Crystals of polycyclic carbamoylpyridone derivatives

Abstract

The present disclosure provides crystals of polycyclic carbamoylpyridone derivatives useful as pharmaceuticals. The present inventors have found that crystals of polycyclic carbamoylpyridone derivatives are useful as pharmaceutical ingredients for LAP formulations.

Description

CRYSTALS OF POLYCYCLIC CARBAMOYLPYRIDONE DERIVATIVES

[0001] The present invention relates to crystals of polycyclic carbamoylpyridone derivatives having an antiviral effect, particularly HIV integrase inhibitory activity, and pharmaceutical compositions comprising the same.

[0002] Among viruses, human immunodeficiency virus (hereinafter, abbreviated to HIV), one type of retrovirus, is known to cause acquired immunodeficiency syndrome (hereinafter, abbreviated to AIDS). For long-term treatment of AIDS, a therapeutic drug with a longer medication interval, i.e., a long-acting parenteral (LAP) formulation with which treatment is completed merely by one injection at 1-month or longer intervals have been developed for improving medication fatigue ascribable to the long-term medication and improving QOL (quality of life) of patients in such a way that the patients more enjoy daily life. However, the current LAP formulations require injections at most once every two months, and the development of LAP formulations with longer medication intervals is desirable. On the other hand, polycyclic carbamoylpyridone derivatives are known as long-acting compounds having integrase inhibitory activity (Patent Literatures 1 to 4).

[0003] International Publication WO 2007 / 049675International Publication WO 2019 / 230858JP 2021-091670 AInternational Publication WO 2021 / 107066

[0004] The pharmaceutically active ingredients may have substantially different physical properties depending on the respective solid form. Such differences in physical properties may affect, for example, the bioavailability, purity and production method of a pharmaceutically active ingredient (drug), a pharmaceutical composition (formulation of preparation) containing the pharmaceutically active ingredient or the method of administration thereof. The present invention relates to a crystal of a polycyclic carbamoylpyridone derivative that is very useful as compared to other solid forms in a method for producing or administering a pharmaceutically active ingredient, or in a pharmaceutical composition containing a pharmaceutically active ingredient. In general, physical properties of a crystal of a compound useful as a pharmaceutical product have a great influence on the bioavailability, purity and production method of a pharmaceutically active ingredient (drug), a pharmaceutical composition (formulation of preparation) containing the pharmaceutically active ingredient, the method of administration thereof, and the like, and thus are extremely important in development of pharmaceutical products. Therefore, with regard to the compounds represented by polycyclic carbamoylpyridone derivatives, it is necessary to study which crystalline form is most excellent as a pharmaceutical product. That is, since their physical properties depend on the attributes of individual compounds, it is generally difficult to predict a crystal form of a drug substance having good physical properties, and it is required to actually variously examine each compound. Therefore, an object of the present invention is to provide a crystalline form of a polycyclic carbamoylpyridone derivative which has good physical properties as a drug substance, in particular, long-lasting efficacy and is therefore suitable for an LAP formulation with a longer medication interval.

[0005] As a result of intensive studies, the inventors of the present invention have found that the crystal of a compound represented by the following Formula (I) is a crystal having high stability, low solubility (e.g., powder solubility) and a slow dissolution rate in vivo, i.e., a crystal having long-lasting efficacy, and therefore a crystalline form suitable for an LAP formulation.

[0006] The present invention relates to the following: (1) A crystal of a compound represented by Formula (I): . (2) The crystal according to the above item (1), wherein the crystal is crystal Form B having characteristic peaks at diffraction angles (2θ) of: 6.4°±0.2°, 8.4°±0.2°, 11.0°±0.2°, 17.7°±0.2° and 21.7°±0.2° in a powder X-ray diffraction pattern. (3) The crystal according to the above item (1), wherein the crystal is crystal Form B having characteristic peaks at diffraction angles (2θ) of: 6.4°±0.2°, 8.4°±0.2°, 11.0°±0.2°, 12.7°±0.2°, 13.9°±0.2°, 17.7°±0.2°, 20.5°±0.2°, 21.7°±0.2°, 22.7°±0.2° and 25.3°±0.2° in a powder X-ray diffraction pattern. (4) The crystal according to any one of the above items (1) to (3), wherein the crystal is crystal Form B having one or more absorption peaks selected from the group consisting of absorption peaks at 1388cm-1±2cm-1, 1426cm-1±2cm-1, 1451cm-1±2cm-1, 1564cm-1±2cm-1and 2938cm-1±2cm-1in a Raman spectrum. (5) The crystal according to any one of the above items (1) to (3), wherein the crystal is crystal Form B having absorption peaks at 1388cm-1±2cm-1, 1426cm-1±2cm-1, 1451cm-1±2cm-1, 1564cm-1±2cm-1and 2938cm-1±2cm-1in a Raman spectrum. (5A) The crystal according to any one of the above items (1) to (5), wherein the crystal is crystal Form B characterized by the space group of P212121and the following unit lattice parameters when measured at 298 K; a=4.7ű0.5Å b=16.0ű0.5Å c=27.7ű0.5Å α=90° β=90° γ=90°. (5B) The crystal according to any one of the above items (1) to (5) and (5A), wherein the crystal is crystal Form B having a melting point of 180°C±2°C in differential scanning calorimetry. (6) The crystal according to the above item (1), wherein the crystal is crystal Form B characterized by one or more physicochemical properties selected from the group consisting of the following (i) to (iv): (i) having characteristic peaks at diffraction angles (2θ) of: 6.4°±0.2°, 8.4°±0.2°, 11.0°±0.2°, 17.7°±0.2° and 21.7°±0.2° in a powder X-ray diffraction pattern; (ii) having absorption peaks at 1388cm-1±2cm-1, 1426cm-1±2cm-1, 1451cm-1±2cm-1, 1564cm-1±2cm-1and 2938cm-1±2cm-1in a Raman spectrum; (iii) characterized by the space group of P212121and the following unit lattice parameters when measured at 298 K; a=4.7ű0.5Å b=16.0ű0.5Å c=27.7ű0.5Å α=90° β=90° γ=90°; and (iv) having a melting point of 180°C±2°C in differential scanning calorimetry. (7) The crystal according to the above item (1), wherein the crystal is crystal Form B characterized by one or more spectra and / or curves selected from the group consisting of the following (a) to (c): (a) a powder X-ray diffraction pattern substantially identical to that shown in Fig. 6; (b) a Raman spectrum substantially identical to that shown in Fig. 11; and (c) a differential scanning calorimetry curve substantially identical to that shown in Fig. 7.

[0007] (8) The crystal according to the above item (1), wherein the crystal is crystal Form A having characteristic peaks at diffraction angles (2θ) of: 5.9°±0.2°, 8.6°±0.2°, 8.9°±0.2°, 12.5°±0.2° and 20.0°±0.2° in a powder X-ray diffraction pattern. (9) The crystal according to the above item (1), wherein the crystal is crystal Form A having characteristic peaks at diffraction angles (2θ) of: 5.9°±0.2°, 8.6°±0.2°, 8.9°±0.2°, 12.5°±0.2°, 14.0°±0.2°, 16.3°±0.2°, 17.8°±0.2°, 18.6°±0.2°, 20.0°±0.2° and 23.8°±0.2° in a powder X-ray diffraction pattern. (10) The crystal according to any one of the above items (1), (8) and (9), wherein the crystal is crystal Form A having one or more absorption peaks selected from the group consisting of absorption peaks at 889cm-1±2cm-1, 1441cm-1±2cm-1, 1516cm-1±2cm-1, 1558cm-1±2cm-1and 3088cm-1±2cm-1in a Raman spectrum. (11) The crystal according to any one of the above items (1), (8) and (9), wherein the crystal is crystal Form A having absorption peaks at 889cm-1±2cm-1, 1441cm-1±2cm-1, 1516cm-1±2cm-1, 1558cm-1±2cm-1and 3088cm-1±2cm-1in a Raman spectrum. (11A) The crystal according to any one of the above items (1) and (8) to (11), wherein the crystal is crystal Form A having a melting point of 173°C±2°C in differential scanning calorimetry. (12) The crystal according to the above item (1), wherein the crystal is crystal Form A characterized by one or more physicochemical properties selected from the group consisting of the following (i) to (iii): (i) having characteristic peaks at diffraction angles (2θ) of: 5.9°±0.2°, 8.6°±0.2°, 8.9°±0.2°, 12.5°±0.2° and 20.0°±0.2° in a powder X-ray diffraction pattern; (ii) having absorption peaks at 889cm-1±2cm-1, 1441cm-1±2cm-1, 1516cm-1±2cm-1, 1558cm-1±2cm-1and 3088cm-1±2cm-1in a Raman spectrum; and (iii) having a melting point of 173°C±2°C in differential scanning calorimetry. (13) The crystal according to the above item (1), wherein the crystal is crystal Form A characterized by one or more spectra and / or curves selected from the group consisting of the following (a) to (c): (a) a powder X-ray diffraction pattern substantially identical to that shown in Fig. 1; (b) a Raman spectrum substantially identical to that shown in Fig. 4; and (c) a differential scanning calorimetry curve substantially identical to that shown in Fig. 2.

[0008] (14) A pharmaceutical composition comprising the crystal according to any one of the above items (1) to (13), (5A), (5B) and (11A). (15) The pharmaceutical composition according to the above items (14), wherein the pharmaceutical composition is an anti-HIV agent. (16) An HIV integrase inhibitor comprising the crystal according to any one of the above items (1) to (13), (5A), (5B) and (11A). (17) A method for treating and / or preventing HIV infection, comprising administering the crystal according to any one of the above items (1) to (13), (5A), (5B) and (11A) to a human. (18) The crystal according to any one of the above items (1) to (13), (5A), (5B) and (11A) for use in treating and / or preventing HIV infection.

[0009] The crystal of the compound represented by Formula (I) of the present invention is useful as an active pharmaceutical ingredient for an LAP formulation. That is, the LAP formulation containing the crystal of the compound represented by Formula (I) of the present invention is a very useful as a therapeutic agent for HIV infections such as AIDS.

[0010] [Fig. 1] Fig. 1 shows a powder X-ray diffraction pattern of crystal Form A of the compound represented by Formula (I). The horizontal axis represents 2θ (°), and the vertical axis represents an intensity. [Fig. 2] Fig.2 shows DSC analysis results of crystal Form A of the compound represented by Formula (I). The horizontal axis represents temperature (°C), and the vertical axis represents a calorie (W / g). [Fig. 3] Fig.3 shows TG / DTA analysis results of crystal Form A of the compound represented by Formula (I). The vertical axis represents a calorie (μV) or a weight change (%), and the horizontal axis represents temperature (°C). “Cel” in the figure means a degree Celsius (°C). [Fig. 4] Fig.4 shows a Raman spectrum of crystal Form A of the compound represented by Formula (I). The horizontal axis represents a Raman shift (cm-1), and the vertical axis represents a peak intensity. [Fig. 5] Fig.5 shows a powder X-ray diffraction pattern of an amorphous form of the compound represented by Formula (I). The horizontal axis represents 2θ (°), and the vertical axis represents an intensity. [Fig. 6] Fig.6 shows a powder X-ray diffraction pattern of crystal Form B of the compound represented by Formula (I). The horizontal axis represents 2θ (°), and the vertical axis represents an intensity. [Fig. 7] Fig.7 shows DSC analysis results of crystal Form B of the compound represented by Formula (I). The horizontal axis represents temperature (°C), and the vertical axis represents a calorie (W / g). [Fig. 8] Fig.8 shows TG / DTA analysis results of crystal Form B of the compound represented by Formula (I). The vertical axis represents a calorie (μV) or a weight change (%), and the horizontal axis represents temperature (°C). “Cel” in the figure means a degree Celsius (°C). [Fig. 9] Fig.9 shows moisture adsorption / desorption isotherm of crystal Form B of the compound represented by Formula (I). The horizontal axis represents relative humidity (%), and the vertical axis represents the increase in mass (%) relative to that at 0% RH. [Fig. 10] Fig.10 shows a structural diagram of crystal Form B of the compound represented by Formula (I) in an asymmetric unit. [Fig. 11] Fig.11 shows a Raman spectrum of crystal Form B of the compound represented by Formula (I). The horizontal axis represents a Raman shift (cm-1), and the vertical axis represents a peak intensity. [Fig. 12] Fig.12 shows a powder X-ray diffraction pattern of a calcium salt crystal of the compound represented by Formula (I). The horizontal axis represents 2θ (°), and the vertical axis represents an intensity. [Fig. 13] Fig.13 shows the results of dissolution test of crystals Form A and Form B of the compound represented by Formula (I). [Fig. 14] Fig.14 shows the HPLC analysis results of crystal Form B of the compound represented by Formula (I).

[0011] The meanings of the terms as used herein are described below. Unless otherwise specified, each term has the same meaning when used alone or in combination with other terms. The term "consisting of" means to have only the described elements. The term "comprising" or "containing" means not to limit to the described elements and not to exclude undescribed elements. Furthermore, it should be understood that, throughout the present specification, the expression of a singular form includes the concept of its plural form unless specified otherwise. Therefore, it should be understood that the article of the singular form (for example, in English, "a", "an", "the", and the like) includes the concept of its plural form unless specified otherwise. Furthermore, it should be understood that the terms used herein are used in a meaning normally used in the art unless specified otherwise. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in the field to which the present invention pertains. If there is a contradiction, the present specification (including definitions) precedes.

[0012] If there is no reference in particular, a numerical value in the present specification and claims is an approximate value. A numerical change originates from a device calibration, a device error, substance purity, a crystal size, a sample size, temperature, and other factors.

[0013] The "crystal" used herein means a solid in which constituent atoms, ions, molecules, etc. are three-dimensionally arranged with regularity, and is distinguished from a non-crystalline solid not having such a regular inner structure. The crystal of the present invention may be a single crystal, a twin crystal, a polycrystal, and the like. Further, in the "crystal", there may be a "crystalline polymorphism" which has the same composition but has different arrangement in the crystal, and crystals including these are referred to as the "crystalline form". In addition, the compounds represented by Formula (I) may be converted into its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate. The crystals of the present invention may be any of salts, hydrates, solvates, and crystalline polymorphisms thereof, even the case of a mixture of two or more kinds thereof is intended to be encompassed in the scope of the invention. The crystalline form and the degree of crystallinity can be measured by many techniques including, for example, powder X-ray diffraction measurement, Raman spectroscopy, an infrared absorption spectrum measurement method, moisture adsorption-desorption measurement, differential scanning calorimetry, and dissolution properties.

[0014] The term “pharmaceutically acceptable salt” as used herein refers to, for example, a salt consisting of the compound represented by Formula (I) and a counter molecule or a counter ion, both of which are bonded via an ionic bond.

[0015] The compound represented by Formula (I) may be converted into a pharmaceutically acceptable salt. In one aspect of the present invention, the compound is in the form of an acid addition salt. The acid addition salt includes salts made from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Examples of inorganic acids include, but are not limited to, hydrofluoric acid, hydrochloric acid, hydrobromic acid, orthophosphoric acid, hydroiodic acid, nitric acid, phosphoric acid, boric acid or sulfuric acid, and the like. Examples of organic acids include, but are not limited to, 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 or acetyl salicylic acid and the like. The acid addition salt may be a mixed acid salt of a combination of two or more acids selected from these acids.

[0016] In one aspect of the present invention, the compound is in the form of a base addition salt. The base addition salt includes salts made from pharmaceutically acceptable non-toxic bases including inorganic and organic bases. Examples of salts derived from inorganic bases include, but are not limited to, salts of aluminum, calcium, lithium, potassium, magnesium, sodium, zinc, and other metal salts. Examples of salts derived from pharmaceutically acceptable non-toxic bases include salts of primary, secondary or tertiary amines, and substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as, arginine, betaine, benzathine, caffeine, choline, chloroprocaine, cycloprocaine, N'N'-dibenzylethylenediamine, diethanolamine, diethylamine, 2-diethyl-aminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, meglumine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, tertiary butylamine (2-methylpropane-2-amine), theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine; as well as nontoxic ammonium and quaternary ammonium, and salts of cations including, but not limited to, ammonium, tetramethylammonium, and tetraethylammonium.

[0017] The "pharmaceutically acceptable co-crystal" used herein means that the compound represented by Formula (I) and a counter molecule are regularly arranged in the same crystal lattice and may include any number of counter molecules. Further, the co-crystal indicates one in which the intermolecular interaction between the compound and the counter molecule is mediated with non-covalent and non-ionic chemical interaction such as hydrogen bonding or van der Waals' force. The co-crystal is distinguished from a salt in that the compound is essentially uncharged or neutral. The co-crystal is distinguished from or a solvate (e.g., a hydrate) in that the counter molecule is not water or a solvent. In general, salts are considered to be a state in which proton transfer occurs between a compound and a counter molecule, but it is known that in some cases, proton transfer is not complete. This state is sometimes called a co-crystal because it is not a true salt. It is also known that proton transfer can change continuously depending on temperature. Thus, as used herein, "pharmaceutically acceptable salt of the compound represented by Formula (I)" includes co-crystals and refers to a pharmaceutically acceptable salt or co-crystal of the compound represented by Formula (I).

[0018] The compound represented by Formula (I) may be converted into a pharmaceutically acceptable co-crystal. Examples of counter molecules of the "pharmaceutically acceptable co-crystal" include, but are not limited to, oxalic acid, fumaric acid, adipic acid, L-tartaric acid, D-tartaric acid, benzoic acid, 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid, saccharine, orotic acid, 1-hydroxy-2-naphthoic acid, L-pyroglutamic acid, D-pyroglutamic acid, benzamide, ethyl maltol, nicotinamide, glycolic acid, sorbic acid, L-camphoric acid, D-camphoric acid, urea, taurine, malonic acid, L-mandelic acid, D-mandelic acid, maleic acid, anthranilic acid, L-alanine, D-alanine, L-lactamide, D-lactamide, glycine, L-tryptophan, D-tryptophan, N-acetylglycine, L-valine, D-valine, ascorbic acid, citric acid, glutaric acid, erythorbic acid, galactaric acid, L-malic acid, D-malic acid, sorbitol, myo-inositol, glucuronic acid, sebacic acid, succinic acid, D-histidine and the like. Also, the co-crystal may be a co-crystal of a compound and a combination of two or more of these.

[0019] In the "solvate" used herein, any number of solvent molecules (for example, water molecule, etc.) may be coordinated, for example, to the compound represented by Formula (I) or the like. Examples of the solvent molecule include acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethane, xylene, acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-butyl methyl ether, cumene, dimethylsulfoxide, ethyl acetate, 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, water (that is, hydrate), ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, iso-octane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid, and trifluoroacetic acid, preferably, acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-butyl methyl ether, cumene, dimethylsulfoxide, ethyl acetate, 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, water (that is, hydrate), ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, iso-octane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid, and trifluoroacetic acid, and more preferably, water (that is, hydrate), ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, iso-octane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid, and trifluoroacetic acid. The compound represented by Formula (I) may absorb moisture when left in the atmosphere, and the moisture may adhere to the compound or form a hydrate with the compound.

[0020] The term "anhydride" used herein is synonymous with "ansolvate", "non-solvate," "anhydrate," and "non-hydrate".

[0021] The crystal of the present invention may be a deuterium conversion product. The crystal of the present invention may be labeled with an isotope (examples:3H,13C,14C,35S,125I).

[0022] The compound represented by Formula (I): is an HIV integrase inhibitor described in International Publication No. WO 2019 / 230858. It is very useful as a therapeutic agent for HIV infections such as AIDS. The compound represented by Formula (I) can be prepared by the method described in International Publication No. WO 2019 / 230858 or the like.

[0023] (Powder X-Ray Diffraction (XRPD)) The powder X-ray diffraction (XRPD) is one of the most sensitive analytical methods for measuring the crystalline form and crystallinity of solid. When crystals are irradiated with X-rays, the X-rays are reflected by the crystal lattice planes and mutually interfere, and the ordered diffraction lines corresponding to the periodicity of the structure are observed. On the other hand, in the case of amorphous solids, usually, since they do not have the ordered iteration periodicity in the structure, diffraction phenomenon does not occur, and featureless broad XRPD patterns (also called halo patterns) are shown.

[0024] The crystalline form of the compound represented by Formula (I) can be identified by the powder X-ray diffraction pattern and characteristic diffraction peaks. The crystalline form of the compound represented by Formula (I) can be distinguished from the other crystalline form (such as other crystalline forms in disclosed herein) by the presence of characteristic diffraction peaks. The characteristic diffraction peaks used herein are peaks selected from the observed diffraction pattern. The characteristic diffraction peaks are selected from preferably about ten, more preferably about five in the diffraction pattern. In order to distinguish between multiple crystals, a peak which is shown for the crystal and not shown for the other crystal becomes a more preferable characteristic peak than the intensity of a peak when the crystal is specified. The crystal can be characterized by one or two peak(s) if it is such characteristic peak(s). By comparing the chart obtained by measuring, if these characteristic peaks coincide, the powder X-ray diffraction pattern can be said to substantially match up.

[0025] Since an error within a range of ±0.2° may occur in diffraction angles (2θ) in powder X-ray diffraction, in general, the value of the diffraction angle of powder X-ray diffraction should be understood as the one including values within a range of about ±0.2°. Therefore, the present invention includes not only crystals in which the diffraction angles of the peaks in powder X ray diffraction perfectly coincide with each other, but also crystals in which the diffraction angles of the peaks coincide with each other within an error of about ±0.2°.

[0026] In general, it is known that the intensities of the peaks shown in the following tables and drawings may vary depending on a number of factors, for example, selected orientation effects of crystals in the X-ray beam, effect of coarse particle, purity of the material to be analyzed, or degree of crystallinity of the sample. Furthermore, the peak positions may also shift for variations in sample height. Further, measurements using a different wavelength will result in different shifts according to the Bragg equation (nλ = 2dsinθ). Such another XRPD patterns obtained by using a different wavelength are also within the scope of the present invention.

[0027] (Single Crystal Structural Analysis) By one of methods of identifying a crystal, crystallographic parameters in the crystal, atomic coordinates (values indicating spatial positional relationship of individual atoms), and the three-dimensional structural model can be obtained. Refer to "Manual of X-ray structural analysis" written by Sakurai Toshio, published by Shokabo Co., Ltd. (1983), X-Ray Structure Determination: A Practical Guide, written by Stout & Jensen, Macmillan Co., New York (1968), and the like. The single crystal structural analysis is useful to identify the crystalline structures of the crystal of the present invention.

[0028] (Raman Spectroscopy) The Raman spectrum shows vibrational features of molecules or a complex system. Its origin lies in inelastic collisions between molecules and photons as particles of light including light rays. The collision of molecules with photons leads to an exchange of energy, which results in a change in energy, which in turn changes the wavelength of the photons. That is, since the Raman spectrum are spectral line that are emitted when photons are incident on a target molecule and have an extremely narrow wavelength, a laser or the like is used as a light source. The wavelength of each Raman line is represented by a wavenumber shift from an incident light, which is a difference between an inverse of the wavelength of the Raman line and that of the incident light. The Raman spectrum is used for measuring a vibrational state of a molecule, which is determined by its molecular structure. In general, since a Raman spectrum peak (cm-1) in a Raman spectrum may have an error within a range of ±2cm-1, the value of the Raman spectrum peak should be understood as including a numerical value within a range of about ±2cm-1. Therefore, the present invention encompasses not only crystals in which the Raman spectrum peaks in the Raman spectra completely coincide with each other, but also crystals in which the Raman spectrum peaks coincide with each other within an error of about ±2cm-1.

[0029] (Infrared Absorption Spectroscopy (IR method)) The infrared absorption spectroscopy is a method for measuring, for each wavenumber, a degree of absorption of infrared rays when the infrared rays pass through a sample. The infrared absorption spectrum is typically represented by a graph in which the horizontal axis represents a wavenumber and the vertical axis represents a transmittance or an absorbance. The wavenumber and transmittance (or absorbance) of the absorption peak can be read on a graph, and values calculated by a data processing device can be used. The infrared absorption spectrum is determined by the chemical structure of the substance. Therefore, absorption at various wavenumbers can be measured to confirm or quantify a substance. The discrimination of a crystal polymorph can be performed by comparing absorption bands of functional groups characteristic of crystal polymorphs, that is, a functional group mainly involved in a hydrogen bond in the crystal structure such as a C=O bond, an OH bond, and an NH bond, as well as other characteristic functional groups such as a C-X (halogen) bond, a C=C bond, and a C=C bond. The absorption bands for characteristic functional group are selected from about 20 absorption peaks, more preferably about 10 absorption peaks, and most preferably about 5 absorption peaks corresponding to the characteristic functional groups. Typically, an absorption spectrum of a sample is measured in a wavenumber range of 4000cm-1to 400cm-1. The absorption spectrum is measured under the same operating conditions as those when the resolution, the wavenumber scale, and the wavenumber accuracy of the apparatus were confirmed.

[0030] In general, since an absorption band (cm-1) in infrared absorption spectroscopy may have an error within a range of ±2cm-1, the value of the absorption peak should be understood as including a numerical value within a range of about ±2cm-1. Therefore, the present invention encompasses not only crystals in which the peaks in the absorption bands in the infrared absorption spectroscopy completely coincide with each other, but also crystals in which the peaks in the absorption bands coincide with each other within an error of about ±2cm-1.

[0031] Examples of the method for measuring an infrared absorption spectrum include the potassium bromide tablet method, the solution method, the paste method, the liquid film method, the thin film method, the gas sample measurement method, the ATR method, and the diffuse reflection method. Among them, the attenuated total reflection (ATR) method is called the total reflection measurement method and is one of the reflection methods. In this method, a sample is brought into close contact with a surface of a prism made of a substance having a high refractive index such as KRS-5, light is incident on the prism at an angle equal to or larger than a critical angle, and light totally reflected at a boundary between the prism and the sample is measured to obtain an absorption spectrum. One of the conditions enabling the measurement by the ATR method is that the refractive index of the prism is larger than that of the sample, and thus it is necessary to change the material of the prism depending on the sample. In addition, as another condition, the prism and the sample must be in close contact with each other. Therefore, it is suitable for measurement of liquid, powder, plastic, soft rubber, and the like, and there is an advantage that measurement can be performed without chemically or physically treating the sample. On the other hand, the diffuse reflection method is a method of measuring a powder sample as it is without forming a potassium bromide tablet. When light is applied to a sample, light that is specularly reflected on the powder surface and exits to the outside and diffusely reflected light (scattered light) that enters the sample, repeats transmission and diffusion, and then exits to the surface are generated. In the diffuse reflection method, the latter is used to obtain an absorption spectrum.

[0032] (Solid13C-NMR (Nuclear Magnetic Resonance)) Solid state13C-NMR is useful for specifying a crystal form because (i) the number of spectra coincides with the number of carbon atoms of a target compound, (ii) the chemical shift range is wider than that of1H-NMR, (iii) a signal is sharper than that of solid state1H-NMR, and (iv) even if an additive is contained, the chemical shift does not change when there is no interaction. Note that an observed chemical shift is expected to vary slightly depending on the particular spectrometer used and the analyst's sample preparation technique. The error range in the solid13C-NMR spectrum is approximately ±0.5 ppm.

[0033] (Differential Scanning Calorimetry (DSC)) DSC is one of the main measurement methods of thermal analysis, and is a method for measuring thermal properties of a substance as an aggregate of atoms and molecules. A differential scanning calorimetry curve is obtained by measuring a change in heat quantity of a pharmaceutically active ingredient with respect to temperature or time by DSC and plotting the obtained data with respect to temperature or time. From the differential scanning calorimetry curve, it is possible to obtain information on the onset temperature when the pharmaceutically active ingredient is melted, the maximum value of the endothermic peak curve associated with melting, and enthalpy. For DSC, it is known that the observed temperature may depend on temperature change rate as well as a sample preparation technique and specific equipment used. Thus, the "melting point" in DSC refers to onset temperature that is less susceptible to sample preparation techniques. An error range at the onset temperature obtained from the differential scanning calorimetry curve is approximately ±2°C. In recognition of the identity of crystals, not only the melting point but also the overall pattern is important, and the overall pattern may slightly vary depending on measurement conditions and a measuring instrument.

[0034] (Thermogravimetry / Differential Thermal Analysis (TG / DTA)) TG / DTA is one of the main measurement methods of thermal analysis, and is a method for measuring weight and thermal properties of a substance as an aggregate of atoms and molecules. TG / DTA is a method for measuring changes in weight and heat quantity of a pharmaceutically active ingredient with respect to temperature or time, and curves of TG (thermogravimetry) and DTA (differential thermal analysis) are obtained by plotting the obtained data with respect to temperature or time. From the TG / DTA curves, it is possible to obtain information on weight and heat quantity change regarding decomposition, dehydration, oxidation, reduction, sublimation, and evaporation of the pharmaceutically active ingredient. For TG / DTA, it is known that the observed temperature and weight change may depend on temperature change rate as well as a sample preparation technique and specific equipment used. Thus, the "melting point" in TG / DTA refers to onset temperature that is less susceptible to sample preparation techniques. In recognition of the identity of crystals, not only the melting point but also the overall pattern is important, and the overall pattern may slightly vary depending on measurement conditions and a measuring instrument.

[0035] (Moisture Sorption / Desorption Isotherm Measurement Method (DVS)) The moisture adsorption / desorption isotherm measurement is a measurement method for measuring the adsorption and desorption behavior of moisture by measuring mass change in a solid as a measurement target 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 every 5% or 10%, and after the weight is stabilized at each relative humidity, the amount of adsorbed water can be determined from the weight increase from the reference value. Similarly, the desorption amount of water can be measured by decreasing the relative humidity every 5% or 10% from 100% RH. By plotting the value of the weight change at each relative humidity, an adsorption / desorption isotherm can be obtained. From this result, it is possible to consider a phenomenon of adsorption and desorption of adhering moisture at each humidity. In addition, when an anhydride crystal and a hydrate crystal mutually undergo crystal transition due to humidity, it is possible to calculate the humidity at which the crystal transition occurs and the amount of crystal water. Sorption and desorption of adhering water and crystal water are affected by particle size, crystallinity, crystal habit, and the like, so that the measurement results may slightly change.

[0036] The crystal of the present invention is useful as a medicament, for example, an antiviral drug. The crystal of the present invention has a marked inhibitory effect on virus integrase. Accordingly, the compound of the present invention can be expected to have a prophylactic or therapeutic effect on various diseases caused by viruses that grow by producing at least integrase at the time of infection in animal cells, and is useful as, for example, a retrovirus (e.g., HIV-1, HIV-2, HTLV-1, SIV, or FIV) integrase inhibitor and as an anti-HIV drug. The crystal of the present invention also has the following characteristics as pharmacokinetics in the body: the blood concentration is high; the duration of an effect is long; the transitivity to tissue is remarkable; and / or the like. In addition, the crystal of the present invention is safe with regard to a side effect (e.g., inhibition of CYP enzymes, mutagenicity, the QT interval prolongation of the electrocardiogram, and arrhythmia).

[0037] The crystal of the present invention can also be used in combination therapy with an anti-HIV drug having the different action mechanism, such as a reverse transcriptase inhibitor, a protease inhibitor, and / or an entry inhibitor. The use described above includes not only use as an anti-HIV combination but use as a concomitant agent that elevates the anti-HIV activity of another anti-HIV drug, as in cocktail therapy or the like. The crystal of the present invention can be used for preventing infection with a retrovirus vector from spreading to tissues other than a tissue of interest when a retrovirus vector based on HIV or MLV is used in the field of gene therapy. Particularly, when cells or the like are infected with the vector in vitro and brought back to the body, the administration of the crystal of the present invention beforehand can prevent the unnecessary infection of the body.

[0038] A pharmaceutical composition containing the crystal of the present invention can be administered orally or parenterally. Examples of the parenteral administration method include percutaneous administration, subcutaneous administration, intravenous administration, intraarterial administration, intramuscular administration, intraperitoneal administration, transmucosal administration, inhalation, transnasal administration, eye drop, ear drop, and intravaginal administration.

[0039] For oral administration, any dosage form usually used such as a solid preparation for internal use (e.g., a tablet, a powder, a granule, a capsule, a pill, and a film) or a liquid preparation for internal use (e.g., a suspension, an emulsion, an elixir, a syrup, a lemonade, a spirit, an aromatic water, an extract, a decoction, and a tincture) can be prepared according to a routine method, and administered. The tablet may be a sugar-coated tablet, a film-coated tablet, an enteric coated tablet, a sustained-release tablet, a troche tablet, a sublingual tablet, a buccal tablet, a chewable tablet or an orally disintegrating tablet. The powder and the granule may be a dry syrup. The capsule may be a soft capsule, a microcapsule or a sustained-release capsule.

[0040] For parenteral administration, any dosage form usually used such as an injection, a drop, and an external preparation (e.g., an eye drop, a nasal drop, an ear drop, an aerosol, an inhalant, a lotion, an infusion, a liniment, a gargle, an enema, an ointment, a plaster, a jelly, a cream, a patch, a poultice, a powder for external use, and a suppository) can be suitably administered. The injection may be an emulsion of O / W, W / O, O / W / O, W / O / W type, or the like.

[0041] The pharmaceutical composition may be manufactured by mixing an effective amount of the crystal of the present invention with various pharmaceutical additives suitable for the formulation, such as excipients, binders, disintegrants, lubricants, and the like. Furthermore, the pharmaceutical composition can be for pediatric patients, geriatric patients, serious cases or operations by appropriately changing the effective amount of the crystal of the present invention, formulation and / or various pharmaceutical additives. For example, the pediatric pharmaceutical compositions can be administered to neonate (under 4 weeks after the birth), infant (4 weeks after birth to under 1 year old), toddler (1 or more and under 7 years old), child (7 or more and under 15 years old) or patients of 15 to 18 years old. The geriatric pharmaceutical compositions, for example, are administered to patients of 65 or more years old.

[0042] The dose of the pharmaceutical composition containing the crystal of the present invention is desirably set in consideration of the age or body weight of a patient, the type or severity of a disease, an administration route, etc. For oral administration, the dose is within the range of usually 0.05 to 100 mg / kg / day, preferably 0.1 to 10 mg / kg / day. For parenteral administration, the dose differs largely depending on an administration route and is within the range of usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This dose can be administered once a day to once a month or once three months.

[0043] The present invention provides an anhydride crystal or a hydrate crystal of the compound represented by Formula (I). The crystal has at least one of the following characteristics: (1) having good stability against heat, humidity, solvent, light and the like, and high storage stability; (2) having low powder solubility; (3) having a slow dissolution rate in vivo; (4) having good coloring stability; (5) having good solubility in water or organic solvents; (6) having high purity; (7) having a low rate of residual organic solvent; (8) having excellent operability in filtration, centrifugation, and formulation; (9) having a small specific volume; (10) being hardly charged; (11) being produced at a high yield under conditions with reduced loads on the environment, and being able to be mass-produced; (12) being useful as a pharmaceutically active ingredient for an injection, or an active material for the production thereof; and (13) being controllable to a pH range suitable for intravenous injection without vascular pain, thereby being advantageous for liquid amount control, reduction of excipients, etc. at the time of formulation; In particular, the crystal of the invention is highly stable over a wide humidity range (e.g., 25-99% RH etc.) and in harsh environments (e.g. high humidity), with low powder solubility and a slow dissolution rate in vivo.Example

[0044] The present invention will be described in more detail by the following examples. These do not limit the present invention. For numerical values (For example, the amount, temperature, and the like), some error and deviation should be considered. Unless otherwise noted, "%" means % by weight of the component and % by weight of the total weight of the composition, and "pressure" means a pressure at or near atmospheric pressure.

[0045] (Measurement of powder X-ray diffraction pattern) Powder X-ray diffraction measurement of the crystal obtained in each Example was performed according to the powder X-ray diffraction measurement method described in "General Tests, Processes, and Apparatus" of Japanese Pharmacopoeia. The measurement conditions are shown below. Measurement Condition 1: (Apparatus) SmartLab manufactured by Rigaku Corporation (Operation Method) Measurement method: reflection method Used wavelength: CuKα ray Tube current: 200 mA Tube voltage: 45 kV Sample plate: aluminium Incident angle of X-ray: 2.5° Sampling width: 0.02° Detector: HyPix-3000 (two-dimensional detection mode) Measurement Condition 2: (Apparatus) D-8 Discover manufactured by Bruker Corporation (Operation Method) Measurement method: reflection method Used wavelength: CuKα ray Tube current: 40 mA Tube voltage: 40 kV Sample plate: aluminum Incident angle of X-ray: 3°

[0046] (Measurement and analysis method of single crystal structure analysis) Single crystal structure analysis of the crystal obtained in each Example was performed. Measurement conditions and analysis methods are shown below. (Apparatus) XtaLAB P 200 MM007 manufactured by Rigaku Corporation (Measurement Conditions) measurement temperature: 25°C temperature controller: sample spray low temperature device manufactured by Rigaku Corporation Used wavelength: CuKα ray (λ=1.5418Å) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) (Data processing) Software: CrysAlisPro 1.171.39.46e (Rigaku Oxford Diffraction, 2018) The data were subjected to Lorentz, and polarization correction, and absorption correction. (Crystal structure analysis) The phase determination was performed using the direct method program ShelXT (Sheldrick, G.M., 2015), and was refined by the full-matrix least squares method using ShelXL (Sheldrick, G.M., 2015). All temperature factors of non-hydrogen atoms were refined with anisotropy. Hydrogen atoms were introduced by calculation using default parameters of ShelXL and treated as riding atoms. Hydrogen atoms were refined with isotropic parameters. PLATON (Spek, 1991) / ORTEP (Johnson, 1976) was used to plot Fig. 10 (30% PROBABILITY level).

[0047] (Measurement of Raman spectrum) Raman spectra of the crystal and amorphous form obtained in each Example was measured and baseline correction was performed. The measurement conditions are shown below. Measurement Condition 1 measurement method: micro laser Raman spectroscopy Laser wavelength: 671 nm Number of integrations: 5 times Exposure time: 0.1 seconds or 0.5 seconds

[0048] (Measurement of differential scanning calorimetry (DSC)) DSC of the crystal obtained in each Example was measured. About 3 mg of a sample was weighed in an aluminum pan, and the weight was measured by simple sealing. The measurement conditions are shown below. Incidentally, an error may occur within a range of ±2°C in the measurement by differential scanning calorimetry (DSC). Apparatus: TA Instrument Discovery Measurement temperature range: -10°C to 210°C Heating rate: 10°C / min Atmosphere: N250 mL / min

[0049] (Measurement of TG / DTA data) About 1 to 3 mg of the crystals obtained in each Example was weighed, was put in an aluminum pan, and was measured in an open system. The measurement conditions are shown below. Apparatus: Hitachi High-Technologies TG / DTA STA7200RV Measurement temperature range: room temperature to 300°C or room temperature to 350°C Heating rate: 10°C / min

[0050] (Moisture adsorption / desorption isotherm measurement) Moisture adsorption / desorption isotherm measurement of the crystal obtained in each Example was measured. About 11.5 mg of a sample was weighed into a sample pan, and measurement was performed. The measurement conditions are shown below. Device: DVS Advantage manufactured by Surface Measurement Systems Ltd. Measurement points: 0% RH to 95% every 5% Temperature: 25°C

[0051] In addition, the abbreviations used herein have the following meanings: Bn: benzyl Boc: tert-butoxycarbonyl DMEAD: di-2-methoxyethyl azodicarboxylate DMF: N,N-dimethylformamide THF: tetrahydrofuran

[0052] (Method for Identifying compounds) NMR analysis of each Example was performed by 400 MHz using DMSO-d6and CDCl3. Furthermore, in NMR data shown in Examples, not all measured peaks may be described. The term "MS (ESI): m / z" herein refers to the mass of a molecule observed by LC / MS: liquid chromatography / mass spectrometry. Measurement conditions for LC / MS include, but are not limited to, the conditions shown below. Unless otherwise specified, MS (ESI): m / z refers to [M+H]+. (Measurement Condition 1) Column: Ascentis (registered trademark) Express Phenyl-Hexyl (2.7 μm i.d. 4.6 x 150 mm) (Supelco) Column temperature: constant temperature around 40°C UV detection wavelength: 220 nm Mobile phase: [A] is a 0.05% trifluoroacetic acid-containing aqueous solution, and [B] is a 0.05% trifluoroacetic acid-containing acetonitrile solution Gradient: 53% solvent [B] was maintained for 40 minutes, and then linear gradient of 53 to 95% solvent [B] was performed for 10 minutes. Flow rate: 1.0 mL / min Injection volume: 10 μL (Measurement Condition 2) Column: XBridge C18 (3.5 μm i.d. 4.6 x 150 mm) (Waters) Column temperature: constant temperature around 30°C UV detection wavelength: 220 nm Mobile phase: [A] is a 0.05% trifluoroacetic acid-containing aqueous solution, and [B] is a 0.05% trifluoroacetic acid-containing acetonitrile solution Gradient: Linear gradient of 35 to 58% solvent [B] was performed for 30 minutes, and then linear gradient of 58 to 95% solvent [B] was performed for 10 minutes. Flow rate: 1.0 mL / min Injection volume: 10 μL (Measurement Condition 3) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm i.d. 2.1 x 100 mm) (Waters) Column temperature: constant temperature around 40°C UV detection wavelength: 260 nm Mobile phase: [A] is 0.1 mmol / L disodium dihydrogen ethylenediamine tetraacetic acid, 8 mmol / L ammonium formate and 0.02% formic acid-containing aqueous solution, and [B] is a mixture of acetonitrile for liquid chromatography and methanol for liquid chromatography (1:3) Gradient: 5% solvent [B] was maintained for 1 minute, and then linear gradient of 5 to 60% solvent [B] was performed for 16 minutes, and then linear gradient of 60 to 95% solvent [B] was performed for 5 minutes. Flow rate: 0.4 mL / min Injection volume: 2 μL (Measurement Condition 4) 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 0.1% formic acid-containing aqueous solution, and [B] is 0.1% formic acid-containing acetonitrile solution Gradient: linear gradient of 5% to 100% solvent [B] was performed for 3.5 minutes, and then 100% solvent [B] was maintained for 0.5 minutes. (Measurement Condition 5) 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 10mM ammonium carbonate-containing aqueous solution, and [B] is acetonitrile Gradient: linear gradient of 5% to 100% solvent [B] was performed for 3.5 minutes, and then 100% solvent [B] was maintained for 0.5 minutes.

[0053] Example 1 Synthesis of crystal Form A and amorphous form of the compound represented by Formula (I) Step 1 Compound 1 (250 mg, 0.447 mmol) was dissolved in THF (5 mL), and Compound 2 (116 mg, 0.894 mmol), triphenylphosphine (352 mg, 1.34 mmol) and DMEAD (314 mg, 1.34 mmol) were added, and the mixture was stirred at 80°C for 4 hr. To the reaction solution was added ethyl acetate, and the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 3 (256 mg, yield 85%). MS:m / z=671[M+H]+ Step 2 Compound 3 (255 mg, 0.380 mmol), sodium periodate (244 mg, 1.14 mmol) and 2,6-lutidine (81.0 mg, 0.760 mmol) were added to a mixture of dioxane (5.1 mL) and water (1.5 mL), and then potassium osmate(VI) dihydrate (2.80 mg, 0.00760 mmol) was added, and the mixture was stirred at room temperature for 3 hr. 10% Sodium thiosulfate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic layer was washed with water, and dried over sodium sulfate. The solvent was evaporated to give Compound 4 (256 mg, yield 100%). MS:m / z=673[M+H]+ Step 3 Compound 4 (256 mg, 0.380 mmol) and p-toluenesulfonic acid monohydrate (217 mg, 1.14 mmol) were added to acetonitrile (2.6 mL), and the mixture was stirred at 60°C for 1 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, to the obtained residue was added DMF (2.0 mL), and then cesium carbonate (248 mg, 0.760 mmol) and benzyl bromide (130 mg, 0.760 mmol) were added, and the mixture was stirred at room temperature for 18 hr. To the reaction solution was added ethyl acetate, and the mixture was washed with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol). The obtained compound was purified by preparative SFC to give Compound 5 (142 mg, yield 67%). MS:m / z=555[M+H]+ Step 4 Compound 5 (2.49 g, 4.49 mmol) and lithium chloride (1.90 g, 44.9 mmol) was added to DMF (25 mL), and the mixture was stirred at 90°C for 3 hr. To the reaction solution was added 10% citric acid aqueous solution, and the mixture was extracted with ethyl acetate, and the organic layer was washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the precipitated white solid was collected by filtration, dissolved in chloroform, and the solution was dried over sodium sulfate. The solvent was evaporated, and the obtained compound was collected by filtration, and washed with diisopropyl ether to give crystal Form A of the compound represented by Formula (I) (1.92 g, yield 92%). Furthermore, a part of crystal Form A of the compound represented by Formula (I) was freeze-dried to give an amorphous form (35 mg) of the compound represented by Formula (I). MS:m / z=465[M+H]+

[0054] Example 2 Powder X-RAY diffraction experiment was performed under Measurement Condition 1 for crystal Form A of the compound represented by Formula (I) obtained in Example 1 above. In the powder X-RAY diffraction pattern, peaks were observed at diffraction angles (2θ) of: 5.9°±0.2°, 8.6°±0.2°, 8.9°±0.2°, 12.5°±0.2°, 14.0°±0.2°, 16.3°±0.2°, 17.8°±0.2°, 18.6°±0.2°, 20.0°±0.2° and 23.8°±0.2°. As a result, in the powder X-RAY diffraction pattern, peaks at diffraction angles (2θ) of: 5.9°±0.2°, 8.6°±0.2°, 8.9°±0.2°, 12.5°±0.2° and 20.0°±0.2° are particularly characteristic of crystal Form A of the compound represented by Formula (I). The powder X-ray diffraction pattern is shown in Fig. 1, and a peak list of the powder X-ray diffraction pattern is shown in Table 1. In the table, Position represents 2θ (°), and Intensity represents intensity.

[0055] Example 3 The DSC analysis results of crystal Form A of the compound represented by Formula (I) are shown in Fig. 2. The onset temperature was about 173°C.

[0056] Example 4 The thermogravimetry / differential thermal analysis (TG / DTA) results of crystal Form A of the compound represented by Formula (I) are shown in Fig.3. The crystal showed an endothermic peak with an onset temperature of about 174°C. No endothermic peak or weight loss associated with dehydration / desolvation was observed, confirming that crystal Form A was anhydrous crystal.

[0057] Example 5 The results of a Raman spectrum of crystal Form A of the compound represented by Formula (I) (Measurement Condition 1) are shown in Fig. 4. The absorption peaks are shown in Table 2.

[0058] In one embodiment, crystal Form A of the compound represented by Formula (I) has major absorption peaks at 889cm-1±2cm-1, 1441cm-1±2cm-1, 1516cm-1±2cm-1, 1558cm-1±2cm-1and 3088cm-1±2cm-1. In one embodiment, crystal Form A of the compound represented by Formula (I) has one or more absorption peaks selected from the group consisting of absorption peaks at 889cm-1±2cm-1, 1441cm-1±2cm-1, 1516cm-1±2cm-1, 1558cm-1±2cm-1and 3088cm-1±2cm-1.

[0059] Example 6 Powder X-RAY diffraction experiment was performed under Measurement Condition 2 for the amorphous form of the compound represented by Formula (I) obtained in Example 1 above. The powder X-ray diffraction pattern is shown in Fig. 5. No characteristic peaks were observed, and a halo pattern was confirmed.

[0060] Example 7 Synthesis of crystal Form B of the compound represented by Formula (I) Step 1 Compound 3 (177.0 kg, 263.7 mol), ethyl acetate (534 L) and 75% sulfuric acid (106.4 kg) were mixed, and stirred at 20°C for 11 hr. To the reaction solution were added ethyl acetate and water, and the mixture was adjusted to pH 8 by addition of triethylamine. Ethyl acetate was added, the mixture was subjected to liquid separation operation. The organic layer was washed with 10% sodium chloride aqueous solution, and the organic layer was treated with activated carbon. The organic layer was concentrated under reduced pressure, and 2-propanol was added. The operations of concentration under reduced pressure and addition of 2-propanol were repeated twice in the same manner, and then the mixture was concentrated under reduced pressure and cooled. To the slurry were added water and 2-propanol, and the mixture was stirred. The solid was collected by filtration, washed with a mixed solvent of purified water and 2-propanol, and dried to give Compound 6 (137.20 kg, 240.3 mol, yield: 91.1%). HPLC (UV=220 nm): RT=26.7 min, Measurement Condition 2 Step 2 Compound 6 (40.0 kg, 70.0 mol), acetonitrile (200 L), purified water (220 L), ruthenium(III) chloride hydrate (35 g, 0.14 mol), synthetic hydrochloric acid (8.0 kg, 77.1 mol) and orthoperiodic acid (35.1kg, 154.1 mol) were mixed, and stirred at 0°C for 2 hr. To the reaction solution containing Compound 7 was added isopropyl acetate, and the mixture was subjected to liquid separation operation. Then, the organic layer was washed successively with 5% sodium pyrosulfite aqueous solution and 5% sodium hydrogencarbonate aqueous solution. Then, 5% sodium chloride aqueous solution and isopropyl acetate (184 L) were added, and the mixture was subjected to liquid separation operation. The operations of concentration of the organic layer under reduced pressure and addition of isopropyl acetate were repeated twice, and then the organic layer was concentrated under reduced pressure. To the concentrate were added (-)-10-camphorsulfonic acid (24.4 kg, 105.1 mol) and 2-propanol (64 L), and the mixture was stirred at 80°C for 15 hr. The reaction solution was cooled to 55°C, and isopropyl acetate and 2-propanol were added. To the slurry was stirred at 55°C, neutralized with triethylamine, stirred, and cooled to 25°C. To the slurry was added methyl tert-butyl ether, and the mixture was stirred for 60 min. The solid was collected by filtration, washed with a mixed solvent of isopropyl acetate, 2-propanol and methyl tert-butyl ether, and a mixed solvent of acetone and water to give crude crystals of the compound represented by Formula (I). The crude crystals, acetone (476 L) and purified water (52 L) were mixed, and heated to 53°C. The solution was cooled to 40°C, purified water was added, the mixture was stirred, and purified water was added. The slurry was cooled to 0°C, and stirred, the solid was collected by filtration, washed with a mixed solvent of acetone and water, and dried to give crystal Form B of the compound represented by Formula (I) (22.84 kg, 49.1 mol, yield: 70.1%). HPLC (UV=260 nm): RT=18.1 min, Measurement Condition 3 The HPLC analysis results are shown in Figure 14 and Table 3.

[0061] Example 8 Powder X-RAY diffraction experiment was performed under Measurement Condition 1 for crystal Form B of the compound represented by Formula (I) obtained in Example 7 above. In the powder X-RAY diffraction pattern, peaks were observed at diffraction angles (2θ) of: 6.4°±0.2°, 8.4°±0.2°, 11.0°±0.2°, 12.7°±0.2°, 13.9°±0.2°, 17.7°±0.2°, 20.5°±0.2°, 21.7°±0.2°, 22.7°±0.2° and 25.3°±0.2°. As a result, in the powder X-RAY diffraction pattern, peaks at diffraction angles (2θ) of: 6.4°±0.2°, 8.4°±0.2°, 11.0°±0.2°, 17.7°±0.2° and 21.7°±0.2° are particularly characteristic of crystal Form B of the compound represented by Formula (I). The powder X-ray diffraction pattern is shown in Fig. 6, and a peak list of the powder X-ray diffraction pattern is shown in Table 4. In the table, Position represents 2θ (°), and Intensity represents intensity.

[0062] Example 9 The DSC analysis results of crystal Form B of the compound represented by Formula (I) are shown in Fig. 7. The onset temperature was about 180°C.

[0063] Example 10 The thermogravimetry / differential thermal analysis (TG / DTA) results of crystal Form B of the compound represented by Formula (I) are shown in Fig.8. The crystal showed an endothermic peak with an onset temperature of about 180°C. No endothermic peak or weight loss associated with dehydration / desolvation was observed, confirming that crystal Form A was anhydrous crystal.

[0064] Example 11 The results of moisture adsorption / desorption isotherm measurement of crystal Form B of the compound represented by Formula (I) are shown in Fig.9 and Table 5. The moisture adsorption / desorption isotherm measurement may have an error within a range of ±0.5%. The moisture increase (%) represents the increase in mass of crystal Form B relative to that at 0% RH. The difference in moisture content between 0% RH (relative humidity 0%) and 95% RH (relative humidity 95%) was about 0.3%.

[0065] Example 12 Crystal Form B of the compound represented by Formula (I) was coated with paraffin oil and fixed on a MicroMount (MiTeGen Co., Ltd.). Then, the crystals were set in the measurement section of a diffraction apparatus set at 25°C, and subjected to a single crystal X-ray diffraction experiment.

[0066] Crystallographic data are shown in Table 6.

[0067] Here, V represents a volume of a unit lattice. The atomic coordinates x, y, z(Å×104) and equivalent isotropic temperature factors U(eq)(Å2×103) of non-hydrogen atoms are shown Table 7. U(eq) is defined as 1 / 3 of the trace of the orthogonalized Uijtensor.

[0068]

[0069] Next, the atomic coordinates x, y, z (Å×104) and isotropic temperature factors U(iso) (Å2×103) of hydrogen atoms are shown in Table 8. The numbers of hydrogen atom in Table 8 were assigned in relation to the number of the non-hydrogen atom to which the hydrogen atom is bonded.

[0070] Further, interatomic bond distances (unit: Å) are shown in Table 9.

[0071] The structural diagram of the crystal in an asymmetric unit is shown in Fig. 10. From the crystal structure, the powder X-ray diffraction pattern simulated using Mercury (The Cambridge Crystallographic Data Centre, Ver.4.0.0) was confirmed to be generally consistent with the powder X-ray diffraction pattern of Example 8 (Fig.6).

[0072] Example 13 The results of a Raman spectrum of crystal Form B of the compound represented by Formula (I) (Measurement Condition 1) are shown in Fig. 11. The absorption peaks are shown in Table 10.

[0073] In one embodiment, crystal Form B of the compound represented by Formula (I) has major absorption peaks at 1388cm-1±2cm-1, 1426cm-1±2cm-1, 1451cm-1±2cm-1, 1564cm-1±2cm-1and 2938cm-1±2cm-1. In one embodiment, crystal Form B of the compound represented by Formula (I) has one or more absorption peaks selected from the group consisting of absorption peaks at 1388cm-1±2cm-1, 1426cm-1±2cm-1, 1451cm-1±2cm-1, 1564cm-1±2cm-1and 2938cm-1±2cm-1.

[0074] Reference Example 1 Synthesis of seed crystals of calcium salt of the compound represented by Formula (I) To the compound represented by Formula (I) (210 mg, 0.452 mmol) was added methanol (4.2 mL), and then 1.0 M sodium methoxide methanol solution (0.45 mL) was added while stirring at 0°C, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated to give a sodium salt (236 mg) of the compound represented by Formula (I). To a part (5 mg, 0.01 mmol) of the obtained sodium salt was added a mixture of acetonitrile (0.50 mL) and water (0.20 mL), and then 0.5M calcium acetate monohydrate aqueous solution (0.01 mL) was added while stirring at 70°C. The mixture was cooled to room temperature, and the obtained solid was collected by filtration to give seed crystals of calcium salt of the compound represented by Formula (I).

[0075] Reference Example 2 Synthesis of crystal of calcium salt of the compound represented by Formula (I) To the compound represented by Formula (I) (842 mg, 1.81 mmol) was added methanol (17 mL), and then 1.0M sodium methoxide methanol solution (1.8 mL) was added while stirring at 0°C, and the mixture was stirred at room temperature for 80 min. The reaction solution was concentrated, diethyl ether (17 mL) was added, and the obtained solid was collected by filtration, and washed with diethyl ether to give a sodium salt (901 mg, yield 100%) of the compound represented by Formula (I). To a part (200 mg, 0.411 mmol) of the sodium salt was added a mixture of acetonitrile (10 mL) and water (2.0 mL), 0.5M calcium acetate monohydrate aqueous solution (0.41 mL) was added while stirring at 60°C, and then the seed crystals prepared in Reference Example 1 was added, and the mixture was kept stand at room temperature for 27 hr. The obtained compound was collected by filtration, and washed with a mixture of acetonitrile and water (5:1) to give crystals (93.3 mg, yield 45%) of calcium salt of the compound represented by Formula (I). Powder X-RAY diffraction experiment was performed under Measurement Condition 1 for crystals of the calcium salt of the compound represented by Formula (I). The powder X-ray diffraction pattern is shown in Fig. 12.

[0076] Reference Example 3 Synthesis of an isotopically labeled analog of the compound represented by Formula (I) Step 1 Compound 8 (16 g, 173 mmol) was dissolved in THF (160 mL), and copper(I) iodide (3.29 g, 17.3 mmol) was added. The mixture was stirred in at -78°C, and 2.0 mol / L allyl magnesium chloride THF solution (95 mL, 190 mmol) was added dropwise. After stirring at the same temperature for 30 min, the mixture was warmed to 0°C. To the reaction solution was added saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with ether. The organic layer was washed with saturated aqueous ammonium chloride solution, and dried over sodium sulfate, and the solvent was evaporated to give Compound 9 (30.4 g, yield 77%). Step 2 NMP (279 mL) was cooled to 0°C, and potassium t-butoxide (41.3 g, 368 mmol), methanol (13C;d4) (41.3 g, 368 mmol) and Compound 9 (29.4 g, 167 mmol) were added. The mixture was warmed to room temperature, stirred for 2 hr, and then kept stand at room temperature for 13 hr. The reaction solution was cooled to 0°C, 2 mol / L hydrochloric acid was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, and dried over sodium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 10 (12.3 g, yield 38%). Step 3 To DMF (231 mL) were added methyl-d3-amine hydrochloride (3.58 g, 50.8 mmol), Compound 11 (23.1 g, 42.3 mmol) and triethylamine (7.04 mL, 50.8 mmol). After cooling to 0°C, HOBt (6.86 g, 50.8 mmol) and EDC (12.2 g, 63.5 mmol) were added. After stirring at room temperature for 1 hr, DMAP (517 mg, 4.23 mmol) was added, and the mixture was kept stand for 14 hr. Methyl-d3-amine hydrochloride (895 mg, 12.7 mmol) and triethylamine (1.76 mL, 12.7 mmol) were added, and the reaction solution was diluted with ethyl acetate (250 mL). To the reaction solution were added saturated aqueous ammonium chloride solution and water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium hydrogencarbonate solution, and dried over sodium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 12 (18.2 g, yield 95%). MS:m / z=562[M+H]+

[0077] Step 4 Compound 12 (12.1 g, 20.3 mmol) was dissolved in THF (121 mL), and Compound 10 (5.79 g, 30.5 mmol), triphenylphosphine (8.00 g, 30.5 mmol) and DMEAD (7.15 g, 30.5 mmol) were added, and the mixture was stirred at room temperature for 4 hr. To the reaction solution was added ethyl acetate, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 13 (12.3 g, yield 89%). MS:m / z=678[M+H]+ Step 5 Compound 13 (12.3 g, 18.1 mmol) was added to methanol (37 mL), followed by methanesulfonic acid (2.61 g, 27.2 mmol) at room temperature, and the mixture was stirred at 65°C for 3 hr and 20 min. To the reaction solution was added ethyl acetate, and the mixture was washed with water (100 mL) and sodium hydrogencarbonate (4.57 g, 54.4 mmol). The organic layer was washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated to give Compound 14 (10.4 g, yield 99%). MS:m / z=578[M+H]+ Step 6 Compound 14 (10.4 g, 18.0 mmol), sodium periodate (11.6 g, 54.1 mmol) and 2,6-lutidine (3.86 mg, 36.1 mmol) were added to a mixture of dioxane (104 mL) and water (34 mL), followed by potassium osmate(VI) dihydrate (133 mg, 0.361 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with water, 10% sodium thiosulfate aqueous solution, saturated aqueous sodium hydrogencarbonate solution and water. The organic layer was dried over sodium sulfate, and the solvent was evaporated to give Compound 15 (11.0 g, yield 100%). MS:m / z=580[M+H]+

[0078] Step 7 To Compound 15 (11.0 g, 18.1 mmol) was added ethyl acetate (110 mL), followed by T3P (21.5 mL, 36.1 mmol) at room temperature, and the mixture was stirred at room temperature for 18 hr. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol). The obtained compound was purified by preparative SFC to give Compound 16 (6.89 g, yield 68%). Column: Two CHIRALPAK IA columns connected in series / SFC Flow rate: 20 mL / min UV detection wavelength: 220 nm Preparative condition: The mobile phase was delivered while maintaining a composition ratio of MeOH / CO2=80 / 20. MS:m / z=562[M+H]+ Step 8 Compound 16 (256 mg, 0.455 mmol) and lithium chloride (193 mg, 4.55 mmol) were added to DMF (2.6 mL), and the mixture was stirred at 90°C for 3 hr. To the reaction solution was added 2-propanol (0.5 mL), followed by 2 mol / L hydrochloric acid (0.455 mL, 0.911 mmol) and water (2 mL), resulting in the formation of a white solid. The obtained white solid was washed with water, and dried at 40°C to give Compound 17 (202 mg, yield 94%). MS:m / z=472[M+H]+1H-NMR(CDCl3) δ: 11.93(s, 1H), 10.41(t, J=5.6Hz, 1H), 8.49(s, 1H), 7.31-7.27(m, 2H), 7.02(t, J=7.8Hz, 1H), 5.07(d, J=3.9Hz, 1H), 4.71(d, J=5.9Hz, 2H), 3.48-3.41(m, 3H), 2.37-1.87(m, 4H).

[0079] Such isotopically labeled analogs exhibit increased resistance to metabolism and are therefore useful for extending the half-life of the compound represented by Formula (I) when administered to mammals such as humans. Moreover, these isotopically labeled analogs can possess improved DMPK (drug metabolism and pharmacokinetics) properties with respect to absorption, distribution, metabolism, and excretion (ADME). Labeling with heavier isotopes, such as deuterium, can provide certain therapeutic advantages due to increased metabolic stability, for example, prolongation of in vivo half-life, reduction of the required dosage, and / or improvement of the therapeutic index.

[0080] Such isotopically labeled analogs can also be synthesized in a similar manner by replacing non-isotopic reagents with readily available isotopic reagents.

[0081]

[0082]

[0083]

[0084] Test Example 1 Solid Stability Test The solid stability of the crystal of the present invention was evaluated for chemical stability under temperature or temperature and humidity conditions and under light irradiation. Evaluation was performed by the percentage (%) of related substances generated as determined by HPLC method and changes in appearance. (Storage stability test) About 30 mg of the crystals was weighed into a 4 mL glass container with a stopper made of polyethylene. After closing the glass container, it was stored at 60°C or 80°C for one or two weeks. The sample stored at 60°C was called the 60°C sealed storage product, and the sample stored at 80°C was called the 80°C sealed storage product. The glass container was opened and stored at 60°C and 75±5% relative humidity for two weeks or two months. The sample stored at 60°C and 75±5% relative humidity was called the 60°C and 75% relative humidity (also written as 60±2°C / 75±5% RH) storage product. The -40°C sealed storage product was used as the standard product. Each sample was measured with n=3, and the average value is shown. (Photostability test) A photostability test was performed for the crystals of the present invention. About 5 mg of the crystals was accurately weighed into a glass cell, and made into a thin, uniform state. The crystals were irradiated at 25°C with D65 lamp light with a cumulative illuminance of 1.2 million and 3.6 million lx・hr. This sample is called the light-irradiated sample. In addition, the -40°C sealed storage product was used as the standard, and stability (content of related substances) was measured using HPLC method under the following conditions by the absolute calibration curve method. Each sample was measured with n=3, and the average value is shown. (Method for measuring the related substance content) The related substance content was measured by the area percentage method using HPLC method under the following conditions. For the crystals of the present invention, HPLC Condition 1 was used. (HPLC Condition 1) ・Detector: ultraviolet absorptiometer (measurement wavelength 280 nm) ・Column: Мeteoric Core C18, 2.7 μm, 3.0 × 100 mm ・Column temperature: constant temperature around 40°C ・Mobile phase A: 0.1% formic acid-containing aqueous solution ・Mobile phase B: acetonitrile ・Flow rate: about 0.6 mL / min ・Injection volume: 2 μL ・Sample cooler temperature: about 10°C ・Delivery of mobile phase: The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 14 to control the concentration gradient.

[0085] (Preparation of sample solution) Sample solutions were prepared using the following method. 5 mg of the crystals was accurately weighed out from the 60°C sealed storage product, the 80°C sealed storage product, the 60°C and 75% relative humidity storage product, or the -40°C sealed storage product, and dissolved in an acetonitrile aqueous solution (acetonitrile:water = 1:1) to prepare a sample solution at exactly 500 μg / mL. For the light-irradiated sample, the crystals after storage were dissolved in an acetonitrile solution aqueous (acetonitrile:water = 1:1) to prepare a sample solution at exactly 500 μg / mL. (Results) The results of the storage stability test of crystal Form B are shown in Table 15.

[0086] In storage stability tests, it was confirmed that crystal Form B is stable, with no increase in the total related substances, when stored for two months at 60°C and 75% relative humidity. Long-term stability is necessary for long-acting formulations, as they remain subcutaneously for long periods. Crystal Form B are stable for long periods even under high temperature and humidity conditions, so the crystal can be said to be a drug substance form suitable for long-acting formulations. The results of the photostability test are shown in Table 16.

[0087] In the photostability test, the increase in the total related substances in crystal Form B was smaller than that in crystal Form A, confirming that crystal Form B is stable. Since long-acting formulations are exposed to light through the skin for long periods, crystal Form B, which is more stable to light, is more suitable as a drug substance for long-acting formulations.

[0088] Test Example 2 Powder solubility test The solubility of the crystal of the present invention was evaluated based on the solubility when PBS was used as a measurement medium. The evaluation was performed using the concentration (μg / mL) dissolved by HPLC method. (Solubility test) About 1 mg of the crystals of the present invention was weighed into a 4 mL glass container, and 2 mL of PBS (pH 7.4, 1X, Gibco) was added to each container. The containers were sealed with polyethylene stoppers with Teflon and silicone packing, shaken at 37°C for 24 hours, and then filtered. 400 μL of methanol was added to 800 μL of the filtrate to dilute it 1.5 times. After checking for the absence of air bubbles and precipitates, the compound of the crystal of the present invention was quantified using HPLC Condition 2 by the absolute calibration curve method, and the solubility was calculated. In addition, each sample was measured with n=3, and the average value was shown. (HPLC Condition 2) ・Detector: ultraviolet absorptiometer (measurement wavelength 259 nm) ・Column: Zorbax SB-C18 (1.8 μm 2.1 x 30 mm) ・Column temperature: constant temperature around 60°C ・Mobile phase A: 0.1% trifluoroacetic acid-containing water ・Mobile phase B: acetonitrile ・Flow rate: 1.2 mL / min ・Injection volume: 0.2 μL ・Sample cooler temperature: about 10°C ・Delivery of mobile phase: The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 17 to control the concentration gradient.

[0089] (Results) The powder solubility of crystal Form A of the compound represented by Formula (I) was 33.0 μg / mL ± 0.6 μg / mL, and the powder solubility of crystal Form B of the compound represented by Formula (I) was 15.8 μg / mL ± 0.8 μg / mL. It was confirmed that crystal Form B of the compound represented by Formula (I) have lower solubility than crystal Form A of the compound represented by Formula (I). Since low solubility is expected to result in long-lasting efficacy, it can be said that crystal Form B is a drug substance form suitable for long-acting formulations.

[0090] Test Example 3 Dissolution test in biomimetic solution. The dissolution rate of the crystal of the present invention was evaluated based on the dissolution behavior when PBS was used as a measurement medium. The dissolution rate was evaluated by measuring the solubility over time using a μDiss small dissolution tester (Pion), and expressing the dissolution rate per the unit surface area (μg / min*cm2). About 10 mg of the crystals of the present invention was compressed at 120 bar for 1 min using a mini tablet press system (Mini-IDR, Health Scientific) to prepare a disc (diameter: 3 mm, area: 0.0707 cm2), and the disc was attached to a dedicated stirrer. The disc and stirrer were placed in a 24 mm vial and set in a tester preheated to 37°C. 20 mL of degassed and preheated PBS (pH 7.4, 1X, Gibco) was poured into the vial, and the mixture was stirred at 100 rpm. The spectra shown in Table 18 were collected using a UV probe (Rainbow, Pion) equipped with a 20 mm optical path length tip. The analysis software used was AuPro (Pion, Ver. 7.1.0.757). The analysis wavelength was set to 346 to 360 nm, and the quantitative results from the second derivative spectrum of the compound by the absolute calibration curve method were fitted to the dissolution curve (Disc) in the analysis software, and the dissolution rate was calculated in the measurement time range of 0 hr to 8 hr. In Fig. 13, the error bars indicate the standard deviation between n=3.

[0091] (Results) The dissolution rate of crystal Form A of the compound represented by Formula (I) was 2.3 μg / min*cm2±0.6 μg / min*cm2, and the dissolution rate of crystal Form B of the compound represented by Formula (I) was 1.2 μg / min*cm2±0.2 μg / min*cm2. It was confirmed that crystal Form B of the compound represented by Formula (I) have a slower dissolution rate in a biomimetic solution than crystal Form A of the compound represented by Formula (I). Since slower dissolution rate in a biomimetic solution are expected to result in long-lasting efficacy, it can be said that crystal Form B is a drug substance form suitable for long-acting formulations.

[0092] Test Example 4 Evaluation of duration of efficacy (Subcutaneous administration test) Materials and methods (1) Animals used: Rats were used. (2) Rearing conditions: Solid feed and tap water were given ad libitum. (3) Dose: Subcutaneous administration at 5 mg / ml / kg (n=2). (4) Administration medium: 2% Tween 20 + 2% PEG 4000 in pH 6.8 PBS (5) Administration method: Each form of the compound represented by Formula (I) was suspended in the administration medium, and administered subcutaneously using a syringe with an injection needle. (6) Evaluation items: Blood was collected over time, and the plasma concentration of the compound represented by Formula (I) was measured using LC / MS / MS. (Results) The results are shown in Table 19. The plasma concentration of crystal Form B of the compound represented by Formula (I) tended to decrease more slowly (ka) and to be more sustained compared with crystal Form A and the amorphous form.

[0093] Formulation Example The following formulation examples are merely examples and not intended to limit the scope of the invention. The crystal of the present invention can be administered as a pharmaceutical composition in any conventional route, particularly, in an enteral route, for example, orally, for example in the form of a tablet or a capsule, or parenterally, for example, in the form of an injection or a suspension, locally, for example, in the form of a lotion, a gelling agent, an ointment, or a cream, or in the intranasal form or suppository form. The pharmaceutical composition comprising the crystal of the present invention in the free form or in the form of a pharmaceutically acceptable salt can be produced together with at least one kind of pharmaceutically acceptable carrier or diluent by a conventional method such as a mixing, granulating, or coating method. For example, as a composition for oral, tablets, granules, and capsules containing excipients, disintegrants, binders, lubricants, etc. and an active ingredient, etc. can be used. Furthermore, as a composition for injection, solutions or suspensions can be used, and sterilization can be carried out, or preservatives, stabilizing agents, buffer agents, and the like may be contained. (Note) As described above, the present invention has been illustrated using preferred embodiments, but it should be understood that the scope of the invention is defined solely by the scope of the claims. The patents, patent applications (including Japanese Patent Application No. 2024-224642 filed with the Japan Patent Office on December 20, 2024, to which the present application claims priority), and literature cited herein should be understood to be incorporated by reference to the present specification to the same extent as if their contents were specifically described herein.

[0094] The crystal of the compound represented by Formula (I) of the present invention is useful as an active pharmaceutical ingredient for an LAP formulation. That is, the LAP formulation containing the crystal of the compound represented by Formula (I) of the present invention is a very useful as a therapeutic agent for HIV infections such as AIDS.

Claims

1. A crystal of a compound represented by Formula (I): .

2. The crystal according to claim 1, wherein the crystal is crystal Form B having characteristic peaks at diffraction angles (2θ) of: 6.4°±0.2°, 8.4°±0.2°, 11.0°±0.2°, 17.7°±0.2° and 21.7°±0.2° in a powder X-ray diffraction pattern.

3. The crystal according to claim 1, wherein the crystal is crystal Form B having characteristic peaks at diffraction angles (2θ) of: 6.4°±0.2°, 8.4°±0.2°, 11.0°±0.2°, 12.7°±0.2°, 13.9°±0.2°, 17.7°±0.2°, 20.5°±0.2°, 21.7°±0.2°, 22.7°±0.2° and 25.3°±0.2°in a powder X-ray diffraction pattern.

4. The crystal according to claim 1, wherein the crystal is crystal Form B having one or more absorption peaks selected from the group consisting of absorption peaks at 1388cm-1±2cm-1, 1426cm-1±2cm-1, 1451cm-1±2cm-1, 1564cm-1±2cm-1and 2938cm-1±2cm-1in a Raman spectrum.

5. The crystal according to claim 1, wherein the crystal is crystal Form B having absorption peaks at 1388cm-1±2cm-1, 1426cm-1±2cm-1, 1451cm-1±2cm-1, 1564cm-1±2cm-1and 2938cm-1±2cm-1in a Raman spectrum.

6. The crystal according to claim 1, wherein the crystal is crystal Form B characterized by one or more physicochemical properties selected from the group consisting of the following (i) to (iv): (i) having characteristic peaks at diffraction angles (2θ) of: 6.4°±0.2°, 8.4°±0.2°, 11.0°±0.2°, 17.7°±0.2° and 21.7°±0.2° in a powder X-ray diffraction pattern; (ii) having absorption peaks at 1388cm-1±2cm-1, 1426cm-1±2cm-1, 1451cm-1±2cm-1, 1564cm-1±2cm-1and 2938cm-1±2cm-1in a Raman spectrum; (iii) characterized by the space group of P212121and the following unit lattice parameters when measured at 298 K; a=4.7ű0.5Å b=16.0ű0.5Å c=27.7ű0.5Å α=90° β=90° γ=90°; and (iv) having a melting point of 180°C±2°C in differential scanning calorimetry.

7. The crystal according to claim 1, wherein the crystal is crystal Form B characterized by one or more spectra and / or curves selected from the group consisting of the following (a) to (c): (a) a powder X-ray diffraction pattern substantially identical to that shown in Fig. 6; (b) a Raman spectrum substantially identical to that shown in Fig. 11; and (c) a differential scanning calorimetry curve substantially identical to that shown in Fig. 7.

8. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 7.

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is an anti-HIV agent.

10. An HIV integrase inhibitor comprising the crystal according to any one of claims 1 to 7.

11. A method for treating and / or preventing HIV infection, comprising administering the crystal according to any one of claims 1 to 7 to a human.

12. The crystal according to any one of claims 1 to 7 for use in treating and / or preventing HIV infection.

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