A DRUG CONTAINING A URACIL DERIVATIVE

Abstract

The present invention provides a preparation (pharmaceutical composition) containing, as an active ingredient, a uracil derivative exhibiting coronavirus 3 CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a solvate thereof. The present invention also provides crystals of a uracil derivative exhibiting coronavirus 3 CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a solvate thereof.

Description

Preparations containing uracil derivatives

[0001] The present invention relates to a formulation containing a uracil derivative. More specifically, the present invention relates to a formulation containing a uracil derivative exhibiting coronavirus 3 CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a solvate thereof. The present invention also relates to a solid state (crystalline and amorphous) of a uracil derivative exhibiting coronavirus 3 CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0002] Coronaviruses, which belong to the Orthocoronavirus subfamily of the Coronaviridae family of the Nidovirales order, have a genome size of approximately 30 kilobases and are among the largest single-stranded positive-strand RNA viruses known. Coronaviruses are classified into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. Seven types of coronaviruses that infect humans are known: two types in the Alphacoronavirus genus (HCoV-229E and HCoV-NL63) and five types in the Betacoronavirus genus (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, and SARS-CoV-2). Of these, four (HCoV-229E, HCoV-NL63, HCoV-HKU1, and HCoV-OC43) are pathogens that cause the common cold, while the remaining three are severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV), and novel coronavirus (SARS-CoV-2), which cause severe pneumonia.

[0003] The novel coronavirus disease (COVID-19) that emerged in December 2019 rapidly spread internationally, and on March 11, 2020, the WHO declared it a pandemic. The main routes of SARS-CoV-2 transmission have been reported to be droplet, contact, and aerosol transmission, and it has been confirmed that SARS-CoV-2 remains airborne with aerosols for approximately three hours, maintaining its infectiousness (Non-Patent Document 1). The incubation period is approximately two to 14 days, and typical symptoms include cold-like symptoms such as fever (87.9%), dry cough (67.7%), fatigue (38.1%), and phlegm (33.4%) (Non-Patent Document 2). In severe cases, respiratory failure due to acute respiratory distress syndrome, acute lung injury, and interstitial pneumonia occurs. Multiple organ failure, including renal and liver failure, has also been reported.

[0004] When coronaviruses infect cells, they synthesize two polyproteins. These two polyproteins contain the replication complex that creates the viral genome and two proteases. Proteases cleave the polyproteins synthesized by the virus, playing an essential role in enabling each protein to function. Of the two proteases, the 3CL protease (main protease) is responsible for most of the polyprotein cleavage (Non-Patent Document 3). Compounds with various chemical structures are known as active ingredients in COVID-19 therapeutics that target the 3CL protease, but their chemical structures differ from those of the compounds used in the present invention.

[0005] Compounds having 3CL protease inhibitory activity are disclosed in Patent Documents 1 to 4 and Non-Patent Documents 4 to 14, but none of these documents describe or suggest the compounds to be used in the present invention.

[0006] International Publication No. 2021 / 205298 International Publication No. 2021 / 250648 International Publication No. 2022 / 138987 International Publication No. 2022 / 138988

[0007] The New England Journal of Medicine (2020), Vol. 382, ​​pp. 1564-1567, "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> Science (2003), Vol. 300, pp. 1763-1767 "A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19", Journal of Virology, 2021 Mar 10; 95(7), e01819-20 Cell Research (2020), Vol. 30, pp. 678-692 Science (2020), Vol. 368, pp. 409-412 ACS Central Science (2021), Vol. 7, No. 3, pp. 467-475 261st Am Chem Soc (ACS) Natl Meet ・ 2021-04-05 / 2021-04-16 ・ Virtual, N / A ・ Abst 243Science (2021), Vol. 374, pp. 1586-1593 "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>Molecules (2020), Vol. 25, p. 3193Molecules (2020), Vol. 25, p. 3920European Journal of Medicinal Chemistry (2020), Vol. 206, p. 112711Journal of the American Chemical Society (2022), Vol. 144, p. 2905-2920.

[0008] An object of the present invention is to provide a preparation containing, as an active ingredient, a uracil derivative exhibiting coronavirus 3CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a solvate thereof. Preferably, the present invention is to provide an oral preparation containing a uracil derivative exhibiting antiviral activity, particularly coronavirus growth inhibitory activity, a pharmaceutically acceptable salt thereof, or a solvate thereof. Another object of the present invention is to provide a solid state (crystalline and amorphous) of a uracil derivative exhibiting coronavirus 3CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0009] The present invention relates to the following: (1) A compound of formula (I): (2) The formulation according to (1) above, wherein the active ingredient is an amorphous compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. (3) The formulation according to (2) above, wherein the active ingredient is an amorphous compound represented by formula (I). (4) The formulation according to (3) above, wherein the amorphous compound represented by formula (I) is contained in a solid dispersion. (5) The formulation according to (4) above, wherein the solid dispersion further contains a polymer. (6) The formulation according to (5) above, wherein the polymer is one or more selected from vinyl-based polymers, cellulose-based polymers, and acrylic acid-based polymers. (7) The formulation according to (6) above, wherein the polymer is a vinyl polymer, and the vinyl polymer is one or more selected from the group consisting of copovidone, polyvinylpyrrolidone, polyvinylpolypyrrolidone, 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, and hydroxypropyl methylcellulose, and polyvinyl acetal diethylaminoacetate. (8) The formulation according to (7) above, wherein the vinyl polymer is copovidone. (9) The formulation according to (6) above, wherein the polymer is a cellulose-based polymer, and the cellulose-based polymer is one or more selected from the group consisting of hypromellose acetate succinate, hypromellose phthalate, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, phthalate, methylcellulose, methylhydroxyethyl cellulose, carboxymethylethyl cellulose, ethyl cellulose, crystalline cellulose, microcrystalline cellulose, crystalline cellulose-carmellose sodium, carmellose, carmellose sodium, carmellose calcium, powdered cellulose, and a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose.(10) The formulation according to (6) above, wherein the polymer is an acrylic acid-based polymer, and the acrylic acid-based polymer is one or more selected from 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, ammonia alkyl methacrylate copolymer, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, and 2-methyl-5-vinylpyridine methyl acrylate-methacrylic acid copolymer. (11) The formulation according to (1) above, wherein the active ingredient is a crystal of the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. (12) The formulation according to (11) above, wherein the active ingredient is an anhydrous crystal of the compound represented by formula (I). (13) The formulation according to any of (1) to (12) above, further comprising a disintegrant, an excipient, and / or a lubricant. (14) The formulation according to (13) above, wherein the disintegrant is one or more selected from the group consisting of croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, powdered cellulose, partially pregelatinized starch, potato starch, corn starch, hydroxypropyl starch, sodium carboxymethyl starch, low-substituted sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, starch, polyvinyl alcohol, and crospovidone. (15) The formulation according to (14) above, wherein the disintegrant is croscarmellose sodium. (16) The formulation according to (14) above, wherein the disintegrant is crospovidone.(17) The excipient is selected from the group consisting of crystalline cellulose, silicic acid-treated crystalline cellulose, lactose, anhydrous lactose, sucrose, glucose, fructose, sucrose, mannitol, sorbitol, erythritol, xylitol, powdered maltose syrup, maltitol, starch, potato starch, corn starch, rice starch, partially pregelatinized starch, pregelatinized starch, porous starch, sodium carboxystarch, hydroxypropyl starch, low-substituted sodium carboxymethyl starch, powdered cellulose, carmellose sodium, carmellose, carmellose calcium, carboxymethylethyl cellulose, low-substituted hydroxypropyl cellulose, silicate derivatives, and phosphates. , carbonate, sulfate, magnesium oxide, titanium oxide, calcium lactate, synthetic hydrotalcite, talc, kaolin, dried aluminum hydroxide, magnesium oxide, bentonite, hydrous silicon dioxide, silicon dioxide such as light anhydrous silicic acid, magnesium aluminometasilicate, 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 preparation according to any one of (13) to (17), wherein the lubricant is one or more selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, polyoxyl 40 stearate, talc, light anhydrous silicic acid, hydrous silicon dioxide, magnesium carbonate, precipitated calcium carbonate, dried aluminum hydroxide gel, magnesium aluminometasilicate, magnesium silicate, synthetic aluminum silicate, magnesium oxide, magnesium sulfate, cocoa butter, carnauba wax, glycerin fatty acid ester, hydrogenated oil, white beeswax, hydrogenated soybean oil, beeswax, cetanol, sodium laurate, sucrose fatty acid ester, and polyethylene glycol (macrogol). (19) The preparation according to any one of (1) to (18), which has a coating layer.(20) The preparation according to (19) above, wherein the coating layer contains a photostabilizer and a polymer. (21) The preparation according to (20) above, wherein the photostabilizer in the coating layer is one or more selected from the group consisting of Food Red No. 2, Food Red No. 3, Food Red No. 102, Food Red No. 104, Food Red No. 105, Food Red No. 106, Food Yellow No. 4, Food Yellow No. 5, Food Green No. 3, Food Blue No. 1, Food Blue No. 2, Food Red No. 3 Aluminum Lake, Food Yellow No. 4 Aluminum Lake, Food Yellow No. 5 Aluminum Lake, Food Blue No. 1 Aluminum Lake, Food Blue No. 2 Aluminum Lake, carmine, sodium copper chlorophyllin, copper chlorophyll, red iron oxide, black iron oxide, yellow iron oxide, titanium oxide, red iron sesquioxide, yellow iron sesquioxide, and talc. (22) The formulation according to (21) above, wherein the photostabilizer is ferric oxide, yellow ferric oxide, and / or talc. (23) The formulation according to any one of (20) to (22) above, wherein the polymer in the coating layer is one or more selected from hypromellose, hydroxypropyl cellulose, carboxymethylethyl cellulose, hypromellose phthalate, hydroxypropyl methylcellulose acetate succinate, ethyl cellulose, and polyvinyl alcohol. (24) The formulation according to (23) above, wherein the polymer in the coating layer is hypromellose. (25) The formulation according to any one of (1) to (24) above, wherein the formulation is an oral formulation. (26) The formulation according to (25) above, wherein the formulation is in the form of a tablet, granule, powder, or capsule. (27) The formulation according to (11) above, wherein the active ingredient is an ethyl acetate solvate crystal of the compound represented by formula (I). (28) The formulation according to (27) above, wherein the formulation is in the form of a capsule. (29) Formula (I): (30) Amorphous compound represented by formula (I): (31) A crystal of an ethyl acetate solvate of the compound represented by formula (I): and a polymer. (32) The solid dispersion according to (31) above, wherein the polymer is one or more selected from the group consisting of vinyl polymers, cellulose polymers, and acrylic polymers. (33) A solid dispersion according to (32), wherein the polymer is a vinyl polymer, and the vinyl polymer is one or more selected from the group consisting of copovidone (polyvinylpyrrolidone-vinyl acetate copolymer, PVPVA), polyvinylpyrrolidone (povidone), polyvinylpolypyrrolidone, 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, and hydroxypropyl methylcellulose, and a poly(vinyl acetal diethylaminoacetate). The solid dispersion according to (32) above, wherein the vinyl polymer is one or more selected from the group consisting of vinyl acetal diethylaminoacetate. (34) The solid dispersion according to (33) above, wherein the vinyl polymer is copovidone. (35) The solid dispersion according to (34) above, wherein the weight ratio of the compound represented by formula (I) to copovidone is 1:3. (36) The formulation according to (25) above, comprising 20.0 mg of the compound represented by formula (I) as an active ingredient. (37) The ethyl acetate solvate crystal according to (30) above, having 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. (38) The ethyl acetate solvate crystal according to (30) above, having peaks at diffraction angles (2θ): 421.2 cm －１ ±2cm －１ , 509.7 cm －１ ±2cm －１ , 1585.3 cm －１ ±2cm －１ , 1709.9 cm －１ ±2cm －１ and 3052.9 cm －１ ±2cm －１(39) The formulation according to (17) above, wherein the excipient is crystalline cellulose and / or mannitol. (40) The formulation according to any one of (18) above, wherein the lubricant is sodium stearyl fumarate and / or light anhydrous silicic acid.

[0010] The preparation according to the present invention has inhibitory activity against coronavirus 3 CL protease and is useful as a therapeutic and / or preventive agent for coronavirus infection. Furthermore, the solid state (crystalline and amorphous) according to the present invention has inhibitory activity against coronavirus 3 CL protease and is useful as a pharmaceutical ingredient for a therapeutic and / or preventive agent for coronavirus infection.

[0011] 1 shows the powder X-ray diffraction pattern of the anhydrous crystal of the compound represented by formula (I). The horizontal axis represents 2θ (°), and the vertical axis represents intensity. A peak list for the powder X-ray diffraction pattern of FIG. 1 is shown. In the table, "Position" represents 2θ (°), and "Intensity" represents intensity. The crystal structure (structure in the asymmetric unit) of the anhydrous crystal of the compound represented by formula (I) is shown. The results of differential scanning calorimetry (DSC) of the anhydrous crystal of the compound represented by formula (I) are shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat quantity (W / g). The results of simultaneous differential thermal and thermogravimetric analysis (TG / DTA) of the anhydrous crystal of the compound represented by formula (I) are shown. The vertical axis represents heat quantity (μV) or weight change (%), and the horizontal axis represents temperature (°C). Cel in the figure means degrees Celsius (°C). The Raman spectrum of the anhydrous crystal of the compound represented by formula (I) is shown. The horizontal axis is the Raman shift (cm －１) and the vertical axis represents peak intensity. Figure 1 shows the particle size distribution of the anhydrous crystals of the compound represented by formula (I) before pulverization used in Example 2A. Figure 2 shows the particle size distribution of the anhydrous crystals of the compound represented by formula (I) after pulverization obtained in Example 2A. Figure 3 shows the NMR of the ethyl acetate solvate crystals 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. Figure 4 shows the powder X-ray diffraction pattern of the ethyl acetate solvate crystals of the compound represented by formula (I). The horizontal axis represents 2θ (°), and the vertical axis represents intensity (Count). Figure 5 shows a peak list of the powder X-ray diffraction pattern of Figure 10. In the table, Position represents 2θ (°), and Intensity represents intensity. Figure 6 shows the Raman spectrum of the ethyl acetate solvate crystals of the compound represented by formula (I). The horizontal axis represents the Raman shift (cm －１) and the vertical axis represents peak intensity. The figure shows the results of simultaneous differential thermal analysis and thermogravimetry (TG / DTA) of the ethyl acetate solvate crystals of the compound represented by formula (I). The vertical axis represents heat quantity (μV) or weight change (%), and the horizontal axis represents temperature (°C). Cel in the figure means degrees Celsius (°C). The figure shows the particle size distribution of the ethyl acetate solvate crystals of the compound represented by formula (I) before pulverization used in Example 3E. The figure shows the particle size distribution of the ethyl acetate solvate crystals of the compound represented by formula (I) after pulverization obtained in Example 3E. The figure shows a chromatogram obtained by liquid chromatography of the anhydrous crystals of the compound represented by formula (I) (particle size distribution D10: 0.86 μm, D50: 3.29 μm, D90: 10.15 μm). The figure shows the powder X-ray diffraction pattern of the solid dispersion of Example 4B-1 (a solid dispersion comprising the compound represented by formula (I) and copovidone). The horizontal axis represents 2θ (°), and the vertical axis represents intensity. The four patterns, from top to bottom, are obtained after one week of storage in a capped glass bottle at 60°C, one week of storage in a capped glass bottle at 40°C and 75% relative humidity, one week of storage in an opened glass bottle at 40°C and 75% relative humidity, and one week of storage immediately after preparation. This figure shows the powder X-ray diffraction pattern of the solid dispersion of Example 4B-2 (a solid dispersion consisting of the compound of formula (I) and hypromellose acetate succinate (grade MF)). The horizontal axis represents 2θ (°), and the vertical axis represents intensity. The four patterns, from top to bottom, are obtained after one week of storage in a capped glass bottle at 60°C, one week of storage in a capped glass bottle at 40°C and 75% relative humidity, one week of storage in an opened glass bottle at 40°C and 75% relative humidity, and one week of storage in an opened glass bottle at 40°C and 75% relative humidity, and one week of storage immediately after preparation.

[0033] Figure 1 shows the powder X-ray diffraction pattern of the solid dispersion of Example 4B-3 (a solid dispersion comprising the compound of formula (I) and povidone). The horizontal axis represents 2θ (°), and the vertical axis represents intensity. The four patterns, from top to bottom, are those obtained after storage in a capped glass bottle at 60°C for one week, after storage in a capped glass bottle at 40°C and 75% relative humidity for one week, after storage in an opened glass bottle at 40°C and 75% relative humidity for one week, and immediately after preparation.

[0034] Figure 1 shows the powder X-ray diffraction pattern of the solid dispersion of Example 4B-4 (a solid dispersion comprising the compound of formula (I) and hypromellose acetate succinate (grade LF)). The horizontal axis represents 2θ (°), and the vertical axis represents intensity.The four patterns, from top to bottom, are after one week of storage in a 60°C environment with the glass bottle capped, one week of storage in a 40°C environment with a 75% relative humidity environment with the glass bottle capped, one week of storage in an open glass bottle with a 40°C environment with a 75% relative humidity environment with the glass bottle capped, and immediately after preparation. The dissolution behavior of Example 5C-1 (plain tablet) and Example 5D-1 (suspension) is shown. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%). For the tablet of Example 5E-1, the dissolution behavior is shown at the start of the test, after one month of storage in a 40°C environment with a 75% relative humidity environment with the polyethylene bottle capped, and after three months of storage in a 40°C environment with a 75% relative humidity environment with the polyethylene bottle capped. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%). For the tablet of Example 6B-1, the dissolution behavior is shown at the start of the test, after two weeks of storage in a 60°C brown glass bottle capped, after one month of storage in a 40°C brown glass bottle capped, and after one month of storage in a 40°C brown glass bottle with a 75% relative humidity environment with the brown glass bottle capped. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%). For the tablets of Example 6B-2, the dissolution behavior at the start of the test, after two weeks of storage at 60°C in a stoppered brown glass bottle, one month of storage at 40°C in a stoppered brown glass bottle, and one month of storage at 40°C in a stoppered brown glass bottle at 75% relative humidity, is shown. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%). For the tablets of Example 6C-1, the dissolution behavior at the start of the test, after one week of storage at 60°C in a stoppered brown glass bottle, and one week of storage at 40°C in a stoppered brown glass bottle at 75% relative humidity, is shown. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%). For the tablets of Example 6C-2, the dissolution behavior at the start of the test, after one week of storage at 60°C in a stoppered brown glass bottle, and one week of storage at 40°C in a stoppered brown glass bottle at 75% relative humidity, is shown. The dissolution profile of the solution formulation of Example 8-1 is shown. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%). The dissolution profiles of the capsules of Examples 9C-1, 9C-2, 9C-3, and 9C-4 are shown. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%). The dissolution profiles of the capsules of Examples 10-1 and 10-2 are shown. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%). The dissolution profiles of the solution formulations of Examples 11-1, 11-2, and 11-3, stored in a heated environment at 5°C for 3 days, are shown. The horizontal axis represents time (minutes), and the vertical axis represents dissolution rate (%).

[0012] The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The terms "comprise" and "include" mean that the term is not limited to the constituent elements and does not exclude unrecited elements. The present invention will be described below with reference to exemplary embodiments. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to have the meaning commonly used in the art unless otherwise specified. 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 belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0013] Unless otherwise stated, numerical values ​​in this specification and claims are approximate and variations in numerical values ​​are due to instrument calibration, instrument error, purity of material, crystal size, sample size, temperature, and other factors.

[0014] Formula (I): is compound (I-077) described in WO 2023 / 195529 and WO 2023 / 195530, and can be produced by the synthesis methods described in Examples 5 and 6 of these publications. Furthermore, it is described in these publications that the compound represented by formula (I) has a coronavirus 3 CL protease inhibitory activity and inhibits coronavirus 3 CL protease. In this specification, the compound represented by formula (I) may also be referred to as compound (I).

[0015] The compound represented by formula (I) is not limited to a particular isomer, and includes all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, etc.), racemates, or mixtures thereof.

[0016] One or more hydrogen, carbon and / or other atoms of the compounds of formula (I) may be replaced with isotopes of the respective hydrogen, carbon and / or other atoms. Examples of such isotopes include, but are not limited to, 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 The isotope-substituted compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as Cl. The compounds of formula (I) also include compounds substituted with such isotopes (e.g., deuterium-substituted compounds, etc.). The isotope-substituted compounds are also useful as pharmaceuticals. The compounds of formula (I) include all radiolabeled compounds substituted with radioisotopes contained in the isotopes. Also included in the present invention is a "radiolabeling method" for producing the "radiolabeled compounds," and the "radiolabeled compounds" are useful as research and / or diagnostic tools in metabolism pharmacokinetic studies and binding assays.

[0017] Radiolabeled compounds of formula (I) can be prepared by methods well 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) via catalytic dehalogenation using tritium. This method involves reacting a precursor of a compound of formula (I) in which the appropriate halogen is substituted with tritium gas in the presence of a suitable catalyst, such as Pd / C, with or without 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 are １４ It can be prepared by using a raw material having C carbon.

[0018] The compound of formula (I) used herein may form a prodrug, and the present invention also encompasses such various prodrugs. Prodrugs are derivatives of the compounds of the present invention having a chemically or metabolically decomposable group, and are compounds that become pharmaceutically active compounds of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted to compounds of formula (I) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, and compounds that are converted to compounds of formula (I) by hydrolysis with gastric acid, etc. Methods for selecting and preparing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985." Prodrugs may themselves be active.

[0019] The compounds according to the present invention have inhibitory activity against coronavirus 3CL protease and are therefore useful as therapeutic and / or preventive agents for diseases associated with coronavirus 3CL protease. In the present invention, the term "therapeutic and / or preventive agent" also encompasses symptom-ameliorating agents. Diseases associated with coronavirus 3CL protease include viral infections, preferably coronavirus infections. Examples of coronavirus infections include infections caused by HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV, and / or SARS-CoV-2. Examples of coronavirus infections include infections caused by HCoV-229E, HCoV-OC43, and / or SARS-CoV-2, with SARS-CoV-2 being particularly preferred. Examples of coronavirus infections include novel coronavirus infection (COVID-19).

[0020] As used herein, the "compound represented by formula (I)" may form a salt, a cocrystal, or a solvate thereof. As used herein, the "compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof" also encompasses such various salts, cocrystals, and solvates thereof.

[0021] The term "salt" as used herein means, for example, that a "compound represented by formula (I)" and a counter molecule are regularly arranged in the same crystal lattice, and may contain any number of counter molecules. This refers to a salt formed via an ionic bond by proton transfer between the compound and the counter molecule in the crystal lattice.

[0022] As used herein, the term "cocrystal" refers to a compound in which counter molecules (co-former molecules) are regularly arranged within the same crystal lattice, and may contain any number of counter molecules (co-former molecules). A cocrystal also refers to a compound in which the intermolecular interaction between the compound and the counter molecules (co-former molecules) is mediated by non-covalent, non-ionic chemical interactions such as hydrogen bonding or van der Waals forces.

[0023] Generally, salts are considered to be those in which proton transfer occurs between a compound and a counter molecule; however, it is known that in some cases, proton transfer may not be complete. This state is sometimes called a cocrystal because it is not a true salt. It is also known that proton transfer may change continuously depending on temperature. Therefore, as used herein, "a pharmaceutically acceptable salt of a compound represented by formula (I)" includes cocrystals and refers to a pharmaceutically acceptable salt or cocrystal of a compound represented by formula (I).

[0024] One embodiment herein is a pharmaceutically acceptable salt or co-crystal of a compound represented by formula (I) with hydrofluoric acid, hydrochloric acid, hydrobromic acid, orthophosphoric acid, hydroiodic acid, nitric acid, phosphoric acid, boric acid, sulfuric acid, methanesulfonic acid, 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, glycerophosphoric acid, tartaric acid, benzoic acid, glutamic acid, aspartic acid, 2-naphthalenesulfonic acid, hexanoic acid, acetylsalicylic acid, or the like.

[0025] The study of salt and co-crystal formation provides a means to modify the physicochemical and resulting biological characteristics of a drug without altering its chemical structure. Salt and co-crystal formation can dramatically affect the properties of a drug. Hygroscopicity, stability, solubility, and processing characteristics are also important considerations in selecting an appropriate salt or co-crystal. The solubility of a salt or co-crystal can affect its suitability for use as a drug. If aqueous solubility is low, the dissolution rate upon in vivo administration may be rate-limited by the absorption process, resulting in low bioavailability. In addition, low water solubility can make administration by injection difficult, limiting the selection of an appropriate administration route.

[0026] The "compound represented by formula (I)" can form a solvate with water (i.e., a hydrate) or a solvate with common organic solvents. The "pharmaceutically acceptable salt of the compound represented by formula (I)" can form a solvate with water (i.e., a hydrate) or a solvate with common organic solvents.

[0027] The term "solvate" as used herein refers to, for example, a compound of formula (I) in which any number of solvent molecules are regularly arranged. 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, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-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, pentane, pentane-1-one, pentane-2-one ... Examples of suitable solvents include ethanol, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, 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, tetralin, toluene, 1,1,2-trichloroethene, xylene, and t-butanol.Preferred examples include ethyl acetate, water, ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-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. More preferred are ethyl acetate, water, ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid, and trifluoroacetic acid. Ethyl acetate is the most preferred. Furthermore, when the "compound represented by formula (I)" is left in the air, it may absorb moisture, resulting in the adhesion of adsorbed water or the formation of a hydrate.

[0028] One embodiment herein is an "ethyl acetate solvate of the compound represented by formula (I)." For example, the solvate contains about 1 molar equivalent of ethyl acetate molecules relative to the "compound represented by formula (I)."

[0029] The present invention relates to the solid state (crystalline and amorphous) of the compound represented by formula (I), its pharmaceutically acceptable salt, or a solvate thereof. The solid state may be either a single state or a mixed state. The crystal may be either a single-phase crystal or a mixed crystal.

[0030] A pharmaceutically active ingredient may have substantially different physical properties depending on the solid state it is in. Such differences in physical properties have a significant impact on, for example, the bioavailability, purity, manufacturing method, pharmaceutical composition (formulation) containing the pharmaceutically active ingredient, or administration method of the pharmaceutically active ingredient (drug), so the selection of the solid state is extremely important in drug development.

[0031] The present invention provides an ethyl acetate solvate crystal of the compound represented by formula (I), an amorphous compound represented by formula (I), and a solid dispersion of the compound represented by formula (I), which are highly useful compared to other solid forms. The present invention also provides a formulation containing a solid dispersion of the compound represented by formula (I), a formulation containing an anhydrous crystal of the compound represented by formula (I), and a formulation containing an ethyl acetate solvate crystal of the compound represented by formula (I), which are highly useful compared to other pharmaceutical formulations. The solid forms and formulations have at least any of the following characteristics: (1) good stability against heat, humidity, solvents, light, etc., and high storage stability; (2) no significant coloration after light exposure; (3) good solubility in water or organic solvents; (4) rapid dissolution rate in water or organic solvents; (5) high purity; (6) low residual rate of organic solvents; (7) excellent operability in filtration, centrifugation, formulation, etc.; (8) small specific volume; and (9) resistance to electrostatic charge. (10) It can be produced in high yield under conditions with little environmental impact, and mass production is possible. (11) It is useful as a pharmaceutically active ingredient for oral agents, injections, etc., or as a bulk material for their production. (12) It can be controlled to a pH range suitable for intravenous injection without causing vascular pain, which is advantageous for controlling the liquid volume during formulation and reducing the amount of excipients used. (13) It has good fluidity. (14) It has a low compressibility (%).

[0032] As used herein, "crystal" refers to a solid in which constituent atoms, ions, molecules, etc. are regularly arranged three-dimensionally, and is distinguished from amorphous solids which do not have such a regular internal structure. As used herein, crystals may be single crystals, twin crystals, polycrystals, etc. Furthermore, "crystals" may have "crystalline polymorphs" which have the same composition but different arrangements within the crystal, and these are all referred to as "crystalline forms." "The compound represented by formula (I), its pharmaceutically acceptable salt, or a solvate thereof" encompasses these crystalline polymorphs. As used herein, crystals may be deuterium-converted forms. As used herein, crystals may be isotopes (e.g., ３ H. １４ C. ３５ S. １２５ The crystal form and / or crystallinity can be confirmed by spectroscopic methods such as X-ray diffraction, Raman spectroscopy, infrared absorption spectroscopy, solid-state NMR, etc. The physical properties of the crystals can also be confirmed by a number of techniques such as differential scanning calorimetry, moisture adsorption / desorption measurements, and dissolution characteristics.

[0033] One embodiment of the present specification is an anhydrous crystal of the compound represented by formula (I). As used herein, "anhydrous" is synonymous with "solvate-free," "nonsolvate," "anhydrate," and "nonhydrate." The theoretical content of water of crystallization in an anhydrous crystal of the compound represented by formula (I) is 0% by weight. However, in analyzing the amount of water and / or solvent, values ​​higher than the theoretical content of water of crystallization may be obtained due to the influence of water and / or solvent attached to the crystal surface.

[0034] One embodiment of the present specification is an anhydrous crystal of the compound represented by formula (I), which has 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 radiation, λ=1.5418 Å).

[0035] One embodiment of the present specification is an anhydrous crystal of the compound of formula (I), characterized by the following crystallographic data when single crystal structure analysis was performed using CuKα radiation (λ=1.5418 Å) at 298 K (25° C.): space group: Pbca a=14.67 ű0.05 Å b=11.83 ű0.05 Å c=27.10 ű0.05 Å α=90° β=90° γ=90°

[0036] One embodiment herein is an anhydrous crystalline form of the compound represented by formula (I), which has a melting point of 261.3°C ± 2°C as measured by differential scanning calorimetry (DSC). Another embodiment herein is an anhydrous crystalline form of the compound represented by formula (I), which has a melting point of 265.6°C ± 2°C as measured by simultaneous differential thermal analysis-thermogravimetry (TG / DTA).

[0037] One aspect of the present specification is a Raman spectrum of 415.2 cm －１ ±2cm －１ , 502.7 cm －１ ±2cm －１ , 1431.4 cm －１ ±2cm －１ , 1714.8 cm －１ ±2cm －１ and 3065.4 cm －１ ±2cm －１ The anhydrous crystals of the compound of formula (I) have characteristic peaks at

[0038] The D50 of the anhydrous crystals of the compound represented by formula (I) herein is, for example, 0.02 to 200 μm, preferably 0.1 to 150 μm, and more preferably 0.2 to 100 μm. The D90 of the anhydrous crystals of the compound represented by formula (I) herein is, for example, 0.05 to 300 μm, preferably 0.5 to 200 μm, and more preferably 1.0 to 150 μm. The D50 of the anhydrous crystals of the compound represented by formula (I) used in the formulations of the present invention is, for example, 0.02 to 20 μm, preferably 0.1 to 10 μm, and more preferably 0.2 to 8 μm. The D90 of the anhydrous crystals of the compound represented by formula (I) used in the formulations of the present invention is, for example, 0.05 to 40 μm, preferably 0.2 to 20 μm, and more preferably 0.5 to 16 μm. Depending on the type of formulation, particles of anhydrous crystals of the compound represented by formula (I) having a D50 of about 200 to 1500 nm can be used.

[0039] One embodiment of the present invention is an ethyl acetate solvate crystal of the compound represented by formula (I). For example, the crystal contains approximately 1 molar equivalent of ethyl acetate molecules relative to the compound represented by formula (I). Another embodiment of the present invention is an "ethyl acetate solvate crystal of the compound represented by formula (I)" consisting of 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 wt%. The ethyl acetate content of the "ethyl acetate solvate crystal of the compound represented by formula (I)" of the present invention is, for example, 4 to 20 wt%, preferably 9 to 18 wt%, and more preferably 12 to 16 wt%. Note that in the analysis of the ethyl acetate content, if the content is high due to the influence of water or ethyl acetate adhering to the crystal, some of the ethyl acetate in the crystal may be released before measurement, resulting in a lower content.

[0040] One embodiment of the present invention is an ethyl acetate solvate crystal of the compound represented by formula (I), which has 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 radiation, λ=1.5418 Å).

[0041] One embodiment of the present invention is an ethyl acetate solvate crystal of the compound represented by formula (I), which shows an endothermic peak at 129.5°C ± 2°C and a weight loss in simultaneous thermogravimetry-differential thermal analysis (TG / DTA).

[0042] One aspect of the present invention is a Raman spectrum showing a peak at 421.2 cm －１ ±2cm －１ , 509.7 cm －１ ±2cm －１ , 1585.3 cm －１ ±2cm －１ , 1709.9 cm －１ ±2cm －１ and 3052.9 cm －１ ±2cm －１ The compound of formula (I) is an ethyl acetate solvate crystal having a characteristic peak at 1000 nm.

[0043] The D50 of the ethyl acetate solvate crystals 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 solvate crystals 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. The D50 of the ethyl acetate solvate crystals of the compound represented by formula (I) used in the formulation of the present invention is, for example, 0.1 to 25 μm, preferably 0.5 to 10 μm, and more preferably 1 to 8 μm. The D90 of the ethyl acetate solvate crystals of the compound represented by formula (I) of the present invention used in the formulation of the present invention is, for example, 0.2 to 40 μm, preferably 1 to 20 μm, and more preferably 2 to 15 μm.

[0044] One embodiment herein is an amorphous form of the compound represented by formula (I).

[0045] As used herein, "amorphous" is synonymous with "amorphous solid," "amorphous," and "glass," and refers to a solid state that does not have a regular structure like a crystal. The constituent atoms, ions, molecules, etc. do not have a three-dimensionally ordered repeating period. As used herein, "amorphous" refers to a substantially 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 amorphous form. Furthermore, the crystallinity refers to, for example, 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. Amorphous solids do not have an ordered repeating period in their structure, so they do not exhibit diffraction phenomena and can be confirmed by powder X-ray diffraction measurement. The powder X-ray diffraction pattern of an amorphous solid is a featureless, broad XRPD pattern, also known as a halo pattern. Furthermore, because amorphous solids do not exhibit polarized light like crystals, they can be confirmed using a microscope or a digital microscope in a polarized observation mode. Alternatively, they can be confirmed by other techniques, such as spectroscopic methods such as Raman spectroscopy, infrared absorption spectroscopy, and solid-state NMR, and differential scanning calorimetry.

[0046] One aspect of the present invention is a solid dispersion of a compound represented by formula (I). Another aspect of the present invention is a solid dispersion of a compound represented by formula (I), wherein the compound represented by formula (I) is amorphous. Another aspect of the present invention is a solid dispersion of a compound represented by formula (I), which shows a halo pattern in powder X-ray diffraction measurement. Another aspect of the present invention is a solid dispersion containing a compound represented by formula (I) and a polymer.

[0047] As used herein, the term "solid dispersion" refers to a matrix containing a pharmaceutically active ingredient (drug) and a polymer. The term "solid dispersion" refers to a matrix in which the pharmaceutically active ingredient (drug) and a polymer are mixed and then solidified, resulting in a stable molecular dispersion of the amorphous pharmaceutically active ingredient (drug) in the polymer. Specifically, the term "solid dispersion" refers to a matrix in which the pharmaceutically active ingredient (drug) and a polymer are dissolved and mixed in a cosolvent, then solidified, resulting in a stable molecular dispersion of the amorphous pharmaceutically active ingredient (drug) in the polymer. Examples of production methods include spray drying (solvent removal), heat melting, and co-grinding (mechanochemical). For crystalline, poorly soluble drugs, solid dispersion can render the pharmaceutically active ingredient (drug) amorphous, thereby improving its solubility and dissolution rate.

[0048] As used herein, "improving solubility" means increasing the solubility of the compound represented by formula (I) in water, a buffer solution, etc. Specifically, for example, when a solid dispersion or a pharmaceutical composition (formulation) containing the solid dispersion is evaluated by a dissolution test, the solubility of the solid dispersion containing the compound represented by formula (I) (or compound (I) in the solid dispersion of the compound represented by formula (I)) is specified to be 1.5 times or more, in another embodiment 2 times or more, in yet another embodiment 5 times or more, and in a further embodiment 10 times or more of the solubility of compound (I) itself.

[0049] As used herein, the phrase "solid dispersion is stable" means that the compound of formula (I) in an amorphous state in the solid dispersion does not crystallize in a stability test over time of the solid dispersion.

[0050] The polymer used in the solid dispersion of the present invention may be any polymer that can be used pharmaceutical preparations, and may be a mixture of two or more types. Examples of such polymers include vinyl polymers, cellulose polymers, acrylic acid polymers, polyether polymers, etc. Preferred are vinyl polymers, cellulose polymers, and acrylic acid polymers, and more preferred are vinyl polymers.

[0051] Examples of vinyl polymers used in the solid dispersion of the present invention include copovidone (sometimes referred to herein as polyvinylpyrrolidone-vinyl acetate copolymer, PVPVA), polyvinylpyrrolidone (sometimes referred to herein as povidone), polyvinylpolypyrrolidone, 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, and hydroxypropyl methylcellulose, and polyvinyl acetal diethylaminoacetate. Preferred are copovidone and polyvinylpyrrolidone, and particularly preferred is copovidone.

[0052] One aspect of the present invention is a solid dispersion containing a compound of formula (I) and copovidone.

[0053] Examples of the cellulose-based polymer used in the solid dispersion of the present invention include hypromellose acetate succinate (sometimes referred to as hydroxypropyl methylcellulose acetate succinate in the present specification), hypromellose phthalate, hydroxypropyl cellulose (sometimes referred to as HPC in the present specification), low-substituted hydroxypropyl cellulose, hypromellose (sometimes referred to as hydroxypropyl methylcellulose, HPMC in the present specification), hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose phthalate, methylcellulose (sometimes referred to as MC in the present specification), methylhydroxyethyl cellulose, carboxymethylethyl cellulose, ethyl cellulose, crystalline cellulose, microcrystalline cellulose, crystalline cellulose-carmellose sodium, carmellose, carmellose sodium, carmellose calcium, powdered cellulose, and a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose. Preferred are hypromellose acetate succinate, hypromellose phthalate, and hydroxypropyl cellulose, and particularly preferred is hypromellose acetate succinate.

[0054] Examples of acrylic acid-based 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, ammonia alkyl methacrylate copolymer, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, 2-methyl-5-vinylpyridine methyl acrylate-methacrylic acid copolymer, etc. Methacrylic acid copolymer L is preferred.

[0055] In the solid dispersion of the present invention, the weight ratio of the "compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof" 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. One embodiment of the present invention is a solid dispersion in which the weight ratio of the compound represented by formula (I) to copovidone is 1:3.

[0056] The solid dispersion of the present invention can be produced by known methods. For example, the solid dispersion can be produced by dissolving and / or suspending the "compound represented by formula (I), its pharmaceutically acceptable salt, or solvate thereof" and a polymer in a pharmaceutically acceptable solvent, followed by distilling off the solvent. The solvent is not particularly limited as long as it is capable of maintaining the compound represented by formula (I) in an amorphous state in the presence of the polymer. Examples of such solvents include Class 3 solvents (solvents considered to be low in toxicity and low in risk to human health) in ICH-Q3C (Guideline for Residual Solvents in Pharmaceuticals). Specific examples include ketones such as acetone, alcohols such as methanol, ethanol, and propanol, methylene chloride, or mixed solvents of these with water. Acetone or a mixed solvent of acetone and ethanol is preferred, with acetone being more preferred. The amount of the solvent is not particularly limited as long as it is the amount necessary to maintain the compound represented by formula (I) in an amorphous state. The amount is, for example, 1 to 100 times (w / w), preferably 5 to 20 times (w / w), relative to the weight of the "compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof" and the polymer. The method for distilling off the solvent is not particularly limited as long as it is a method for distilling off the solvent, and examples thereof include spray drying, reduced pressure drying, and forced air drying.

[0057] The D50 of the solid dispersion of the compound represented by formula (I) of the present invention is, for example, 0.1 to 500 μm, preferably 0.5 to 200 μm, more preferably 1 to 100 μm. The powder X-ray diffraction pattern of the "solid dispersion of the compound represented by formula (I)" of the present invention exhibits a halo pattern.

[0058] The present invention relates to a preparation containing "a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof" as an active ingredient. The pharmaceutical composition of the present invention may contain 1 to 100 mg, preferably 5 to 50 mg, of the compound represented by formula (I). 20 to 40 mg is particularly preferred. Such preparations include, for example, oral preparations, parenteral preparations, preferably oral preparations, more preferably solid preparations for oral administration, and particularly preferably tablets, granules, powders, or capsules.

[0059] Oral preparations include solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.), liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, perfumes, extracts, decoctions, tinctures, etc.), etc. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets, powders and granules may be dry syrups, and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0060] Examples of parenteral preparations include injections, infusions, and topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, powders for topical use, suppositories, etc.) Injections may be emulsions such as O / W, W / O, O / W / O, and W / O / W types.

[0061] One aspect of the present invention is a preparation containing a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. The "preparation containing a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient" of the present invention can be produced by known methods. The preparation may contain pharmaceutically acceptable additives, such as disintegrants, excipients, lubricants, binders, coating agents, etc.

[0062] One embodiment of the present invention is a preparation containing a solid dispersion of the compound represented by formula (I) as an active ingredient. Another embodiment of the present invention is a preparation containing a solid dispersion containing the compound represented by formula (I) and copovidone as active ingredients. Another embodiment of the present invention is a preparation containing an anhydrous crystal of the compound represented by formula (I) as an active ingredient. Another embodiment of the present invention is a preparation containing an ethyl acetate solvate crystal of the compound represented by formula (I) as an active ingredient. Preferred forms of the preparation include solid preparations, and particularly preferred are granules, powders, capsules, and tablets.

[0063] The method for producing "granules containing the compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient" is not particularly limited, but specifically includes a method of mixing the "compound of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof" with additives such as a disintegrant and excipient to produce a mixed powder, and then granulating the mixed powder. Preferred methods include wet granulation, in which granulation is performed by adding water or water containing a binder or a solvent, or dry granulation or melt granulation, in which compression molding is performed without using water. A V-type mixer or container blender can be used as a machine for mixing the pharmaceutically active ingredient (drug), additives, etc. Furthermore, a wet extrusion granulator, a fluidized bed granulator, agitator granulator, a dry crusher granulator, or a melt extrusion granulator can be used as a machine for granulation.

[0064] The manufacturing method of "tablets containing the compound represented by formula (I), its pharmaceutically acceptable salt, or a solvate thereof as an active ingredient" is not particularly limited, but specifically, granules are manufactured by the above-mentioned method, and then excipients, disintegrants, lubricants, etc. are mixed with the granules, and the mixed granules are tableted using a tablet press; alternatively, a pharmaceutically active ingredient (drug), excipients, disintegrants, lubricants, etc. are mixed, and the mixture is tableted using a tablet press. A V-type mixer or container blender can be used as a machine for mixing the active ingredient, additives, etc. Furthermore, a single-punch tablet press, a rotary tablet press, etc. can be used as the tablet press.

[0065] Examples of the disintegrant include croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, crystalline cellulose, powdered cellulose, partially pregelatinized starch, potato starch, corn starch, hydroxypropyl starch, sodium carboxymethyl starch, low-substituted sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, starch, polyvinyl alcohol, crospovidone, etc. Preferred are croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, and crospovidone, and particularly preferred are croscarmellose sodium and crospovidone.

[0066] One embodiment of the present invention is a solid formulation containing a solid dispersion of the compound represented by formula (I) and croscarmellose sodium. Another embodiment of the present invention is a solid formulation containing a solid dispersion containing the compound represented by formula (I) and copovidone, and croscarmellose sodium. Another embodiment of the present invention is a solid formulation containing anhydrous crystals of the compound represented by formula (I) and crospovidone. Preferred forms of the solid formulation include granules, powders, capsules, and tablets, with tablets being particularly preferred.

[0067] Examples of such excipients include crystalline cellulose, silicic acid-treated crystalline cellulose, lactose, anhydrous lactose, sucrose, glucose, fructose, sucrose, mannitol, sorbitol, erythritol, xylitol, powdered maltose syrup, maltitol, starch, potato starch, corn starch (sometimes referred to as cornstarch in this specification), rice starch, partially pregelatinized starch, pregelatinized starch, porous starch, sodium carboxystarch, hydroxypropyl starch, low-substituted sodium carboxymethyl starch, powdered cellulose, carmellose sodium, carmellose, carmellose calcium, carboxymethylethyl cellulose, low-substituted hydroxypropyl cellulose, and the like. Examples of suitable cellulose derivatives include hydroxypropyl cellulose, silicate derivatives, phosphates, carbonates, sulfates, magnesium oxide, titanium oxide, calcium lactate, synthetic hydrotalcite, talc, kaolin, dried aluminum hydroxide, magnesium oxide, bentonite, hydrous silicon dioxide, silicon dioxide such as light anhydrous silicic acid, magnesium aluminometasilicate, 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, calcium sulfate, etc. Preferred are crystalline cellulose and / or mannitol.

[0068] One embodiment of the present invention is a solid formulation containing a solid dispersion of the compound represented by formula (I), croscarmellose sodium, microcrystalline cellulose, and mannitol. Another embodiment of the present invention is a solid formulation containing a solid dispersion containing the compound represented by formula (I) and copovidone, croscarmellose sodium, microcrystalline cellulose, and mannitol. Another embodiment of the present invention is a solid formulation containing anhydrous crystals of the compound represented by formula (I), crospovidone, and microcrystalline cellulose. Preferred forms of the solid formulation include granules, powders, capsules, and tablets, with tablets being particularly preferred.

[0069] Examples of the lubricant include sodium stearyl fumarate, light anhydrous silicic acid, magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, polyoxyl 40 stearate, talc, hydrated silicon dioxide, magnesium carbonate, precipitated calcium carbonate, dried aluminum hydroxide gel, magnesium aluminometasilicate, magnesium silicate, synthetic aluminum silicate, magnesium oxide, magnesium sulfate, cocoa butter, carnauba wax, glycerin 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. Preferred are sodium stearyl fumarate, light anhydrous silicic acid, magnesium stearate, and calcium stearate, and particularly preferred are sodium stearyl fumarate and / or light anhydrous silicic acid.

[0070] One embodiment of the present invention is a solid formulation containing a solid dispersion of the compound represented by formula (I), croscarmellose sodium, crystalline cellulose, mannitol, sodium stearyl fumarate, and light anhydrous silicic acid. Another embodiment of the present invention is a solid formulation containing a solid dispersion containing the compound represented by formula (I) and copovidone, croscarmellose sodium, crystalline cellulose, mannitol, sodium stearyl fumarate, and light anhydrous silicic acid. Another embodiment of the present invention is a solid formulation containing anhydrous crystals of the compound represented by formula (I), crospovidone, crystalline cellulose, and sodium stearyl fumarate. Preferred forms of the solid formulation include granules, powders, capsules, and tablets, with tablets being particularly preferred.

[0071] The "preparation containing the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient" of the present invention may contain a photostabilizer. One aspect of the present invention is a "preparation containing the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, and a photostabilizer."

[0072] The photostabilizer of the formulation of the present invention may be incorporated into the formulation or may coat the surface of the formulation. Preferably, the formulation contains the photostabilizer in a coating layer that coats the surface of the formulation. By including the photostabilizer 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.

[0073] The formulation of the present invention may have a coating layer, and the coating layer may contain a photostabilizing substance and a polymer. For the formulation of the present invention, after producing granules or tablets, the granules or tablets may be coated with a coating layer. The formulation of the present invention may be a coated tablet or coated granules. When forming a coating layer on granules, a fluidized bed granulation coating machine, a fluidized bed tumbling coating machine, or the like may be used. When forming a coating layer on tablets, a pan coating machine, an aerated coating machine, or the like may be used. While fluidizing the granules or tablets in the coating machine, the coating liquid is sprayed onto the granules or tablets, followed by drying, to form a coating layer.

[0074] One aspect of the present invention is a "solid formulation having a coating layer and containing, as an active ingredient, a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof." Another aspect of the present invention is a "solid formulation having a coating layer containing a photostabilizer and a polymer and containing, as an active ingredient, a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof." Preferred forms of the "compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof" include a solid dispersion of the compound represented by formula (I), an anhydrous crystal of the compound represented by formula (I), or an ethyl acetate solvate crystal of the compound represented by formula (I). Preferred forms of the solid formulation include granules, powders, capsules, and tablets, with tablets and capsules being particularly preferred.

[0075] Examples of light stabilizers include light-shielding substances with a light-shielding effect and light-absorbing substances with a light-absorbing effect. Examples include Food Red No. 2, Food Red No. 3, Food Red No. 102, Food Red No. 104, Food Red No. 105, Food Red No. 106, Food Yellow No. 4, Food Yellow No. 5, Food Green No. 3, Food Blue No. 1, Food Blue No. 2, Food Red No. 3 Aluminum Lake, Food Yellow No. 4 Aluminum Lake, Food Yellow No. 5 Aluminum Lake, Food Blue No. 1 Aluminum Lake, Food Blue No. 2 Aluminum Lake, carmine, copper chlorophyllin sodium, copper chlorophyll, red iron oxide, black iron oxide, yellow iron oxide, titanium oxide, iron sesquioxide, yellow iron sesquioxide, and talc. Preferably, the light stabilizer is iron sesquioxide, yellow iron sesquioxide, and / or talc.

[0076] Examples of the polymer in the coating layer include hypromellose, hydroxypropyl cellulose, carboxymethylethyl cellulose, hypromellose phthalate, hydroxypropylmethyl cellulose acetate succinate, ethyl cellulose, polyvinyl alcohol, etc. Hypromellose is preferred.

[0077] One embodiment of the present invention is a "solid preparation comprising, as an active ingredient, a solid dispersion of the compound represented by formula (I), which has a coating layer containing ferric oxide, yellow ferric oxide, and / or talc." Another embodiment of the present invention is a "solid preparation comprising, as an active ingredient, a solid dispersion of the compound represented by formula (I), which has a coating layer containing ferric oxide, yellow ferric oxide, talc, and hypromellose." Another embodiment of the present invention is a "solid preparation comprising, as an active ingredient, an anhydrous crystalline form of the compound represented by formula (I), which has a coating layer containing ferric oxide, yellow ferric oxide, and / or talc." Another embodiment of the present invention is a "solid preparation comprising, as an active ingredient, an anhydrous crystalline form of the compound represented by formula (I), which has a coating layer containing ferric oxide, yellow ferric oxide, talc, and hypromellose." Preferred forms of the solid preparation include granules, powders, capsules, and tablets, with tablets being particularly preferred.

[0078] The content of the coating layer in the solid preparation of the present invention is not particularly limited, but is 0.1 to 20 wt %, preferably 0.5 to 10 wt %, more preferably 1 to 8 wt %, based on the total weight of the preparation. When two or more types of coating layers are used, the total amount of the coating layers may be within the above content range.

[0079] The solid preparation of the present invention may contain a plasticizer together with the photostabilizer and the polymer, and plasticizers listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Standards for Pharmaceuticals Other Than the Japanese Pharmacopoeia, the Pharmaceutical Additives Standards, the Official Specification of Food Additives, etc. Examples of plasticizers include citric acid esters, glycerin fatty acid esters, surfactants, monostearin, diethyl phthalate, dibutyl phthalate, diethyl sebacate, dibutyl sebacate, etc.

[0080] One aspect of the present invention is a solid formulation containing an ethyl acetate solvate crystal of the compound of formula (I), croscarmellose sodium, mannitol, microcrystalline cellulose, and sodium stearyl fumarate. Preferred forms of the solid formulation include granules, powders, capsules, and tablets, with capsules being particularly preferred.

[0081] X-ray Powder Diffraction (XRPD) X-ray powder diffraction (XRPD) is one of the most sensitive analytical methods for measuring the crystalline form and crystallinity of solids. When X-rays are irradiated onto a crystal, they reflect off the crystal lattice planes and interfere with each other, producing ordered diffraction lines corresponding to the periodicity of the structure. On the other hand, amorphous solids generally do not have an ordered repeating period in their structure, and therefore do not exhibit diffraction phenomena, producing a featureless, broad XRPD pattern (also called a halo pattern).

[0082] As used herein, a characteristic diffraction peak is a peak selected from the observed diffraction pattern. The characteristic diffraction peak is preferably selected from about 10, more preferably about 5, peaks in the diffraction pattern. When distinguishing between multiple crystals, a peak that is confirmed in the crystal and not in other crystals is a preferred characteristic peak for identifying the crystal, rather than peak intensity. Even one or two such characteristic peaks can characterize the crystal. When the measured patterns are compared and the characteristic peaks match, it can be said that the powder X-ray diffraction patterns substantially match.

[0083] Generally, the diffraction angle (2θ) in powder X-ray diffraction can have an error within a range of ±0.2°, and therefore the value of the diffraction angle in powder X-ray diffraction should be understood to include values ​​within a range of about ±0.2°. Therefore, not only crystals in which the diffraction angles of peaks in powder X-ray diffraction perfectly match, but also crystals in which the diffraction angles of peaks match with an error of about ±0.2° are included in the present invention.

[0084] It is generally known that the intensities of the peaks displayed in the following figures may vary depending on many factors, such as the effect of preferred orientation of the crystal relative to the X-ray beam, the influence of large particles, the purity of the material being analyzed, or the crystallinity of the sample. Peak positions may also shift based on sample height variations. Furthermore, measurements using different wavelengths will result in different shifts according to the Bragg equation (nλ=2d sin θ), and other XRPD patterns obtained using such different wavelengths are also within the scope of the present invention.

[0085] Combining a powder X-ray diffractometer with a temperature and / or relative humidity control device allows powder X-ray diffraction measurements to be performed at a specific temperature and / or relative humidity. For example, in cases where anhydrous crystals change to hydrate crystals due to moisture absorption, where hydrate crystals change to anhydrous crystals due to dehydration, where solvate crystals transition to anhydrous crystals due to solvent desorption, or where anhydrous crystals and hydrate crystals change reversibly due to moisture absorption and dehydration, measurements at a specific temperature and / or relative humidity or measurements in which the temperature and / or relative humidity are continuously changed are suitable. In such cases, it is possible to estimate the relative humidity at which the change occurs and the amount of water of crystallization and / or crystallization solvent.

[0086] The crystalline form of the compound of formula (I) can be identified by the powder X-ray diffraction pattern and the diffraction angle (2θ) of a characteristic peak. The crystalline form of the compound of formula (I) (e.g., an anhydrous form of the compound of formula (I) and an ethyl acetate solvate crystal of the compound of formula (I)) can be distinguished from other crystalline forms by the presence of a characteristic peak.

[0087] (Simultaneous Powder X-ray Diffraction-Differential Scanning Calorimetry (XRD-DSC)) Simultaneous powder X-ray diffraction and differential scanning calorimetry (XRD-DSC) measurements allow simultaneous observation of changes in crystalline form (crystalline structure) and changes in calorific value with respect to temperature and / or relative humidity. For example, XRD-DSC measurements are suitable for observing changes in crystalline form (crystalline structure), such as when anhydrous crystals transition to hydrate crystals due to moisture absorption, when hydrate crystals transition to anhydrous crystals due to dehydration, when solvate crystals transition to anhydrous crystals due to solvent desorption, and when anhydrous crystals and hydrate crystals reversibly transition from one to the other due to moisture absorption and dehydration.

[0088] (Single Crystal Structure Analysis) Single crystal structure analysis is a method for identifying crystalline forms, and can obtain crystallographic parameters, atomic coordinates (values ​​indicating the spatial relationship of each atom), and a three-dimensional structural model. For single crystal structure analysis, see "X-Ray Structure Analysis Handbook" by Toshio Sakurai, published by Shokabo (1983), and "X-Ray Structure Determination: A Practical Guide" by Stout & Jensen, published by Macmillan Co., New York (1968). Single crystal structure analysis is useful for identifying the structures of optical isomers, tautomers, geometric isomers, salts, cocrystals, and solvates (hydrates). It is known that data quality improves when single crystal X-ray diffraction experiments are performed at low temperatures, so measurements are performed at room temperature or low temperatures depending on the crystal being measured. Furthermore, it is known that the quality of data obtained from single crystal X-ray diffraction experiments of hydrates and / or solvates can be improved by coating the crystals with paraffin oil or the like before measurement.

[0089] (Raman spectroscopy) Raman spectra show the vibrational characteristics of molecules or complex systems. Its origin is the inelastic collision between molecules and photons, which are light particles that comprise light rays. The collision between a molecule and a photon results in an exchange of energy, which changes the energy and thus the wavelength of the photon. In other words, Raman spectra are spectral lines with extremely narrow wavelengths that are emitted when a photon is incident on a molecule of interest, so a laser or the like is used as a light source. The wavelength of each Raman line is expressed by the wavenumber shift from the incident light, which is the difference between the reciprocal of the wavelength of the Raman line and that of the incident light. Raman spectra measure the vibrational state of a molecule, which is determined by its molecular structure. Generally, the amount of wavelength shift (cm) in a Raman spectrum is －１ ) is ±2cm －１ Since there may be an error within the range of ±2 cm －１ Therefore, it should be understood that the Raman spectrum includes not only crystals in which the Raman spectrum peaks completely coincide, but also crystals in which the Raman spectrum peaks are within ±2 cm. －１Crystals that match within a certain degree of error are also included in the present invention.

[0090] (Infrared Absorption Spectroscopy (IR Method)) Infrared absorption spectroscopy is a method for measuring the degree of absorption of infrared light at each wavenumber when it passes through a sample. An infrared absorption spectrum is typically shown as a graph with the wavenumber on the horizontal axis and the transmittance or absorbance on the vertical axis. The wavenumber and transmittance (or absorbance) of the absorption peak can be read on the graph, or values ​​calculated by a data processing device can be used. The infrared absorption spectrum is determined by the chemical structure of the substance. Therefore, a substance can be identified or quantified by measuring absorption at various wavenumbers. Crystal polymorphs can be identified by comparing the absorption bands of functional groups characteristic of the polymorph, i.e., functional groups primarily involved in hydrogen bonding in the crystal structure, such as C═O bonds, OH bonds, and NH bonds, as well as other characteristic functional groups, such as C—X (halogen) bonds, C═C bonds, and C≡C bonds. A selection is made from approximately 20 absorption peaks, more preferably approximately 10 absorption peaks, and most preferably approximately 5 absorption peaks, corresponding to characteristic functional groups. Typically, the absorption spectrum of a sample is measured at a wavenumber of 4000 cm －１ ~400cm －１ The absorption spectrum is measured under the same operating conditions as when the resolution, wavenumber scale, and wavenumber accuracy of the instrument were confirmed.

[0091] Generally, the absorption band (cm) in infrared absorption spectroscopy －１ ) is ±2cm －１ Since there may be an error within the range of ±2 cm －１ Therefore, it should be understood that the values ​​include not only crystals in which the absorption band peaks in infrared absorption spectroscopy are completely the same, but also crystals in which the absorption band peaks are within ±2 cm. －１ Crystals that match within a certain degree of error are also included in the present invention.

[0092] Infrared absorption spectrum measurement methods include the potassium bromide tablet method, solution method, paste method, liquid film method, thin film method, gas sample measurement method, ATR method, and diffuse reflectance method. Among these, ATR (attenuated total reflection) is a type of reflection method. This method involves placing a sample in close contact with the surface of a prism made of a material with a high refractive index, such as KRS-5, irradiating light onto the prism at an angle greater than the critical angle, and measuring the light totally reflected at the boundary between the prism and the sample to obtain an absorption spectrum. One of the conditions for ATR measurement is that the refractive index of the prism must be higher than that of the sample, so the prism material must be different depending on the sample. Another condition is that the prism and the sample must be in close contact. Therefore, it is suitable for measuring liquids, powders, plastics, soft rubber, etc., and has the advantage of being able to measure without chemical or physical sample treatment. On the other hand, diffuse reflectance is a method for measuring powder samples without preparing potassium bromide tablets, and measuring the powder as is. When light is shone on a sample, two types of light are produced: specularly reflected light from the powder surface and emitted to the outside, and diffusely reflected light (scattered light) that enters the sample, passes through and diffuses repeatedly, and then emerges on the surface. In the diffuse reflectance method, the latter is used to obtain an absorption spectrum.

[0093] (solid １３ C-NMR (Nuclear Magnetic Resonance)) Solid １３ C-NMR requires that (i) the number of spectra matches the number of carbon atoms in the target compound, and (ii) the chemical shift range is １ (iii) the signal is broader than that of H-NMR; １ It is useful for identifying crystalline forms because (i) it is sharper than H-NMR, and (ii) even if additives are present, the chemical shifts do not change if there is no interaction. However, the observed chemical shifts are expected to vary slightly depending on the specific spectrometer used and the analyst's sample preparation technique. １３ The error margin in the C-NMR spectrum is approximately ±0.5 ppm.

[0094] (Differential Scanning Calorimetry (DSC)) Differential scanning calorimetry (DSC) is one of the main methods of thermal analysis, and is a method for measuring the thermal properties of substances as an aggregate of atoms and molecules. DSC measures the change in heat quantity with temperature or time of a pharmaceutical active ingredient, and a differential scanning calorimetry curve is obtained by plotting the obtained data against temperature or time. From the differential scanning calorimetry curve, information can be obtained regarding the onset temperature (extrapolated melting point onset temperature) when the pharmaceutical active ingredient melts, the maximum value of the endothermic peak curve accompanying melting, and the enthalpy. It is known that the observed temperature in DSC can depend on the rate of temperature change, the sample preparation technique used, and the specific instrument. Therefore, the "melting point" in DSC refers to the onset temperature (extrapolated melting point onset temperature), which is less affected by the sample preparation technique. The error range for the onset temperature (extrapolated melting point onset temperature) obtained from a differential scanning calorimetry curve is approximately ±2°C. When determining the identity of a crystal, not only the melting point but also the overall pattern is important, and this may vary somewhat depending on the measurement conditions and instrument.

[0095] (Simultaneous Differential Thermal Analysis / Thermogravimetry (TG / DTA)) Simultaneous differential thermal analysis / thermogravimetry (TG / DTA) is one of the major thermal analysis methods, and is used to measure the weight and thermal properties of substances as an assembly of atoms and molecules. TG / DTA measures the changes in weight and heat quantity of a pharmaceutical active ingredient with respect to temperature or time. By plotting the obtained data against temperature or time, TG (thermogravimetry) and DTA (differential thermal analysis) curves can be obtained. TG / DTA curves can provide information on the weight and heat quantity changes associated with the decomposition, dehydration, oxidation, reduction, sublimation, and evaporation of a pharmaceutical active ingredient. It is known that the observed temperature and weight changes in TG / DTA can depend on the rate of temperature change, the sample preparation technique used, and the specific instrument. Therefore, the "melting point" in TG / DTA refers to the onset temperature (extrapolated melting point onset temperature), which is less affected by sample preparation techniques. In determining the identity of a crystal, not only the melting point but also the overall pattern is important, and this may vary somewhat depending on the measurement conditions and equipment.

[0096] (Moisture Adsorption / Desorption Isotherm (DVS)) Moisture adsorption / desorption isotherm (DVS) is a method for measuring the adsorption and desorption behavior of moisture by measuring the weight change of a solid under various relative humidity conditions. As a basic measurement method, the dry weight at 0% RH (0% relative humidity) is used as the base, and the relative humidity is increased by 5% or 10%. After the weight stabilizes at each relative humidity, the amount of adsorbed water can be determined from the weight increase from the base value. Similarly, the amount of desorbed water can be measured by decreasing the relative humidity from 100% RH or 95% RH in 5% or 10% increments. By plotting the weight change values ​​at each relative humidity, an adsorption / desorption isotherm can be obtained. From these results, it is possible to consider the adsorption and desorption phenomena of attached moisture at each humidity. The adsorption and desorption of attached water and crystallized water are affected by particle size, crystallinity, crystal habit, etc., so the measurement results may vary slightly.

[0097] Differential scanning calorimetry (DSC), simultaneous differential thermal / thermogravimetry (TG / DTA), moisture adsorption / desorption isotherm (DVS), Karl Fischer moisture meter, and gas chromatography are analytical methods that also detect adhering water and / or solvent (residual solvent) on the crystal "surface." When measuring a sample in which adhering water and / or solvent is present on the crystal surface, these analyses may show a higher water content and / or solvent content than the theoretical content of water of crystallization in a hydrate crystal and / or the theoretical content of solvent of crystallization in a solvate crystal. In contrast, powder X-ray diffraction and single crystal structure analysis are measurement methods that analyze the "internal structure" of a crystal, and show characteristic peaks at the same position regardless of the presence or absence of adhering water and / or solvent (residual solvent) on the crystal "surface." The same is true for Raman spectroscopy and infrared absorption spectroscopy (IR). Therefore, even if the water content and / or solvent content in the crystal is higher than the theoretical content in the crystal in powder X-ray diffraction, single crystal structure analysis, Raman spectroscopy, or infrared absorption spectroscopy (IR method), the crystal can be interpreted as being substantially the same crystal as long as it has the characteristic peaks described in the specification.

[0098] (Particle size distribution) As used herein, "D10, D50, D90" refer to particle sizes at points where the cumulative curve is 10%, 50%, and 90% when the total volume of the powder aggregate is taken as 100%, and can be measured by a dry method or a wet method.

[0099] The present invention will be described in more detail below with reference to examples, reference examples, and test examples. The present invention is not limited to these examples. Some errors and deviations should be taken into account with respect to numerical values ​​(e.g., amounts, temperatures, etc.). Unless otherwise specified, percentages are by weight of components and by weight of the total weight of the composition, and pressures are at or near atmospheric pressure.

[0100] (Method for identifying compounds) NMR analysis obtained in each example was carried out at 400 MHz, and DMSO-d ６ , CDCl ３ Measurement was performed using a NMR spectrometer. When NMR data is presented, not all measured peaks may be listed. In the specification, RT represents the retention time in LC / MS (liquid chromatography / mass spectrometry), and was measured under the following conditions. (Measurement Condition A) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 x 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: A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes. (Measurement Condition B) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 x 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: A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes. In the specification, the term MS (m / z) refers to a value observed by mass spectrometry.

[0101] (Method for producing the compound represented by formula (I)) The "compound represented by formula (I)" is compound (I-077) described in WO 2023 / 195529 and WO 2023 / 195530, and can be produced by the synthesis methods of Examples 5 and 6 described in the documents. In addition, the compound can be synthesized by referring to methods known in the art. Extraction, purification, etc. can be carried out by treatments performed in ordinary organic chemistry experiments.

[0102] Example 1: Synthesis of Compound Represented by Formula (I) (Compound (I)) Step 1: Synthesis of Compound 3 To a mixed solution of 2.64 mol / L n-butyllithium in hexane (31 mL, 82.4 mmol) and tetrahydrofuran (20 mL), a solution of compound 1 (12 g, 68.7 mmol) in tetrahydrofuran (70 mL) was added dropwise over 15 minutes at −78°C. The mixture was stirred at −78°C for 1 hour. A 1.9 mol / L solution of 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, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and isopropanol (40 mL) was added to the resulting residue. The precipitate was collected by filtration, washed with isopropanol, and air-dried to give compound 3 (14.8 g, 49 mmol). １ H-NMR (CDCl ３ ) δ: 3.95 (s, 3H), 4.05 (s, 3H), 7.18-7.23 (m, 2H), 7.35 (d, J = 6.8Hz, 1H) LC / MS (ESI): m / z = 303, RT = 2.70min, LC / MS measurement conditions A

[0103] Step 2: Synthesis of Compound 4 Compound 3 (14.8 g, 48.8 mmol) was added with acetic acid (40 mL) and concentrated hydrochloric acid (41 mL), and the mixture was stirred at 110°C for 5 hours. The reaction mixture was cooled to room temperature, and then water (80 mL) was added. The precipitate was collected by filtration and washed with water. The mixture was air-dried to obtain Compound 4 (11.6 g, 42.2 mmol). １H-NMR (DMSO-d ６ ) δ: 7.31 (ddd, J=8.8, 4.9, 2.1Hz, 1H), 7.45 (t, J=8.8Hz, 1H), 7.53 (dd, J=7.3, 2.1Hz, 1H), 11.57 (s, 1H), 12.24 (brs, 1H) LC / MS (ESI): m / z = 275, RT = 1.81 min, LC / MS measurement conditions A

[0104] 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 the solution was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate solution (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 90:10), and the solvent was evaporated under reduced pressure. The resulting residue was dried under reduced pressure to give compound 5 (1.15 g, 2.97 mmol, 82% yield). １ H-NMR (DMSO-d ６ ) δ: 7.35-7.37 (1H, m), 7.49 (1H, t, J = 9.0Hz), 7.54-7.56 (1H, m), 8 .07 (1H, t, J=2.1Hz), 8.54 (1H, d, J=2.0Hz), 8.70 (1H, d, J=2.3Hz). LC / MS (ESI): m / z = 386, RT = 1.98 min, LC / MS measurement conditions A

[0105] Step 4: Synthesis of Compound 6 To a mixed solution of compound 5 (520 mg, 1.345 mmol), N,N-diisopropylethylamine (0.705 mL, 4.04 mmol), and DMF (5.2 mL), 2-bromoacetonitrile (269 μL, 4.04 mmol) was added and stirred at room temperature overnight. 2 mol / L hydrochloric acid (2 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 99:1), and the solvent was evaporated under reduced pressure. The resulting residue was dried under reduced pressure to give compound 6 (291 mg, 0.684 mmol, yield 51%). １ H-NMR (CDCl ３ ) δ: 5.13 (2H, s), 7.23-7.24 (2H, m), 7.42 (1H, d, J = 7.3Hz), 7.67 (1H, t, J = 2.1Hz), 8.45 (1H, d, J = 2.3Hz), 8.67 (1H, d, J = 2.3Hz). LC / MS (ESI): m / z = 425, RT = 2.17 min, LC / MS measurement conditions A

[0106] 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 solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over 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 resulting precipitate was collected by filtration and washed with diisopropyl ether. The resulting solid was dried under reduced pressure to obtain Compound (I) (22.0 mg, 0.042 mmol, yield 72%). １ H-NMR (CDCl ３) δ: 2.75 (4H, t, J = 12.0Hz), 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=2.1Hz), 8.43 (1H, d, J=2.3Hz), 8.61 (1H, d, J=2.3Hz). LC / MS (ESI): m / z = 522, RT = 2.27 min, LC / MS measurement conditions A

[0107] (Example 1A: Biological test of compound (I)) The following describes an example of a biological test of the compound according to the present invention. The compound represented by formula (I) according to the present invention has a coronavirus 3 CL protease inhibitory activity and may be any compound that inhibits coronavirus 3 CL protease. Specifically, in the evaluation method described below, the IC ５０ is preferably 50 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less. ５０ is preferably 10 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less. The biological test results of the compound represented by formula (I) are described as compound (I-077) in WO 2023 / 195529 and WO 2023 / 195530.

[0108] Test Example 1: Cytopathic effect (CPE) inhibitory effect confirmation test using human TMPRSS2 and ACE2-expressing HEK293T cells (HEK293T / ACE2-TMPRSS2 cells) <Procedure> - Dilution and dispensing of test sample: The test sample is diluted to an appropriate concentration with DMSO in advance, and a 2- to 5-fold serial dilution series is prepared, and then dispensed into a 384-well plate. - Dilution and dispensing of cells and SARS-CoV-2: HEK293T / ACE2-TMPRSS2 cells (GCP-SL222, 5 x 10 ３ cells / well) and SARS-CoV-2 (200-600 TCID ５０ / well) was mixed with a medium (MEM, 2% FBS, penicillin-streptomycin), and the mixture was dispensed into the wells containing the test samples. ２Culture in an incubator for 3 days. Dispensing CellTiter-Glo® 2.0 and measuring luminescence signals After 3 days of culture, return the plate to room temperature, then dispense CellTiter-Glo® 2.0 into each well and mix using a plate mixer. After a certain period of time, measure the luminescence signal (Lum) using a plate reader. <Calculation of values ​​for each measurement item> 50% SARS-CoV-2-infected cell death inhibitory concentration (EC ５０ ) Calculation When x is the logarithm of the compound concentration and y is % efficacy, the inhibition curve is approximated by the following logistic regression equation, and the value of x when y = 50 (%) is substituted is the EC ５０ Calculated as follows: y = min + (max - min) / {1 + (X50 / x) ^Hill} %Efficacy = {(Sample - virus control) / (cell control - virus control)} * 100% cell control: the average of Lum of cell control wells virus control: the average of Lum of virus control wells min: lower limit of y-axis, max: upper limit of y-axis, X50: x-coordinate of inflection point, Hill: slope of the curve at the midpoint between min and max

[0109] Compounds of formula (I) according to the present invention were tested essentially as described above. ５０ The values ​​are shown below. (Results) Compound (I): 1.66 nM

[0110] Test Example 2: Inhibitory activity test against SARS-CoV-2 3CL protease <Materials> Commercially available recombinant SARS-CoV-2 3CL protease Commercially available substrate peptide Dabcyl-Lys-Thr-Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe-Arg-Lys-Met-Glu(Edans)-NH ２ (SEQ ID NO: 1) Internal Standard Peptide Dabcyl-Lys-Thr-Ser-Ala-Val-Leu ( １３ C ６, １５ N)-Gln (SEQ ID NO: 2) Dabcyl-Lys-Thr-Ser-Ala-Val-Leu ( １３ C ６ , １５ N)-Gln can be synthesized with reference to the literature (Atherton, E.; Sheppard, R.C., "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. H-Lys-Thr-Ser-Ala-Val-Leu ( １３ C ６ , １５N)-Glu(resin)-OαOtBu (Lys side chain is protected with Boc, Thr side chain is protected with a tert-butyl group, Ser side chain is protected with a tert-butyl group, the C-terminal OH of Glu is protected with a tert-butyl group, and the carboxylic acid of the Glu side chain is condensed to the resin) is synthesized. The N-terminal Dabcyl group is modified by condensing 4-dimethylaminoazobenzene-4'-carboxylic acid (Dabcyl-OH) on the resin using EDC / HOBT. Final deprotection and cleavage from the resin are performed by treatment with TFA / EDT = 95:5. The product is then purified by reverse-phase HPLC. RapidFire Cartridge C4 Type A <Procedure> Assay buffer preparation: This test uses an assay buffer consisting of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, and 0.01% BSA. Test sample dilution and dispensing: Test samples are diluted to an appropriate concentration with DMSO in advance, and a 2- to 5-fold serial dilution series is prepared and dispensed into a 384-well plate. Addition of enzyme and substrate: Enzyme reaction: 8 μM substrate and 6 nM or 0.6 nM enzyme solution are added to the prepared compound plate and incubated at room temperature for 3 to 5 hours. The enzyme reaction is then stopped by adding a reaction stop solution (0.067 μM Internal Standard, 0.1% formic acid, 10 or 25% acetonitrile). Measurement of reaction products The plate after the reaction is completed is measured using a RapidFire System 360 and a mass spectrometer (Agilent, 6550 iFunnel Q-TOF) or a RapidFire System 365 and a mass spectrometer (Agilent, 6495C Triple Quadruple). Solution A (75% isopropanol, 15% acetonitrile, 5 mM ammonium formate) and solution B (0.01% trifluoroacetic acid, 0.09% formic acid) are used as the mobile phase during measurement. The reaction products detected by the mass spectrometer are calculated using RapidFire Integrator or an equivalent analysis program to obtain the product area value. At the same time, the internal standard detected is also calculated and used as the internal standard area value.<Calculation of each measurement item value> Calculation of P / IS The area value obtained in the previous item is calculated using the following formula to calculate P / IS: P / IS = Product area value / Internal Standard area value 50% SARS-CoV-2 3CL protease inhibitory concentration (IC ５０ ) Calculation When x is the logarithm of the compound concentration and y is % Inhibition, the inhibition curve is approximated by the following logistic regression equation, and the value of x when y = 50 (%) is substituted is used to calculate the IC ５０ Calculated as follows: y = min + (max - min) / {1 + (X50 / x) ^Hill} %Inhibition = {1-(Sample - Control(-)) / Control(+)-Control(-))} * 100 Control(-): the average of P / IS of enzyme inhibited condition wells Control(+): the average of P / IS of DMSO control wells min: lower limit of y-axis, max: upper limit of y-axis, X50: x-coordinate of inflection point, Hill: slope of the curve at the midpoint between min and max

[0111] Compounds of formula (I) according to the present invention were tested essentially as described above. ５０ The values ​​are shown below. (Results) Compound (I): 0.00036 μM

[0112] Test Example 3: Powder X-ray Diffraction Experiment (XRPD) Powder X-ray diffraction measurements were carried out for the solid state (crystalline and amorphous) and solid dispersion obtained in each example according to the powder X-ray diffraction measurement method described in the general test methods of the Japanese Pharmacopoeia. The measurement conditions are as follows. Measurement Condition 1: Powder X-ray diffractometer: SmartLab manufactured by Rigaku Corporation Measurement method: Reflection method Wavelength used: CuKα ray (λ=1.5418 Å) Tube current: 200 mA Tube voltage: 45 kV Sample plate: Aluminum X-ray incident angle: 2.5° Sampling width: 0.02° Detector: HyPix-3000 (two-dimensional detection mode)

[0113] Test Example 4: Measurement of powder X-ray diffraction pattern under temperature and / or relative humidity control Using attachments provided with the X-ray diffractometer, the temperature and relative humidity of the measurement sample area are controlled, and powder X-ray diffraction measurement is performed according to the powder X-ray diffraction measurement method described in the general test methods of the Japanese Pharmacopoeia. The measurement conditions are as follows. Measurement Condition 2: (X-ray Diffraction Measurement) Powder X-ray diffractometer: Rigaku RINT2100Ultima+ Measurement method: Reflection method Wavelength used: CuKα ray (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° Scan speed: 60° / min (Control of temperature and relative humidity) Temperature controller: Rigaku ThermoPlus Humidity controller: Rigaku HUM-1

[0114] Test Example 5: Measurement and Analysis Method for Single Crystal Structure Analysis Single crystal structure analysis was performed on the crystals obtained in each example. The measurement conditions and analysis method are shown below. (Apparatus) Rigaku XtaLAB P200 MM007 (Measurement Conditions) Measurement temperature: 25°C Temperature controller: Rigaku sample spray cryogenic device Wavelength used: CuKα radiation (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) Data was Lorentz- and polarization-corrected, and absorption-corrected. (Crystal structure analysis) Phase determination was performed using the direct method program ShelXT (Sheldrick, G.M., 2015), and refinement was performed using full-matrix least-squares using ShelXL (Sheldrick, G.M., 2015). All non-hydrogen atom temperature factors were refined anisotropically. Hydrogen atoms were introduced by calculation using the default parameters of ShelXL unless otherwise specified and treated as riding atoms. Hydrogen atoms were also refined using isotropic parameters. PLATON (Spek, 1991) / ORTEP (Johnson, 1976) was used to draw the following structure diagram (30% PROBABILITY level).

[0115] Test Example 6: Measurement of Raman Spectrum The measurement conditions for measuring the Raman spectrum of the crystals obtained in each example and performing baseline correction are shown below. Measurement Condition 1 Measurement method: Microscopic laser Raman spectroscopy Laser wavelength: 671 nm Number of accumulations: 1 Exposure time: 1 second

[0116] Test Example 7: Differential Scanning Calorimetry (DSC) DSC measurements were carried out on the crystals obtained in each example. A sample was weighed into an aluminum pan, which was then simply sealed and measured. The measurement conditions are shown below. Note that measurements by differential scanning calorimetry (DSC) may have an error within a range of ±2°C. Apparatus: Discovery DSC / TA Instrument Measurement temperature range: -10°C to 270°C Heating rate: 10°C / min Atmosphere: N ２ 50mL / min

[0117] Test Example 8: Simultaneous Differential Thermal Analysis - Thermogravimetry (TG / DTA) Simultaneous differential thermal analysis - thermogravimetry (TG / DTA) was carried out on the solid state (crystalline and amorphous) and solid dispersion obtained in each example. The sample obtained in each example was weighed, placed in an aluminum pan, and measured in an open system. The measurement conditions were as follows. Apparatus: Hitachi High-Technologies TG / DTA STA7200RV Measurement temperature range: room temperature - 350°C Heating rate: 10°C / min

[0118] Test Example 9: Moisture adsorption / desorption isotherm measurement (DVS) The moisture adsorption / desorption isotherm measurement (DVS) was carried out for the crystals obtained in each example. The crystals obtained in each example were weighed into an aluminum pan and allowed to stand at 25°C and 0% relative humidity. Measurement was started after the compound was sufficiently dried and the weight stabilized, and the weight was recorded when the relative humidity changed by 5% from 0% to 95%. Next, the weight was recorded when the relative humidity changed by 5% from 95% to 0%. Apparatus: DVS Adventure manufactured by Surface Measurement Systems.

[0119] Test Example 10: Particle size distribution / dry method The particle size distribution of the crystals and solid dispersions obtained in each example was measured. The particle size distribution was measured by a dry method using a laser diffraction particle size distribution measuring device. Measurement condition 1: Device: HELOS&RODOS (manufactured by Sympatec Co., Ltd.) Range: R1 Dispersion pressure: 2 bar Trigger condition: Stop 2 seconds, measurement concentration ≦ 0.5% or 10 seconds real time Measurement condition 2: Device: HELOS&RODOS (manufactured by Sympatec Co., Ltd.) Range: R3 Dispersion pressure: 2 bar Trigger condition: Stop 2 seconds, measurement concentration ≦ 0.5% or 10 seconds real time Measurement condition 3: Device: Microtrac MT3200II type (manufactured by MicrotracBEL Co., Ltd.)

[0120] Test Example 11: Particle size distribution / wet method The particle size distribution of the crystals obtained in each example was measured. The particle size distribution was measured by a wet method using a laser diffraction / scattering particle size distribution measuring device, Microtrac MT3200II (manufactured by Microtrac BEL). Measurement range: 0.243 to 1408 μm Solvent: water Solvent refractive index: 1.333 Measurement time: 30 seconds Particle shape: aspherical Particle transmittance: transmittance Particle refractive index: 1.81

[0121] (Example 1B: Analysis of solid state of compound (I)) Compound (I) produced by the synthesis method of Example 1 above was subjected to powder X-ray diffraction experiments and simultaneous differential thermal analysis-thermogravimetry (TG / DTA), and was confirmed to be an anhydrous crystalline form of the compound represented by formula (I).

[0122] Example 2: Analysis of anhydrous crystals of the compound represented by formula (I) Anhydrous crystals of the compound represented by formula (I) were pulverized and subjected to powder X-ray diffraction experiments, single crystal structure analysis, differential scanning calorimetry (DSC), simultaneous differential thermal / thermogravimetry (TG / DTA), moisture adsorption / desorption isotherm (DVS), Raman spectroscopy, and particle size distribution measurement.

[0123] (Example 2A: Pulverization of anhydrous crystals of the compound represented by formula (I)) The anhydrous crystals of the compound represented by formula (I) were sieved through a 1000 μM mesh and then pulverized under the following conditions: Apparatus: A-O jet mill (Seishin Enterprise Co., Ltd.) Feeding method: feeder Feeding rate: 20 g / hour Pulverization pressure: 0.30 MPa Feeding pressure: 0.40 MPa

[0124] Example 2B: Powder X-ray diffraction experiment of anhydrous crystals of the compound of formula (I) A powder X-ray diffraction experiment was carried out on the pulverized anhydrous crystals of the compound of formula (I) under the measurement condition 1 described in Test Example 3 above. The powder X-ray diffraction pattern is shown in FIG. 1, and a peak list of the powder X-ray diffraction pattern is shown in FIG. 2. In the table below listing the peaks of the powder X-ray diffraction pattern, Position indicates 2θ (°), and Intensity indicates intensity. In the powder X-ray diffraction pattern, peaks were observed 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°. The anhydrous crystals of the compound represented by formula (I) showed 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°. The anhydrous crystals of the compound represented by formula (I) showed 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°.

[0125] Example 2C: Single Crystal Structure Analysis of Anhydrous Crystals of the Compound of Formula (I) <Single Crystal Preparation Method> 400 μL of methanol was added to 1 mg of crystals of the compound of formula (I) and dissolved by heating to 50° C. The solution was dispensed into 1.5 mL HPLC vials, the HPLC vials were capped, a syringe needle was pierced into the cap, and the solution was allowed to stand at room temperature. Single crystals were prepared by the solvent evaporation method. <Single Crystal Structure Analysis> Single crystal diffraction experiments and analysis were performed using the method described in Test Example 5 above. Note that, since Cl1 and Cl7C, and H5CA and H6CA are in a disordered relationship, analysis was performed with occupancy ratios of Cl1:Cl7C = 0.75:0.25 and H5CA:H6CA = 0.25:0.75.

[0126] The results of the single crystal structure analysis are shown below. １ (I>2.00s(I)) was 0.0555, and the final difference Fourier confirmed that there were no missing or misplaced electron densities.

[0127] The crystallographic data are shown in Table 1. Here, V means the unit cell volume, and Z means the number of molecules in the unit cell.

[0128] Atomic fraction coordinates x, y, z (Å × 10 ４ ) and the equivalent isotropic temperature factor U(eq) (Equivalent Isotropic Displacement Parameters, Å ２ x10 ３ ) are shown in Table 2. Here, U(eq) is the orthogonalized U ｉｊ Define it as one-third of the locus of the tensor.

[0129] Next, the atomic coordinates x, y, z of the hydrogen atom (Å×10 ４ ) and isotropic temperature factor U(eq) (Isotropic Displacement Parameters, Å ２ x10 ３ ) are shown in Table 3.

[0130] The structure in the asymmetric unit of the crystal structure is shown in Figure 3. The label numbers of the non-hydrogen atoms shown in Figure 3 correspond to the numbers of the non-hydrogen atoms in Table 2.

[0131] The crystal structure was identified as an anhydrous crystal of the compound represented by formula (I) because only one molecule of the compound represented by formula (I) was present in the asymmetric unit.

[0132] From the crystal structure, the powder X-ray diffraction pattern (λ=1.5418 Å) calculated using Mercury (The Cambridge Crystallographic Data Centre, Ver. 4.0.0) was confirmed to be generally consistent with the powder X-ray diffraction pattern of Example 2B ( FIG. 1 ).

[0133] (Example 2D: Differential scanning calorimetry of anhydrous crystals of the compound of formula (I)) Approximately 2 mg of the anhydrous crystals of the compound of formula (I) after pulverization was weighed into an aluminum pan and measured by the method described in Test Example 7 above. The results are shown in Figure 4. An endothermic peak was observed with an onset temperature of approximately 261.3°C.

[0134] (Example 2E: Simultaneous Differential Thermal and Thermogravimetric Measurement of Anhydrous Crystals of the Compound of Formula (I)) The anhydrous crystals of the compound of formula (I) after pulverization were measured by the method described in Test Example 8 above. The results are shown in Figure 5. An endothermic peak with an onset temperature of approximately 265.6°C was observed. No weight loss was observed.

[0135] Example 2F: Raman spectroscopy of anhydrous crystals of the compound of formula (I) After pulverization, the anhydrous crystals of the compound of formula (I) were subjected to Raman spectroscopy under the measurement condition 1 described in Test Example 6. The results are shown in Figure 6. The main Raman peaks are shown below. The anhydrous crystal of the compound represented by formula (I) has a Raman spectrum of 415.2 cm －１ ±2cm －１ , 502.7 cm －１ ±2cm －１ , 1431.4 cm －１ ±2cm －１ , 1714.8 cm －１ ±2cm －１ , and 3065.4 cm －１ ±2cm －１showed a characteristic peak.

[0136] (Example 2G: 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) before grinding used in Example 2A was measured by the method described in Measurement Condition 2 of Test Example 10. The results were D10 of 1.16 μm, D50 of 4.42 μm, and D90 of 13.13 μm. The particle size distribution is shown in FIG.

[0137] (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) after pulverization obtained in Example 2A was measured by the method described in Measurement Condition 1 of Test Example 10. The results were D10 of 0.79 μm, D50 of 2.90 μm, and D90 of 7.32 μm. The particle size distribution is shown in FIG.

[0138] Example 3 Preparation and Analysis of Ethyl Acetate Solvate Crystals of the Compound Represented by Formula (I) Ethyl acetate solvate crystals of the compound represented by formula (I) were prepared, and each crystal was subjected to NMR measurement, powder X-ray diffraction experiment, single crystal structure analysis, differential scanning calorimetry (DSC), simultaneous differential thermal / thermogravimetry (TG / DTA), moisture adsorption / desorption isotherm measurement (DVS), Raman spectrum measurement, and particle size distribution measurement.

[0139] Example 3A: Preparation of ethyl acetate solvate crystals of the compound represented by formula (I) Compound 6 (800 mg, 1.880 mmol) and 6,6-difluoro-2-azaspiro[3.3]heptane trifluoroacetate (557 mg, 2.256 mmol) described in Example 1 were dissolved in DMF (8.0 mL), and N,N-diisopropylethylamine (985 μL, 5.64 mmol) was added, followed by stirring at 60° C. for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, dried over magnesium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure, and the filtrate was subjected to silica gel column chromatography. After elution with hexane / ethyl acetate, fractions containing the desired compound were collected. The solvent was concentrated under reduced pressure, and diisopropyl ether was added, and the precipitated solid was collected by filtration. The resulting residue was dried under reduced pressure to obtain compound (I) (954 mg, 1.563 mmol, yield 83%). NMR measurement was carried out by the method described above (Method for identifying the compound). In the NMR chart, a peak of ethyl acetate was observed. １ H-NMR (DMSO-D ６ ) δ: 1.18 (3H, t , J=7.0Hz), 1.99 (3H, s), 2.79 (4H, t, J=12.4Hz), 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 measurement conditions B

[0140] (Example 3B: Powder X-ray diffraction experiment of solid prepared by the method of Example 3A) A powder X-ray diffraction experiment was performed on the sample prepared by the method of Example 3A under the measurement condition 1 described in Test Example 3 above. As a result, it was confirmed that the sample prepared by the method of Example 3A was a crystal different from the anhydrous crystal of the compound represented by formula (I). From the results of the NMR measurement of Example 3A and Example 3B, it was estimated that the sample prepared by the method of Example 3A was an "ethyl acetate solvate crystal of the compound represented by formula (I)."

[0141] (Example 3C: Single crystal structure analysis of ethyl acetate solvate crystal of the compound represented by formula (I)) A single crystal diffraction experiment and analysis were carried out on the ethyl acetate solvate crystal of the compound represented by formula (I) by the method described in Test Example 5 above. As a result, it was confirmed that the compound represented by formula (I) and ethyl acetate were present in an ethyl acetate solvate crystal in a molar ratio of 1:1. Note that a part of the compound represented by formula (I) had a disordered structure.

[0142] Example 3D: NMR measurement of ethyl acetate solvate crystals of the compound represented by formula (I) The ethyl acetate solvate crystals of the compound represented by formula (I) were air-dried overnight at room temperature and subjected to NMR measurement by the method described above in (Method for identifying the compound). １ The results of H-NMR are shown in Figure 9. In the NMR chart, a peak for ethyl acetate was observed. １ Based on the integral ratio of H-NMR, the molar ratio of the compound represented by formula (I) to ethyl acetate was approximately 1:1. Because the crystals were air-dried at room temperature before measurement, they were presumed to be ethyl acetate solvate crystals, in which ethyl acetate was not attached to the crystal surface but was encapsulated in the crystal lattice. This result was consistent with the single crystal structure analysis of Example 3C.

[0143] (Example 3E: Pulverization of ethyl acetate solvate crystals of the compound represented by formula (I)) The ethyl acetate solvate crystals of the compound represented by formula (I) were pulverized under the following conditions: Apparatus: Hosokawa / ALPINE SPIRAL JET MILL 50AS (Hosokawa Micron Corporation) Feeding method: Manual Feeding rate: 30.15 g / 25 min Pulverization pressure: 0.10 MPa Feeding pressure: 0.20 MPa

[0144] (Example 3F: Powder X-ray diffraction experiment of ethyl acetate solvate crystals of the compound represented by formula (I)) For the pulverized ethyl acetate solvate crystals of the compound represented by formula (I), a powder X-ray diffraction experiment was carried out under the measurement condition 1 described in the above Test Example 3. The powder X-ray diffraction pattern is shown in Figure 10, and a peak list of the powder X-ray diffraction pattern is shown in Figure 11. In the powder X-ray diffraction pattern, diffraction angles (2θ): 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°, 21.2° Peaks were observed 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°. The ethyl acetate solvate crystal of the compound represented by formula (I) 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°, 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°. The ethyl acetate solvate crystal of the compound represented by formula (I) 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°.

[0145] Example 3G: Raman spectroscopy of ethyl acetate solvate crystals of the compound represented by formula (I) After pulverization, the ethyl acetate solvate crystals of the compound represented by formula (I) were subjected to Raman spectroscopy under the measurement condition 1 described in Test Example 6 above. The results are shown in Figure 12. The main Raman peaks are shown below. The ethyl acetate solvate crystal of the compound represented by formula (I) has a Raman spectrum of 421.2 cm －１ ±2cm －１ , 509.7 cm －１ ±2cm －１ , 1585.3 cm －１ ±2cm －１ , 1709.9 cm －１ ±2cm －１ and 3052.9 cm －１ ±2cm －１ showed a characteristic peak.

[0146] Example 3H: Simultaneous Differential Thermal and Thermogravimetric Measurement of Ethyl Acetate Solvate Crystals of the Compound of Formula (I) The ethyl acetate solvate crystals of the compound of formula (I) were measured by the method described in Test Example 8 above. The results are shown in FIG. 13. An endothermic peak with an onset temperature of approximately 129.5°C was observed, and a weight loss of approximately 14% was confirmed almost simultaneously. This change is thought to be due to desolvation (elimination) of ethyl acetate from the "ethyl acetate solvate crystals of the compound of formula (I)." Note that the "ethyl acetate solvate crystals of the compound of formula (I)" in which the molar ratio of the compound of formula (I) to ethyl acetate is 1:1 has a theoretical ethyl acetate content of 14.4 wt %, which is generally consistent with the results of this thermogravimetry (TG).

[0147] Several lots of ethyl acetate solvate crystals of the compound of formula (I) were measured by the method described in Test Example 8 above. Each measurement showed endothermic peaks at 92.5°C, 95.7°C, and 116.7°C, respectively, and weight loss was confirmed at the temperatures of the endothermic peaks. Powder X-ray diffraction experiments were also performed on these samples under Measurement Condition 1 described in Test Example 3 above, and the powder X-ray diffraction patterns were very similar. The main peaks coincided within a range of ±0.2°, with slight differences in relative intensity. The powder X-ray diffraction patterns of all these samples 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°.

[0148] (Example 3I: Particle size distribution of ethyl acetate solvate crystals of the compound represented by formula (I)) The particle size distribution of the ethyl acetate solvate crystals of the compound represented by formula (I) before grinding used in Example 3E was measured by the method described in Measurement Condition 2 of Test Example 10. The results were D10 of 18.73 μm, D50 of 71.82 μm, and D90 of 114.67 μm. The particle size distribution is shown in FIG.

[0149] (Example 3J: Particle size distribution of ethyl acetate solvate crystals of the compound represented by formula (I)) The particle size distribution of the ethyl acetate solvate crystals of the compound represented by formula (I) after pulverization obtained in Example 3E was measured by the method described in Measurement Condition 1 of Test Example 10. The results were D10 of 0.68 μm, D50 of 3.59 μm, and D90 of 8.80 μm. The particle size distribution is shown in FIG.

[0150] The present invention will be described in detail below with reference to examples, reference examples, and test examples relating to formulations of the compound represented by formula (I). The present invention is not limited thereto. The anhydrous crystals of the compound represented by formula (I) used were (1) a compound having particle sizes of D10 of 0.78 μm, D50 of 2.09 μm, and D90 of 4.77 μm, (2) a compound having particle sizes of D10 of 0.86 μm, D50 of 3.29 μm, and D90 of 10.15 μm, and (3) a compound having particle sizes of D10 of 0.7 μm, D50 of 2.7 μm, and D90 of 8.8 μm, with purities (quantitative values) of (2) and (3) being 101.7% and 99.7%, respectively. The chromatogram of the compound (2) having particle sizes of D10 of 0.86 μm, D50 of 3.29 μm, and D90 of 10.15 μm measured by the liquid chromatography method shown in Test Example 12 is shown in Figure 16. The compound represented by formula (I) was detected with a purity (p%) of 99.58% at a retention time of 24.941 minutes.

[0151] Test Example 12: Analytical Method 1 for Related Substances The amount of related substances was measured by liquid chromatography using the following method and conditions: Detector: ultraviolet absorptiometer (measurement wavelength: 247 nm) Column: ACQUITY UPLC BEH C18 (1.7 μm, 2.1 × 100 mm, Waters) Column temperature: constant temperature around 40°C Mobile phase A: water / formic acid mixture (1000:1) Mobile phase B: acetonitrile / formic acid mixture for liquid chromatography (2000:1) Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was changed as follows to control the concentration gradient. Flow rate: 0.4 mL / min Injection volume: 5 μL Sample cooler temperature: Constant temperature around 10°C Needle washing solvent or auto injector washing solution: acetonitrile Area measurement range: Up to 43 minutes after sample solution injection

[0152] Example 4: Preparation and analysis of solid dispersions of the compound represented by formula (I) Solid dispersions of the compound represented by formula (I) were prepared, and each solid dispersion was observed with a digital microscope, subjected to powder X-ray diffraction experiments, differential scanning calorimetry (DSC), and measurements of particle size distribution and related substances.

[0153] Example 4A: Selection of polymer used in solid dispersion of compound of formula (I) Anhydrous crystals of the compound of formula (I) and a polymer were dissolved in acetone, ethanol, or a mixture thereof, and then dropped onto a slide glass. A solid dispersion was obtained by evaporating the solvent. The anhydrous crystals of the compound of formula (I) were pulverized under the following conditions, and the pulverized product was used. Apparatus: Hosokawa / ALPINE SPIRAL JET MILL 50AS (Hosokawa Micron Corporation) Feeding method: Feeder Feeding rate: 60 g / hr Grinding pressure: 0.05 MPa Feeding pressure: 0.10 MPa The particle size distribution of the anhydrous crystals of the compound of formula (I) after pulverization was measured using the method described in Measurement Condition 1 of Test Example 10. The results were D10: 0.78 μm, D50: 2.09 μm, and D90: 4.77 μm. <Preparation of Solid Dispersion> The solid dispersion was examined at a content of the compound represented by formula (I) of 10 wt%, 25 wt%, and 50 wt%. The polymers used were copovidone (polyvinylpyrrolidone-vinyl acetate copolymer, PVPVA) (manufactured by BASF), polyvinylpyrrolidone (povidone) (manufactured by BASF), hypromellose acetate succinate (hydroxypropyl methylcellulose acetate succinate) (manufactured by Shin-Etsu Chemical Co., Ltd., grades LF and MF), hypromellose phthalate (manufactured by Shin-Etsu Chemical Co., Ltd.), hydroxypropyl cellulose (manufactured by Nippon Soda), and methacrylic acid copolymer L (manufactured by Evonik). The formulations are shown below. <Evaluation of Presence of Crystal Precipitation> Immediately after dropping onto the slide glass, after storage for one week in an environment of 40°C and 75% relative humidity, and after storage for one week in an environment of 60°C, the presence or absence of crystal precipitation was observed using a polarized observation mode of a digital microscope (VHX-7000, manufactured by KEYENCE). As a result, the solid dispersion using polyvinylpyrrolidone, when the content of the compound represented by formula (I) was 10 wt%, 25 wt%, or 50 wt%, showed no crystal precipitation immediately after preparation or after storage under each condition, and was good. The solid dispersion using copovidone, when the content of the compound represented by formula (I) was 10 wt% or 25 wt%, showed no crystal precipitation immediately after preparation or after storage under each condition, and was good. The solid dispersions using hypromellose acetate succinate (Grade 1 and MF) at a content of the compound represented by formula (I) of 10 wt % and 25 wt % were favorable, with no precipitation of coarse crystals of 100 μm or more observed immediately after preparation or after storage under each condition.

[0154] Example 4B: Preparation 1 of solid dispersion of compound of formula (I) Anhydrous crystals of the compound of formula (I) (the pulverized product of Example 4A) and each polymer were dissolved in acetone, and after confirming complete dissolution, a solid dispersion was produced using a spray dryer (Advance B-290 model spray dryer for organic solvents, manufactured by BUCHI) under conditions of an inlet temperature of 90°C, a liquid pump at 20%, and a nitrogen flow rate scale of 40. As the polymer, copovidone (manufactured by BASF), povidone (manufactured by BASF), and hypromellose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd., grades MF and LF) were used. The content of the compound of formula (I) in the solid dispersion was 25% by weight. The formulation is shown below.

[0155] (Example 4C: Powder X-ray Diffraction Experiment of Solid Dispersion of Compound of Formula (I)) For the solid dispersion obtained in Example 4B, immediately after preparation, after 1 week of storage in an opened glass bottle at 40°C and 75% relative humidity, after 1 week of storage in a closed glass bottle at 40°C and 75% relative humidity, and after 1 week of storage in a closed glass bottle at 60°C, a powder X-ray diffraction experiment was performed under measurement condition 1 described in Test Example 3 above. The results of Example 4B-1 are shown in Figure 17, the results of Example 4B-2 in Figure 18, the results of Example 4B-3 in Figure 19, and the results of Example 4B-4 in Figure 20. Immediately after preparation and after storage under each condition, each solid dispersion obtained in Example 4B showed no diffraction peaks and only a halo pattern. It was confirmed that all of the solid dispersions remained amorphous. Note that the anhydrous crystals of the compound of formula (I) alone showed good powder X-ray diffraction patterns, as described in Example 2B above.

[0156] (Example 4D: Preparation 2 of solid dispersion of compound of formula (I)) Anhydrous crystals of the compound of formula (I) and copovidone (manufactured by ASHLAND) were dissolved in acetone, and after confirming complete dissolution, spray drying was carried out using a spray dryer under conditions of an outlet temperature of 50°C, a feed flow rate of approximately 6 kg / hour, and a spray pressure of 1.0 bar. Thereafter, the solution was vacuum dried for approximately 40 hours using a benchtop vacuum dryer to obtain a solid dispersion. The formulation is shown below.

[0157] <Particle Size Distribution of Solid Dispersion of Compound Represented by Formula (I)> The particle size distribution of the solid dispersion of Example 4D-1 was measured under measurement condition 3 (dry method) described in Test Example 10, and the results were D10: 2.08 μm, D50: 5.01 μm, and D90: 11.00 μm.

[0158] <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) used in Example 4D-1 was measured under measurement condition 3 (dry method) described in Test Example 10, and the results were D10: 0.86 μm, D50: 3.29 μm, and D90: 10.15 μm. Furthermore, the particle size distribution of the anhydrous crystals of the compound represented by formula (I) used in Example 4D-1 was measured under Test Example 11 (wet method), and the results were D10: 3.94 μm, D50: 9.18 μm, and D90: 20.32 μm.

[0159] Example 4E: Stability test of solid dispersion of compound of formula (I) over time The solid dispersion obtained in Example 4D was stored in an environment of 25°C and 60% relative humidity for 3 months and in an environment of 40°C and 75% relative humidity for 3 months, and the increase in the amount of related substances was measured.

[0160] Test Example 13: Analytical Method 2 for Related Substances The amount of related substances was measured by liquid chromatography using the following method and conditions: Detector: ultraviolet absorptiometer (measurement wavelength: 247 nm) Column: ACQUITY UPLC BEH C18 (1.7 μm, 2.1 × 100 mm, Waters) Column temperature: constant temperature around 40°C Mobile phase A: water / formic acid mixture (1000:1) Mobile phase B: acetonitrile / formic acid mixture for liquid chromatography (2000:1) Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was changed as follows to control the concentration gradient. Flow rate: 0.4 mL / min Injection volume: 5 μL Sample cooler temperature: Constant temperature around 25°C Needle washing solvent or auto injector washing solution: acetonitrile Area measurement range: Up to 53 minutes after sample solution injection

[0161] The amounts of related substances with a relative retention time of 0.44 at the start of the test, after three months of storage in an environment of 25°C and 60% relative humidity, and after three months of storage in an environment of 40°C and 75% relative humidity are shown below. Although the amount of a related substance with a relative retention time of 0.44 increased slightly compared to the start of the test, it was confirmed that the solid dispersion was stable.

[0162] Example 4F: Solubility test of solid dispersion of compound represented by formula (I) The solubility of the solid dispersion obtained in Example 4D and the anhydrous crystal of the compound represented by formula (I) alone was measured.

[0163] Test Example 14: Solubility test The solid dispersion obtained in Example 4D and the anhydrous crystals of the compound of formula (I) (Example 4F-1) were added to various test solutions to prepare 30 to 50 mL suspensions. The prepared suspensions were placed in centrifuge tubes and shaken at a shaking speed of 100 rpm or higher. 60 minutes after the start of shaking, 5 mL was sampled and quickly filtered through a filter (chromatodisc 0.45 μm, 25A) to obtain samples.

[0164] The solubilities in various test solutions are shown below: The solid dispersion of the compound represented by formula (I) showed significantly improved solubility compared to the anhydrous crystal of the compound represented by formula (I) alone.

[0165] Example 4G: PK test of solid dispersion of compound of formula (I) in rats A suspension of a solid dispersion consisting of anhydrous crystals of the compound of formula (I) alone and copovidone was prepared, and its oral absorbability in rats was evaluated.

[0166] Test Example 15: Rat PK Study Male rats were fed, and then orally administered the test sample. The dose of the suspension was adjusted so that the dose of the compound of formula (I) was 3 mg / kg body weight. After administration of Examples 4G-1, 4G-2, and 4G-3 shown below, blood samples were collected at the respective sampling times, and the maximum plasma drug concentration (Cmax), the time to reach the maximum plasma drug concentration (Tmax), and the area under the plasma drug concentration-time curve (AUC) from the time of administration up to 24 hours later were calculated using LC / MS / MS. Example 4G-1: Preparation of a suspension of a solid dispersion of the compound of formula (I) The compound of formula (I) and copovidone (manufactured by ASHLAND) were dissolved in acetone at a weight ratio of 1:3. After confirming complete dissolution, the solution was spray-dried using a spray dryer under the following conditions: outlet temperature 50°C, feed flow rate of approximately 6 kg / hour, and spray pressure 1.0 bar. The solid dispersion was dried in a tabletop vacuum dryer for approximately 40 hours to obtain a solid dispersion. The obtained solid dispersion was suspended in an aqueous solution containing 0.5% methylcellulose to obtain a suspension at a concentration of 6 mg / mL. Example 4G-2: Preparation of a suspension of anhydrous crystals of the compound of formula (I) Anhydrous crystals of the compound of formula (I) were suspended in an aqueous solution containing 0.5% methylcellulose to obtain a suspension at a concentration of 6 mg / mL. Example 4G-3: Preparation of a suspension of ethyl acetate solvate crystals of the compound of formula (I) Ethyl acetate solvate crystals of the compound of formula (I) were suspended in an aqueous solution containing 0.5% methylcellulose to obtain a suspension at a concentration of 6 mg / mL.

[0167] The results of Cmax, Tmax and AUC of the compound represented by formula (I) in each example are shown below. Example 4G-1 had increased Cmax and AUC compared to Examples 4G-2 and 4G-3, and the oral absorbability was significantly improved. Furthermore, Example 4G-1 had a shorter Tmax compared to Examples 4G-2 and 4G-3, and showed rapid absorbability.

[0168] The manufacturing method and evaluation results of the "preparation containing the compound represented by formula (I) as an active ingredient" are shown below.

[0169] (Example 5: Preparation containing anhydrous crystals of the compound represented by formula (I)) The production method and evaluation results of the "preparation containing anhydrous crystals of the compound represented by formula (I) as an active ingredient" are shown below.

[0170] (Example 5A: Study 1 of uncoated tablets containing anhydrous crystals of the compound of formula (I)) Uncoated tablets containing 50% by weight of anhydrous crystals of the compound of formula (I) and 5% by weight of a disintegrant were produced, and a dissolution test was carried out. <Method for producing uncoated tablets> Anhydrous crystals of the compound of formula (I), D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium (manufactured by Dupont), low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), sodium starch glycolate (manufactured by JRS Pharma), crospovidone (grades CLM and CL, manufactured by BASF), and magnesium stearate (manufactured by MALLINCKRODT) were used. The formulation is shown below (units are mg). Anhydrous crystals of the compound represented by formula (I), excipients, disintegrants, and half of the magnesium stearate were mixed with a spatula and sieved through a wire mesh. The mixture was then compressed into tablets using a simple tableting machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.). The mixture was then sized using a 20-mesh sieve, and the remaining magnesium stearate was added and mixed with a spatula. The resulting granules for tableting were compressed with a simple tableting machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.) to obtain plain tablets.

[0171] <Dissolution Test> Test Example 16: Dissolution Test A dissolution test was carried out on the preparations obtained in each Example (one tablet in the case of tablets) according to the dissolution test method of the 18th edition of the Japanese Pharmacopoeia. The test fluid used was the dissolution test fluid 2 containing a surfactant, and the test was carried out using the paddle method at a paddle rotation speed of 50 rpm (changed to 250 rpm 120 minutes after the start of the test).

[0172] As a result, Example 5A-1, which used crospovidone (grade CLM), showed the best dissolution properties.

[0173] (Example 5B: Study 2 of uncoated tablets containing anhydrous crystals of the compound of formula (I)) Uncoated tablets containing 50% by weight of anhydrous crystals of the compound of formula (I) and 10% by weight of a disintegrant were produced, and a dissolution test was carried out. <Production method of uncoated tablets> Uncoated tablets were produced in the same manner as in Example 5A. The formulation is shown below.

[0174] <Dissolution test> A dissolution test was carried out in Test Example 16. As a result, Examples 5B-1, 5B-2 and 5B-3 (disintegrant blending ratio 10% by weight) showed improved dissolution rates for all disintegrants compared to Examples 5A-1, 5A-2 and 5A-5 (disintegrant blending ratio 5% by weight). Moreover, Example 5B-1, which used crospovidone as the disintegrant, showed the most rapid dissolution.

[0175] (Example 5C: Study 3 of uncoated tablets containing anhydrous crystals of the compound of formula (I)) Uncoated tablets containing 10% by weight of anhydrous crystals of the compound of formula (I) and 10% by weight of a disintegrant were produced, and a dissolution test was carried out. <Method for producing uncoated tablets> Anhydrous crystals of the compound of formula (I), D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), crospovidone (grade INF-10, manufactured by ASHLAND), croscarmellose sodium (manufactured by Dupont), and sodium stearyl fumarate (manufactured by JRS Pharma) were used. The production method was the same as in Examples 5A and 5B. The formulation is shown below.

[0176] <Dissolution test> A dissolution test was carried out in Test Example 16. As a result, Example 5C-1, which used crospovidone as a disintegrant, showed good dissolution properties. Therefore, it is considered that crospovidone is optimal as a disintegrant when the blending ratio of anhydrous crystals of the compound represented by formula (I) is 10 to 50 wt %.

[0177] (Example 5D: Suspension containing anhydrous crystals of the compound of formula (I)) A suspension containing anhydrous crystals of the compound of formula (I) was prepared. A dissolution test was conducted on this suspension and the above Example 5C-1 (uncoated tablets containing anhydrous crystals of the compound of formula (I)). <Method of preparing suspension> Anhydrous crystals of the compound of formula (I), hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.), and titanium oxide (manufactured by Merck) were mixed with a spatula, and then a small amount of water for injection (manufactured by Otsuka Pharmaceutical Factory, Ltd.) was added and kneaded with the spatula. Thereafter, the remaining water for injection was added while irradiating with ultrasound to obtain a suspension. The formulation is shown below.

[0178] <Dissolution test> A dissolution test was carried out in accordance with Test Example 16. The results of the dissolution tests for Examples 5C-1 and 5D-1 are shown in Figure 21. As a result, Example 5C-1 (plain tablet) showed more rapid dissolution than Example 5D-1 (suspension).

[0179] Example 5E: Study 1 of tablets containing anhydrous crystals of the compound of formula (I) In order to investigate the effect of a light stabilizer, uncoated tablets containing anhydrous crystals of the compound of formula (I) were coated with a light stabilizer and a polymer, and the amount of related substances in the formulation and the appearance were evaluated. Stability tests were conducted on the uncoated tablets and tablets in a heated and humidified environment, and the dissolution properties of each were evaluated. <Tablet manufacturing method> Anhydrous crystals of the compound of formula (I), D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), crospovidone (grade INF-10, manufactured by ASHLAND), and half of the amount of sodium stearyl fumarate (manufactured by JRS Pharma) were mixed in a polyethylene bag and sieved through a 30-mesh sieve. The mixture was then granulated using a roller compactor under conditions of a roll pressure of 7 MPa, a roll rotation speed of approximately 4 rpm, and a screw rotation speed of approximately 30 rpm. Subsequently, sizing was carried out using a sizing machine at a rotation speed of approximately 1800 rpm. The resulting sizing granules and half of the sodium stearyl fumarate were mixed in a mixer for 5 minutes and then compressed into tablets using a rotary tablet press at a turntable rotation speed of 20-30 rpm to produce uncoated tablets. Subsequently, coating was carried out using a coating machine under the following conditions: inlet air volume of 0.80 m3 / min, inlet air temperature setting of 60°C, liquid flow rate of 2.0-2.9 g / min, spray atomization pressure of approximately 0.18 MPa, and spray air volume of approximately 50 NL / min to obtain tablets of Example 5E-1. Talc, red ferric oxide, and yellow red ferric oxide were used as light stabilizers, and hypromellose was used as the polymer. The formulation is shown below.

[0180] <Dissolution test> The tablets of Example 5E-1 were stored in a sealed polyethylene bottle at 40°C and 75% relative humidity for one month, and then stored in a sealed polyethylene bottle at 40°C and 75% relative humidity for three months. Dissolution tests were carried out at the start of the test and after storage in each environment using the method of Test Example 16. The results are shown in Figure 22. It was confirmed that the dissolution rate did not decrease even after storage in a heated and humidified environment for three months.

[0181] <Stability Test> Plain tablets containing anhydrous crystals of the compound of formula (I) (see Example 5C-1 above) and tablets coated with a stabilizing substance and a polymer (see Example 5E-1 above) were irradiated with a total exposure of 1.2 million lux-hr, and the amount of related substances in the formulation and the external appearance were evaluated at the start of the test and after exposure to 1.2 million lux-hr. The amount of related substances measured was the relative retention time of 0.84 and the total amount of related substances. The external appearance was also evaluated visually.

[0182] Test Example 17: Analytical Method 3 for Related Substances The amount of related substances was measured by liquid chromatography using the following method and conditions: Detector: ultraviolet absorptiometer (measurement wavelength: 247 nm) Column: ACQUITY UPLC BEH C18 (1.7 μm, 2.1 × 100 mm, Waters) Column temperature: constant temperature around 40°C Mobile phase A: water / formic acid mixture (1000:1) Mobile phase B: acetonitrile / formic acid mixture for liquid chromatography (2000:1) Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was changed as follows to control the concentration gradient. Flow rate: 0.4 mL / min Injection volume: 5 μL Sample cooler temperature: Constant temperature around 25°C Needle washing solvent or auto injector washing solution: acetonitrile Area measurement range: Up to 43 minutes after sample solution injection

[0183] The amounts of related substances with a relative retention time of 0.84 at the start of the test and after irradiation with light of 1.2 million lux·hr are shown below. The total amount of related substances at the start of the test and after irradiation with 1.2 million lux·hr of light is shown below. After irradiation with a total light intensity of 1.2 million lux hr, Example 5E-1 showed significantly reduced amounts of related substances with a relative retention time of 0.84 and total related substances compared to Example 5C-1. Furthermore, with regard to the appearance after irradiation with a total light intensity of 1.2 million lux hr, Example 5C-1 showed a yellowish discoloration compared to before irradiation, while Example 5E-1 showed no change in appearance compared to before irradiation.

[0184] (Example 5F: Study of capsules and uncoated tablets containing anhydrous crystals of the compound of formula (I)) Granules containing anhydrous crystals of the compound of formula (I) were filled into capsules to prepare capsules. The amount of related substances in the capsules and uncoated tablets was evaluated. The amount of related substances was measured using a relative retention time of 0.98 and the total amount of related substances. <Method for manufacturing capsules and uncoated tablets> Anhydrous crystals of the compound of formula (I), D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium (manufactured by Dupont), and half the amount of magnesium stearate (manufactured by MALLINCKRODT) were mixed with a spatula and sieved through a wire mesh. The mixture was then compressed into tablets using a simple tablet molding machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.). The mixture was then sieved through a 20-mesh sieve, half the amount of magnesium stearate was added, and the mixture was mixed with a spatula to obtain granules. The granules were manually filled into hypromellose capsules (manufactured by Qualicaps) using a spatula to prepare the capsules of Example 5F-1. The granules were also compressed into tablets using a simple tablet molding machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.) to prepare the plain tablets of Example 5F-2. The formulations are shown below.

[0185] Test Example 18: Analytical Method 4 for Related Substances The amount of related substances was measured by liquid chromatography using the following method and conditions: Detector: ultraviolet absorptiometer (measurement wavelength: 254 nm) Column: ACQUITY UPLC BEH C18 (1.7 μm, 2.1 × 100 mm, Waters) Column temperature: constant temperature around 40°C Mobile phase A: water / trifluoroacetic acid mixture (1000:1) Mobile phase B: acetonitrile for liquid chromatography Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was changed as follows to control the concentration gradient. Flow rate: 0.3 mL / min Injection volume: 4 μL Sample cooler temperature: constant temperature around 10°C Needle washing solvent: methanol

[0186] <Stability Test> The amounts of related substances with a relative retention time of 0.98 at the start of the test and after irradiation with light of 1.2 million lux·hr are shown below. The total amount of related substances at the start of the test and after irradiation with 1.2 million lux·hr of light is shown below. It was confirmed that Example 5F-1 significantly reduced the amount of the related substance with a relative retention time of 0.98 and the total amount of related substances compared to Example 5F-2. The light-blocking effect of encapsulation was confirmed.

[0187] Example 6: Preparation containing solid dispersion of compound represented by formula (I) Formulation studies of a preparation containing a solid dispersion of compound represented by formula (I) are shown below.

[0188] Example 6A: Study of uncoated tablets containing a solid dispersion of the compound of formula (I) Uncoated tablets containing a solid dispersion of the compound of formula (I) were produced and subjected to a dissolution test. <Method for producing uncoated tablets> Anhydrous crystals of the compound of formula (I) and copovidone were dissolved in acetone. After confirming complete dissolution, spray drying was carried out using a spray dryer under the following conditions: outlet temperature 50°C, feed flow rate approximately 6 kg / hr, and spray pressure 1.0 bar. Subsequently, the mixture was vacuum dried for approximately 40 hours using a benchtop vacuum dryer to obtain a solid dispersion. The obtained solid dispersion, D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium (manufactured by Dupont) or crospovidone (manufactured by ASHLAND), light anhydrous silicic acid (manufactured by Cabot), and half of the amount of sodium stearyl fumarate (manufactured by JRS Pharma) were mixed with a spatula and sieved through a wire mesh. Then, the mixture was compressed into tablets using a simple tableting machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.). The mixture was then sized using a 20-mesh sieve, and half of the amount of sodium stearyl fumarate was added and mixed with a spatula. The obtained granules were compressed into tablets using a simple tableting machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.) to obtain plain tablets. The formulation is shown below.

[0189] <Dissolution test> A dissolution test was carried out in Test Example 16. As a result, Example 6A-1, which used croscarmellose sodium, showed good dissolution properties. Therefore, it is considered that croscarmellose sodium is a suitable disintegrant for tablets containing a solid dispersion.

[0190] (Example 6B-1: Study 1 of tablets containing a solid dispersion of the compound of formula (I)) A tablet was produced by coating a light stabilizer and a polymer on an uncoated tablet containing a solid dispersion of the compound of formula (I). A stability test was conducted on the tablet in a heated and humidified environment. <Method for producing tablets> Anhydrous crystals of the compound of formula (I) and copovidone were dissolved in acetone, and after confirming complete dissolution, spray drying was carried out using a spray dryer under conditions of an outlet temperature of 50°C, a feed flow rate of approximately 6 kg / hr, and a spray pressure of 1.0 bar. The solution was then vacuum dried for approximately 40 hours using a benchtop vacuum dryer to obtain a solid dispersion. The obtained solid dispersion was mixed with D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium (manufactured by Dupont), light anhydrous silicic acid (manufactured by Cabot), and half of the amount of sodium stearyl fumarate (manufactured by JRS Pharma) in a mixer for 8 minutes and sieved through a 30 mesh sieve. Then, using a roller compactor, dry granulation was performed under conditions of a roll pressure of 7 MPa, a roll rotation speed of about 4 rpm, and a screw rotation speed of about 40 rpm. Then, dry granulation was performed using a granulator at a rotation speed of about 3000 rpm. The obtained granulated granules and half of the amount of sodium stearyl fumarate were mixed in a mixer for 5 minutes, and then uncoated tablets were produced using a rotary tablet press at a turntable rotation speed of about 30 rpm. Thereafter, coating was carried out using a coating machine under the conditions of an intake air volume of 0.80 m3 / min, an intake air temperature setting of 60°C, a liquid flow rate of 2.0 to 2.9 g / min, a spray atomization pressure of approximately 0.18 MPa, and a spray air volume of approximately 50 NL / min, to obtain tablets. The formulation is shown below.

[0191] <Stability test and dissolution test> The tablets of Example 6B-1 were stored in a sealed brown glass bottle at 60°C for two weeks, at 40°C for one month in a sealed brown glass bottle, and at 40°C and 75% relative humidity for one month in a sealed brown glass bottle. At the start of the test and after storage in each environment, dissolution tests were carried out using the method of Test Example 16. The results are shown in Figure 23. It was confirmed that the dissolution rate did not decrease after storage under any of the conditions.

[0192] (Example 6B-2: Study 2 of tablets containing a solid dispersion of the compound of formula (I)) Uncoated tablets with a different content of solid dispersion consisting of the compound of formula (I) and copovidone than those in Example 6B-1 were produced, and coated with a light stabilizer and a polymer to produce tablets. A stability test was conducted on the tablets in a heated and humidified environment. <Tablet production method> Anhydrous crystals of the compound of formula (I) and copovidone were dissolved in acetone, and after confirming complete dissolution, spray drying was carried out using a spray dryer under conditions of an outlet temperature of 50°C, a feed flow rate of approximately 80 kg / hr, and a spray pressure of 2.5 bar. The solution was then vacuum dried for approximately 37 hours in a rotary vacuum dryer to obtain a solid dispersion. The obtained solid dispersion was mixed with D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium (manufactured by Dupont), light anhydrous silicic acid (manufactured by Cabot), and half of the amount of sodium stearyl fumarate (manufactured by JRS Pharma) in a mixer for 15 minutes and sieved using a screen with a hole diameter of 1.6 mm. Then, dry granulation was performed using a roller compactor under conditions of a roll pressure of 5 MPa, a roll rotation speed of about 5 rpm, and a screw rotation speed of about 5 rpm. Then, dry granulation was performed using a granulator at a rotation speed of about 100 rpm. The obtained granulated granules and half of the amount of sodium stearyl fumarate were mixed in a mixer for 3 minutes, and then uncoated tablets were produced using a rotary tablet press at a turntable rotation speed of about 20 rpm. Thereafter, coating was carried out using a coating machine under the conditions of an air intake volume of 12 m3 / min, an air intake temperature setting of 60°C, a liquid flow rate of 40 to 80 g / min, a spray atomization pressure of approximately 0.4 MPa, and a spray air volume of approximately 130 NL / min, to obtain tablets. The formulation is shown below.

[0193] <Stability Test and Dissolution Test> The tablets of Example 6B-2 were stored in a sealed brown glass bottle at 60°C for two weeks, at 40°C for one month in a sealed brown glass bottle, and at 40°C and 75% relative humidity for one month in a sealed brown glass bottle. At the start of the test and after storage in each environment, dissolution tests were conducted using the following method. (Dissolution Test Method) A dissolution test was conducted on one tablet of each tablet using the dissolution test method of the Japanese Pharmacopoeia, 18th Edition. The test fluid was dissolution test fluid 2, and the test was performed using the paddle method with a paddle rotation speed of 50 rpm. The results are shown in Figure 24. It was confirmed that the dissolution rate did not decrease after storage under any of the conditions.

[0194] Example 6C: Study of tablets containing a solid dispersion of the compound of formula (I) 3 Two types of uncoated tablets were produced, each having a different blending ratio from that of Example 6B-1 of a solid dispersion consisting of anhydrous crystalline compound of formula (I) and copovidone. Each uncoated tablet was coated with a light stabilizer and a polymer to produce a tablet. A stability test was conducted on the tablets in a heated and humidified environment. <Tablet production method> Anhydrous crystalline compound of formula (I) and copovidone were dissolved in acetone, and after confirming complete dissolution, a solid dispersion was obtained using a spray dryer under conditions of an inlet temperature of 90°C, a liquid pump at 20%, and a nitrogen flow rate of 40. The obtained solid dispersion, D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium (manufactured by Dupont), and half of the amount of sodium stearyl fumarate (manufactured by JRS Pharma) were mixed with a spatula and sieved through a wire mesh. Thereafter, the mixture was compressed into tablets using a simple tableting machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.). The mixture was then sized using a 20-mesh sieve, and half the amount of sodium stearyl fumarate was added and mixed with a spatula. The obtained granules for tableting were compressed into tablets using a simple tableting machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.), and then coated using a coating machine (Powrex) to obtain tablets. The formulation is shown below.

[0195] <Stability test and dissolution test> The tablets of Example 6C-1 and Example 6C-2 were stored in a sealed brown glass bottle in a heated environment of 60°C for one week and in a sealed brown glass bottle in a 40°C, 75% relative humidity environment for one week, and then a dissolution test was performed. The dissolution test was performed in Test Example 16. The results of Example 6C-1 are shown in Figure 25 and the results of Example 6C-2 in Figure 26. It was confirmed that the dissolution rate did not decrease when the tablets were stored in a sealed glass bottle in a heated environment of 60°C for one week and in a sealed glass bottle in a 40°C, 75% relative humidity environment for one week.

[0196] (Example 6D: Study of tablets containing a solid dispersion of the compound of formula (I) 4) Uncoated tablets containing a solid dispersion consisting of anhydrous crystals of the compound of formula (I) and copovidone, and tablets coated with a light stabilizer and a polymer were produced. The uncoated tablets and tablets were irradiated with a total light dose of 1.2 million lux-hr, and the amount of related substances in the formulation and the appearance were evaluated at the start of the test and after irradiation with 1.2 million lux-hr. <Production method of uncoated tablets and tablets> Anhydrous crystals of the compound of formula (I) and copovidone were dissolved in acetone. After confirming complete dissolution, spray drying was carried out under conditions of an outlet temperature of 50°C, a feed flow rate of approximately 6 kg / hr, and a spray pressure of 1.0 bar. The mixture was then vacuum dried for approximately 40 hours in a benchtop vacuum dryer to obtain a solid dispersion. The obtained solid dispersion, D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium (manufactured by Dupont), light anhydrous silicic acid (manufactured by Cabot), and half of the sodium stearyl fumarate (manufactured by JRS Pharma) were mixed in a mixer for 8 minutes and sieved through a 30-mesh sieve. Then, using a roller compactor, dry granulation was performed under conditions of a roll pressure of 7 MPa, a roll rotation speed of about 4 rpm, and a screw rotation speed of about 40 rpm. Then, dry granulation was performed using a granulator at a rotation speed of about 3000 rpm. The obtained granulated granules and half of the sodium stearyl fumarate were mixed in a mixer for 5 minutes, and then uncoated tablets (Example 6D-1) were produced using a rotary tablet press at a turntable rotation speed of about 30 rpm. For Example 6D-2, coating was then carried out using a coating machine under the conditions of an intake air volume of 0.80 m3 / min, an intake air temperature setting of 60°C, a liquid flow rate of 2.0 to 2.9 g / min, a spray atomization pressure of about 0.18 MPa, and a spray air volume of about 50 NL / min to obtain tablets. The formulation is shown below.

[0197] The formulations of Example 6D-1 and Example 6D-2 were irradiated with a total light dose of 1.2 million lux-hr, and the amount of related substances in the formulation and the external appearance were evaluated at the start of the test and after irradiation with 1.2 million lux-hr. The amount of related substances was measured using the method of Test Example 17, measuring the relative retention time of 1.59 and the total amount of related substances. The external appearance was also evaluated visually.

[0198] <Results> The amounts of related substances with a relative retention time of 1.59 at the start of the test and after irradiation with light of 1.2 million lux·hr are shown below. The total amount of related substances at the start of the test and after irradiation with 1.2 million lux·hr of light is shown below. After irradiation with a total light intensity of 1.2 million lux-hr, Example 6D-2 showed a significant suppression of the amount of related substances with a relative retention time of 1.59 and the total amount of related substances compared to Example 6D-1. Furthermore, with regard to the appearance after irradiation with a total light intensity of 1.2 million lux-hr, Example 6D-1 turned yellow compared to before irradiation, but Example 6D-2 showed no change in appearance compared to before irradiation.

[0199] Example 6E: Study of Tablets Containing a Solid Dispersion of the Compound of Formula (I) 5 Uncoated tablets containing a solid dispersion of the compound of formula (I) and copovidone different from those in Example 6D were prepared, as were tablets coated with a light stabilizer and a polymer. The uncoated tablets and tablets were irradiated with a total light dose of 1.2 million lux-hr, and the amount of related substances in the formulation and the appearance were evaluated at the start of the test and after irradiation with 1.2 million lux-hr. <Method for Manufacturing Uncoated Tablets and Tablets> The anhydrous crystals of the compound of formula (I) and copovidone were dissolved in acetone. After confirming complete dissolution, spray drying was carried out using a spray dryer under conditions of an outlet temperature of 50°C, a feed flow rate of approximately 80 kg / hr, and a spray pressure of 2.5 bar. The solution was then vacuum dried for approximately 37 hours in a rotary vacuum dryer to obtain a solid dispersion. The obtained solid dispersion was mixed with D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahikasei), croscarmellose sodium (manufactured by Dupont), light anhydrous silicic acid (manufactured by Cabot), and half of the amount of sodium stearyl fumarate (manufactured by JRS Pharma) in a mixer for 15 minutes, and then sieved using a screen with a hole diameter of 1.6 mm. Then, dry granulation was carried out using a roller compactor at a roll pressure of 5 MPa, a roll rotation speed of about 5 rpm, and a screw rotation speed of about 5 rpm. Then, dry granulation was carried out using a granulator at a rotation speed of about 100 rpm. The obtained granulated granules and half of the amount of sodium stearyl fumarate were mixed in a mixer for 3 minutes, and then uncoated tablets (Example 6E-2) were produced using a rotary tablet press at a turntable rotation speed of about 20 rpm. For Example 6E-1, coating was then carried out using a coating machine under the conditions of an intake air volume of 12 m3 / min, an intake air temperature setting of 60°C, a liquid flow rate of 40 to 80 g / min, a spray atomization pressure of about 0.4 MPa, and a spray air volume of about 130 NL / min to obtain tablets. The formulation is shown below.

[0200] The formulations of Example 6E-1 and Example 6E-2 were irradiated with a total light exposure of 1.2 million lux-hr, and the amount of related substances in the formulation and the external appearance were evaluated at the start of the test and after irradiation with 1.2 million lux-hr. The amount of related substances was measured using the relative retention time of 1.59 and the total amount of related substances according to the method of Test Example 17. The external appearance was also evaluated visually.

[0201] <Results> The amounts of related substances with a relative retention time of 1.59 at the start of the test and after irradiation with light of 1.2 million lux·hr are shown below. The total amount of related substances at the start of the test and after irradiation with 1.2 million lux·hr of light is shown below. Compared with Example 6E-2, in Example 6E-1, both the amount of related substances with a relative retention time of 1.59 and the amount of total related substances were significantly suppressed. Regarding appearance, when the plain tablets of Example 6E-2 were irradiated with light of 1.2 million lx hr, they turned yellow compared to before irradiation, but when the tablets of Example 6E-1 were irradiated with light of 1.2 million lx hr, no change in appearance was observed compared to before irradiation.

[0202] (Example 7: Capsules containing a solution of the compound represented by formula (I)) The capsules shown below were produced to investigate a pharmaceutical formulation that would enable confirmation of oral absorption, distribution, metabolism, and excretion (ADME test). Capsules containing a solution of the compound represented by formula (I) were produced, and the stability of the capsules was evaluated. Capsules with the formulation shown below were produced, and a stability test was carried out. <Production method> Anhydrous crystals of the compound of formula (I), copovidone (manufactured by ASHLAND), ascorbic acid (manufactured by Kanto Chemical), citric acid (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), and α-tocopherol polyethylene glycol succinate (manufactured by BLD Pharmatech) were added to Macrogol 400 (manufactured by BASF) stirred with a stirrer. After confirming that the solution was clear, it was filled into gelatin capsules (manufactured by Capsugel) to obtain samples for evaluation.

[0203] <Stability test> Examples 7-1 to 7-4 shown in Table 36 were stored in sealed brown glass bottles in a heated environment at 25°C for 6 days, and the amount of related substances in the formulations was evaluated. The related substance test was carried out under the conditions of Test Example 17, and the injection volume was 25 μL.

[0204] <Results> The total amount of related substances at 0.1% or more at the start of the test and after storage at 25°C for 6 days 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 individual related substances were found to be at 0.1% or more from the start of the test until after storage at 25°C for 6 days.

[0205] (Example 8: Solution formulation of compound of formula (I)) The following solution formulations were prepared to examine formulations that would enable confirmation of oral absorption, distribution, metabolism, and excretion (ADME test). Solution formulations with the formulations shown in Table 38 were prepared and stored in a heated environment at 5°C or 25°C for 7 days, and then a dissolution test was performed. <Production Method> The compound represented by formula (I) was added to Macrogol 400 (manufactured by BASF) stirred with a stirrer and dissolved. Copovidone (manufactured by ASHLAND) and ascorbic acid (manufactured by DSM) were added and stirred with a stirrer to dissolve. After confirming that the solution was clear, propylene glycol (manufactured by BASF) was added and stirred with a stirrer to obtain a solution preparation.

[0206] <Dissolution Test> A dissolution test was carried out on the solution preparations obtained in each Example according to the dissolution test method of the Japanese Pharmacopoeia, 18th Edition. The test fluid was the second dissolution test fluid, and the test was carried out using the paddle method at a paddle rotation speed of 50 rpm (which was changed to 250 rpm 120 minutes after the start of the test).

[0207] <Results> The results of the dissolution test of Example 8-1 are shown in Figure 27. The formulation of Example 8-1 showed good dissolution properties even at the start of the test, and the dissolution rate did not decrease even after storage in a heated environment at 5°C or 25°C for 7 days.

[0208] Example 9: Preparation containing ethyl acetate solvate crystals of the compound of formula (I) Formulation studies of a preparation containing ethyl acetate solvate crystals of the compound of formula (I) as an active ingredient are shown below.

[0209] (Example 9A: Study of uncoated tablets containing ethyl acetate solvate crystals of the compound represented by formula (I)) Uncoated tablets containing ethyl acetate solvate crystals of the compound represented by formula (I) as an active ingredient were produced, and stability tests and dissolution tests were conducted. <Method for producing uncoated tablets> Ethyl acetate solvate 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 of the amount of magnesium stearate (manufactured by MALLINCKRODT) were mixed with a spatula and sieved through a wire mesh. Thereafter, tablets were formed using a simple tablet molding machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.). Thereafter, the mixture was sieved using a 20-mesh sieve, and half of the amount of magnesium stearate was added and mixed with a spatula. The obtained granules for tableting were tableted using a simple tablet molding machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.) to obtain uncoated tablets. The formulation is shown below.

[0210] <Stability test and dissolution test> The uncoated tablets of Example 9A-1 were stored in a closed brown glass bottle in a heated environment of 60°C for 2 weeks and in an opened brown glass bottle in a 40°C, 75% relative humidity environment for 2 weeks, and then subjected to a dissolution test. The dissolution test was carried out according to Test Example 19.

[0211] <Dissolution Test> Test Example 19: Dissolution Test A dissolution test was carried out for the preparations obtained in each Example (one tablet in the case of tablets) according to the dissolution test method of the Japanese Pharmacopoeia, 18th Edition. The test fluid was fed artificial intestinal fluid and the test was carried out using the paddle method at a paddle rotation speed of 50 rpm (changed to 250 rpm 120 minutes after the start of the test).

[0212] Example 9B: Study 1 of Capsules Containing Ethyl Acetate Solvate Crystals of the Compound of Formula (I) Capsules containing ethyl acetate solvate crystals of the compound of formula (I) were produced, and a PK test was conducted on the capsules in dogs. <Method for producing capsules> The ethyl acetate solvate crystals of the compound of formula (I), D-mannitol (manufactured by ROQUETTE), microcrystalline cellulose (manufactured by Asahikasei), croscarmellose sodium (manufactured by Dupont), and half of the amount of magnesium stearate (manufactured by MALLINCKRODT) were mixed with a spatula and sieved through a wire mesh. The mixture was then compressed into tablets using a simple tablet molding machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.). The mixture was then sieved through a 20-mesh sieve, and half of the amount of magnesium stearate was added and mixed with a spatula to obtain granules. The granules were manually filled into gelatin capsules with the spatula to prepare capsules. The prescription is shown below.

[0213] Test Example 20: Dog PK Study Male beagle dogs were fed 30 minutes to 2 hours before administration, and then orally administered one capsule. Table 33 shows the formulation of capsules containing 120.0 mg of granules of the compound of formula (I). In this test, the mass of granules per capsule was adjusted according to the body weight of the male beagle dog so that the dose of the compound of formula (I) was 3 mg / kg body weight. After administration of each sample, blood was collected at each sampling time, and the maximum plasma drug concentration (Cmax), the time to reach the maximum plasma drug concentration (Tmax), and the area under the plasma drug concentration-time curve (AUC) from the time of administration to 48 hours later were calculated using LC / MS / MS.

[0214] (Example 9C: Study 2 of capsules containing the ethyl acetate solvate of the compound of formula (I)) Capsules containing the ethyl acetate solvate of the compound of formula (I) were produced, with a formulation different from that of Example 9B, and the dissolution properties of the capsules were evaluated. <Method for producing capsules> The ethyl acetate solvate of the compound of formula (I), copovidone (manufactured by ASHLAND), microcrystalline 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 through a wire mesh, and then filled into hypromellose capsules (manufactured by Qualicaps) with the spatula to prepare capsules. The formulation is shown below.

[0215] <Dissolution test> The preparations (one capsule) obtained in each example were subjected to a dissolution test according to the 18th edition of the Japanese Pharmacopoeia. Fasting artificial intestinal fluid (FaSSIF-V2) was used as the test fluid, and the test was carried out using the paddle method at a paddle rotation speed of 50 rpm (which was changed to 250 rpm 120 minutes after the start of the test).

[0216] <Results> The results of the dissolution tests for Examples 9C-1 to 9C-4 are shown in Figure 28. Although Example 9C-1, in which the ethyl acetate solvate of the compound of formula (I) was filled into a hypromellose capsule, did not exhibit sufficient dissolution, the dissolution was improved by adding 30.0 mg of copovidone and 7.5 mg of croscarmellose sodium (Examples 9C-2 and 9C-3). Furthermore, by adding D-mannitol and magnesium stearate and adjusting the amount of copovidone from 30 mg to 7.5 mg, even better dissolution was exhibited (Example 9C-4).

[0217] (Example 10: Capsules containing a solution of the ethyl acetate solvate of the compound represented by formula (I)) The capsules shown below were produced to investigate a pharmaceutical formulation that would enable confirmation of oral absorption, distribution, metabolism, and excretion (ADME test). Capsules containing a solution of the ethyl acetate solvate of the compound represented by formula (I) were produced, and the dissolution properties of the capsules were evaluated. Capsules with the formulation shown below were produced, and a dissolution test was carried out. <Production method> The ethyl acetate solvate of the compound of formula (I) and copovidone (manufactured by ASHLAND) were added to Macrogol 400 (manufactured by BASF) that had been stirred using a stirrer. After confirming that the mixture was clear, the mixture was filled into hypromellose capsules (manufactured by Qualicaps) to obtain capsules.

[0218] <Dissolution test> The preparations (2 capsules) obtained in each example were subjected to a dissolution test according to the Japanese Pharmacopoeia, 18th Edition. The test fluid was the second dissolution test fluid, and the test was carried out using the paddle method at a paddle rotation speed of 50 rpm (which was changed to 250 rpm 120 minutes after the start of the test).

[0219] <Results> The results of the dissolution test of Examples 10-1 and 10-2 are shown in Figure 29. When the ethyl acetate solvate of the compound of formula (I) was dissolved in Macrogol 400, good dissolution was observed (Example 10-1). When 150.4 mg of copovidone was added, even better dissolution was observed (Example 10-2).

[0220] (Example 11: Solution preparation of ethyl acetate solvate of compound of formula (I)) The following capsules were produced to investigate a formulation that would enable confirmation of oral absorption, distribution, metabolism, and excretion (ADME test). A solution preparation with the following formulation was produced and stored in a heated environment at 5°C for 3 days, after which a dissolution test was carried out. <Production method> The ethyl acetate solvate of the compound represented by formula (I) was added to Macrogol 400 (manufactured by BASF) stirred with a stirrer and dissolved. Copovidone (manufactured by ASHLAND) was added to water for injection and stirred with a stirrer to dissolve. An aqueous solution of copovidone (manufactured by ASHLAND) was added to the Macrogol 400 solution of the ethyl acetate solvate of the compound represented by formula (I), and the mixture was stirred with a stirrer to obtain a solution preparation.

[0221] <Dissolution Test> A dissolution test was carried out on the solution preparations obtained in each Example according to the dissolution test method of the Japanese Pharmacopoeia, 18th Edition. The test fluid was the second dissolution test fluid, and the test was carried out using the paddle method at a paddle rotation speed of 50 rpm (which was changed to 250 rpm 120 minutes after the start of the test).

[0222] <Results> The results of the dissolution test for Examples 11-1, 11-2, and 11-3 are shown in Figure 30. When the formulation of Example 11-1 was stored in a heated environment at 5°C for 3 days, the dissolution rate decreased. In Examples 11-2 and 11-3, in which 1107.6 mg and 1418.6 mg of copovidone were added, the decrease in dissolution rate was suppressed, and a high dissolution rate was maintained.

[0223] Example 12: Rat PK study of formulations containing the compound of formula (I) and the ethyl acetate solvate of the compound of formula (I) In order to investigate formulations that allow for confirmation of oral absorption, distribution, metabolism, and excretion (ADME test), formulations having the following formulations were produced and rat PK studies were carried out. In the rat PK study, male rats were fed, and then the compound of formula (I) was administered at 0.3 mg / head or 1 mg / kg. After administration of Examples 12-1 to 12-6 shown below, blood samples were taken at each blood sampling time, and the maximum plasma drug concentration (Cmax) and the area under the plasma drug concentration-time curve (AUC) from the time of administration up to 24 hours later were calculated using LC / MS / MS. <Production Method> Example 12-1 Anhydrous crystals of the compound of formula (I), copovidone (manufactured by ASHLAND), and ascorbic acid (manufactured by DSM) were added to Macrogol 400 (manufactured by BASF) that had been stirred using a stirrer. After confirming that the mixture was clear, propylene glycol (manufactured by BASF) was added and the mixture was mixed using a stirrer to obtain a sample for administration. Example 12-2 An ethyl acetate solvate of the compound of formula (I) and copovidone (manufactured by ASHLAND) were added to Macrogol 400 (manufactured by BASF) that had been stirred using a stirrer. After confirming that the mixture was clear, the mixture was filled into gelatin capsules (manufactured by Capsugel) to obtain a sample for administration. Example 12-3: The ethyl acetate solvate of the compound of formula (I), copovidone (manufactured by ASHLAND), microcrystalline 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 through a wire mesh. The mixture was then filled into gelatin capsules (manufactured by Capsugel) using the spatula to obtain a test sample. Example 12-4: The ethyl acetate solvate of the compound of formula (I) was suspended in an aqueous solution containing 1% hydroxypropyl cellulose (manufactured by Nippon Soda), and the suspension was filled into gelatin capsules (manufactured by Capsugel) to obtain a test sample. Example 12-5: A test sample was obtained by suspending a solid dispersion powder of the compound of formula (I) in an aqueous solution containing 0.5% methylcellulose. Example 12-6 Anhydrous crystals of the compound of formula (I) were suspended in an aqueous solution containing 0.5% methylcellulose to obtain a sample for administration.

[0224] <Results> The results of Cmax and AUC of the compound represented by formula (I) in each example are shown below: Examples 12-1 to 12-5 showed high absorbability.

[0225] The formulations and crystals of the present invention have an inhibitory effect on coronavirus 3 CL protease and are considered to be useful as therapeutic and / or preventive agents for diseases or conditions associated with coronavirus 3 CL protease.

Claims

1. A preparation comprising, as an active ingredient, a compound represented by formula (I): [Chemical formula 1] its pharmaceutically acceptable salt or solvate thereof.

2. The preparation according to claim 1, wherein the active ingredient is an amorphous form of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof.

3. The preparation according to claim 2, wherein the active ingredient is an amorphous form of a compound represented by formula (I).

4. The preparation according to claim 3, wherein the amorphous form of the compound represented by formula (I) is contained in a solid dispersion.

5. The preparation according to claim 4, wherein the solid dispersion further comprises a polymer.

6. The preparation according to claim 5, wherein the polymer is one or more selected from a vinyl-based polymer, a cellulose-based polymer, or an acrylic acid-based polymer.

7. The preparation of claim 6, wherein the polymer is a vinyl-based polymer, and the vinyl-based polymer is one or more selected from the group consisting of copovidone, polyvinylpyrrolidone, polyvinylpolypyrrolidone, polyvinyl alcohol, a copolymer of polyvinyl alcohol, acrylic acid and methyl methacrylate, a graft copolymer of poly(vinyl alcohol) and poly(ethylene glycol), polyvinyl acetal diethylaminoacetate, and a mixture of fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose.

8. The preparation according to claim 7, wherein the vinyl-based polymer is copovidone.

9. The preparation according to claim 6, wherein the polymer is a cellulose-based polymer, and the cellulose-based polymer is one or more selected from the group consisting of hypromellose acetate succinate, hypromellose phthalate, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose phthalate, methylcellulose, methylhydroxyethyl cellulose, carboxymethylethylcellulose, ethylcellulose, crystalline cellulose, microcrystalline cellulose, crystalline cellulose-sodium carmellose, carmellose, sodium carmellose, calcium carmellose, powdered cellulose and a mixture of fumaric acid, stearic acid, poly(vinyl acetal) diethylaminoacetate and hydroxypropyl methylcellulose.

10. The preparation according to claim 6, wherein the polymer is an acrylic acid-based polymer, and the acrylic acid-based polymer is one or more selected from 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 and methyl methacrylate copolymer, ammonioalkyl methacrylate copolymer, methyl acrylate, methacrylic acid and methyl methacrylate copolymer and 2-methyl-5-vinylpyridinemethyl acrylate and methacrylic acid copolymer.

11. The preparation according to claim 1, wherein the active ingredient is a crystal of a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof.

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

13. The preparation according to any one of paragraphs 1-12, additionally comprising a disintegrant, a filler and / or a lubricant.

14. The preparation according to claim 13, wherein the disintegrant is one or more selected from the group consisting of croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, powdered cellulose, partially pregelatinized starch, potato starch, corn starch, hydroxypropyl starch, sodium carboxymethyl starch, low-substituted sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, starch, polyvinyl alcohol and crospovidone.

15. The preparation according to claim 14, wherein the disintegrating agent is sodium croscarmellose.

16. The preparation according to claim 14, wherein the disintegrant is crospovidone.

17. The drug according to any of paragraphs. 13-16, wherein the filler is one or more selected from the group consisting of crystalline cellulose, silicified microcrystalline cellulose, lactose, anhydrous lactose, sucrose, glucose, fructose, sucrose, mannitol, sorbitol, erythritol, xylitol, maltodextrin, maltitol, starch, potato starch, corn starch, rice starch, partially pregelatinized starch, pregelatinized starch, porous starch, sodium carboxystarch, hydroxypropyl starch, low-substituted sodium carboxymethyl starch, powdered cellulose, sodium carmellose, carmellose, calcium carmellose, carboxymethyl ethylcellulose, low-substituted hydroxypropyl cellulose, silicate derivative, phosphate, carbonate, sulfate, magnesium oxide, titanium oxide, calcium lactate, synthetic hydrotalcite, talc, kaolin, dried aluminum hydroxide, magnesium oxide, bentonite, silicon dioxide,such as silicon hydroxide and light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, calcium silicate, anhydrous dibasic calcium phosphate, calcium monohydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, dibasic potassium phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, precipitated calcium carbonate, calcium carbonate, magnesium carbonate and calcium sulfate., 18. The drug according to any of paragraphs. 13-17, wherein the lubricant is one or more selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, polyoxyl stearate 40, talc, light anhydrous silicic acid, hydrated silicon dioxide, magnesium carbonate, precipitated calcium carbonate, dried aluminum hydroxide gel, magnesium aluminometasilicate, magnesium silicate, synthetic aluminum silicate, magnesium oxide, magnesium sulfate, cocoa butter, carnauba wax, fatty acid ester of glycerin, hydrogenated oil, bleached beeswax, hydrogenated soybean oil, beeswax, cetanol, sodium laurate, fatty acid ester of sucrose, and polyethyleneglycol.

19. The preparation according to any one of paragraphs 1-18, further comprising a coating layer.

20. The preparation according to claim 19, wherein the coating layer comprises a photostabilizer and a polymer.

21. The preparation according to claim 20, wherein the photostabilizer in the coating layer is one or more selected from the group consisting of Food Red No. 2, Food Red No. 3, Food Red No. 102, Food Red No. 104, Food Red No. 105, Food Red No. 106, Food Yellow No. 4, Food Yellow No. 5, Food Green No. 3, Food Blue No. 1, Food Blue No. 2, Food Red No. 3 aluminum varnish, Food Yellow No. 4 aluminum varnish, Food Yellow No. 5 aluminum varnish, Food Blue No. 1 aluminum varnish, Food Blue No. 2 aluminum varnish, carmine, sodium copper chlorophyllin, copper chlorophyll complex, red iron oxide, black iron oxide, yellow iron oxide, titanium oxide, red iron (III) oxide, yellow iron (III) oxide and talc.

22. The preparation according to claim 21, wherein the photostabilizer is red iron (III) oxide, yellow iron (III) oxide and / or talc.

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

24. The preparation according to claim 23, wherein the polymer in the coating layer is hypromellose.

25. The drug according to any one of claims 1-24, wherein the drug is an oral drug.

26. The drug according to claim 25, wherein the drug is a tablet, granule, powder or capsule.

27. The preparation according to claim 11, wherein the active ingredient is a crystal of ethyl acetate solvate of a compound represented by formula (I).

28. The drug according to claim 27, wherein the drug is a capsule.

29. An amorphous form of the compound represented by formula (I): [Chemical formula 2] 30. A crystal of ethyl acetate solvate of the compound represented by formula (I): [Chemical formula 3] .

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