WO2023025270A1 - 一种吲哚类化合物的固体形式及其制备方法和用途 - Google Patents

一种吲哚类化合物的固体形式及其制备方法和用途 Download PDF

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WO2023025270A1
WO2023025270A1 PCT/CN2022/115010 CN2022115010W WO2023025270A1 WO 2023025270 A1 WO2023025270 A1 WO 2023025270A1 CN 2022115010 W CN2022115010 W CN 2022115010W WO 2023025270 A1 WO2023025270 A1 WO 2023025270A1
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compound
formula
solvent
crystal form
crystalline form
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PCT/CN2022/115010
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English (en)
French (fr)
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邓永奇
田元
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凯复(苏州)生物医药有限公司
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Priority to AU2022334637A priority Critical patent/AU2022334637A1/en
Priority to CA3230102A priority patent/CA3230102A1/en
Publication of WO2023025270A1 publication Critical patent/WO2023025270A1/zh

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring

Definitions

  • the application relates to a solid form of an indole compound and a preparation method and use thereof.
  • this application relates to 3-(1-(1-(benzofuran-2-ylmethyl)-1H-indole-7-carboxamido)cyclopropyl)bicyclo[1.1.1]pentane - Solid form of 1-carboxylic acid (hereinafter referred to as "compound of formula (1)”), process for producing said solid form, pharmaceutical composition comprising said solid form, and use of said solid form in the treatment of diseases the use of.
  • E-type prostaglandin 2 is an arachidonic acid derivative, which can inhibit the function of immune cells and escape anti-tumor immunity.
  • PGE2 regulates biological functions through four E-type PGE2 receptors (EP1, EP2, EP3 and EP4).
  • EP4 is the main PGE2 receptor in tumor tissue, and participates in the promotion of tumor development by PGE2.
  • EP4 receptor is increased in many tumor tissues.
  • a large amount of evidence also shows that the level of PGE2 in many tumor tissues increases, and at the same time inhibits the function of immune cells in tumor tissues through the EP4 receptor, making tumor cells escape the anti-tumor immune system and accelerating tumor growth and metastasis.
  • EP4 receptor antagonists can block these effects of PGE2, thereby enhancing anti-tumor immune function.
  • EP4 antagonists may be effective inflammatory pain-relieving drugs with better gut tolerability than current standard anti-inflammatory analgesics such as NSAIDs and COX-2 inhibitors. It is noteworthy that since EP4 antagonists do not directly interfere with the biosynthesis of prostaglandin E (PGE2) and other prostaglandins (such as prostacyclin and thromboxane), such drugs may have better cardiovascular safety.
  • PGE2 prostaglandin E
  • other prostaglandins such as prostacyclin and thromboxane
  • One aspect of the present application provides a compound (3-(1-(1-(benzofuran-2-ylmethyl)-1H-indole-7-carboxamido)cyclopropyl) of formula (1) as shown below base) bicyclo[1.1.1]pentane-1-carboxylic acid, which is a compound that inhibits PGE2/EP4 signaling) crystal form:
  • the preferred crystal form of the compound of formula (1) of the present application has excellent physical properties (including solubility, dissolution rate, low hygroscopicity, high temperature resistance, high humidity resistance, fluidity, etc.), and has excellent properties such as bioavailability, physical And/or properties such as chemical stability and ease of preparation, the preferred crystal form of the present invention may have more excellent properties.
  • the preferred crystal form of the present application has good powder properties, and is more suitable and convenient for mass production and for the formation of preparations, effectively ensuring the quality and efficacy of pharmaceutical products.
  • the preferred crystal form of the compound of formula (1) in the present application exhibits good chemical stability and thermal stability, so it is more conducive to sufficient dissolution during administration and preparation, and can maintain sufficient biological activity.
  • the preferred crystalline form of the compound of formula (1) of the present application exhibits high bioavailability and can provide a therapeutically effective dose of the compound of formula (1) in vivo.
  • the preferred crystal form of the compound of formula (1) in the present application has good fluidity and particle shape, as well as significantly improved viscosity, which can significantly reduce filtration time, shorten production cycle, and save costs during the preparation process.
  • Another aspect of the present application provides a method for preparing the crystalline form of the present application, which includes but not limited to room temperature solvent evaporation method, suspension stirring method, anti-solvent addition method, cooling method and the like.
  • compositions which comprises any one or more crystal forms in the present application, and one or more pharmaceutically acceptable carriers.
  • crystal form of the present application is used in the preparation for the treatment of acute or chronic pain, migraine, osteoarthritis, rheumatoid arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea , cancer or atherosclerosis medicine purposes.
  • Fig. 1 is the XRPD pattern of the crystal form I of the compound of formula (1).
  • Figure 2 is the DSC and TGA spectra of the crystal form I of the compound of formula (1).
  • Fig. 3 is the XRPD pattern of the crystal form II of the compound of formula (1).
  • Figure 4 is the DSC and TGA spectra of the crystal form II of the compound of formula (1).
  • Fig. 5 is the XRPD pattern of the crystal form III of the compound of formula (1).
  • Fig. 6 is the DSC and TGA spectra of the crystal form III of the compound of formula (1).
  • Fig. 7 is the XRPD pattern of the crystal form IV of the compound of formula (1).
  • Fig. 8 is the DSC and TGA spectra of the crystal form IV of the compound of formula (1).
  • Fig. 9 is an XRPD pattern of Form V of the compound of formula (1).
  • Figure 10 is the DSC and TGA spectra of the crystal form V of the compound of formula (1).
  • FIG. 11 is a comparison of XRPD patterns of the samples before and after the grinding experiment of Experimental Example 1.
  • Figure 12 is a comparison of the XRPD patterns of Form IV in Experimental Example 2 before and after heating.
  • Figure 13 is a comparison of the XRPD patterns of Form II in Experimental Example 3 before and after testing.
  • the word "about” means that one of ordinary skill in the art considers within an acceptable standard error of the stated value, such as ⁇ 0.05, ⁇ 0.1, ⁇ 0.2, ⁇ 0.3, ⁇ 1, ⁇ 2, or ⁇ 3 etc.
  • solid form includes all solid forms, such as crystalline or amorphous forms, of the compound of formula (1).
  • amorphous refers to any solid substance that is not ordered in three dimensions.
  • amorphous solids can be characterized by known techniques including XRPD crystallography, solid state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques. As explained below, amorphous solids give rise to diffuse XRPD patterns that typically include one or two broad peaks (ie, peaks with a base width of about 5° 2 ⁇ or greater).
  • crystalline form or “crystal” as used herein refers to any solid material that exhibits a three-dimensional order, as opposed to amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.
  • X-ray powder diffraction pattern refers to an experimentally observed diffraction pattern or parameters derived therefrom. XRPD patterns are usually characterized by peak positions (abscissa) and/or peak intensities (ordinate).
  • the XRPD collection of illustrative plates in the present application is preferably collected on PANalytacal Empyrean and X'Pert3 X-ray powder diffraction analyzer, and the transmission mode is preferably collected on PANalytacal Empyrean X-ray powder diffraction analyzer.
  • 2 ⁇ refers to the peak position in degrees based on the experimental setup of an X-ray diffraction experiment, and is generally a unit of abscissa in a diffraction pattern. If the reflections are diffracted when the incident beam forms an angle ⁇ with a certain lattice plane, the experimental setup requires recording the reflected beam at 2 ⁇ angles. It should be understood that references herein to specific 2 ⁇ values for particular crystalline forms are intended to represent 2 ⁇ values (expressed in degrees) as measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, using Cu-K ⁇ (K ⁇ 1 : 1.540598 and K ⁇ 2 : 1.544426) as the radiation source.
  • DSC differential scanning calorimetry
  • the term "substantially the same" for X-ray diffraction peak positions means taking representative peak positions and intensity variations into account. For example, those skilled in the art will understand that peak position (2 ⁇ ) will show some variation, typically by as much as 0.1-0.2 degrees, and that the instrumentation used to measure diffraction will also show some variation. Additionally, those skilled in the art will appreciate that relative peak intensities will exhibit inter-instrument variation as well as variations due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be considered only for qualitative measurement. Similarly, as used herein, “substantially the same” with respect to a DSC profile is also intended to cover variations associated with these analytical techniques known to those skilled in the art. For example, differential scanning calorimetry profiles will typically have as much as ⁇ 0.2°C variation for well-defined peaks, and even greater (eg, as much as ⁇ 1°C) for broad peaks.
  • liquid-state NMR spectra in this application are preferably collected on a Bruker 400M NMR instrument, unless otherwise specified, using DMSO-d 6 as a solvent.
  • hydrocarbons as used herein preferably means hydrocarbons having 1-10 carbon atoms, including alkanes, halogenated alkanes, alkenes, alkynes and aromatics, specifically including but not limited to dichloro Methane, chloroform (chloroform), n-hexane, n-heptane, and toluene.
  • alcohols as used herein preferably means alcohols having 1-10 carbon atoms, including but not limited to methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropanol alcohol), 1-butanol, 2-butanol and tert-butanol.
  • ether as used herein preferably means an ether having 2-6 carbon atoms, including chain ethers and cyclic ethers (such as furans (including tetrahydrofuran) and dioxane class), specifically including but not limited to diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, anisole and dimethoxy ethane.
  • chain ethers and cyclic ethers such as furans (including tetrahydrofuran) and dioxane class
  • nitriles as used herein preferably means nitriles having 2-6 carbon atoms, including but not limited to acetonitrile and propionitrile.
  • ketone solvent preferably means a ketone having 2-6 carbon atoms, including but not limited to acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and diethyl base ketones.
  • esters as used herein preferably means esters having 3-10 carbon atoms, including but not limited to ethyl acetate, propyl acetate, isopropyl acetate, ethyl isopropionate, dicarbonate methyl ester and butyl acetate.
  • organic acids as used herein preferably means organic acids having 1-10 carbon atoms, including but not limited to formic acid and acetic acid.
  • sulfones as used herein preferably means sulfones or sulfoxides having 2-10 carbon atoms, including but not limited to dimethyl sulfoxide.
  • amides as used herein preferably means amides having 1-10 carbon atoms, including but not limited to dimethylformamide or dimethylacetamide.
  • nitrogen heterocycle preferably means a nitrogen-containing heterocycle having 3-10 carbon atoms and at least one nitrogen atom, including but not limited to N-methylpyrrolidone.
  • the prepared salt or its crystalline form may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration or any other technique for solid recovery under increased or reduced pressure.
  • the recovered solid can optionally be dried.
  • "Drying" in the present invention is carried out under reduced pressure (preferably vacuum) until the content of residual solvent is reduced to the limit given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines within range.
  • the residual solvent content depends on the type of solvent, but does not exceed about 5000 ppm, or preferably about 4000 ppm, or more preferably about 3000 ppm.
  • the drying can be in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, etc. conduct.
  • the drying may be at atmospheric pressure or reduced pressure ( Preferably under vacuum) for any desired period of time (such as about 1, 2, 3, 5, 10, 15, 20, 24 hours or overnight) to achieve the desired result, provided the quality of the salt does not deteriorate.
  • the drying can be performed any desired number of times until the desired product quality is achieved.
  • the dried product can optionally be subjected to a comminution operation to produce the desired particle size. Grinding or micronization may be performed before drying of the product or after drying is complete. Techniques that can be used to reduce particle size include, but are not limited to, ball, roller, and hammer milling, and jet milling.
  • anhydrous crystal form as used herein preferably means a crystal form in which no water molecule is contained as a structural element.
  • the present invention provides the crystalline form I of the compound of formula (1)
  • the XRPD pattern of the crystalline form I includes the crystal form I at about 6.3 ⁇ 0.2°, 11.0 ⁇ 0.2°, 13.5 ⁇ 0.2°, 16.7 ⁇ 0.2° , 18.3 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.0 ⁇ 0.2°, 22.1 ⁇ 0.2°, 22.8 ⁇ 0.2° and 25.3 ⁇ 0.2° at diffraction angles (2 ⁇ ).
  • the XRPD pattern of Form I of the compound of formula (1) includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of Form I of the compound of formula (1) includes peaks at substantially the same diffraction angle (2 ⁇ ) as shown in FIG. 1 .
  • the XRPD pattern of the crystalline form I of the compound of formula (1) is substantially as shown in FIG. 1 , and preferably as shown in FIG. 1 .
  • the DSC profile of Form I of the compound of formula (1) of the present invention comprises a characteristic peak at about 220 ⁇ 2°C (onset temperature).
  • Form I of the compound of formula (1) of the present invention has a weight loss of less than about 0.2% upon heating to about 200°C.
  • the DSC-TGA spectrum of the crystalline form I of the compound of formula (1) includes characteristic peaks at substantially the same temperature as shown in FIG. 2 .
  • the DSC-TGA spectrum of the crystal form I of the compound of formula (1) is substantially as shown in Figure 2, and preferably as shown in Figure 2 .
  • the crystalline form I of the compound of formula (1) is an anhydrous crystalline form.
  • the present invention provides the crystalline form II of the compound of formula (1)
  • the XRPD pattern of the crystalline form II includes the crystal form II at about 6.3 ⁇ 0.2°, 11.1 ⁇ 0.2°, 13.8 ⁇ 0.2°, 16.6 ⁇ 0.2° , 16.8 ⁇ 0.2°, 18.2 ⁇ 0.2°, 19.2 ⁇ 0.2°, 22.4 ⁇ 0.2°, 22.8 ⁇ 0.2° and 25.2 ⁇ 0.2° at diffraction angles (2 ⁇ ).
  • the XRPD pattern of the crystalline form II of the compound of formula (1) includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of Form II of the compound of formula (1) includes peaks at substantially the same diffraction angle (2 ⁇ ) as shown in FIG. 3 .
  • the XRPD pattern of the crystalline form II of the compound of formula (1) is substantially as shown in FIG. 3 , and preferably as shown in FIG. 3 .
  • the DSC profile of the crystalline form II of the compound of formula (1) of the present invention comprises a characteristic peak at about 224 ⁇ 2°C (onset temperature).
  • the crystalline form II of the compound of formula (1) of the present invention exhibits little weight loss upon heating to about 200°C.
  • the DSC-TGA spectrum of the crystalline form II of the compound of formula (1) includes characteristic peaks at substantially the same temperature as shown in FIG. 4 .
  • the DSC-TGA spectrum of the crystalline form II of the compound of formula (1) is substantially as shown in FIG. 4 , and preferably as shown in FIG. 4 .
  • the crystalline form II of the compound of formula (1) is an anhydrous crystalline form.
  • the present invention provides the crystalline form III of the compound of formula (1)
  • the XRPD pattern of the crystalline form III includes the crystal form III at about 5.3 ⁇ 0.2°, 10.7 ⁇ 0.2°, 12.0 ⁇ 0.2°, 17.7 ⁇ 0.2° , 18.1 ⁇ 0.2°, 21.6 ⁇ 0.2°, 22.1 ⁇ 0.2°, 26.9 ⁇ 0.2°, 31.9 ⁇ 0.2° and 32.6 ⁇ 0.2° at diffraction angles (2 ⁇ ).
  • the XRPD pattern of the crystal form III of the compound of formula (1) includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of Form III of the compound of formula (1) includes peaks at substantially the same diffraction angle (2 ⁇ ) as shown in FIG. 5 .
  • the XRPD pattern of Form III of the compound of formula (1) is substantially as shown in FIG. 5 , and preferably as shown in FIG. 5 .
  • the DSC profile of Form III of the compound of formula (1) of the present invention comprises characteristic peaks at about 97 ⁇ 2°C and 223 ⁇ 2°C (onset temperature).
  • the crystalline form III of the compound of formula (1) of the present invention has a weight loss of about 14% upon heating to about 125°C.
  • the DSC-TGA spectrum of the crystalline form III of the compound of formula (1) includes characteristic peaks at substantially the same temperature as shown in FIG. 6 .
  • the DSC-TGA spectrum of the crystal form III of the compound of formula (1) is substantially as shown in FIG. 6 , and preferably as shown in FIG. 6 .
  • the crystal form III of the compound of formula (1) is a tetrahydrofuran solvate, wherein the molar ratio of the compound of formula (1) to tetrahydrofuran is preferably 1:1.
  • the present invention provides the crystalline form IV of the compound of formula (1)
  • the XRPD pattern of the crystalline form IV includes the crystal form IV at about 8.7 ⁇ 0.2°, 12.1 ⁇ 0.2°, 12.7 ⁇ 0.2°, 15.5 ⁇ 0.2° , 18.3 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.3 ⁇ 0.2°, 19.9 ⁇ 0.2°, 21.5 ⁇ 0.2°, 24.4 ⁇ 0.2° and 27.8 ⁇ 0.2° at the diffraction angles (2 ⁇ ).
  • the XRPD pattern of the crystalline form IV of the compound of formula (1) includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of the crystalline form IV of the compound of formula (1) includes peaks at substantially the same diffraction angle (2 ⁇ ) as shown in FIG. 7 .
  • the XRPD pattern of the crystalline form IV of the compound of formula (1) is substantially as shown in Figure 7, and preferably as shown in Figure 7.
  • the DSC profile of Form IV of the compound of formula (1) of the present invention comprises characteristic peaks at about 169 ⁇ 2°C and 222 ⁇ 2°C (onset temperature).
  • the crystalline form IV of the compound of formula (1) of the present invention exhibits little weight loss upon heating to about 200°C.
  • the DSC-TGA spectrum of the crystalline form IV of the compound of formula (1) includes characteristic peaks at substantially the same temperature as shown in FIG. 8 .
  • the DSC-TGA spectrum of the crystalline form IV of the compound of formula (1) is substantially as shown in FIG. 8 , and preferably as shown in FIG. 8 .
  • the crystalline form IV of the compound of formula (1) is an anhydrous crystalline form.
  • the present invention provides a crystalline form V of a compound of formula (1)
  • the XRPD pattern of the crystalline form V includes a temperature at about 5.9 ⁇ 0.2°, 8.3 ⁇ 0.2°, 11.9 ⁇ 0.2°, 13.4 ⁇ 0.2° , 16.8 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.5 ⁇ 0.2°, 20.7 ⁇ 0.2°, 24.0 ⁇ 0.2° and 28.2 ⁇ 0.2° at diffraction angles (2 ⁇ ).
  • the XRPD pattern of Form V of the compound of formula (1) includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of Form V of the compound of formula (1) includes peaks at substantially the same diffraction angle (2 ⁇ ) as shown in FIG. 9 .
  • the XRPD pattern of Form V of the compound of formula (1) is substantially as shown in FIG. 9 , and preferably as shown in FIG. 9 .
  • the DSC profile of Form V of the compound of formula (1) of the present invention comprises characteristic peaks at about 102 ⁇ 2°C, 113 ⁇ 2°C and 224 ⁇ 2°C (onset temperature).
  • the crystalline form V of the compound of formula (1) of the present invention has a weight loss of about 15% upon heating to about 200°C.
  • the DSC-TGA spectrum of Form V of the compound of formula (1) includes characteristic peaks at substantially the same temperature as shown in FIG. 10 .
  • the DSC-TGA spectrum of Form V of the compound of formula (1) is substantially as shown in FIG. 10 , and preferably as shown in FIG. 10 .
  • the crystal form V of the compound of formula (1) is a dimethyl sulfoxide solvate, wherein the molar ratio of the compound of formula (1) to dimethyl sulfoxide is preferably 1:1 .
  • the present invention also provides a method for preparing any one of the above crystal forms I-V, the method includes but not limited to room temperature solvent evaporation method, suspension stirring method, anti-solvent addition method, cooling method and the like.
  • the crystalline form is prepared by solvent evaporation at room temperature, the method comprising completely dissolving the solid of the compound of formula (1) in a solvent to form a clear solution (if necessary, the solution can be filtered to obtain a clear solution), The obtained solution was placed at room temperature to completely evaporate the solvent to obtain a crystal form.
  • the solvent includes, but is not limited to, organic solvents, such as alcohols, hydrocarbons (including alkanes, halogenated alkanes, alkenes, alkynes, and aromatics) having 1-10 carbon atoms, Ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofuran) and dioxanes)), ketones, nitriles or esters, such as methanol, ethanol, isopropanol, Dichloromethane, chloroform (chloroform), tetrahydrofuran, acetone, butanone, methyl tert-butyl ether, ethyl acetate, or acetonitrile, or a mixed solvent of two or more of the above solvents.
  • organic solvents such as alcohols, hydrocarbons (including alkanes, halogenated alkanes, alkenes, alkynes, and aromatics) having 1-10 carbon atoms, Et
  • the solvents used include but are not limited to organic solvents, such as hydrocarbons with 1-10 carbon atoms (including alkanes, halogenated alkanes, alkenes , alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofuran) and dioxanes)) or ketones, such as dichloromethane, Tetrahydrofuran, acetone or methyl ethyl ketone, or a mixed solvent formed of two or more of the above solvents.
  • organic solvents such as hydrocarbons with 1-10 carbon atoms (including alkanes, halogenated alkanes, alkenes , alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofuran) and dioxanes)) or ketones, such as dichloromethane, Tetrahydrofuran, acetone or
  • the solvent used when using the room temperature solvent evaporation method to prepare the crystal form II, includes but is not limited to organic solvents, such as alcohols or nitriles with 1-10 carbon atoms, specifically ethanol or acetonitrile, Or a mixed solvent formed of two or more of the above-mentioned solvents.
  • organic solvents such as alcohols or nitriles with 1-10 carbon atoms, specifically ethanol or acetonitrile, Or a mixed solvent formed of two or more of the above-mentioned solvents.
  • the weight-to-volume ratio (mg/mL) of the compound of formula (1) to the solvent is (5-20):1, preferably about 10:1.
  • the crystal form is prepared by a suspension-stirring method, which comprises adding the solid compound of formula (1) into a solvent to obtain a suspension, stirring, and then separating to obtain the crystal form.
  • the stirring is performed at room temperature or elevated temperature (eg, 40-60°C, preferably about 50°C).
  • the solvents include, but are not limited to, inorganic solvents (such as water) and organic solvents (such as alcohols, ketones, hydrocarbons (including alkanes, halogenated alkanes, alkenes) having 1-10 carbon atoms alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofuran) and dioxanes)), esters, nitriles and organic acids , such as methanol, n-propanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, n-hexane, n-heptane, di Chloromethane, methyl tert-butyl ether, dioxane
  • the mixed solvent is preferably a mixed solvent shown in the following table:
  • Solvent 1 Solvent 2 Methanol water acetone water Acetonitrile water Methanol ethyl acetate Methanol methyl tert-butyl ether Methanol Acetonitrile ethanol Butyl acetate ethanol n-heptane acetone Isopropanol acetone ethyl acetate Acetonitrile Methyl acetate acetone n-heptane acetone Acetonitrile butanone n-heptane
  • the volume ratio of solvent 1 to solvent 2 is 1:1 to 1:5, preferably 1:1 to 1:3.
  • the weight-to-volume ratio (mg/mL) of the compound of formula (1) to the solvent is (20-350): 1, preferably (20-300): 1, more preferably (60-300) :1, most preferably (60-150):1.
  • the crystalline form is prepared by an anti-solvent addition method, which comprises dissolving the solid of the compound of formula (1) in a good solvent to form a clear solution (if necessary, the solution can be filtered to obtain a clear solution) , then anti-solvent was added to the clear solution, a solid was precipitated and filtered to obtain the crystalline form.
  • an anti-solvent addition method comprises dissolving the solid of the compound of formula (1) in a good solvent to form a clear solution (if necessary, the solution can be filtered to obtain a clear solution) , then anti-solvent was added to the clear solution, a solid was precipitated and filtered to obtain the crystalline form.
  • the good solvents include, but are not limited to, organic solvents, such as alcohols, ketones, hydrocarbons (including alkanes, halogenated alkanes, alkenes, alkynes and Aromatic hydrocarbons), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofuran) and dioxanes)), sulfones, amides and organic acids, such as methanol, ethanol, Acetone, tetrahydrofuran, acetic acid, chloroform, dimethylsulfoxide, or dimethylacetamide.
  • organic solvents such as alcohols, ketones, hydrocarbons (including alkanes, halogenated alkanes, alkenes, alkynes and Aromatic hydrocarbons), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofuran) and dioxanes)), sulfones, amides and
  • the anti-solvents include but are not limited to inorganic solvents (such as water) and organic solvents (such as ketones with 1-10 carbon atoms, hydrocarbons (including alkanes, halogenated alkanes, alkenes, Alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofuran) and dioxanes)), esters and nitriles), such as n-hexane, n-heptane, cyclopentyl methyl ether, acetonitrile, methyl isobutyl ketone, 2-methyl tetrahydrofuran, dioxane, isopropyl acetate, dichloromethane, toluene, acetonitrile, methyl ethyl ketone, methyl tert-butyl ether, ethyl isopropionate, dimethyl carbonate and
  • the good solvent used is a ketone solvent (preferably acetone) with 1-10 carbon atoms; and the anti-solvent used is an inorganic solvent (preferably water) or a hydrocarbon solvent having 1-10 carbon atoms (preferably n-heptane).
  • the good solvent used is an ether solvent having 1-10 carbon atoms (preferably tetrahydrofuran); and the anti-solvent used is - a hydrocarbon solvent of 10 carbon atoms (preferably n-heptane).
  • the good solvent used is an alcohol solvent (preferably methanol) or a sulfone solvent (preferably dimethyl methoxide) with 1-10 carbon atoms. sulfone); and the anti-solvent used is an inorganic solvent (preferably water).
  • the volume ratio of the good solvent to the anti-solvent is (0.5-1):(1-20), preferably about 1:10.
  • the weight-to-volume ratio (mg/mL) of the compound of formula (1) to the good solvent is (50-200):1, preferably (90-150):1.
  • the cooling method is used to prepare the crystal form.
  • the method includes adding the solid of the compound of formula (1) to the solvent, heating and stirring to dissolve it, and filtering the resulting clear solution (if necessary, the solution can be filtered to obtain Obtain a clear solution) place, slowly cool down, obtain crystal form.
  • the solvents include but are not limited to inorganic solvents (such as water) and organic solvents, such as alcohols, ketones, hydrocarbons (including alkanes, halogenated alkanes, alkenes) having 1-10 carbon atoms alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofuran) and dioxanes)), nitriles, esters and sulfones, Specifically, for example, isopropanol, acetone, butanone, chloroform, acetonitrile, tetrahydrofuran, methanol, n-hexane, cyclohexane, methyl acetate, ethyl acetate or dimethyl sulfoxide, or by two or more of the above solvents More variety of mixed solvents formed.
  • organic solvents such as alcohols, ketones, hydrocarbons (including alkanes, halogen
  • the mixed solvent is preferably a mixed solvent shown in the following table:
  • Solvent 1 Solvent 2 acetone water Tetrahydrofuran Cyclohexane Dimethyl sulfoxide water
  • the volume ratio of solvent 1 to solvent 2 is from 5:1 to 1:5, preferably about 1:1.
  • the solvent used is an alcoholic solvent with 1-10 carbon atoms, preferably isopropanol.
  • the solvent used is nitriles (preferably acetonitrile), ketones (preferably methyl ethyl ketone), esters (preferably methyl acetate) solvent, or a mixed solvent of water and a ketone (preferably acetone) solvent having 1 to 10 carbon atoms.
  • the solvent used is a mixed solvent of tetrahydrofuran and a hydrocarbon solvent having 1-10 carbon atoms (preferably cyclohexane).
  • the solvent used is a mixed solvent of water and dimethyl sulfoxide.
  • the weight-to-volume ratio (mg/mL) of the compound of formula (1) to the solvent is (60-150):1.
  • the application provides a pharmaceutical composition, which comprises any one or more of the crystal forms I, II, III, IV or V of the compound of formula (1) of the present invention, and one or Various pharmaceutically acceptable carriers.
  • the application provides the crystal form I, II, III, IV or V of the compound of formula (1) of the present invention in the preparation for the treatment of acute or chronic pain, migraine, osteoarthritis, rheumatoid Drugs for arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea, cancer or arteriosclerosis.
  • the application provides the crystal form I, II, III, IV or V of the compound of formula (1) of the present invention, which is used for the treatment of acute or chronic pain, migraine, osteoarthritis, rheumatoid arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea, cancer, or atherosclerosis.
  • the present application provides for the treatment of acute or chronic pain, migraine, osteoarthritis, rheumatoid arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea, cancer or atherosclerosis
  • a method comprising administering to an individual (preferably a mammal) in need thereof a prophylactically or therapeutically effective amount of any one of the crystal forms I, II, III, IV or V of the compound of formula (1) of the present invention or Various.
  • the present application provides the use of the crystal form I, II, III, IV or V of the compound of formula (1) of the present invention in the preparation of a medicament for treating cancer.
  • the present application provides the crystalline form I, II, III, IV or V of the compound of formula (1) of the present invention for use in the treatment of cancer.
  • the present application provides a method for treating cancer, which comprises administering a prophylactically or therapeutically effective amount of the crystal form I, II of the compound of formula (1) of the present invention to an individual (preferably a mammal) in need thereof Any one or more of , III, IV or V.
  • the cancer is selected from breast cancer, cervical cancer, colorectal cancer, endometrial cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer , pancreatic, prostate, skin and urinary tract cancers.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle with which a therapeutic agent is administered, and which is within the scope of sound medical judgment suitable for contacting Human and/or other animal tissues without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol etc.
  • the composition if desired, can also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents.
  • Oral formulations can contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the invention may act systemically and/or locally.
  • they can be administered by suitable routes, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, It is administered as an ophthalmic preparation or by inhalation.
  • compositions of the present invention can be administered in suitable dosage forms.
  • the dosage forms can be solid preparations, semi-solid preparations, liquid preparations or gaseous preparations, specifically including but not limited to tablets, capsules, powders, granules, lozenges, hard candies, powders, sprays, creams, ointments elixirs, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, suspensions, elixirs, syrups.
  • the pharmaceutical composition of the present invention can be prepared by any method well known in the art, for example, by mixing, dissolving, granulating, sugar coating, milling, emulsifying, freeze-drying and other treatments.
  • terapéuticaally effective amount refers to the amount of a compound which, when administered, alleviates to some extent one or more symptoms of the condition being treated.
  • Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may comprise single or multiple doses. It is further understood that for any given individual, the specific dosing regimen will be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • the amount of a compound of this invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician.
  • the effective dosage is about 0.0001 to about 50 mg per kg body weight per day, for example about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg human this would amount to about 0.007 mg/day to about 3500 mg/day, eg about 0.7 mg/day to about 700 mg/day.
  • Dosage levels up to the lower limit of the foregoing range may be sufficient in some cases, while in other cases larger doses may still be employed without causing any deleterious side effects, provided that the larger dose is first administered.
  • the dose is divided into several smaller doses to be administered throughout the day.
  • the content or amount of the compound of the present invention in the pharmaceutical composition can be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2mg, 4mg, 10mg and 25mg etc.
  • treating means reversing, alleviating, inhibiting the disorder or condition to which such term applies or the progression of one or more symptoms of such disorder or condition, or Such a disorder or condition or one or more symptoms of such a disorder or condition is prevented.
  • “Individual” as used herein includes a human or non-human animal.
  • Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • the crystal form of the solid obtained in the examples was analyzed using PANalytical EMPYREAN equipped with a PIXceI 1D detector.
  • the instrument parameters are as follows: scanning range: 3° (2 ⁇ ) to 40° (2 ⁇ ); step size: 0.013° (2 ⁇ ); light tube voltage and current are 45KV and 40mA, respectively.
  • TGA 55 (TAInstruments, US) to carry out thermogravimetric analysis to the sample.
  • the sample was placed in an open aluminum sample pan, and after the sample was automatically weighed in the TGA heating furnace, the sample was heated to the final temperature at a rate of 10°C/min.
  • the samples were thermally analyzed using a Discovery DSC 250 (TA Instruments, US). Weigh ⁇ 2 mg of sample into the DSC sample pan. The sample was equilibrated at 25°C and heated to the final temperature at a rate of 10°C/min.
  • the measuring instrument of HPLC is Agilent HPLC 1260 series instrument.
  • the HPLC measurement methods are listed below.
  • Step 1 Synthesis of methyl 3-(1-aminocyclopropyl)bicyclo[1.1.1]pentane-1-carboxylate B
  • BF 3 ⁇ Et 2 O (27.6 g, 194 mmol, 24 mL) was added dropwise and stirred at -20°C for 30 minutes, then at 25°C for 12 hours.
  • Aqueous hydrochloric acid (1 N, 30 mL) was added slowly at 0°C to quench the reaction mixture, and the separated organic layer was discarded.
  • the aqueous phase was basified to pH ⁇ 12 with 10M aqueous sodium hydroxide solution at 0°C and extracted with ethyl acetate (200 mL x 2).
  • Step 4 Synthesis of 1-(benzofuran-2-ylmethyl)-1H-indole-7-carboxylic acid methyl ester G
  • Step 7 3-(1-(1-(benzofuran-2-ylmethyl)-1H-indole-7-carboxamido)cyclopropyl)bicyclo[1.1.1]pentane-1-carboxy combination of acid 1 become
  • Embodiment 2 room temperature solvent volatilization method
  • Example 1 The solid of the compound of formula (1) obtained in Example 1 was completely dissolved in the following solvent (the solution concentration was about 10 mg/mL), and then the resulting solution was left at room temperature to completely evaporate the solvent to obtain a solid. Carry out XRPD analysis to gained solid, and judge crystal form by gained XRPD collection of illustrative plates (when XRPD collection of illustrative plates and Fig.
  • Embodiment 3 single solvent room temperature suspension stirring method
  • Example 1 30 mg of the solid compound of formula (1) obtained in Example 1 was weighed and added to the following volume of solvent to form a suspension. The resulting suspension was stirred at room temperature for 3 days, then filtered to obtain a solid. The obtained solid was subjected to XRPD analysis, and the crystal form was judged from the obtained XRPD pattern. The results are shown in the table below.
  • Embodiment 4 mixed solvent room temperature suspension stirring method
  • Example 2 Weigh 30 mg of the solid compound of formula (1) obtained in Example 1, place it in each mixed solvent shown in the following table, and prepare a suspension. The resulting suspension was stirred at room temperature for 3 days, then filtered to obtain a solid. The obtained solid was subjected to XRPD analysis, and the crystal form was judged from the obtained XRPD pattern. The results are shown in the table below.
  • Solvent 1 Solvent 2 Volume 1 / Volume 2 Total solvent volume (mL) crystal form Methanol water 1/1 0.5 Form II acetone water 1/1 0.5 Form II Acetonitrile water 1/1 0.5 Form II Methanol ethyl acetate 1/3 0.5 Form II Methanol methyl tert-butyl ether 1/3 0.5 Form II Methanol Acetonitrile 1/3 0.5 Form II ethanol Butyl acetate 1/3 0.5 Form II ethanol n-heptane 1/1 0.5 Form II acetone Isopropanol 1/3 0.5 Form II acetone ethyl acetate 1/1 0.5 Form II Acetonitrile Methyl acetate 1/1 0.5 Form II acetone n-heptane 1/1 0.5 Form II acetone Acetonitrile 1/1 0.5 Form II
  • Embodiment 5 single solvent high temperature suspension stirring method
  • Example 2 Weigh 30 mg of the solid compound of formula (1) obtained in Example 1, and add it to the following volume of solvent to form a suspension. The resulting suspension was stirred at 50°C for 3 days, then filtered to obtain a solid. The obtained solid was subjected to XRPD analysis, and the crystal form was judged from the obtained XRPD pattern. The results are shown in the table below.
  • Embodiment 6 mixed solvent high temperature suspension stirring method
  • Example 2 Weigh 30 mg of the solid compound of formula (1) obtained in Example 1, place it in each mixed solvent shown in the following table, and prepare a suspension. The resulting suspension was stirred at 50°C for 3 days, then filtered to obtain a solid. The obtained solid was subjected to XRPD analysis, and the crystal form was judged from the obtained XRPD pattern. The results are shown in the table below.
  • Solvent 1 Solvent 2 Volume 1 / Volume 2 Total solvent volume (mL) crystal form Methanol ethyl acetate 1/3 0.5 Form II acetone ethyl acetate 1/1 0.5 Form II acetone Isopropanol 1/3 0.5 Form II Acetonitrile Methyl acetate 1/1 0.5 Form II acetone Acetonitrile 1/3 0.5 Form II
  • Embodiment 7 anti-solvent addition method
  • Example 1 weigh the indicated amount of solid compound of formula (1) obtained in Example 1, put it into a good solvent, filter the resulting solution, and slowly add the filtrate to the antisolvent. The precipitated solid was filtered and subjected to XRPD analysis. The crystal form was judged from the obtained XRPD pattern, and the results are shown in the table below.
  • Embodiment 8 single solvent cooling method
  • Example 1 Weigh about 30 mg of the solid compound of formula (1) obtained in Example 1, add it to each solvent shown in the table below, and heat the obtained suspension to completely dissolve the solid. The solution was then cooled. The precipitated solid was filtered and subjected to XRPD analysis. The crystal form was judged from the obtained XRPD pattern, and the results are shown in the table below.
  • Embodiment 9 mixed solvent cooling method
  • Example 1 Weigh about 30 mg of the solid compound of formula (1) obtained in Example 1, add it to each mixed solvent shown in the following table, and heat the obtained suspension to completely dissolve the solid. The solution was filtered, and the filtrate was cooled to room temperature. The precipitated solid was filtered and subjected to XRPD analysis. The crystal form was judged from the obtained XRPD pattern, and the results are shown in the table below.
  • Solvent 1 Solvent 2 Volume 1 / Volume 2 Total solvent volume (mL) crystal form acetone water 1/1 0.2mL Form II Tetrahydrofuran Cyclohexane 1/1 0.2mL Form III Dimethyl sulfoxide water 1/1 0.2mL Form V
  • the XRPD patterns of the starting sample and the milled sample are shown in FIG. 11 .
  • Form IV was slowly heated to 200°C and then cooled to room temperature. Samples before and after heating were collected for XRPD detection.
  • the crystalline form II was stored at 60°C closed and 40°C/75%RH for 7 days respectively.
  • the purity of the samples was determined by HPLC before and after storage, and the XRPD patterns of the samples were determined.
  • test results show that the samples are placed under light conditions (total illuminance not lower than 1.2x10 6 Lux ⁇ hr, near-ultraviolet energy not lower than 200w ⁇ hr/m 2 ) for 30 days. Compared with the results of day 0, the water content and content of the samples have no significant changes, and no new impurities greater than 0.05% are produced.
  • the XRPD pattern shows that the crystal form of the sample has not changed.
  • the crystal form II of the compound of formula (1) was placed at a high temperature of 60°C for 30 days, and samples were taken at 0 days, 5 days, 10 days and 30 days respectively, and the changes in the properties of the samples were observed, and the specific rotation was measured with a polarimeter. The loss on drying was detected, the total impurity content was measured by HPLC, and the XRPD spectrum of the sample was determined.
  • test results show that when the sample is placed at a high temperature of 60°C for 30 days, there is no significant difference in appearance, moisture, content and crystal form compared with the results at 0 day, and no new impurities greater than 0.05% are produced.
  • test results show that: the sample is placed under high humidity 92.5% RH for 30 days, and the water absorption is 0.03%, less than 5%; the appearance, moisture, content and crystal form are not significantly different from the 0-day results, and no more than 0.05% of new impurities.
  • the crystal form II of the compound of formula (1) was formulated into a clear solution of 10% DMSO, 60% PEG 400, and 30% water for injection, and administered intravenously to SD rats.
  • the crystal form II of the compound of formula (1) was prepared as a suspension solution in 0.5% sodium carboxymethylcellulose (CMC.Na), and administered to SD rats by intragastric administration, and its pharmacokinetic characteristics were investigated.
  • the drug exposure AUC 0-t of the compound in SD rats was 78,811ng*hr/mL, and the clearance rate (CL) and The steady-state apparent volumes of distribution (Vss) were 3.59 mL/min/kg and 1.18 L/kg, respectively.
  • the maximum plasma concentration Cmax and exposure AUC 0-t of the compound were 27,700 ng/mL and 153,279 ng*hr/mL, respectively.
  • crystal form II of the compound of formula (1) in the present invention has excellent blood drug concentration and exposure.
  • the crystal form II of the compound of formula (1) was formulated into a clear solution of 10% DMSO, 60% PEG 400, and 30% water for injection, and administered intravenously to Beagle dogs.
  • the crystalline form II of the compound of formula (1) was prepared as a suspension solution in 0.5% sodium carboxymethylcellulose (CMC.Na), administered to Beagle dogs by intragastric administration, and its pharmacokinetic characteristics were investigated.
  • the drug exposure (AUC 0-t ) of the compound in Beagle dogs was 12,649 ng*hr/mL, and the clearance rate (CL) and the steady-state apparent volume of distribution (Vss) were 6.64mL/min/kg and 1.50L/kg, respectively, indicating that the compound of formula (1) is a low clearance compound and is widely distributed in the body.
  • the maximum plasma concentration Cmax and exposure AUC 0-t of the compound were 32,917 ng/mL and 79,576 ng*hr/mL, respectively.
  • crystal form II of the compound of formula (1) in the present invention has excellent blood drug concentration and exposure.

Abstract

本申请涉及一种吲哚类化合物的固体形式及其制备方法和用途。具体而言，本申请涉及式(1)的化合物的固体形式，制备所述固体形式的方法、包含所述固体形式的药物组合物，以及所述固体形式在治疗疾病中的用途。

Description

一种吲哚类化合物的固体形式及其制备方法和用途 发明领域
本申请涉及一种吲哚类化合物的固体形式及其制备方法和用途。具体而言，本申请涉及3-(1-(1-(苯并呋喃-2-基甲基)-1H-吲哚-7-甲酰胺基)环丙基)双环[1.1.1]戊烷-1-羧酸(在下文中称作“式(1)的化合物”)的固体形式，制备所述固体形式的方法、包含所述固体形式的药物组合物，以及所述固体形式在治疗疾病中的用途。
发明背景
E型前列腺素2(PGE2)是花生四烯酸衍生物，它可以抑制免疫细胞功能，逃逸抗肿瘤免疫力。PGE2通过4种E型PGE2受体(EP1、EP2、EP3和EP4)调节生物学功能。EP4是肿瘤组织中的主要PGE2受体，并参与PGE2促进肿瘤发展。有证据表明，EP4受体的表达在许多肿瘤组织中增加。大量证据还表明，许多肿瘤组织中PGE2的水平增加，同时通过EP4受体抑制了肿瘤组织中免疫细胞的功能，使肿瘤细胞逃脱了抗肿瘤免疫系统，加速了肿瘤的生长和转移。EP4受体拮抗剂可以阻断PGE2的这些作用，从而增强抗肿瘤免疫功能。
此外，科学证据表明，选择性EP4拮抗剂可能是一种有效的炎症性疼痛缓解药物，其肠道耐受性优于NSAID和COX-2抑制剂等目前的标准消炎镇痛药物。值得关注的是，由于EP4拮抗剂不直接干扰前列腺素E(PGE2)和其他前列腺素(例如前列环素和血栓素)的生物合成，因此该类药物可具有更好的心血管安全性。
鉴于EP4拮抗剂在肿瘤免疫和消炎镇痛方面的应用前景，已有多款EP4拮抗剂处于临床研究阶段，但截至目前，尚没有该类药物获批上市。对于该类药物的固体形式也鲜有报道。
发明概述
本申请的一个方面提供如下所示的式(1)的化合物(3-(1-(1-(苯并呋喃-2-基甲基)-1H-吲哚-7-甲酰胺基)环丙基)双环[1.1.1]戊烷-1-羧酸，其为抑制PGE2/EP4信号传导的化合物)的晶型：
Figure PCTCN2022115010-appb-000001
本申请的式(1)的化合物的优选晶型具有优良的物理性质(包括溶解度、溶出率、低吸湿性、耐高温性、耐高湿性、流动性等)，并且在诸如生物利用度、物理和/或化学稳定性及易于制备性等性质上，本发明的优选晶体形式可具有更优异的性质。本申请的优选晶体形式具有良好的粉体学性质，更适合和便于大量制造和用于形成制剂，有效保证了药物产品的质量和效能。
优选的本申请的式(1)的化合物的晶型表现出良好的化学稳定性和热稳定性，因而其更利于给药和配制时的充分溶解，并能保持足够的生物活性。此外，优选的本申请的式(1)的化合物的晶型表现出高生物利用度，可在体内提供式(1)的化合物的有效治疗剂量。
通过对优选的本申请的式(1)的化合物的晶型进行碾磨，使其产生精细粉末，通过对上述精细粉末进行X射线粉末衍射(XRPD)检测，实验结果表明并未发生晶型改变。这表明本申请的优选晶型具有良好的稳定性，易于制备并且更适合用于制剂的制备。
优选的本申请的式(1)的化合物的晶型具有的良好的流动性和微粒形状，以及明显改善的粘黏性，在制剂过程中可明显降低过滤时间，缩短生产周期，节约成本。
本申请的另一方面提供制备本申请的晶型的方法，所述方法包括但不限于室温溶剂挥发法、悬浮搅拌法、反溶剂添加法和冷却法等。
本申请的另一方面提供药物组合物，其包含本申请中的任意一种或多种晶型，以及一种或多种药学上可接受的载体。
本申请的另一方面提供本申请的晶型在制备用于治疗急性或慢性疼痛、偏头痛、骨关节炎、类 风湿性关节炎、痛风、粘液囊炎、强直性脊柱炎、原发性痛经、癌症或动脉硬化症的药物中的用途。
附图简要说明
图1为式(1)的化合物的晶型I的XRPD图谱。
图2为式(1)的化合物的晶型I的DSC和TGA图谱。
图3为式(1)的化合物的晶型II的XRPD图谱。
图4为式(1)的化合物的晶型II的DSC和TGA图谱。
图5为式(1)的化合物的晶型III的XRPD图谱。
图6为式(1)的化合物的晶型III的DSC和TGA图谱。
图7为式(1)的化合物的晶型IV的XRPD图谱。
图8为式(1)的化合物的晶型IV的DSC和TGA图谱。
图9为式(1)的化合物的晶型V的XRPD图谱。
图10为式(1)的化合物的晶型V的DSC和TGA图谱。
图11为实验例1的研磨实验前后样品的XRPD图谱对比。
图12为实验例2中晶型IV在加热前后的XRPD图谱对比。
图13为实验例3中晶型II在测试前后的XRPD图谱对比。
发明详述
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
如本文中所使用的术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
如本文中所使用的词语“约”是指本领域的普通技术人员认为在所述值的可接受的标准误差内，例如±0.05、±0.1、±0.2、±0.3、±1、±2或±3等。
本发明所使用的术语“固体形式”包括式(1)的化合物的所有固态形式，例如晶体形式或无定形形式。
如本文中所使用的术语“无定形”是指三维上无排序的任意固体物质。在一些情况中，无定形固体可通过已知技术表征，所述技术包括XRPD晶体学、固态核磁共振(ssNMR)波谱学、DSC或这些技术的一些组合。如以下所说明，无定形固体产生弥散的XRPD图谱，其通常包括一个或两个宽峰(即具有约5°2θ或更大的基宽的峰)。
如本文中所使用的术语“晶型”或“晶体”是指呈现三维排序的任意固体物质，与无定形固体物质相反，其产生具有边界清楚的峰的特征性XRPD图谱。
如本文中所使用的术语“X射线粉末衍射图谱(XRPD图谱)”是指实验观察的衍射图或源于其的参数。XRPD图谱通常由峰位(横坐标)和/或峰强度(纵坐标)表征。本申请中的XRPD图谱优选在PANalytacal Empyrean和X’Pert3X射线粉末衍射分析仪上采集，透射模式优选在PANalytacal Empyrean X射线粉末衍射分析仪上采集。
如本文中所使用的术语“2θ”是指基于X射线衍射实验的实验设置的以度数表示的峰位，并且通常是在衍射图谱中的横坐标单位。如果当入射束与某晶格面形成θ角时反射被衍射，则实验设置需要以2θ角记录反射束。应当理解，在本文中提到的特定晶体形式的特定2θ值意图表示使用本文所述的X射线衍射实验条件所测量的2θ值(以度数表示)。例如，如本文所述，使用Cu-Kα(Kα1
Figure PCTCN2022115010-appb-000002
：1.540598和Kα2
Figure PCTCN2022115010-appb-000003
：1.544426)作为辐射源。
如本文中所使用的术语“差示扫描量热(DSC)图谱”是指由差示扫描量热仪记录到的曲线。本申请中的DSC图谱优选在Discovery DSC 250(TA Instruments，US)差示扫描量热仪上采集。
如本文中所使用的，对于X射线衍射峰位的术语“基本上相同”意指将代表性峰位和强度变化考虑在内。例如，本领域技术人员会理解峰位(2θ)会显示一些变化，通常多达0.1-0.2度，并且用于测量衍射的仪器也会显示一些变化。另外，本领域技术人员会理解相对峰强度会显示仪器间的变化以及由于结晶性程度、择优取向、制备的样品表面以及本领域技术人员已知的其它因素的变化，并应将其 看作仅为定性测量。相似地，如本文中所使用，对于DSC图谱的“基本上相同”也意图涵盖本领域技术人员已知的与这些分析技术有关的变化。例如，对于边界清楚的峰，在差示扫描量热图谱通常会具有多达±0.2℃的变化，对于宽峰甚至更大(例如多达±1℃)。
本申请中的液态核磁谱图优选在Bruker 400M核磁共振仪上采集，除非另外说明，以DMSO-d 6作为溶剂。
如本文中所使用的术语“烃类”优选意指具有1-10个碳原子的烃，其包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类，具体包括但不限于二氯甲烷、三氯甲烷(氯仿)、正己烷、正庚烷和甲苯。
如本文中所使用的术语“醇类”优选意指具有1-10个碳原子的醇，其包括但不限于甲醇、乙醇、1-丙醇(正丙醇)、2-丙醇(异丙醇)、1-丁醇、2-丁醇和叔丁醇。
如本文中所使用的术语“醚类”优选意指具有2-6个碳原子的醚，其包括包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类)，具体包括但不限于乙醚、二异丙基醚、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、二氧六环、环戊基甲醚、苯甲醚和二甲氧基乙烷。
如本文中所使用的术语“腈类”优选意指具有2-6个碳原子的腈，其包括但不限于乙腈和丙腈。
如本文中所使用的术语“酮类溶剂”优选意指具有2-6个碳原子的酮，其包括但不限于丙酮、丁酮、甲基乙基酮、甲基异丁基酮和二乙基酮。
如本文中所使用的术语“酯类”优选意指具有3-10个碳原子的酯，其包括但不限于乙酸乙酯、乙酸丙酯、乙酸异丙酯、异丙酸乙酯、碳酸二甲酯和乙酸丁酯。
如本文中所使用的术语“有机酸类”优选意指具有1-10个碳原子的有机酸，其包括但不限于甲酸和乙酸。
如本文中所使用的术语“砜类”优选意指具有2-10个碳原子的砜或亚砜，其包括但不限于二甲基亚砜。
如本文中所使用的术语“酰胺类”优选意指具有1-10个碳原子的酰胺，其包括但不限于二甲基甲酰胺或二甲基乙酰胺。
如本文中所使用的术语“氮杂环类”优选意指具有3-10个碳原子和至少一个氮原子的含氮杂环，其包括但不限于N-甲基吡咯烷酮。
如本文中所使用的数值范围(如“1-10个”)及其子范围(如“2-10个”、“2-6个”、“3-10个”)等涵盖所述数值范围中的任意个(例如1个、2个、3个、4个、5个、6个、7个、8个、9个或10个)。
可将制备的盐或其晶体形式通过包括倾析、离心、蒸发、重力过滤、抽滤或者在加压下或在减压下的任何其它用于固体回收的技术在内的方法进行回收。可将回收的固体任选地进行干燥。本发明中的“干燥”是在减压(优选真空)下进行直到残留溶剂的含量降低至International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use(“ICH”)指南所给出的限度的范围内。残留溶剂含量取决于溶剂的类型，但不超过约5000ppm、或优选约4000ppm、或更优选约3000ppm。所述干燥可以在盘式干燥器、真空烘箱、空气烘箱、锥形真空干燥器(cone vacuum dryer)、旋转式真空干燥器、流化床干燥器、旋转闪蒸干燥器、快速干燥器等中进行。所述干燥可以在低于约100℃、低于约80℃、低于约60℃、低于约50℃、低于约30℃的温度或任何其它合适的温度下，在大气压或减压(优选真空)下在能够实现期望的结果的任何期望的时间内(如约1、2、3、5、10、15、20、24小时或者过夜)进行，只要盐的品质不劣化。所述干燥可以进行任何期望的次数，直到实现所需的产物品质。干燥的产物可以任选地经历粉碎操作，以产生期望的粒度。可在产物的干燥前或干燥完成后进行研磨或微粉化。可用于减小粒度的技术包括但不限于球磨、辊磨和锤磨，以及喷射研磨(jet milling)。
如本文中所使用的术语“无水晶型”优选意指其中不含有水分子作为结构要素的晶型。
晶型及其制备方法
在一个实施方案中，本发明提供式(1)的化合物的晶型I，所述晶型I的XRPD图谱包括在约6.3±0.2°、11.0±0.2°、13.5±0.2°、16.7±0.2°、18.3±0.2°、18.6±0.2°、19.0±0.2°、22.1±0.2°、22.8±0.2°和25.3±0.2°的衍射角(2θ)处的特征峰。
在优选的实施方案中，所述式(1)的化合物的晶型I的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％±5％
6.3 64
11.0 47
13.5 38
16.7 100
18.3 30
18.6 20
19.0 22
22.1 17
22.8 15
25.3 21
在更优选的实施方案中，所述式(1)的化合物的晶型I的XRPD图谱包括与图1所示基本上相同的衍射角(2θ)处的峰。在最优选的实施方案中，所述式(1)的化合物的晶型I的XRPD图谱基本上如图1所示，并且优选如图1所示。
在优选的实施方案中，本发明的式(1)的化合物的晶型I的DSC图谱包括在约220±2℃(起始温度)处的特征峰。
在优选的实施方案中，本发明的式(1)的化合物的晶型I在加热至约200℃时有小于约0.2％的失重。
在更优选的实施方案中，所述式(1)的化合物的晶型I的DSC-TGA图谱包括与图2所示基本上相同的温度处的特征峰。在最优选的实施方案中，所述式(1)的化合物的晶型I的DSC-TGA图谱基本上如图2所示，并且优选如图2所示。
在优选的实施方案中，所述式(1)的化合物的晶型I为无水晶型。
在一个实施方案中，本发明提供式(1)的化合物的晶型II，所述晶型II的XRPD图谱包括在约6.3±0.2°、11.1±0.2°、13.8±0.2°、16.6±0.2°、16.8±0.2°、18.2±0.2°、19.2±0.2°、22.4±0.2°、22.8±0.2°和25.2±0.2°的衍射角(2θ)处的特征峰。
在优选的实施方案中，所述式(1)的化合物的晶型II的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％±5％
6.3 45
11.1 38
13.8 34
16.6 36
16.8 100
18.2 22
19.2 13
22.4 18
22.8 23
25.2 17
在更优选的实施方案中，所述式(1)的化合物的晶型II的XRPD图谱包括与图3所示基本上相同的衍射角(2θ)处的峰。在最优选的实施方案中，所述式(1)的化合物的晶型II的XRPD图谱基本上如图3所示，并且优选如图3所示。
在优选的实施方案中，本发明的式(1)的化合物的晶型II的DSC图谱包括在约224±2℃(起始温度)处的特征峰。
在优选的实施方案中，本发明的式(1)的化合物的晶型II在加热至约200℃时几乎无失重。
在更优选的实施方案中，所述式(1)的化合物的晶型II的DSC-TGA图谱包括与图4所示基本上相同的温度处的特征峰。在最优选的实施方案中，所述式(1)的化合物的晶型II的DSC-TGA图谱基本上如图4所示，并且优选如图4所示。
在优选的实施方案中，所述式(1)的化合物的晶型II为无水晶型。
在一个实施方案中，本发明提供式(1)的化合物的晶型III，所述晶型III的XRPD图谱包括在约5.3±0.2°、10.7±0.2°、12.0±0.2°、17.7±0.2°、18.1±0.2°、21.6±0.2°、22.1±0.2°、26.9±0.2°、31.9±0.2°和32.6±0.2°的衍射角(2θ)处的特征峰。
在优选的实施方案中，所述式(1)的化合物的晶型III的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％±5％
5.3 64
10.7 59
12.0 7
17.7 8
18.1 60
21.6 100
22.1 36
26.9 10
31.9 8
32.6 7
在更优选的实施方案中，所述式(1)的化合物的晶型III的XRPD图谱包括与图5所示基本上相同的衍射角(2θ)处的峰。在最优选的实施方案中，所述式(1)的化合物的晶型III的XRPD图谱基本上如图5所示，并且优选如图5所示。
在优选的实施方案中，本发明的式(1)的化合物的晶型III的DSC图谱包括在约97±2℃和223±2℃(起始温度)处的特征峰。
在优选的实施方案中，本发明的式(1)的化合物的晶型III在加热至约125℃时有约14％的失重。
在更优选的实施方案中，所述式(1)的化合物的晶型III的DSC-TGA图谱包括与图6所示基本上相同的温度处的特征峰。在最优选的实施方案中，所述式(1)的化合物的晶型III的DSC-TGA图谱基本上如图6所示，并且优选如图6所示。
在优选的实施方案中，所述式(1)的化合物的晶型III为四氢呋喃溶剂合物，其中式(1)的化合物和四氢呋喃的摩尔比优选为1∶1。
在一个实施方案中，本发明提供式(1)的化合物的晶型IV，所述晶型IV的XRPD图谱包括在约8.7±0.2°、12.1±0.2°、12.7±0.2°、15.5±0.2°、18.3±0.2°、18.8±0.2°、19.3±0.2°、19.9±0.2°、21.5±0.2°、24.4±0.2°和27.8±0.2°的衍射角(2θ)处的特征峰。
在优选的实施方案中，所述式(1)的化合物的晶型IV的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％±5％
8.7 83
12.1 35
12.7 83
15.5 100
18.3 31
18.8 62
19.3 53
19.9 48
21.5 72
24.4 37
27.8 37
在更优选的实施方案中，所述式(1)的化合物的晶型IV的XRPD图谱包括与图7所示基本上相同的衍射角(2θ)处的峰。在最优选的实施方案中，所述式(1)的化合物的晶型IV的XRPD图谱基本 上如图7所示，并且优选如图7所示。
在优选的实施方案中，本发明的式(1)的化合物的晶型IV的DSC图谱包括在约169±2℃和222±2℃(起始温度)处的特征峰。
在优选的实施方案中，本发明的式(1)的化合物的晶型IV在加热至约200℃时几乎无失重。
在更优选的实施方案中，所述式(1)的化合物的晶型IV的DSC-TGA图谱包括与图8所示基本上相同的温度处的特征峰。在最优选的实施方案中，所述式(1)的化合物的晶型IV的DSC-TGA图谱基本上如图8所示，并且优选如图8所示。
在优选的实施方案中，所述式(1)的化合物的晶型IV为无水晶型。
在一个实施方案中，本发明提供式(1)的化合物的晶型V，所述晶型V的XRPD图谱包括在约5.9±0.2°、8.3±0.2°、11.9±0.2°、13.4±0.2°、16.8±0.2°、17.6±0.2°、18.5±0.2°、20.7±0.2°、24.0±0.2°和28.2±0.2°的衍射角(2θ)处的特征峰。
在优选的实施方案中，所述式(1)的化合物的晶型V的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％±5％
5.9 11
8.3 43
11.9 46
13.4 11
16.8 100
17.6 15
18.5 41
20.7 31
24.0 18
28.2 14
在更优选的实施方案中，所述式(1)的化合物的晶型V的XRPD图谱包括与图9所示基本上相同的衍射角(2θ)处的峰。在最优选的实施方案中，所述式(1)的化合物的晶型V的XRPD图谱基本上如图9所示，并且优选如图9所示。
在优选的实施方案中，本发明的式(1)的化合物的晶型V的DSC图谱包括在约102±2℃、113±2℃和224±2℃(起始温度)处的特征峰。
在优选的实施方案中，本发明的式(1)的化合物的晶型V在加热至约200℃时有约15％的失重。
在更优选的实施方案中，所述式(1)的化合物的晶型V的DSC-TGA图谱包括与图10所示基本上相同的温度处的特征峰。在最优选的实施方案中，所述式(1)的化合物的晶型V的DSC-TGA图谱基本上如图10所示，并且优选如图10所示。
在优选的实施方案中，所述式(1)的化合物的晶型V为二甲基亚砜溶剂合物，其中式(1)的化合物和二甲基亚砜的摩尔比优选为1∶1。
在一些实施方案中，本发明还提供制备上述晶型I-V中任意一种的方法，所述方法包括但不限于室温溶剂挥发法、悬浮搅拌法、反溶剂添加法和冷却法等。
在一些实施方案中，采用室温溶剂挥发法制备晶型，所述方法包括将式(1)的化合物的固体在溶剂中完全溶解形成澄清溶液(视需要可将溶液进行过滤以得到澄清溶液)，将所得溶液在室温下放置，使溶剂完全挥发，得到晶型。
在一些实施方案中，所述溶剂包括但不限于有机溶剂，例如具有1-10个碳原子的醇类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、酮类、腈类或酯类，具体例如甲醇、乙醇、异丙醇、二氯甲烷、三氯甲烷(氯仿)、四氢呋喃、丙酮、丁酮、甲基叔丁基醚、乙酸乙酯或乙腈，或者由上述溶剂中的两种或更多种形成的混合溶剂。
在一些实施方案中，当使用室温溶剂挥发法制备晶型I时，所使用的溶剂包括但不限于有机溶剂，例如具有1-10个碳原子的烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链 状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))或酮类，具体例如二氯甲烷、四氢呋喃、丙酮或丁酮，或者由上述溶剂中的两种或更多种形成的混合溶剂。
在一些实施方案中，当使用室温溶剂挥发法制备晶型II时，所使用的溶剂包括但不限于有机溶剂，例如具有1-10个碳原子的醇类或腈类，具体例如乙醇或乙腈，或者由上述溶剂中的两种或更多种形成的混合溶剂。
在一些实施方案中，所述式(1)的化合物与溶剂的重量体积比(mg/mL)为(5-20)∶1，优选约10∶1。
在一些实施方案中，采用悬浮搅拌法制备晶型，所述方法包括将式(1)的化合物的固体加入溶剂中得到悬浮液，搅拌，然后分离得到晶型。
在一些实施方案中，所述搅拌在室温或高温(例如40-60℃，优选约50℃)下进行。
在一些实施方案中，所述溶剂包括但不限于无机溶剂(例如水)以及有机溶剂(例如具有1-10个碳原子的醇类、酮类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、酯类、腈类和有机酸类，例如甲醇、正丙醇、异丙醇、丙酮、丁酮、甲基异丁基甲酮、乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸丁酯、乙腈、正己烷、正庚烷、二氯甲烷、甲基叔丁基醚、二氧六环、碳酸二甲酯、四氢呋喃、2-甲基四氢呋喃、乙酸、甲苯、三氯甲烷、环戊基甲醚)，或者选自上述溶剂中的两种或更多种的混合溶剂。
在一些实施方案中，所述混合溶剂优选为下表中所示的混合溶剂：
溶剂 1 溶剂 2
甲醇 水
丙酮 水
乙腈 水
甲醇 乙酸乙酯
甲醇 甲基叔丁基醚
甲醇 乙腈
乙醇 乙酸丁酯
乙醇 正庚烷
丙酮 异丙醇
丙酮 乙酸乙酯
乙腈 乙酸甲酯
丙酮 正庚烷
丙酮 乙腈
丁酮 正庚烷
在一些实施方案中，溶剂 1和溶剂 2的体积比为1∶1至1∶5，优选为1∶1至1∶3。
在一些实施方案中，所述式(1)的化合物与溶剂的重量体积比(mg/mL)为(20-350)∶1，优选(20-300)∶1，更优选(60-300)∶1，最优选(60-150)∶1。
在一些实施方案中，采用反溶剂添加法制备晶型，所述方法包括将式(1)的化合物的固体在良溶剂中溶解，形成澄清溶液(视需要可将溶液进行过滤以得到澄清溶液)，然后向所述澄清溶液中添加反溶剂，使固体析出并将其过滤得到晶型。
在一些实施方案中，所述良溶剂包括但不限于有机溶剂，如具有1-10个碳原子的醇类、酮类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、砜类、酰胺类和有机酸类，例如甲醇、乙醇、丙酮、四氢呋喃、乙酸、三氯甲烷、二甲亚砜或二甲基乙酰胺。在一些实施方案中，所述反溶剂包括但不限于无机溶剂(例如水)以及有机溶剂(例如具有1-10个碳原子的酮类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、酯类和腈类)，例如正己烷、正庚烷、环戊基甲醚、乙腈、甲基异丁基甲酮、2-甲基四氢呋喃、二氧六环、乙酸异丙酯、二氯甲烷、甲苯、乙腈、丁酮、甲基叔丁基醚、异丙酸乙酯、碳酸二甲酯和乙酸乙酯。
在一些实施方案中，当使用反溶剂添加法制备晶型I时，所使用的良溶剂为具有1-10个碳原子的酮类溶剂(优选为丙酮)；并且所使用的反溶剂为无机溶剂(优选为水)或具有1-10个碳原子的烃类溶剂(优选为正庚烷)。
在一些实施方案中，当使用反溶剂添加法制备晶型III时，所使用的良溶剂为具有1-10个碳原子的醚类溶剂(优选为四氢呋喃)；并且所使用的反溶剂为具有1-10个碳原子的烃类溶剂(优选为正庚烷)。
在一些实施方案中，当使用反溶剂添加法制备晶型IV时，所使用的良溶剂为具有1-10个碳原子的醇类溶剂(优选为甲醇)或砜类溶剂(优选为二甲亚砜)；并且所使用的反溶剂为无机溶剂(优选为水)。
在一些实施方案中，所述良溶剂与反溶剂的体积比为(0.5-1)∶(1-20)，优选为约1∶10。在一些实施方案中，所述式(1)的化合物与良溶剂的重量体积比(mg/mL)为(50-200)∶1，优选为(90-150)∶1。
在一些实施方案中，采用冷却法制备晶型，所述方法包括将式(1)的化合物的固体加入至溶剂中，加热搅拌使其溶解，将所得澄清溶液(视需要可将溶液进行过滤以得到澄清溶液)放置，缓慢降温，得到晶型。
在一些实施方案中，所述溶剂包括但不限于无机溶剂(例如水)以及有机溶剂，例如具有1-10个碳原子的醇类、酮类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、腈类、酯类和砜类，具体例如异丙醇、丙酮、丁酮、三氯甲烷、乙腈、四氢呋喃、甲醇、正己烷、环己烷、乙酸甲酯、乙酸乙酯或二甲亚砜，或者由上述溶剂中的两种或更多种形成的混合溶剂。
在一些实施方案中，所述混合溶剂优选为下表中所示的混合溶剂：
溶剂 1 溶剂 2
丙酮 水
四氢呋喃 环己烷
二甲亚砜 水
在一些实施方案中，溶剂1和溶剂2的体积比为5∶1至1∶5，优选为约1∶1。
在一些实施方案中，当使用冷却法制备晶型I时，所使用的溶剂为具有1-10个碳原子的醇类溶剂，优选为异丙醇。
在一些实施方案中，当使用冷却法制备晶型II时，所使用的溶剂为具有1-10个碳原子的腈类(优选为乙腈)、酮类(优选为丁酮)、酯类(优选为乙酸甲酯)溶剂，或者为水和具有1-10个碳原子的酮类(优选为丙酮)溶剂的混合溶剂。
在一些实施方案中，当使用冷却法制备晶型III时，所使用的溶剂为四氢呋喃和具有1-10个碳原子的烃类(优选为环己烷)溶剂的混合溶剂。
在一些实施方案中，当使用冷却法制备晶型V时，所使用的溶剂为水和二甲亚砜的混合溶剂。
在一些实施方案中，所述式(1)的化合物与溶剂的重量体积比(mg/mL)为(60-150)∶1。
药物组合物和用途
在另一实施方案中，本申请提供药物组合物，其包含本发明的式(1)的化合物的晶型I、II、III、IV或V中的任意一种或多种，以及一种或多种药学上可接受的载体。
在另一实施方案中，本申请提供本发明的式(1)的化合物的晶型I、II、III、IV或V在制备用于治疗急性或慢性疼痛、偏头痛、骨关节炎、类风湿性关节炎、痛风、粘液囊炎、强直性脊柱炎、原发性痛经、癌症或动脉硬化症的药物中的用途。
在另一实施方案中，本申请提供本发明的式(1)的化合物的晶型I、II、III、IV或V，其用于治疗急性或慢性疼痛、偏头痛、骨关节炎、类风湿性关节炎、痛风、粘液囊炎、强直性脊柱炎、原发性痛经、癌症或动脉硬化症。
在另一实施方案中，本申请提供治疗急性或慢性疼痛、偏头痛、骨关节炎、类风湿性关节炎、痛风、粘液囊炎、强直性脊柱炎、原发性痛经、癌症或动脉硬化症的方法，其包括向需要其的个体(优选哺乳动物)给药预防或治疗有效量的本发明的式(1)的化合物的晶型I、II、III、IV或V中的任意一种或多种。
在另一实施方案中，本申请提供本发明的式(1)的化合物的晶型I、II、III、IV或V在制备用于治疗癌症的药物中的用途。
在另一实施方案中，本申请提供本发明的式(1)的化合物的晶型I、II、III、IV或V，其用于治疗癌症。
在另一实施方案中，本申请提供治疗癌症的方法，其包括向需要其的个体(优选哺乳动物)给药预防或治疗有效量的本发明的式(1)的化合物的晶型I、II、III、IV或V中的任意一种或多种。
在一优选实施方案中，所述癌症选自乳腺癌、宫颈癌、结肠直肠癌、子宫内膜癌、胶质母细胞瘤、头颈癌、肾癌、肝癌、肺癌、髓母细胞瘤、卵巢癌、胰腺癌、前列腺癌、皮肤癌和尿道癌。
如本文中所使用的术语“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒 性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。
本发明的组合物可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射、静脉内、动脉内、皮下、腹膜内、肌内或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
对于这些给药途径，可以适合的剂型给药本发明的组合物。
所述剂型可为固体制剂、半固体制剂、液体制剂或气态制剂，具体包括但不限于片剂、胶囊剂、散剂、颗粒剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、混悬剂、酏剂、糖浆剂。
本发明所述的药物组合物可以通过本领域熟知的任何方法来制备，例如通过混合、溶解、制粒、糖包衣、碾磨、乳化、冻干等处理来制备。
如本文中所使用的术语“治疗有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg，例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计为约0.007mg/日至约3500mg/日，例如约0.7mg/日至约700mg/日。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而在其它情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。
本发明的化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg，适合地是0.1-500mg，优选0.5-300mg，更优选1-150mg，特别优选1-50mg，例如1.5mg、2mg、4mg、10mg和25mg等。
除非另外说明，否则如本文中所使用，术语“治疗(treating)”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
实施例
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非用于限定本发明的范围，本领域技术人员可进行一些非本质的改进和调整，仍属于本发明的保护范围。
实施例和实验例中所使用的仪器型号和参数如下。
1.X射线粉末衍射(XRPD)
利用配备了PIXceI 1D检测器的PANalytical EMPYREAN对实施例中所得的固体进行晶型分析。仪器参数如下所示：扫描范围：3°(2θ)至40°(2θ)；步长：0.013°(2θ)；光管电压和电流分别为45KV和40mA。
2.热重分析(TGA)
利用TGA 55(TAInstruments，US)对样品进行热重分析。将样品置于开口铝制样品盘中，样品质 量在TGA加热炉内自动称量后，将样品以10℃/min的速率加热到最后的温度。
3.差示扫描量热分析(DSC)
利用Discovery DSC 250(TA Instruments，US)对样品进行热分析。称取～2mg样品置于DSC样品盘中。将样品在25℃平衡后以10℃/min的速率加热至最后的温度。
4.高效液相色谱分析(HPLC)
HPLC的测定仪器为Agilent HPLC 1260系列仪器。HPLC测量方法如下列表所示。
HPLC测量方法参数
Figure PCTCN2022115010-appb-000004
实施例1
式(1)的化合物(3-(1-(1-(苯并呋喃-2-基甲基)-1H-吲哚-7-甲酰胺基)环丙基)双环[1.1.1]戊烷-1-羧酸)的制备
Figure PCTCN2022115010-appb-000005
步骤1：3-(1-氨基环丙基)双环[1.1.1]戊烷-1-羧酸甲酯B的合成
在氮气保护及-20℃的温度下，向3-氰基双环[1.1.1]戊烷-1-羧酸甲酯(A)(22.5g，99.2mmol)的甲苯(240mL)溶液中加入四异丙氧基钛(29.8g，99.7mmol，31mL，95％纯度)。然后在氮气保护及-20℃的温度下，在30分钟内逐滴加入EtMgBr(3M，60mL)，保持温度在-20～-10℃之间。搅拌30分钟后，逐滴加入BF 3·Et 2O(27.6g，194mmol，24mL)并在-20℃下搅拌30分钟，然后在25℃下搅拌12小时。在0℃下缓慢加入盐酸水溶液(1N，30mL)将反应混合物淬灭，然后弃去分离的有机层。在0℃下用10M氢氧化钠水溶液将水相碱化至pH～12，并用乙酸乙酯(200mL×2)萃取。将合并的有机层浓缩，得到残余物，将其通过快速硅胶柱色谱纯化，得到化合物B(3.9g，21.7mmol，21.9％收率)，为黄色固体。MS(ESI)：182.3[M+1] +。
1H NMR(400MHz，DMSO-d 6)δ：3.58(s，3H)，1.77(s，6H)，0.39-0.37(m，4H).
步骤2：苯并呋喃-2-基甲醇D的合成
在反应瓶中，依次加入苯并呋喃-2-甲醛(C)(3g，20.5mmol)和无水甲醇(40ml)，冷却至0℃，将硼氢化钠(0.545g，14.4mmol)分批加入其中，保持温度低于25℃。加料完毕，在室温下搅拌1小时。反应完毕，减压蒸除溶剂，加入1N HCl水溶液(15ml)，室温搅拌5分钟，然后用饱和碳酸氢钠水溶液调pH至8-9，乙酸乙酯(10ml x 3)萃取，合并的有机相用饱和食盐水水洗，无水硫酸钠干燥，减压蒸除溶剂，得化合物D(3.0g，20.27mmol，收率：98.9％)为黄色油状物。MS(ESI)：149.1[M+1] +。
1H NMR(400MHz，CDCl 3)δ：7.55(dd，J＝8.4，7.2Hz，1H)，7.47(dd，J＝8.8，7.6Hz，1H)，7.29-7.19(m，2H)，6.66(s，1H)，4.77(d，J＝4.8Hz，2H)。
步骤3：2-(溴甲基)苯并呋喃E的合成
在反应瓶中，依次加入化合物D(2.47g，16.7mmol)和干燥的二氯甲烷(32ml)，冷却至0℃。将三溴化磷(1.72mL，18.4mmol)缓慢滴加其中，加料完毕，升温至室温搅拌1小时。经TLC监测反应完毕后，用饱和碳酸氢钠水溶液调pH至8-9，二氯甲烷(10ml x 3)萃取，合并的有机相用饱和食盐水水洗，无水硫酸钠干燥，减压蒸除溶剂，得化合物E(3.36g，收率：95.9％)为黄色油状物。该化合物未经进一步纯化，直接用于下一步反应。
步骤4：1-(苯并呋喃-2-基甲基)-1H-吲哚-7-羧酸甲酯G的合成
在0℃，向1H-吲哚-7-甲酸甲酯F(1.59g，9.09mmol)的DMF(80mL)溶液中加入叔丁醇钾(1.53g，13.63mmol)，然后加入2-(溴甲基)苯并呋喃E(2.5g，11.36mmol)。将得到的混合物升至25℃，搅拌3小时。经TLC监测(石油醚∶乙酸乙酯＝9∶1)反应完毕，将反应混合物倒入200mL水中，然后用乙酸乙酯(100mL x 2)萃取。将有机层用盐水(200mL)洗涤，用无水硫酸钠干燥，过滤并浓缩，将得到的残余物通过快速硅胶色谱法纯化得到化合物G(2.0g，6.56mmol，72.2％收率)，为黄色油状物。MS(ESI)：306.2[M+1] +。
步骤5：1-(苯并呋喃-2-基甲基)-1H-吲哚-7-羧酸H的合成
向化合物G(2.0g，6.56mmol)的甲醇(40mL)和四氢呋喃(40mL)溶液中加入KOH水溶液(2M，33mL)，并将所得混合物加热至50℃，搅拌12小时。LCMS显示起始材料消耗完并且检测到有目标产物生成后，将反应混合物在45℃下浓缩以除去大部分甲醇和四氢呋喃，用1N盐酸水溶液酸化至pH～6-7，然后用1N盐酸洗涤并用乙酸乙酯(60mL x 3)萃取。将有机层用无水硫酸钠干燥，过滤并浓缩，得到化合物H(1.8g，6.19mmol，94.3％收率)，为淡黄色固体。MS(ESI)：292.1[M+1] +。
步骤6：3-(1-(1-(苯并呋喃-2-基甲基)-1H-吲哚-7-甲酰胺基)环丙基)双环[1.1.1]戊烷-1-羧酸甲酯J 的合成
向化合物H(1.8g，6.18mmol)、化合物B(1.4g，7.73mmol)和HATU(3.08g，8.12mmol)的DMF(40mL)溶液中加入DIEA(2.8g，21.6mmol)。将所得混合物在氮气下在25℃下搅拌3小时。LCMS显示反应完毕后，将反应混合物倒入100mL水中。用乙酸乙酯(50mL x 3)萃取，将有机层用盐水(50mL×2)洗涤。将有机层用无水硫酸钠干燥，过滤并减压浓缩，得到残余物，将其通过快速硅胶柱色谱纯化，获得化合物J(2.3g，5.07mmol，82.0％收率)，为淡黄色固体。MS(ESI)：455.0[M+1] +。
步骤7：3-(1-(1-(苯并呋喃-2-基甲基)-1H-吲哚-7-甲酰胺基)环丙基)双环[1.1.1]戊烷-1-羧酸1的合 成
向化合物J(2.3g，5.07mmol)在甲醇(50mL)的溶液中加入LiOH·H 2O(2M，3.3mL，6.6mmol)，将得到的混合物在50℃下搅拌24小时。LCMS显示反应完毕后，将反应混合物在50℃下浓缩以除去大部分甲醇。加入30mL水，用1N盐酸酸化至pH～5，用乙酸乙酯(40mL×3)萃取。合并有机层经盐水(50mL×2)洗涤，用无水硫酸钠干燥，过滤并浓缩，得到残余物用乙醚(20mL)洗涤后，经冷冻干燥得到式(1)的化合物(1.8g，4.09mmol，80.7％收率)，为类白色粉末。MS(ESI)：441.0[M+1] +。
1H NMR(400MHz，DMSO-d 6)δ：12.24(s，1H)，8.75(s，1H)，7.69(d，J＝7.6Hz，1H)，7.51(d，J＝ 3.2Hz，1H)，7.45(t，J＝7.8Hz，2H)，7.24-7.06(m，4H)，6.60(d，J＝3.2Hz，1H)，6.18(s，1H)，5.76(s，2H)，1.76(s，6H)，0.63(d，J＝7.2Hz，2H)，0.50(t，J＝5.6Hz，2H).
实施例2：室温溶剂挥发法
将实施例1中得到的式(1)的化合物的固体在以下溶剂中完全溶解(溶液浓度为约10mg/mL)，然后将所得溶液在室温下放置，使溶剂完全挥发，得到固体。对所得固体进行XRPD分析，并由所得XRPD图谱判断晶体形式(当XRPD图谱与图1基本上相同时判定为晶型I；当XRPD图谱与图3基本上相同时判定为晶型II；当XRPD图谱与图5基本上相同时判定为晶型III；当XRPD图谱与图7基本上相同时判定为晶型IV；当XRPD图谱与图9基本上相同时判定为晶型V；在实施例3-9中采用相同的判定标准)。结果如下表中所示。
溶剂 晶型
四氢呋喃 晶型I
丙酮 晶型I
丁酮 晶型I
二氯甲烷 晶型I
乙腈 晶型II
乙醇 晶型II
实施例3：单一溶剂室温悬浮搅拌法
称取30毫克的实施例1中得到的式(1)的化合物的固体，加入以下体积的溶剂中，形成悬浮液。将所得悬浮液在室温下搅拌3天，然后过滤得到固体。对所得固体进行XRPD分析，并由所得XRPD图谱判断晶体形式。结果如下表中所示。
溶剂 体积(mL) 晶型
甲醇 0.1 晶型II
异丙醇 0.5 晶型II
丙酮 0.1 晶型II
丁酮 0.5 晶型II
乙酸甲酯 0.5 晶型II
乙酸乙酯 0.5 晶型II
乙酸丁酯 0.5 晶型II
乙酸异丙酯 0.5 晶型II
乙腈 0.5 晶型II
实施例4：混合溶剂室温悬浮搅拌法
称取30毫克的实施例1中得到的式(1)的化合物的固体，将其置于如下表中所示的各混合溶剂中，配成悬浮液。将所得悬浮液在室温下搅拌3天，然后过滤得到固体。对所得固体进行XRPD分析，并由所得XRPD图谱判断晶体形式。结果如下表中所示。
溶剂 1 溶剂 2 体积 1/体积 2 溶剂总体积(mL) 晶型
甲醇 水 1/1 0.5 晶型II
丙酮 水 1/1 0.5 晶型II
乙腈 水 1/1 0.5 晶型II
甲醇 乙酸乙酯 1/3 0.5 晶型II
甲醇 甲基叔丁基醚 1/3 0.5 晶型II
甲醇 乙腈 1/3 0.5 晶型II
乙醇 乙酸丁酯 1/3 0.5 晶型II
乙醇 正庚烷 1/1 0.5 晶型II
丙酮 异丙醇 1/3 0.5 晶型II
丙酮 乙酸乙酯 1/1 0.5 晶型II
乙腈 乙酸甲酯 1/1 0.5 晶型II
丙酮 正庚烷 1/1 0.5 晶型II
丙酮 乙腈 1/1 0.5 晶型II
丁酮 正庚烷 1/1 0.5 晶型II
实施例5：单一溶剂高温悬浮搅拌法
称取30毫克实施例1中得到的式(1)的化合物的固体，加入以下体积的溶剂中，形成悬浮液。将所得悬浮液在50℃下搅拌3天，然后过滤得到固体。对所得固体进行XRPD分析，并由所得XRPD图谱判断晶体形式。结果如下表中所示。
溶剂 体积(mL) 晶型
甲醇 0.1 晶型II
异丙醇 0.2 晶型II
丁酮 0.2 晶型II
乙腈 0.2 晶型II
二氯甲烷 0.2 晶型II
乙酸甲酯 0.2 晶型II
乙酸乙酯 0.2 晶型II
乙酸异丙酯 0.2 晶型II
实施例6：混合溶剂高温悬浮搅拌法
称取30毫克实施例1中得到的式(1)的化合物的固体，将其置于如下表中所示的各混合溶剂中，配成悬浮液。将所得悬浮液在50℃下搅拌3天，然后过滤得到固体。对所得固体进行XRPD分析，并由所得XRPD图谱判断晶体形式。结果如下表中所示。
溶剂 1 溶剂 2 体积 1/体积 2 溶剂总体积(mL) 晶型
甲醇 乙酸乙酯 1/3 0.5 晶型II
丙酮 乙酸乙酯 1/1 0.5 晶型II
丙酮 异丙醇 1/3 0.5 晶型II
乙腈 乙酸甲酯 1/1 0.5 晶型II
丙酮 乙腈 1/3 0.5 晶型II
实施例7：反溶剂添加法
如下表中所示，称取所示量的实施例1中得到的式(1)的化合物的固体，将其放入良溶剂中，将所得溶液过滤，并将滤液缓慢加入反溶剂中。将析出的固体过滤，并进行XRPD分析。由所得XRPD图谱判断晶体形式，结果如下表中所示。
Figure PCTCN2022115010-appb-000006
实施例8：单一溶剂冷却法
称取约30mg的实施例1中得到的式(1)的化合物的固体，将其加入如下表所示的各溶剂中，将所得悬浮液加热，使固体完全溶解。然后将溶液冷却。将析出的固体过滤，并进行XRPD分析。由所得XRPD图谱判断晶体形式，结果如下表中所示。
溶剂(0.5mL) 晶型
异丙醇 晶型I
乙腈 晶型II
丁酮 晶型II
乙酸甲酯 晶型II
实施例9：混合溶剂冷却法
称取约30mg的实施例1中得到的式(1)的化合物的固体，将其加入如下表所示的各混合溶剂中， 将所得悬浮液加热，使固体完全溶解。将溶液过滤，并将滤液冷却至室温。将析出的固体过滤，并进行XRPD分析。由所得XRPD图谱判断晶体形式，结果如下表中所示。
溶剂 1 溶剂 2 体积 1/体积 2 溶剂总体积(mL) 晶型
丙酮 水 1/1 0.2mL 晶型II
四氢呋喃 环己烷 1/1 0.2mL 晶型III
二甲亚砜 水 1/1 0.2mL 晶型V
实施例10：晶型的热重分析和差示扫描量热分析
对晶型I、II、III、IV和V进行热重分析和差示扫描量热分析，晶型I、II、III、IV和V的DSC和TGA图谱分别如图2、4、6、8和10中所示。
实验例
实验例1：机械研磨实验
将0.5g晶型II置于研钵进行研磨约5分钟，然后收集固体进行XRPD检测。
起始样品和研磨后样品的XRPD图谱如图11所示。结果表明，研磨后晶型II的晶体形式保持不变。
实验例2：晶型转化实验
将晶型IV缓慢加热至200℃，然后冷却至室温。收集加热前后样品进行XRPD检测。
加热前后样品的XRPD谱图与晶型II参比对照结果如图12所示。结果表明，晶型IV加热后转晶为晶型II。因此，与晶型IV相比，晶型II具有更好的稳定性。
实验例3：固体稳定性实验
将晶型II分别在60℃闭口和40℃/75％RH的条件下保存7天。在保存前后通过HPLC测定样品的纯度，并测定样品的XRPD图谱。
样品纯度测定结果如下表中所示。结果表明，在60℃闭口和40℃/75％RH的条件下保存后，样品的纯度未下降。
Figure PCTCN2022115010-appb-000007
保存前后样品的XRPD图谱如图13所示。结果表明晶型II在60℃闭口和40℃/75％RH条件下放置7天后，样品的晶体形式保持不变。
实验例4：光照实验
将式(1)的化合物的晶型II于光照强度不低于1.2×10 6Lux·hr，近紫外能量不低于200w·hr/m 2、25℃、RH 25％的条件下放置30天，分别在0天、5天、10天和30天进行取样，观察样品性状变化，检测干燥失重，通过HPLC测量总的杂质含量，并测定样品的XRPD图谱。
试验结果表明：样品在光照条件(总照度不低于1.2x10 6Lux·hr，近紫外能量不低于200w·hr/m 2)下放置30天。样品水分和含量同0天结果相比均无明显变化，无大于0.05％的新杂质产生。XRPD图谱表明样品晶型未发生变化。
结果表明晶型II在光照条件(总照度不低于1.2x10 6Lux·hr，近紫外能量不低于200w·hr/m 2)下稳定。
实验例5：高温实验
将式(1)的化合物的晶型II在60℃的高温下放置30天，分别在0天、5天、10天和30天进行取样，观察样品性状变化，用旋光仪测量比旋度，检测干燥失重，通过HPLC测量总的杂质含量，并测定样品的XRPD图谱。
试验结果表明：样品在高温60℃条件下放置30天，外观、水分、含量和晶体形式同0天结果相比均无明显差异，无大于0.05％的新杂质产生。
结果表明，样品对于高温(60℃)条件稳定。
实验例6：高湿实验
将式(1)的化合物的晶型II在25℃和92.5％的高湿条件下分别放置30天，分别在0天、5天、10天和30天进行取样，观察样品性状变化，检测干燥失重，通过HPLC测量总的杂质含量，并测定样品的XRPD图谱。
试验结果显示：样品在高湿92.5％RH条件下放置30天，吸水量为0.03％，小于5％；外观、水分、含量和晶体形式同0天结果相比均无明显差异，无大于0.05％的新杂质产生。
结果表明，样品对于高湿(RH 92.5％)条件稳定。
实验例7：SD大鼠中的药代动力学实验
将式(1)的化合物的晶型II配制成10％DMSO，60％PEG 400，30％的注射用水的澄清溶液，对SD大鼠进行静脉注射给药。将式(1)的化合物的晶型II配制成0.5％羧甲基纤维素钠(CMC.Na)中的悬浮水溶液，对SD大鼠进行灌胃给药，考察其药代动力学特征。
向SD大鼠单次静脉注射给予15mg/kg的式(1)的化合物后，该化合物在SD大鼠体内的药物暴露量AUC 0-t为78,811ng*hr/mL，清除率(CL)和稳态表观分布容积(Vss)分别为3.59mL/min/kg和1.18L/kg。
向SD大鼠单次灌胃给予40mg/kg的式(1)的化合物后，该化合物的最大血药浓度Cmax和暴露量AUC 0-t分别为27,700ng/mL和153,279ng*hr/mL。
可见，本发明式(1)化合物的晶型II具有优良的血药浓度和暴露量。
实验例8：比格犬中的药代动力学实验
将式(1)的化合物的晶型II配制成10％DMSO，60％PEG 400，30％的注射用水的澄清溶液，对比格犬进行静脉注射给药。将式(1)的化合物的晶型II配制成0.5％羧甲基纤维素钠(CMC.Na)中的悬浮水溶液，对比格犬进行灌胃给药，考察其药代动力学特征。
向比格犬单次静脉注射给予5mg/kg的式(1)的化合物后，该化合物在比格犬体内的药物暴露(AUC 0-t)为12,649ng*hr/mL，清除率(CL)和稳态表观分布容积(Vss)分别为6.64mL/min/kg和1.50L/kg，说明式(1)的化合物是低清除率化合物，并且广泛分布在体内。
向比格犬单次灌胃给予45mg/kg的式(1)的化合物后，该化合物的最大血药浓度Cmax和暴露量AUC 0-t分别为32,917ng/mL和79,576ng*hr/mL。
可见，本发明式(1)化合物的晶型II具有优良的血药浓度和暴露量。
上述具体实施方式对本发明作进一步的详细描述。但不应将此理解为本发明上述主题的范围仅限于所列的实施例，凡基于本发明内容所实施的技术方案均落入于本发明的范围。

Claims (12)

  1. 式(1)的化合物的晶型I：
    Figure PCTCN2022115010-appb-100001
    所述晶型I的XRPD图谱包括在约6.3±0.2°、11.0±0.2°、13.5±0.2°、16.7±0.2°、18.3±0.2°、18.6±0.2°、19.0±0.2°、22.1±0.2°、22.8±0.2°和25.3±0.2°的衍射角(2θ)处的特征峰。
  2. 制备权利要求1的式(1)的化合物的晶型I的方法，所述方法选自室温溶剂挥发法、反溶剂添加法和冷却法。
  3. 式(1)的化合物的晶型II：
    Figure PCTCN2022115010-appb-100002
    所述晶型II的XRPD图谱包括在6.3±0.2°、11.1±0.2°、13.8±0.2°、16.6±0.2°、16.8±0.2°、18.2±0.2°、19.2±0.2°、22.4±0.2°、22.8±0.2°和25.2±0.2°的衍射角(2θ)处的特征峰。
  4. 制备权利要求3的式(1)的化合物的晶型II的方法，所述方法选自室温溶剂挥发法、悬浮搅拌法和冷却法。
  5. 式(1)的化合物的晶型III：
    Figure PCTCN2022115010-appb-100003
    所述晶型III的XRPD图谱包括在5.3±0.2°、10.7±0.2°、12.0±0.2°、17.7±0.2°、18.1±0.2°、21.6±0.2°、22.1±0.2°、26.9±0.2°、31.9±0.2°和32.6±0.2°的衍射角(2θ)处的特征峰；
    所述晶型III优选为四氢呋喃溶剂合物，其中式(1)的化合物和四氢呋喃的摩尔比优选为1∶1。
  6. 制备权利要求5的式(1)的化合物的晶型III的方法，所述方法选自反溶剂添加法和冷却法。
  7. 式(1)的化合物的晶型IV：
    Figure PCTCN2022115010-appb-100004
    所述晶型IV的XRPD图谱包括在8.7±0.2°、12.1±0.2°、12.7±0.2°、15.5±0.2°、18.3±0.2°、18.8±0.2°、19.3±0.2°、19.9±0.2°、21.5±0.2°、24.4±0.2°和27.8±0.2°的衍射角(2θ)处的特征峰。
  8. 制备权利要求7的式(1)的化合物的晶型IV的方法，所述方法为反溶剂添加法，其包括将式(1)的化合物的固体在良溶剂中溶解，形成澄清溶液(视需要可将溶液进行过滤以得到澄清溶液)，然后向所述澄清溶液中添加反溶剂，使固体析出并将其过滤得到晶型IV；
    所使用的良溶剂优选为具有1-10个碳原子的醇类溶剂(优选为甲醇)或砜类溶剂(优选为二甲亚砜)；并且所使用的反溶剂优选为无机溶剂(优选为水)。
  9. 式(1)的化合物的晶型V：
    Figure PCTCN2022115010-appb-100005
    所述晶型V的XRPD图谱包括在5.9±0.2°、8.3±0.2°、11.9±0.2°、13.4±0.2°、16.8±0.2°、17.6±0.2°、18.5±0.2°、20.7±0.2°、24.0±0.2°和28.2±0.2°的衍射角(2θ)处的特征峰；
    所述晶型V优选为二甲基亚砜溶剂合物，其中式(1)的化合物和二甲基亚砜的摩尔比优选为1∶1。
  10. 制备权利要求9的式(1)的化合物的晶型V的方法，所述方法为冷却法，其包括将式(1)的化合物的固体加入至溶剂中，加热搅拌使其溶解，将所得澄清溶液(视需要可将溶液进行过滤以得到澄清溶液)放置，缓慢降温，得到晶型V；
    所使用的溶剂优选为水和二甲亚砜的混合溶剂。
  11. 药物组合物，其包含权利要求1、3、5、7和9中任一项的式(1)的化合物的晶型I、II、III、IV或V，以及一种或多种药学上可接受的载体。
  12. 权利要求1、3、5、7和9中任一项的式(1)的化合物的晶型I、II、III、IV或V在制备用于治疗急性或慢性疼痛、偏头痛、骨关节炎、类风湿性关节炎、痛风、粘液囊炎、强直性脊柱炎、原发性痛经、癌症或动脉硬化症的药物中的用途。
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Publication number Priority date Publication date Assignee Title
CN101622230A (zh) * 2007-02-26 2010-01-06 默克弗罗斯特加拿大有限公司 作为ep4受体拮抗剂的吲哚和二氢吲哚环丙基酰胺衍生物
CN110891935A (zh) * 2017-04-18 2020-03-17 泰普斯特医疗公司 双环化合物及其在癌症治疗中的用途
WO2020151566A1 (zh) * 2019-01-22 2020-07-30 凯复制药有限公司 抑制pge2/ep4信号传导的化合物、其制备方法及其在医药上的应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101622230A (zh) * 2007-02-26 2010-01-06 默克弗罗斯特加拿大有限公司 作为ep4受体拮抗剂的吲哚和二氢吲哚环丙基酰胺衍生物
CN110891935A (zh) * 2017-04-18 2020-03-17 泰普斯特医疗公司 双环化合物及其在癌症治疗中的用途
WO2020151566A1 (zh) * 2019-01-22 2020-07-30 凯复制药有限公司 抑制pge2/ep4信号传导的化合物、其制备方法及其在医药上的应用

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