Formulation 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

Technical Field

[0001] The present invention relates to a pharmaceutical preparation containing a uracil derivative. Specifically, it relates to a pharmaceutical preparation containing a uracil derivative showing coronavirus 3CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a solvate thereof. Furthermore, the present invention relates to the solid state (crystalline and amorphous) of a uracil derivative showing coronavirus 3CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a solvate thereof.

Background Art

[0002] Coronaviruses belonging to the subfamily Orthocoronavirinae of the family Coronaviridae, order Nidovirales, have a genome size of about 30 kilobases and are the largest single-stranded + strand RNA viruses among known RNA viruses. Coronaviruses are classified into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. As coronaviruses that infect humans, a total of seven types are known, including two types in the genus Alphacoronavirus (HCoV-229E, HCoV-NL63) and five types in the genus Betacoronavirus (HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV, SARS-CoV-2). Among these, four types (HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43) are pathogens of the common cold, while the remaining three types 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 across the international community and was declared a pandemic by the WHO on March 11, 2020. Droplet infection, contact infection, and aerosol infection have been reported as the main routes of infection of SARS-CoV-2. It has been confirmed that SARS-CoV-2 can continue to float in the air with aerosols for about 3 hours and maintain its infectivity (Non-Patent Document 1). The incubation period is about 2 to 14 days, and typical cold-like symptoms such as fever (87.9%), dry cough (67.7%), fatigue (38.1%), and sputum (33.4%) are common (Non-Patent Document 2). In severe cases, respiratory failure due to acute respiratory distress syndrome, acute lung injury, interstitial pneumonia, etc. occurs. In addition, multiple organ failure such as renal failure and liver failure has also been reported.

[0004] When a coronavirus infects a cell, it synthesizes two polyproteins. These two polyproteins contain a replication complex that makes the viral genome and two proteases. Proteases are essential for cleaving the polyproteins synthesized from the virus and enabling each protein to function. Among the two proteases, 3CL protease (main protease) is responsible for most of the cleavage of the polyprotein (Non-Patent Document 3). As the active ingredient of COVID-19 therapeutic drugs targeting 3CL protease, compounds with various chemical structures are known, but the compounds used in the present invention have different chemical structures.

[0005] Compounds having 3CL protease inhibitory activity are disclosed in Patent Documents 1 to 4 and Non-Patent Documents 4 to 14, but neither the compounds used in the present invention are described nor suggested in any of these documents.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

[0007] [Non-Patent Document 1] The NEW ENGLAND JOURNAL of MEDICINE (2020), Vol. 382, pp. 1564 - 1567 [Non-Patent Document 2] “Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)”, [online], February 28, 2020, WHO, [searched on March 16, 2023], Internet <URL:https: / / www.who.int / docs / default-source / coronaviruse / who-china-joint-mission-on-covid-19-final-report.pdf> [Non-Patent Document 3] Science (2003), Vol. 300, pp. 1763 - 1767 [Non-Patent Document 4] “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 [Non-Patent Document 5] Cell Research (2020), Vol. 30, pp. 678 - 692 [Non-Patent Document 6] Science (2020), Vol. 368, pp. 409 - 412 [Non-Patent Document 7] ACS Central Science (2021), 7, 3, 467 - 475 [Non - Patent Document 8] 261st Am Chem Soc (ACS) Natl Meet · 2021 - 04 - 05 / 2021 - 04 - 16 · Virtual, N / A · Abst 243 [Non - Patent Document 9] Science (2021), 374, 1586 - 1593 [Non - Patent Document 10] "Discovery and Development of PBI - 0451", [online], March 24, 2022, 35th International Conference on Antiviral Research (ICAR), [searched on March 16, 2023], Internet <URL:https: / / ir.pardesbio.com / static-files / fc7c4f8c - e0bd - 4b97 - 8c9c - eff09bafd4db> [Non - Patent Document 11] Molecules (2020), 25, 3193 [Non - Patent Document 12] Molecules (2020), 25, 3920 [Non - Patent Document 13] European Journal of Medicinal Chemistry (2020), 206, 112711 [Non - Patent Document 14] Journal of the American Chemical Society (2022), 144, 2905 - 2920 [Summary of the Invention] [Problems to be Solved by the Invention]

[0008] An object of the present invention is to provide a pharmaceutical preparation containing, as an active ingredient, a uracil derivative having a coronavirus 3CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a solvate thereof. Preferably, the present invention provides an oral preparation containing, as an active ingredient, a uracil derivative having an antiviral action, particularly an inhibitory action on the growth of coronavirus, 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 having a coronavirus 3CL protease inhibitory activity, a pharmaceutically acceptable salt thereof, or a solvate thereof.

Means for Solving the Problems

[0009] The present invention relates to the following. (1) A pharmaceutical preparation containing, as an active ingredient, a compound represented by formula (I):

Chemical formula

Chemical formula

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

[0011]

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Mode for Carrying Out the Invention

[0012] The meanings of the terms used in this specification are explained below. Unless otherwise specified, each term is used with the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The terms "comprising" and "including" mean not being limited to the constituent elements and not excluding elements not described. Hereinafter, the present invention will be described while showing embodiments. Throughout this specification, it should be understood that singular expressions also include the concepts of their plural forms unless otherwise stated. Therefore, singular articles (for example, "a", "an", "the", etc. in English) should be understood to also include the concepts of their plural forms unless otherwise stated. In addition, it should be understood that the terms used in this specification are used in the meanings commonly used in the above field unless otherwise stated. Therefore, unless otherwise defined, all technical terms and scientific and technological terms used in this specification have the same meanings as generally understood by those skilled in the art to which the present invention pertains. In case of contradiction, this specification (including definitions) shall prevail.

[0013] Unless otherwise specified, the numerical values described in this specification and the claims are approximate values. Variations in numerical values are due to device calibration, device errors, purity of substances, crystal size, sample size, temperature, and other factors.

[0014] Formula (I):

Chemical Formula

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

[0016] One or more hydrogens, carbons and / or other atoms of the compound represented by formula (I) may each be substituted with an isotope of hydrogen, carbon and / or other atoms. Examples of such isotopes include 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 including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine such as Cl. The compound represented by formula (I) also includes compounds substituted with such isotopes (e.g., deuterium-converted products, etc.). The compounds substituted with such isotopes are also useful as pharmaceuticals. The compound represented by formula (I) includes all radiolabeled forms substituted with radioactive isotopes contained in said isotopes. Also included in the present invention is a "radiolabeling method" for producing said "radiolabeled form", and said "radiolabeled form" is useful as a tool for metabolic pharmacokinetic studies, studies in binding assays and / or diagnosis.

[0017] The radiolabeled form of the compound represented by formula (I) can be prepared by methods well known in the art. For example, a tritium-labeled compound represented by formula (I) can be prepared by introducing tritium into a specific compound represented by formula (I) by a catalytic dehalogenation reaction using tritium. This method involves reacting a compound represented by formula (I) with a tritium gas in the presence or absence of a base in the presence of a suitable catalyst, such as Pd / C, with the compound represented by formula (I) being appropriately halogen-substituted. Other suitable methods for preparing tritium-labeled compounds can be referred to "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". 14 The C-labeled compound can be 14 prepared by using a starting material having C carbon.

[0018] The compounds represented by formula (I) used herein may form prodrugs, and the present invention also includes such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically decomposed, and is a compound that becomes a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into the compound represented by formula (I), compounds that are hydrolyzed by gastric acid, etc. to be converted into the compound represented by formula (I), and the like. Methods for selecting and producing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs may themselves have activity.

[0019] Since the compound according to the present invention has an inhibitory activity against coronavirus 3CL protease, it is useful as a therapeutic agent and / or prophylactic agent for diseases involving coronavirus 3CL protease. In the present invention, the term "therapeutic agent and / or prophylactic agent" also includes an agent for improving symptoms. Examples of diseases involving 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. Preferably, infections caused by HCoV-229E, HCoV-OC43, and / or SARS-CoV-2, particularly preferably, infections caused by SARS-CoV-2 are included. As the coronavirus infection, particularly preferably, coronavirus disease 2019 (COVID-19) is included.

[0020] The "compound represented by formula (I)" used in the present specification may form a salt, a co-crystal, or a solvate thereof. The "compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof" used in the present specification also includes such various salts, co-crystals, and solvates thereof.

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

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

[0023] Generally, it is considered that proton transfer occurs between a compound and counter molecules in a salt, but it is also known that in some cases, the proton transfer may not be complete. Since this state is not a true salt, it may be called a cocrystal. It is also known that proton transfer may change continuously depending on temperature. Therefore, the "pharmaceutically acceptable salt of the compound represented by formula (I)" as used herein includes a cocrystal and refers to a pharmaceutically acceptable salt or cocrystal of the compound represented by formula (I).

[0024] One aspect herein is a pharmaceutically acceptable salt or cocrystal of the compound represented by formula (I) with hydrofluoric acid, hydrochloric acid, hydrobromic acid, orthophosphoric acid, hydroiodic acid, nitric acid, phosphoric acid, boric 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, etc.

[0025] Studies on salt formation and co-crystal formation provide a means of altering the physicochemical and resulting biological characteristics of a drug without changing its chemical structure. Salt formation and co-crystal formation can have a dramatic impact on the properties of a drug. In the selection of an appropriate salt or co-crystal, hygroscopicity, stability, solubility, and processing characteristics are also important aspects. The solubility of a salt or co-crystal can affect its suitability for use as a drug. If the aqueous solubility is low, the dissolution rate in in vivo administration is rate-limiting in the absorption process and can result in low bioavailability. Also, due to low water solubility, administration by injection can be difficult, which can limit the choice of an appropriate administration route.

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

[0027] As used herein, "solvate" refers to, for example, a compound represented by formula (I) that is regularly arranged with any number of solvent molecules. Examples of the solvent molecule 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, 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, methyl cyclohexane, N - methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2 - trichloroethene, xylene, and t - butanol. Preferably, 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 are included. More preferably, 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 and the like can be mentioned. Most preferably, it is ethyl acetate. In addition, when the "compound represented by formula (I)" is left in the air, it may absorb moisture and adsorbed water may adhere, or a hydrate may be formed.

[0028] One aspect in this specification is the "ethyl acetate solvate of the compound represented by formula (I)". For example, it contains about 1 molar equivalent of ethyl acetate molecules with respect 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 salts, or their solvates. 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] The pharmaceutical active ingredient may have substantially different physical properties depending on each solid state. Such differences in physical properties can have a great impact on, for example, the bioavailability, purity, manufacturing method of the pharmaceutical active ingredient (drug), the pharmaceutical composition (formulation) containing the pharmaceutical active ingredient, or the administration method. Therefore, the selection of the solid state is extremely important in pharmaceutical development.

[0031] The present invention provides an ethyl acetate solvate crystal of the compound represented by formula (I), an amorphous form of the compound represented by formula (I), and a solid dispersion of the compound represented by formula (I), which are very useful as compared with other solid states. In addition, the present invention 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 very useful as compared with other pharmaceutical formulations. The solid state and the preparation have at least any one of the following characteristics. (1) It has good stability against heat, humidity, solvents, light, etc., and high storage stability. (2) It does not show significant coloring after light irradiation. (3) It has good solubility in water or organic solvents. (4) It has a high dissolution rate in water or organic solvents. (5) It is of high purity. (6) The residual rate of organic solvents is low. (7) It is excellent in operability such as filtration, centrifugation, and formulation. (8) It has a small specific volume. (9) It is difficult to charge. (10) It is manufactured in a high yield under conditions with low environmental impact and can be mass-produced. (11) It is useful as a pharmaceutical active ingredient such as an oral preparation or an injection, or a starting material for its production. (12) Since it can be controlled within a pH range suitable for intravenous injection without vascular pain, it is advantageous for liquid volume control and excipient reduction during formulation. (13) It has good fluidity. (14) It has a low compressibility (%).

[0032] In addition, the "crystal" used in this specification means a solid in which the constituent atoms, ions, molecules, etc. are arranged regularly in three dimensions, and is distinguished from an amorphous solid that does not have such a regular internal structure. The crystals used in this specification may be single crystals, twins, polycrystals, etc. Furthermore, there may be "crystal polymorphs" in the "crystal" that have the same composition but different arrangements in the crystal, and these are included in the "crystal form". The "compound represented by formula (I), its pharmaceutically acceptable salt, or their solvates" includes their crystal polymorphs. The crystals used in this specification may be deuterium-converted forms. The crystals used in this specification may be labeled with isotopes (e.g., 3 H, 14 C, 35 S, 125 I, etc.). 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. Also, the physical properties of the crystal can be confirmed by many techniques such as differential scanning calorimetry, moisture adsorption / desorption measurement, dissolution properties, etc.

[0033] One aspect herein is the anhydrous crystal of the compound represented by formula (I). As used herein, "anhydride" is synonymous with "non-solvate", "unsolvated", "anhydrate" and "non-hydrate". The anhydrous crystal of the compound represented by formula (I) has a theoretical content of crystal water of 0 wt%. However, in the analysis of the water content and / or solvent content, it may take a value higher than the theoretical content of crystal water due to the influence of the adsorbed water and / or adsorbed solvent adhering to the crystal surface.

[0034] One aspect herein is the 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 the powder X-ray diffraction pattern (CuKα ray, λ = 1.5418 Å).

[0035] One aspect herein is when single crystal structure analysis is performed at 298 K (25 °C) with CuKα ray (λ = 1.5418 Å), the following crystallographic data: Space group: Pbca a = 14.67 Å ± 0.05 Å b = 11.83 Å ± 0.05 Å c = 27.10 Å ± 0.05 Å α = 90° β = 90° γ = 90° is the anhydrous crystal of the compound represented by formula (I), characterized thereby.

[0036] One aspect herein is the anhydrous crystal of the compound represented by formula (I), which has a melting point of 261.3 °C ± 2 °C in differential scanning calorimetry (DSC). One aspect described herein is the anhydrous crystal of the compound represented by formula (I) having a melting point of 265.6 °C ± 2 °C in differential thermal - thermogravimetric simultaneous measurement (TG / DTA).

[0037] One aspect described herein is, in the Raman spectrum, at 415.2 cm -1 ±2 cm -1 , 502.7 cm -1 ±2 cm -1 , 1431.4 cm -1 ±2 cm -1 , 1714.8 cm -1 ±2 cm -1 and 3065.4 cm -1 ±2 cm -1 is the anhydrous crystal of the compound represented by formula (I) having characteristic peaks.

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

[0039] One aspect of the present invention is the ethyl acetate solvate crystal of the compound represented by formula (I). For example, it is a crystal containing about 1 molar equivalent of ethyl acetate molecules with respect to the compound represented by formula (I). One aspect of the present invention is the ethyl acetate solvate crystal of the compound represented by formula (I), which consists of the compound represented by formula (I) and ethyl acetate and has a molar ratio of 1:1. The theoretical content of ethyl acetate in the crystal is about 14.4% by weight. 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% by weight, preferably 9 to 18% by weight, more preferably 12 to 16% by weight. In the analysis of the ethyl acetate content, when the content is high due to the influence of water or ethyl acetate adhering to the crystal, a part of the ethyl acetate in the crystal may desorb before measurement, resulting in a lower content.

[0040] One aspect of the present invention is the 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 the powder X-ray diffraction pattern (CuKα ray, λ = 1.5418 Å).

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

[0042] One aspect of the present invention is that in the Raman spectrum, it is the ethyl acetate solvate crystal of the compound represented by formula (I) having characteristic peaks at 421.2 cm -1 ±2 cm -1 , 509.7 cm -1 ±2 cm -1 , 1585.3 cm -1 ±2 cm -1 , 1709.9 cm -1 ±2 cm -1 and 3052.9 cm -1 ±2 cm -1

[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, 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, more preferably 1 to 150 μm. The D50 of the ethyl acetate solvate crystals of the compound represented by formula (I) used in the preparation of the present invention is, for example, 0.1 to 25 μm, preferably 0.5 to 10 μm, 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 preparation of the present invention is, for example, 0.2 to 40 μm, preferably 1 to 20 μm, more preferably 2 to 15 μm.

[0044] One aspect in the present specification is that the compound represented by formula (I) is amorphous.

[0045] As used herein, "amorphous" is synonymous with "amorphous solid", "amorphous", and "glass", and means a solid state that does not have a regular structure like a crystal. The constituent atoms, ions, molecules, etc. do not have a three-dimensional repeating period with order. In the present specification, "amorphous" means being substantially in an amorphous state. For example, it means that 80% or more, preferably 90% or more, more preferably 95% or more, and most preferably 99% or more of the pharmaceutically active ingredient (drug) present in the composition is in an amorphous form. Also, the crystallinity means having, 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. Since amorphous solids do not have an ordered repeating period in their structure, they do not cause 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 called a halo pattern. In addition, since amorphous solids do not exhibit polarization like crystals, they can be confirmed in the polarization observation mode of a microscope or a digital microscope. In addition, for example, it can be confirmed by spectroscopic methods such as Raman spectroscopy, infrared absorption spectrum, solid NMR, and techniques such as differential scanning calorimetry.

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

[0047] As used herein, a "solid dispersion" contains a pharmaceutical active ingredient (drug) and a polymer. A solid dispersion refers to a matrix in which a pharmaceutical active ingredient (drug) and a polymer are mixed and then solidified, and the amorphous pharmaceutical active ingredient (drug) is stably molecularly dispersed in the polymer. Specifically, a solid dispersion refers to a matrix in which a pharmaceutical active ingredient (drug) and a polymer are once dissolved and mixed in a co-solvent and then solidified, and the amorphous pharmaceutical active ingredient (drug) is stably molecularly dispersed in the polymer. Examples of its production methods include spray drying method (solvent removal method), hot melt method, and mixing and grinding method (mechanochemical method). For crystalline poorly soluble drugs, by forming a solid dispersion, the pharmaceutical active ingredient (drug) can be made amorphous, and the solubility and dissolution rate can be improved.

[0048] As used herein, "improving solubility" means an increase in the solubility of the compound represented by formula (I) in water or a buffer solution. Specifically, for example, when evaluating a solid dispersion or a pharmaceutical composition (formulation) containing a solid dispersion in an elution test, for example, the solubility of the solid dispersion containing the compound represented by formula (I) (or the compound (I) in the solid dispersion of the compound represented by formula (I)) is 1.5 times or more, in another aspect 2 times or more, in yet another aspect 5 times or more, and in a further aspect 10 times or more the solubility of compound (I) itself.

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

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

[0051] Examples of the vinyl polymer used in the solid dispersion of the present invention include copovidone (which may also be referred to as polyvinylpyrrolidone-vinyl acetate copolymer, PVPVA in this specification), polyvinylpyrrolidone (which may also be referred to as povidone in this specification), polyvinylpolypyrrolidone, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol-polyethylene glycol-graft copolymer , F Examples include a mixture of malic acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropylmethylcellulose, and polyvinyl acetal diethylaminoacetate. Preferably, copovidone and polyvinylpyrrolidone are used, and particularly preferably, copovidone is used.

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

[0053] Examples of the cellulose polymer used in the solid dispersion of the present invention include hypromellose acetate succinate (which may also be referred to as hydroxypropylmethylcellulose acetate succinate in this specification), hypromellose phthalate, hydroxypropyl cellulose (which may also be referred to as HPC in this specification), low-substituted hydroxypropyl cellulose, hypromellose (which may also be referred to as hydroxypropylmethylcellulose or HPMC in this specification), hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethylcellulose sph tartrate, methyl cellulose (which may also be referred to as MC in this specification), methylhydroxyethyl cellulose 、 Examples include carboxymethylethyl cellulose, ethyl cellulose, crystalline cellulose, microcrystalline cellulose, crystalline cellulose - sodium carboxymethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, powdered cellulose, fumaric acid - stearic acid - polyvinyl acetal diethylaminoacetate - hydroxypropylmethylcellulose mixture, etc. Preferably, they are hypromellose acetate succinate, hypromellose phthalate, and hydroxypropyl cellulose, and particularly preferably hypromellose acetate succinate.

[0054] Examples of the acrylic polymer 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, ammoni o alkyl methacrylate copolymer, methyl acrylate - methacrylic acid - methyl methacrylate copolymer, 2 - methyl - 5 - vinylpyridine methyl acrylate - methacrylic acid copolymer, etc. Preferably, it is methacrylic acid copolymer L.

[0055] In the solid dispersion of the present invention, the weight ratio of the "compound represented by formula (I), its pharmaceutically acceptable salt, or their solvate" 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] For the method for producing the solid dispersion of the present invention, known methods can be employed. For example, the "compound represented by formula (I), its pharmaceutically acceptable salt, or their solvate" and the polymer are dissolved and / or suspended in a pharmaceutically acceptable solvent, and then the solvent is distilled off for production. The solvent is not particularly limited as long as it is a solvent in which the compound represented by formula (I) can be maintained in an amorphous state in the presence of the polymer. For example, in ICH-Q3C (Guideline for Residual Solvents in Pharmaceuticals), Class 3 solvents (solvents with low toxicity and considered to pose a low risk to human health) can be mentioned. Specifically, ketones such as acetone, alcohols such as methanol, ethanol, and propanol, methylene chloride, or a mixed solvent thereof and a mixed solvent with water can be mentioned. Preferably, acetone, or a mixed solvent of acetone and ethanol, and more preferably acetone. The amount of the solvent is not particularly limited as long as it is an amount necessary for the compound represented by formula (I) to be in an amorphous state. It is, for example, 1 to 100 times the weight (w / w), preferably 5 to 20 times the weight (w / w) of the "compound represented by formula (I), its pharmaceutically acceptable salt, or their solvate" 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. Examples include spray drying, vacuum drying, and ventilation 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, and 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 shows a halo pattern.

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

[0059] Examples of oral preparations include internal solid preparations (e.g., tablets, powders, granules, capsules, pills, films, etc.), internal liquid preparations (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, aromatic waters, extracts, decoctions, tinctures, 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, external preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, gargles, enemas, ointments, plasters, jellies, creams, patches, poultices, external powders, suppositories, etc.). Injections may be emulsions of the O / W, W / O, O / W / O, W / O / W type, etc.

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

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

[0063] The method for producing the "granules containing, as an active ingredient, the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof" is not particularly limited, but specifically, it is a method of mixing the "compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof", additives such as disintegrants and excipients, to produce a mixed powder, and then granulating the mixed powder. Preferably, it is a wet granulation method of adding water or a solvent containing a binder to granulate, or a dry granulation method or melt granulation method of compression molding without using water. As a machine for mixing pharmaceutical active ingredients (drugs), additives, etc., a V-type mixer or a container blender can be used. Also, as a machine for granulating, a wet extrusion granulator, a fluidized bed granulator, a stirring granulator, a dry crushing granulator, or a melt extrusion granulator can be used.

[0064] The manufacturing method of "tablets containing a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient" is not particularly limited. Specifically, granules are manufactured by the above method, and further, an excipient, a disintegrant, a lubricant, etc. are mixed with these granules, and the mixed granules are tabletted with a tabletting machine, or a pharmaceutical active ingredient (drug), an excipient, a disintegrant, a lubricant, etc. are mixed, and the mixture is tabletted with a tabletting machine. As a machine for mixing the active ingredient and additives, etc., a V-type mixer or a container blender can be used. Also, as a tabletting machine, a single-shot tabletting machine, a rotary tabletting machine, etc. can be used.

[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. Preferably, they are croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, crospovidone, and particularly preferably, croscarmellose sodium, crospovidone.

[0066] One aspect of the present invention is a solid preparation containing a solid dispersion of a compound represented by formula (I) and croscarmellose sodium. One aspect of the present invention is a solid preparation containing a solid dispersion containing a compound represented by formula (I) and copovidone and croscarmellose sodium. One aspect of the present invention is a solid preparation containing an anhydrous crystal of a compound represented by formula (I) and crospovidone. Preferred forms of the solid preparation include granules, powders, capsules, or tablets, and particularly preferably tablets.

[0067] Examples of the excipient include crystalline cellulose, silicified 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 corn starch in this specification), rice starch, partially pregelatinized starch, pregelatinized starch, porous starch, sodium carboxymethyl starch, hydroxypropyl starch, sodium carboxymethyl starch with a low degree of substitution, powdered cellulose, sodium carboxymethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylethylcellulose, hydroxypropylcellulose with a low degree of substitution, silicate derivatives, phosphates, carbonates, sulfates, magnesium oxide, titanium oxide, calcium lactate, synthetic hydrotalcite, talc, kaolin, dried aluminum hydroxide, magnesium oxide, bentonite, silicon dioxide such as hydrous silicon dioxide, light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate, calcium silicate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate monohydrate, 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. Preferably, it is crystalline cellulose and / or mannitol.

[0068] One aspect of the present invention is a solid preparation containing a solid dispersion of a compound represented by formula (I), croscarmellose sodium, crystalline cellulose, and mannitol. One aspect of the present invention is a solid preparation containing a solid dispersion of a compound represented by formula (I) and copovidone, croscarmellose sodium, crystalline cellulose, and mannitol. One aspect of the present invention is a solid preparation containing an anhydrous crystal of a compound represented by formula (I), crospovidone, and crystalline cellulose. Preferred forms of the solid preparation include granules, powders, capsules, or tablets, and particularly preferably tablets.

[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, 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, polyethylene glycol (sometimes referred to as macrogol in this specification), and the like. 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 aspect of the present invention is a solid preparation containing a solid dispersion of a compound represented by formula (I), croscarmellose sodium, crystalline cellulose, mannitol, sodium stearyl fumarate, and light anhydrous silicic acid. One aspect of the present invention is a solid preparation containing a solid dispersion of a compound represented by formula (I) and copovidone, croscarmellose sodium, crystalline cellulose, mannitol, sodium stearyl fumarate, and light anhydrous silicic acid. One aspect of the present invention is a solid preparation containing an anhydrous crystal of a compound represented by formula (I), crospovidone, crystalline cellulose, and sodium stearyl fumarate. Preferred forms of the solid preparation include granules, powders, capsules, or tablets, and particularly preferred is a tablet.

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

[0072] The photo-stabilizing substance of the pharmaceutical preparation of the present invention may be formulated in the preparation or may coat the surface of the preparation. Preferably, it is a pharmaceutical preparation that coats the surface of the preparation and contains the photo-stabilizing substance in the coating layer. By containing the photo-stabilizing substance in the coating layer of the preparation, the photo-stability of the compound represented by formula (I) contained in the preparation can be improved, or discoloration of the preparation can be prevented.

[0073] The pharmaceutical preparation of the present invention may have a coating layer and may contain a photo-stabilizing substance and a polymer in the coating layer. After manufacturing granules or tablets, the granules or tablets may be coated with the coating layer in the pharmaceutical preparation of the present invention. The pharmaceutical preparation of the present invention may be a coated tablet or a coated granule. When forming a coating layer on granules, a fluidized bed granulation coating machine, a fluidized bed rolling coating machine, etc. can be used. When forming a coating layer on tablets, a pan coating machine, a vented coating machine, etc. can be used. Among coating machines, while fluidizing the granules or tablets, the coating solution is sprayed onto the granules or tablets and dried to form a coating layer.

[0074] One aspect of the present invention is "a solid pharmaceutical preparation 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." One aspect of the present invention is "a solid pharmaceutical preparation having a coating layer containing a photo-stabilizing substance and a polymer and containing, as an active ingredient, a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof." As a preferred form of "the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof", 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) can be used. Preferred forms of the solid pharmaceutical preparation include granules, powders, capsules, or tablets, and tablets or capsules are particularly preferred.

[0075] Examples of the photo-stabilizing substance include a light-shielding substance having a light-shielding effect for shielding light and a light-absorbing substance having an effect of absorbing light. For example, 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 color 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 Chlorophyll Sodium, Copper Chlorophyll, Red Iron Oxide, Black Iron Oxide, Yellow Iron Oxide, Titanium Oxide, Ferric Oxide, Yellow Ferric Oxide, Talc, etc. are mentioned. Preferably, the photo-stabilizing substance is ferric oxide, yellow ferric oxide and / or talc.

[0076] Examples of the polymer in the coating layer include hypromellose, hydroxypropyl cellulose, carboxymethyl ethyl cellulose, hypromellose phthalate, hydroxypropyl methylcellulose acetate succinate, ethyl cellulose, polyvinyl alcohol, etc. Preferably, it is hypromellose.

[0077] One aspect of the present invention is "a solid preparation containing, as an active ingredient, a solid dispersion of a compound represented by formula (I) having a coating layer containing ferric oxide, yellow ferric oxide and / or talc". One aspect of the present invention is "a solid preparation containing, as an active ingredient, a solid dispersion of a compound represented by formula (I) having a coating layer containing ferric oxide, yellow ferric oxide, talc and hypromellose". One aspect of the present invention is "a solid preparation containing, as an active ingredient, an anhydrous crystal of a compound represented by formula (I) having a coating layer containing ferric oxide, yellow ferric oxide and / or talc". One aspect of the present invention is "a solid preparation containing, as an active ingredient, an anhydrous crystal of a compound represented by formula (I) having a coating layer containing ferric oxide, yellow ferric oxide, talc and hypromellose". Preferred forms of the solid preparation include granules, powders, capsules or tablets, and tablets are 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% by weight, preferably 0.5 to 10% by weight, more preferably 1 to 8% by weight, based on the total amount of the preparation. When two or more 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 a light stabilizer and a polymer, and a plasticizer described in the Japanese Pharmacopoeia, Japanese Pharmaceutical Excipients Standards, Pharmaceutical Additives Standards or Food Additives Compendium can be used. For example, examples of the plasticizer include citrate esters, glycerin fatty acid esters, surfactants, monostearin, diethyl phthalate, dibutyl phthalate, diethyl sebacate, dibutyl sebacate and the like.

[0080] One aspect of the present invention is a "solid preparation containing an ethyl acetate solvate crystal of the compound represented by formula (I), croscarmellose sodium, mannitol, crystalline cellulose and sodium stearyl fumarate". Preferred forms of the solid preparation include granules, powders, capsules or tablets, and capsules are particularly preferred.

[0081] (Powder X-ray diffraction (XRPD)) Powder X-ray diffraction (XRPD) is one of the most sensitive analytical methods for measuring the crystal form and crystallinity of solids. When X-rays irradiate a crystal, they are reflected by the crystal lattice planes, interfere with each other, and show diffraction lines corresponding to the periodicity of the structure. On the other hand, for an amorphous solid, since it usually does not have an ordered repeating period in its structure, the diffraction phenomenon does not occur, and it shows a characteristic broad XRPD pattern (also called a halo pattern).

[0082] The characteristic diffraction peaks used in this specification are the peaks selected from the observed diffraction patterns. The characteristic diffraction peaks are preferably selected from about 10 peaks, more preferably about 5 peaks, in the diffraction pattern. In differentiating multiple crystals, peaks that are identified in the crystal and not in other crystals are preferred characteristic peaks for identifying the crystal, rather than the peak intensities. Even one or two such characteristic peaks can characterize the crystal. By comparing the patterns obtained by measurement, if these characteristic peaks match, it can be said that the powder X-ray diffraction patterns substantially match.

[0083] Generally, since an error can occur in the diffraction angle (2θ) in powder X-ray diffraction within a range of ±0.2°, it is necessary to understand that the values of the diffraction angles in powder X-ray diffraction also include numerical values within a range of about ±0.2°. Therefore, the present invention includes not only crystals with exactly matching diffraction angles of the peaks in powder X-ray diffraction, but also crystals with matching diffraction angles of the peaks with an error of about ±0.2°.

[0084] The intensities of the peaks shown in the following figures generally can vary due to many factors, such as the effect of the preferred orientation of the crystal with respect to the X-ray beam, the influence of coarse particles, the purity of the substance being analyzed, or the crystallinity of the sample. Also, the peak positions can shift based on the height variation of the sample. Furthermore, different shifts are obtained according to the Bragg equation (nλ = 2dsinθ) when measuring using different wavelengths, and another XRPD pattern obtained using such a different wavelength is also included in the scope of the present invention.

[0085] By combining a powder X-ray diffractometer with a temperature and / or relative humidity control device, powder X-ray diffraction measurements can be performed under specific temperatures and / or relative humidities. For example, when anhydrous crystals change to hydrate crystals due to moisture absorption, when hydrate crystals change to anhydrous crystals due to dehydration, when solvate crystals undergo a crystal transition to anhydrous crystals due to solvent desorption, or when anhydrous crystals and hydrate crystals reversibly change due to moisture absorption and dehydration, measurements at specific temperatures and / or relative humidities, or measurements in which the temperature and / or relative humidity are continuously changed, are suitable. In such cases, it is possible to infer the relative humidity at which the change occurs and the amount of crystal water and / or crystal solvent.

[0086] The crystal form of the compound represented by formula (I) can be identified by its powder X-ray diffraction pattern and the diffraction angle (2θ) of characteristic peaks. The crystal forms of the compound represented by formula (I) (for example, the anhydrate of the compound represented by formula (I), the ethyl acetate solvate crystals of the compound represented by formula (I)) can be distinguished from other crystal forms by the presence of characteristic peaks.

[0087] (Powder X-ray diffraction - simultaneous differential scanning calorimetry (XRD-DSC)) Simultaneous measurement of powder X-ray diffraction and differential scanning calorimetry (XRD-DSC measurement) can simultaneously observe changes in crystal form (crystal structure) and heat quantity changes with respect to temperature and / or relative humidity. For example, it is suitable for observing changes in crystal form (crystal structure) such as when anhydrous crystals undergo a crystal transition to hydrate crystals due to moisture absorption, when hydrate crystals undergo a crystal transition to anhydrous crystals due to dehydration, when solvate crystals undergo a crystal transition to anhydrous crystals due to solvent desorption, or when anhydrous crystals and hydrate crystals reversibly undergo a crystal transition due to moisture absorption and dehydration.

[0088] (Single crystal structure analysis) Single crystal structure analysis is one method for specifying crystal form, and crystallographic parameters, and further, atomic coordinates (values indicating the spatial positional relationship of each atom) and a three-dimensional structure model can be obtained. For single crystal structure analysis, refer to "Guide to X-ray Structure Analysis" by Toshio Sakurai, published by Shoeka Publishing Co., Ltd. (1983), "X-Ray Structure Determination: A Practical Guide" by Stout & Jensen, Macmillan Co., New York (1968), etc. Single crystal X-ray diffraction analysis is useful for identifying the structures of optical isomers, tautomers, geometric isomers, salts, co-crystals, and solvates (hydrates). Note that the quality of data in single crystal X-ray diffraction experiments is known to improve by performing measurements at low temperatures. Therefore, measurements are performed at room temperature or low temperature depending on the crystal to be measured. Also, in single crystal X-ray diffraction experiments of hydrates and / or solvates, it is known that the quality of data improves by coating the crystal with paraffin oil or the like before measurement.

[0089] (Raman spectroscopy) Raman spectra show the characteristics of the vibrations of molecules or composite systems. Their origin lies in the inelastic collisions between molecules and photons, which are the particles of light that include the light beam. The collision between a molecule and a photon results in an energy exchange, and as a result, the energy changes, causing the wavelength of the photon to change. That is, since Raman spectra are extremely narrow spectral lines emitted when photons are incident on the target molecule, a laser or the like is used as the light source. The wavelength of each Raman line is indicated 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, since the amount of wavelength shift (cm -1 ) in Raman spectra can have an error within the range of ±2 cm -1 , it is necessary to understand that the values of Raman spectral peaks also include numerical values within a range of about ±2 cm -1 . Therefore, not only crystals with exactly matching Raman spectral peaks in Raman spectra, but also crystals with Raman spectral peaks that match with an error of about ±2 cm -1 are included in the present invention.

[0090] (Infrared absorption spectroscopy (IR method)) The infrared absorption spectrum measurement method is a method of measuring the degree of absorption when infrared rays pass through a sample for each frequency. The infrared absorption spectrum is usually shown as a graph with the frequency on the horizontal axis and the transmittance or absorbance on the vertical axis. The frequency of the absorption peak and the transmittance (or absorbance) can be read from the graph, or the calculated values by a data processing device can be used. The infrared absorption spectrum is determined by the chemical structure of the substance. Therefore, the substance can be identified or quantified by measuring the absorption at various frequencies. The discrimination of crystal polymorphs can be carried out by comparing the absorption bands of functional groups characteristic of the crystal polymorphs, that is, functional groups mainly involved in hydrogen bonds 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. It is selected from about 20 absorption peaks corresponding to characteristic functional groups, more preferably about 10 absorption peaks, and most preferably about 5 absorption peaks. Usually, the absorption spectrum of the sample is measured in the range of a wave number of 4000 cm -1 ~400 cm -1 . The measurement of the absorption spectrum is carried out under the same operating conditions as when confirming the resolution, wave number scale, and wave number accuracy of the device.

[0091] Generally, since an error can occur within the range of ±2 cm -1 for the absorption band (cm -1 ) in the infrared absorption spectrum measurement, it is necessary to understand that the values of the above absorption peaks also include numerical values within the range of about ±2 cm -1 . Therefore, not only crystals with completely coincident peaks of the absorption band in the infrared absorption spectrum measurement but also crystals with coincident peaks of the absorption band with an error of about ±2 cm -1 are included in the present invention.

[0092] The measurement methods of infrared absorption spectra include the potassium bromide tablet method, solution method, paste method, liquid film method, thin film method, gas sample measurement method, ATR method, diffuse reflection method, etc. Among these, the ATR method (Attenuated total reflection) is called the total reflection measurement method and is one of the reflection methods. In this method, the sample is brought into close contact with the surface of a prism made of a substance with a high refractive index such as KRS-5, light is incident on the prism at an angle greater than the critical angle, and the light totally reflected at the boundary between the prism and the sample is measured to obtain the absorption spectrum. One of the conditions that can be measured by the ATR method is that the refractive index of the prism is greater than that of the sample, so it is necessary to change the material of the prism according to the sample. Also, as other conditions, the prism and the sample must be in close contact. Therefore, it is suitable for the measurement of liquids, powders, plastics, soft rubbers, etc., and has the advantage that it can be measured without chemically or physically treating the sample. On the other hand, the diffuse reflection method is a method of measuring a powder sample without making a potassium bromide tablet and measuring it as a powder. When light is applied to the sample, light that is specularly reflected from the powder surface and exits to the outside and diffuse reflection light (scattered light) that enters the sample, repeats transmission and diffusion inside the sample, and then exits to the surface are generated. In the diffuse reflection method, the latter is used to obtain the absorption spectrum.

[0093] (Solid 13 C-NMR (Nuclear Magnetic Resonance)) Solid 13 C-NMR has the following characteristics: (i) the number of spectra matches the number of carbon atoms in the target compound, (ii) the chemical shift range is 1 wider than that of 1H-NMR, (iii) the signals are solid 1 sharper than those of 1H-NMR, (iv) when there is no interaction even if additives are included, the chemical shift does not change, etc. Therefore, it is useful for identifying crystal forms. Note that the chemical shifts observed depending on the specific spectrometer used and the analyst's sample preparation techniques are expected to vary slightly. Solid 13 The error range in the 13C-NMR spectrum is approximately ±0.5 ppm.

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

[0095] (Differential thermal - thermogravimetric simultaneous measurement method (TG / DTA)) Differential thermal - thermogravimetric simultaneous measurement method (TG / DTA) is one of the main measurement methods in thermal analysis and is a method for measuring the weight and thermal properties of substances as aggregates of atoms and molecules. TG / DTA is a method for measuring the changes in weight and heat quantity of a pharmaceutical active ingredient with respect to temperature or time, and by plotting the obtained data against temperature or time, TG (thermogravimetric) and DTA (differential thermal) curves are obtained. From the TG / DTA curve, information on the weight and heat quantity changes related to the decomposition, dehydration, oxidation, reduction, sublimation, and evaporation of the pharmaceutical active ingredient can be obtained. Regarding TG / DTA, it is known that the observed temperature and weight change can depend on the temperature change rate, the sample preparation technique used, and the specific apparatus. Therefore, the "melting point" in TG / DTA refers to the onset temperature (extrapolated melting start temperature) that is less affected by the sample preparation technique. In the identification of crystal identity, not only the melting point but also the overall pattern is important and can vary somewhat depending on the measurement conditions and measuring instrument.

[0096] (Measurement Method of Moisture Sorption Isotherm (DVS)) The measurement method of moisture sorption isotherm (DVS) is a measurement method for measuring the adsorption and desorption behavior of moisture by measuring the weight change of the solid to be measured under each relative humidity condition. As a basic measurement method, based on the dry weight at 0% RH (relative humidity 0%), the relative humidity is increased by 5% or 10% each time. After the weight is stabilized at each relative humidity, the amount of adsorbed water can be obtained from the weight increase from the reference value. Similarly, by decreasing the relative humidity by 5% or 10% each time from 100% RH or 95% RH, the amount of desorbed water can be measured. By plotting the weight change values at each relative humidity, a sorption isotherm can be obtained. From this result, it is possible to consider the adsorption and desorption phenomena of the adsorbed moisture at each humidity. The adsorption and desorption of adsorbed water and water of crystallization are affected by factors such as particle size, crystallinity, and crystal habit, so the measurement results may vary slightly.

[0097] Differential scanning calorimetry (DSC), simultaneous differential thermal-thermogravimetric measurement (TG / DTA), measurement method of moisture sorption isotherm (DVS), Karl Fischer moisture meter, and gas chromatography are analytical methods that can also detect the adsorbed water and / or adsorbed solvent (residual solvent) on the crystal "surface". In this analysis, when a sample with adsorbed water and / or adsorbed solvent present on the crystal surface is measured, it may show a higher moisture content and / or solvent content than the theoretical content of the water of crystallization in the hydrate crystal and / or the theoretical content of the crystal solvent in the solvate crystal. On the other hand, powder X-ray diffraction and single crystal structure analysis are measurement methods for analyzing the "internal structure" of crystals, and show characteristic peaks at the same positions regardless of the presence or absence of adsorbed water and / or adsorbed solvent (residual solvent) on the crystal "surface". The same is true for Raman spectroscopy and infrared absorption spectrum measurement (IR method). Therefore, in powder X-ray diffraction, single crystal structure analysis, Raman spectroscopy, and infrared absorption spectrum measurement (IR method), even if the measured moisture content and / or solvent content is higher than the theoretical content in the crystal, as long as it has the characteristic peaks described in the specification, it can be interpreted as being substantially the same crystal.

[0098] (Particle Size Distribution) As used in this specification, "D10, D50, D90" mean the particle diameters at the points where the cumulative curve reaches 10%, 50%, and 90% when the total volume of the powder aggregate is taken as 100% and the cumulative curve is obtained, and can be measured by the dry method or the wet method.

Examples

[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 thereto. Regarding numerical values (for example, amounts, temperatures, etc.), some errors and deviations should be taken into account. Unless otherwise noted, % is the weight % of the component and the weight % of the total weight of the composition, and the pressure is atmospheric pressure or a pressure close thereto.

[0100] (Method for Identifying Compounds) The NMR analysis obtained in each example was performed at 400 MHz and measured using DMSO-d6 and CDCl3. Also, when showing NMR data, there are cases where not all measured peaks are described. RT in the specification represents the retention time in LC / MS: liquid chromatography / mass spectrometry and was measured under the following conditions. (Measurement Conditions 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 for 3.5 minutes, and then 100% solvent [B] was maintained for 0.5 minutes. (Measurement Conditions 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, and [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 5% - 100% solvent [B] was carried out over 3.5 minutes, and then 100% solvent [B] was maintained for 0.5 minutes. In the specification, the description of MS (m / z) indicates the value observed by mass spectrometry.

[0101] (Production method of the compound represented by formula (I)) The "compound represented by formula (I)" is compound (I-077) described in International Publication No. 2023 / 195529 and International Publication No. 2023 / 195530, and can be produced by the synthesis methods of Examples 5 - 6 described in the literature. Also, it can be synthesized with reference to methods known in the art. Extraction, purification, etc. may be carried out by performing the treatments commonly used in organic chemistry experiments.

[0102] (Example 1: Synthesis of the compound represented by formula (I) (compound (I)))

Chemical formula

[0103] Step 2: Synthesis of compound 4 Acetic acid (40 mL) and concentrated hydrochloric acid (41 mL) were added to compound 3 (14.8 g, 48.8 mmol), and the mixture was stirred at 110 °C for 5 hours. After the reaction mixture was cooled to room temperature, water (80 mL) was added. The precipitate was collected by filtration and washed with water. After air drying, compound 4 (11.6 g, 42.2 mmol) was obtained. 1 1H-NMR (DMSO-d6) δ: 7.31 (ddd, J = 8.8, 4.9, 2.1 Hz, 1H), 7.45 (t, J = 8.8 Hz, 1H), 7.53 (dd, J = 7.3, 2.1 Hz, 1H), 11.57 (s, 1H), 12.24 (brs, 1H) LC / MS (ESI): m / z = 275, RT = 1.81 min, LC / MS measurement condition 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 hydrogen carbonate 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 obtained residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 90:10), and the solvent was distilled off under reduced pressure. The obtained residue was dried under reduced pressure to obtain Compound 5 (1.15 g, 2.97 mmol, yield 82%). 1 1H-NMR (DMSO-d6) δ: 7.35 - 7.37 (1H, m), 7.49 (1H, t, J = 9.0 Hz), 7.54 - 7.56 (1H, m), 8.07 (1H, t, J = 2.1 Hz), 8.54 (1H, d, J = 2.0 Hz), 8.70 (1H, d, J = 2.3 Hz). LC / MS (ESI): m / z = 386, RT = 1.98 min, LC / MS measurement condition 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 the mixture was stirred at room temperature overnight. Under ice-cooling, 2 mol / L hydrochloric acid (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 the obtained residue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 99:1), and the solvent was distilled off under reduced pressure. The obtained residue was dried under reduced pressure to obtain Compound 6 (291 mg, 0.684 mmol, yield 51%). 11H-NMR (CDCl3) δ: 5.13 (2H, s), 7.23 - 7.24 (2H, m), 7.42 (1H, d, J = 7.3 Hz), 7.67 (1H, t, J = 2.1 Hz), 8.45 (1H, d, J = 2.3 Hz), 8.67 (1H, d, J = 2.3 Hz). LC / MS (ESI): m / z = 425, RT = 2.17 min, LC / MS measurement condition 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 obtained solid was dried under reduced pressure to obtain compound (I) (22.0 mg, 0.042 mmol, yield 72%). 1 1H-NMR (CDCl3) δ: 2.75 (4H, t, J = 12.0 Hz), 4.02 (4H, s), 4.74 (2H, s), 7.16 - 7.18 (2H, m), 7.32 - 7.35 (1H, m), 7.65 (1H, t, J = 2.1 Hz), 8.43 (1H, d, J = 2.3 Hz), 8.61 (1H, d, J = 2.3 Hz). LC / MS (ESI): m / z = 522, RT = 2.27 min, LC / MS measurement condition A

[0107] (Example 1A: Biological test of compound (I)) The following describes biological test examples of the compounds according to the present invention. The compound represented by formula (I) according to the present invention has an inhibitory effect on coronavirus 3CL protease, and any compound that inhibits coronavirus 3CL protease may be used. Specifically, in the evaluation method described below, for IC 50 it is preferably 50 μM or less, more preferably 1 μM or less, and even more preferably 100 nM or less. For EC 50 it 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 International Publication No. 2023 / 195529 and International Publication No. 2023 / 195530.

[0108] Test Example 1: Confirmation test of Cytopathic effect (CPE) inhibitory effect using human TMPRSS2 and ACE2-expressing HEK293T cells (HEK293T / ACE2-TMPRSS2 cells) <Operation procedure> · Dilution and dispensing of the test sample Dilute the test sample to an appropriate concentration with DMSO in advance. After preparing a 2- to 5-fold serial dilution series, dispense it into a 384-well plate. · Dilution and dispensing of cells and SARS-CoV-2 Mix HEK293T / ACE2-TMPRSS2 cells (GCP-SL222, 5×10 3 cells / well) and SARS-CoV-2 (200 - 600 TCID 50 / well) with the medium (MEM, 2% FBS, penicillin-streptomycin), dispense it into the wells containing the test sample, and then culture it in a CO2 incubator for 3 days. · Dispensing of CellTiter-Glo® 2.0 and measurement of luminescence signal After returning the plate cultured for 3 days to room temperature, dispense CellTiter-Glo® 2.0 into each well and mix with a plate mixer. After leaving it for a certain time, measure the luminescence signal (Lum) with a plate reader. <Calculation of each measurement item value> · Calculation of 50% SARS-CoV-2-infected cell death inhibitory concentration (EC 50 ) 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 defined as EC 50 and 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 value of the y-axis, max: upper limit value of the y-axis, X50: x-coordinate of the inflection point, Hill: slope of the curve at the midpoint between min and max

[0109] The compound represented by formula (I) according to the present invention was essentially tested as described above. The EC 50 value is shown below. (Results) Compound (I): 1.66 nM

[0110] Test Example 2: Inhibition 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)-NH2 (SEQ ID NO: 1) · Internal Standard peptide Dabcyl-Lys-Thr-Ser-Ala-Val-Leu( 13 C6, 15N)-Gln (SEQ ID NO: 2) Dabcyl-Lys-Thr-Ser-Ala-Val-Leu( 13 C6, 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. Using Rink amide resin, by Fmoc solid-phase synthesis, H-Lys-Thr-Ser-Ala-Val-Leu( 13 C6, 15 N)-Glu(resin)-OαOtBu (the Lys side chain is protected by Boc, the Thr side chain is protected by a tert-butyl group, the Ser side chain is protected by a tert-butyl group, the C-terminal OH of Glu is protected by a tert-butyl group, and the carboxylic acid of the Glu side chain is condensed with the resin) is synthesized. The modification of the N-terminal Dabcyl group is carried out 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. Then, it is purified by reverse-phase HPLC. ·RapidFire Cartridge C4 typeA <Operation Procedure> ·Preparation of Assay Buffer In this test, an assay buffer consisting of 20 mM Tris-HCl, 1 mM EDTA, 10 mM DTT, and 0.01% BSA is used. ·Dilution and Dispensing of Test Samples The test samples are previously diluted to an appropriate concentration with DMSO, and after preparing a 2- to 5-fold serial dilution series, they are dispensed into a 384-well plate. ·Addition of Enzyme and Substrate, Enzyme Reaction To the prepared compound plate, add 8 μM of substrate and 6 nM or 0.6 nM of enzyme solution, and incubate at room temperature for 3 to 5 hours. Then, add the reaction stop solution (0.067 μM Internal Standard, 0.1% formic acid, 10 or 25% acetonitrile) to stop the enzyme reaction. · Measurement of reaction products The completed reaction plate is measured using a RapidFire System 360 and a mass spectrometer (Agilent, 6550 iFunnel Q-TOF), or a Rapid Fire System 365 and a mass spectrometer (Agilent, 6495C Triple Quadrupole). As the mobile phase during measurement, use Solution A (75% isopropanol, 15% acetonitrile, 5 mM ammonium formate) and Solution B (0.01% trifluoroacetic acid, 0.09% formic acid). The reaction products detected by the mass spectrometer are calculated using a RapidFire Integrator or a program capable of equivalent analysis to obtain the Product area value. At the same time, the simultaneously detected Internal Standard is also calculated to obtain the Internal Standard area value. <Calculation of each measurement item value> · Calculation of P / IS Calculate the area value obtained in the previous item 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 logarithmic value of the compound concentration and y is %Inhibition, approximate the inhibition curve with the following Logistic regression equation, and calculate the value of x when y = 50 (%) as IC 50 as. 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 value of the y-axis, max: upper limit value of the y-axis, X50: x-coordinate of the inflection point, Hill: slope of the curve at the midpoint between min and max

[0111] The compound represented by the formula (I) according to the present invention was tested essentially as described above. IC 50 values are shown below. (Results) Compound (I): 0.00036 μM

[0112] Test Example 3: Powder X-ray diffraction experiment (XRPD) According to the powder X-ray diffraction measurement method described in the general test method of the Japanese Pharmacopoeia, powder X-ray diffraction measurements of the solid state (crystals and amorphous) and solid dispersions obtained in each example were performed. The measurement conditions are shown below. Measurement condition 1: Powder X-ray diffractometer: SmartLab manufactured by Rigaku Measurement method: reflection method Wavelength used: CuKα ray (λ = 1.5418 Å) Tube current: 200 mA Tube voltage: 45 kV Sample plate: aluminum Incident angle of X-ray: 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 the attachment attached to the X-ray diffractometer, the temperature and relative humidity of the measurement sample section are controlled, and powder X-ray diffraction measurement is performed according to the powder X-ray diffraction measurement method described in the general test method of the Japanese Pharmacopoeia. The measurement conditions are shown below. Measurement condition 2: (X-ray diffraction measurement) Powder X-ray diffractometer: RINT2100Ultima+ manufactured by Rigaku Measurement method: Reflection method Wavelength used: CuKα ray (λ = 1.5418 Å) Tube current: 40 mA Tube voltage: 40 kV Sample plate: Aluminum Measurement range of X-ray: 5° - 35° Sampling width: 0.02° Scan speed: 60° / min (Control of temperature and relative humidity) Temperature controller: ThermoPlus manufactured by Rigaku Humidity controller: HUM-1 manufactured by Rigaku

[0114] Test example 5: Measurement and analysis method for single crystal structure analysis Single crystal structure analysis of the crystals obtained in each example was performed. The measurement conditions and analysis methods are shown below. (Equipment) XtaLAB P200 MM007 manufactured by Rigaku (Measurement conditions) Measurement temperature: 25°C Temperature controller: Sample spraying low temperature device manufactured by Rigaku Wavelength used: CuKα ray (λ = 1.5418 Å) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) (Data processing) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) The data was subjected to Lorentz and polarization correction, and absorption correction. (Crystal structure analysis) Phase determination was carried out using the direct method program ShelXT (Sheldrick, G.M., 2015), and refinement was performed using ShelXL (Sheldrick, G.M., 2015) with the full-matrix least-squares method. The temperature factors of non-hydrogen atoms were all refined anisotropically. Hydrogen atoms were introduced by calculation using the default parameters of ShelXL unless otherwise specified and were treated as riding atoms. Also, hydrogen atoms were refined with isotropic parameters. For the drawing of the following structural diagrams, PLATON (Spek, 1991) / ORTEP (Johnson, 1976) was used (30% PROBABILITY level).

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

[0116] Test Example 7: Differential Scanning Calorimetry (DSC) DSC measurements were performed on the crystals obtained in each example. The sample was weighed into an aluminum pan and measured after simple sealing. The measurement conditions are shown below. Note that measurements by differential scanning calorimetry (DSC) may have errors within the range of ±2°C. Apparatus: Discovery DSC / TA Instrument Measurement temperature range: -10°C - 270°C Heating rate: 10°C / min Atmosphere: N2 50 mL / min

[0117] Test Example 8: Simultaneous Differential Thermal-Thermogravimetric Measurement (TG / DTA) Differential thermal - thermogravimetric simultaneous measurements (TG / DTA) were performed on the solid states (crystalline and amorphous) and solid dispersions obtained in each example. The samples obtained in each example were weighed and filled into an aluminum pan, and the measurements were carried out in an open system. The measurement conditions are 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: Measurement of water adsorption - desorption isotherm (DVS) The water adsorption - desorption isotherm measurements (DVS) were performed on the crystals obtained in each example. The crystals obtained in each example were weighed into an aluminum pan and left standing at 25 °C and 0% relative humidity. After the compound was sufficiently dried and the weight was stable, the measurement was started, and the weights were recorded when the relative humidity changed from 0% to 95% in 5% increments. Next, the weights were recorded when the relative humidity changed from 95% to 0% in 5% increments. Apparatus: DVS Adventure manufactured by Surface Measurement Systems

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

[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 the wet method using a laser diffraction / scattering particle size distribution analyzer Microtrac MT3200II type (manufactured by MicrotracBEL). Measurement range: 0.243 to 1408 μm Solvent: Water Solvent refractive index: 1.333 Measurement time: 30 seconds Particle shape: Non-spherical Particle permeability: Permeable Particle refractive index: 1.81

[0121] (Example 1B: Analysis of the Solid State of Compound (I)) For the compound (I) produced by the synthesis method of Example 1 above, powder X-ray diffraction experiment and differential thermal-thermogravimetric simultaneous measurement (TG / DTA) were carried out, and it was confirmed that it is an anhydrous crystal of the compound represented by formula (I).

[0122] (Example 2: Analysis of Anhydrous Crystals of the Compound Represented by Formula (I)) The anhydrous crystals of the compound represented by formula (I) were pulverized, and powder X-ray diffraction experiment, single crystal structure analysis, differential scanning calorimetry (DSC), differential thermal-thermogravimetric simultaneous measurement (TG / DTA), water adsorption / desorption isotherm measurement method (DVS), Raman spectrum measurement, and particle size distribution measurement were carried out.

[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 speed: 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 Represented by Formula (I)) For the anhydrous crystal of the compound represented by formula (I) after pulverization, a powder X-ray diffraction experiment was conducted under the measurement condition 1 described in Test Example 3 above. The powder X-ray diffraction pattern is shown in Figure 1, and the peak list of the powder X-ray diffraction pattern is shown in Figure 2. Hereinafter, in the table of the peak list of the powder X-ray diffraction pattern, Position indicates 2θ (°) and Intensity indicates the 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 crystal of the compound represented by formula (I) showed characteristic peaks 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° in the powder X-ray diffraction pattern. The anhydrous crystal of the compound represented by formula (I) showed 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 the powder X-ray diffraction pattern.

[0125] (Example 2C: Single crystal structure analysis of the anhydrous crystal of the compound represented by formula (I)) <Method for preparing single crystal> To 1 mg of the crystal of the compound represented by formula (I), 400 μL of methanol was added, and the mixture was heated to 50 °C to dissolve it. The solution was dispensed into a 1.5 mL HPLC vial, the lid of the HPLC vial was put on, and a syringe needle was pierced into the lid, and then it was allowed to stand at room temperature. A single crystal was prepared by the solvent evaporation method. <Single crystal structure analysis> The single crystal diffraction experiment and analysis were carried out by the method described in Test Example 5 above. Since Cl1 and Cl7C, and H5CA and H6CA are in a disorder relationship, they were analyzed with an occupancy ratio 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. R1 (I>2.00s(I)) was 0.0555, and it was confirmed that there were no deficiencies or misplacements of electron density from the final difference Fourier.

[0127] The crystallographic data are shown in Table 1.

Table 1

[0128] The fractional atomic coordinates x, y, z (Å×10 4 ) and the equivalent isotropic temperature factor U(eq) (Equivalent Isotropic Displacement Parameters, Å 2 ×10 3 ) of non-hydrogen atoms are shown in Table 2. Here, U(eq) is defined as one-third of the trace of the rectified U ij tensor.

Table 2

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

Table 3

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

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

[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 (FIG. 1) of Example 2B.

[0133] (Example 2D: Differential Scanning Calorimetry of Anhydrous Crystal of Compound Represented by Formula (I)) About 2 mg of the anhydrous crystal of the compound represented by the formula (I) after pulverization was weighed into an aluminum pan, and measurement was carried out by the method described in Test Example 7 above. The results are shown in FIG. 4. An endothermic peak with an onset temperature of about 261.3 °C was shown.

[0134] (Example 2E: Simultaneous Differential Thermal-Thermogravimetric Measurement of Anhydrous Crystal of Compound Represented by Formula (I)) About the anhydrous crystal of the compound represented by the formula (I) after pulverization, measurement was carried out by the method described in Test Example 8 above. The results are shown in FIG. 5. An endothermic peak with an onset temperature of about 265.6 °C was shown. Also, no weight loss was confirmed.

[0135] (Example 2F: Raman Spectrum Measurement of Anhydrous Crystal of Compound Represented by Formula (I)) About the anhydrous crystal of the compound represented by the formula (I) after pulverization, Raman spectrum measurement was carried out under Measurement Condition 1 described in Test Example 6 above. The results are shown in FIG. 6. Also, the main Raman peaks are shown below.

Table 4

[0136] (Example 2G: Particle Size Distribution of Anhydrous Crystals of the Compound Represented by Formula (I)) For the anhydrous crystals of the compound represented by formula (I) before pulverization used in Example 2A, the particle size distribution was measured by the method described in Measurement Condition 2 of Test Example 10. As a result, D10 was 1.16 μm, D50 was 4.42 μm, and D90 was 13.13 μm. The particle size distribution is shown in Fig. 7.

[0137] (Example 2H: Particle Size Distribution of Anhydrous Crystals of the Compound Represented by Formula (I)) For the anhydrous crystals of the compound represented by formula (I) after pulverization obtained in Example 2A, the particle size distribution was measured by the method described in Measurement Condition 1 of Test Example 10. As a result, D10 was 0.79 μm, D50 was 2.90 μm, and D90 was 7.32 μm. The particle size distribution is shown in Fig. 8.

[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 for each crystal, NMR measurement, powder X-ray diffraction experiment, single crystal structure analysis, differential scanning calorimetry (DSC), differential thermal-thermogravimetric simultaneous measurement (TG / DTA), moisture adsorption-desorption isotherm measurement method (DVS), Raman spectrum measurement, and particle size distribution measurement were performed.

[0139] (Example 3A: Preparation of Ethyl Acetate Solvate Crystals of the Compound Represented by Formula (I)) In Example 1, compound 6 (800 mg, 1.880 mmol) and 6,6-difluoro-2-azaspiro[3.3]heptane trifluoroacetate (557 mg, 2.256 mmol) were dissolved in DMF (8.0 mL). After adding N,N-diisopropylethylamine (985 μL, 5.64 mmol), the mixture was stirred at 60 °C for 2 hours. Water was added to the reaction mixture, 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 distilled off under reduced pressure from the filtrate, and then the residue was subjected to silica gel column chromatography. After eluting with hexane / ethyl acetate, the fractions containing the desired compound were collected. The solvent was concentrated under reduced pressure, diisopropyl ether was added, and the precipitated solid was collected by filtration. The obtained residue was dried under reduced pressure to obtain compound (I) (954 mg, 1.563 mmol, yield 83%). NMR measurement was performed by the method described in the above (method for identifying compounds). In the NMR chart, the peak of ethyl acetate was observed. 1 1H-NMR (DMSO-D6) δ: 1.18 (3H, t, J = 7.0 Hz), 1.99 (3H, s), 2.79 (4H, t, J = 12.4 Hz), 4.03 - 4.06 (6H, m), 4.82 (2H, s), 7.21 (1H, s), 7.39 - 7.42 (2H, m), 7.96 (1H, s), 8.46 (1H, s), 8.69 (1H, s). LC / MS (ESI): m / z = 522, RT = 2.30 min, LC / MS measurement condition B

[0140] (Example 3B: Powder X-ray diffraction experiment of the solid prepared by the method of Example 3A) For the sample prepared by the method of Example 3A, a powder X-ray diffraction experiment was performed 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 NMR measurement of Example 3A and the results of Example 3B, it was estimated that the sample prepared by the method of Example 3A was "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)) For the ethyl acetate solvate crystal of the compound represented by formula (I), single crystal diffraction experiments and analysis were carried out by the method described in Test Example 5 above. As a result, it was confirmed that the ethyl acetate solvate crystal had a molar ratio of the compound represented by formula (I) to ethyl acetate 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 Crystal of the Compound Represented by Formula (I)) For the ethyl acetate solvate crystal of the compound represented by formula (I) that had been air-dried overnight at room temperature, NMR measurement was carried out by the method described in the above (Compound Identification Method). 1 The results of 1H-NMR are shown in Figure 9. In the NMR chart, peaks of ethyl acetate were observed. 1 From the integration ratio of 1H-NMR, the molar ratio of the compound represented by formula (I) to ethyl acetate was approximately 1:1. Since the crystal had been air-dried at room temperature before measurement, it was presumed that the crystal was an ethyl acetate solvate crystal in which ethyl acetate was included in the crystal lattice rather than being attached to the crystal surface. This result was also consistent with the single crystal structure analysis in Example 3C.

[0143] (Example 3E: Grinding of Ethyl Acetate Solvate Crystal of the Compound Represented by Formula (I)) The ethyl acetate solvate crystal of the compound represented by formula (I) was ground under the following conditions. Apparatus: Hosokawa / ALPINE SPIRAL JET MILL50AS (Hosokawa Micron Corporation) Feeding method: Manual Feeding rate: 30.15 g / 25 min Grinding pressure: 0.10 MPa Feeding pressure: 0.20 MPa

[0144] (Example 3F: Powder X-ray Diffraction Experiment of Ethyl Acetate Solvate Crystal of the Compound Represented by Formula (I)) For the ethyl acetate adduct crystals of the compound represented by formula (I) after pulverization, a powder X-ray diffraction experiment was conducted under the measurement condition 1 described in Test Example 3 above. The powder X-ray diffraction pattern is shown in FIG. 10, and the peak list of the powder X-ray diffraction pattern is shown in FIG. 11. In the powder X-ray diffraction pattern, peaks were observed at 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° ± 0.2°, 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 adduct crystals of the compound represented by formula (I) showed characteristic peaks at diffraction angles (2θ): 6.9° ± 0.2°, 8.8° ± 0.2°, 13.1° ± 0.2°, 13.6° ± 0.2°, 16.3° ± 0.2°, 17.6° ± 0.2°, 18.6 ± 0.2°, 20.9 ± 0.2°, 21.7 ± 0.2°, and 23.7° ± 0.2° in the powder X-ray diffraction pattern. The ethyl acetate adduct crystals of the compound represented by formula (I) 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° in the powder X-ray diffraction pattern.

[0145] (Example 3G: Raman Spectrum Measurement of Ethyl Acetate Adduct Crystals of the Compound Represented by Formula (I)) For the ethyl acetate adduct crystals of the compound represented by formula (I) after pulverization, a Raman spectrum measurement was conducted under the measurement condition 1 described in Test Example 6 above. The results are shown in FIG. 12. The main Raman peaks are shown below. [Table 5] The ethyl acetate solvate crystals of the compound represented by formula (I) show peaks characteristic of 421.2 cm -1 ±2 cm -1 , 509.7 cm -1 ±2 cm -1 , 1585.3 cm -1 ±2 cm -1 , 1709.9 cm -1 ±2 cm -1 and 3052.9 cm -1 ±2 cm -1 in the Raman spectrum.

[0146] (Example 3H: Simultaneous differential thermal - thermogravimetric measurement of ethyl acetate solvate crystals of the compound represented by formula (I)) For the ethyl acetate solvate crystals of the compound represented by formula (I), measurement was carried out by the method described in Test Example 8 above. The results are shown in Figure 13. An endothermic peak with an onset temperature of about 129.5 °C was shown, and a weight loss of about 14% was confirmed almost simultaneously. This change is considered to be due to the desolvation (desorption) of ethyl acetate from the "ethyl acetate solvate crystals of the compound represented by formula (I)". In addition, for the "ethyl acetate solvate crystals of the compound represented by formula (I)" in which the molar ratio of the compound represented by formula (I) to the presence of ethyl acetate is 1:1, the theoretical content of ethyl acetate in the crystals is 14.4% by weight, which was generally consistent with the results of this thermogravimetric measurement (TG).

[0147] When multiple lots of the ethyl acetate solvate crystals of the compound represented by formula (I) were measured by the method described in Test Example 8 above, in each measurement, endothermic peaks at 92.5 °C, 95.7 °C, and 116.7 °C were shown, and a weight loss was confirmed at the temperature of the endothermic peak. In addition, for this sample, a powder X - ray diffraction experiment was carried out under the measurement condition 1 described in Test Example 3 above, and the powder X - ray diffraction patterns were very similar. The main peaks were in agreement within the range of ±0.2 °, and the relative intensities were slightly different. All of the 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° in the powder X-ray diffraction pattern.

[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 pulverization used in Example 3E was measured by the method described in Measurement Condition 2 of Test Example 10. As a result, D10 was 18.73 μm, D50 was 71.82 μm, and D90 was 114.67 μm. The particle size distribution is shown in FIG. 14.

[0149] (Example 3J: Particle size distribution of ethyl acetate solvate crystals of the compound represented by formula (I)) For the ethyl acetate solvate crystals of the compound represented by formula (I) after pulverization obtained in Example 3E, the particle size distribution was measured by the method described in Measurement Condition 1 of Test Example 10. As a result, D10 was 0.68 μm, D50 was 3.59 μm, and D90 was 8.80 μm. The particle size distribution is shown in FIG. 15.

[0150] Examples, reference examples, and test examples regarding the preparations of the compound represented by formula (I) are given below to explain the present invention in detail. The present invention is not limited thereto. Regarding the anhydrous crystals of the compound represented by formula (I), (1) a compound having a particle size with D10 of 0.78 μm, D50 of 2.09 μm, and D90 of 4.77 μm, (2) a compound having a particle size with D10 of 0.86 μm, D50 of 3.29 μm, and D90 of 10.15 μm, and (3) a compound having D10 of 0.7 μm, D50 of 2.7 μm, and D90 of 8.8 μm, and compounds with purities (quantitative values) of 101.7% and 99.7% for (2) and (3) respectively were used. The chromatogram obtained when measuring a compound with a particle size of D10 = 0.86 μm, D50 = 3.29 μm, and D90 = 10.15 μm in (2) by the liquid chromatography method shown in Test Example 12 is shown in FIG. 16. The compound represented by formula (I) was detected at a retention time of 24.941 minutes with a purity (pa%) of 99.58%.

[0151] Test Example 12: Analysis Method of Related Substances 1 The amount of related substances was measured by liquid chromatography under the following methods and conditions. Detector: Ultraviolet absorption photometer (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) Liquid delivery of the mobile phase: The concentration gradient control was performed by changing the mixing ratio of mobile phase A and mobile phase B as follows.

Table 6

[0152] (Example 4: Production and Analysis of Solid Dispersion of Compound Represented by Formula (I)) A solid dispersion of the compound represented by formula (I) was prepared, and for each solid dispersion, observation with a digital microscope, powder X-ray diffraction experiment, differential scanning calorimetry (DSC), measurement of particle size distribution, and measurement of related substances were performed.

[0153] (Example 4A: Selection of Polymer Used in Solid Dispersion of Compound Represented by Formula (I)) The anhydrous crystals and polymer of the compound represented by formula (I) were dissolved in acetone, ethanol or a mixed solution thereof, and then dropped onto a slide glass. A solid dispersion was obtained by evaporation of the solvent. The anhydrous crystals of the compound represented by formula (I) were pulverized under the following conditions, and the pulverized product was used. Apparatus: Hosokawa / ALPINE SPIRAL JET MILL50AS (manufactured by Hosokawa Micron Corporation) Feeding method: Feeder Feeding rate: 60 g / hour Pulverization pressure: 0.05 MPa Feeding pressure: 0.10 MPa When the particle size distribution of the anhydrous crystals of the compound represented by formula (I) after pulverization was measured by the method described in Measurement Condition 1 of Test Example 10, D10 was 0.78 μm, D50 was 2.09 μm, and D90 was 4.77 μm. <Preparation of solid dispersion> The content of the compound represented by formula (I) in the solid dispersion was examined at 10 wt%, 25 wt% and 50 wt%. As the polymer, copovidone (polyvinylpyrrolidone-vinyl acetate copolymer, PVPVA) (manufactured by BASF), polyvinylpyrrolidone (povidone) (manufactured by BASF), hypromellose acetate succinate (hydroxypropylmethylcellulose acetate succinate) (manufactured by Shin-Etsu Chemical Co., grades LF and MF), hypromellose phthalate (manufactured by Shin-Etsu Chemical Co.), hydroxypropylcellulose (manufactured by Nippon Soda Co.) and methacrylic acid copolymer L (manufactured by Evonik) were used. The formulations are shown below.

Table 7

[0154] (Example 4B: Preparation 1 of the solid dispersion of the compound represented by the formula (I)) The anhydrous crystals of the compound represented by the formula (I) (ground product of Example 4A) and each polymer were dissolved in acetone. After confirming complete dissolution, a solid dispersion was produced using a spray dryer (Advance B-290 type for organic solvents, manufactured by BUCHI) under the conditions of an inlet temperature of 90 °C, a liquid feed pump of 20%, and a nitrogen flow scale of 40. As the polymers, 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 represented by the formula (I) in the solid dispersion was 25% by weight. The formulation is shown below.

Table 8

[0155] (Example 4C: Powder X-ray diffraction experiment of the solid dispersion of the compound represented by the formula (I)) Regarding the solid dispersion obtained in Example 4B, powder X-ray diffraction experiments were carried out under the measurement conditions 1 described in Test Example 3 immediately after preparation, after storage for 1 week with the glass bottle uncapped in an environment of 40 °C and 75% relative humidity, after storage for 1 week with the glass bottle capped in an environment of 40 °C and 75% relative humidity, and after storage for 1 week with the glass bottle capped in an environment of 60 °C. The results of Example 4B-1 are shown in FIG. 17, the results of Example 4B-2 are shown in FIG. 18, the results of Example 4B-3 are shown in FIG. 19, and the results of Example 4B-4 are shown in FIG. 20. Each solid dispersion obtained in Example 4B showed only a halo pattern without showing diffraction peaks immediately after preparation and after storage under each condition. It was confirmed that all of the solid dispersions maintained an amorphous state. Incidentally, the anhydrous crystal alone of the compound represented by formula (I) showed a good powder X-ray diffraction pattern as described in Example 2B above.

[0156] (Example 4D: Preparation 2 of Solid Dispersion of Compound Represented by Formula (I)) The anhydrous crystal of the compound represented by formula (I) and copovidone (manufactured by ASHLAND) were dissolved in acetone. After confirming complete dissolution, spray drying was carried out using a spray dryer under the conditions of an outlet temperature of 50 ° C., a feed flow rate of about 6 kg / hour, and a spray pressure of 1.0 bar. Thereafter, vacuum drying was carried out using a tabletop vacuum dryer for about 40 hours to obtain a solid dispersion. The formulation is shown below.

Table 9

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

[0158] <Particle Size Distribution of Anhydrous Crystal of Compound Represented by Formula (I)> Regarding the anhydrous crystal of the compound represented by formula (I) used in Example 4D-1, when the particle size distribution was measured under Measurement Condition 3 (dry method) described in Test Example 10, D10 was 0.86 μm, D50 was 3.29 μm, and D90 was 10.15 μm. Also, regarding the anhydrous crystal of the compound represented by formula (I) used in Example 4D-1, when the particle size distribution was measured by Test Example 11 (wet method), D10 was 3.94 μm, D50 was 9.18 μm, and D90 was 20.32 μm.

[0159] (Example 4E: Stability Test over Time of Solid Dispersion of Compound Represented by Formula (I)) The solid dispersion obtained in Example 4D was stored for 3 months under the environment of 25°C and 60% relative humidity and for 3 months under the environment of 40°C and 75% relative humidity, and the increased 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 under the following methods 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: Mixture of water / formic acid (1000:1) Mobile phase B: Mixture of acetonitrile / formic acid for liquid chromatography (2000:1) Liquid delivery of mobile phase: The mixing ratio of mobile phase A and mobile phase B was changed as follows to control the concentration gradient.

Table 10

[0161] Regarding the start of the test, after storage for 3 months under the environment of 25°C and 60% relative humidity, and after storage for 3 months under the environment of 40°C and 75% relative humidity, the amount of related substances with a relative retention time of 0.44 is shown below.

Table 11

[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 simple substance of the compound represented by Formula (I) was measured.

[0163] Test Example 14: Solubility Test The solid dispersion obtained in Example 4D and the anhydrous crystal simple substance of the compound represented by Formula (I) (Example 4F-1) were added to various test solutions to prepare a suspension of 30 to 50 mL. The prepared suspension was placed in a centrifuge tube and shaken under the condition that the shaking speed was 100 rpm or more. After 60 minutes from the start of shaking, 5 mL was collected and immediately filtered through a filter (chromatodisk 0.45 μm, 25A) to obtain a specimen.

[0164] The solubility in various test solutions is shown below. The solid dispersion of the compound represented by Formula (I) was significantly improved as compared with the solubility of the anhydrous crystal simple substance of the compound represented by Formula (I). [Table 12]

[0165] (Example 4G: Rat PK Test of Solid Dispersion of Compound Represented by Formula (I)) A suspension of a solid dispersion composed of the anhydrous crystal simple substance of the compound represented by Formula (I) and copovidone was prepared, and the oral absorbability in rats was evaluated.

[0166] Test Example 15: Rat PK Test After feeding male rats, the specimen was orally administered. The dosage of the suspension was adjusted so that the dosage of the compound represented by Formula (I) was 3 mg / kg body weight. After administering Example 4G-1, Example 4G-2, and Example 4G-3 shown below, blood was collected at each blood collection time, and the maximum plasma drug concentration (Cmax), the time to reach the highest plasma drug concentration (Tmax), and the area under the plasma drug concentration-time curve from the time of administration to 24 hours later (AUC) were calculated using LC / MS / MS. <Example 4G-1: Preparation of a suspension of a solid dispersion of the compound represented by formula (I)> The compound represented by formula (I) and copovidone (manufactured by ASHLAND) were dissolved in acetone at a weight ratio of 1:3. After confirming complete dissolution, spray drying was carried out using a spray dryer under the conditions of an outlet temperature of 50 °C, a feed flow rate of about 6 kg / hour, and a spray pressure of 1.0 bar. Vacuum drying was performed for about 40 hours using a bench-top vacuum dryer to obtain a solid dispersion. The obtained solid dispersion was suspended in an aqueous solution containing 0.5% methylcellulose to a concentration of 6 mg / mL to obtain a suspension. <Example 4G-2: Preparation of a suspension of anhydrous crystals of the compound represented by formula (I)> A suspension was obtained by suspending the anhydrous crystals of the compound represented by formula (I) in an aqueous solution containing 0.5% methylcellulose to a concentration of 6 mg / mL. <Example 4G-3: Preparation of a suspension of ethyl acetate solvate crystals of the compound represented by formula (I)> A suspension was obtained by suspending the ethyl acetate solvate crystals of the compound represented by formula (I) in an aqueous solution containing 0.5% methylcellulose to a concentration of 6 mg / mL.

[0167] Regarding Cmax, Tmax, and AUC of the compound represented by formula (I) in each example, the results are shown below.

Table 13

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

[0170] (Example 5A: Examination 1 of tablets containing the anhydrous crystal of the compound represented by formula (I)) Tablets containing 50% by weight of the anhydrous crystal of the compound represented by formula (I) and 5% by weight of a disintegrant were manufactured, and a dissolution test was carried out. <Method for manufacturing tablets> The anhydrous crystal of the compound represented by formula (I), D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahi Kasei), 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).

Table 14

[0171] <Dissolution test> Test Example 16: Dissolution test For the preparations obtained in each example (in the case of tablets, 1 tablet), a dissolution test was carried out according to the dissolution test method of the 18th revised Japanese Pharmacopoeia. As the test solution, dissolution test solution No. 2 containing a surfactant was used, and the paddle method was carried out 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 using crospovidone (grade CLM) showed the best dissolution property.

[0173] (Example 5B: Examination 2 of tablets containing anhydrous crystals of the compound represented by formula (I)) Tablets containing 50% by weight of anhydrous crystals of the compound represented by formula (I) and 10% by weight of a disintegrant were manufactured, and a dissolution test was conducted. <Tablet manufacturing method> Manufactured in the same manner as in Example 5A. The formulation is shown below.

Table 15

[0174] <Dissolution test> The dissolution test was conducted as in Test Example 16. As a result, in Examples 5B-1, 5B-2, and 5B-3 (disintegrant blending ratio 10% by weight), the dissolution rate of any disintegrant was improved compared to Examples 5A-1, 5A-2, and 5A-5 (disintegrant blending ratio 5% by weight). Also, Example 5B-1 using crospovidone as the disintegrant showed the fastest dissolution property.

[0175] (Example 5C: Examination 3 of tablets containing anhydrous crystals of the compound represented by formula (I)) Tablets containing 10% by weight of anhydrous crystals of the compound represented by formula (I) and 10% by weight of a disintegrant were manufactured, and a dissolution test was conducted. <Tablet manufacturing method> Anhydrous crystals of the compound represented by 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 manufacturing method was carried out in the same manner as in Examples 5A and 5B. The formulation is shown below.

Table 16

[0176] <Dissolution test> The dissolution test was carried out in Test Example 16. As a result, Example 5C-1 using crospovidone as a disintegrant showed good dissolution properties. Therefore, in the blending ratio of 10 to 50% by weight of the anhydrous crystal of the compound represented by the formula (I), crospovidone is considered to be optimal as the disintegrant.

[0177] (Example 5D: Suspension containing anhydrous crystal of the compound represented by the formula (I)) A suspension containing the anhydrous crystal of the compound represented by the formula (I) was prepared. The dissolution test was carried out on the suspension and the above Example 5C-1 (tablet containing the anhydrous crystal of the compound represented by the formula (I)). <Preparation of suspension manufactured <method> The anhydrous crystal of the compound represented by the formula (I), hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) ) and titanium oxide (manufactured by Merck) were mixed with a spatula, and then while adding a small amount of water for injection (manufactured by Otsuka Pharmaceutical Factory), kneading was carried out using a spatula. Thereafter, the remaining water for injection was added while performing ultrasonic irradiation to obtain a suspension. The formulation is shown below.

Table 17

[0178] <Dissolution test> The dissolution test was carried out in Test Example 16. The dissolution test results of Example 5C-1 and Example 5D-1 are shown in Fig. 21. As a result, Example 5C-1 (tablet) showed rapid dissolution as compared with Example 5D-1 (suspension).

[0179] (Example 5E: Examination 1 of tablets containing anhydrous crystal of the compound represented by the formula (I)) In order to examine the influence of the photo-stabilizing substance, a tablet containing the anhydrous crystal of the compound represented by the formula (I) was coated with a photo-stabilizing substance and a polymer, and the amount of related substances in the preparation and the appearance properties were evaluated. The stability test of the tablet and the tablet was carried out under a heated and humidified environment, and the dissolution properties were evaluated respectively. <Tablet manufacturing method> The anhydrous crystals of the compound represented by formula (I), D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahi Kasei), crospovidone (grade INF-10, manufactured by ASHLAND), and half of the sodium stearyl fumarate (manufactured by JRS Pharma) were mixed in a polyethylene bag and sieved through a 30-mesh sieve. Then, granulation was carried out using a roller compactor under the conditions of a roll pressure of 7 MPa, a roll rotation speed of about 4 rpm, and a screw rotation speed of about 30 rpm. Subsequently, sizing was carried out using a sizing machine at a rotation speed of about 1800 rpm. The obtained sized granules and half of the sodium stearyl fumarate were mixed in a mixer for 5 minutes, and then tableting was carried out using a rotary tablet press at a turret rotation speed of 20 - 30 rpm to produce the core tablets. Thereafter, coating was carried out using a coating machine under the conditions of an air supply volume of 0.80 m3 / min, a set air supply temperature of 60 °C, a liquid flow rate of 2.0 - 2.9 g / min, a spray pressure of about 0.18 MPa, and an amount of spray air of about 50 NL / min to obtain the tablets of Example 5E-1. Talc, ferric sesquioxide, and yellow ferric sesquioxide were used as the light-stabilizing substances, and hypromellose was used as the polymer. The formulation is shown below.

Table 18

[0180] <Dissolution test> The tablets of Example 5E-1 were stored in a polyethylene bottle with the cap closed for 1 month and 3 months under the conditions of 40 °C and 75% relative humidity. The dissolution test was carried out by the method of Test Example 16 at the start of the test and after storage in each environment. The results are shown in Figure 22. It was confirmed that the dissolution rate did not decrease even when stored for 3 months in a heated and humidified environment.

[0181] <Stability test> Tablets containing anhydrous crystals of the compound represented by formula (I) (Example 5C-1 above) and tablets coated with a stabilizing substance and a polymer (Example 5E-1 above) were irradiated with light having a total irradiation light amount of 1,200,000 lux·hr, and the amount of related substances and the appearance properties in the preparation were evaluated at the start of the test and after irradiation with 1,200,000 lux·hr of light. As the amount of related substances, the relative retention time 0.84 and the total amount of related substances were measured. The appearance properties were evaluated visually.

[0182] Test Example 17: Analytical Method 3 for Related Substances The amount of related substances was measured by liquid chromatography under the following methods 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) Liquid feeding of the mobile phase: The mixing ratio of mobile phase A and mobile phase B was changed as follows to control the concentration gradient. [Table 19] Flow rate: 0.4 mL / min Injection volume: 5 μL Sample cooler temperature: Constant temperature around 25°C Needle washing solvent or autoinjector cleaning solution: Acetonitrile Area measurement range: Up to 43 minutes after injection of the sample solution

[0183] The amount of related substances with a relative retention time of 0.84 at the start of the test and after irradiation with 1,200,000 lux·hr of light is shown below. [Table 20] The total amount of related substances at the start of the test and after irradiation with 1,200,000 lux·hr of light is shown below.

Table 21

[0184] (Example 5F: Examination of Capsule and Tablet Containing Anhydrous Crystal of Compound Represented by Formula (I)) Granules containing anhydrous crystals of the compound represented by formula (I) were filled into capsules to prepare capsule agents. The amount of related substances in the capsule agents and tablets was evaluated. As the amount of related substances, the relative retention time of 0.98 and the total amount of related substances were measured. <Manufacturing Method of Capsule Agent and Tablet>[ The anhydrous crystal of the compound represented by formula (I), D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahi Kasei), croscarmellose sodium (manufactured by Dupont), and half amount of magnesium stearate (manufactured by MALLINCKRODT) were mixed with a spatula and sieved through a wire mesh. Then, it was tabletted using a simple tablet molding machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.). Then, it was sized with a 20-mesh sieve, half amount of magnesium stearate was added and mixed with a spatula to obtain granules. The granules were manually filled into hypromellose capsules (manufactured by Kyoricaps) using a spatula to prepare the capsule agent of Example 5F-1. Also, the granules were tabletted using a simple tablet molding machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.) to prepare the tablet of Example 5F-2. Each formulation is shown below.

Table 22

[0185] Test Example 18: Analytical Method 4 for Related Substances The amount of related substances was measured by liquid chromatography under the following methods 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: Mixture of water / trifluoroacetic acid (1000:1) Mobile phase B: Acetonitrile for liquid chromatography Liquid feeding of mobile phase: The mixing ratio of mobile phase A and mobile phase B was changed as follows to perform concentration gradient control.

Table 23

[0186] <Stability test> Regarding the start of the test and after light irradiation of 1.2 million lux·hr, the amount of related substances with a relative retention time of 0.98 is shown below.

Table 24

Table 25

[0187] (Example 6: Preparation containing a solid dispersion of the compound represented by formula (I)) The formulation study of the preparation containing the solid dispersion of the compound represented by formula (I) is shown below.

[0188] (Example 6A: Examination of tablets containing a solid dispersion of the compound represented by formula (I)) Tablets containing a solid dispersion of the compound represented by formula (I) were manufactured and dissolution tests were carried out. (Tablet manufacturing method) The anhydrous crystals of the compound represented by formula (I) and copovidone were dissolved in acetone. After confirming complete dissolution, spray drying was carried out using a spray dryer under the conditions of an outlet temperature of 50°C, a feed flow rate of about 6 kg / hr, and a spray pressure of 1.0 bar. Thereafter, vacuum drying was carried out using a tabletop vacuum dryer for about 40 hours 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 the amount of sodium stearyl fumarate (manufactured by JRS Pharma) were mixed with a spatula and sieved through a wire mesh. Thereafter, tableting was carried out using a simple tablet molding machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.). Thereafter, sizing was carried out with a 20-mesh sieve, and half the amount of sodium stearyl fumarate was added and mixed with a spatula. The obtained granules were tableted using a simple tablet molding machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.) to obtain tablets. The formulation is shown below.

Table 26

[0189] (Dissolution test) Dissolution tests were carried out in Test Example 16. As a result, Example 6A-1 using croscarmellose sodium showed good dissolution properties. Therefore, for tablets containing a solid dispersion, croscarmellose sodium is considered to be a suitable disintegrant.

[0190] (Example 6B-1: Examination 1 of tablets containing a solid dispersion of the compound represented by formula (I)) Tablets containing a solid dispersion of the compound represented by formula (I) were coated with a light stabilizer and a polymer to produce tablets. For the tablets, stability tests were carried out under a heated and humidified environment. <Tablet manufacturing method> The anhydrous crystal of the compound represented by formula (I) and copovidone were dissolved in acetone. After confirming complete dissolution, spray drying was carried out using a spray dryer under the conditions of an outlet temperature of 50 °C, a feed flow rate of about 6 kg / hr, and a spray pressure of 1.0 bar. Thereafter, vacuum drying was carried out using a tabletop vacuum dryer for about 40 hours to obtain a solid dispersion. The obtained solid dispersion was mixed with D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahi Kasei), croscarmellose sodium (manufactured by Dupont), light anhydrous silicic acid (manufactured by Cabot), and half the amount of sodium stearyl fumarate (manufactured by JRS Pharma) in a mixer for 8 minutes and sieved through a 30-mesh sieve. Thereafter, dry granulation was carried out using a roller compactor under the 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. Thereafter, dry sizing was carried out using a sizing machine at a rotation speed of about 3000 rpm. The obtained sized granules and half the amount of sodium stearyl fumarate were mixed in a mixer for 5 minutes, and then tablets were manufactured using a rotary tablet press at a rotation speed of the turntable of about 30 rpm. Thereafter, coating was carried out using a coating machine under the conditions of an air supply volume of 0.80 m3 / min, a set air supply temperature of 60 °C, a liquid flow rate of 2.0 - 2.9 g / min, a spray pressure of about 0.18 MPa, and a spray air volume of about 50 NL / min to obtain tablets. The formulation is shown below.

Table 27

[0191] <Stability test and dissolution test> The tablets of Example 6B-1 were stored in a brown glass bottle with the stopper closed for 2 weeks under heating at 60 °C, for 1 month at 40 °C, and for 1 month in a brown glass bottle with the stopper closed under an environment of 40 °C and 75% relative humidity. At the start of the test and after storage in each environment, dissolution tests were carried out by the method of Test Example 16. The results are shown in Fig. 23. It was confirmed that the elution rate did not decrease after storage under any conditions.

[0192] (Example 6B-2: Examination 2 of tablets containing a solid dispersion of the compound represented by formula (I)) Tablets were produced with a different content of the solid dispersion composed of the compound represented by formula (I) and copovidone from that in Example 6B-1, and the tablets were produced by coating with a photo-stabilizing substance and a polymer. The stability test of the tablets was carried out under a heated and humidified environment. (Tablet manufacturing method) The anhydrous crystal of the compound represented by formula (I) and copovidone were dissolved in acetone. After confirming complete dissolution, spray drying was carried out using a spray dryer under the conditions of an outlet temperature of 50 °C, a feed flow rate of about 80 kg / hr, and a spray pressure of 2.5 bar. Then, vacuum drying was carried out using a rotary vacuum dryer for about 37 hours to obtain a solid dispersion. The obtained solid dispersion was mixed with D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahi Kasei), croscarmellose sodium (manufactured by Dupont), light anhydrous silicic acid (manufactured by Cabot), and half 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 carried out using a roller compactor under the 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 sizing was carried out using a sizing machine at a rotation speed of about 100 rpm. After mixing the obtained sized granules and half the amount of sodium stearyl fumarate in a mixer for 3 minutes, tablets were produced using a rotary tablet press at a rotation speed of the turntable of about 20 rpm. Then, coating was carried out using a coating machine under the conditions of an air supply volume of 12 m3 / min, a set value of the air supply temperature of 60 °C, a liquid flow rate of 40 - 80 g / min, a spray pressure of about 0.4 MPa, and an air volume of the spray of about 130 NL / min to obtain tablets. The formulation is shown below.

Table 28

[0193] <Stability Test and Dissolution Test> The tablets of Example 6B-2 were stored in a brown glass bottle with the cap closed at 60 °C for 2 weeks, at 40 °C for 1 month, and in an environment of 40 °C and 75% relative humidity in a brown glass bottle with the cap closed for 1 month. At the start of the test and after storage in each environment, the dissolution test was carried out by the following method. (Dissolution Test Method) One tablet of each was subjected to a dissolution test according to the Dissolution Test Method of the 18th Revision of the Japanese Pharmacopoeia. Dissolution Test Solution 2 was used as the test solution, and the paddle method was carried out at 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 conditions.

[0194] (Example 6C: Examination 3 of Tablets Containing a Solid Dispersion of the Compound Represented by Formula (I)) Two kinds of plain tablets were produced in which the blending ratio of the anhydrous crystal of the compound represented by formula (I) and copovidone was different from that of Example 6B-1. Each plain tablet was coated with a photo-stabilizing substance and a polymer to produce tablets. The stability test of the tablets was carried out under a heating and humidifying environment. (Tablet Manufacturing Method) The anhydrous crystal of the compound represented by formula (I) and copovidone were dissolved in acetone, and after confirming complete dissolution, a solid dispersion was obtained using a spray dryer under the conditions of an inlet temperature of 90 °C, a liquid feed pump of 20%, and a nitrogen flow scale of 40. The obtained solid dispersion, D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahi Kasei), croscarmellose sodium (manufactured by Dupont), and half the amount of sodium stearyl fumarate (manufactured by JRS Pharma) were mixed with a spatula and sieved through a wire mesh. Then, tableting was carried out using a simple tablet molding machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.). Then, sizing was carried out with a 20-mesh sieve, half the amount of sodium stearyl fumarate was added, and the mixture was mixed with a spatula. After tableting the obtained granulation for tableting using a simple tablet molding machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.), coating was carried out using a coating machine (Pauleck type) to obtain tablets. The formulation is shown below.

Table 29

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

[0196] (Example 6D: Examination 4 of tablets containing a solid dispersion of the compound represented by formula (I)) A core tablet containing a solid dispersion composed of an anhydrous crystal of the compound represented by formula (I) and copovidone, and a tablet obtained by coating the core tablet with a photo-stabilizing substance and a polymer were manufactured. For the core tablet and the tablet, light with a total irradiation light amount of 1.2 million lux·hr was irradiated, and the amount of related substances and the appearance properties in the preparation were evaluated at the start of the test and after irradiation with 1.2 million lux·hr of light. <Manufacturing method of core tablet and tablet> The anhydrous crystal of the compound represented by formula (I) and copovidone were dissolved in acetone, and after confirming complete dissolution, spray drying was carried out under the conditions of an outlet temperature of 50 °C, a feed flow rate of about 6 kg / hr, and a spray pressure of 1.0 bar. Then, vacuum drying was carried out using a tabletop vacuum dryer for about 40 hours 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. Thereafter, dry granulation was performed using a roller compactor under the 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. Thereafter, dry sizing was performed using a sizing machine at a rotation speed of about 3000 rpm. The obtained sized granules and half of the sodium stearyl fumarate were mixed in a mixer for 5 minutes, and then, using a rotary tablet press, a core tablet (Example 6D-1) was manufactured at a rotation speed of the turntable of about 30 rpm. For Example 6D-2, thereafter, using a coating machine, coating was performed under the conditions of an air supply volume of 0.80 m3 / min, a set value of the air supply temperature of 60 °C, a liquid flow rate of 2.0 to 2.9 g / min, a spray pressure of about 0.18 MPa, and an amount of spray air of about 50 NL / min to obtain tablets. The formulation is shown below.

Table 30

[0197] Examples 6D-1 and 6D-2 were irradiated with light having a total irradiation light amount of 1,200,000 lux·hr, and the amount of related substances in the preparation and the appearance properties at the start of the test and after irradiation with light of 1,200,000 lux·hr were evaluated. The amount of related substances was measured by the method of Test Example 17, and the relative retention time of 1.59 and the total amount of related substances were measured. Further, the appearance properties were evaluated visually.

[0198] <Results> The amounts of related substances having a relative retention time of 1.59 at the start of the test and after irradiation with light of 1,200,000 lux·hr are shown below.

Table 31

Table 32

[0199] (Example 6E: Examination 5 of tablets containing a solid dispersion of the compound represented by formula (I)) Tablets were produced that were different from Example 6D in the content of the solid dispersion composed of the anhydrous crystal of the compound represented by formula (I) and copovidone, and tablets coated with a light stabilizer and a polymer on the core tablets. For the core tablets and tablets, light with a total irradiation light amount of 1.2 million lux·hr was irradiated, and the amount of related substances and appearance properties in the preparation were evaluated at the start of the test and after 1.2 million lux·hr light irradiation. <Method for producing core tablets and tablets> The anhydrous crystal of the compound represented by formula (I) and copovidone were dissolved in acetone, and after confirming complete dissolution, spray drying was carried out using a spray dryer under the conditions of an outlet temperature of 50°C, a feed flow rate of about 80 kg / hr, and a spray pressure of 2.5 bar. Then, vacuum drying was carried out using a rotary vacuum dryer for about 37 hours 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 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. After that, dry granulation was performed using a roller compactor under the 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 sizing was carried out using a sizing machine at a rotation speed of about 100 rpm. The obtained sized granules and half of the sodium stearyl fumarate were mixed in a mixer for 3 minutes, and then tablets (Example 6E-2) were manufactured using a rotary tablet press at a rotation speed of the turntable of about 20 rpm. For Example 6E-1, thereafter, coating was carried out using a coating machine under the conditions of an air supply volume of 12 m3 / min, an air supply temperature set value of 60 °C, a liquid flow rate of 40 - 80 g / min, a spray pressure of about 0.4 MPa, and an air volume of the spray of about 130 NL / min to obtain tablets. The formulation is shown below.

Table 33

[0200] Examples 6E-1 and 6E-2 were irradiated with light having a total irradiation light amount of 1.2 million lux·hr, and the amount of related substances and the appearance properties in the formulation were evaluated at the start of the test and after irradiation with 1.2 million lux·hr of light. The amount of related substances was measured for the relative retention time of 1.59 and the total amount of related substances by the method of Test Example 17. Also, the appearance properties were evaluated visually.

[0201] <Results> The amount of related substances with a relative retention time of 1.59 at the start of the test and after irradiation with 1.2 million lux·hr of light is shown below.

Table 34

Table 35

[0202] (Example 7: Capsule containing a solution of the compound represented by formula (I)) As a study on a formulation recipe that enables confirmation of absorption, distribution, metabolism, and excretion (ADME test) in oral administration, the following capsules were manufactured. Capsules containing a solution of the compound represented by formula (I) were manufactured, and the stability of the capsules was evaluated. Capsules with the following formulations were manufactured and a stability test was carried out.

Table 36

[0203] <Stability test> Examples 7-1 to 7-4 shown in Table 36 were stored in a brown glass bottle with the cap closed for 6 days under a heating environment of 25°C, and the amount of related substances in the formulation 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 of 0.1% or more at the start of the test and when stored at 25°C for 6 days is shown below. In Example 7-1 and Example 7-2, the generation of related substances was suppressed. Also, in Example 7-1 and Example 7-2, no individual related substances showing 0.1% or more were observed from the start of the test until after storage at 25°C for 6 days.

Table 37

[0205] (Example 8: Solution preparation of the compound represented by formula (I)) As an examination of a formulation recipe enabling confirmation of absorption, distribution, metabolism, and excretion in oral administration (ADME test), the solution preparations shown below were manufactured. Solution preparations with the formulations shown in Table 38 were manufactured, stored for 7 days in a warming environment at 5°C or 25°C, and an elution test was conducted.

Table 38

[0206] <Elution test> Regarding the solution preparations obtained in each example, an elution test was conducted according to the elution test method of the 18th revised Japanese Pharmacopoeia. The second elution test solution was used as the test solution, and the paddle method was conducted at a paddle rotation speed of 50 rpm (changed to 250 rpm 120 minutes after the start of the test).

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

[0208] (Example 9: Preparation Containing Ethyl Acetate Solvate Crystals of the Compound Represented by Formula (I)) The formulation study of a preparation containing ethyl acetate solvate crystals of the compound represented by formula (I) is shown below.

[0209] (Example 9A: Examination of Tablets Containing Ethyl Acetate Solvate Crystals of the Compound Represented by Formula (I)) Tablets containing ethyl acetate solvate crystals of the compound represented by formula (I) as an active ingredient were manufactured, and stability tests and dissolution tests were carried out. <Tablet Manufacturing Method> Ethyl acetate solvate crystals of the compound represented by formula (I), D-mannitol (manufactured by ROQUETTE), crystalline cellulose (manufactured by Asahi Kasei), 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. Then, tableting was carried out using a simple tablet molding machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.). Then, sizing was carried out with a 20-mesh sieve, and half the amount of magnesium stearate was added and mixed with a spatula. The obtained granulated material for tableting was tableted using a simple tablet molding machine (model: HANDTAB-200, manufactured by Ichihashi Seiki Co., Ltd.) to obtain tablets. The formulation is shown below.

Table 39

[0210] <Stability Test and Dissolution Test> The tablets of Example 9A-1 were stored in a brown glass bottle with the cap closed for 2 weeks under a heating environment of 60 °C and in a brown glass bottle with the cap open for 2 weeks under an environment of 40 °C and 75% relative humidity, and dissolution tests were carried out. The dissolution test was carried out as in Test Example 19.

[0211] <Dissolution Test> Test Example 19: Dissolution Test For the preparations obtained in each example (one tablet in the case of tablets), a dissolution test was carried out according to the dissolution test method of the 18th revised Japanese Pharmacopoeia. Artificial intestinal fluid during meals was used as the test solution, and the paddle method was carried out at a paddle rotation speed of 50 rpm (changed to 250 rpm 120 minutes after the start of the test).

[0212] (Example 9B: Examination 1 of a capsule containing ethyl acetate solvate crystals of the compound represented by formula (I)) A capsule containing ethyl acetate solvate crystals of the compound represented by formula (I) was manufactured, and an in - dog PK test of the capsule was carried out. <Manufacturing method of capsule> 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 - amount of magnesium stearate (manufactured by MALLINCKRODT) were mixed with a spatula and sieved through a wire mesh. Then, tableting was carried out using a simple tablet molding machine (model: HANDTAB - 20, manufactured by Ichihashi Seiki Co., Ltd.). After that, sizing was carried out with a 20 - mesh sieve, half - amount of magnesium stearate was added and mixed with a spatula to obtain granules. The granules were manually filled into gelatin capsules using a spatula to prepare capsules. The formulation is shown below.

Table 40

[0213] Test Example 20: In - dog PK test To male beagle dogs, after feeding was carried out 30 minutes to 2 hours before administration, one capsule was orally administered. In addition, Table 40A formulation of a capsule containing 120.0 mg of granules of the compound represented by formula (I) was shown. In this test, the mass of the granules per capsule was adjusted according to the body weight of male beagle dogs so that the dose of the compound represented by formula (I) would be 3 mg / kg body weight. After administration of each specimen, blood was collected at each blood collection 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: Examination 2 of a capsule containing an ethyl acetate adduct of the compound represented by formula (I)) A capsule formulation different from that in Example 9B containing an ethyl acetate adduct of the compound represented by formula (I) was manufactured, and the elution property of the capsule was evaluated. <Method for manufacturing the capsule> The ethyl acetate adduct of the compound represented by formula (I), copovidone (manufactured by ASHLAND), crystalline cellulose (manufactured by Asahikasei), D-mannitol (manufactured by ROQUETTE), croscarmellose sodium (manufactured by Dupont), and magnesium stearate (manufactured by MALLINCKRODT) were mixed with a spatula and sieved through a wire mesh, and then filled into hypromellose capsules (manufactured by Quoricaps) using a spatula to prepare capsules. The formulation is shown below.

Table 41

[0215] <Dissolution test> The preparation (1 capsule) obtained in each example was subjected to a dissolution test according to the dissolution test method of the 18th revised Japanese Pharmacopoeia. Fasted artificial intestinal fluid (FaSSIF-V2) was used as the test solution, and the paddle method was carried out at a paddle rotation speed of 50 rpm (changed to 250 rpm 120 minutes after the start of the test).

[0216] <Results> The dissolution test results of Examples 9C-1 to 9C-4 are shown in Fig. 28. In Example 9C-1 in which the ethyl acetate adduct of the compound represented by formula (I) was filled in hypromellose capsules, sufficient dissolution property was not shown, but the dissolution property was improved by adding 30.0 mg of copovidone and 7.5 mg of croscarmellose sodium (Examples 9C-2 and 9C-3). Further, by adding D-mannitol and magnesium stearate and adjusting the blending amount of copovidone from 30 mg to 7.5 mg, better dissolution property was shown (Example 9C-4).

[0217] (Example 10: Capsule containing a solution of the ethyl acetate adduct of the compound represented by formula (I)) As a study on a formulation capable of confirming absorption, distribution, metabolism, and excretion (ADME test) by oral administration, the following capsules were produced. A capsule containing a solution of the ethyl acetate adduct of the compound represented by formula (I) was produced, and the dissolution property of the capsule was evaluated. Capsules having the following formulations were produced and a dissolution test was carried out.

Table 42

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

[0219] <Results> The dissolution test results of Example 10-1 and Example 10-2 are shown in Fig. 29. As a result of dissolving the ethyl acetate adduct of the compound represented by formula (I) in Macrogol 400, good dissolution was shown (Example 10-1). As a result of adding 150.4 mg of copovidone, even better dissolution was shown (Example 10-2).

[0220] (Example 11: Solution preparation of the ethyl acetate adduct of the compound represented by formula (I)) As an examination of a formulation recipe capable of confirming absorption, distribution, metabolism, and excretion (ADME test) by oral administration, the following capsule preparations were manufactured. A solution preparation of the following formulation was manufactured, stored for 3 days in a 5°C heating environment, and a dissolution test was carried out.

Table 43

[0221] <Dissolution test> For the solution preparations obtained in each example, a dissolution test was carried out according to the dissolution test method of the 18th revised Japanese Pharmacopoeia. Dissolution test solution 2 was used as the test solution, and the paddle method was carried out at a paddle rotation speed of 50 rpm (changed to 250 rpm 120 minutes after the start of the test).

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

[0223] (Example 12: Rat PK Test of a Preparation Containing a Compound Represented by Formula (I) and an Ethyl Acetate Adduct of the Compound Represented by Formula (I)) As an examination of a formulation recipe enabling confirmation of absorption, distribution, metabolism, and excretion (ADME test) by oral administration, a formulation of the following recipe was manufactured and a rat PK test was conducted. The rat PK test was performed on male rats by the formula and the compound represented by (I) was administered at 0.3 mg / head or 1 mg / kg. After administering Examples 12-1 to 12-6 shown below, blood was collected at each blood collection time, and the maximum plasma drug concentration (Cmax) and the area under the plasma drug concentration-time curve (AUC) from the time of administration to 24 hours later were calculated using LC / MS / MS. [Table 44] [Table 45] [Table 46] <Manufacturing Method> Example 12-1 To macrogol 400 (manufactured by BASF) stirred using a stirrer, an anhydrous crystal of the compound represented by formula (I), copovidone (manufactured by ASHLAND), and ascorbic acid (manufactured by DSM) were added. After confirming clarity, propylene glycol (manufactured by BASF) was added, and the sample for administration was obtained by mixing using a stirrer. Example 12-2 To macrogol 400 (manufactured by BASF) stirred using a stirrer, an ethyl acetate adduct of the compound represented by formula (I), and copovidone (manufactured by ASHLAND) were added. After confirming clarity, it was filled into gelatin capsules (manufactured by Capsugel) to obtain the sample for administration. Example 12-3 The ethyl acetate adduct of the compound represented by formula (I), copovidone (manufactured by ASHLAND), crystalline cellulose (manufactured by Asahikasei), D-mannitol (manufactured by ROQUETTE), croscarmellose sodium (manufactured by Dupont), and magnesium stearate (manufactured by MALLINCKRODT) were mixed with a spatula and sieved through a wire mesh, and then filled into gelatin capsules (manufactured by Capsugel) using a spatula to obtain a test specimen for administration. Example 12-4 The ethyl acetate adduct of the compound represented by formula (I) was suspended in an aqueous solution containing 1% hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) and filled into gelatin capsules (manufactured by Capsugel) to obtain a test specimen for evaluation. Example 12-5 The solid dispersion powder of the compound represented by formula (I) was suspended in an aqueous solution containing 0.5% methyl cellulose to obtain a test specimen for administration. Example 12-6 The anhydrous crystal of the compound represented by formula (I) was suspended in an aqueous solution containing 0.5% methyl cellulose to obtain a test specimen for administration.

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

Table 47

Industrial Applicability

[0225] The preparation and crystal of the present invention have an inhibitory effect on coronavirus 3CL protease and are considered useful as a therapeutic agent and / or prophylactic agent for diseases or conditions involving coronavirus 3CL protease.

Claims

1. Formula (I): 【Chemistry 1】 A preparation comprising a compound represented by the formula (I) or a pharma- ceutically acceptable salt thereof, or a solvate thereof, as an active ingredient.

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

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

4. The formulation according to claim 3, comprising an amorphous form of the compound of formula (I) in a solid dispersion.

5. The formulation according to claim 4, further comprising a polymer in the solid dispersion.

6. The preparation according to claim 5, wherein the polymer is one or more selected from the group consisting of vinyl-based polymers, cellulose-based polymers, and acrylic acid-based polymers.

7. The formulation according to claim 6, 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, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose, and polyvinyl acetal diethylaminoacetate.

8. 8. The formulation of claim 7, wherein the vinyl polymer is copovidone.

9. The formulation of 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, 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 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-methyl methacrylate copolymer, ammonioalkyl methacrylate copolymer, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, and 2-methyl-5-vinylpyridine methylacrylate-methacrylic acid copolymer.

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

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

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

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

16. 15. The formulation of claim 14, 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, carboxymethylethylcellulose, low-substituted hydroxypropylcellulose, silicate derivatives, phosphates, The formulation according to claim 13, which is one or more selected from the group consisting of 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, and calcium sulfate.

18. The formulation according to claim 13, 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, 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 esters, hydrogenated oils, white beeswax, hydrogenated soybean oil, beeswax, cetanol, sodium laurate, sucrose fatty acid esters and polyethylene glycol.

19. The preparation according to any one of claims 1 to 12, which has a coating layer.

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

21. The preparation according to claim 20, wherein the light stabilizer 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. 22. The formulation of claim 21, wherein the light stabilizing agent is ferric oxide, yellow ferric oxide and / or talc.

23. The formulation according to claim 20, 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. 24. The formulation of claim 23, wherein the polymer in the coating layer is hypromellose.

25. The formulation according to any one of claims 1 to 12, wherein the formulation is an oral formulation.

26. 26. The formulation of claim 25, wherein the formulation is a tablet, granule, powder or capsule.

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

28. 28. The formulation of claim 27, which is a capsule.

29. Formula (I): 【Chemistry 2】 Amorphous form of the compound represented by the formula:

30. Formula (I): 【Chemistry 3】 A crystal of an ethyl acetate solvate of the compound represented by the formula:

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