Solid form of indole compounds, method of preparation thereof, and use thereof

Abstract

This document provides the solid form of indole compounds, a method for preparing them, and their uses. [Solution] Formula (1) TIFF2026048666000025.tif39129 This invention provides the crystalline form I of the compound, a method for preparing it, a pharmaceutical composition containing it, and its use in the treatment of diseases.

Description

[Technical Field]

[0001] This application relates to the solid form of an indole compound, a method for preparing the same, and its use. In particular, this application relates to the solid form of 3-(1-(1-(benzofuran-2-ylmethyl)-1H-indole-7-carboxamide)cyclopropyl)bicyclo[1.1.1]pentane-1-carboxylic acid (hereinafter referred to herein as "the compound of formula (1)"), a method for preparing the same, a pharmaceutical composition containing the same, and its use in the treatment of diseases. [Background technology]

[0002] Prostaglandin E2 (PGE2) is a derivative of arachidonic acid that inhibits the function of immune cells and can evade anti-tumor immunity. PGE2 modulates biological function through four types of PGE2 receptors (EP1, EP2, EP3, and EP4). EP4 is the major PGE2 receptor in tumor tissue and is involved in PGE2-promoting tumor progression. There is evidence that EP4 receptor expression is increased in many types of tumor tissue. Much evidence also suggests that elevated PGE2 levels in many tumor tissues suppress the function of immune cells in tumor tissue through the EP4 receptor, allowing tumor cells to evade the anti-tumor immune system, thereby accelerating tumor growth and metastasis. EP4 receptor antagonists can block these effects of PGE2, thereby enhancing anti-tumor immune function.

[0003] Furthermore, scientific evidence suggests that selective EP4 antagonists are effective in reducing inflammatory pain and may have better gastrointestinal tolerability than current standard anti-inflammatory analgesics such as NSAIDs and COX-2 inhibitors. In particular, because EP4 antagonists do not directly interfere with the biosynthesis of prostaglandin E (PGE2) and other prostaglandins (e.g., prostacyclins and thromboxanes), these drugs may have better cardiovascular safety.

[0004] Given the potential applications of EP4 antagonists in tumor immunology and anti-inflammatory analgesia, several EP4 antagonists are in clinical research. However, so far, no such drugs have been approved for sale. There are also few reports on the solid form of drugs in this class. [Overview of the project]

[0005] One aspect of this application provides a crystalline form of the compound of formula (1) shown below (3-(1-(1-(benzofuran-2-ylmethyl)-1H-indole-7-carboxamide)cyclopropyl)bicyclo[1.1.1]pentane-1-carboxylic acid, which is a compound that inhibits the PGE2 / EP4 signaling pathway):

[0006] [ka]

[0007] The preferred crystalline form of the compound of formula (1) in this application has excellent physical properties (including solubility, dissolution rate, low hygroscopicity, high temperature resistance, high humidity resistance, and fluidity), and the preferred crystalline form of the present invention can exhibit excellent properties with respect to bioavailability, physical and / or chemical stability, and ease of preparation. The preferred crystalline form of this application exhibits good powder flow properties, which makes it suitable and convenient for mass production and formulation, and effectively guarantees the quality and efficacy of pharmaceuticals.

[0008] The preferred crystalline form of the compound of formula (1) in this application demonstrates good chemical and thermal stability, thereby promoting complete dissolution during administration and formulation and maintaining sufficient biological activity. Furthermore, the preferred crystalline form of the compound of formula (1) in this application exhibits high bioavailability, providing an effective therapeutic dose of the compound of formula (1) in vivo.

[0009] The preferred crystalline form of the compound of formula (1) of this application was pulverized to produce a fine powder, and then subjected to X-ray powder diffraction (XRPD) analysis. The experimental results showed that there was no change in the crystalline form. This demonstrates that the preferred crystalline form of this application has good stability, is easy to prepare, and is more suitable for the preparation of formulations.

[0010] The preferred crystalline form of the compound of formula (1) of this application has good fluidity and particle shape, as well as significantly improved viscosity, which can greatly reduce filtration time during the formulation process, shorten the production cycle, and save costs.

[0011] Another aspect of this application provides a method for preparing the crystalline form of this application, which includes, but is not limited to, a room-temperature solvent evaporation method, a suspension stirring method, an anti-solvent addition method, and a cooling method.

[0012] Another aspect of this application provides a pharmaceutical composition comprising one or more crystalline forms of this application and one or more pharmaceutically acceptable carriers.

[0013] Another aspect of this application provides the use of the crystalline form of this application in the manufacture of a pharmaceutical product for the treatment of acute or chronic pain, migraine, osteoarthritis, rheumatoid arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea, cancer, or arteriosclerosis. [Brief explanation of the drawing]

[0014] [Figure 1] Figure 1 shows the XRPD pattern of crystalline form I of the compound of formula (1). [Figure 2] Figure 2 shows the DSC and TGA graphs of crystalline form I of the compound of formula (1). [Figure 3] Figure 3 shows the XRPD pattern of crystalline form II of the compound of formula (1). [Figure 4] Figure 4 shows the DSC and TGA graphs of crystalline form II of the compound of formula (1). [Figure 5]Figure 5 is the XRPD pattern of crystalline form III of the compound of formula (1). [Figure 6] Figure 6 is the DSC and TGA graphs of crystalline form III of the compound of formula (1). [Figure 7] Figure 7 is the XRPD pattern of crystalline form IV of the compound of formula (1). [Figure 8] Figure 8 is the DSC and TGA graphs of crystalline form IV of the compound of formula (1). [Figure 9] Figure 9 is the XRPD pattern of crystalline form V of the compound of formula (1). [Figure 10] Figure 10 is the DSC and TGA graphs of crystalline form V of the compound of formula (1). [Figure 11] Figure 11 is a comparison of the XRPD patterns of the samples before and after the grinding test in Experimental Example 1. [Figure 12] Figure 12 is a comparison of the XRPD patterns of crystalline form IV before and after heating in Experimental Example 2. [Figure 13] Figure 13 is a comparison of the XRPD patterns of crystalline form II before and after the test in Experimental Example 3.

Mode for Carrying Out the Invention

[0015] Definition Unless otherwise defined in the context, all technical and scientific terms used in this specification are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art (including variations of those techniques or substitutions of equivalent techniques that would be apparent to one of ordinary skill in the art). Most of the following terms are believed to be readily understood by one of ordinary skill in the art, but nevertheless, the following definitions are presented to better explain the present invention.

[0016] The terms “contain,” “include,” “comprise,” “possess,” or “relate to,” and other variations used herein, are comprehensive or open-ended and do not exclude any additional unlisted elements or method steps.

[0017] When used herein, the word "about" refers to a range of values ​​within the allowable standard error, such as ±0.05, ±0.1, ±0.2, ±0.3, ±1, ±2, or ±3, as understood by those skilled in the art.

[0018] As used herein, the term "solid form" includes all solid forms of the compound of formula (1), such as crystalline or amorphous forms.

[0019] As used herein, the term "amorphous" refers to any solid material that lacks order in three dimensions. In some cases, amorphous solids may be characterized by known techniques, including XRPD crystallography, solid-state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or any combination thereof. As shown below, amorphous solids typically give an extended XRPD pattern consisting of one or two broad peaks (i.e., peaks with a base width of about 5°2θ or more).

[0020] The term "crystalline morphology" or "crystal," as used herein, refers to any solid material exhibiting three-dimensional order that gives a distinctive XRPD pattern with clearly defined peaks, in contrast to amorphous solid materials.

[0021] The term "X-ray powder diffraction pattern (XRPD pattern)," as used herein, refers to an experimentally observed diffractogram or parameters derived therefrom. XRPD patterns are typically characterized by peak positions (horizontal coordinates) and peak intensities (vertical coordinates). In this invention, XRPD patterns are preferably collected using PANalytacal Empyrean and X'Pert3 X-ray powder diffractometers, and transmission modes are preferably collected using a PANalytacal Empyrean X-ray powder diffractometer.

[0022] The term "2θ," as used herein, refers to the peak position in degrees based on the experimental setup of an X-ray diffraction experiment and is a common transverse coordinate unit in the diffraction pattern. The experimental setup requires that the reflected beam be recorded at an angle of 2 theta (2θ) when the reflection is diffracted as the incident beam forms an angle theta (θ) with a particular lattice plane. It should be understood that any specific reference to a specific 2θ value for a particular solid morphology herein is intended to mean the 2θ value (degree) measured using the X-ray diffraction experimental conditions described herein. For example, Cu-Kα (Kα1 (Å): 1.540598 and Kα2 (Å): 1.544426 Å) was used as the radiation source, as described herein.

[0023] The term “differential scanning calorimetry (DSC) graph” as used herein refers to a curve recorded by a differential scanning calorimetry instrument. In this application, DSC graphs are preferably collected by a Discovery DSC 250 (TA Instruments, US).

[0024] As used herein, the term “essentially the same” with respect to X-ray diffraction peak position means that typical variations in peak position and intensity are taken into consideration. For example, those skilled in the art will understand that the peak position (2θ) will exhibit some variation, typically around 0.1–0.2 degrees, as in the instruments used to measure diffraction. Furthermore, those skilled in the art will understand that relative peak intensity should be taken only as a qualitative measure, as it reflects variations due to crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, as well as variations between instruments. Similarly, as used herein, “essentially the same” with respect to DSC graphs is intended to encompass variations associated with these analytical techniques known to those skilled in the art. For example, differential scanning calorimetry graphs typically have variations of up to ±0.2°C for clearly defined peaks and even larger variations for broader lines (e.g., up to ±1°C).

[0025] Unless otherwise specified, the liquid nuclear magnetic resonance spectra in this application are preferably collected using a Bruker 400M nuclear magnetic resonance spectrometer with DMSO-d6 as the solvent.

[0026] As used herein, the term "hydrocarbon" preferably means a hydrocarbon having 1 to 10 carbon atoms, and includes alkanes, halogenated alkanes, alkenes, alkynes, and aromatic hydrocarbons, and specifically, but not limited to, dichloromethane, trichloromethane (chloroform), n-hexane, n-heptane, and toluene.

[0027] As used herein, the term “alcohol” preferably means an alcohol having 1 to 10 carbon atoms, and includes, but is not limited to, methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol, and tert-butanol.

[0028] As used herein, the term "ether" preferably means an ether having 2 to 6 carbon atoms, and includes linear ethers and cyclic ethers (e.g., furan (including tetrahydrofuran) and dioxane), and specifically, but not limited to, diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, anisole, and dimethoxyethane.

[0029] As used herein, the term "nitrile" preferably means a nitrile having 2 to 6 carbon atoms, and includes, but is not limited to, acetonitrile and propionitrile.

[0030] As used herein, the term "ketone solvent" preferably means a ketone having 2 to 6 carbon atoms, and includes, but is not limited to, acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone.

[0031] As used herein, the term "ester" preferably means an ester having 3 to 10 carbon atoms, and includes, but is not limited to, ethyl acetate, propyl acetate, isopropyl acetate, ethyl isopropionate, dimethyl carbonate, and butyl acetate.

[0032] As used herein, the term "organic acid" preferably means an organic acid having 1 to 10 carbon atoms, and includes, but is not limited to, formic acid and acetic acid.

[0033] As used herein, the term "sulfone" preferably means a sulfone or sulfoxide having 2 to 10 carbon atoms, and includes, but is not limited to, dimethyl sulfoxide.

[0034] As used herein, the term "amide" preferably means an amide having 1 to 10 carbon atoms, and includes, but is not limited to, dimethylformamide or dimethylacetamide.

[0035] As used herein, the term "nitrogen-containing heterocycle" preferably means a nitrogen-containing heterocycle having 3 to 10 carbon atoms and at least 1 nitrogen atom, and includes, but is not limited to, N-methylpyrrolidone.

[0036] Numerical ranges (e.g., "1 to 10") and their subranges (e.g., "2 to 10", "2 to 6", "3 to 10"), as used herein, encompass any point within the numerical range (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0037] 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 recovering the solid under pressure or reduced pressure. The recovered solid may optionally be dried. In this invention, “drying” is carried out under reduced pressure (preferably vacuum) until the residual solvent content is reduced to within the limits given by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. The residual solvent content does not exceed about 5000 ppm, preferably about 4000 ppm, or more preferably about 3000 ppm, depending on the type of solvent. Drying may be carried out in a tray dryer, vacuum oven, air oven, conical vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, etc. Drying may be carried out at a temperature below approximately 100°C, below approximately 80°C, below approximately 60°C, below approximately 50°C, below approximately 30°C, or any other suitable temperature, at atmospheric pressure or under reduced pressure (preferably vacuum), for any desired period (e.g., approximately 1, 2, 3, 5, 10, 15, 20, 24 hours, or overnight) until the desired result is achieved, provided that the quality of the salt does not deteriorate. Drying may be carried out any desired number of times until the desired product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce the desired particle size. Milling or particle reduction may be carried out before drying the product or after drying is complete. Techniques that can be used for particle size reduction include, but are not limited to, ball, roller and hammer milling and jet milling.

[0038] When used herein, the term "anhydrous crystalline form" preferably means a crystalline form that does not contain water molecules as structural elements.

[0039] Crystal morphology and method for preparing the same In one embodiment, the present invention provides a crystalline form I of a compound of formula (1), wherein the crystalline form I has an XRPD pattern that includes characteristic peaks at diffraction angles (2θ) of approximately 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°.

[0040] In a preferred embodiment, the crystalline form I of the compound of formula (1) has an XRPD pattern that includes a peak at the following diffraction angle (2θ):

[0041] [Table 1]

[0042] In a more preferred embodiment, crystalline form I of the compound of formula (1) has an XRPD pattern that includes a peak at essentially the same diffraction angle (2θ) as shown in Figure 1. In the most preferred embodiment, the XRPD pattern of crystalline form I of the compound of formula (1) is essentially the same as that shown in Figure 1, and preferably as shown in Figure 1.

[0043] In a preferred embodiment, the crystalline form I of the compound of formula (1) of the present invention has a DSC graph that includes characteristic peaks at approximately 220 ± 2°C (start temperature).

[0044] In a preferred embodiment, crystalline form I of the compound of formula (1) of the present invention exhibits a weight loss of less than about 0.2% when heated to about 200°C.

[0045] In a more preferred embodiment, crystalline form I of the compound of formula (1) has a DSC-TGA graph containing essentially the same characteristic peaks as that shown in Figure 2. In the most preferred embodiment, the DSC-TGA graph of crystalline form I of the compound of formula (1) is essentially the same as that shown in Figure 2, and preferably as shown in Figure 2.

[0046] In a preferred embodiment, the crystalline form I of the compound of formula (1) is anhydrous crystalline form.

[0047] In one embodiment, the present invention provides a crystalline form II of the compound of formula (1), wherein the crystalline form II has an XRPD pattern that includes characteristic peaks at diffraction angles (2θ) of approximately 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°.

[0048] In a preferred embodiment, the crystalline form II of the compound of formula (1) has an XRPD pattern that includes a peak at the following diffraction angle (2θ):

[0049] [Table 2]

[0050] In a more preferred embodiment, crystalline form II of the compound of formula (1) has an XRPD pattern that includes a peak at essentially the same diffraction angle (2θ) as shown in Figure 3. In the most preferred embodiment, the XRPD pattern of crystalline form II of the compound of formula (1) is essentially the same as that shown in Figure 3, and preferably as shown in Figure 3.

[0051] In a preferred embodiment, crystalline form II of the compound of formula (1) of the present invention has a DSC graph that includes characteristic peaks at approximately 224 ± 2°C (start temperature).

[0052] In a preferred embodiment, crystalline form II of the compound of formula (1) of the present invention exhibits almost no weight loss when heated to about 200°C.

[0053] In a more preferred embodiment, crystalline form II of the compound of formula (1) has a DSC-TGA graph containing essentially the same characteristic peaks as that shown in Figure 4. In the most preferred embodiment, the DSC-TGA graph of crystalline form II of the compound of formula (1) is essentially the same as that shown in Figure 4, and preferably as shown in Figure 4.

[0054] In a preferred embodiment, crystalline form II of the compound of formula (1) is anhydrous crystalline form.

[0055] In one embodiment, the present invention provides a crystalline form III of the compound of formula (1), wherein the crystalline form III has an XRPD pattern that includes characteristic peaks at diffraction angles (2θ) of approximately 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°.

[0056] In a preferred embodiment, crystalline form III of the compound of formula (1) has an XRPD pattern that includes a peak at the following diffraction angle (2θ):

[0057] [Table 3]

[0058] In a more preferred embodiment, crystalline form III of the compound of formula (1) has an XRPD pattern that includes a peak at essentially the same diffraction angle (2θ) as shown in Figure 5. In the most preferred embodiment, the XRPD pattern of crystalline form III of the compound of formula (1) is essentially the same as that shown in Figure 5, and preferably as shown in Figure 5.

[0059] In a preferred embodiment, crystalline form III of the compound of formula (1) of the present invention has a DSC graph that includes characteristic peaks at approximately 97±2°C and 223±2°C (start temperature).

[0060] In a preferred embodiment, crystalline form III of the compound of formula (1) of the present invention exhibits a weight loss of approximately 14% when heated to approximately 125°C.

[0061] In a more preferred embodiment, crystalline form III of the compound of formula (1) has a DSC-TGA graph containing essentially the same characteristic peaks as that shown in Figure 6. In the most preferred embodiment, the DSC-TGA graph of crystalline form III of the compound of formula (1) is essentially the same as that shown in Figure 6, and preferably as shown in Figure 6.

[0062] In a preferred embodiment, crystalline form III of the compound of formula (1) is a solvate with tetrahydrofuran, and the molar ratio of the compound of formula (1) to tetrahydrofuran is preferably 1:1.

[0063] In one embodiment, the present invention provides a crystalline form IV of the compound of formula (1), wherein the crystalline form IV has an XRPD pattern that includes characteristic peaks at diffraction angles (2θ) of approximately 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°.

[0064] In a preferred embodiment, crystalline form IV of the compound of formula (1) has an XRPD pattern that includes a peak at the following diffraction angle (2θ):

[0065] [Table 4]

[0066] In a more preferred embodiment, crystalline form IV of the compound of formula (1) has an XRPD pattern that includes a peak at essentially the same diffraction angle (2θ) as shown in Figure 7. In the most preferred embodiment, the XRPD pattern of crystalline form IV of the compound of formula (1) is essentially the same as that shown in Figure 7, and preferably as shown in Figure 7.

[0067] In a preferred embodiment, crystalline form IV of the compound of formula (1) of the present invention has a DSC graph that includes characteristic peaks at approximately 169±2°C and 222±2°C (start temperature).

[0068] In a preferred embodiment, crystalline form IV of the compound of formula (1) exhibits almost no weight loss when heated to about 200°C.

[0069] In a more preferred embodiment, crystalline form IV of the compound of formula (1) has a DSC-TGA graph containing essentially the same characteristic peaks as that shown in Figure 8. In the most preferred embodiment, the DSC-TGA graph of crystalline form IV of the compound of formula (1) is essentially the same as that shown in Figure 8, and preferably as shown in Figure 8.

[0070] In a preferred embodiment, crystalline form IV of the compound of formula (1) is the anhydrous crystalline form.

[0071] In one embodiment, the present invention provides a crystalline form V of the compound of formula (1), wherein the crystalline form V has an XRPD pattern that includes characteristic peaks at diffraction angles (2θ) of approximately 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°.

[0072] In a preferred embodiment, the crystalline form V of the compound of formula (1) has an XRPD pattern that includes a peak at the following diffraction angle (2θ):

[0073] [Table 5]

[0074] In a more preferred embodiment, the crystalline form V of the compound of formula (1) has an XRPD pattern that includes a peak at essentially the same diffraction angle (2θ) as shown in Figure 9. In the most preferred embodiment, the XRPD pattern of the crystalline form V of the compound of formula (1) is essentially the same as that shown in Figure 9, and preferably as shown in Figure 9.

[0075] In a preferred embodiment, the crystalline form V of the compound of formula (1) has a DSC graph that includes characteristic peaks at approximately 102±2°C, 113±2°C, and 224±2°C (start temperature).

[0076] In a preferred embodiment, the crystalline form V of the compound of formula (1) of the present invention exhibits a weight loss of about 15% when heated to about 200°C.

[0077] In a more preferred embodiment, the crystalline form V of the compound of formula (1) has a DSC-TGA graph containing essentially the same characteristic peaks as that shown in Figure 10. In the most preferred embodiment, the DSC-TGA graph of the crystalline form V of the compound of formula (1) is essentially the same as that shown in Figure 10, and preferably as shown in Figure 10.

[0078] In a preferred embodiment, the crystalline form V of the compound of formula (1) is a solvate with dimethyl sulfoxide, and the molar ratio of the compound of formula (1) to dimethyl sulfoxide is preferably 1:1.

[0079] In some embodiments, the present invention further provides a method for preparing one of the crystalline forms I to V, which includes, but is not limited to, a room-temperature solvent evaporation method, a suspension stirring method, a poor solvent addition method, and a cooling method.

[0080] In some embodiments, the crystalline form is prepared by a room-temperature solvent evaporation method, which involves completely dissolving a solid of the compound of formula (1) in a solvent to form a clear solution (the solution may be filtered as necessary to obtain a clear solution), and then leaving the resulting solution at room temperature to obtain the crystalline form, so that the solvent completely evaporates.

[0081] In some embodiments, the solvent is an organic solvent, but is not limited to, alcohols, hydrocarbons (including alkanes, halogenated alkanes, alkenes, alkynes, and aromatic hydrocarbons), ethers (including linear ethers and cyclic ethers (e.g., furan (including tetrahydrofuran) and dioxane)), ketones, nitriles, or esters having 1 to 10 carbon atoms, specifically, for example, methanol, ethanol, isopropanol, dichloromethane, trichloromethane (chloroform), tetrahydrofuran, acetone, butanone, methyl tert-butyl ether, ethyl acetate, or acetonitrile, or a mixed solvent formed by two or more of the above solvents.

[0082] In some embodiments, when crystalline form I is prepared using a room-temperature solvent volatilization method, the solvent used is not limited to, but includes organic solvents such as hydrocarbons (including alkanes, halogenated alkanes, alkenes, alkynes, and aromatic hydrocarbons), ethers (including linear ethers and cyclic ethers (e.g., furan (including tetrahydrofuran) and dioxane)), or ketones having 1 to 10 carbon atoms, specifically, for example, dichloromethane, tetrahydrofuran, acetone, or butanone, or a mixed solvent formed by two or more of the above solvents.

[0083] In some embodiments, when crystalline form II is prepared using a room-temperature solvent evaporation method, the solvent used may include, but is not limited to, organic solvents, such as alcohols or nitriles having 1 to 10 carbon atoms, specifically ethanol or acetonitrile, or a mixed solvent formed by two or more of the above solvents.

[0084] In some embodiments, the weight-to-volume ratio (mg / mL) of the compound of formula (1) to the solvent is (5-20):1, preferably about 10:1.

[0085] In some embodiments, the crystalline form is prepared by a suspension stirring method, which involves adding a solid of the compound of formula (1) to a solvent to obtain a suspension, stirring, and then separating to obtain the crystalline form.

[0086] In some embodiments, stirring is carried out at room temperature or at an elevated temperature (e.g., 40-60°C, preferably about 50°C).

[0087] In some embodiments, the solvent includes, but is not limited to, inorganic solvents (e.g., water) and organic solvents (e.g., alcohols, ketones, hydrocarbons (including alkanes, halogenated alkanes, alkenes, alkynes, and aromatic hydrocarbons), ethers (including linear ethers and cyclic ethers (e.g., furan (including tetrahydrofuran) and dioxane)), esters, nitriles, and organic acids having 1 to 10 carbon atoms, e.g., methanol, n-propanol, isopropanol, acetone, butanone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, hexane, heptane, dichloromethane, methyl tert-butyl ether, dioxane, dimethyl carbonate, tetrahydrofuran, 2-methyltetrahydrofuran, acetic acid, toluene, trichloromethane, cyclopentyl methyl ether), or a mixture of two or more solvents selected from the above solvents.

[0088] In some embodiments, preferred solvent mixtures are as shown in the table below:

[0089] [Table 6]

[0090] In some embodiments, the volume ratio of solvent 1 to solvent 2 is 1:1 to 1:5, preferably 1:1 to 1:3.

[0091] In some embodiments, 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, and most preferably (60-150):1.

[0092] In some embodiments, the crystalline form is prepared by a poor solvent addition method, which includes the steps of dissolving a solid of the compound of formula (1) in a good solvent to form a clear solution (the solution may be filtered as necessary to obtain a clear solution), then adding a poor solvent to the clear solution to precipitate the solid, and filtering this to obtain the crystalline form.

[0093] In some embodiments, a good solvent includes, but is not limited to, organic solvents such as alcohols, ketones, hydrocarbons (including alkanes, halogenated alkanes, alkenes, alkynes, and aromatic hydrocarbons), ethers (including linear ethers and cyclic ethers (e.g., furan (including tetrahydrofuran) and dioxane)), sulfones, amides, and organic acids having 1 to 10 carbon atoms, such as methanol, ethanol, acetone, tetrahydrofuran, acetic acid, trichloromethane, dimethyl sulfoxide, or dimethylacetamide. In some embodiments, the poor solvent is an inorganic solvent (e.g., water) and an organic solvent (e.g., ketones, hydrocarbons (including alkanes, halogenated alkanes, alkenes, alkynes, and aromatic hydrocarbons), ethers (including linear ethers and cyclic ethers (e.g., furan (including tetrahydrofuran) and dioxane)), esters, and nitriles having 1 to 10 carbon atoms), such as n-hexane, n-heptane, cyclopentyl methyl ether, acetonitrile, methyl isobutyl ketone, 2-methyltetrahydrofuran, dioxane, isopropyl acetate, dichloromethane, toluene, acetonitrile, butanone, methyl tert-butyl ether, ethyl isopropionate, dimethyl carbonate, and ethyl acetate.

[0094] In some embodiments, when crystalline form I is prepared using a poor solvent addition method, the good solvent used is a ketone having 1 to 10 carbon atoms (preferably acetone); the poor solvent used is an inorganic solvent (preferably water) or a hydrocarbon having 1 to 10 carbon atoms (preferably n-heptane).

[0095] In some embodiments, when crystalline form III is prepared using a poor solvent addition method, the good solvent used is an ether having 1 to 10 carbon atoms (preferably tetrahydrofuran); the poor solvent used is a hydrocarbon having 1 to 10 carbon atoms (preferably n-heptane).

[0096] In some embodiments, when crystalline form IV is prepared using a poor solvent addition method, the good solvent used is an alcohol (preferably methanol) or sulfone (preferably dimethyl sulfoxide) having 1 to 10 carbon atoms; the poor solvent used is an inorganic solvent (preferably water).

[0097] In some embodiments, the volume ratio of the good solvent to the poor solvent is (0.5-1):(1-20), preferably about 1:10. In some embodiments, 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.

[0098] In some embodiments, the crystalline form is prepared by a cooling method, which includes adding a solid of the compound of formula (1) to a solvent, heating and stirring to dissolve the solid, allowing the resulting clear solution (the solution may be filtered as necessary to obtain a clear solution) to stand, and slowly cooling to obtain the crystalline form.

[0099] In some embodiments, the solvent is not limited to, but includes inorganic solvents (e.g., water) and organic solvents, such as alcohols, ketones, hydrocarbons (including alkanes, halogenated alkanes, alkenes, alkynes, and aromatic hydrocarbons), ethers (including linear ethers and cyclic ethers (e.g., furan (including tetrahydrofuran) and dioxane)), nitriles, esters, and sulfones having 1 to 10 carbon atoms, specifically, for example, isopropanol, acetone, butanone, trichloromethane, acetonitrile, tetrahydrofuran, methanol, n-hexane, cyclohexane, methyl acetate, ethyl acetate, or dimethyl sulfoxide, or a mixture of two or more solvents selected from the above solvents.

[0100] In some embodiments, preferred solvent mixtures are as shown in the table below:

[0101] [Table 7]

[0102] In some embodiments, the volume ratio of solvent 1 to solvent 2 is 5:1 to 1:5, preferably about 1:1.

[0103] In some embodiments, when crystalline form I is prepared using a cooling method, the solvent used is an alcohol having 1 to 10 carbon atoms, preferably isopropanol.

[0104] In some embodiments, when crystalline form II is prepared using a cooling method, the solvent used is a nitrile (preferably acetonitrile), a ketone (preferably butanone), an ester (preferably methyl acetate), or a mixed solvent of water and a ketone solvent (preferably acetone) having 1 to 10 carbon atoms.

[0105] In some embodiments, when crystalline form III is prepared using a cooling method, the solvent used is a mixed solvent of tetrahydrofuran and a hydrocarbon solvent having 1 to 10 carbon atoms (preferably cyclohexane).

[0106] In some embodiments, when crystalline form V is prepared using a cooling method, the solvent used is a mixed solvent of water and dimethyl sulfoxide.

[0107] In some embodiments, the weight-to-volume ratio (mg / mL) of the compound of formula (1) to the solvent is (60-150):1.

[0108] Pharmaceutical composition and use In another embodiment, the present application provides a pharmaceutical composition comprising one or more crystalline forms I, II, III, IV, or V of the compound of formula (1) of the present invention, and one or more pharmaceutically acceptable carriers.

[0109] In another embodiment, the present application provides the use of crystalline forms I, II, III, IV, or V of the compound of formula (1) of the present invention in the manufacture of pharmaceuticals for the treatment of acute or chronic pain, migraines, osteoarthritis, rheumatoid arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea, cancer, or arteriosclerosis.

[0110] In another embodiment, the present application provides crystalline forms I, II, III, IV, or V of the compound of formula (1) of the present invention for use in the treatment of acute or chronic pain, migraine, osteoarthritis, rheumatoid arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea, cancer, or arteriosclerosis.

[0111] In another embodiment, the present application provides a method for treating acute or chronic pain, migraine, osteoarthritis, rheumatoid arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea, cancer, or arteriosclerosis, comprising administering a preventive or therapeutically effective amount of one or more crystalline forms I, II, III, IV, or V of the compound of formula (1) of the present invention to a subject in need, preferably a mammal.

[0112] In another embodiment, this application provides the use of crystalline forms I, II, III, IV, or V of the compound of formula (1) of the present invention in the manufacture of a pharmaceutical for the treatment of cancer.

[0113] In another embodiment, this application provides crystalline forms I, II, III, IV, or V of the compound of formula (1) of the present invention for use in the treatment of cancer.

[0114] In another embodiment, the present application provides a method for treating cancer, comprising administering a preventive or therapeutically effective amount of one or more crystalline forms I, II, III, IV, or V of the compound of formula (1) of the present invention to a subject, preferably a mammal, that requires it.

[0115] In a preferred embodiment, the cancer is selected from the group consisting of breast cancer, cervical cancer, colorectal cancer, endometrial cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, and urethral cancer.

[0116] As used herein, the term “pharmaceutically acceptable carrier” in the present invention means a diluent, adjuvant, excipient, or vehicle with which a therapeutic agent is administered together, which is suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and which is balanced by a reasonable benefit-risk ratio, within the bounds of sound medical judgment.

[0117] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oil, and are of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Not only physiological saline, but also aqueous solutions of dextrose and glycerol can be used as liquid carriers, especially for injectable solutions. 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, and ethanol. The composition may also contain small amounts of wetting agents or emulsifiers, or pH buffers, if desired. Oral formulations may include standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. Examples of suitable drug carriers are described, for example, in Remington's Pharmaceutical Sciences (1990).

[0118] The compositions of the present invention can act systemically and / or locally. For this purpose, the compositions of the present invention may be administered by a preferred route, for example, by injection, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or transdermal administration, or by oral, buccal, nasal, transmucosal, or topical administration as an ophthalmic preparation, or by inhalation.

[0119] Regarding these routes of administration, the compositions of the present invention can be administered in a suitable dosage form.

[0120] The dosage form may be a solid, semi-solid, liquid, or gaseous preparation, and specifically includes, but is not limited to, tablets, capsules, powders, granules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, suspensions, elixirs, and syrups.

[0121] The pharmaceutical compositions of the present invention may be produced by any process well known in the art, such as mixing, dissolving, granulation, sugar-coated tablet production, powdering, emulsification, or freeze-drying processes.

[0122] As used herein, the term “therapeutic dose” refers to the amount of compound administered that reduces, to some extent, one or more symptoms of the disorder being treated.

[0123] The medication regimen may be adjusted to provide the optimal desired response. For example, a single bolus may be administered, or the dose may be divided into several doses over time, or the dose may be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that the dosage values ​​may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. It should be further understood that for any particular subject, the specific medication regimen should be adjusted over time in accordance with the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0124] The amount of the compound of the present invention administered depends on the subject being treated, the severity of the disorder or condition, the administration rate, the properties of the compound, and the judgment of the prescribing physician. Generally, an effective dosage is in the range of about 0.0001 to about 50 mg per kg of body weight per day, for example, about 0.01 to about 10 mg / kg / day, either as a single dose or in divided doses. For a 70 kg person, this would be about 0.007 mg to about 3500 mg / day, for example, about 0.7 mg to about 700 mg / day. In some cases, a dosage level below the lower limit of the aforementioned range may be more than sufficient, while in other cases, a larger dose can be used without causing adverse side effects, however, such a larger dose should first be divided into several smaller doses for administration throughout the day.

[0125] The content or dosage of the compound of the present invention in the pharmaceutical composition is approximately 0.01 mg to approximately 1000 mg, preferably 0.1 to 500 mg, more preferably 0.5 to 300 mg, more preferably 1 to 150 mg, and particularly preferably 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, and 25 mg.

[0126] Unless otherwise indicated, the terms “to treat” or “treatment” as used herein mean to reverse, alleviate, inhibit the progression of, or prevent one or more symptoms of a disorder, condition, or disease to which such terms apply.

[0127] As used herein, the term “subject” includes humans and non-human animals. Examples of human subjects include human subjects with a disease (e.g., those described herein) (referred to as patients), or healthy subjects. The term “non-human animals” as used herein includes all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles) and mammals, e.g., non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cattle, pigs, etc.). [Examples]

[0128] The present invention will be described in more detail below with reference to examples, but these examples are used solely to illustrate the technical solutions of the present invention and are not intended to limit the scope of the invention. Those skilled in the art may make several non-essential improvements and modifications that still fall within the scope of the invention.

[0129] The models and parameters of the apparatus used in the examples and experimental cases are as follows:

[0130] 1. X-ray powder diffraction (XRPD) The solid sample obtained in the example was processed using PIXceI 1DCrystal morphology was analyzed using a PANalytical EMPYREAN equipped with a detector. The instrument parameters were as follows: scan range: 3°(2θ)~40°(2θ); step size: 0.013°(2θ); tube voltage and current were 45KV and 40mA, respectively.

[0131] 2. Thermogravimetric analysis (TGA) Thermogravimetric analysis of the samples was performed using a TGA 55 (TA Instruments, US). The samples were placed in an open aluminum sample pan, automatically weighed in the TGA furnace, and then heated to the final temperature at a rate of 10°C / min.

[0132] 3. Differential Scanning Calorimetry (DSC) Thermal analysis of the sample was performed using a Discovery DSC 250 (TA Instruments, US). Approximately 2 mg of the sample was weighed and placed in the DSC sample pan. The sample was equilibrated at 25°C and then heated to the final temperature at a rate of 10°C / min.

[0133] 4. High-performance liquid chromatography (HPLC) analysis HPLC measurements were performed using an Agilent HPLC 1260 series instrument. The parameters for the HPLC measurement method are listed in the table below.

[0134] [Table 8]

[0135] Example 1 Preparation of the compound of formula (1) (3-(1-(1-(benzofuran-2-ylmethyl)-1H-indole-7-carboxamide)cyclopropyl)bicyclo[1.1.1]pentane-1-carboxylic acid)

[0136] [ka]

[0137] Step 1: Synthesis of methyl 3-(1-aminocyclopropyl)bicyclo[1.1.1]pentane-1-carboxylate B Titanium tetraisopropoxide (29.8 g, 99.7 mmol, 31 mL, purity: 95%) was added to a solution of methyl 3-cyanobicyclo[1.1.1]pentane-1-carboxylate (A) (22.5 g, 99.2 mmol) in toluene (240 mL) under a nitrogen atmosphere at -20°C. EtMgBr (3 M, 60 mL) was added dropwise within 30 minutes under a nitrogen atmosphere at -20°C, and the temperature was maintained between -20 and -10°C. After stirring for 30 minutes, BF3·Et2O (27.6 g, 194 mmol, 24 mL) was added dropwise. The reaction mixture was stirred at -20°C for 30 minutes, and then at 25°C for 12 hours. The reaction mixture was quenched by slowly adding aqueous hydrochloric acid (1 N, 30 mL) at 0°C, and the separated organic layer was discarded. The aqueous phase was basicized to approximately pH 12 with a 10 M sodium hydroxide aqueous solution at 0°C and extracted with ethyl acetate (200 mL x 2). The combined organic layer was concentrated, and the resulting residue was purified by flash column chromatography on silica gel to obtain compound B (3.9 g, 21.7 mmol, yield: 21.9%) as a yellow solid. MS (ESI): 182.3 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ: 3.58 (s, 3H), 1.77 (s, 6H), 0.39-0.37 (m, 4H).

[0138] Step 2: Synthesis of Benzofuran-2-ylmethanol D Benzofuran-2-carboaldehyde (C) (3 g, 20.5 mmol) and anhydrous methanol (40 ml) were continuously added to a reaction flask, and the resulting mixture was cooled to 0°C. Sodium borohydride (0.545 g, 14.4 mmol) was added in batches, and the temperature was maintained below 25°C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed under reduced pressure. 15 ml of 1 N aqueous HCl was added, and the resulting mixture was stirred at room temperature for 5 minutes. The mixture was adjusted to pH 8-9 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (10 ml x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the solvent was removed to obtain compound D (3.0 g, 20.27 mmol, yield: 98.9%) as a yellow oil. MS (ESI): 149.1 [M+1] + . 1 H NMR (400 MHz, CDCl3) δ: 7.55 (dd, J = 8.4, 7.2 Hz, 1H), 7.47 (dd, J = 8.8, 7.6 Hz, 1H), 7.29-7.19 (m, 2H), 6.66 (s, 1H), 4.77 (d, J = 4.8 Hz, 2H).

[0139] Step 3: Synthesis of 2-(bromomethyl)benzofuran E Compound D (2.47 g, 16.7 mmol) and dried dichloromethane (32 ml) were continuously added to a reaction flask, and the resulting mixture was cooled to 0°C. Phosphorus tribromide (1.72 mL, 18.4 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 1 hour. TLC indicated that the reaction was complete. The reaction mixture was adjusted to pH 8-9 with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane (10 ml x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and compound E (3.36 g, yield: 95.9%) was obtained as a yellow oil. The compound was used directly in the next reaction without further purification.

[0140] Step 4: Synthesis of methyl 1-(benzofuran-2-ylmethyl)-1H-indole-7-carboxylate G At 0°C, potassium tert-butoxide (1.53 g, 13.63 mmol) was added to a solution of methyl 1H-indole-7-carboxylate F (1.59 g, 9.09 mmol) in DMF (80 mL), followed by the addition of 2-(bromomethyl)benzofuran E (2.5 g, 11.36 mmol). The resulting mixture was then heated to 25°C and stirred for 3 hours. After confirming completion of the reaction by TLC (petroleum ether:ethyl acetate = 9:1), the reaction mixture was poured into 200 mL of water and extracted with ethyl acetate (100 mL x 2). The organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography on silica gel to obtain compound G (2.0 g, 6.56 mmol, yield: 72.2%) as a yellow oil. MS (ESI): 306.2 [M+1] + .

[0141] Step 5: Synthesis of 1-(benzofuran-2-ylmethyl)-1H-indole-7-carboxylic acid H To a solution of compound G (2.0 g, 6.56 mmol) in methanol (40 mL) and tetrahydrofuran (40 mL), an aqueous solution of KOH (2 M, 33 mL) was added. The resulting mixture was heated to 50°C and stirred for 12 hours. After the starting material was completely consumed and the target product was detected by LC-MS, the reaction mixture was concentrated at 45°C to remove most of the methanol and tetrahydrofuran. The mixture was acidified to approximately pH 6-7 with 1 N hydrochloric acid aqueous solution, washed with 1 N hydrochloric acid, and extracted with ethyl acetate (60 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound H (1.8 g, 6.19 mmol, yield: 94.3%) as a bright yellow solid. MS (ESI): 292.1 [M+1] + .

[0142] Step 6: Synthesis of methyl 3-(1-(1-(benzofuran-2-ylmethyl)-1H-indole-7-carboxamido)cyclopropyl)bicyclo[1.1.1]pentane-1-carboxylate J DIEA (2.8 g, 21.6 mmol) was added to a solution of compound H (1.8 g, 6.18 mmol), compound B (1.4 g, 7.73 mmol) and HATU (3.08 g, 8.12 mmol) in DMF (40 mL). The resulting mixture was stirred at 25 °C under nitrogen for 3 hours. After the reaction was shown to be complete by LCMS, the reaction mixture was poured into 100 mL of water and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give compound J (2.3 g, 5.07 mmol, yield: 82.0%) as a pale yellow solid. MS (ESI): 455.0 [M+1] + .

[0143] Step 7: Synthesis of 3-(1-(1-(benzofuran-2-ylmethyl)-1H-indole-7-carboxamido)cyclopropyl)bicyclo[1.1.1]pentane-1-carboxylic acid 1 LiOH·H2O (2 M, 3.3 mL, 6.6 mmol) was added to a solution of compound J (2.3 g, 5.07 mmol) in methanol (50 mL). The resulting mixture was stirred at 50 °C for 24 hours. After the reaction was shown to be complete by LCMS, the reaction mixture was concentrated at 50 °C to remove most of the methanol. Water (30 mL) was added, the mixture was acidified to pH about 5 with 1 N hydrochloric acid and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was washed with ethyl ether (20 mL) and lyophilized to give the compound of formula (1) (1.8 g, 4.09 mmol, yield: 80.7%) as an off-white powder. MS (ESI): 4,410 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ: 12.24 (s, 1H), 8.75 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 3.2 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 7.24-7.06 (m, 4H), 6.60 (d, J = 3.2 Hz, 1H), 6.18 (s, 1H), 5.76 (s, 2H), 1.76 (s, 6H), 0.63 (d, J = 7.2 Hz, 2H), 0.50 (t, J = 5.6 Hz, 2H).

[0144] Example 2: Room temperature solvent volatilization method The solid of the compound of formula (1) obtained in Example 1 was completely dissolved in the following solvent (the concentration of the solution was approximately 10 mg / mL). The resulting solution was then left at room temperature to completely evaporate the solvent and obtain a solid. XRPD analysis was performed on the obtained solid, and the crystalline form was determined from the obtained XRPD pattern (if the XRPD pattern was essentially the same as that shown in Figure 1, the crystalline form was determined to be form I; if the XRPD pattern was essentially the same as that shown in Figure 3, the crystalline form was determined to be form II; if the XRPD pattern was essentially the same as that shown in Figure 5, the crystalline form was determined to be form III; if the XRPD pattern was essentially the same as that shown in Figure 7, the crystalline form was determined to be form IV; and if the XRPD pattern was essentially the same as that shown in Figure 9, the crystalline form was determined to be form V. The same criteria were applied to Examples 3-9). The results are shown in the table below.

[0145] [Table 9]

[0146] Example 3: Stirring method of room temperature suspension in a single solvent A 30-milligram solid of the compound of formula (1) obtained from Example 1 was added to the following solvent in a specified volume to form a suspension. The suspension was then stirred at room temperature for 3 days, and then filtered to obtain a solid. XRPD analysis was performed on the obtained solid, and the crystalline morphology was determined from the XRPD pattern. The results are shown in the table below.

[0147] [Table 10]

[0148] Example 4: Stirring of a room-temperature suspension in a mixed solvent 30 milligrams of the solid of the compound of formula (1) obtained from Example 1 were placed in each of the mixed solvents shown in the table below to form suspensions. The suspensions were then stirred at room temperature for 3 days, and then filtered to obtain a solid. XRPD analysis was performed on the obtained solid, and the crystalline morphology was determined from the XRPD pattern. The results are shown in the table below.

[0149] [Table 11]

[0150] Example 5: High-temperature suspension stirring method in a single solvent A 30-milligram solid of the compound of formula (1) obtained from Example 1 was added to the following solvent in a specified volume to form a suspension. The suspension was then stirred at 50°C for 3 days, and then filtered to obtain a solid. XRPD analysis was performed on the obtained solid, and the crystalline morphology was determined from the XRPD pattern. The results are shown in the table below.

[0151] [Table 12]

[0152] Example 6: High-temperature suspension stirring method in mixed solvent 30 milligrams of the solid of the compound of formula (1) obtained from Example 1 were placed in each of the mixed solvents shown in the table below to form suspensions. The suspensions were then stirred at 50°C for 3 days, and then filtered to obtain a solid. XRPD analysis was performed on the obtained solid, and the crystalline morphology was determined from the XRPD pattern. The results are shown in the table below.

[0153] [Table 13]

[0154] Example 7: Poor solvent addition method As shown in the table below, a specified amount of the solid of the compound of formula (1) obtained from Example 1 was weighed, placed in a good solvent, the resulting solution was filtered, and the filtrate was slowly added to a poor solvent. The precipitated solid was filtered and subjected to XRPD analysis. The crystal morphology was determined from the XRPD pattern, and the results are shown in the table below.

[0155] [Table 14]

[0156] Example 8: Cooling method in a single solvent Approximately 30 mg of the solid of the compound of formula (1) obtained from Example 1 was weighed and added to each solvent as shown in the table below. The resulting suspension was heated to completely dissolve the solid. The solution was then cooled. The precipitated solid was filtered and analyzed by XRPD. The crystal morphology was determined from the XRPD pattern, and the results are shown in the table below.

[0157] [Table 15]

[0158] Example 9: Cooling method in a mixed solvent Approximately 30 mg of the solid compound of formula (1) obtained from Example 1 was weighed and added to each mixed solvent as shown in the table below. The resulting suspension was heated to completely dissolve the solid. The solution was filtered, and the filtrate was cooled to room temperature. The precipitated solid was filtered and analyzed by XRPD. The crystal morphology was determined from the XRPD pattern, and the results are shown in the table below.

[0159] [Table 16]

[0160] Example 10: Thermogravimetric analysis and differential scanning calorimetry of crystalline morphology Thermogravimetric analysis and differential scanning calorimetry were performed on crystal morphologies I, II, III, IV, and V. DSC and TGA graphs for crystal morphologies I, II, III, IV, and V are shown in Figures 2, 4, 6, 8, and 10, respectively.

[0161] Experimental example Experimental Example 1: Mechanical Grinding Test 0.5 g of crystalline form II was placed in a mortar and ground for approximately 5 minutes, and then the solid was collected for XRPD testing.

[0162] Figure 11 shows the XRPD patterns of the starting sample and the sample after grinding. The results indicate that the crystal morphology of crystal morphology II remained unchanged after grinding.

[0163] Experimental Example 2: Crystal Form Transformation Test Crystal morphology IV was slowly heated to 200°C and then cooled to room temperature. Samples were collected before and after heating for XRPD testing.

[0164] Figure 12 shows the XRPD patterns before and after heating, compared to the reference crystal morphology II. The results indicate that heating changes crystal morphology IV to crystal morphology II. Therefore, crystal morphology II exhibits better stability compared to crystal morphology IV.

[0165] Experimental Example 3: Solid Stability Test Crystal morphology II was stored separately under sealed conditions at 60°C and at 40°C / 75%RH for 7 days. The purity of the samples was determined by HPLC before and after storage, and the XRPD patterns were measured.

[0166] The results of the sample purity determination are shown in the table below. The results indicate that the purity of the sample did not decrease after storage under sealed conditions at 60°C and at 40°C / 75%RH.

[0167] [Table 17]

[0168] Figure 13 shows the XRPD patterns of the samples before and after storage. The results showed that the crystal morphology of crystal morphology II remained unchanged after being stored under sealed conditions at 60°C and at 40°C / 75%RH for 7 days.

[0169] Experimental Example 4: Light Exposure Test The crystalline form II of the compound in formula (1) is 1.2 × 10 6 Under conditions of light intensity of Lux·hr or higher, 200 w·hr / m 2 The samples were exposed to near-ultraviolet energy at 25°C and 25% RH for 30 days. Samples were taken at days 0, 5, 10, and 30, and changes in the sample properties were observed. Drying loss was tested, the total impurity content was measured by HPLC, and the XRPD patterns of the samples were determined.

[0170] The test results showed that the sample was subjected to light exposure conditions (1.2 × 10⁻⁶). 6 Total illuminance of Lux·hr or more, 200w·hr / m 2 After being placed under near-ultraviolet energy (as described above) for 30 days, the results compared to day 0 showed no significant changes in moisture content or composition, and no new impurities exceeding 0.05% were formed. The XRPD pattern showed that the crystal morphology of the sample remained unchanged.

[0171] The results showed that crystal morphology II was under light exposure conditions (1.2 × 10⁻⁶). 6 Total illuminance of Lux·hr or more, 200w·hr / m 2We demonstrated that it is stable under the above near-ultraviolet energy conditions.

[0172] Experimental Example 5: High Temperature Test The crystalline form II of the compound of formula (1) was placed at a high temperature of 60°C for 30 days. Samples were taken at days 0, 5, 10, and 30, and changes in the properties of the samples were observed. Specific rotation was measured using a polarimeter, drying loss was tested, total impurity content was measured by HPLC, and the XRPD patterns of the samples were measured.

[0173] The test results showed that after being exposed to a high temperature of 60°C for 30 days, there were no significant changes in appearance, moisture content, content, or crystal morphology compared to the results on day 0, and no new impurities exceeding 0.05% were formed.

[0174] The results showed that the sample was stable under high temperature (60°C) conditions.

[0175] Experimental Example 6: High Humidity Test Crystalline form II of the compound of formula (1) was placed at 25°C and 92.5% high humidity for 30 days. Samples were taken at days 0, 5, 10, and 30, respectively, and changes in the properties of the samples were observed. Drying loss was tested, the total impurity content was measured by HPLC, and the XRPD patterns of the samples were measured.

[0176] The test results showed that after being placed under high humidity conditions of 92.5%RH for 30 days, water absorption was 0.03% (less than 5%), and compared to the results on day 0, there were no significant changes in appearance, moisture content, content, or crystal morphology, and no new impurities exceeding 0.05% were formed.

[0177] The results showed that the sample was stable under high humidity conditions (RH 92.5%).

[0178] Experimental Example 7: Pharmacokinetic study in SD rats A clear solution of the crystalline form II of the compound of formula (1) was prepared in 10% DMSO, 60% PEG 400, and 30% water for injection, and administered intravenously to SD rats. An aqueous suspension of the crystalline form II of the compound of formula (1) in 0.5% sodium carboxymethylcellulose (CMC.Na) was prepared and administered orally to SD rats, and its pharmacokinetic properties were investigated.

[0179] After a single intravenous administration of 15 mg / kg of the compound of formula (1) to SD rats, the drug exposure (AUC) of the compound in SD rats was measured. 0-t The glycemic index (L) was 78,811 ng*hr / mL, and the clearance (CL) and steady-state apparent volume of distribution (Vss) were 3.59 mL / min / kg and 1.18 L / kg, respectively.

[0180] After a single oral administration of 40 mg / kg of the compound of formula (1) to SD rats, the maximum blood drug concentration (Cmax) and exposure (AUC) of the compound were measured. 0-t The values ​​were 27,700 ng / mL and 153,279 ng*hr / mL, respectively.

[0181] It is clear that crystalline form II of the compound of formula (1) has excellent blood drug concentration and exposure.

[0182] Experimental Example 8: Pharmacokinetic study in Beagle dogs A clear solution of the crystalline form II of the compound of formula (1) was prepared in 10% DMSO, 60% PEG 400, and 30% sterile water for injection, and administered intravenously to beagle dogs. An aqueous suspension of the crystalline form II of the compound of formula (1) in 0.5% sodium carboxymethylcellulose (CMC.Na) was prepared and administered orally to beagle dogs to investigate its pharmacokinetic properties.

[0183] After a single intravenous administration of 5 mg / kg of the compound of formula (1) to beagle dogs, the drug exposure (AUC) of the compound in beagle dogs was measured. 0-tThe glycemic index (CL) was 12,649 ng*hr / mL, and the clearance (CL) and steady-state apparent volume of distribution (Vss) were 6.64 mL / min / kg and 1.50 L / kg, respectively. This indicates that the compound of formula (1) is a compound with low clearance and is widely distributed in the body.

[0184] After a single oral administration of 45 mg / kg of the compound of formula (1) to beagle dogs, the peak blood drug concentration (Cmax) and exposure (AUC) of the compound were measured. 0-t The values ​​were 32,917 ng / mL and 79,576 ng*hr / mL, respectively.

[0185] It is clear that crystalline form II of the compound of formula (1) has excellent blood drug concentration and exposure.

[0186] The specific embodiments described above further illustrate the present invention. However, the scope of the subject matter of the present invention should not be construed as being limited to the above embodiments, and all technical solutions implemented based on the disclosure of the present invention are within the scope of the present invention.

Claims

1. Formula (1): 【Chemistry 1】 The crystalline form I of the compound, Crystal morphology I of the compound of formula (1), wherein crystal morphology I has an XRPD pattern containing characteristic peaks at diffraction angles (2θ) of approximately 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°.

2. A method for preparing crystalline form I of the compound of formula (1) described in claim 1, wherein the method is selected from the group consisting of room temperature solvent evaporation, poor solvent addition, and cooling.

3. Formula (1): 【Chemistry 2】 The crystalline form II of the compound, Crystal morphology II of the compound of formula (1), wherein crystal morphology II has an XRPD pattern containing characteristic peaks at diffraction angles (2θ) of 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°.

4. A method for preparing crystalline form II of the compound of formula (1) described in claim 3, wherein the method is selected from the group consisting of room temperature solvent evaporation, suspension stirring, and cooling.

5. Formula (1): 【Transformation 3】 The compound is in crystalline form III, Crystal morphology III has an XRPD pattern containing characteristic peaks at diffraction angles (2θ) of 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°. Crystallographic form III of the compound of formula (1), wherein the crystalline form III is preferably a solvate with tetrahydrofuran, and the molar ratio of the compound of formula (1) to tetrahydrofuran is preferably 1:

1.

6. A method for preparing crystalline form III of the compound of formula (1) described in claim 5, wherein the method is selected from the group consisting of a poor solvent addition method and a cooling method.

7. Formula (1): 【Chemistry 4】 The crystalline form IV of the compound, Crystal morphology IV of the compound of formula (1), wherein crystal morphology IV has an XRPD pattern containing characteristic peaks at diffraction angles (2θ) of 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°.

8. A method for preparing crystalline form IV of the compound of formula (1) described in claim 7, the method comprising: dissolving the solid of the compound of formula (1) in a good solvent to form a clear solution (the solution may be filtered as necessary to obtain a clear solution); then adding a poor solvent to the clear solution to precipitate the solid; filtering the solution to obtain crystalline form IV, the method being a poor solvent addition method. A method wherein the good solvent used is preferably an alcohol (preferably methanol) or sulfone (preferably dimethyl sulfoxide) having 1 to 10 carbon atoms, and the poor solvent used is preferably an inorganic solvent (preferably water).

9. Formula (1): 【Transformation 5】 The crystalline form V of the compound, The crystal morphology V exhibits an XRPD pattern containing characteristic peaks at diffraction angles (2θ) of 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°. Crystal form V of the compound of formula (1), wherein the crystal form V is preferably a solvate with dimethyl sulfoxide, and the molar ratio of the compound of formula (1) to dimethyl sulfoxide is preferably 1:

1.

10. A method for preparing crystalline form V of the compound of formula (1) described in claim 9, the method comprising: adding a solid of the compound of formula (1) to a solvent; heating and stirring to dissolve the solid; allowing the resulting clear solution (the solution may be filtered as necessary to obtain a clear solution) to stand; and slowly cooling to obtain crystalline form V, the method being a cooling method. A method wherein the solvent used is preferably a mixed solvent of water and dimethyl sulfoxide.

11. A pharmaceutical composition comprising a crystalline form I, II, III, IV, or V of the compound of formula (1) as described in any one of claims 1, 3, 5, 7, and 9, and one or more pharmaceutically acceptable carriers.

12. Use of crystalline form I, II, III, IV, or V of the compound of formula (1) described in any one of claims 1, 3, 5, 7, and 9 in the manufacture of a pharmaceutical product for the treatment of acute or chronic pain, migraine, osteoarthritis, rheumatoid arthritis, gout, bursitis, ankylosing spondylitis, primary dysmenorrhea, cancer, or arteriosclerosis.

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