、助流剂和润滑剂。In some embodiments of the present disclosure, excipients in the solid pharmaceutical composition comprising Crystalline A of the compound of Formula (I) include fillers, glidants and lubricants.

在本公开的一些实施方案中，所述填充剂选自淀粉、预胶化淀粉、蔗糖、乳糖(例如一水乳糖)、果糖、麦芽糖、海藻糖、普鲁兰多糖、聚右旋糖、糊精、麦芽糊精、微晶纤维素、低取代羟丙纤维素、乙酸纤维素、乙基纤维素、甘露醇、山梨醇、赤藓糖醇、异麦芽糖醇、乳糖醇、麦芽糖醇、聚乙二醇、木糖醇、山梨糖醇、碳酸钙、磷酸钙、无水磷酸氢钙、硫酸钙、碳酸镁、氧化镁、碳酸钠、碳酸氢钠、氯化钠或它们中任意二种及以上的混合物；优选的，所述填充剂选自甘露醇、微晶纤维素、预胶化淀粉、低取代羟丙纤维素、无水磷酸氢钙、一水乳糖或它们中任意二种及以上的混合物；进一步优选的，所述填充剂选自甘露醇、微晶纤维素、预胶化淀粉、低取代羟丙纤维素、无水磷酸氢钙和一水乳糖中任意二种的混合物；在本公开的一些具体的实施方案中，所述填充剂选自甘露醇和微晶纤维素的混合物、甘露醇和预胶化淀粉的混合物、甘露醇和低取代羟丙纤维素的混合物、甘露醇和无水磷酸氢钙的混合物、或晶纤维素和一水乳糖的混合物；在本公开的一个具体的实施方案中，所述填充剂选自甘露醇和无水磷酸氢钙的混合物；在本公开的一个具体的实施方案中，所述填充剂选自微晶纤维素和一水乳糖的混合物。In some embodiments of the present disclosure, the filler is selected from starch, pregelatinized starch, sucrose, lactose (eg, lactose monohydrate), fructose, maltose, trehalose, pullulan, polydextrose, paste Essence, maltodextrin, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cellulose acetate, ethyl cellulose, mannitol, sorbitol, erythritol, isomalt, lactitol, maltitol, polyethylene glycol Diol, xylitol, sorbitol, calcium carbonate, calcium phosphate, anhydrous calcium hydrogen phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate, sodium chloride or any two or more of them A mixture; preferably, the filler is selected from mannitol, microcrystalline cellulose, pregelatinized starch, low-substituted hydroxypropylcellulose, anhydrous calcium hydrogen phosphate, lactose monohydrate or any two or more of them Mixture; further preferably, the filler is selected from a mixture of any two of mannitol, microcrystalline cellulose, pregelatinized starch, low-substituted hydroxypropylcellulose, anhydrous calcium hydrogen phosphate and lactose monohydrate; in this application In some specific embodiments disclosed, the filler is selected from a mixture of mannitol and microcrystalline cellulose, a mixture of mannitol and pregelatinized starch, a mixture of mannitol and low-substituted hydroxypropylcellulose, mannitol and anhydrous hydrogen phosphate. A mixture of calcium, or a mixture of crystalline cellulose and lactose monohydrate; in a specific embodiment of the present disclosure, the filler is selected from a mixture of mannitol and anhydrous calcium hydrogen phosphate; in a specific embodiment of the present disclosure In the solution, the filler is selected from a mixture of microcrystalline cellulose and lactose monohydrate.

在本公开的一些实施方案中，所述助流剂选自二氧化硅、胶态二氧化硅、三硅酸镁、淀粉、粉状纤维素、微粉硅胶或滑石粉或它们中任意二种及以上的混合物；优选的，所述助流剂选自二氧化硅、胶态二氧化硅、微粉硅胶或滑石粉；进一步优选的，所述助流剂选自胶态二氧化硅或滑石粉；在本申请一个具体的实施方案中，所述助流剂选自胶态二氧化硅。In some embodiments of the present disclosure, the glidant is selected from silica, colloidal silica, magnesium trisilicate, starch, powdered cellulose, micronized silica gel or talc, or any two thereof and The above mixture; preferably, the glidant is selected from silica, colloidal silica, micronized silica gel or talc powder; further preferably, the glidant is selected from colloidal silica or talc powder; In a specific embodiment of the present application, the glidant is selected from colloidal silica.

在本公开的一些实施方案中，所述润滑剂选自硬脂酸、硬脂酸钙、硬脂酸钠、硬脂酸锌、硬脂酸镁、单硬脂酸甘油酯、山嵛酸甘油酯、二山嵛酸甘油酯、三山嵛酸甘油酯、棕榈酰硬脂酰甘油酯、亮氨酸、豆蔻酸、棕榈酸、泊洛沙姆、聚乙二醇、苯甲酸钾、苯甲酸钠、月桂醇硫酸钠、月桂醇硫酸镁、硬脂酰富马酸钠或滑石粉；优选的，所述润滑剂选自硬脂酸镁、山嵛酸甘油酯、月桂醇硫酸钠或硬脂酰富马酸钠；在本申请一个具体的实施方案中，所述润滑剂选自硬脂酸镁。In some embodiments of the present disclosure, the lubricant is selected from the group consisting of stearic acid, calcium stearate, sodium stearate, zinc stearate, magnesium stearate, glyceryl monostearate, glyceryl behenate Ester, glyceryl dibehenate, glyceryl tribehenate, palmitoylstearoylglyceride, leucine, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, Sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate or talc; preferably, the lubricant is selected from magnesium stearate, glyceryl behenate, sodium lauryl sulfate or stearyl fumarate. Sodium Malate; In a specific embodiment of the present application, the lubricant is selected from magnesium stearate.

在本公开的一些实施方案中，所述式(I)化合物的结晶A占固体药物组合物总重量的10～90wt％；优选20～85wt％、25～80wt％、25～75wt％、30～75wt％、40～75wt％、45～75wt％、45～65wt％、45～ 55wt％或50～55wt％；更优选50wt％、51wt％、52wt％、53wt％、54wt％或55wt％。在本公开的一个具体实施方案中，所述式(I)化合物的结晶A占固体药物组合物总重量的50wt％。In some embodiments of the present disclosure, the crystalline A of the compound of formula (I) accounts for 10 to 90 wt% of the total weight of the solid pharmaceutical composition; preferably 20 to 85 wt%, 25 to 80 wt%, 25 to 75 wt%, 30 to 75wt%, 40～75wt%, 45～75wt%, 45～65wt%, 45～ 55wt% or 50-55wt%; more preferably 50wt%, 51wt%, 52wt%, 53wt%, 54wt% or 55wt%. In a specific embodiment of the present disclosure, the crystalline A of the compound of formula (I) accounts for 50 wt% of the total weight of the solid pharmaceutical composition.

在本公开的一些实施方案中，所述填充剂占固体药物组合物总重量的10～98wt％；优选20～98wt％、25～80wt％、25～75wt％、30～75wt％、40～75wt％、45～75wt％、45～65wt％、45～55wt％或45～50wt％；更优选45wt％、45.5wt％、46wt％、46.5wt％、46wt％、47.5wt％、48wt％、48.5wt％、49wt％、49.5wt％或50wt％。在本公开的一个具体实施方案中，所述填充剂选自甘露醇和无水磷酸氢钙的混合物，所述甘露醇和无水磷酸氢钙的重量比为1：0.5～2；优选1:0.5、1:0.6、1:0.7、1:0.8、1:0.9、1:1.0、1:1.1、1:1.2、1:1.3、1:1.4、1:1.5、1:1.6、1:1.7、1:1.8、1:1.9或1:2.0。在本公开的一个具体实施方案中，所述填充剂选自甘露醇和无水磷酸氢钙的混合物，所述甘露醇和无水磷酸氢钙占固体药物组合物总重量的47.5wt％，所述甘露醇和无水磷酸氢钙的重量比为1：1.0。In some embodiments of the present disclosure, the filler accounts for 10-98wt% of the total weight of the solid pharmaceutical composition; preferably 20-98wt%, 25-80wt%, 25-75wt%, 30-75wt%, 40-75wt %, 45-75wt%, 45-65wt%, 45-55wt% or 45-50wt%; more preferably 45wt%, 45.5wt%, 46wt%, 46.5wt%, 46wt%, 47.5wt%, 48wt%, 48.5wt %, 49wt%, 49.5wt% or 50wt%. In a specific embodiment of the present disclosure, the filler is selected from a mixture of mannitol and anhydrous calcium hydrogen phosphate, and the weight ratio of the mannitol and anhydrous calcium hydrogen phosphate is 1:0.5~2; preferably 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1: 1.8, 1:1.9 or 1:2.0. In a specific embodiment of the present disclosure, the filler is selected from a mixture of mannitol and anhydrous calcium hydrogen phosphate, and the mannitol and anhydrous calcium hydrogen phosphate account for 47.5 wt% of the total weight of the solid pharmaceutical composition. The weight ratio of alcohol and anhydrous calcium hydrogen phosphate is 1:1.0.

在本公开的一些实施方案中，所述助流剂占固体药物组合物总重量的0.5～5wt％；优选0.8wt％、1.0wt％、1.2wt％、1.5wt％、2.0wt％、2.2wt％、2.5wt％、2.8wt％、3.0wt％、3.2wt％、3.5wt％、3.8wt％、4.0wt％、4.2wt％、4.5wt％或4.8wt％；在本公开的一个具体实施方案中，所述助流剂占固体药物组合物总重量的1.0wt％。In some embodiments of the present disclosure, the glidant accounts for 0.5 to 5wt% of the total weight of the solid pharmaceutical composition; preferably 0.8wt%, 1.0wt%, 1.2wt%, 1.5wt%, 2.0wt%, 2.2wt %, 2.5wt%, 2.8wt%, 3.0wt%, 3.2wt%, 3.5wt%, 3.8wt%, 4.0wt%, 4.2wt%, 4.5wt% or 4.8wt%; in a specific embodiment of the present disclosure , the glidant accounts for 1.0 wt% of the total weight of the solid pharmaceutical composition.

在本公开的一些实施方案中，所述润滑剂占固体药物组合物总重量的0.5～5wt％；优选0.8wt％、1.0wt％、1.2wt％、1.5wt％、2.0wt％、2.2wt％、2.5wt％、2.8wt％、3.0wt％、3.2wt％、3.5wt％、3.8wt％、4.0wt％、4.2wt％、4.5wt％或4.8wt％；在本公开的一个具体实施方案中，所述润滑剂占固体药物组合物总重量的1.5wt％。In some embodiments of the present disclosure, the lubricant accounts for 0.5 to 5wt% of the total weight of the solid pharmaceutical composition; preferably 0.8wt%, 1.0wt%, 1.2wt%, 1.5wt%, 2.0wt%, 2.2wt% , 2.5wt%, 2.8wt%, 3.0wt%, 3.2wt%, 3.5wt%, 3.8wt%, 4.0wt%, 4.2wt%, 4.5wt% or 4.8wt%; in a specific embodiment of the present disclosure , the lubricant accounts for 1.5wt% of the total weight of the solid pharmaceutical composition.

在本公开的一个实施方案中，式(I)化合物的结晶A的固体药物组合物包含：式(I)化合物的结晶A；甘露醇和无水磷酸氢钙；胶体二氧化硅；硬脂酸镁。在本公开的一个实施方案中，式(I)化合物的结晶A的固体药物组合物包含：10～90wt％的式(I)化合物的结晶A；10～98wt％的甘露醇和无水磷酸氢钙；0.5～5wt％的胶体二氧化硅；0.5～5wt％的硬脂酸镁。In one embodiment of the present disclosure, a solid pharmaceutical composition of crystalline A of the compound of formula (I) comprises: crystalline A of the compound of formula (I); mannitol and anhydrous calcium hydrogen phosphate; colloidal silicon dioxide; magnesium stearate . In one embodiment of the present disclosure, the solid pharmaceutical composition of crystalline A of the compound of formula (I) includes: 10 to 90 wt% of crystalline A of the compound of formula (I); 10 to 98 wt% of mannitol and anhydrous calcium hydrogen phosphate ; 0.5-5wt% colloidal silica; 0.5-5wt% magnesium stearate.

在本公开的一个实施方案中，式(I)化合物的结晶A的固体药物组合物包含：50～55wt％的式(I)化合物的结晶A；45～50wt％的甘露醇和无水磷酸氢钙；1.0wt％的胶体二氧化硅；1.2wt％的硬脂酸镁。In one embodiment of the present disclosure, the solid pharmaceutical composition of crystalline A of the compound of formula (I) includes: 50 to 55 wt% of crystalline A of the compound of formula (I); 45 to 50 wt% of mannitol and anhydrous calcium hydrogen phosphate ; 1.0wt% colloidal silica; 1.2wt% magnesium stearate.

在一些实施方案中，所述式(I)化合物的结晶A的固体药物组合物中，式(I)化合物的结晶A作为活性成分，甘露醇和无水磷酸氢钙作为填充剂，胶体二氧化硅作为助流剂，硬脂酸镁作为润滑剂。In some embodiments, in the solid pharmaceutical composition of the crystalline A of the compound of formula (I), crystalline A of the compound of formula (I) is used as the active ingredient, mannitol and anhydrous calcium hydrogen phosphate are used as fillers, and colloidal silicon dioxide As glidant, magnesium stearate acts as lubricant.

在本公开的一个实施方案中，式(I)化合物的结晶A的固体药物组合物包含：式(I)化合物的结晶A；微晶纤维素和一水乳糖；胶体二氧化硅；硬脂酸镁。In one embodiment of the present disclosure, a solid pharmaceutical composition of crystalline A of the compound of formula (I) comprises: crystalline A of the compound of formula (I); microcrystalline cellulose and lactose monohydrate; colloidal silicon dioxide; stearic acid magnesium.

在一些实施方案中，所述式(I)化合物的结晶A作为活性成分，微晶纤维素和一水乳糖作为填充剂，胶态二氧化硅作为助流剂，硬脂酸镁作为润滑剂。 In some embodiments, the crystalline A of the compound of formula (I) serves as the active ingredient, microcrystalline cellulose and lactose monohydrate as fillers, colloidal silica as glidant, and magnesium stearate as lubricant.

本公开的固体药用组合物可以通过多种旨在形成为适合于口服给药至人的制剂形式，例如包括片剂、丸剂、胶囊剂、粉剂或颗粒剂等。在本公开的一些实施方案中，所述的固体药物组合物制剂形式为胶囊剂。The solid pharmaceutical composition of the present disclosure can be formed into a variety of preparation forms suitable for oral administration to humans, including, for example, tablets, pills, capsules, powders or granules, and the like. In some embodiments of the present disclosure, the solid pharmaceutical composition is in the form of a capsule.

在本公开的一些实施方案中，式(I)化合物的结晶A的固体药物组合物制剂形式为胶囊剂，所述胶囊剂的胶囊壳选自植物胶囊壳或明胶胶囊壳，所述植物胶囊壳选自羟丙甲纤维素空心胶囊。In some embodiments of the present disclosure, the solid pharmaceutical composition preparation form of crystalline A of the compound of formula (I) is a capsule, and the capsule shell of the capsule is selected from the group consisting of plant capsule shells or gelatin capsule shells. The plant capsule shell Selected from hypromellose hollow capsules.

在本公开的一些实施方案中，式(I)化合物的结晶A的固体药物组合物中，式(I)化合物的结晶A的粒径分布满足X50≤5μm，X90≤15μm；优选的，式(I)化合物的结晶A的粒径分布满足X50＝1～5μm，X90＝3～15μm。In some embodiments of the present disclosure, in the solid pharmaceutical composition of crystalline A of the compound of formula (I), the particle size distribution of crystalline A of the compound of formula (I) satisfies X50≤5μm, X90≤15μm; preferably, the formula ( I) The particle size distribution of crystal A of the compound satisfies X50=1 to 5 μm and X90=3 to 15 μm.

在本公开的一些实施方案中，所述式(I)化合物的结晶A的固体药物组合物制剂为每单位含50mg式(I)化合物的结晶A的胶囊。In some embodiments of the present disclosure, the solid pharmaceutical composition formulation of Crystalline A of the compound of Formula (I) is a capsule containing 50 mg of Crystalline A of the compound of Formula (I) per unit.

在本公开的一些实施方案中，所述制剂为每单位含60mg式(I)化合物的结晶A的胶囊。In some embodiments of the present disclosure, the formulation is a capsule containing 60 mg of Crystalline A of a compound of Formula (I) per unit.

在本公开的一些实施方案中，每单位制剂的所述式(I)化合物的结晶A的固体药物组合物包含式(I)化合物的结晶A 50mg、甘露醇23.75mg、无水磷酸氢钙23.75mg、胶态二氧化硅1mg、硬脂酸镁1.5mg。In some embodiments of the present disclosure, the solid pharmaceutical composition of the crystal A of the compound of formula (I) per unit preparation includes 50 mg of crystal A of the compound of formula (I), 23.75 mg of mannitol, and 23.75 mg of anhydrous calcium hydrogen phosphate. mg, colloidal silica 1mg, magnesium stearate 1.5mg.

在本公开的一些实施方案中，每单位制剂的所述式(I)化合物的结晶A的固体药物组合物包含式(I)化合物的结晶A 60mg、甘露醇28.5mg、无水磷酸氢钙28.5mg、胶态二氧化硅1.2mg、硬脂酸镁1.8mg。In some embodiments of the present disclosure, the solid pharmaceutical composition of the crystalline A of the compound of formula (I) per unit preparation includes 60 mg of crystalline A of the compound of formula (I), 28.5 mg of mannitol, and 28.5 mg of anhydrous calcium hydrogen phosphate. mg, colloidal silica 1.2mg, magnesium stearate 1.8mg.

另一方面，本公开提供了式(I)化合物的结晶A、式(I)化合物的结晶A的结晶组合物或所述式(I)化合物的结晶A的固体药物组合物在制备用于治疗或预防选择性CDK4/6抑制相关疾病的药物中的用途，所述选择性CDK4/6抑制相关疾病包括乳腺癌，非小细胞肺癌，食道癌，直肠癌和急性髓细胞白血病癌。In another aspect, the present disclosure provides crystal A of the compound of formula (I), a crystal composition of crystal A of the compound of formula (I), or a solid pharmaceutical composition of crystal A of the compound of formula (I) prepared for use in the treatment of Or use in drugs to prevent diseases related to selective CDK4/6 inhibition, including breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer and acute myeloid leukemia cancer.

另一方面，本公开提供了式(I)化合物的结晶A、式(I)化合物的结晶A的结晶组合物或所述式(I)化合物的结晶A的固体药物组合物用于治疗或预防选择性CDK4/6抑制相关疾病的用途，所述选择性CDK4/6抑制相关疾病包括乳腺癌，非小细胞肺癌，食道癌，直肠癌和急性髓细胞白血病癌。In another aspect, the present disclosure provides crystal A of the compound of formula (I), a crystal composition of crystal A of the compound of formula (I), or a solid pharmaceutical composition of crystal A of the compound of formula (I) for treatment or prevention. Use of diseases related to selective CDK4/6 inhibition, including breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer and acute myeloid leukemia cancer.

另一方面，本公开提供了治疗或预防选择性CDK4/6抑制相关疾病的方法，其包括向有需要的哺乳动物给予治疗有效量的所述式(I)化合物的结晶A、式(I)化合物的结晶A的结晶组合物或所述式(I)化合物的结晶A的固体药物组合物，所述选择性CDK4/6抑制相关疾病包括乳腺癌，非小细胞肺癌，食道癌，直肠癌和急性髓细胞白血病癌。On the other hand, the present disclosure provides a method for treating or preventing diseases related to selective CDK4/6 inhibition, which comprises administering to a mammal in need thereof a therapeutically effective amount of Crystal A, Formula (I) of the compound of Formula (I) A crystalline composition of crystalline A of the compound or a solid pharmaceutical composition of crystalline A of the compound of formula (I), the selective CDK4/6 inhibition-related diseases include breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer and Acute myeloid leukemia cancer.

另一方面，本公开提供了用于治疗或预防选择性CDK4/6抑制相关疾病的式(I)化合物的结晶A、式(I)化合物的结晶A的结晶组合物或所述式(I)化合物的结晶A的固体药物组合物，所述选择性CDK4/6抑制相关疾病包括乳腺癌，非小细胞肺癌，食道癌，直肠癌和急性髓细胞白血病癌。On the other hand, the present disclosure provides crystal A of the compound of formula (I), a crystal composition of crystal A of the compound of formula (I), or said formula (I) for treating or preventing diseases related to selective CDK4/6 inhibition. A solid pharmaceutical composition of a crystalline compound A, said selective CDK4/6 inhibition-related diseases include breast cancer, non-small cell lung cancer, esophageal cancer, rectal cancer and acute myeloid leukemia cancer.

在本公开的一些实施方案中，所述哺乳动物为人类。In some embodiments of the disclosure, the mammal is a human.

另一方面，本公开提供了所述式(I)化合物的结晶A的固体药物组合物的制备方法，包括如下步骤： On the other hand, the present disclosure provides a method for preparing a solid pharmaceutical composition of crystalline A of the compound of formula (I), comprising the following steps:

1)将式(I)化合物的结晶A与填充剂、助流剂和润滑剂过筛混合；1) Sieve and mix the crystal A of the compound of formula (I) with the filler, glidant and lubricant;

2)将混合后的混合物干法制粒后与润滑剂混合；2) Dry granulate the mixed mixture and mix it with lubricant;

3)胶囊填充。3) Capsule filling.

在本公开的一些实施方案中，所述式(I)化合物的结晶A的固体药物组合物的制备方法中所述填充剂如上所述，例如所述填充剂为甘露醇和无水磷酸氢钙的混合物，或者微晶纤维素和一水乳糖的混合物。In some embodiments of the present disclosure, in the preparation method of the solid pharmaceutical composition of crystalline A of the compound of formula (I), the filler is as described above, for example, the filler is mannitol and anhydrous calcium hydrogen phosphate. mixture, or a mixture of microcrystalline cellulose and lactose monohydrate.

在本公开的一些实施方案中，所述式(I)化合物的结晶A的固体药物组合物的制备方法中所述助流剂如上所述，例如所述助流剂为胶态二氧化硅。In some embodiments of the present disclosure, in the preparation method of the solid pharmaceutical composition of crystalline A of the compound of formula (I), the glidant is as described above, for example, the glidant is colloidal silica.

在本公开的一些实施方案中，所述式(I)化合物的结晶A的固体药物组合物的制备方法中所述内加润滑剂和外加润滑剂相同，所述润滑剂如上所述，例如所述润滑剂为硬脂酸镁。In some embodiments of the present disclosure, the internal lubricant and the external lubricant in the preparation method of the solid pharmaceutical composition of crystalline A of the compound of formula (I) are the same, and the lubricant is as described above, such as The lubricant is magnesium stearate.

本公开中，样品的X-射线粉末衍射光谱在下述条件下测定：仪器：布鲁克D8advance X-射线衍射仪。In this disclosure, the X-ray powder diffraction spectra of the samples were measured under the following conditions: Instrument: Bruker D8advance X-ray diffractometer.

需要说明的是，在X-射线粉末衍射光谱中，峰的位置或峰的相对强度可能会因为测定仪器、测定方法/条件等因素而产生差异。对任何特定的结晶，峰的位置可能存在误差，2θ值的测定误差为±0.2。因此，在确定每种结晶时，应该将此误差考虑在内，在误差内也属于本申请的范围。It should be noted that in the X-ray powder diffraction spectrum, the position of the peak or the relative intensity of the peak may vary due to factors such as the measuring instrument and the measuring method/conditions. For any particular crystal, there may be errors in the position of the peaks, and the error in determining the 2θ value is ±0.2. Therefore, this error should be taken into account when determining each crystallization, and it is within the scope of this application.

需要说明的是，对于同种结晶，DSC的吸热峰出现位置可能会因为测定仪器、测定方法/条件等因素而产生差异。对任何特定的结晶，吸热峰的位置可能存在误差，误差可以为±5℃。因此，在确定每种结晶时，应该将此误差考虑在内，在误差内也属于本申请的范围。It should be noted that for the same type of crystal, the position of the endothermic peak of DSC may differ due to factors such as measuring instruments, measuring methods/conditions, etc. For any particular crystal, there may be an error in the position of the endothermic peak, which may be ±5°C. Therefore, this error should be taken into account when determining each crystallization, and it is within the scope of this application.

本公开中，式(I)化合物结晶A的XRPD谱图如图1和图2所示，两者代表相同结晶不同批次的检测结果。In the present disclosure, the XRPD spectra of crystal A of the compound of formula (I) are shown in Figures 1 and 2, both of which represent the detection results of different batches of the same crystal.

技术效果Technical effect

本公开所述式(I)化合物的结晶A溶解性好，在高湿、高温、光照、气流粉碎及高压研磨等条件下表现出良好的稳定性，在长期试验条件下也表现出良好的稳定性。本公开所述式(I)化合物的结晶A及其药物组合物在药物活性、药代动力学、生物利用度、吸湿性、稳定性、熔点、溶解性、制剂溶出度、辅料相容性、纯度、易制备等方面具备优势，以满足药物在生产、储存、运输和制剂等方面的需求。例如，式(I)化合物的结晶A相比式(I)化合物结晶B而言具有更好的水溶性，以及在制剂方面表现出了更好的溶出度，还表现出了更优的药代动力学性质。Crystalline A of the compound of formula (I) disclosed in the present disclosure has good solubility, shows good stability under conditions such as high humidity, high temperature, light, jet pulverization and high-pressure grinding, and also shows good stability under long-term test conditions. sex. Crystalline A of the compound of formula (I) and its pharmaceutical composition disclosed in the present disclosure have excellent performance in pharmaceutical activity, pharmacokinetics, bioavailability, hygroscopicity, stability, melting point, solubility, preparation dissolution, excipient compatibility, It has advantages in purity and ease of preparation to meet the needs of drug production, storage, transportation and preparation. For example, crystal A of the compound of formula (I) has better water solubility than crystal B of the compound of formula (I), shows better dissolution in preparation, and also shows better pharmacokinetics. Dynamic properties.

定义和说明Definition and Description

除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。 Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.

“哺乳动物”包括人和家畜如实验室哺乳动物与家庭宠物(例如猫、狗、猪、羊、牛、绵羊、山羊、马、家兔)，及非驯养哺乳动物，如野生哺乳动物等。"Mammals" include humans and domestic animals, such as laboratory mammals and household pets (such as cats, dogs, pigs, sheep, cattle, sheep, goats, horses, rabbits), and non-domesticated mammals, such as wild mammals.

术语“药物组合物”是指本公开化合物与本领域中通常接受的用于传递生物活性化合物至哺乳动物例如人的介质的制剂。所述介质包括所有供其使用的药物可接受的载体。药物组合物有利于化合物向生物体的给药。The term "pharmaceutical composition" refers to the formulation of a compound of the present disclosure with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal, such as a human. Such media include all pharmaceutically acceptable carriers for their use. Pharmaceutical compositions facilitate the administration of compounds to an organism.

术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。The term "therapeutically effective amount" refers to a non-toxic amount of a drug or agent sufficient to achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.

术语“治疗”意为将本公开所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：The term "treating" means administering a compound or formulation of the present disclosure to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i)抑制疾病或疾病状态，即遏制其发展；(i) To inhibit a disease or disease state, that is, to arrest its progression;

(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。(ii) Alleviation of a disease or condition, i.e. resolution of the disease or condition.

术语“预防”意为将本公开所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。The term "prevention" means the administration of a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with said disease, and includes: preventing a disease or disease state from occurring in a mammal, particularly when Such mammals are susceptible to the disease state but have not yet been diagnosed as having the disease state.

本公开中，“药学上可接受的载体”是指与活性成份一同给药的、对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。In the present disclosure, "pharmaceutically acceptable carriers" refer to those carriers that are administered together with the active ingredients, have no obvious irritating effect on the organism, and do not impair the biological activity and performance of the active compound. For additional information on vectors, please refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising或等同物应理解为开放的、非排他性的意义，即“包括但不限于”，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。The word "comprise" or "comprise" and its English variations such as compris or comprising or equivalents should be understood in an open, non-exclusive sense, that is, "including but not limited to", meaning in addition to those listed In addition to the listed elements, components and steps, other unspecified elements, components and steps may also be covered.

在本文中，除非上下文另有明确规定，否则单数术语涵盖复数指代物，反之亦然。In this document, unless the context clearly dictates otherwise, singular terms encompass plural referents and vice versa.

在本文中，除非另有说明，各参数值(包括2θ值、反应条件)均被视为由术语“约”修饰，以反映各值存在的测量等误差，例如相对于给定值，存在±5％的误差。In this article, unless otherwise stated, each parameter value (including 2θ value, reaction condition) is deemed to be modified by the term "about" to reflect the measurement error of each value, such as ± relative to a given value. 5% error.

为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。 All patents, patent applications, and other identified publications are expressly incorporated by reference herein for purposes of description and disclosure. These publications are provided solely because their disclosures preceded the filing date of this application. All statements as to the date of these documents or representations of the contents of these documents are based on information available to the applicant and do not constitute any admission as to the correctness of the date of these documents or the contents of these documents. Furthermore, any reference herein to these publications does not constitute an admission that the publications form part of the common general knowledge in the art in any country.

附图说明Description of drawings

图1和图2为式(I)化合物结晶A的XRPD谱图。Figures 1 and 2 are XRPD spectra of crystal A of the compound of formula (I).

图3为式(I)化合物结晶A的DSC谱图。Figure 3 is the DSC spectrum of crystal A of the compound of formula (I).

图4为式(I)化合物结晶A胶囊和式(I)化合物结晶B胶囊溶出度比较图。Figure 4 is a comparison chart of the dissolution rates of crystal A capsules of compound of formula (I) and crystal B capsules of compound of formula (I).

具体实施方式Detailed ways

下面通过实施例对本申请进行详细描述，但并不意味着对本申请任何不利限制。本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。The present application is described in detail through examples below, but does not mean any adverse limitations to the present application. The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred implementations include but are not limited to the embodiments of this application. It will be apparent to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

实施例1式(I)化合物结晶A的制备Example 1 Preparation of Crystal A of Compound of Formula (I)

方法1：method 1:

在20℃下，将式(I)化合物1.877kg、二氯甲烷12.5L、甲醇2.5L依次加入50L反应釜，并搅拌至固体完全溶解，将反应体系加热至30℃，并在此温度下搅拌22小时。过滤，滤饼用二氯甲烷5L洗涤，将滤液减压浓缩至干，所得固体于45℃真空烘箱中干燥72小时，得到式(I)化合物的结晶A。At 20°C, add 1.877kg of the compound of formula (I), 12.5L of methylene chloride, and 2.5L of methanol into the 50L reaction kettle in sequence, and stir until the solid is completely dissolved. Heat the reaction system to 30°C and stir at this temperature. 22 hours. Filter, wash the filter cake with 5L of dichloromethane, and concentrate the filtrate to dryness under reduced pressure. The solid obtained is dried in a vacuum oven at 45°C for 72 hours to obtain crystal A of the compound of formula (I).

方法2：Method 2:

配制氢氧化钠溶液：向反应罐中加入氢氧化钠4.2kg，水29.2kg搅拌至溶解，控制温度15～25℃，过滤后使用。Prepare sodium hydroxide solution: Add 4.2kg of sodium hydroxide and 29.2kg of water into the reaction tank, stir until dissolved, control the temperature to 15-25°C, and filter before use.

将式(I)化合物14.62kg、无水乙醇115.4kg、水146.2kg、盐酸5.5L搅拌至溶解后过滤。滤液降温至0～10℃，加入上述配制的氢氧化钠溶液，搅拌10分钟。升温至70～80℃搅拌1.5小时，降温至室温后，过滤，得到式(I)化合物结晶A。Stir 14.62kg of the compound of formula (I), 115.4kg of absolute ethanol, 146.2kg of water, and 5.5L of hydrochloric acid until dissolved and then filter. Cool the filtrate to 0-10°C, add the sodium hydroxide solution prepared above, and stir for 10 minutes. The temperature was raised to 70-80°C and stirred for 1.5 hours. After cooling to room temperature, the mixture was filtered to obtain crystal A of the compound of formula (I).

实施例2式(I)化合物结晶A和结晶B的胶囊的制备Example 2 Preparation of capsules of crystal A and crystal B of compound of formula (I)

式(I)化合物结晶A的胶囊的制备Preparation of capsules of crystal A of compound of formula (I)

将式(I)化合物结晶A、甘露醇、无水磷酸氢钙、胶态二氧化硅及硬脂酸镁混合后再过筛混合，得混合物Ⅰ；将混合物Ⅰ进行干法制粒；向干法制粒后的物料中加入硬脂酸镁后混合；分装至胶囊充填，得到表2配方的式(I)化合物结晶A的胶囊。Mix crystal A of the compound of formula (I), mannitol, anhydrous calcium hydrogen phosphate, colloidal silica and magnesium stearate and then sieve and mix to obtain mixture I; carry out dry granulation of mixture I; Magnesium stearate is added to the granulated materials and mixed; the mixture is divided into capsules for filling to obtain capsules of compound crystal A of formula (I) formulated in Table 2.

表2
Table 2

式(I)化合物结晶B的胶囊的制备Preparation of capsules of crystalline B of compound of formula (I)

参照式(I)化合物结晶A的胶囊的制备方法，仅将式(I)化合物结晶A替换为式(I)化合物结晶B(即WO2018045993A1中公开的式(I)化合物的B晶型)，得到式(I)化合物结晶B的胶囊。Referring to the preparation method of capsules of compound formula (I) crystal A, only replacing formula (I) compound crystal A with formula (I) compound crystal B (i.e., the B crystal form of formula (I) compound disclosed in WO2018045993A1), we obtain Capsules of crystalline B of compound of formula (I).

实验例1溶出度Experimental Example 1 Dissolution

以pH4.5醋酸盐缓冲液为溶出介质，介质体积900ml，37±0.5℃，150rpm，篮法，于10、15、20、30min取样10ml，回补同体积介质，样品过滤，弃适量初滤液，精密量取续滤液稀释，摇匀，紫外分光光度法测定吸光度，计算溶出度，结果如图4所示。Use pH 4.5 acetate buffer as the dissolution medium, medium volume 900ml, 37±0.5℃, 150rpm, basket method, sample 10ml at 10, 15, 20, and 30 minutes, replenish the same volume of medium, filter the sample, discard appropriate amount of the initial The filtrate, accurately measure the diluted filtrate, shake well, measure the absorbance using UV spectrophotometry, and calculate the dissolution rate. The results are shown in Figure 4.

实验例2大鼠体内药代动力学Experimental Example 2 Pharmacokinetics in Rats

a)分组给药a)Group administration

SD大鼠，体重180～220g，适应3-5天后，随机分为2组，每组4只，按12mg/kg剂量分别灌胃给予式I化合物结晶A、式I化合物B晶型。大鼠给药前禁食12h，给药后4h给食物，实验前后和实验过程中均自由饮水。SD rats, weighing 180-220g, were randomly divided into 2 groups after adapting for 3-5 days, with 4 rats in each group. Compound A of formula I and crystal form B of compound of formula I were administered by gavage at a dose of 12 mg/kg. The rats were fasted for 12 hours before administration and were given food 4 hours after administration. They had free access to water before, before, and during the experiment.

b)取样b) Sampling

给药后采集时间点为0.25h、0.5h、1h、2h、4h、6h、8h、10h、24h、30h、48h，分别于眼眶静脉丛采血约0.3mL置于含EDTA-K2离心管中，4℃保存，于1h内在4℃，4000rpm，10min条件下离心，-20℃保存待测。The collection time points after administration are 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 24h, 30h, and 48h. About 0.3mL of blood was collected from the orbital venous plexus and placed in centrifuge tubes containing EDTA-K2. Store at 4°C, centrifuge at 4°C, 4000rpm, 10min within 1 hour, and store at -20°C for testing.

吸取50μL待测血浆样品，加入300μL含内标的乙腈溶液，振荡混匀10min，13000rpm离心10min，取上清80μL，加入80μL 50％乙腈水溶液，吸取2μL用于LC/MS/MS分析测定。Take 50 μL of plasma sample to be tested, add 300 μL of acetonitrile solution containing internal standard, shake and mix for 10 min, centrifuge at 13000 rpm for 10 min, take 80 μL of supernatant, add 80 μL of 50% acetonitrile aqueous solution, and pipet 2 μL for LC/MS/MS analysis.

c)检测方法c)Detection method

利用液相色谱-串联质谱法(LC-MS/MS)，使用地西泮作为内标(IS)，采用蛋白沉淀法从血浆中提取待测物和内标，采用反相色谱柱来分离化合物和内标，使用串联四极杆质谱仪的电喷雾离子化方式(ESI)对分析物进行定量分析Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used, using diazepam as the internal standard (IS), using protein precipitation to extract the analyte and internal standard from plasma, and using a reversed-phase chromatography column to separate the compounds. and internal standards, and the analytes were quantified using electrospray ionization (ESI) on a tandem quadrupole mass spectrometer.

结果如表3所示。The results are shown in Table 3.

表3药代动力学结果

Table 3 Pharmacokinetic results

Claims (11)

式(I)化合物的结晶，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92±0.20°、10.47±0.20°和11.41±0.20°，
A crystal of a compound of formula (I) whose X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.47±0.20° and 11.41±0.20°,
权利要求1所述的式(I)化合物的结晶，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92±0.20°、10.47±0.20°、11.41±0.20°、17.25±0.20°、19.02±0.20°和24.09±0.20°。The crystallization of the compound of formula (I) according to claim 1, whose X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 17.25 ±0.20°, 19.02±0.20° and 24.09±0.20°. 权利要求1所述的式(I)化合物的结晶，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92±0.20°、10.47±0.20°、11.41±0.20°、13.87±0.20°、17.25±0.20°、18.21±0.20°、19.02±0.20°、23.52±0.20°、24.09±0.20°、25.24±0.20°和26.61±0.20°。The crystallization of the compound of formula (I) according to claim 1, whose X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 13.87 ±0.20°, 17.25±0.20°, 18.21±0.20°, 19.02±0.20°, 23.52±0.20°, 24.09±0.20°, 25.24±0.20° and 26.61±0.20°. 权利要求1所述的式(I)化合物的结晶，其使用Cu Kα辐射的X射线粉末衍射图谱在下列2θ角处具有衍射峰：6.92±0.20°、10.47±0.20°、11.41±0.20°、13.36±0.20°、13.87±0.20°、15.53±0.20°、16.22±0.20°、17.25±0.20°、18.21±0.20°、19.02±0.20°、20.87±0.20°、21.10±0.20°、23.52±0.20°、24.09±0.20°、25.24±0.20°、26.21±0.20°、26.61±0.20°和27.91±0.20°。The crystallization of the compound of formula (I) according to claim 1, whose X-ray powder diffraction pattern using Cu Kα radiation has diffraction peaks at the following 2θ angles: 6.92±0.20°, 10.47±0.20°, 11.41±0.20°, 13.36 ±0.20°, 13.87±0.20°, 15.53±0.20°, 16.22±0.20°, 17.25±0.20°, 18.21±0.20°, 19.02±0.20°, 20.87±0.20°, 21.10±0.20°, 23.52±0.20°, 24.09 ±0.20°, 25.24±0.20°, 26.21±0.20°, 26.61±0.20° and 27.91±0.20°. 式(I)化合物的结晶，其使用Cu Kα辐射的X射线粉末衍射图谱中，包含选自下述2θ角处的3、4、5、6、7或8个衍射峰：6.92±0.20°、10.45±0.20°、11.40±0.20°、13.88±0.20°、17.24±0.20°、18.18±0.20°、19.01±0.20°和24.07±0.20°
The X-ray powder diffraction pattern of the crystal of the compound of formula (I) using Cu Kα radiation contains 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following 2θ angles: 6.92±0.20°, 10.45±0.20°, 11.40±0.20°, 13.88±0.20°, 17.24±0.20°, 18.18±0.20°, 19.01±0.20° and 24.07±0.20°
权利要求5所述的式(I)化合物的结晶，其使用Cu Kα辐射的XRPD图谱如图2所示。The crystallization of the compound of formula (I) according to claim 5, whose XRPD pattern using Cu Kα radiation is as shown in Figure 2. 式(I)化合物的结晶，其差示扫描量热曲线分别在213.2±5.0℃和228.5±5.0℃处具有吸热峰的峰值，
The differential scanning calorimetry curves of the crystallization of the compound of formula (I) have endothermic peaks at 213.2±5.0°C and 228.5±5.0°C, respectively.
权利要求1-7中任一项所述的式(I)化合物的结晶的制备方法，包括：将式(I)化合物从有机溶剂中 析出的步骤。The preparation method of crystallizing the compound of formula (I) according to any one of claims 1 to 7, comprising: removing the compound of formula (I) from an organic solvent. Precipitation step. 权利要求1-7中任一项所述的式(I)化合物的结晶的结晶组合物，其中式(I)化合物的结晶A占所述结晶组合物重量的50％以上，较好是75％以上，更好是90％以上，最好是95％以上。The crystalline composition of the crystallization of the compound of formula (I) according to any one of claims 1 to 7, wherein the crystallization A of the compound of formula (I) accounts for more than 50% by weight of the crystalline composition, preferably 75% Above, preferably above 90%, more preferably above 95%. 一种药物组合物，其包含治疗有效量的权利要求1-7中任一项所述的式(I)化合物的结晶，或其结晶组合物；所述药物组合物可以包含至少一种药学上可接受的辅料。A pharmaceutical composition, which contains a therapeutically effective amount of the crystallization of the compound of formula (I) described in any one of claims 1-7, or a crystalline composition thereof; the pharmaceutical composition may contain at least one pharmaceutical Acceptable excipients. 权利要求1-7中任一项所述的式(I)化合物的结晶、权利要求9所述的式(I)化合物的结晶的结晶组合物或权利要求10所述式(I)化合物的结晶的固体药物组合物在制备用于治疗或预防选择性CDK4/6抑制相关疾病的药物中的用途，所述选择性CDK4/6抑制相关疾病包括乳腺癌，非小细胞肺癌，食道癌，直肠癌和急性髓细胞白血病癌。 The crystal of the compound of formula (I) according to any one of claims 1 to 7, the crystallization composition of the crystal of the compound of formula (I) according to claim 9, or the crystal of the compound of formula (I) according to claim 10 Use of a solid pharmaceutical composition in the preparation of medicaments for the treatment or prevention of diseases related to selective CDK4/6 inhibition, including breast cancer, non-small cell lung cancer, esophageal cancer, and rectal cancer and acute myeloid leukemia cancer.
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