Formulations containing uracil derivatives

Abstract

The present application provides a preparation (pharmaceutical composition) containing an uracil derivative showing coronavirus 3CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a solvate thereof as an effective ingredient. In addition, the present application provides a crystal of an uracil derivative showing coronavirus 3CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a solvate thereof.

Description

Technical Field

[0001] This invention relates to a formulation containing a uracil derivative. More specifically, this invention relates to a formulation containing a uracil derivative exhibiting inhibitory activity against coronavirus 3CL protease, a pharmaceutically permissible salt thereof, or a solvate thereof.

[0002] In addition, the present invention relates to a uracil derivative exhibiting coronavirus 3CL protease inhibitory activity, its pharmaceutically permissible salts, or the solid state (crystalline and amorphous) of their solvates. Background Technology

[0003] Coronaviruses, belonging to the subfamily Coronaviridae of the family Coronaviridae in the order Nidoviruses, have a genome size of approximately 30,000 base pairs, making them the largest known single-stranded plus-stranded RNA viruses. Coronaviruses are classified into four genera: α-coronavirus, β-coronavirus, γ-coronavirus, and δ-coronavirus. Of these, seven are known to infect humans: two species of α-coronavirus (HCoV-229E and HCoV-NL63) and five species of β-coronavirus (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2). Four of these (HCoV-229E, HCoV-NL63, HCoV-HKU1, and HCoV-OC43) are pathogens of the common cold, while the remaining three are the severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), the Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV), and the novel coronavirus (SARS-CoV-2), which cause severe pneumonia.

[0004] The novel coronavirus infectious disease (COVID-19) was declared an epidemic by the WHO on March 11, 2020. As the main route of infection for SARS-CoV-2, droplet infection, contact infection, and aerosol infection have been reported. It has been confirmed that SARS-CoV-2, when suspended in the air with aerosols, maintains its infectivity for approximately 3 hours (Non-Patent Literature 1). The incubation period is approximately 2–14 days. Typical symptoms include fever (87.9%), dry cough (67.7%), fatigue (38.1%), and sputum (33.4%), resembling cold symptoms (Non-Patent Literature 2). Severe cases have developed acute respiratory distress syndrome or respiratory organ failure due to acute lung injury, interstitial pneumonia, etc. In addition, multiple organ failure, including renal failure and liver failure, has also been reported.

[0005] When a coronavirus infects a cell, it synthesizes two polyproteins. These two polyproteins contain a replication complex that forms the viral genome and two proteases. The proteases cleave the polyproteins synthesized by the virus, playing an indispensable role in enabling each protein to function. Of the two proteases, the protease responsible for cleaving almost all polyproteins is 3CL protease (the main protease) (Non-Patent Literature 3).

[0006] As an active ingredient in COVID-19 therapeutics targeting 3CL protease, compounds with various chemical structures are known, but their chemical structures differ from those used in this invention.

[0007] Compounds with 3CL protease inhibitory activity are disclosed in Patent Documents 1-4 and Non-Patent Documents 4-14, but no compound used in this invention is described or mentioned in any of the documents.

[0008] Existing technical documents Patent documents Patent Document 1: International Publication No. 2021 / 205298 Patent Document 2: International Publication No. 2021 / 250648 Patent Document 3: International Publication No. 2022 / 138987 Patent Document 4: International Publication No. 2022 / 138988 Non-patent literature Non-patent literature 1: The New England Journal of Medicine (2020), Volume 382, ​​pp. 1564-1567 Non-Patent Document 2: "Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)", [online], February 28, 2020, WHO, [retrieved March 16, 2023], Internet <URL:https: / / www.who.int / docs / default-source / coronaviruse / who-china-joint-mission-on-covid-19-final-report.pdf> Non-patent literature 3: Science (2003), Volume 300, pp. 1763-1767 Non-patent literature 4: "A comparative analysis of SARS-CoV-2 antiviralscharacterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19", Journal of Virology, 2021 Mar 10; 95 (7), e01819-20 Non-patent literature 5: Cell Research (2020), Volume 30, pp. 678–692 Non-patent literature 6: Science (2020), Volume 368, pp. 409-412 Non-patent literature 7: ACS Central Science (2021), Volume 7, Issue 3, pp. 467-475 Non-Patent Literature 8: 261st Am Chem Soc (ACS) Natl Meet · 2021-04-05 / 2021-04-16 · Virtual, N / A · Abst 243 Non-patent literature 9: Science (2021), Volume 374, pp. 1586-1593 Non-patent document 10: "Discovery and Development of PBI-0451", [online], March 24, 2022, 35th International Conference on Antiviral Research (ICAR), [retrieved March 16, 2023], Internet<URL:https: / / ir.pardesbio.com / static-files / fc7c4f8c-e0bd-4b97-8c9c-eff09bafd4db> Non-patent literature 11: Molecules (2020), Volume 25, 3193 pages Non-Patent Literature 12: Molecules (2020), Volume 25, 3920 pages Non-patent literature 13: European Journal of Medicinal Chemistry (2020), Volume 206, 112,711 pages Non-patent literature 14: Journal of the American Chemical Society (2022), Volume 144, pp. 2905-2920 Summary of the Invention

[0009] The problem that the invention aims to solve The object of this invention is to provide a formulation containing a uracil derivative exhibiting inhibitory activity against coronavirus 3CL protease, a pharmaceutically permissible salt thereof, or a solvate thereof as an active ingredient. Preferably, this invention provides an oral formulation containing a uracil derivative exhibiting antiviral activity, particularly inhibitory activity against coronavirus proliferation, a pharmaceutically permissible salt thereof, or a solvate thereof.

[0010] In addition, the present invention aims to provide a solid state (crystalline and amorphous) of a uracil derivative exhibiting coronavirus 3CL protease inhibitory activity, its pharmaceutically permissible salt, or its solvates.

[0011] Methods for solving problems This invention relates to the following:

[0012] (1) A formulation containing, as an active ingredient, a compound represented by formula (I), a pharmaceutically permissible salt thereof, or a solvate thereof: [Chemical Formula 1] .

[0013] (2) The preparation described in (1) above, wherein the active ingredient is a compound represented by formula (I), a pharmaceutically permissible salt thereof, or an amorphous form of a solvate thereof.

[0014] (3) The preparation described in (2) above, wherein the active ingredient is an amorphous form of the compound represented by formula (I).

[0015] (4) The formulation described in (3) above contains an amorphous form of the compound represented by formula (I) in a solid dispersion.

[0016] (5) As described in (4) above, the preparation also contains a polymer in the solid dispersion.

[0017] (6) The preparation described in (5) above, wherein the polymer is selected from one or more of ethylene-based polymers, cellulose-based polymers, and acrylic polymers.

[0018] (7) The formulation described in (6) above, wherein the polymer is an ethylene-based polymer, and the ethylene-based polymer is selected from one or more of the group consisting of copovidone, polyvinylpyrrolidone, polyvinyl polypyrrolidone, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol-polyethylene glycol-graft copolymer, polyvinyl acetal diethylaminoacetate, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose mixture and polyvinyl acetal diethylaminoacetate.

[0019] (8) The formulation described in (7) above, wherein the ethylene polymer is copolyvinyl ketone.

[0020] (9) The formulation described in (6) above, wherein the polymer is a cellulose polymer, and the cellulose polymer is selected from one or more of the following groups: hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, phthalate, methyl cellulose, methyl hydroxyethyl cellulose, carboxymethyl ethyl cellulose, ethyl cellulose, crystalline cellulose, microcrystalline cellulose, crystalline cellulose-sodium carboxymethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, powdered cellulose, and a mixture of fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methyl cellulose.

[0021] (10) The formulation described in (6) above, wherein the polymer is an acrylic polymer, and the acrylic polymer is selected from one or more of the group consisting of methacrylic acid copolymer L, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, methyl acrylate-methacrylic acid-methyl methacrylate copolymer and 2-methyl-5-vinylpyridine acrylate-methyl methacrylate copolymer.

[0022] (11) The preparation described in (1) above, wherein the active ingredient is a compound represented by formula (I), a pharmaceutically permissible salt thereof, or a crystallization of their solvates.

[0023] (12) The preparation described in (11) above, wherein the active ingredient is an anhydrous crystal of the compound represented by formula (I).

[0024] (13) The preparation described in any of (1) to (12) above further contains a disintegrant, an excipient and / or a lubricant.

[0025] (14) The preparation described in (13) above, wherein the disintegrant is selected from one or more of the group consisting of croscarmellose sodium, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, powdered cellulose, partially α-substituted starch, potato starch, corn starch, hydroxypropyl starch, sodium carboxymethyl starch, low-substituted sodium carboxymethyl starch, sodium starch glycolate, α-substituted starch, starch, polyvinyl alcohol and croscarmellose.

[0026] (15) The formulation described in (14) above, wherein the disintegrant is croscarmellose sodium.

[0027] (16) The formulation described in (14) above, wherein the disintegrant is crospovidone.

[0028] (17) The preparation described in any one of (13) to (16) above, wherein the excipient is selected from crystalline cellulose, silica-treated crystalline cellulose, lactose, anhydrous lactose, white sugar, glucose, fructose, sucrose, mannitol, sorbitol, erythritol, xylitol, powdered maltose maltose, maltitol, starch, potato starch, corn starch (corn starch), rice starch, partially α-starch, α-starch, porous starch, sodium carboxymethyl starch, hydroxypropyl starch, sodium carboxymethyl starch with low degree of substitution, powdered cellulose, sodium carboxymethyl cellulose, ... The group consisting of one or more of the following: calcium methylcellulose, carboxymethyl ethyl cellulose, low-substituted hydroxypropyl cellulose, silicate derivatives, phosphates, carbonates, sulfates, magnesium oxide, titanium oxide, calcium lactate, synthetic hydrotalcite, talc, kaolin, dried aluminum hydroxide, magnesium oxide, bentonite, hydrated silica, light anhydrous silica, magnesium aluminum silicate, synthetic aluminum silicate, calcium silicate, anhydrous calcium hydrogen phosphate, calcium monohydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, dipotassium phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, precipitated calcium carbonate, calcium carbonate, magnesium carbonate, and calcium sulfate.

[0029] (18) The preparation described in any one of (13) to (17) above, wherein the lubricant is selected from one or more of the following groups: sodium stearate fumarate, magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, stearic acid-40-polyhydroxy ester, talc, light anhydrous silica, hydrated silica, magnesium carbonate, precipitated calcium carbonate, dried aluminum hydroxide gel, magnesium aluminum silicate, magnesium silicate, synthetic aluminum silicate, magnesium oxide, magnesium sulfate, cocoa butter, carnauba wax, glycerol fatty acid ester, hydrogenated oil, white beeswax, hydrogenated soybean oil, beeswax, cetyl alcohol, sodium lauryl ester, sucrose fatty acid ester and polyethylene glycol (macrogol).

[0030] (19) The formulation described in any of (1) to (18) above has a coating layer.

[0031] (20) The formulation described in (19) above contains light-stabilizing substances and polymers in the coating layer.

[0032] (21) As described in (20) above, wherein the light-stabilizing substance in the coating layer is selected from one or more of the following groups: Edible Red No. 2, Edible Red No. 3, Edible Red No. 102, Edible Red No. 104, Edible Red No. 105, Edible Red No. 106, Edible Yellow No. 4, Edible Yellow No. 5, Edible Green No. 3, Edible Blue No. 1, Edible Blue No. 2, Edible Red No. 3 aluminum lake, Edible Yellow No. 4 aluminum lake, Edible Yellow No. 5 aluminum lake, Edible Blue No. 1 aluminum lake, Edible Blue No. 2 aluminum lake, Carmine, Sodium Copper Chloride, Copper Chloride, Iron Oxide Red, Iron Oxide Black, Iron Oxide Yellow, Titanium Oxide, Ferric Oxide, Yellow Ferric Oxide and Talc.

[0033] (22) The formulation described in (21) above, wherein the light stabilizer is ferric oxide, yellow ferric oxide and / or talc.

[0034] (23) The formulation described in any one of (20) to (22) above, wherein the polymer in the coating layer is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, ethyl cellulose and polyvinyl alcohol.

[0035] (24) The formulation described in (23) above, wherein the polymer in the coating layer is hydroxypropyl methylcellulose.

[0036] (25) The preparation described in any of (1) to (24) above, wherein the preparation is an oral preparation.

[0037] (26) The preparation described in (25) above, wherein the preparation is a tablet, granule, powder or capsule.

[0038] (27) The preparation described in (11) above, wherein the active ingredient is an ethyl acetate compound crystal of the compound represented by formula (I).

[0039] (28) The preparation described in (27) above is a capsule.

[0040] (29) An amorphous form of a compound, represented by formula (I): [Chemical Formula 2] .

[0041] (30) Crystallization of an ethyl acetate compound, wherein the compound is represented by formula (I): [Chemical Formula 3] .

[0042] (31) A solid dispersion comprising a compound represented by formula (I) and a polymer: [Chemical Formula 4] .

[0043] (32) The solid dispersion described in (31) above, wherein the polymer is selected from one or more of ethylene-based polymers, cellulose-based polymers, and acrylic polymers.

[0044] (33) A solid dispersion as described in (32) above, wherein the polymer is an ethylene-based polymer selected from one or more of the group consisting of polyvinylpyrrolidone (PVPVA), polyvinylpyrrolidone (polyvinylpyrrolidone), polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol-polyethylene glycol-graft copolymer, polyvinyl acetal diethylaminoacetate, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose mixture, and solid dispersions containing water-soluble polymers.

[0045] (34) The solid dispersion described in (33) above, wherein the ethylene polymer is copolyvinyl ketone.

[0046] (35) The solid dispersion described in (34) above, wherein the weight ratio of the compound represented by formula (I) to copovidone is 1:3.

[0047] (36) The formulation described in (25) above contains 20.0 mg of the compound represented by formula (I) as the active ingredient.

[0048] (37) The ethyl acetate compound crystals described in (30) above have peaks at diffraction angles (2θ): 6.9°±0.2°, 8.8°±0.2°, 13.1°±0.2°, 16.3°±0.2° and 23.7°±0.2° in the powder X-ray diffraction pattern.

[0049] (38) The ethyl acetate compound crystals described in (30) or (37) above, in the Raman spectrum, at 421.2 cm⁻¹ -1 ±2 cm -1 509.7 cm -1 ±2 cm -1 1585.3 cm -1±2 cm -1 1709.9 cm -1 ±2 cm -1 and 3052.9 cm -1 ±2 cm -1 It has a peak.

[0050] (39) The formulation described in (17) above, wherein the excipient is crystalline cellulose and / or mannitol.

[0051] (40) The preparation described in (18) above, wherein the lubricant is sodium stearate fumarate and / or light anhydrous silica.

[0052] Invention Effects The formulation of the present invention has inhibitory activity against coronavirus 3CL protease and is useful as a therapeutic and / or preventive agent for coronavirus infectious diseases.

[0053] In addition, the solid state (crystalline and amorphous) of the present invention has inhibitory activity against coronavirus 3CL protease, and is useful as a raw material for therapeutic and / or preventive agents of coronavirus infectious diseases. Attached Figure Description

[0054] Figure 1 The powder X-ray diffraction pattern of the anhydrous crystals of the compound represented by formula (I). The horizontal axis represents 2θ (°), and the vertical axis represents intensity.

[0055] Figure 2 express Figure 1 A list of peak values ​​for the powder X-ray diffraction pattern. In the table, position represents 2θ (°), and intensity represents intensity.

[0056] Figure 3 The crystal structure of the anhydrous crystal of the compound represented by formula (I) (structure in the asymmetric unit).

[0057] Figure 4 Differential scanning calorimetry (DSC) results of the anhydrous crystallization of the compound represented by formula (I). The horizontal axis represents temperature (°C), and the vertical axis represents heat (W / g).

[0058] Figure 5 The results of differential thermal-thermogravimetric analysis (TG / DTA) of the anhydrous crystallization of the compound represented by formula (I) are shown. The vertical axis represents heat (μV) or weight change (%), and the horizontal axis represents temperature (°C). Cel in the figure refers to degrees Celsius (°C).

[0059] Figure 6 Raman spectrum of the anhydrous crystal of the compound represented by formula (I). The horizontal axis represents the Raman shift (cm).-1 The vertical axis represents peak intensity.

[0060] Figure 7 The particle size distribution of the anhydrous crystals of the compound represented by formula (I) before pulverization used in Example 2A is shown.

[0061] Figure 8 The particle size distribution of the anhydrous crystals of the compound represented by formula (I) obtained after pulverization in Example 2A is shown.

[0062] Figure 9 NMR spectroscopy of the ethyl acetate complex of the compound represented by formula (I). The horizontal axis represents the chemical shift (δ) value, and the vertical axis represents the relative intensity of the proton signal.

[0063] Figure 10 Powder X-ray diffraction pattern of the ethyl acetate compound crystals of the compound represented by formula (I). The horizontal axis represents 2θ (°), and the vertical axis represents intensity (Count).

[0064] Figure 11 express Figure 10 A list of peak values ​​for the powder X-ray diffraction pattern. In the table, position represents 2θ (°), and intensity represents intensity.

[0065] Figure 12 Raman spectra of the ethyl acetate complex of the compound represented by formula (I). The horizontal axis represents the Raman shift (cm). -1 The vertical axis represents peak intensity.

[0066] Figure 13 The results of differential thermal-thermogravimetric analysis (TG / DTA) for the crystallization of the ethyl acetate compound represented by formula (I) are shown. The vertical axis represents heat (μV) or weight change (%), and the horizontal axis represents temperature (°C). Cel in the figure refers to degrees Celsius (°C).

[0067] Figure 14 The particle size distribution of the ethyl acetate complex crystals of the compound represented by formula (I) before pulverization used in Example 3E is shown.

[0068] Figure 15 The particle size distribution of the ethyl acetate complex crystals of the compound represented by formula (I) obtained in Example 3E after pulverization is shown.

[0069] Figure 16 The chromatogram shows the anhydrous crystals (particle size distribution D10: 0.86 μm, D50: 3.29 μm, D90: 10.15 μm) of the compound represented by formula (I) determined by liquid chromatography.

[0070] Figure 17The powder X-ray diffraction pattern of the solid dispersion of Example 4B-1 (a solid dispersion composed of the compound represented by formula (I) and copovidone) is shown. The horizontal axis represents 2θ (°), and the vertical axis represents intensity. The four patterns, from top to bottom, represent the following conditions: after being sealed in a glass bottle at 60°C for 1 week, after being sealed in a glass bottle at 40°C and 75% relative humidity for 1 week, after being stored in an open glass bottle at 40°C and 75% relative humidity for 1 week, and immediately after preparation.

[0071] Figure 18 The powder X-ray diffraction pattern of the solid dispersion of Example 4B-2 (a solid dispersion composed of the compound represented by formula (I) and hydroxypropyl methylcellulose acetate succinate (MF grade)) is shown. The horizontal axis represents 2θ (°), and the vertical axis represents intensity. The four patterns, from top to bottom, represent the following conditions: after one week of sealed storage in a glass bottle at 60°C, after one week of sealed storage in a glass bottle at 40°C and 75% relative humidity, after one week of open storage in a glass bottle at 40°C and 75% relative humidity, and immediately after preparation.

[0072] Figure 19 The powder X-ray diffraction patterns of the solid dispersion (composed of the compound represented by formula (I) and povidone) of Example 4B-3 are shown. The horizontal axis represents 2θ (°), and the vertical axis represents intensity. The four patterns, from top to bottom, represent the following conditions: after one week of sealed storage in a glass bottle at 60°C, after one week of sealed storage in a glass bottle at 40°C and 75% relative humidity, after one week of open storage in a glass bottle at 40°C and 75% relative humidity, and immediately after preparation.

[0073] Figure 20 The powder X-ray diffraction patterns of the solid dispersions of Examples 4B-4 (consisting of the compound represented by formula (I) and hydroxypropyl methylcellulose acetate succinate (LF grade)) are shown. The horizontal axis represents 2θ (°), and the vertical axis represents intensity. The four patterns, from top to bottom, represent the following conditions: after one week of sealed storage in a glass bottle at 60°C, after one week of sealed storage in a glass bottle at 40°C and 75% relative humidity, after one week of open storage in a glass bottle at 40°C and 75% relative humidity, and immediately after preparation.

[0074] Figure 21 The dissolution behavior of Example 5C-1 (uncoated tablets) and Example 5D-1 (suspension) is shown. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%).

[0075] Figure 22The figures show the dissolution behavior of the tablets of Example 5E-1 at the start of the test, after one month of sealed storage in polyethylene bottles at 40°C and 75% relative humidity, and after three months of sealed storage in polyethylene bottles at 40°C and 75% relative humidity. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%).

[0076] Figure 23 The figures show the dissolution behavior of the tablets of Example 6B-1 at the start of the test, after being stored in a sealed brown glass bottle at 60°C for 2 weeks, at 40°C for 1 month, and at 40°C and 75% relative humidity for 1 month. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%).

[0077] Figure 24 The figures show the dissolution behavior of the tablets of Example 6B-2 at the start of the test, after being stored in a sealed brown glass bottle at 60°C for 2 weeks, at 40°C for 1 month, and at 40°C and 75% relative humidity for 1 month. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%).

[0078] Figure 25 The figures show the dissolution behavior of the tablets of Example 6C-1 at the start of the test, after being stored in a sealed brown glass bottle at 60°C for 1 week, and after being stored in a sealed brown glass bottle at 40°C and 75% relative humidity for 1 week. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%).

[0079] Figure 26 The figures show the dissolution behavior of the tablets of Example 6C-2 at the start of the test, after being stored in a sealed brown glass bottle at 60°C for 1 week, and after being stored in a sealed brown glass bottle at 40°C and 75% relative humidity for 1 week. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%).

[0080] Figure 27 The dissolution behavior of the solution formulation in Example 8-1 is shown. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%).

[0081] Figure 28 The dissolution behavior of the capsules from Examples 9C-1, 9C-2, 9C-3, and 9C-4 is shown. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%).

[0082] Figure 29 The dissolution behavior of the capsules in Examples 10-1 and 10-2 is shown. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%).

[0083] Figure 30The data represents the dissolution behavior of the solution formulations of Examples 11-1, 11-2, and 11-3 after being stored at 5°C for 3 days. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%). Detailed Implementation

[0084] The following explains the meaning of each term used in this specification. Unless otherwise specified, each term shall have the same meaning when used alone or in combination with other terms.

[0085] The term "composed of" means that it only has the constituent elements. The terms "containing" and "including" mean that it is not limited to the constituent elements and does not exclude elements not described.

[0086] The present invention will now be described with reference to embodiments. Throughout this specification, unless otherwise specified, the singular form should be understood to also include the concept of its plural form. Therefore, unless otherwise specified, articles in the singular form (e.g., "a", "an", "the", etc. in the case of English) should also be understood to include the concept of their plural forms.

[0087] Furthermore, unless otherwise specified, the terminology used in this specification should be understood to have the meaning commonly used in the aforementioned fields. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of conflict, this specification (including definitions) takes precedence.

[0088] Unless otherwise specified, the values ​​described in this specification and claims are approximate values. Variations in values ​​may be due to apparatus calibration, apparatus error, purity of the substance, crystal size, sample size, temperature, and other factors.

[0089] The compound represented by formula (I) is compound (I-077) described in International Publications No. 2023 / 195529 and No. 2023 / 195530, and can be prepared by the synthesis method described in Examples 5 and 6 of those documents. Furthermore, those documents describe that the compound represented by formula (I) has inhibitory activity against coronavirus 3CL protease, inhibiting coronavirus 3CL protease. In this specification, the compound represented by formula (I) is sometimes also referred to as compound (I).

[0090] [Chemical Formula 5] The compound represented by formula (I) is not limited to a specific isomer, but includes all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereomers, optical isomers, rotational isomers, etc.), racemates, or mixtures thereof.

[0091] One or more hydrogen, carbon, and / or other atoms in the compound represented by formula (I) may be substituted with isotopes of hydrogen, carbon, and / or other atoms, respectively. Examples of such isotopes are as follows: 2 H, 3 H, 11 C 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F, 123 I and 36 Cl contains hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine. Compounds represented by formula (I) also include compounds substituted with this isotope (e.g., deuterium derivatives). These isotopically substituted compounds are also useful as pharmaceuticals. Compounds represented by formula (I) include all radiolabeled forms substituted with the radioactive isotope contained within this isotope. Furthermore, a "radiolabeling method" for manufacturing this "radiolabeled form" is also included in this invention, and this "radiolabeled form" is useful as a tool in drug metabolism dynamics studies, conjugation analysis, and / or diagnosis.

[0092] Radiolabeled compounds of formula (I) can be prepared using methods known in the art. For example, tritium-labeled compounds of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) using a catalytic dehalogenation reaction employing tritium. This method involves reacting a precursor, obtained by suitably halogenating the compound of formula (I), with tritium gas in the presence or absence of a suitable catalyst, such as Pd / C, a base, or a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". 14 C-labeled compounds can be used with... 14 Preparation of raw materials for carbon C.

[0093] The compounds represented by formula (I) used in this specification can form prodrugs, and the present invention also includes the various prodrugs described above. A prodrug is a derivative of the compound of the present invention having a group that can be decomposed chemically or metabolically, and is a compound of the present invention that becomes pharmaceutically active in vivo through solvent decomposition or under physiological conditions. Prodrugs include: compounds that are converted into compounds represented by formula (I) by enzymatic oxidation, reduction, hydrolysis, etc., under physiological conditions in vivo, and compounds that are converted into compounds represented by formula (I) by hydrolysis by gastric acid, etc. Methods for selecting and manufacturing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs may be active in themselves.

[0094] The compounds of the present invention possess coronavirus 3CL protease inhibitory activity, and are therefore useful as therapeutic and / or preventive agents for diseases involving coronavirus 3CL protease. In the present invention, when referred to as "therapeutic and / or preventive agents," symptom-modifying agents are also included. Diseases involving coronavirus 3CL protease include viral infectious diseases, preferably coronavirus infectious diseases.

[0095] Examples of coronavirus infectious diseases include those caused by HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. Infectious diseases caused by HCoV-229E, HCoV-OC43, and / or SARS-CoV-2 are preferred, and those caused by SARS-CoV-2 are particularly preferred.

[0096] As a coronavirus infectious disease, the novel coronavirus infectious disease (COVID-19) is particularly preferred.

[0097] The compounds represented by formula (I) used in this specification are present in the form of salts, co-crystallizations, or solvates thereof.

[0098] The phrase “the compound represented by formula (I), its pharmaceutically permissible salt, or its solvates” as used in this specification also includes the various salts, cocrystallizations, and their solvates.

[0099] As used in this specification, "salt" refers to, for example, a compound represented by formula (I) arranged regularly within the same crystal lattice as a countermolecule, and may contain any number of countermolecules. It refers to a salt formed by proton transfer between the compound and the countermolecule within the crystal lattice via ionic bonds.

[0100] As used in this specification, "co-crystallization" refers to the regular arrangement of counter molecules (co-former molecules) within the same crystal lattice, and can contain any number of counter molecules (co-former molecules). Furthermore, co-crystallization refers to the formation of non-covalent and non-ionic chemical interactions between the compound and its counter molecules (co-former molecules) through hydrogen bonds, van der Waals forces, and other non-covalent bonds.

[0101] It is generally believed that proton transfer occurs between the salt and the counter molecule, although incomplete proton transfer is known to exist under certain conditions. This state is not a true salt, and therefore a condition known as co-crystallization also exists. It is also known that proton transfer varies continuously with temperature.

[0102] Therefore, the phrase “a pharmaceutically permissible salt of the compound represented by formula (I)” as used in this specification, which includes co-crystallization, refers to a pharmaceutically permissible salt or co-crystallization of the compound represented by formula (I).

[0103] One method described herein is the use of the compound represented by formula (I) in pharmaceutically permissible salts or co-crystallization with hydrofluoric acid, hydrochloric acid, hydrobromic acid, orthophosphoric acid, hydroiodic acid, nitric acid, phosphoric acid, boric acid, methanesulfonic acid sulfate, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoromethylbenzenesulfonic acid, chlorobenzenesulfonic acid, methoxybenzenesulfonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malonic acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphate, tartaric acid, benzoic acid, glutamic acid, aspartic acid, 2-naphthalenesulfonic acid, hexanoic acid, acetylsalicylic acid, etc.

[0104] Studies of salt formation and co-crystallization provide a means to modify the physicochemical and resulting biological characteristics of a drug without altering its chemical structure. Salt formation and co-crystallization can significantly affect the properties of a drug. Hygroscopicity, stability, solubility, and processing characteristics are also important aspects in the selection of a suitable salt or co-crystallization. The solubility of a salt or co-crystallization can affect its suitability for use as a drug. In cases of low aqueous solubility, the rate of dissolution during in vivo administration is limited by the absorption process, resulting in lower bioavailability. Furthermore, low aqueous solubility may make administration by injection difficult, thus limiting the choice of a suitable route of administration.

[0105] "The compound represented by formula (I)" can form a solvate with water (i.e., a hydrate) or a solvate with a common organic solvent. "The pharmaceutically permissible salt of the compound represented by formula (I)" can form a solvate with water (i.e., a hydrate) or a solvate with a common organic solvent.

[0106] As used in this specification, "solvent compound" refers to a substance in which any number of solvent molecules are arranged in a regular pattern, for example, relative to "the compound represented by formula (I)".

[0107] Examples of solvent molecules include: ethyl acetate, water, ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl- 1-Propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydronaphthalene, toluene, 1,1,2-trichloroethylene, xylene, and tert-butanol.

[0108] Preferably, the following ingredients are used: ethyl acetate, water, ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

[0109] More preferably, ethyl acetate, water, ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid, and trifluoroacetic acid, etc.

[0110] Ethyl acetate is the preferred choice.

[0111] In addition, there are cases where water is adsorbed or formed by placing the "compound represented by formula (I)" in the atmosphere to absorb moisture.

[0112] One way to describe this specification is "ethyl acetate compound of the compound represented by formula (I)". For example, "containing about 1 molar equivalent of ethyl acetate molecules relative to "the compound represented by formula (I)".

[0113] This invention relates to the solid state (crystalline and amorphous) of compounds represented by formula (I), their pharmaceutically permissible salts, or their solvates. The solid state can be any state, either a single state or a mixed state. The crystal can be any crystal, either a single-phase crystal or a mixed crystal.

[0114] Pharmaceutical active ingredients can have substantially different physical properties depending on their solid state. These differences in physical properties can significantly affect the bioavailability, purity, manufacturing method, pharmaceutical composition (formulation) containing the pharmaceutical active ingredient, or method of administration of the drug. Therefore, the choice of solid state is extremely important in pharmaceutical development.

[0115] The present invention provides ethyl acetate precipitates of compounds represented by formula (I), amorphous forms of compounds represented by formula (I), and solid dispersions of compounds represented by formula (I), which are very useful compared to other solid states.

[0116] In addition, the present invention provides formulations containing solid dispersions of compounds represented by formula (I), anhydrous crystals of compounds represented by formula (I), and ethyl acetate complexes of compounds represented by formula (I) that are very useful compared to other formulations.

[0117] The solid state and the formulation have at least one of the following characteristics.

[0118] (1) It has good stability against heat, humidity, solvents, light, etc., and has high storage stability.

[0119] (2) No obvious coloration is shown after being exposed to light.

[0120] (3) It has good solubility relative to water or organic solvents.

[0121] (4) It dissolves faster than water or organic solvents.

[0122] (5) High purity.

[0123] (6) The residual rate of organic solvents is low.

[0124] (7) Excellent operability in filtration, centrifugation, formulation and other processes.

[0125] (8) The specific volume is relatively small.

[0126] (9) It is not easy to carry electricity.

[0127] (10) It can be manufactured in large quantities with high yield under conditions of low environmental impact.

[0128] (11) It is useful as a pharmaceutical active ingredient in oral preparations, injections, etc., or as a raw material for manufacturing them.

[0129] (12) It can be controlled within a pH range suitable for intravenous injection without vascular pain, which is beneficial for liquid volume control and excipient reduction during formulation.

[0130] (13) Good liquidity.

[0131] (14) The compression ratio (%) is low.

[0132] It should be noted that, as used in this specification, "crystal" refers to a solid composed of atoms, ions, molecules, etc., arranged in a three-dimensional and regular manner, distinguishing it from amorphous solids that do not possess this regular internal structure. The crystals used in this specification can be single crystals, twin crystals, polycrystalline, etc.

[0133] In addition, sometimes there are polymorphs in crystals that have the same composition but different arrangements in the crystals. These are collectively referred to as "crystal forms".

[0134] "The compounds represented by formula (I), their pharmaceutically permissible salts, or their solvates" include their polymorphs.

[0135] The crystals used in this specification may be deuterated transforms. The crystals used in this specification may be isotopes (e.g., 3 H, 14 C 35 S, 125 Mark (I, etc.)

[0136] Crystal form and / or crystallinity can be confirmed by spectroscopic methods such as X-ray diffraction, Raman spectroscopy, infrared absorption spectroscopy, and solid-state NMR. Furthermore, the physical properties of crystals can be confirmed using various techniques such as differential scanning calorimetry, water adsorption-desorption assays, and solubility characteristics.

[0137] One method described in this specification is the anhydrous crystallization of the compound represented by formula (I).

[0138] In this specification, "anhydrous" has the same meaning as "solvent-free," "non-solvent-free," "anhydrous," and "non-hydrated."

[0139] In the anhydrous crystallization of the compound represented by formula (I), the theoretical content of water of crystallization is 0% by weight. However, in the analysis of water content and / or solvent content, there are cases where the value of water of crystallization is higher than the theoretical content due to the influence of adhering water and / or adhering solvent on the crystal surface.

[0140] One method described herein is the anhydrous crystallization of the compound represented by formula (I) with characteristic peaks at diffraction angles (2θ): 6.5°±0.2°, 15.6°±0.2°, 17.4°±0.2°, 19.9°±0.2°, and 20.3°±0.2° in a powder X-ray diffraction pattern (CuKα rays, λ=1.5418 Å).

[0141] One method described in this specification is the anhydrous crystallization of the compound represented by formula (I), and its single-crystal structure analysis under CuKα radiation (λ = 1.5418 Å) at 298 K (25 °C). Characterization was achieved using the following crystallographic data: Space group: Pbca a = 14.67 Å ± 0.05 Å b = 11.83 Å ± 0.05 Å c = 27.10 Å ± 0.05 Å α=90° β=90° γ=90°.

[0142] One method described in this specification is the anhydrous crystallization of the compound represented by formula (I) with a melting point of 261.3 °C ± 2 °C in differential scanning calorimetry (DSC).

[0143] One method described in this specification is the anhydrous crystallization of the compound represented by formula (I) with a melting point of 265.6 °C ± 2 °C in a differential thermal-thermal gravimetric assay (TG / DTA).

[0144] One method described in this specification is to use Raman spectroscopy at 415.2 cm⁻¹. -1 ±2 cm -1 502.7 cm -1 ±2cm -1 1431.4 cm -1 ±2 cm -1 1714.8 cm -1 ±2 cm -1 and 3065.4 cm -1 ±2 cm -1 Anhydrous crystals of the compound represented by formula (I) with characteristic peaks.

[0145] The anhydrous crystals of the compounds represented by formula (I) in this specification have a D50 of, for example, 0.02 to 200 μm, preferably 0.1 to 150 μm, and more preferably 0.2 to 100 μm. The anhydrous crystals of the compounds represented by formula (I) in this specification have a D90 of, for example, 0.05 to 300 μm, preferably 0.5 to 200 μm, and more preferably 1.0 to 150 μm.

[0146] The anhydrous crystals of the compound represented by formula (I) used in the formulations of the present invention have a D50 of, for example, 0.02–20 μm, preferably 0.1–10 μm, and more preferably 0.2–8 μm. The anhydrous crystals of the compound represented by formula (I) used in the formulations of the present invention have a D90 of, for example, 0.05–40 μm, preferably 0.2–20 μm, and more preferably 0.5–16 μm. It should be noted that, depending on the type of formulation, particles of anhydrous crystals of the compound represented by formula (I) with a D50 of approximately 200–1500 nm can be used.

[0147] One aspect of the present invention is the crystallization of an ethyl acetate compound of the compound represented by formula (I). For example, crystallization containing about 1 molar equivalent of ethyl acetate molecules relative to the compound represented by formula (I).

[0148] One aspect of the present invention is a crystallization of an ethyl acetate compound of the compound represented by formula (I) formed from the compound represented by formula (I) and ethyl acetate in a molar ratio of 1:1. The theoretical content of ethyl acetate in the crystal is approximately 14.4% by weight.

[0149] The ethyl acetate content of the "ethyl acetate compound crystallization of the compound represented by formula (I)" of the present invention is, for example, 4 to 20% by weight, preferably 9 to 18% by weight, and more preferably 12 to 16% by weight. It should be noted that in the analysis of ethyl acetate content, there may be cases where the content is higher due to the influence of water or ethyl acetate adhering to the crystals, or cases where the content is lower due to some of the ethyl acetate in the crystals being removed before the measurement.

[0150] One aspect of the invention is the crystallization of an ethyl acetate compound of the compound represented by formula (I) having characteristic peaks at diffraction angles (2θ): 6.9°±0.2°, 8.8°±0.2°, 13.1°±0.2°, 16.3°±0.2°, and 23.7°±0.2° in a powder X-ray diffraction pattern (CuKα rays, λ=1.5418 Å).

[0151] One aspect of the present invention is the crystallization of an ethyl acetate compound of the compound represented by formula (I) that exhibits an endothermic peak and weight reduction at 129.5 °C ± 2 °C during differential thermal-thermal gravimetric analysis (TG / DTA).

[0152] One aspect of the invention is that, in Raman spectroscopy, at 421.2 cm⁻¹ -1 ±2 cm -1 509.7 cm -1 ±2 cm -1 1585.3 cm -1 ±2 cm -1 1709.9 cm -1 ±2 cm -1 and 3052.9 cm -1 ±2 cm -1 Ethyl acetate compound of the compound represented by formula (I) with characteristic peaks.

[0153] The D50 of the ethyl acetate complex of the compound represented by formula (I) of the present invention is, for example, 0.1 to 200 μm, preferably 0.3 to 150 μm, and more preferably 0.5 to 100 μm. The D90 of the ethyl acetate complex of the compound represented by formula (I) of the present invention is, for example, 0.2 to 300 μm, preferably 0.5 to 200 μm, and more preferably 1 to 150 μm.

[0154] The ethyl acetate complex of the compound represented by formula (I) used in the formulations of the present invention has a crystallization D50 of, for example, 0.1 to 25 μm, preferably 0.5 to 10 μm, and more preferably 1 to 8 μm. The ethyl acetate complex of the compound represented by formula (I) used in the formulations of the present invention has a crystallization D90 of, for example, 0.2 to 40 μm, preferably 1 to 20 μm, and more preferably 2 to 15 μm.

[0155] One approach in this specification is the amorphous form of the compound represented by formula (I).

[0156] In this specification, "amorphous" has the same meaning as "amorphous solid," "amorphous," and "glass," referring to a solid state that does not have a regular structure like that of crystals. The atoms, ions, and molecules that make up it do not have a three-dimensional ordered repeating period.

[0157] In this specification, "amorphous" refers to a materially amorphous state. For example, it means that 80% or more, preferably 90% or more, more preferably 95% or more, and most preferably 99% or more of the pharmaceutically active ingredient (drug) present in the composition is in an amorphous form. Furthermore, crystallinity refers to a crystallinity of about 20% or less, preferably about 10% or less, more preferably about 5% or less, and most preferably about 1% or less.

[0158] Amorphous solids do not possess an ordered, repeating periodicity in their structure, and therefore do not exhibit diffraction. This can be confirmed using powder X-ray diffraction (PXRD). The PXRD pattern of amorphous solids is a featureless, broad XRPD pattern, also known as a halo pattern. Furthermore, amorphous solids do not exhibit polarized light like crystals, and can be confirmed using the polarized light observation mode of a microscope or digital microscope. Additionally, confirmation can be achieved through techniques such as Raman spectroscopy, infrared absorption spectroscopy, solid-state NMR, and differential scanning calorimetry.

[0159] One aspect of the present invention is a solid dispersion of the compound represented by formula (I).

[0160] One aspect of the present invention is a solid dispersion, which is a solid dispersion of a compound represented by formula (I), wherein the compound represented by formula (I) is amorphous.

[0161] One aspect of the present invention is a solid dispersion of a compound represented by formula (I) that displays a halo pattern in powder X-ray diffraction measurements.

[0162] One aspect of the present invention is a solid dispersion containing a compound represented by formula (I) and a polymer.

[0163] The term "solid dispersion" as used in this specification refers to a matrix containing a pharmaceutical active ingredient (drug) and a polymer. A solid dispersion is a matrix formed by mixing and solidifying a pharmaceutical active ingredient (drug) with a polymer, thereby stably dispersing the amorphous pharmaceutical active ingredient (drug) in molecular form within the polymer. More specifically, a solid dispersion is a matrix formed by dissolving and mixing a pharmaceutical active ingredient (drug) with a polymer in a co-solvent in a single step, followed by solidification, thereby stably dispersing the amorphous pharmaceutical active ingredient (drug) in molecular form within the polymer. Manufacturing methods include spray drying (solvent removal method), heating and melting method, and mixing and pulverizing method (mechanical-chemical method).

[0164] For crystalline, poorly soluble drugs, their solubility and dissolution rate can be improved by dispersing them into solids, thereby making the active pharmaceutical ingredient (drug) amorphous.

[0165] In this specification, "improved solubility" means an increase in the solubility of the compound represented by formula (I) in water or a buffer solution. Specifically, for example, it is specified that when evaluating a solid dispersion or a pharmaceutical composition (preparation) containing a solid dispersion using a dissolution test, the solubility of the solid dispersion containing the compound represented by formula (I) (or compound (I) in a solid dispersion of the compound represented by formula (I)) is 1.5 times or more the solubility of compound (I) itself, or 2 times or more otherwise, or 5 times or more further otherwise, or 10 times or more further otherwise.

[0166] In this specification, "stable solid dispersion" means that, in a time-stability test of the solid dispersion, the compound represented by formula (I) in the amorphous state of the solid dispersion does not crystallize.

[0167] The polymer used in the solid dispersion of the present invention can be any polymer that is pharmaceutically applicable, and can be a mixture of two or more polymers. Examples of such polymers include: vinyl polymers, cellulose polymers, acrylic polymers, polyether polymers, etc. Vinyl polymers, cellulose polymers, and acrylic polymers are preferred, and vinyl polymers are more preferred.

[0168] Examples of ethylene-based polymers used in the solid dispersion of this invention include: copovidone (sometimes referred to in this specification as polyvinylpyrrolidone-vinyl acetate copolymer, PPVVA), polyvinylpyrrolidone (sometimes referred to in this specification as povidone), polyvinyl polypyrrolidone, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol-polyethylene glycol-graft copolymer, polyvinyl acetal diethylaminoacetate, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose mixture, polyvinyl acetal diethylaminoacetate, etc. Copovidone and polyvinylpyrrolidone are preferred, and copovidone is particularly preferred.

[0169] One aspect of the present invention is a solid dispersion containing the compound represented by formula (I) and copovidone.

[0170] Examples of cellulose-based polymers used in the solid dispersion of this invention include: hydroxypropyl methylcellulose acetate succinate (sometimes referred to as hydroxypropyl methylcellulose acetate succinate in this specification), hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose (sometimes referred to as HPC in this specification), low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (sometimes referred to as hydroxypropyl methylcellulose, HPMC in this specification), hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, phthalate, methylcellulose (sometimes referred to as MC in this specification), methyl hydroxyethyl cellulose, carboxymethyl ethyl cellulose, ethyl cellulose, crystalline cellulose, microcrystalline cellulose, crystalline cellulose-sodium carboxymethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, powdered cellulose, and mixtures of fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose, etc. Hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl cellulose are preferred, with hydroxypropyl methylcellulose acetate succinate being particularly preferred.

[0171] Examples of acrylic polymers used in the solid dispersion of the present invention include: methacrylic acid copolymer L, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, and 2-methyl-5-vinylpyridine acrylate-methacrylic acid copolymer. Methacrylic acid copolymer L is preferred.

[0172] In the solid dispersion of the present invention, the weight ratio of "the compound represented by formula (I), its pharmaceutically permissible salt, or their solvates" to the polymer is, for example, 1:0.1 to 1:50, preferably 1:0.5 to 1:25, more preferably 1:1 to 1:10, and particularly preferably 1:1 to 1:6.

[0173] One aspect of the present invention is a solid dispersion of the compound represented by formula (I) in a weight ratio of 1:3 to copovidone.

[0174] The method for manufacturing the solid dispersion of the present invention can employ known methods. For example, it can be manufactured by dissolving and / or suspending "the compound represented by formula (I), its pharmaceutically permissible salt, or their solvates" and polymers in a pharmaceutically permissible solvent, and then removing the solvent by distillation.

[0175] There are no particular limitations as long as the solvent is one that can maintain the compound represented by formula (I) in an amorphous state in the presence of a polymer. For example, solvents of category 3 in ICH-Q3C (Guidelines for Residual Solvents in Pharmaceuticals) (solvents considered to have lower toxicity and pose a lower risk to human health) can be cited. Specifically, examples include ketones such as acetone, alcohols such as methanol, ethanol, and propanol, dichloromethane, or mixtures thereof, and mixtures thereof with water. Acetone, or mixtures of acetone and ethanol, is preferred, and acetone is more preferred.

[0176] The amount of solvent is not particularly limited as long as it is the amount necessary for the compound represented by formula (I) to become amorphous. The amount relative to the weight of the compound represented by formula (I), its pharmaceutically permissible salt, or their solvates, and the polymer is, for example, 1 to 100 times (w / w), preferably 5 to 20 times (w / w).

[0177] As for the method of removing the solvent by distillation, there is no particular limitation as long as it is a method of removing the solvent by distillation, such as spray drying, vacuum drying, and ventilation drying.

[0178] The solid dispersion of the compound represented by formula (I) of the present invention has a D50 of, for example, 0.1 to 500 μm, preferably 0.5 to 200 μm, and more preferably 1 to 100 μm.

[0179] The powder X-ray diffraction pattern of the solid dispersion of the compound represented by formula (I) of the present invention shows a halo pattern.

[0180] This invention relates to a formulation containing "a compound represented by formula (I), a pharmaceutically permissible salt thereof, or a solvate thereof" as an active ingredient.

[0181] In the pharmaceutical composition of the present invention, the compound represented by formula (I) may contain 1 to 100 mg, preferably 5 to 50 mg. Particularly preferred is 20 to 40 mg.

[0182] The formulation may be, for example, an oral or non-oral formulation, preferably an oral formulation, more preferably an orally administered solid formulation, and particularly preferably a tablet, granule, powder, or capsule.

[0183] Examples of oral dosage forms include: solid dosage forms (such as tablets, powders, granules, capsules, pills, films, etc.) and liquid dosage forms (such as suspensions, emulsions, elixirs, syrups, lemon juice, alcoholic preparations, aromatic liquids, extracts, decoctions, tinctures, etc.). Tablets can be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, lozenges, sublingual tablets, oral tablets, chewable tablets, or intraorally disintegrating tablets. Powders and granules can be dry syrups, and capsules can be soft capsules, microcapsules, or sustained-release capsules.

[0184] Examples of non-oral preparations include: injections, drops, and topical preparations (such as eye drops, nasal drops, ear drops, aerosols, inhalers, lotions, injections, ointments, lozenges, enemas, ointments, plasters, gels, creams, patches, poultices, powders, suppositories, etc.). Injectable preparations can be emulsions of O / W, W / O, O / W / O, W / O / W types, etc.

[0185] One aspect of the present invention is a formulation containing a compound represented by formula (I), a pharmaceutically permissible salt thereof, or a solvate thereof as an active ingredient.

[0186] The formulation of the present invention, comprising a compound represented by formula (I), a pharmaceutically permissible salt thereof, or a solvate thereof as an active ingredient, can be manufactured using known methods. This formulation may be combined with pharmaceutically permissible additives, such as disintegrants, excipients, lubricants, binders, coating agents, etc.

[0187] One aspect of the present invention is a formulation containing a solid dispersion of a compound represented by formula (I) as an active ingredient. Another aspect of the present invention is a formulation containing a solid dispersion comprising a compound represented by formula (I) and copovidone as an active ingredient.

[0188] One aspect of the present invention is a formulation containing anhydrous crystals of the compound represented by formula (I) as the active ingredient.

[0189] One aspect of the present invention is a formulation containing an ethyl acetate compound of the compound represented by formula (I) as an active ingredient.

[0190] As preferred forms of formulations, solid dosage forms are mentioned, with granules, powders, capsules or tablets being particularly preferred.

[0191] There are no particular limitations on the manufacturing method of "granules containing the compound represented by formula (I), its pharmaceutically permissible salt, or their solvates as active ingredients". Specifically, the method involves mixing the compound represented by formula (I), its pharmaceutically permissible salt, or their solvates, disintegrants, excipients, and other additives to produce a mixed powder, and then granulating the mixed powder. Preferably, wet granulation is used, where water or water or a binder-containing solvent is added for granulation; or dry granulation or melt granulation is used, where compression molding is performed without water. A V-type mixer or a container blender can be used as the equipment for mixing the pharmaceutical active ingredient (drug), additives, etc. Furthermore, wet extrusion granulators, fluidized bed granulators, stirred granulators, dry crushing granulators, and melt extrusion granulators can be used as the granulation equipment.

[0192] There are no particular limitations on the manufacturing method of "tablets containing a compound represented by formula (I), its pharmaceutically permissible salt, or their solvates as active ingredients". Specifically, granules are manufactured by the above method, and then excipients, disintegrants, and lubricants are mixed with the granules, and the mixed granules are compressed into tablets using a tableting machine. Alternatively, the active pharmaceutical ingredient (drug), excipients, disintegrants, and lubricants are mixed, and the mixture is compressed into tablets using a tableting machine. As equipment for mixing active ingredients, additives, etc., a V-type mixer or a container mixer can be used. In addition, as a tableting machine, a single-punch tableting machine or a rotary tableting machine can be used.

[0193] Examples of disintegrants include: croscarmellose sodium, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, crystalline cellulose, powdered cellulose, partially α-substituted starch, potato starch, corn starch, hydroxypropyl starch, sodium carboxymethyl starch, low-substituted sodium carboxymethyl starch, sodium starch glycolate, α-substituted starch, starch, polyvinyl alcohol, and croscarmellose. Croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, and croscarmellose are preferred, with croscarmellose sodium and croscarmellose being particularly preferred.

[0194] One aspect of the present invention is a solid dispersion containing a compound represented by formula (I) and a solid formulation containing cross-linked sodium carboxymethyl cellulose.

[0195] One aspect of the present invention is a solid dispersion comprising a compound represented by formula (I) and copovidone, and a solid formulation comprising croscarmellose sodium.

[0196] One aspect of the present invention is a solid formulation comprising anhydrous crystals of the compound represented by formula (I) and cross-linked polyvinylpyrrolidone.

[0197] Preferred forms of solid dosage forms include granules, powders, capsules, or tablets, with tablets being particularly preferred.

[0198] Examples of excipients include: crystalline cellulose, silica-treated crystalline cellulose, lactose, anhydrous lactose, white sugar, glucose, fructose, sucrose, mannitol, sorbitol, erythritol, xylitol, powdered maltose syrup, maltitol, starch, potato starch, corn starch (sometimes referred to as corn starch in this specification), rice starch, partially α-starch, α-starch, porous starch, sodium carboxymethyl starch, hydroxypropyl starch, sodium carboxymethyl starch with low substitution degree, powdered cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose, and carboxymethyl cellulose. Vitamin B1, carboxymethyl ethyl cellulose, low-substituted hydroxypropyl cellulose, silicate derivatives, phosphates, carbonates, sulfates, magnesium oxide, titanium oxide, calcium lactate, synthetic hydrotalcite, talc, kaolin, dried aluminum hydroxide, magnesium oxide, bentonite, hydrated silica, light anhydrous silica, magnesium aluminum silicate, synthetic aluminum silicate, calcium silicate, anhydrous calcium hydrogen phosphate, monocalcium phosphate, sodium hydrogen phosphate, dipotassium phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, precipitated calcium carbonate, calcium carbonate, magnesium carbonate, calcium sulfate, etc. Crystalline cellulose and / or mannitol are preferred.

[0199] One aspect of the present invention is a solid dispersion containing a compound represented by formula (I), croscarmellose sodium, crystalline cellulose and mannitol.

[0200] One aspect of the present invention is a solid formulation comprising a compound represented by formula (I) and a copovidone, croscarmellose sodium, crystalline cellulose and mannitol.

[0201] One aspect of the present invention is a solid preparation containing anhydrous crystals of the compound represented by formula (I), cross-linked polyvinylpyrrolidone, and crystalline cellulose.

[0202] Preferred forms of solid dosage forms include granules, powders, capsules, or tablets, with tablets being particularly preferred.

[0203] Examples of lubricants include: sodium stearate fumarate, light anhydrous silica, magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, stearate-40-polyhydroxy ester, talc, hydrated silica, magnesium carbonate, precipitated calcium carbonate, dried aluminum hydroxide gel, magnesium aluminum silicate, magnesium silicate, synthetic aluminum silicate, magnesium oxide, magnesium sulfate, cocoa butter, carnauba wax, glyceryl fatty acid ester, hydrogenated oil, white beeswax, hydrogenated soybean oil, beeswax, cetyl alcohol, sodium laurate, sucrose fatty acid ester, polyethylene glycol (sometimes referred to as macrogol in this specification), etc. Sodium stearate fumarate, light anhydrous silica, magnesium stearate, and calcium stearate are preferred, with sodium stearate fumarate and / or light anhydrous silica being particularly preferred.

[0204] One embodiment of the present invention comprises a solid dispersion of a compound represented by formula (I), croscarmellose sodium, crystalline cellulose, mannitol, sodium stearate fumarate, and a solid formulation of light anhydrous silica.

[0205] One aspect of the present invention is a solid formulation comprising a compound represented by formula (I) and a copovidone, croscarmellose sodium, crystalline cellulose, mannitol, sodium stearate fumarate, and light anhydrous silica.

[0206] One aspect of the present invention is a solid preparation containing anhydrous crystals of the compound represented by formula (I), crospovidone, crystalline cellulose, and sodium stearate fumarate.

[0207] Preferred forms of solid dosage forms include granules, powders, capsules, or tablets, with tablets being particularly preferred.

[0208] The formulation of the present invention comprising, as an active ingredient, a compound represented by formula (I), a pharmaceutically permissible salt thereof, or a solvate thereof, may contain a light-stabilizing substance.

[0209] One aspect of the present invention is "a formulation containing a compound represented by formula (I), a pharmaceutically permissible salt thereof, or a solvate thereof, and a light-stabilizing substance".

[0210] The light-stabilizing substance in the formulation of the present invention can be incorporated into the formulation or coated onto the surface of the formulation. Preferably, the formulation is coated onto the surface of the formulation and contains the light-stabilizing substance. By containing the light-stabilizing substance in the coating layer of the formulation, the photostability of the compound represented by formula (I) contained in the formulation can be improved or discoloration of the formulation can be prevented.

[0211] The formulations of the present invention may have a coating layer, and the coating layer contains a light-stabilizing substance and a polymer. The formulations of the present invention may be coated with the coating layer after the granules or tablets have been manufactured. The formulations of the present invention may be coated tablets or coated granules.

[0212] When forming a coating layer for granules, fluidized bed granulation and coating machines, or fluidized bed rotary coating machines, can be used. When forming a coating layer for tablets, pan-type coating machines, or aerated coating machines, can be used. In the coating machine, the granules or tablets are flowed while the coating solution is sprayed onto them and then dried to form a coating layer.

[0213] One aspect of the present invention is a "solid dosage form having a coating containing a compound represented by formula (I), a pharmaceutically permissible salt thereof, or a solvate thereof as an active ingredient." Another aspect of the present invention is a "solid dosage form having a coating containing a light-stabilizing substance and a polymer having a coating containing a compound represented by formula (I), a pharmaceutically permissible salt thereof, or a solvate thereof as an active ingredient."

[0214] As a preferred form of "the compound represented by formula (I), its pharmaceutically permissible salt, or their solvates", a solid dispersion of the compound represented by formula (I), an anhydrous crystal of the compound represented by formula (I), or an ethyl acetate compound crystal of the compound represented by formula (I) may be used.

[0215] Preferred forms of solid dosage forms include granules, powders, capsules, or tablets, with tablets or capsules being particularly preferred.

[0216] As light-stabilizing substances, there are light-blocking substances that block light and light-absorbing substances that absorb light. Examples include: Edible Red No. 2, Edible Red No. 3, Edible Red No. 102, Edible Red No. 104, Edible Red No. 105, Edible Red No. 106, Edible Yellow No. 4, Edible Yellow No. 5, Edible Green No. 3, Edible Blue No. 1, Edible Blue No. 2, Edible Red No. 3 aluminum lake, Edible Yellow No. 4 aluminum lake, Edible Yellow No. 5 aluminum lake, Edible Blue No. 1 aluminum lake, Edible Blue No. 2 aluminum lake, Carmine, Sodium Copper Chloride, Copper Chloride, Iron Oxide Red, Iron Oxide Black, Iron Oxide Yellow, Titanium Oxide, Ferric Oxide, Yellow Ferric Oxide, Talc, etc. Preferred light-stabilizing substances are ferric oxide, yellow ferric oxide, and / or talc.

[0217] Examples of polymers used in the coating layer include: hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, ethyl cellulose, and polyvinyl alcohol. Hydroxypropyl methylcellulose is preferred.

[0218] One aspect of the present invention is a "solid dosage form having a solid dispersion containing a compound represented by formula (I) as an active ingredient, comprising a coating layer containing ferric oxide, yellow ferric oxide, and / or talc". Another aspect of the present invention is a "solid dosage form having a solid dispersion containing a compound represented by formula (I) as an active ingredient, comprising a coating layer containing ferric oxide, yellow ferric oxide, talc, and hydroxypropyl methylcellulose".

[0219] One aspect of the present invention is a "solid dosage form having an anhydrous crystal of a compound represented by formula (I) as an active ingredient, comprising a coating layer containing ferric oxide, yellow ferric oxide, and / or talc." Another aspect of the present invention is a "solid dosage form having an anhydrous crystal of a compound represented by formula (I) as an active ingredient, comprising a coating layer containing ferric oxide, yellow ferric oxide, talc, and hydroxypropyl methylcellulose."

[0220] Preferred forms of solid dosage forms include granules, powders, capsules, or tablets, with tablets being particularly preferred.

[0221] The content of the coating layer in the solid dosage form of the present invention is not particularly limited, but is 0.1 to 20% by weight relative to the total dosage form, preferably 0.5 to 10% by weight, and more preferably 1 to 8% by weight. When using two or more coating layers, it is acceptable as long as the total amount of the coating layer is within the above-mentioned range.

[0222] The solid dosage form of the present invention may contain a plasticizer along with a light stabilizer and a polymer. Plasticizers listed in the Japanese Pharmacopoeia, the Standards for Pharmaceuticals Outside the Japanese Pharmacopoeia, the Standards for Pharmaceutical Additives, or the Codex Alimentarius of Food Additives may be used. Examples of plasticizers include: citrate esters, glycerol fatty acid esters, surfactants, monoglycerides, diethyl phthalate, dibutyl phthalate, diethyl sebacate, and dibutyl sebacate.

[0223] One aspect of the present invention is "a solid preparation comprising an ethyl acetate complex crystal of a compound represented by formula (I), cross-linked sodium carboxymethyl cellulose, mannitol, crystalline cellulose and sodium stearate".

[0224] Preferred forms of solid dosage forms include granules, powders, capsules, or tablets, with capsules being particularly preferred.

[0225] (Powder X-ray Diffraction (XRPD)) Powder X-ray diffraction (XRPD) is one of the most sensitive analytical methods for determining the crystal form and crystallinity of solids. When X-rays irradiate a crystal, they are reflected at the lattice planes and interfere with each other, displaying ordered diffraction lines corresponding to the periodicity of the structure. On the other hand, for amorphous solids, which typically do not have ordered repeating periods in their structure, diffraction does not occur, and they display a featureless, broad XRPD pattern (also known as a halo pattern).

[0226] The characteristic diffraction peaks used in this specification are peaks selected from the observed diffraction pattern. Preferably, the characteristic diffraction peaks are selected from about 10, more preferably about 5, peaks in the diffraction pattern.

[0227] In distinguishing between various crystals, a peak identified in one crystal but not in others is considered a preferred characteristic peak for identifying that crystal, compared to its intensity. If such a characteristic peak is present, even one or two peaks can characterize the crystal. By comparing the measured patterns, if these characteristic peaks are consistent, the powder X-ray diffraction patterns can be considered substantially consistent.

[0228] Typically, the diffraction angle (2θ) in powder X-ray diffraction can have an error within ±0.2°. Therefore, it should be understood that the value of the diffraction angle in powder X-ray diffraction also includes values ​​within a range of approximately ±0.2°. Thus, this invention not only includes crystals with completely uniform diffraction angles in powder X-ray diffraction, but also crystals with uniform diffraction angles within an error range of approximately ±0.2°.

[0229] It is known that the intensity of the peaks shown in the following figures can vary due to a number of factors, such as the effect of preferred orientation of crystallization against the X-ray beam, the influence of coarse particles, the purity of the analyzed substance, or the crystallinity of the sample. Furthermore, the peak position can also be shifted based on variations in sample height. Moreover, different shifts are obtained according to Bragg's formula (nλ = 2dsinθ) when different wavelengths are used for measurement, but other XRPD patterns obtained by using other wavelengths are also included within the scope of this invention.

[0230] Powder X-ray diffraction measurements at specific temperatures and / or relative humidity can be performed by combining a powder X-ray diffraction apparatus with a temperature and / or relative humidity control device.

[0231] For example, in cases where anhydrous crystals transform into hydrate crystals due to moisture absorption, hydrate crystals transform into anhydrous crystals due to dehydration, solvate crystals undergo a crystallization transformation into anhydrous crystals due to solvent removal, or anhydrous and hydrate crystals reversibly change due to moisture absorption and dehydration, it is suitable to measure specific temperatures and / or relative humidity, or to measure continuously changing temperatures and / or relative humidity. In these cases, the changing relative humidity and the amount of water of crystallization and / or crystallization solvent can be estimated.

[0232] The crystal form of the compound represented by formula (I) is identified by the powder X-ray diffraction pattern and the diffraction angle (2θ) of the characteristic peak. The crystal form of the compound represented by formula (I) (e.g., the anhydrous form of the compound represented by formula (I), the ethyl acetate complex crystal of the compound represented by formula (I)) can be distinguished from other crystal forms by the presence of characteristic peaks.

[0233] (Simultaneous determination of powder X-ray diffraction-differential scanning calorimetry (XRD-DSC)) Simultaneous X-ray diffraction and differential scanning calorimetry (XRD-DSC) can simultaneously observe changes in crystal form (crystal structure) and thermal changes relative to temperature and / or relative humidity. For example, it is suitable for observing changes in crystal form (crystal structure) in the following situations: the transformation of anhydrous crystals into hydrated crystals due to hygroscopic absorption; the transformation of hydrated crystals into anhydrous crystals due to dehydration; the transformation of solvate crystals into anhydrous crystals due to solvent removal; and the reversible crystallization transformation between anhydrous and hydrated crystals due to hygroscopic absorption and dehydration.

[0234] (Single crystal structure analysis) Single-crystal structure analysis is one of the methods for determining crystal form. It can obtain crystallographic parameters, atomic coordinates (values ​​representing the spatial relationships of each atom), and a three-dimensional structural model. For information on single-crystal structure analysis, refer to Toshio Sakurai's "A Guide to X-ray Structure Analysis" (published by Shukafusa, 1983) and Stout & Jensen's "X-Ray Structure Determination: A Practical Guide" (published by Macmillan Co., New York, 1968).

[0235] Single-crystal structure analysis is useful for identifying the structures of optical isomers, tautomers, geometric isomers, salts, cocrystallizations, and solvates (hydrates).

[0236] It should be noted that single-crystal X-ray diffraction experiments are known to improve data quality by performing measurements at low temperatures; therefore, measurements should be performed at room temperature or low temperature, depending on the crystallization required for measurement. Additionally, single-crystal X-ray diffraction experiments of hydrates and / or solvates improve data quality by coating the crystals with paraffin oil or similar substances before measurement.

[0237] (Raman spectroscopy) Raman spectroscopy reveals the vibrational characteristics of molecules or complex systems. It originates from inelastic collisions between molecules and photons, particles containing light. These collisions result in energy exchange, causing a change in energy and consequently, a change in the photon's wavelength. In other words, Raman spectroscopy produces extremely narrow spectral lines when photons are incident on a target molecule; therefore, lasers or similar sources are used as the light source. The wavelength of each Raman line is represented by the wavenumber shift from the incident light, which is the difference between the Raman line's wavelength and the reciprocal of the incident light's wavelength. Raman spectroscopy determines the vibrational states of molecules, which are determined by their molecular structure.

[0238] Typically, the wavelength shift (cm) in Raman spectra -1 It can be within ±2 cm -1 Errors occur within a certain range, therefore it should be understood that the values ​​of Raman spectral peaks also include ±2 cm⁻¹. -1 The values ​​are within the range of ±2 cm⁻¹. Therefore, this invention not only includes crystals with completely consistent Raman spectral peaks, but also crystals with Raman spectral peaks within ±2 cm⁻¹. -1 Consistent crystallization within the left and right margins of error.

[0239] (Infrared absorption spectroscopy (IR method)) Infrared absorption spectroscopy is a method for measuring the degree to which infrared radiation is absorbed as it passes through a sample at various wavenumbers. Infrared absorption spectra are typically represented as a graph with wavenumber on the horizontal axis and transmittance or absorbance on the vertical axis. The wavenumber and transmittance (or absorbance) of the absorption peaks can be read from the graph, or calculated using a data processing device. Infrared absorption spectra are determined by the chemical structure of the substance. Therefore, absorption at various wavenumbers can be measured to confirm or quantify the substance. Polymorphism can be determined by comparing the absorption bands of characteristic functional groups on the polymorph, i.e., functional groups mainly related to hydrogen bonds in the crystal structure, such as C=O, OH, and NH bonds, and other characteristic functional groups, such as CX (halogen) bonds, C=C, and C≡C bonds. Approximately 20 absorption peaks, more preferably approximately 10, and most preferably approximately 5, corresponding to the characteristic functional groups are selected. Typically, the absorption spectrum of the sample is at a wavenumber of 4000 cm⁻¹. -1 ~400 cm -1The measurements were performed within the specified range. The absorption spectra were measured under the same operating conditions as those used to verify the resolution, wavenumber calibration, and wavenumber accuracy of the apparatus.

[0240] Typically, absorption bands (cm) in infrared absorption spectroscopy measurements -1 It can be within ±2 cm -1 Errors occur within a certain range, therefore it should be understood that the above absorption peak values ​​also include ±2 cm⁻¹. -1 The values ​​are within the range of ±2 cm⁻¹. Therefore, this invention not only includes crystals with completely consistent absorption band peaks in infrared absorption spectroscopy measurements, but also crystals with absorption band peaks within ±2 cm⁻¹. -1 Consistent crystallization within the left and right margins of error.

[0241] Methods for measuring infrared absorption spectroscopy include the potassium bromide tablet method, solution method, paste method, liquid film method, thin film method, gas sample method, ATR method, and diffuse reflectance method. Among these, the ATR method (Attenuated Total Reflectance) is a type of reflectance method. This method involves placing the sample in close contact with the surface of a prism made of a high-refractive-index material such as KRS-5, allowing light to be incident on the prism at an angle above the critical angle, and measuring the light that undergoes total internal reflection at the boundary between the prism and the sample to obtain the absorption spectrum. One condition for using the ATR method is that the refractive index of the prism is greater than that of the sample; therefore, the prism material needs to be changed according to the sample. Another condition is that the prism and sample must be in close contact. Therefore, it is suitable for measuring liquids, powders, plastics, soft rubber, etc., and has the advantage of allowing measurement without chemical or physical treatment of the sample. On the other hand, the diffuse reflectance method is a method for measuring powder samples without preparing potassium bromide tablets, but rather in powder form. If light is irradiated onto the sample, light is generated that is specularly reflected off the powder surface and emitted outwards, and diffusely reflected light (scattered light) enters the sample and is repeatedly transmitted and diffused before being emitted back to the surface. The latter is used in the diffuse reflection method to obtain the absorption spectrum.

[0242] (solid 13 C-NMR (nuclear magnetic resonance) solid 13 C-NMR is useful for determining crystal form because of the following reasons: (i) the spectral number matches the number of carbons in the target compound, and (ii) the chemical shift range is wider than that of the target compound. 1 H-NMR, (iii) signal is stronger than solid 1 ¹H NMR is sharp, and (iv) even with additives, the chemical shift remains unchanged in the absence of interactions. It should be noted that the predicted chemical shift may vary slightly depending on the specific spectrometer used and the analyst's sample preparation techniques. Solid 13The error range in C-NMR spectra is approximately ±0.5 ppm.

[0243] (Differential Scanning Calorimetry (DSC)) Differential scanning calorimetry (DSC) is one of the main methods of thermal analysis, used to determine the thermal properties of substances as aggregates of atoms and molecules.

[0244] The change in heat of a pharmaceutical active ingredient in relation to temperature or time is measured by DSC. By plotting the obtained data relative to temperature or time, a differential scanning calorimetry (DSC) curve can be obtained. Based on the DSC curve, information related to the onset temperature (extrapolated melting point onset temperature) of the pharmaceutical active ingredient's melting, the maximum value of the endothermic peak curve accompanying melting, and enthalpy can be obtained.

[0245] Regarding DSC, it is known that the observed temperature can depend on the rate of temperature change, the sample preparation technique used, and the specific apparatus. Therefore, the "melting point" in DSC refers to the initial temperature (extrapolated melting point initial temperature) that is not easily affected by the sample preparation technique. The error range under the initial temperature (extrapolated melting point initial temperature) obtained from the differential scanning calorimetry curve is approximately ±2℃. In determining the identity of crystals, not only the melting point is important, but the overall pattern is also important and can vary to some extent due to the measurement conditions and equipment.

[0246] (Differential thermal-thermal weight analysis (TG / DTA)) Differential thermal-thermogravimetric analysis (TG / DTA) is one of the main methods of thermal analysis. It is a method for determining the weight and thermal properties of substances as aggregates of atoms and molecules.

[0247] TG / DTA is a method for determining the weight and heat changes of pharmaceutical active ingredients relative to temperature or time. By plotting the obtained data against temperature or time, TG (thermogravimetric) and DTA (differential calorimetry) curves can be obtained. Based on the TG / DTA curves, information on the weight and heat changes related to the decomposition, dehydration, oxidation, reduction, sublimation, and evaporation of pharmaceutical active ingredients can be obtained.

[0248] Regarding TG / DTA, it is known that the observed temperature and weight changes can depend on the rate of temperature change, as well as the sample preparation technique and specific apparatus used. Therefore, the "melting point" in TG / DTA refers to the initial temperature (extrapolated melting point onset temperature) that is not easily affected by the sample preparation technique. In determining the identity of crystallization, not only the melting point is important, but the overall pattern is also important and can vary to some extent due to the measurement conditions and equipment.

[0249] (Determination of water adsorption-desorption isotherms (DVS)) The Desorption-Adsorption Isotherm (DVS) method is a method for measuring the adsorption and desorption behavior of water by measuring the weight change of the solid object under various relative humidity conditions.

[0250] As a basic measurement method, the dry weight under 0%RH (0% relative humidity) conditions is used as a baseline. The relative humidity is increased by 5% or 10% each time. After the weight is stabilized under each relative humidity condition, the amount of adsorbed water can be determined based on the increase in weight from the baseline value. Similarly, the amount of water desorbed can be determined by decreasing the relative humidity by 5% or 10% each time from 100%RH or 95%RH.

[0251] By plotting the weight changes under various relative humidity conditions, adsorption-desorption isotherms can be obtained. Based on these results, the adsorption and desorption phenomena of attached moisture under various humidity conditions can be discussed.

[0252] The adsorption and desorption of adsorbed water and water of crystallization are affected by particle size, crystallinity, crystal morphology, etc., so the measurement results may vary to some extent.

[0253] Differential scanning calorimetry (DSC), differential calorimetry-thermogravimetric analysis (TG / DTA), moisture adsorption-desorption isotherm determination (DVS), Karl Fischer moisture analyzer, and gas chromatography are also analytical methods for detecting adhering water and / or adhering solvent (residual solvent) on the "surface" of crystals. In these analyses, when measuring samples with adhering water and / or adhering solvent on the crystal surface, there are instances where the measured water and / or solvent content is higher than the theoretical content of water of crystallization in hydrate crystals and / or the theoretical content of solvent of crystallization in solvate crystals.

[0254] In contrast, powder X-ray diffraction and single-crystal structure analysis are methods for analyzing the "internal structure" of crystals. Regardless of the presence or absence of water and / or solvent adhering to the crystal "surface" (residual solvent), characteristic peaks will appear at the same positions. The same applies to Raman spectroscopy and infrared absorption spectroscopy (IR methods). Therefore, in powder X-ray diffraction, single-crystal structure analysis, Raman spectroscopy, and infrared absorption spectroscopy (IR methods), even if the displayed water and / or solvent content is higher than the theoretical content in the crystal, as long as the characteristic peaks described in the specification are present, it can be interpreted as substantially the same crystal.

[0255] (Particle size distribution) In this specification, "D10, D50, D90" refers to the particle size at the points where the cumulative curve reaches 10%, 50%, and 90% when the total volume of the powder aggregate is set to 100%. This can be determined by dry or wet methods.

[0256] Example The present invention will be described in more detail below with examples, reference examples, and experimental examples. The present invention is not limited thereto. Regarding numerical values ​​(e.g., quantities, temperatures, etc.), some errors and deviations should be taken into account.

[0257] Unless otherwise specified, % refers to the weight percentage of the components and the total weight percentage of the composition, and pressure refers to atmospheric pressure or pressure close to atmospheric pressure.

[0258] (Methods for identifying compounds) The NMR analyses obtained in each embodiment were performed at 400 MHz using DMSO-d6 and CDCl3. Additionally, in cases where NMR data were displayed, not all measured peaks were recorded.

[0259] In the instructions, RT represents the retention time in LC / MS (Liquid Chromatography / Mass Spectrometry), determined under the following conditions.

[0260] (Measurement Condition A) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid. Gradient: After performing a linear gradient of 5%-100% solvent [B] for 3.5 minutes, maintain 100% solvent [B] for 0.5 minutes.

[0261] (Measurement condition B) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid. Gradient: After performing a linear gradient of 5%-100% solvent [B] for 3.5 minutes, maintain 100% solvent [B] for 0.5 minutes.

[0262] It should be noted that in the instruction manual, MS (m / z) refers to the value observed in mass spectrometry.

[0263] (The method for manufacturing the compound represented by formula (I)) The compound represented by formula (I) is compound (I-077) described in International Publications No. 2023 / 195529 and No. 2023 / 195530, and can be prepared by the synthetic method described in Examples 5 and 6 of those documents. Alternatively, it can be synthesized by methods known in the art. Extraction, purification, and other treatments can be performed as in conventional organic chemistry experiments.

[0264] (Example 1: Synthesis of the compound represented by formula (I) (compound (I))) [Chemical Formula 6] Step 1: Synthesis of Compound 3 A solution of compound 1 (12 g, 68.7 mmol) in tetrahydrofuran (70 mL) was added dropwise to a mixture of 2.64 mol / L n-butyllithium in hexane (31 mL, 82.4 mmol) and tetrahydrofuran (20 mL) over 15 minutes at -78°C. The mixture was stirred at -78°C for 1 hour. A solution of 1.9 mol / L zinc chloride in 2-methyltetrahydrofuran (43 mL, 82.4 mmol) was added dropwise over 5 minutes. The mixture was stirred at room temperature for 2 hours. Compound 2 (9.1 mL, 75.6 mmol) and tetrakis(triphenylphosphine)palladium (4.0 g, 3.44 mmol) were added, and the mixture was stirred at 80°C for 1.5 hours. The reaction mixture was cooled to room temperature, and water (80 mL) and 2 mol / L hydrochloric acid (40 mL) were added. The mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and isopropanol (40 mL) was added to the residue. The precipitate was filtered off and washed with isopropanol. It was then air-dried to obtain compound 3 (14.8 g, 49 mmol).

[0265] 1 H-NMR (CDCl3) δ: 3.95 (s, 3H), 4.05 (s, 3H), 7.18 - 7.23 (m, 2H), 7.35 (d, J = 6.8 Hz, 1H) LC / MS (ESI): m / z = 303, RT = 2.70 min, LC / MS determination conditions A Step 2: Synthesis of Compound 4 Acetic acid (40 mL) and concentrated hydrochloric acid (41 mL) were added to compound 3 (14.8 g, 48.8 mmol), and the mixture was stirred at 110 °C for 5 hours. After cooling the reaction solution to room temperature, water (80 mL) was added. The precipitate was filtered off and washed with water. It was then air-dried to obtain compound 4 (11.6 g, 42.2 mmol).

[0266] 1 H-NMR (DMSO - d6) δ: 7.31 (ddd, J = 8.8, 4.9, 2.1 Hz, 1H), 7.45 (t, J= 8.8 Hz, 1H), 7.53 (dd, J = 7.3, 2.1 Hz, 1H), 11.57 (s, 1H), 12.24 (brs, 1H) LC / MS (ESI): m / z = 275, RT = 1.81 min, LC / MS determination conditions A Step 3: Synthesis of Compound 5 Compound 4 (1.00 g, 3.64 mmol), 5-chloropyridine-3-boronic acid (1.14 g, 7.27 mmol), copper(II) acetate (0.99 g, 5.45 mmol), acetonitrile (10 mL), triethylamine (5.04 mL, 36.4 mmol), and pyridine (7.34 mL, 91.0 mmol) were mixed and stirred at room temperature overnight. A saturated sodium bicarbonate aqueous solution (5 mL) was added to the reaction mixture, and extraction was performed using ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0–90:10), with the solvent removed by vacuum distillation. The residue was dried under reduced pressure to obtain compound 5 (1.15 g, 2.97 mmol, 82% yield).

[0267] 1 H-NMR (DMSO - d6) δ: 7.35 - 7.37 (1H, m), 7.49 (1H, t, J = 9.0 Hz), 7.54 - 7.56 (1H, m), 8.07 (1H, t, J = 2.1 Hz), 8.54 (1H, d, J = 2.0 Hz), 8.70 (1H, d, J = 2.3 Hz). LC / MS (ESI): m / z = 386, RT = 1.98 min, LC / MS determination conditions A Step 4: Synthesis of Compound 6 2-Bromoacetonitrile (269 μL, 4.04 mmol) was added to a solution containing compound 5 (520 mg, 1.345 mmol), N,N-diisopropylethylamine (0.705 mL, 4.04 mmol), and DMF (5.2 mL), and the mixture was stirred overnight at room temperature. 2 mol / L hydrochloric acid (2 mL) was added to the reaction mixture under ice-cooling, and extraction was performed using ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol = 100:0–99:1), with the solvent removed by vacuum distillation. The residue was dried under reduced pressure to obtain compound 6 (291 mg, 0.684 mmol, 51% yield).

[0268] 1 H-NMR (CDCl3) δ: 5.13 (2H, s), 7.23 - 7.24 (2H, m), 7.42 (1H, d, J =7.3 Hz), 7.67 (1H, t, J = 2.1 Hz), 8.45 (1H, d, J = 2.3 Hz), 8.67 (1H, d, J =2.3 Hz). LC / MS (ESI): m / z = 425, RT = 2.17 min, LC / MS determination conditions A Step 5 Synthesis of compound (I) Compound 6 (25.0 mg, 0.059 mmol), 6,6-difluoro-2-azaspiro[3.3]heptane trifluoroacetate (17.4 mg, 0.070 mmol), N,N-diisopropylethylamine (20.5 μL, 0.117 mmol), and DMF (0.5 mL) were mixed and the solution was stirred at 60 °C for 2 hours. Water (2 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried with sodium sulfate, and filtered. The filtrate was concentrated, and ethyl acetate (0.05 mL), hexane (0.125 mL), and diisopropyl ether (0.125 mL) were added. The precipitate was filtered off and washed with diisopropyl ether. The solid was dried under reduced pressure to give compound (I) (22.0 mg, 0.042 mmol, 72% yield).

[0269] 1H-NMR (CDCl3) δ: 2.75 (4H, t, J = 12.0 Hz), 4.02 (4H, s), 4.74 (2H, s), 7.16 - 7.18 (2H, m), 7.32 - 7.35 (1H, m), 7.65 (1H, t, J = 2.1 Hz), 8.43 (1H, d, J = 2.3 Hz), 8.61 (1H, d, J = 2.3 Hz). LC / MS (ESI): m / z = 522, RT = 2.27 min, LC / MS determination conditions A (Example 1A: Biological test of compound (I)) The following describes biological test examples of the compounds of the present invention.

[0270] The compound represented by formula (I) of the present invention can be any compound that has the inhibitory effect on coronavirus 3CL protease and inhibits coronavirus 3CL protease.

[0271] Specifically, in the evaluation methods described below, IC 50 Preferably, it is 50 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less. EC 50 Preferably, it is 10 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less.

[0272] The bioassay results of the compound represented by formula (I) are described as compound (I-077) in International Publication Nos. 2023 / 195529 and 2023 / 195530.

[0273] Experiment Example 1: Confirmation Experiment on the Inhibition of Cytopathic Effect (CPE) Using HEK293T Cells Expressed with Human TMPRSS2 and ACE2 (HEK293T / ACE2-TMPRSS2 Cells) <Operation Steps> • Dilution and dispensing of the test sample The test sample was pre-diluted to an appropriate concentration with DMSO, and a 2- to 5-fold serial dilution series was prepared and dispensed into 384-well plates.

[0274] • Dilution and injection of cells and SARS-CoV-2 HEK293T / ACE2-TMPRSS2 cells (GCP-SL222, 5×10⁻⁶) were used. 3 (cells / well) and SARS-CoV-2 (200-600 TCID) 50The samples were mixed in medium (MEM, 2% FBS, penicillin-streptomycin) and dispensed into wells containing the test samples. The mixture was then incubated in a CO2 incubator for 3 days.

[0275] • Measurement of the injection and luminescence signal of CellTiter-Glo (registered trademark) 2.0 After the plates were brought to room temperature after 3 days of incubation, CellTiter-Glo (registered trademark) 2.0 was dispensed into each well and mixed using a plate mixer. After a certain period of time, the luminescence signal (Lum) was measured using a microplate reader.

[0276] <Calculation of values ​​for each measured item> • 50% SARS-CoV-2 infection cell death inhibitory concentration (EC50) 50 ) calculate When x is set as the logarithm of the compound concentration and y is set as the percentage of potency, the inhibition curve is fitted using the following Logistic regression equation. The value of x when y=50 (%) is calculated as the EC value. 50 .

[0277] y=min+(max-min) / {1+(X50 / x) ^ Hill} % potency = {(sample - virus control) / (cell control - virus control)} 100% Cell control: Average Lum of cell control wells Virus control: Average Lum of virus control wells min: lower limit of the y-axis, max: upper limit of the y-axis, X50: x-coordinate of the inflection point, Hill: slope of the curve at the midpoint between min and max. The compounds represented by formula (I) of the present invention were essentially tested as described above. EC 50 The values ​​are shown below.

[0278] (result) Compound (I): 1.66 nM Experimental Example 2: Inhibitory Activity Assay Against SARS-CoV-2 3CL Protease <Materials> Commercially available recombinant SARS-CoV-2 3CL protease Commercially available substrate peptides Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH2 (Serial No.: 1) Internal standard peptide Dabcyl-Lys-Thr-Ser-Ala-Val-Leu( 13 C6, 15 N)-Gln (Serial Number: 2) Dabcyl-Lys-Thr-Ser-Ala-Val-Leu( 13 C6, 15 N)-Gln can be synthesized by referring to the following references (Atherton, E.; Sheppard, RC, “In Solid Phase Peptide Synthesis, A Practical Approach”, IRL Press at Oxford University Press, 1989, and Bioorg. Med. Chem., Vol. 5, No. 9, 1997, pp. 1883-1891, etc.). An example is shown below.

[0279] H-Lys-Thr-Ser-Ala-Val-Leu was synthesized using Rink amide resin via Fmoc solid-phase synthesis. 13 C6, 15 N)-Glu (resin)-OαOtBu (Lys side chain protected by Boc, Thr side chain protected by tert-butyl, Ser side chain protected by tert-butyl, C-terminal OH of Glu protected by tert-butyl, carboxylic acid of Glu side chain condensed with resin). N-terminal Dabcyl modification was performed using EDC / HOBT, condensing 4-dimethylaminoazobenzene-4'-carboxylic acid (Dabcyl-OH) onto the resin. Final deprotection and cleavage from the resin were performed using TFA / EDT = 95:5. Purification was then performed by reversed-phase HPLC.

[0280] ·RapidFire Cartridge C4 typeA <Operation Steps> • Preparation of analytical buffer In this experiment, an analytical buffer consisting of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, and 0.01% BSA was used.

[0281] • Dilution and dispensing of the test sample The test sample was pre-diluted to an appropriate concentration with DMSO, and a 2- to 5-fold serial dilution series was prepared and dispensed into 384-well plates.

[0282] • Addition of enzymes and substrates, enzyme reactions Add 8 μM of substrate and 6 nM or 0.6 nM of enzyme solution to the prepared compound plate and incubate at room temperature for 3–5 hours. Then, add reaction stop solution (0.067 μM internal standard, 0.1% formic acid, 10 or 25% acetonitrile) to stop the enzyme reaction.

[0283] • Determination of reaction products After the reaction, the plates were analyzed using a RapidFire System 360 mass spectrometer (Agilent, 6550iFunnel Q-TOF) or a RapidFire System 365 mass spectrometer (Agilent, 6495C TripleQuadrupole). The mobile phase used for the analysis was solution A (75% isopropanol, 15% acetonitrile, 5 mM ammonium formate) and solution B (0.01% trifluoroacetic acid, 0.09% formic acid).

[0284] The reaction products detected by mass spectrometry were calculated using RapidFire Integrator or a program capable of equivalent analysis, and the calculated product area was used as the product area value. Additionally, the internal standard detected simultaneously was also calculated, and the calculated internal standard area was used as the internal standard area value.

[0285] <Calculation of values ​​for each measured item> Calculation of P / IS Calculate P / IS by using the area value obtained from the previous project using the following formula.

[0286] P / IS = Product area value / Internal standard area value • 50% SARS-CoV-2 3CL protease inhibitory concentration (IC50) 50 ) calculate Setting x as the logarithm of the compound concentration and y as the percentage of inhibition, the inhibition curve is fitted using the following Logistic regression equation. The value of x when y=50 (%) is then calculated as the IC50 value. 50 .

[0287] y=min+(max-min) / {1+(X50 / x) ^ Hill} %inhibition = {1 - (sample - control (-)) / (control (+) - control (-))} 100 Control (-): Average P / IS of wells under enzyme inhibition conditions Control (+): Average P / IS of DMSO control well min: lower limit of the y-axis, max: upper limit of the y-axis, X50: x-coordinate of the inflection point, Hill: slope of the curve at the midpoint between min and max. Essentially, the compounds represented by formula (I) of the present invention were tested as described above. IC 50 The values ​​are shown below.

[0288] (result) Compound (I): 0.00036 μM Experimental Example 3: Powder X-ray Diffraction Experiment (XRPD) Powder X-ray diffraction determination was performed on the solid states (crystalline and amorphous) and solid dispersions obtained in each example according to the general test method described in the Japanese Pharmacopoeia. The determination conditions are as follows.

[0289] Measurement conditions 1: Powder X-ray diffraction apparatus: SmartLab manufactured by Rigaku Corporation Measurement method: Reflectance method Wavelength used: CuKα rays (λ=1.5418 Å) Tube current: 200 mA Tube voltage: 45 kV Sample plate: aluminum The incident angle of the X-rays: 2.5° Sampling width: 0.02° Detector: HyPix-3000 (2D detection mode) Experimental Example 4: Determination of Powder X-ray Diffraction Patterns under Temperature and / or Relative Humidity Control Using the accessories provided with the X-ray diffraction apparatus, the temperature and relative humidity of the sample section were controlled, and powder X-ray diffraction determination was performed according to the powder X-ray diffraction determination method described in the General Test Methods section of the Japanese Pharmacopoeia. The determination conditions are as follows.

[0290] Measurement condition 2: (X-ray diffraction measurement) Powder X-ray diffraction apparatus: RINT2100Ultima+ manufactured by Rigaku Measurement method: Reflectance method Wavelength used: CuKα rays (λ=1.5418 Å) Tube current: 40 mA Tube voltage: 40 kV Sample plate: aluminum X-ray measurement range: 5°-35° Sampling width: 0.02° Scanning speed: 60° / min (Control of temperature and relative humidity) Temperature controller: ThermoPlus manufactured by Rigaku Humidity controller: HUM-1 manufactured by Rigaku Experimental Example 5: Determination and Analytical Methods for Single Crystal Structure Analysis Single-crystal structure analysis was performed on the crystals obtained in each embodiment. The measurement conditions and analytical methods are shown below.

[0291] (Apparatus) Rigaku's XtaLAB P200 MM007 (Measurement conditions) Measurement temperature: 25℃ Temperature controller: Rigaku Corporation sample blowing cryogenic device Wavelength used: CuKα rays (λ=1.5418 Å) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) (Data processing) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) The data were subjected to Lorentz and polarization corrections, as well as absorption corrections.

[0292] (Crystal structure analysis) Phase determination was performed using the direct method ShelXT (Sheldrick, GM, 2015), and refinement was performed using ShelXL (Sheldrick, GM, 2015) with full-matrix least squares. Temperature factors for non-hydrogen atoms were all refined anisotropically. For hydrogen atoms, unless otherwise specified, ShelXL's default parameters were used and introduced through calculation, treating them as riding atoms. Additionally, hydrogen atoms were refined with isotropic parameters.

[0293] The following structural diagrams were drawn using PLATON (Spek, 1991) / ORTEP (Johnson, 1976) (30% probability level).

[0294] Experimental Example 6: Determination of Raman Spectroscopy The measurement conditions for the Raman spectra of the crystals obtained in each embodiment and the baseline correction are as follows.

[0295] Measurement conditions 1 Measurement method: Micro-laser Raman spectroscopy Laser wavelength: 671 nm Total number of times: 1 Exposure time: 1 second Experimental Example 7: Differential Scanning Calorimetry (DSC) The DSC of the crystals obtained in each example was determined. The sample was weighed and placed in an aluminum pot, simply sealed, and then the measurement was performed. The measurement conditions are shown below. It should be noted that measurements based on differential scanning calorimetry (DSC) can introduce errors within ±2°C.

[0296] Device: Discovery DSC / TA Instrument Measurement temperature range: -10℃ to 270℃ Heating rate: 10℃ / min Atmosphere: N 250 mL / min Experimental Example 8: Simultaneous Differential Calorimetry-Thermogravimetric Analysis (TG / DTA) Differential thermal and thermogravimetric analysis (TG / DTA) was performed on the solid states (crystalline and amorphous) and solid dispersions obtained in each embodiment. Samples obtained in each embodiment were weighed, placed in an aluminum pot, and measured in an open system. The measurement conditions are as follows.

[0297] Device: Hitachi High-Technologies TG / DTA STA7200RV Measurement temperature range: room temperature - 350℃ Heating rate: 10℃ / min Experimental Example 9: Determination of the water adsorption-desorption isotherm (DVS) Water adsorption-desorption isotherm (DVS) measurements were performed on the crystals obtained in each example. Crystals obtained in each example were weighed and placed in an aluminum pot, then allowed to stand at 25°C and 0% relative humidity. After the compound was fully dried and its weight stabilized, measurements were started, and the weight was recorded as the relative humidity changed by 5% from 0% to 95%. Subsequently, the weight was recorded as the relative humidity changed by 5% from 95% to 0%.

[0298] Device: DVS Adventure manufactured by Surface Measurement Systems Experimental Example 10: Particle Size Distribution / Dry Method The particle size distribution of the crystals and solid dispersions obtained in each example was determined. The particle size distribution was measured using a laser diffraction particle size distribution measuring device via a dry method.

[0299] Measurement conditions 1 Device: HELOS & RODOS (manufactured by Sympatec) Range: R1 Distributed pressure: 2 bar Triggering conditions: Stop for 2 seconds and the concentration measured is ≤0.5% or measure in real time for 10 seconds. Measurement conditions 2 Device: HELOS & RODOS (manufactured by Sympatec) Range: R3 Distributed pressure: 2 bar Triggering conditions: Stop for 2 seconds and the concentration measured is ≤0.5% or measure in real time for 10 seconds. Measurement conditions 3 Device: Microtrac MT3200II (manufactured by Microtrac BEL) Experimental Example 11: Particle Size Distribution / Wet Method The particle size distribution of the crystals obtained in each example was determined. The particle size distribution was determined using a Microtrac MT3200II laser diffraction scattering particle size distribution measuring device (manufactured by Microtrac BEL) by wet method.

[0300] Measurement range: 0.243~1408 μm Solvent: Water Solvent refractive index: 1.333 Measurement time: 30 seconds Particle shape: Non-spherical Particle transmissivity: transmission Particle refractive index: 1.81 (Example 1B: Analysis of the solid state of compound (I)) The compound (I) prepared by the synthesis method of Example 1 above was subjected to powder X-ray diffraction and differential thermal-thermal gravimetric analysis (TG / DTA) and was confirmed to be an anhydrous crystal of the compound represented by formula (I).

[0301] (Example 2: Analysis of anhydrous crystallization of the compound represented by formula (I)) The anhydrous crystals of the compound represented by formula (I) were pulverized, and powder X-ray diffraction, single crystal structure analysis, differential scanning calorimetry (DSC), differential thermal-thermal gravimetric analysis (TG / DTA), moisture adsorption-desorption isotherm determination (DVS), Raman spectroscopy, and particle size distribution were determined.

[0302] (Example 2A: Pulverization of anhydrous crystals of the compound represented by formula (I)) After sieving the anhydrous crystals of the compound represented by formula (I) using a 1000 μM sieve, they were pulverized under the following conditions.

[0303] Equipment: AO jet mill (SEISHIN ENTERPRISE Co.,Ltd.) Supply method: feeder Feed rate: 20 g / hr Crushing pressure: 0.30 MPa Supply pressure: 0.40 MPa (Example 2B: Powder X-ray diffraction experiment of anhydrous crystallization of the compound represented by formula (I)) Powder X-ray diffraction experiments were conducted on the anhydrous crystals of the compound represented by formula (I) after pulverization under the determination conditions 1 described in Experimental Example 3 above.

[0304] The powder X-ray diffraction pattern is shown in Figure 1 The peak values ​​of the powder X-ray diffraction pattern are represented by... Figure 2 In the table below, which lists the peaks of powder X-ray diffraction patterns, position represents 2θ (°) and intensity represents intensity.

[0305] In the powder X-ray diffraction pattern, peaks were identified at diffraction angles (2θ): 6.5°±0.2°, 10.1°±0.2°, 13.0°±0.2°, 14.1°±0.2°, 15.3°±0.2°, 15.6°±0.2°, 16.2°±0.2°, 17.4°±0.2°, 18.9°±0.2°, 19.9°±0.2°, 20.3°±0.2°, 21.7°±0.2°, 23.0°±0.2°, 23.8°±0.2°, 25.8°±0.2°, 28.8°±0.2°, and 30.6°±0.2°.

[0306] The anhydrous crystals of the compound represented by formula (I) show characteristic peaks in the powder X-ray diffraction pattern at diffraction angles (2θ): 6.5°±0.2°, 10.1°±0.2°, 15.6°±0.2°, 16.2°±0.2°, 17.4°±0.2°, 19.9°±0.2°, 20.3°±0.2°, 21.7°±0.2°, 23.0°±0.2° and 23.8°±0.2°.

[0307] The anhydrous crystals of the compound represented by formula (I) show characteristic peaks in the powder X-ray diffraction pattern at diffraction angles (2θ): 6.5°±0.2°, 15.6°±0.2°, 17.4°±0.2°, 19.9°±0.2° and 20.3°±0.2°.

[0308] (Example 2C: Single crystal structure analysis of the anhydrous crystals of the compound represented by formula (I)) <Preparation methods for single crystals> Add 400 μL of methanol to 1 mg of the crystallization of the compound represented by formula (I) and heat to 50 °C to dissolve it. Aliquot the solution into 1.5 mL HPLC vials, cap the vials, insert a syringe needle into the cap, and allow to stand at room temperature. Prepare single crystals by solvent evaporation.

[0309] Single Crystal Structure Analysis Single-crystal diffraction experiments and analyses were performed using the method described in Experimental Example 5 above. It should be noted that there is a disordered relationship between Cl1 and Cl7C, and between H5CA and H6CA. Therefore, the analysis was conducted using the proportions of Cl1:Cl7C = 0.75:0.25 and H5CA:H6CA = 0.25:0.75.

[0310] The results of the single-crystal structure analysis are shown below. R1 (I>2.00s(I)) is 0.0555, and the lack or misplacement of electron density is confirmed by the final difference Fourier.

[0311] Crystallographic data are shown in Table 1.

[0312] [Table 1] Here, V refers to the volume per unit lattice, and Z refers to the number of molecules per unit lattice.

[0313] The atomic fraction coordinates x, y, z (Å × 10⁻⁶) of non-hydrogen atoms are used. 4 and equivalent isotropic temperature factor U(eq) (equivalent isotropic displacement parameters, Å) 2 ×10 3 The results are shown in Table 2. Here, U(eq) is defined as the orthogonalized U. ij One-third of the tensor's trajectory.

[0314] [Table 2] Then, the atomic coordinates x, y, z (Å × 10⁻⁶) of the hydrogen atom were determined. 4and isotropic temperature factor U(eq) (isotropic displacement parameter, Å) 2 ×10 3 (See Table 3.)

[0315] [Table 3] The structure in the asymmetric unit of this crystal structure is shown in Figure 3 .

[0316] It should be noted that, Figure 3 The label numbers of the non-hydrogen atoms recorded in the table correspond to the non-hydrogen atom numbers in Table 2.

[0317] The crystalline structure contains only one molecule of the compound represented by formula (I) in the asymmetric unit, and is therefore identified as an anhydrous crystal of the compound represented by formula (I).

[0318] Based on this crystal structure, it was confirmed that the powder X-ray diffraction pattern (λ=1.5418 Å) calculated using Mercury (The Cambridge Crystallographic Data Centre, Ver. 4.0.0) is similar to the powder X-ray diffraction pattern of Example 2B. Figure 1 They are roughly the same.

[0319] (Example 2D: Differential scanning calorimetry of anhydrous crystallization of the compound represented by formula (I)) Approximately 2 mg of the anhydrous crystals of the pulverized compound represented by formula (I) were placed in an aluminum pot and analyzed using the method described in Test Example 7 above. The results are shown below. Figure 4 It shows an endothermic peak with an initial temperature of approximately 261.3℃.

[0320] (Example 2E: Simultaneous differential thermal and thermogravimetric determination of anhydrous crystals of the compound represented by formula (I)) The anhydrous crystallization of the pulverized compound represented by formula (I) was determined using the method described in Experimental Example 8 above. The results are shown below. Figure 5 An endothermic peak with an initial temperature of approximately 265.6°C was observed. Furthermore, no weight reduction was confirmed.

[0321] (Example 2F: Raman spectroscopy determination of anhydrous crystals of the compound represented by formula (I)) Raman spectroscopy was performed on the anhydrous crystals of the pulverized compound represented by formula (I) under the determination conditions 1 described in Experimental Example 6 above. The results are shown below. Figure 6 Additionally, the main Raman peaks are shown below.

[0322] [Table 4] The anhydrous crystals of the compound represented by formula (I) show a Raman spectrum at 415.2 cm⁻¹. -1 ±2 cm -1 502.7cm -1 ±2 cm -1 1431.4 cm -1 ±2 cm -1 1714.8 cm -1 ±2 cm -1 and 3065.4 cm -1 ±2 cm -1 Characteristic peaks are displayed at this location.

[0323] (Example 2G: Particle size distribution of anhydrous crystals of the compound represented by formula (I)) For the anhydrous crystals of the compound represented by formula (I) before pulverization used in Example 2A, the particle size distribution was determined using the method described in determination condition 2 of Test Example 10. The results showed that D10 was 1.16 μm, D50 was 4.42 μm, and D90 was 13.13 μm. The particle size distribution is shown in... Figure 7 .

[0324] (Example 2H: Particle size distribution of anhydrous crystals of the compound represented by formula (I)) The particle size distribution of the anhydrous crystals of the compound represented by formula (I) obtained in Example 2A after pulverization was determined using the method described in Test Condition 1 of Test Example 10.

[0325] The results show that D10 is 0.79 μm, D50 is 2.90 μm, and D90 is 7.32 μm. The particle size distribution is shown in... Figure 8 .

[0326] (Example 3: Preparation and analysis of the ethyl acetate complex of the compound represented by formula (I)) The ethyl acetate complex of the compound represented by formula (I) was prepared by crystallization, and each crystal was subjected to NMR determination, powder X-ray diffraction experiment, single crystal structure analysis, differential scanning calorimetry (DSC), differential thermal-thermal gravimetric analysis (TG / DTA), moisture adsorption-desorption isotherm determination (DVS), Raman spectroscopy, and particle size distribution determination.

[0327] (Example 3A: Preparation of ethyl acetate complex of the compound represented by formula (I)) Compound 6 (800 mg, 1.880 mmol) described in Example 1 and 6,6-difluoro-2-azaspiro[3.3]heptane trifluoroacetate (557 mg, 2.256 mmol) were dissolved in DMF (8.0 mL), and N,N-diisopropylethylamine (985 μL, 5.64 mmol) was added. The mixture was stirred at 60 °C for 2 hours. Water was added to the reaction mixture, and extraction was performed using ethyl acetate. The organic layer was washed with water and then with saturated brine, dried with magnesium sulfate, and filtered. The filtrate was distilled off under reduced pressure to remove the solvent and then subjected to silica gel column chromatography. After dissolution with hexane / ethyl acetate, the fraction containing the desired compound was collected. The solvent was concentrated under reduced pressure, diisopropyl ether was added, and the precipitated solid was filtered off. The residue was dried under reduced pressure to give compound (I) (954 mg, 1.563 mmol, 83% yield).

[0328] The NMR determination was performed using the method described above (methods for identifying compounds). The peak of ethyl acetate was confirmed in the NMR spectrum.

[0329] 1 H-NMR (DMSO - D6) δ: 1.18 (3H, t, J = 7.0 Hz), 1.99 (3H, s), 2.79 (4H, t, J = 12.4 Hz), 4.03 - 4.06 (6H, m), 4.82 (2H, s), 7.21 (1H, s), 7.39 -7.42 (2H, m), 7.96 (1H, s), 8.46 (1H, s), 8.69 (1H, s). LC / MS (ESI): m / z = 522, RT = 2.30 min, LC / MS determination conditions B (Example 3B: Powder X-ray diffraction experiment of solid prepared using the method of Example 3A) Powder X-ray diffraction experiments were performed on the sample prepared using the method of Example 3A under the measurement conditions 1 described in Test Example 3 above. As a result, it was confirmed that the sample prepared using the method of Example 3A was a crystal different from the anhydrous crystal of the compound represented by formula (I).

[0330] Based on the NMR determination in Example 3A and the results in Example 3B, it is inferred that the sample prepared using the method in Example 3A is "the ethyl acetate complex crystal of the compound represented by formula (I)".

[0331] (Example 3C: Single crystal structure analysis of the ethyl acetate compound of the compound represented by formula (I)) Using the method described in Experimental Example 5 above, single-crystal diffraction experiments and analyses were performed on the ethyl acetate complex crystals of the compound represented by formula (I). The results confirmed the presence of ethyl acetate complex crystals of the compound represented by formula (I) in a 1:1 molar ratio with ethyl acetate. It should be noted that a portion of the compound represented by formula (I) exhibits a disordered structure.

[0332] (Example 3D: NMR determination of the ethyl acetate complex of the compound represented by formula (I)) Using the method described above (Methods for Identification of Compounds), NMR was performed on the ethyl acetate complex crystals of the compound represented by formula (I) after air drying overnight at room temperature. 1 The H-NMR results are shown in Figure 9 .

[0333] A peak of ethyl acetate was confirmed in the NMR spectrum. According to... 1 The H-NMR integral ratio showed that the molar ratio of the compound represented by formula (I) to ethyl acetate was approximately 1:1. The crystal was air-dried at room temperature prior to the analysis, suggesting that it was an ethyl acetate compound containing ethyl acetate within the crystal lattice, rather than having ethyl acetate adhering to its surface. This result is consistent with the single-crystal structure analysis of Example 3C.

[0334] (Example 3E: Pulverization of the ethyl acetate complex crystals of the compound represented by formula (I)) The ethyl acetate complex of the compound represented by formula (I) was pulverized under the following conditions.

[0335] Device: Hosokawa / ALPINE SPIRAL JET MILL50AS (Hosokawa Micron Co., Ltd.) Supply method: Manual Feed rate: 30.15 g / 25 min Crushing pressure: 0.10 MPa Supply pressure: 0.20 MPa (Example 3F: Powder X-ray diffraction experiment of crystallization of the ethyl acetate compound represented by formula (I)) Under the determination conditions 1 described in Experimental Example 3 above, powder X-ray diffraction experiments were performed on the ethyl acetate compound crystals of the pulverized compound represented by formula (I). The powder X-ray diffraction pattern is shown below. Figure 10 The peak columns of the powder X-ray diffraction pattern are represented in Figure 11 .

[0336] In the powder X-ray diffraction pattern, the diffraction angles (2θ) are: 6.9°±0.2°, 8.8°±0.2°, 11.2°±0.2°, 13.1°±0.2°, 13.6°±0.2°, 13.9°±0.2°, 16.3°±0.2°, 17.6°±0.2°, 18.6°±0.2°, 19.0°±0.2°, 19.8°±0.2°, 20.1°±0.2°, 20.6°±0.2°, 20.9°±0.2°, and 21.2°. Peaks were confirmed at 21.7°±0.2°, 22.1°±0.2°, 22.6°±0.2°, 22.9°±0.2°, 23.7°±0.2°, 24.5°±0.2°, 25.1°±0.2°, 25.4°±0.2°, 25.7°±0.2°, 26.7°±0.2°, 27.0°±0.2°, 27.4°±0.2°, 28.0°±0.2°, 28.7°±0.2°, and 29.7°±0.2°.

[0337] The ethyl acetate complex of the compound represented by formula (I) crystallized in a powder X-ray diffraction pattern showed characteristic peaks at diffraction angles (2θ): 6.9°±0.2°, 8.8°±0.2°, 13.1°±0.2°, 13.6°±0.2°, 16.3°±0.2°, 17.6°±0.2°, 18.6±0.2°, 20.9±0.2°, 21.7±0.2° and 23.7°±0.2°.

[0338] The ethyl acetate complex of the compound represented by formula (I) crystallized in a powder X-ray diffraction pattern showed characteristic peaks at diffraction angles (2θ): 6.9°±0.2°, 8.8°±0.2°, 13.1°±0.2°, 16.3°±0.2° and 23.7°±0.2°.

[0339] (Example 3G: Raman spectroscopy determination of the ethyl acetate complex of the compound represented by formula (I)) Raman spectroscopy was performed on the ethyl acetate complex of the pulverized compound represented by formula (I) under the determination conditions 1 described in Experimental Example 6 above. The results are shown below. Figure 12 Additionally, the main Raman peaks are shown below.

[0340] [Table 5] The ethyl acetate complex of the compound represented by formula (I) crystallized in Raman spectra at 421.2 cm⁻¹. -1 ±2 cm -1 509.7 cm -1 ±2 cm -11585.3 cm -1 ±2 cm -1 1709.9 cm -1 ±2 cm -1 and 3052.9 cm -1 ±2 cm -1 Characteristic peaks are displayed at this location.

[0341] (Example 3H: Differential thermal and thermogravimetric analysis of the crystallization of the ethyl acetate complex of the compound represented by formula (I)) The crystallization of the ethyl acetate compound of formula (I) was determined using the method described in Experimental Example 8 above. The results are shown below. Figure 13 An endothermic peak was observed at an initial temperature of approximately 129.5 °C, almost simultaneously confirming a weight loss of approximately 14%. This change is believed to be due to the desolvation (detachment) of ethyl acetate from the ethyl acetate complex of the compound represented by formula (I).

[0342] It should be noted that the "ethyl acetate complex crystal of the compound represented by formula (I)" with a molar ratio of 1:1 to ethyl acetate is a crystal with a theoretical content of 14.4% by weight of ethyl acetate, which is roughly consistent with the results of this thermogravimetric (TG) determination.

[0343] For the crystallization of the ethyl acetate compound represented by formula (I), multiple batches were measured using the method described in Experimental Example 8 above. The results showed that endothermic peaks were observed at 92.5°C, 95.7°C, and 116.7°C in each measurement, and the weight reduction was confirmed at the temperature of the endothermic peak.

[0344] It should be noted that, under the measurement conditions 1 described in Experiment 3 above, the powder X-ray diffraction experiment on this sample showed that the powder X-ray diffraction patterns were very similar. The main peaks were consistent within ±0.2°, with slight differences in relative intensity.

[0345] The samples all showed characteristic peaks in the powder X-ray diffraction pattern at diffraction angles (2θ): 6.9°±0.2°, 8.8°±0.2°, 13.1°±0.2°, 16.3°±0.2° and 23.7°±0.2°.

[0346] (Example 3I: Particle size distribution of the ethyl acetate complex crystals of the compound represented by formula (I)) The particle size distribution of the ethyl acetate complex crystals of the compound represented by formula (I) before pulverization, used in Example 3E, was determined using the method described in determination condition 2 of Experimental Example 10. The results showed that D10 was 18.73 μm, D50 was 71.82 μm, and D90 was 114.67 μm. The particle size distribution is shown in... Figure 14 .

[0347] (Example 3J: Particle size distribution of the ethyl acetate complex crystals of the compound represented by formula (I)) The particle size distribution of the ethyl acetate complex crystals of the compound represented by formula (I) obtained in Example 3E was determined using the method described in Test Condition 1 of Test Example 10.

[0348] The results show that D10 is 0.68 μm, D50 is 3.59 μm, and D90 is 8.80 μm. The particle size distribution is shown in... Figure 15 .

[0349] The present invention will be described in detail below with reference examples and test examples of formulations of the compound represented by formula (I). The present invention is not limited thereto. Regarding the anhydrous crystallization of the compound represented by formula (I), the following compounds with particle sizes of (1) D10 of 0.78 μm, D50 of 2.09 μm, and D90 of 4.77 μm, (2) D10 of 0.86 μm, D50 of 3.29 μm, and D90 of 10.15 μm, and (3) D10 of 0.7 μm, D50 of 2.7 μm, and D90 of 8.8 μm were used, and the purities (quantitative values) of (2) and (3) were 101.7% and 99.7%, respectively.

[0350] The chromatogram of the compound with particle sizes of D10 of 0.86 μm, D50 of 3.29 μm, and D90 of 10.15 μm determined by liquid chromatography as shown in Example 12 is shown in [the figure]. Figure 16 The compound represented by formula (I) was detected at a purity (pa%) of 99.58% and a holding time of 24.941 minutes.

[0351] Experimental Example 12: Analytical Method 1 for Related Substances The following methods and conditions are used to determine the amount of related substances using liquid chromatography.

[0352] Detector: Ultraviolet spectrophotometer (measurement wavelength: 247 nm) Column: ACQUITY UPLC BEH C18 (1.7 μm, 2.1×100 mm, Waters) Column temperature: a constant temperature around 40℃ Mobile phase A: Water / formic acid mixed solution (1000:1) Mobile phase B: Acetonitrile / formic acid mixed solution for liquid chromatography (2000:1) Liquid delivery of the mobile phase: Concentration gradient control is achieved by changing the mixing ratio of mobile phase A and mobile phase B in the following manner.

[0353] [Table 6] Flow rate: 0.4 mL / min Injection volume: 5 μL Sample cooling temperature: a constant temperature around 10℃ Needle washing solvent or auto-injector washing solution: acetonitrile Area measurement range: up to 43 minutes after sample solution injection. (Example 4: Preparation and analysis of solid dispersion of the compound represented by formula (I)) The solid dispersions of the compounds represented by formula (I) were prepared, and each solid dispersion was observed using a digital microscope, subjected to powder X-ray diffraction experiments, differential scanning calorimetry (DSC), particle size distribution determination, and determination of related substances.

[0354] (Example 4A: Selection of polymers for solid dispersions of compounds represented by formula (I)) The anhydrous crystals of the compound represented by formula (I) and the polymer were dissolved in acetone, ethanol, or a mixture thereof, and then dropped onto a glass slide. A solid dispersion was obtained by solvent evaporation.

[0355] The anhydrous crystals of the compound represented by formula (I) are pulverized under the following conditions, using the pulverized product.

[0356] Device: Hosokawa / ALPINE SPIRAL JET MILL50AS (Hosokawa Micron Co., Ltd.) Supply method: feeder Feed rate: 60 g / hr Crushing pressure: 0.05 MPa Supply pressure: 0.10 MPa Using the method described in Test Condition 1 of Test Example 10, the particle size distribution of the anhydrous crystals of the pulverized compound represented by formula (I) was determined, and the results were D10 = 0.78 μm, D50 = 2.09 μm and D90 = 4.77 μm.

[0357] <Preparation of Solid Dispersions> The contents of the compound represented by formula (I) in the solid dispersion were studied at 10 wt%, 25 wt%, and 50 wt%.

[0358] As polymers, the following are used: copovidone (polyvinylpyrrolidone-vinyl acetate copolymer, PPVVA) (manufactured by BASF), polyvinylpyrrolidone (povidone) (manufactured by BASF), hydroxypropyl methylcellulose acetate succinate (manufactured by Shin-Etsu Chemical Industry, LF and MF grades), hydroxypropyl methylcellulose phthalate (manufactured by Shin-Etsu Chemical Industry), hydroxypropyl cellulose (manufactured by Nippon Soda), and methacrylic acid copolymer L (manufactured by Evonik). The formulation is shown below.

[0359] [Table 7] <Evaluation of whether crystallization occurs> The presence or absence of crystallization was observed using a digital microscope (VHX-7000, manufactured by KEYENCE) in polarized light mode after the sample was dropped onto a glass slide, stored at 40°C and 75% relative humidity for one week, and stored at 60°C for one week.

[0360] As a result, no crystallization was observed immediately after preparation and after storage under various conditions when the solid dispersions using polyvinylpyrrolidone contained 10%, 25%, and 50% of the compound represented by formula (I) were observed, indicating good performance. Similarly, no crystallization was observed immediately after preparation and after storage under various conditions when the solid dispersions using copovidone contained 10% and 25% of the compound represented by formula (I) were observed, indicating good performance.

[0361] The solid dispersion of hydroxypropyl methylcellulose acetate succinate (MF grade) showed good performance when the content of the compound represented by formula (I) was 10% by weight and 25% by weight, and no coarse crystals larger than 100 μm were observed immediately after preparation and after storage under various conditions.

[0362] (Example 4B: Preparation of solid dispersion of the compound represented by formula (I) 1) Anhydrous crystals of the compound represented by formula (I) (the pulverized product of Example 4A) and each polymer were dissolved in acetone. After confirming complete dissolution, a solid dispersion was produced using a spray dryer (Advance B-290 type spray dryer for organic solvents, manufactured by BUCHI) at an inlet temperature of 90°C, a liquid delivery pump of 20%, and a nitrogen flow rate of 40.

[0363] As polymers, copovidone (manufactured by BASF), povidone (manufactured by BASF), and hydroxypropyl methylcellulose acetate succinate (manufactured by Shin-Etsu Chemical Industry, MF and LF grades) were used. The content of the compound represented by formula (I) in the solid dispersion was set at 25% by weight. The formulation is shown below.

[0364] [Table 8] (Example 4C: Powder X-ray diffraction experiment of solid dispersion of the compound represented by formula (I)) For the solid dispersion obtained in Example 4B, powder X-ray diffraction experiments were conducted under the measurement conditions 1 described in the above-mentioned test example 3 after it was freshly prepared, after it was stored in an open glass bottle at 40°C and 75% relative humidity for 1 week, after it was stored in a sealed glass bottle at 40°C and 75% relative humidity for 1 week, and after it was stored in a sealed glass bottle at 60°C for 1 week.

[0365] The results of Example 4B-1 are shown below. Figure 17 The results of Example 4B-2 are shown in Figure 18 The results of Example 4B-3 are shown in Figure 19 The results of Example 4B-4 are shown in Figure 20 In Example 4B, none of the solid dispersions obtained showed diffraction peaks immediately after preparation or after storage under various conditions; only halo patterns were observed. This confirmed that the solid dispersions all maintained an amorphous state.

[0366] It should be noted that the anhydrous crystalline monomer of the compound represented by formula (I) exhibits a good powder X-ray diffraction pattern as described in Example 2B above.

[0367] (Example 4D: Preparation of solid dispersion of the compound represented by formula (I) 2) Anhydrous crystals of the compound represented by formula (I) and copovidone (manufactured by ASHLAND) were dissolved in acetone. After confirming complete dissolution, spray drying was carried out using a spray dryer at an outlet temperature of 50°C, a feed flow rate of approximately 6 kg / hr, and a spray pressure of 1.0 bar. Then, vacuum drying was performed using a benchtop vacuum dryer for approximately 40 hours to obtain a solid dispersion. The formulation is shown below.

[0368] [Table 9] <Particle size distribution of the solid dispersion of the compound represented by formula (I)> Under the determination conditions 3 (dry method) described in Experimental Example 10, the particle size distribution of the solid dispersion of Example 4D-1 was determined, and the results showed that D10 was 2.08 μm, D50 was 5.01 μm, and D90 was 11.00 μm.

[0369] <Particle size distribution of the anhydrous crystals of the compound represented by formula (I)> Under the determination conditions 3 (dry method) described in Test Example 10, the particle size distribution of the anhydrous crystals of the compound represented by formula (I) used in Example 4D-1 was determined, and the results were D10 = 0.86 μm, D50 = 3.29 μm, and D90 = 10.15 μm. Furthermore, under the conditions of Test Example 11 (wet method), the particle size distribution of the anhydrous crystals of the compound represented by formula (I) used in Example 4D-1 was determined, and the results were D10 = 3.94 μm, D50 = 9.18 μm, and D90 = 20.32 μm.

[0370] (Example 4E: Time-dependent stability test of solid dispersion of the compound represented by formula (I)) The solid dispersion obtained in Example 4D was stored at 25°C and 60% relative humidity for 3 months and at 40°C and 75% relative humidity for 3 months, and the increase in related substances was measured.

[0371] Experimental Example 13: Analytical Methods for Related Substances 2 The following methods and conditions are used to determine the amount of related substances using liquid chromatography.

[0372] Detector: Ultraviolet spectrophotometer (measurement wavelength: 247 nm) Column: ACQUITY UPLC BEH C18 (1.7 μm, 2.1×100 mm, Waters) Column temperature: a constant temperature around 40℃ Mobile phase A: Water / formic acid mixed solution (1000:1) Mobile phase B: Acetonitrile / formic acid mixed solution for liquid chromatography (2000:1) Liquid delivery of the mobile phase: Concentration gradient control is achieved by changing the mixing ratio of mobile phase A and mobile phase B in the following manner.

[0373] [Table 10] Flow rate: 0.4 mL / min Injection volume: 5 μL Sample cooling temperature: a constant temperature around 25℃ Needle washing solvent or auto-injector washing solution: acetonitrile Area measurement range: up to 53 minutes after sample solution injection. The following are the relevant quantities of substances with a relative storage time of 0.44 after being stored at 25°C and 60% relative humidity for 3 months at the start of the test and after being stored at 40°C and 75% relative humidity for 3 months.

[0374] [Table 11] The relative retention time of the relevant substances was 0.44, which was slightly higher than at the beginning of the experiment, confirming that it was a stable solid dispersion.

[0375] (Example 4F: Solubility test of solid dispersion of the compound represented by formula (I)) The solubility of the solid dispersion obtained in Example 4D and the anhydrous crystalline monomer of the compound represented by formula (I) was determined.

[0376] Experimental Example 14: Solubility Test The solid dispersion obtained in Example 4D and the anhydrous crystalline monomer of the compound represented by formula (I) (Example 4F-1) were added to various test solutions to prepare suspensions of 30–50 mL. The prepared suspensions were added to centrifuge tubes and shaken at a shaking speed of 100 rpm or higher. After 60 minutes of shaking, 5 mL was collected and quickly filtered through a filter (chromatographic plate 0.45 μm, 25A) to prepare the sample.

[0377] The solubility in various test solutions is shown below. The solubility of the solid dispersion of the compound represented by formula (I) is significantly higher than that of the anhydrous crystalline monomer of the compound represented by formula (I).

[0378] [Table 12] (Example 4G: Rat PK test of solid dispersion of the compound represented by formula (I)) A suspension of a solid dispersion consisting of anhydrous crystalline monomers of the compound represented by formula (I) and copovidone was prepared, and its oral absorption in rats was evaluated.

[0379] Experiment 15: Rat PK Test After feeding male rats, the samples were administered orally. It should be noted that the dosage of the suspension was adjusted so that the dosage of the compound represented by formula (I) was 3 mg / kg body weight.

[0380] After administration of Examples 4G-1, 4G-2 and 4G-3 as shown below, blood samples were collected at each sampling time. Using LC / MS / MS, the maximum plasma drug concentration (Cmax), the time to reach the highest plasma drug concentration (Tmax), and the area under the plasma drug concentration-time curve (AUC) from the time of administration to 24 hours later were calculated.

[0381] <Example 4G-1: Preparation of a suspension of the solid dispersion of the compound represented by formula (I)> The compound represented by formula (I) and copovidone (manufactured by ASHLAND) were dissolved in acetone at a weight ratio of 1:3. After confirming complete dissolution, spray drying was carried out using a spray dryer at an outlet temperature of 50°C, a feed flow rate of approximately 6 kg / hr, and a spray pressure of 1.0 bar. Vacuum drying was then performed using a benchtop vacuum dryer for approximately 40 hours to obtain a solid dispersion.

[0382] The resulting solid dispersion was suspended in an aqueous solution containing 0.5% methylcellulose at a concentration of 6 mg / mL to obtain a suspension.

[0383] <Example 4G-2: Preparation of a suspension of anhydrous crystals of the compound represented by formula (I)> The anhydrous crystals of the compound represented by formula (I) were suspended in an aqueous solution containing 0.5% methylcellulose at a concentration of 6 mg / mL, thereby obtaining a suspension.

[0384] <Example 4G-3: Preparation of a suspension of ethyl acetate complex crystals of the compound represented by formula (I)> The ethyl acetate complex of the compound represented by formula (I) was crystallized and suspended in an aqueous solution containing 0.5% methylcellulose at a concentration of 6 mg / mL, thereby obtaining a suspension.

[0385] The results for Cmax, Tmax, and AUC of the compounds represented by formula (I) in each embodiment are shown below.

[0386] [Table 13] Compared to Examples 4G-2 and 4G-3, Example 4G-1 showed increased Cmax and AUC, indicating significantly improved oral absorption. Furthermore, compared to Examples 4G-2 and 4G-3, Example 4G-1 exhibited a shorter Tmax, demonstrating rapid absorption.

[0387] The following shows the manufacturing method and evaluation results of "preparations containing the compound represented by formula (I) as an active ingredient".

[0388] (Example 5: Formulation containing anhydrous crystals of the compound represented by formula (I)) The following shows the manufacturing method and evaluation results of "a formulation containing anhydrous crystals of the compound represented by formula (I) as the active ingredient".

[0389] (Example 5A: Study on uncoated tablets containing anhydrous crystals of the compound represented by formula (I) 1) An uncoated tablet containing 50% by weight of anhydrous crystals of the compound represented by formula (I) and 5% by weight of disintegrant was manufactured, and a dissolution test was performed.

[0390] <Manufacturing Method of Uncoated Sheets> The following are anhydrous crystals of the compounds represented by formula (I): D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium cellulose (manufactured by DuPont), low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Industry), sodium starch glycolate (manufactured by JRS Pharma), croscarmellose (CLM and CL grades, manufactured by BASF), and magnesium stearate (manufactured by MALLINCKRODT). Formulations are shown below (units are mg).

[0391] [Table 14] Anhydrous crystals of the compound represented by formula (I), excipients, disintegrants, and half-amount of magnesium stearate were mixed using a scraper and sieved using a wire mesh. Then, the mixture was tableted using a simple tablet forming machine (model: HANDTAB-200, manufactured by Ichihashi Precision Machinery Co., Ltd.). Next, the granules were sizing using a 20-mesh sieve, and the remaining magnesium stearate was added and mixed using a scraper. The resulting tableting granules were then compressed using a simple tablet forming machine (model: HANDTAB-200, manufactured by Ichihashi Precision Machinery Co., Ltd.) to obtain uncoated tablets.

[0392] Dissolution Test Test Example 16: Dissolution Test For the formulations obtained in each example (one tablet in the case of tablets), dissolution tests were performed using the dissolution test method of the 18th revised edition of the Japanese Pharmacopoeia. The test solution used was the second dissolution test solution containing a surfactant, and the test was performed using the paddle method at a paddle speed of 50 rpm (changed to 250 rpm after 120 minutes of the test).

[0393] As a result, Example 5A-1, which uses cross-linked polyvinylpyrrolidone (CLM grade), showed the best dissolution.

[0394] (Example 5B: Study of uncoated tablets containing anhydrous crystals of the compound represented by formula (I) 2) An uncoated tablet containing 50% by weight of anhydrous crystals of the compound represented by formula (I) and 10% by weight of disintegrant was prepared, and a dissolution test was performed.

[0395] <Manufacturing Method of Uncoated Sheets> It is manufactured using the same method as in Example 5A. The formulation is shown below.

[0396] [Table 15] Dissolution Test Dissolution tests were conducted in Example 16. The results showed that, compared to Examples 5A-1, 5A-2, and 5A-5 (disintegrant ratio 5% by weight), all disintegrants in Examples 5B-1, 5B-2, and 5B-3 (disintegrant ratio 10% by weight) increased the dissolution rate. Furthermore, Example 5B-1, using crospovidone as the disintegrant, exhibited the fastest dissolution performance.

[0397] (Example 5C: Study of uncoated tablets containing anhydrous crystals of the compound represented by formula (I) 3) An uncoated tablet containing 10% by weight of anhydrous crystals of the compound represented by formula (I) and 10% by weight of disintegrant was prepared, and a dissolution test was performed.

[0398] <Manufacturing Method of Uncoated Sheets> Anhydrous crystals of the compounds represented by formula (I), D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), crospovidone (INF-10 grade, manufactured by ASHLAND), crospovidone sodium carboxymethyl cellulose (manufactured by DuPont), and sodium stearate fumarate (manufactured by JRS Pharma).

[0399] The manufacturing method was carried out using the same method as in Examples 5A and 5B. The formulation is shown below.

[0400] [Table 16] Dissolution Test Dissolution tests were conducted in Example 16. As a result, Example 5C-1, using crospovidone as a disintegrant, showed good dissolution properties. Therefore, crospovidone is considered the most preferred disintegrant when the proportion of anhydrous crystals of the compound represented by formula (I) is 10–50% by weight.

[0401] (Example 5D: A suspension containing anhydrous crystals of the compound represented by formula (I)) A suspension containing anhydrous crystals of the compound represented by formula (I) was prepared. Dissolution tests were performed on the suspension and on Example 5C-1 (an uncoated tablet containing anhydrous crystals of the compound represented by formula (I)).

[0402] <Methods for Adjusting Suspensions> Anhydrous crystals of the compound represented by formula (I), hydroxypropyl cellulose (manufactured by Nippon Soda), and titanium dioxide (manufactured by Merck) were mixed with a spatula, and a small amount of water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.) was added and mixed with a spatula. Then, ultrasonic irradiation was performed and the remaining water for injection was added to obtain a suspension. The formulation is shown below.

[0403] [Table 17] Dissolution Test Dissolution tests were conducted as in Example 16. The results of the dissolution tests for Examples 5C-1 and 5D-1 are shown below. Figure 21 As a result, Example 5C-1 (uncoated tablets) showed faster dissolution compared to Example 5D-1 (suspension).

[0404] (Example 5E: Study of tablets containing anhydrous crystals of the compound represented by formula (I) 1) To investigate the effect of photostabilizing substances, photostabilizing substances and polymers were coated onto anhydrous crystals of the compound represented by formula (I), and the quality and appearance of related substances in the formulation were evaluated. Stability tests were conducted on the uncoated tablets and tablets under heated and humidified conditions to evaluate dissolution.

[0405] <Method for manufacturing tablets> Anhydrous crystals of the compound represented by formula (I), D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), crospovidone (INF-10 grade, manufactured by ASHLAND), and half a quantity of sodium stearate (manufactured by JRSPharma) were mixed in a polyethylene bag and sieved using a 30-mesh sieve. Granulation was then performed using a roller compactor at a roller pressure of 7 MPa, a roller speed of approximately 4 rpm, and a screw speed of approximately 30 rpm. Granulation was then performed using a granulator at a speed of approximately 1800 rpm. The resulting granulated particles and half a quantity of sodium stearate were mixed in a mixer for 5 minutes, and then compressed into tablets using a rotary tableting machine at a rotary speed of 20–30 rpm to produce uncoated tablets.

[0406] Then, using a coating machine, with an air supply volume of 0.80 m³ / h... 3 Coating was performed under the following conditions: air supply temperature set at 60°C, liquid flow rate of 2.0–2.9 g / min, spray pressure of approximately 0.18 MPa, and spray air volume of approximately 50 NL / min, to obtain the tablets of Example 5E-1. Talc, ferric oxide, and yellow ferric oxide were used as light stabilizers, and hydroxypropyl methylcellulose was used as the polymer. The formulation is shown below.

[0407] [Table 18] Dissolution Test The tablets of Example 5E-1 were stored in sealed polyethylene bottles at 40°C and 75% relative humidity for one month, and then again at 40°C and 75% relative humidity for three months. Dissolution tests were conducted using the method of Example 16, both at the start of the tests and after storage under each environment.

[0408] The results are shown in Figure 22 It was confirmed that even when stored under heated and humidified conditions for 3 months, the dissolution rate did not decrease.

[0409] Stability Testing Uncoated tablets containing anhydrous crystals of the compound represented by formula (I) (Example 5C-1 above) and tablets coated with stabilizing substances and polymers (Example 5E-1 above) were irradiated with light at a total irradiation dose of 1,200,000 lux·hr. The amount of related substances and the appearance of the formulations were evaluated at the start of the test and after irradiation with 1,200,000 lux·hr. The relative retention time of 0.84 and the total amount of related substances were measured as related substances. In addition, the appearance was evaluated visually.

[0410] Experimental Example 17: Analytical Methods for Related Substances 3 The following methods and conditions are used to determine the amount of related substances using liquid chromatography.

[0411] Detector: Ultraviolet spectrophotometer (measurement wavelength: 247 nm) Column: ACQUITY UPLC BEH C18 (1.7 μm, 2.1×100mm, Waters) Column temperature: a constant temperature around 40℃ Mobile phase A: Water / formic acid mixed solution (1000:1) Mobile phase B: Acetonitrile / formic acid mixed solution for liquid chromatography (2000:1) Liquid delivery of the mobile phase: Concentration gradient control is achieved by changing the mixing ratio of mobile phase A and mobile phase B in the following manner.

[0412] [Table 19] Flow rate: 0.4 mL / min Injection volume: 5 μL Sample cooling temperature: a constant temperature around 25℃ Needle washing solvent or auto-injector washing solution: acetonitrile Area measurement range: up to 43 minutes after sample solution injection. The following are the relevant quantities of material with a relative holding time of 0.84 at the start of the experiment and after irradiation with 1.2 million lux·hr of light.

[0413] [Table 20] The total amount of relevant matter at the start of the experiment and after irradiation with 1.2 million lux·hr of light is as follows.

[0414] [Table 21] Regarding irradiation with a total light intensity of 1.2 million lux·hr, compared to Example 5C-1, the relative retention time of related substances (0.84) and the total related substances were significantly suppressed in Example 5E-1. Furthermore, regarding the appearance after irradiation with a total light intensity of 1.2 million lux·hr, Example 5C-1 turned yellow compared to before irradiation, but no change in appearance was observed in Example 5E-1 compared to before irradiation.

[0415] (Example 5F: Study on capsules and uncoated tablets containing anhydrous crystals of the compound represented by formula (I)) Capsules were prepared by filling anhydrous crystals of the compound represented by formula (I) into capsules. The relevant matter content in the capsules and uncoated tablets was evaluated. The relative retention time (0.98) and total relevant matter content were determined as the relevant matter content.

[0416] <Manufacturing Methods of Capsules and Uncoated Tablets> Anhydrous crystals of the compound represented by formula (I), D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium (manufactured by Dupont), and half a quantity of magnesium stearate (manufactured by MALLINCKRODT) were mixed using a scraper and sieved using a wire mesh. Then, tablets were formed using a simple tablet forming machine (model: HANDTAB-200, manufactured by Ichihashi Precision Machinery Co., Ltd.). Granulation was then performed using a 20-mesh sieve, and half a quantity of magnesium stearate was added, followed by mixing with a scraper to obtain granules.

[0417] Using a spatula, the granules were manually filled into hydroxypropyl methylcellulose capsules (manufactured by Qualicaps) to prepare the capsule formulation of Example 5F-1. Alternatively, the granules were compressed into tablets using a simple tablet forming machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.) to prepare uncoated tablets of Example 5F-2. The formulations are shown below.

[0418] [Table 22] Experimental Example 18: Related Substances Analysis Method 4 The following methods and conditions are used to determine the amount of related substances using liquid chromatography.

[0419] Detector: Ultraviolet spectrophotometer (measurement wavelength: 254 nm) Column: ACQUITY UPLC BEH C18 (1.7 μm, 2.1×100mm, Waters) Column temperature: a constant temperature around 40℃ Mobile phase A: A mixed solution of water and trifluoroacetic acid (1000:1) Mobile phase B: Acetonitrile for liquid chromatography Liquid delivery of the mobile phase: Concentration gradient control is achieved by changing the mixing ratio of mobile phase A and mobile phase B in the following manner.

[0420] [Table 23] Flow rate: 0.3 mL / min Injection volume: 4 μL Sample cooling temperature: a constant temperature around 10℃ Needle washing solvent: methanol Stability Testing The following are the relevant quantities of material with a relative holding time of 0.98 at the start of the experiment and after irradiation with 1.2 million lux·hr of light.

[0421] [Table 24] The total amount of relevant matter at the start of the experiment and after irradiation with 1.2 million lux·hr of light is as follows.

[0422] [Table 25] It was confirmed that, compared with Example 5F-2, the relative retention time of related substances (0.98) and the total related substances were significantly suppressed in Example 5F-1. The light-blocking effect resulting from capsule filling was also confirmed.

[0423] (Example 6: Formulation containing a solid dispersion of the compound represented by formula (I)) The formulation studies of preparations containing solid dispersions of compounds represented by formula (I) are shown below.

[0424] (Example 6A: Study on uncoated tablets containing solid dispersions of compounds represented by formula (I)) Uncoated tablets containing a solid dispersion of the compound represented by formula (I) are manufactured, and a dissolution test is performed.

[0425] <Manufacturing Method of Uncoated Sheets> The anhydrous crystals of the compound represented by formula (I) and the copovidone were dissolved in acetone. After confirming complete dissolution, spray drying was carried out using a spray dryer at an outlet temperature of 50°C, a feed flow rate of approximately 6 kg / hr, and a spray pressure of 1.0 bar. Then, vacuum drying was performed using a benchtop vacuum dryer for approximately 40 hours to obtain a solid dispersion.

[0426] The obtained solid dispersion, D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium (manufactured by Dupont) or croscarmellose (manufactured by ASHLAND), light anhydrous silica (manufactured by Cabot), and half the amount of sodium stearate fumarate (manufactured by JRS Pharma) were mixed with a spatula and sieved using a wire mesh. Then, the mixture was tableted using a simple tablet forming machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.). Next, the granules were sizing using a 20-mesh sieve, and half the amount of sodium stearate fumarate was added and mixed with a spatula. The resulting granules were then tableted using a simple tablet forming machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.) to obtain uncoated tablets. The formulation is shown below.

[0427] [Table 26] Dissolution Test Dissolution tests were conducted in Example 16. The results showed that Example 6A-1, using croscarmellose sodium, exhibited good dissolution properties. Therefore, croscarmellose sodium is considered a suitable disintegrant for tablets containing solid dispersions.

[0428] (Example 6B-1: Study of tablets containing solid dispersions of compounds represented by formula (I) 1) A tablet was manufactured by coating an uncoated tablet containing a solid dispersion of the compound represented by formula (I) with a light-stabilizing agent and a polymer. The tablet was then subjected to a stability test under a heated and humidified environment.

[0429] <Method for manufacturing tablets> The anhydrous crystals of the compound represented by formula (I) and the copovidone were dissolved in acetone. After confirming complete dissolution, spray drying was carried out using a spray dryer at an outlet temperature of 50°C, a feed flow rate of approximately 6 kg / hr, and a spray pressure of 1.0 bar. Then, vacuum drying was performed using a benchtop vacuum dryer for approximately 40 hours to obtain a solid dispersion.

[0430] The obtained solid dispersion was mixed with D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium cellulose (manufactured by Dupont), light anhydrous silicate (manufactured by Cabot), and half a quantity of sodium stearate fumarate (manufactured by JRS Pharma) in a mixer for 8 minutes, and then sieved using a 30-mesh sieve. Then, dry granulation was performed using a roller compactor at a roller pressure of 7 MPa, a roller speed of approximately 4 rpm, and a screw speed of approximately 40 rpm. Next, dry granulation was performed using a granulator at a speed of approximately 3000 rpm. The resulting granulated particles and half a quantity of sodium stearate fumarate were mixed in a mixer for 5 minutes, and then uncoated tablets were manufactured using a rotary tablet press at a rotary speed of approximately 30 rpm.

[0431] Then, using a coating machine, with an air supply volume of 0.80 m³ / h... 3 Coating was carried out under the following conditions: air supply temperature set at 60°C, liquid flow rate of 2.0–2.9 g / min, spray pressure of approximately 0.18 MPa, and spray air volume of approximately 50 NL / min, to obtain tablets. The formulation is shown below.

[0432] [Table 27] <Stability and Dissolution Tests> The tablets of Example 6B-1 were stored in sealed brown glass bottles at 60°C for 2 weeks, at 40°C for 1 month, and at 40°C and 75% relative humidity for 1 month. Dissolution tests were conducted using the method of Example 16 at the start of the tests and after each storage period.

[0433] The results are shown in Figure 23 It was confirmed that the dissolution rate did not decrease after storage under any conditions.

[0434] (Example 6B-2: Study of tablets containing solid dispersions of compounds represented by formula (I) 2) A solid dispersion consisting of the compound represented by formula (I) and copovidone, with a content different from that of Example 6B-1, was manufactured by coating the tablet with a light-stabilizing agent and a polymer. Stability tests were then conducted on the tablet under heated and humidified conditions.

[0435] <Method for manufacturing tablets> The anhydrous crystals of the compound represented by formula (I) and the copovidone were dissolved in acetone. After confirming complete dissolution, spray drying was carried out using a spray dryer at an outlet temperature of 50°C, a feed flow rate of approximately 80 kg / hr, and a spray pressure of 2.5 bar. Then, vacuum drying was performed using a rotary vacuum dryer for approximately 37 hours to obtain a solid dispersion.

[0436] The obtained solid dispersion was mixed with D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium cellulose (manufactured by Dupont), light anhydrous silicate (manufactured by Cabot), and half a quantity of sodium stearate fumarate (manufactured by JRS Pharma) in a mixer for 15 minutes, and then sieved using a 1.6 mm mesh screen. Dry granulation was then performed using a roller compactor at a roller pressure of 5 MPa, a roller speed of approximately 5 rpm, and a screw speed of approximately 5 rpm. Dry granulation was then performed using a granulator at approximately 100 rpm. The resulting granulated particles and half a quantity of sodium stearate fumarate were mixed in a mixer for 3 minutes, and then uncoated tablets were manufactured using a rotary tablet press at a rotary speed of approximately 20 rpm.

[0437] Then, using a coating machine with an air supply volume of 12 m³ / h 3 Coating was carried out under the following conditions: air supply temperature set at 60°C, liquid flow rate at 40–80 g / min, spray pressure at approximately 0.4 MPa, and spray air volume at approximately 130 NL / min, to obtain tablets. The formulation is shown below.

[0438] [Table 28] <Stability and Dissolution Tests> The tablets of Example 6B-2 were stored in sealed brown glass bottles at 60°C for 2 weeks, at 40°C for 1 month, and at 40°C and 75% relative humidity for 1 month. Dissolution tests were conducted using the following methods at the start of the tests and after storage under each environment.

[0439] (Dissolution test method) Dissolution tests were performed on one tablet of each tablet using the dissolution test method of the 18th revised edition of the Japanese Pharmacopoeia. The second dissolution test solution was used, and the test was conducted using a paddle method at a paddle speed of 50 rpm.

[0440] The results are shown in Figure 24 It was confirmed that the dissolution rate did not decrease after storage under any conditions.

[0441] (Example 6C: Study of tablets containing solid dispersions of compounds represented by formula (I) 3) The formulation ratios of the anhydrous crystals of the two compounds represented by formula (I) and the solid dispersion composed of copovidone differed from those of the uncoated tablets in Example 6B-1. Each uncoated tablet was coated with a light-stabilizing agent and a polymer to manufacture tablets. Stability tests were conducted on these tablets under heated and humidified conditions.

[0442] <Method for manufacturing tablets> Anhydrous crystals of the compound represented by formula (I) and copolyvinyl ketone were dissolved in acetone. After confirming complete dissolution, a solid dispersion was obtained using a spray dryer at an inlet temperature of 90°C, a liquid delivery pump of 20%, and a nitrogen flow rate of 40.

[0443] The obtained solid dispersion, D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium (manufactured by Dupont), and half the amount of sodium stearate fumarate (manufactured by JRS Pharma) were mixed with a spatula and sieved using a wire mesh. Then, the mixture was tableted using a simple tablet forming machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.). Next, the granules were granulated using a 20-mesh sieve, and half the amount of sodium stearate fumarate was added and mixed with a spatula. The resulting tableting granules were then compressed using a simple tablet forming machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.), and then coated using a coating machine (manufactured by Powrex) to obtain tablets. The formulation is shown below.

[0444] [Table 29] <Stability and Dissolution Tests> Dissolution tests were conducted on the tablets of Examples 6C-1 and 6C-2, which were stored in sealed brown glass bottles at 60°C for one week and at 40°C and 75% relative humidity for one week. Example 16 was also included in the dissolution test.

[0445] The results of Example 6C-1 are shown below. Figure 25 The results of Example 6C-2 are shown in Figure 26 It was confirmed that the dissolution rate did not decrease when the glass bottle was sealed and stored at 60°C for one week and at 40°C and 75% relative humidity for one week.

[0446] (Example 6D: Study of tablets containing solid dispersions of compounds represented by formula (I) 4) Uncoated tablets containing anhydrous crystals of the compound represented by formula (I) and a solid dispersion of copovidone, and tablets coated with a light stabilizer and a polymer are manufactured. The uncoated tablets and tablets are irradiated with light at a total intensity of 1.2 million lux·hr, and the quality and appearance of relevant substances in the formulation are evaluated at the start of the test and after irradiation with 1.2 million lux·hr light.

[0447] <Methods for manufacturing uncoated tablets and tablets> The anhydrous crystals of the compound represented by formula (I) and the copovidone were dissolved in acetone. After confirming complete dissolution, spray drying was carried out at an outlet temperature of 50°C, a feed flow rate of approximately 6 kg / hr, and a spray pressure of 1.0 bar. Then, vacuum drying was performed using a benchtop vacuum dryer for approximately 40 hours to obtain a solid dispersion.

[0448] The resulting solid dispersion, D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium (manufactured by Dupont), light anhydrous silicate (manufactured by Cabot), and half a quantity of sodium stearate fumarate (manufactured by JRS Pharma) were mixed in a mixer for 8 minutes and sieved using a 30-mesh sieve. Then, dry granulation was performed using a roller compactor at a roller pressure of 7 MPa, a roller speed of approximately 4 rpm, and a screw speed of approximately 40 rpm. Next, dry granulation was performed using a granulator at a speed of approximately 3000 rpm. The resulting granulated particles and half a quantity of sodium stearate fumarate were mixed in a mixer for 5 minutes, and then uncoated tablets were manufactured using a rotary tablet press at a rotary speed of approximately 30 rpm (Example 6D-1).

[0449] Regarding Example 6D-2, a coating machine was then used with an air supply volume of 0.80 m³. 3 Coating was carried out under the following conditions: air supply temperature set at 60°C, liquid flow rate of 2.0–2.9 g / min, spray pressure of approximately 0.18 MPa, and spray air volume of approximately 50 NL / min, to obtain tablets. The formulation is shown below.

[0450] [Table 30] Examples 6D-1 and 6D-2 were irradiated with light at a total intensity of 1,200,000 lux·hr. The mass and appearance of related substances in the formulations were evaluated at the start of the test and after irradiation with 1,200,000 lux·hr. The mass of related substances was determined using the method of Example 17, measuring the relative retention time of 1.59 and the total mass of related substances. In addition, the appearance was evaluated visually.

[0451] <Results> The following are the relevant mass values ​​for the relative retention time of 1.59 at the start of the experiment and after irradiation with 1.2 million lux·hr of light.

[0452] [Table 31] The total amount of relevant matter at the start of the experiment and after irradiation with 1.2 million lux·hr of light is as follows.

[0453] [Table 32] Regarding irradiation with a total illumination dose of 1.2 million lux·hr, the relative retention time of related substances and the total related substances in Example 6D-2 were significantly suppressed compared to Example 6D-1, with a relative retention time of 1.59. Furthermore, regarding the appearance after irradiation with a total illumination dose of 1.2 million lux·hr, Example 6D-1 turned yellow compared to before irradiation, but no change in appearance was observed in Example 6D-2 compared to before irradiation.

[0454] (Example 6E: Study of tablets containing solid dispersions of compounds represented by formula (I) 5) The anhydrous crystals of the compound represented by formula (I) and the solid dispersion composed of copovidone were prepared with a content different from that of the uncoated tablets of Example 6D, and tablets coated with light stabilizers and polymers were prepared. The uncoated tablets and tablets were irradiated with light at a total intensity of 1.2 million lux·hr, and the quality and appearance of the relevant substances in the formulation were evaluated at the beginning of the test and after irradiation with 1.2 million lux·hr light.

[0455] <Methods for manufacturing uncoated tablets and tablets> The anhydrous crystals of the compound represented by formula (I) and the copovidone were dissolved in acetone. After confirming complete dissolution, spray drying was carried out using a spray dryer at an outlet temperature of 50°C, a feed flow rate of approximately 80 kg / hr, and a spray pressure of 2.5 bar. Then, vacuum drying was performed using a rotary vacuum dryer for approximately 37 hours to obtain a solid dispersion.

[0456] The obtained solid dispersion was mixed with D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium (manufactured by Dupont), light anhydrous silica (manufactured by Cabot), and half a quantity of sodium stearate fumarate (manufactured by JRS Pharma) in a mixer for 15 minutes. After sieving using a 1.6 mm mesh screen, dry granulation was performed using a roller compactor at a roller pressure of 5 MPa, a roller speed of approximately 5 rpm, and a screw speed of approximately 5 rpm. Then, dry granulation was performed using a granulator at a speed of approximately 100 rpm. The resulting granulated particles and half a quantity of sodium stearate fumarate were mixed in a mixer for 3 minutes, and then uncoated tablets were manufactured using a rotary tablet press at a rotary speed of approximately 20 rpm (Example 6E-2).

[0457] Regarding Example 6E-1, then using a coating machine with an air supply volume of 12 m³ / s. 3 Coating was carried out under the following conditions: air supply temperature set at 60℃, liquid flow rate at 40-80 g / min, spray pressure at approximately 0.4 MPa, and spray air volume at approximately 130 NL / min, to obtain tablets.

[0458] The recipe is shown below.

[0459] [Table 33] Examples 6E-1 and 6E-2 were irradiated with light of 1.2 million lux·hr (total irradiation dose). The amount of related substances and appearance of the formulations were evaluated at the start of the test and after irradiation with 1.2 million lux·hr. The amount of related substances was determined using the method of Example 17, with a relative retention time of 1.59 and a total amount of related substances. In addition, the appearance was evaluated visually.

[0460] <Results> The following are the relevant mass values ​​for the relative retention time of 1.59 at the start of the experiment and after irradiation with 1.2 million lux·hr of light.

[0461] [Table 34] The total amount of relevant matter at the start of the experiment and after irradiation with 1.2 million lux·hr of light is as follows.

[0462] [Table 35] Compared to Example 6E-2, the relative retention time of 1.59 and the total related mass of Example 6E-1 were significantly suppressed. Furthermore, regarding appearance, when the uncoated tablets of Example 6E-2 were irradiated with 1.2 million lux·hr of light, they turned yellow compared to before irradiation; however, when the tablets of Example 6E-1 were irradiated with 1.2 million lux·hr of light, no change in appearance was observed compared to before irradiation.

[0463] (Example 7: Capsules containing a solution of the compound represented by formula (I)) As a formulation study to confirm the absorption, distribution, metabolism, and excretion of the drug via oral administration (ADME test), capsules as shown below were manufactured.

[0464] Prepare capsules containing a solution of the compound represented by formula (I) and evaluate the stability of the capsules. Prepare capsules with the formulation shown below and conduct stability tests.

[0465] [Table 36] <Manufacturing Method> Anhydrous crystals of the compound represented by formula (I), copovidone (ASHLAND), ascorbic acid (Kanto Chemical), citric acid (FUJIFILMWako Pure Chemical), and α-vitamin E polyethylene glycol succinate (BLD Pharmatech) were added to polyethylene glycol 400 (manufactured by BASF) after stirring with a stir bar. After confirmation of clarity, the mixture was filled into gelatin capsules (manufactured by Capsugel) to obtain an evaluation sample.

[0466] Stability Testing Examples 7-1 to 7-4 shown in Table 36 were stored in sealed brown glass bottles at 25°C for 6 days to evaluate the related substances in the formulation. The related substances test was performed under the conditions of Test Example 17, with an injection volume of 25 μL.

[0467] <Results> The total amount of related substances exceeding 0.1% at the start of the test and after 6 days of storage at 25°C is shown below. In Examples 7-1 and 7-2, the generation of related substances was suppressed. Furthermore, in Examples 7-1 and 7-2, no related substances exceeding 0.1% were identified from the start of the test until after 6 days of storage at 25°C.

[0468] [Table 37] (Example 8: Solution preparation of the compound represented by formula (I)) As a formulation study to confirm the absorption, distribution, metabolism, and excretion of the drug via oral administration (ADME test), the solution formulation shown below was manufactured.

[0469] Prepare a solution formulation according to the formula shown in Table 38, store it at 5°C or 25°C for 7 days, and conduct a dissolution test.

[0470] [Table 38] <Manufacturing Method> The compound represented by formula (I) was added to polyethylene glycol 400 (manufactured by BASF) after stirring with a stir bar and dissolved. Copovidone (manufactured by ASHLAND) and ascorbic acid (manufactured by DSM) were added and stirred with a stir bar until dissolved. After confirming clarity, propylene glycol (manufactured by BASF) was added and stirred with a stir bar to obtain a solution formulation.

[0471] Dissolution Test Dissolution tests were performed on the solution formulations obtained in each example using the dissolution test method of the 18th revised edition of the Japanese Pharmacopoeia. The second dissolution test solution was used as the test solution, and the test was conducted using a paddle method at a paddle speed of 50 rpm (changed to 250 rpm after 120 minutes of the test).

[0472] <Results> The dissolution test results of Example 8-1 are shown in Figure 27 The formulation of Example 8-1 also showed good dissolution at the start of the test, and the dissolution rate did not decrease even when stored at 5°C or 25°C for 7 days.

[0473] (Example 9: Preparation containing ethyl acetate compound crystals of the compound represented by formula (I)) The formulation study of a preparation containing the ethyl acetate complex crystal of the compound represented by formula (I) as the active ingredient is shown below.

[0474] (Example 9A: Study on the crystallization of uncoated tablets containing ethyl acetate complex of the compound represented by formula (I)) Uncoated tablets containing ethyl acetate complex crystals of the compound represented by formula (I) as the active ingredient were manufactured, and stability and dissolution tests were performed.

[0475] <Manufacturing Method of Uncoated Sheets> The ethyl acetate compound of the compound represented by formula (I), D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium (manufactured by Dupont), and half a quantity of magnesium stearate (manufactured by MALLINCKRODT) were mixed with a spatula and sieved using a wire mesh. Then, tableting was performed using a simple tablet forming machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.). Granulation was then performed using a 20-mesh sieve, and half a quantity of magnesium stearate was added and mixed with a spatula. The resulting tableting granules were then compressed using a simple tablet forming machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.) to obtain uncoated tablets. The formulation is shown below.

[0476] [Table 39] <Stability and Dissolution Tests> Dissolution tests were conducted on the uncoated tablets of Example 9A-1, which were then stored in sealed brown glass bottles at 60°C for 2 weeks and in open brown glass bottles at 40°C and 75% relative humidity for 2 weeks. Example 19 was also included in the dissolution tests.

[0477] Dissolution Test Test Example 19: Dissolution Test Dissolution tests were performed on the formulations obtained in each example (one tablet in the case of tablets) using the dissolution test method of the 18th revised edition of the Japanese Pharmacopoeia. The test solution was artificial intestinal fluid during feeding, and the test was conducted using a paddle method at a paddle speed of 50 rpm (changed to 250 rpm after 120 minutes of testing).

[0478] (Example 9B: Study on capsules containing ethyl acetate complex of the compound represented by formula (I) 1) A capsule containing an ethyl acetate compound crystal of the compound represented by formula (I) is prepared, and a dog PK test is performed on the capsule.

[0479] <Manufacturing Method of Capsules> The ethyl acetate compound of the compound represented by formula (I), D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium (manufactured by Dupont), and half a quantity of magnesium stearate (manufactured by MALLINCKRODT) were mixed with a spatula and sieved using a wire mesh. Then, tablets were formed using a simple tablet forming machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.). The tablets were then granulated using a 20-mesh sieve, and half a quantity of magnesium stearate was added and mixed with a spatula to obtain granules. These granules were then manually filled into gelatin capsules using a spatula to prepare capsules. The formulation is shown below.

[0480] [Table 40] Experiment Example 20: Dog PK Experiment For male beagle dogs, one capsule was administered orally 30 minutes to 2 hours prior to administration. It should be noted that Table 33 shows the formulation of a capsule containing 120.0 mg of the compound represented by formula (I), but in this experiment, the mass of each capsule was adjusted according to the weight of the male beagle dog to ensure an administration dose of 3 mg / kg body weight of the compound represented by formula (I). Blood samples were collected at various time points after administration to each specimen. LC / MS / MS was used to calculate the maximum plasma drug concentration (Cmax), the time to reach the highest plasma drug concentration (Tmax), and the area under the plasma drug concentration-time curve (AUC) from administration to 48 hours later.

[0481] (Example 9C: Study on capsules containing ethyl acetate compounds of the compound represented by formula (I) 2) The formulation for manufacturing the ethyl acetate compound containing the compound represented by formula (I) differs from the capsule formulation of Example 9B, and the solubility of the capsule formulation is evaluated.

[0482] <Manufacturing Method of Capsules> The ethyl acetate compound of the compound represented by formula (I), copovidone (manufactured by ASHLAND), crystalline cellulose (manufactured by Asahikasei), D-mannitol (manufactured by ROQUETTE), croscarmellose sodium (manufactured by DuPont), and magnesium stearate (manufactured by MALLINCKRODT) were mixed with a spatula, sieved using a wire mesh, and then filled into hydroxypropyl methylcellulose capsules (manufactured by Qualicaps) using a spatula to prepare capsules. The formulation is shown below.

[0483] [Table 41] Dissolution Test Dissolution tests were performed on the formulations (one capsule) obtained in each example using the dissolution test method of the 18th revised edition of the Japanese Pharmacopoeia. The test solution used was artificial intestinal fluid during fasting (FaSSIF-V2), and the paddle method was used with a paddle speed of 50 rpm (changed to 250 rpm after 120 minutes of the test).

[0484] <Results> The dissolution test results of Examples 9C-1 to 9C-4 are shown in Figure 28 In Example 9C-1, where the ethyl acetate compound of the compound represented by formula (I) was filled into hydroxypropyl methylcellulose capsules, insufficient solubility was not observed. However, the solubility was improved by adding 30.0 mg of copovidone and 7.5 mg of croscarmellose sodium (Examples 9C-2, 9C-3). Furthermore, even better solubility was observed by adding D-mannitol and magnesium stearate and adjusting the amount of copovidone from 30 mg to 7.5 mg (Example 9C-4).

[0485] (Example 10: Capsules containing a solution of an ethyl acetate compound of the compound represented by formula (I)) As a formulation study to confirm the absorption, distribution, metabolism, and excretion of the drug via oral administration (ADME test), capsules as shown below were manufactured.

[0486] Prepare capsules containing a solution of an ethyl acetate compound of the compound represented by formula (I), and evaluate the solubility of the capsules. Prepare capsules with the formulation shown below, and perform a dissolution test.

[0487] [Table 42] <Manufacturing Method> An ethyl acetate compound of the compound represented by formula (I) and copovidone (manufactured by ASHLAND) were added to polyethylene glycol 400 (manufactured by BASF) after stirring with a stir bar. After confirmation and clarification, the mixture was filled into hydroxypropyl methylcellulose capsules (manufactured by Qualicaps) to obtain capsules.

[0488] Dissolution Test Dissolution tests were performed on the formulations (2 capsules) obtained in each example using the dissolution test method of the 18th revised edition of the Japanese Pharmacopoeia. The second dissolution test solution was used, and the test was conducted using a paddle method at a paddle speed of 50 rpm (changed to 250 rpm after 120 minutes of the test).

[0489] <Results> The dissolution test results of Examples 10-1 and 10-2 are shown in... Figure 29 The dissolution of the ethyl acetate compound of formula (I) in polyethylene glycol 400 resulted in good dissolution (Example 10-1). The addition of 150.4 mg of copovidone resulted in even better dissolution (Example 10-2).

[0490] (Example 11: Solution preparation of the ethyl acetate complex of the compound represented by formula (I)) As a formulation study to confirm the absorption, distribution, metabolism, and excretion of the drug via oral administration (ADME test), capsules as shown below were manufactured.

[0491] Prepare a solution formulation as shown below, store it at 5°C for 3 days, and conduct a dissolution test.

[0492] [Table 43] <Manufacturing Method> An ethyl acetate compound of the compound represented by formula (I) is added to polyethylene glycol 400 (manufactured by BASF) after stirring with a stir bar and dissolved. Copovidone (manufactured by ASHLAND) is added to water for injection and stirred with a stir bar to dissolve. An aqueous solution of copovidone (manufactured by ASHLAND) is added to the polyethylene glycol 400 solution of the ethyl acetate compound of the compound represented by formula (I) and stirred with a stir bar to obtain a solution formulation.

[0493] Dissolution Test Dissolution tests were performed on the solution formulations obtained in each example using the dissolution test method of the 18th revised edition of the Japanese Pharmacopoeia. The second dissolution test solution was used as the test solution, and the test was conducted using a paddle method at a paddle speed of 50 rpm (changed to 250 rpm after 120 minutes of the test).

[0494] <Results> The dissolution test results of Examples 11-1, 11-2, and 11-3 are shown below. Figure 30 When the formulation of Example 11-1 was stored at 5°C for 3 days, the dissolution rate decreased. In Examples 11-2 and 11-3, which contained 1107.6 mg and 1418.6 mg of copovidone, respectively, the decrease in dissolution rate was suppressed, and a higher dissolution rate was maintained.

[0495] (Example 12: Rat PK test of formulations containing the compound represented by formula (I) and the ethyl acetate complex of the compound represented by formula (I)) As a study of formulations capable of confirming absorption, distribution, metabolism, and excretion via oral administration (ADME test), a formulation with the following formulation was manufactured and subjected to a rat PK test.

[0496] In rat PK tests, male rats were fed with the compound represented by formula (I) at a dose of 0.3 mg / rat or 1 mg / kg.

[0497] After administration of the drugs as shown in Examples 12-1 to 12-6, blood samples were collected at each time point. The maximum plasma drug concentration (Cmax) and the area under the plasma drug concentration-time curve (AUC) from the time of administration to 24 hours later were calculated using LC / MS / MS.

[0498] [Table 44] [Table 45] [Table 46] <Manufacturing Method> Example 12-1 Anhydrous crystals of the compound represented by formula (I), copovidone (manufactured by ASHLAND), and ascorbic acid (manufactured by DSM) were added to polyethylene glycol 400 (manufactured by BASF) after stirring with a stir bar. After confirmation of clarity, propylene glycol (manufactured by BASF) was added and mixed with a stir bar to obtain the specimen for administration.

[0499] Example 12-2 An ethyl acetate compound of the compound represented by formula (I) and copovidone (manufactured by ASHLAND) were added to polyethylene glycol 400 (manufactured by BASF) after stirring with a stir bar. After confirmation of clarity, the mixture was filled into gelatin capsules (manufactured by Capsugel) to obtain a specimen for administration.

[0500] Example 12-3 The ethyl acetate compound of the compound represented by formula (I), copovidone (manufactured by ASHLAND), crystalline cellulose (manufactured by Asahikasei), D-mannitol (manufactured by ROQUETTE), croscarmellose sodium (manufactured by DuPont), and magnesium stearate (manufactured by MALLINCKRODT) were mixed with a spatula and sieved with a wire mesh, and then filled into gelatin capsules (manufactured by Capsugel) using a spatula to obtain the specimen for administration.

[0501] Examples 12-4 An ethyl acetate compound of the compound represented by formula (I) was suspended in an aqueous solution containing 1% hydroxypropyl cellulose (manufactured by Nippon Soda), and then filled into a gelatin capsule (manufactured by Capsugel) to obtain an evaluation sample.

[0502] Examples 12-5 The solid dispersion of the compound represented by formula (I) is suspended in an aqueous solution containing 0.5% methylcellulose to obtain a sample for administration.

[0503] Examples 12-6 An anhydrous crystal of the compound represented by formula (I) is suspended in an aqueous solution containing 0.5% methylcellulose to obtain a sample for administration.

[0504] <Results> The Cmax and AUC of the compounds represented by formula (I) in each example are shown below. Examples 12-1 to 12-5 exhibited high absorption.

[0505] [Table 47] Industrial availability The formulations and crystals of the present invention have an inhibitory effect on coronavirus 3CL protease and are considered useful as therapeutic and / or preventive agents for diseases or conditions in which coronavirus 3CL protease is involved.

Claims

1. A formulation comprising, as an active ingredient, a compound represented by formula (I), a pharmaceutically permissible salt thereof, or a solvate thereof: [Chemical Formula 1] 。 2. The formulation of claim 1, wherein, The active ingredient is the compound represented by formula (I), its pharmaceutically permissible salt, or the amorphous form of their solvates.

3. The formulation of claim 2, wherein, The active ingredient is the amorphous form of the compound represented by formula (I).

4. The formulation of claim 3, wherein the solid dispersion contains an amorphous form of the compound represented by formula (I).

5. The formulation as described in claim 4, further comprising a polymer in the solid dispersion.

6. The formulation of claim 5, wherein, The polymer is selected from one or more of the following: ethylene-based polymers, cellulose-based polymers, and acrylic polymers.

7. The formulation of claim 6, wherein, The polymer is an ethylene-based polymer, which is selected from one or more of the following groups: copolyvinylpyrrolidone, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol-polyethylene glycol-graft copolymer, polyvinyl acetal diethylaminoacetate, a mixture of fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose, and polyvinyl acetal diethylaminoacetate.

8. The formulation of claim 7, wherein, The ethylene-based polymer is a copolyvinyl ketone.

9. The formulation of claim 6, wherein, The polymer is a cellulose-based polymer, which is selected from one or more of the following groups: hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, phthalate, methyl cellulose, methyl hydroxyethyl cellulose, carboxymethyl ethyl cellulose, ethyl cellulose, crystalline cellulose, microcrystalline cellulose, crystalline cellulose-sodium carboxymethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, powdered cellulose, and a mixture of fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methyl cellulose.

10. The formulation of claim 6, wherein, The polymer is an acrylic polymer, which is selected from one or more of the group consisting of methacrylic acid copolymer L, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, and 2-methyl-5-vinylpyridine acrylate-methyl methacrylate copolymer.

11. The formulation of claim 1, wherein, The active ingredient is a compound represented by formula (I), its pharmaceutically permissible salt, or a crystallization of their solvates.

12. The formulation of claim 11, wherein, The active ingredient is an anhydrous crystal of the compound represented by formula (I).

13. The formulation according to any one of claims 1 to 12, further comprising a disintegrant, an excipient, and / or a lubricant.

14. The formulation of claim 13, wherein, The disintegrant is selected from one or more of the following groups: croscarmellose sodium, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, powdered cellulose, partially α-substituted starch, potato starch, corn starch, hydroxypropyl starch, sodium carboxymethyl starch, low-substituted sodium carboxymethyl starch, sodium starch glycolate, α-substituted starch, starch, polyvinyl alcohol, and croscarmellose.

15. The formulation of claim 14, wherein, The disintegrant is croscarmellose sodium.

16. The formulation of claim 14, wherein, The disintegrant is crospovidone.

17. The formulation according to any one of claims 13 to 16, wherein, The excipients are selected from crystalline cellulose, silica-treated crystalline cellulose, lactose, anhydrous lactose, white sugar, glucose, fructose, sucrose, mannitol, sorbitol, erythritol, xylitol, powdered maltose maltose, maltitol, starch, potato starch, corn starch, rice starch, partially α-starch, α-starch, porous starch, sodium carboxymethyl starch, hydroxypropyl starch, sodium low-substituted carboxymethyl starch, powdered cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl ethyl cellulose, and low-substituted... One or more of the following groups: hydroxypropyl cellulose, silicate derivatives, phosphates, carbonates, sulfates, magnesium oxide, titanium oxide, calcium lactate, synthetic hydrotalcite, talc, kaolin, dried aluminum hydroxide, magnesium oxide, bentonite, hydrated silica, light anhydrous silica, magnesium aluminum silicate, synthetic aluminum silicate, calcium silicate, anhydrous calcium hydrogen phosphate, calcium monohydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, dipotassium phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, precipitated calcium carbonate, calcium carbonate, magnesium carbonate, and calcium sulfate.

18. The formulation according to any one of claims 13 to 17, wherein, The lubricant is selected from one or more of the following groups: sodium stearate fumarate, magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, stearic acid-40-polyhydroxy ester, talc, light anhydrous silica, hydrated silica, magnesium carbonate, precipitated calcium carbonate, dried aluminum hydroxide gel, magnesium aluminum silicate, magnesium silicate, synthetic aluminum silicate, magnesium oxide, magnesium sulfate, cocoa butter, carnauba wax, glycerol fatty acid ester, hydrogenated oil, white beeswax, hydrogenated soybean oil, beeswax, cetyl alcohol, sodium laurate, sucrose fatty acid ester, and polyethylene glycol.

19. The formulation according to any one of claims 1 to 18, having a coating layer.

20. The formulation of claim 19, wherein the coating layer contains a light stabilizer and a polymer.

21. The formulation of claim 20, wherein, The light-stabilizing substance in the coating layer is selected from one or more of the following groups: Edible Red No. 2, Edible Red No. 3, Edible Red No. 102, Edible Red No. 104, Edible Red No. 105, Edible Red No. 106, Edible Yellow No. 4, Edible Yellow No. 5, Edible Green No. 3, Edible Blue No. 1, Edible Blue No. 2, Edible Red No. 3 Aluminum Lake, Edible Yellow No. 4 Aluminum Lake, Edible Yellow No. 5 Aluminum Lake, Edible Blue No. 1 Aluminum Lake, Edible Blue No. 2 Aluminum Lake, Carmine, Sodium Copper Chloride, Copper Chloride, Iron Oxide Red, Iron Oxide Black, Iron Oxide Yellow, Titanium Oxide, Ferric Oxide, Yellow Ferric Oxide, and Talc.

22. The formulation of claim 21, wherein, The light stabilizer is ferric oxide, yellow ferric oxide, and / or talc.

23. The formulation according to any one of claims 20 to 22, wherein, The polymer in the coating layer is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, ethyl cellulose and polyvinyl alcohol.

24. The formulation of claim 23, wherein, The polymer in the coating is hydroxypropyl methylcellulose.

25. The formulation according to any one of claims 1 to 24, wherein, The formulation is an oral preparation.

26. The formulation of claim 25, wherein, The preparations are tablets, granules, powders, or capsules.

27. The formulation of claim 11, wherein, The active ingredient is the ethyl acetate compound crystal of the compound represented by formula (I).

28. The formulation of claim 27, wherein it is a capsule.

29. An amorphous form of a compound, said compound being represented by formula (I): [Chemical Formula 2] 。 30. Crystallization of an ethyl acetate compound, said compound being represented by formula (I): [Chemical Formula 3] 。

Images