Intracellular ATP enhancers

Abstract

The present invention provides a pharmaceutical composition that is for intracellular ATP enhancement, and that contains a compound represented by general formula (I) (in the formula, R1 represents an unsubstituted or substituted phenyl group, R2 represents a cyano group or a nitro group, R3 represents a hydrogen atom or a hydroxyl group, X represents an oxygen atom or -S(O)n-, n represents an integer of 0-2, and Y represents an oxygen atom or a sulfur atom), or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] This invention relates to a pharmaceutical composition for enhancing intracellular ATP. This application claims priority based on Japanese Patent Application No. 2020-203725, filed in Japan on December 8, 2020, and the contents of that application are incorporated herein by reference. [Background technology]

[0002] ATP (also known as adenosine triphosphate) is known to be an important substance involved in the storage and supply of energy in living organisms. In healthy individuals, a high degree of homeostasis maintains a balance between its production and consumption, keeping its intracellular concentration within a certain range. However, it is known that in certain diseases, disorders, or syndromes, intracellular ATP concentrations are lower than in normal conditions, and it is hoped that increasing the amount of ATP in these cells will be effective in treating or preventing the aforementioned diseases, disorders, or syndromes. Incidentally, a metabolic pathway is known in which ATP is converted in the following order within the body: ADP (also called adenosine diphosphate), AMP (also called adenosine monophosphate), IMP (inosine monophosphate), inosine, hypoxanthine, xanthine, and uric acid. In the aforementioned metabolic pathway, it is known that when the amount of hypoxanthine increases, IMP is produced from hypoxanthine, and then a pathway (sometimes called the intracellular purine salvage pathway) exists in which AMP, ADP, and ATP are further produced. Xanthine oxidoreductase (XOR) inhibitors, which are effective in treating gout, are known to reduce uric acid production by inhibiting XOR, which acts on the conversion reaction from hypoxanthine to xanthine and the conversion reaction from xanthine to uric acid in the aforementioned metabolic pathway. Furthermore, it is expected that by inhibiting the conversion reaction from hypoxanthine to xanthine and then to uric acid using XOR inhibitors, intracellular hypoxanthine will accumulate, and the intracellular purine salvage pathway will function, thereby increasing the amount of intracellular ATP. Currently, examples of XOR inhibitors used to treat hyperuricemia include allopurinol and febuxostat. Patent documents 1 to 5 describe that XOR inhibitors such as allopurinol and febuxostat are effective for conditions such as hemolytic anemia, sickle cell disease, pirubate kinase deficiency, spherocytosis, ellipticosis, labial cell carcinoma, thalassemia, ischemic heart disease, heart failure, cardiovascular disorders, hypertension, tachycardia, arrhythmia, chronic progressive ophthalmoplegia syndrome, red ragweed, myoclonus epilepsy syndrome, mitochondrial encephalomyopathy, lactic acidosis, stroke-like syndrome, Leigh encephalopathy, mitochondrial cardiomyopathy, Leber's disease, mitochondrial diabetes, Pearson's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, adenylosuccinate lyase deficiency, Alzheimer's disease, Lewy body dementia, or frontotemporal dementia. However, it has been disclosed that allopurinol or febuxostat alone do not sufficiently enhance intracellular ATP, and that combination therapy with inosine, inosinic acid, hypoxanthine, or salts thereof is necessary. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Japanese Patent No. 6153281 [Patent Document 2] Japanese Patent Publication No. 2018-80135 [Patent Document 3] International Publication No. 2018 / 092911 [Patent Document 4] Japanese Patent Publication No. 2018-118914 [Patent Document 5] Japanese Patent Publication No. 2018-135278 [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] The inventors of the present invention studied drugs for enhancing intracellular ATP and found that there is still room for improvement in enhancing intracellular ATP by drugs having XOR inhibitory activity.

[0005] An object of the present invention is to provide a drug for enhancing intracellular ATP that is more effective than conventionally known drugs. Another object of the present invention is to provide a drug that has XOR inhibitory activity and enhances intracellular ATP without using inosine, inosinic acid, hypoxanthine or their salts in combination.

Means for Solving the Problems

[0006] As a result of various studies on drugs having XOR inhibitory activity, the inventors of the present invention found that a pharmaceutical composition containing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is effective as a drug for enhancing intracellular ATP, and completed the present invention. That is, the present invention is as follows: [1] General formula (I)

[0007]

Chemical formula

[10] The ATP-related eye diseases include retinitis pigmentosa, cone-rod dystrophy, Oguchi disease, pitted retina, paravenoretinal retinal atrophy, Leber congenital blindness, cone dystrophy, Stargardt disease, Best's disease, familial exudative vitreoretinopathy, Wagner syndrome, Stickler syndrome, central serous choroidal dystrophy, choroideremia, gyral choroidal dystrophy, retinal degeneration secondary to uveitis, drug-induced (including chloroquine) retinal disorders, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, diabetic retinopathy, renal retinopathy, age-related macular degeneration, central A pharmaceutical composition according to any one of items [1] to [7], which is a serous chorioretinopathy, retinal white spot syndrome, retinal pigment streaks, rhegmatogenous retinal detachment extending to the macula, macular hole, retinal schizophrenia, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment associated with high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, nasal optic neuropathy, demyelinating optic neuropathy (including multiple sclerosis), or toxic optic neuropathy (including ethambutol, methanol, and thinner).

[11] A pharmaceutical composition according to any one of [1] to

[10] , wherein a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is administered orally at a dose of 10 to 320 mg per day to a patient requiring enhancement of intracellular ATP, and the oral administration is optionally continued for at least 7 days;

[12] R 1 The pharmaceutical composition according to any one of [1] to

[11] , wherein the phenyl group is unsubstituted or phenyl group is substituted with a halogen atom;

[13] A pharmaceutical composition according to any one of [1] to

[12] , wherein X is an oxygen atom;

[14] A pharmaceutical composition according to any one of [1] to

[13] , wherein Y is a sulfur atom; A pharmaceutical composition according to any one of [1] to

[14] , wherein the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to

[14] contains an amorphous form, and the content of the amorphous form is 80% by weight or more of the total weight of the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to

[14] ;

[16] A pharmaceutical composition described in any one of [1] to

[15] , which is an enteric-coated preparation;

[17] The pharmaceutical composition according to

[16] , wherein the enteric-coated preparation is a hard capsule;

[18] A pharmaceutical composition according to any one of [1] to

[17] further comprising a solid dispersion containing a hypromellose derivative;

[19] The pharmaceutical composition according to

[18] , wherein the weight ratio of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to a hypromellose derivative is 1:0.1 to 1:25;

[20] The pharmaceutical composition according to

[18] or

[19] , wherein the hypromellose derivative is hypromellose acetate succinate or hypromellose phthalate;

[21] A pharmaceutical composition described in any one of [1] to

[20] which is a solid dosage form;

[22] A pharmaceutical composition according to any one of [1] to

[21] , wherein the content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is 10 mg to 320 mg;

[23] A pharmaceutical composition according to any one of [1] to

[22] , wherein the content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit is 10 mg to 320 mg;

[24] A pharmaceutical composition according to any one of [1] to

[23] , wherein the content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit is 10 mg to 160 mg;

[25] A pharmaceutical composition according to any one of [1] to

[24] , wherein the content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit is 10 mg to 80 mg;

[26] A pharmaceutical composition according to any one of [1] to

[25] , wherein the content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit is 20 mg to 80 mg;

[27] A pharmaceutical composition according to any one of [1] to

[26] , which reduces the blood uric acid concentration by 0.5 to 2.0 mg / dL (e.g., 0.5 to 1.5 mg / dL) 12 hours after administration on day 1 compared to before administration;

[28] A pharmaceutical composition according to any one of [1] to

[27] , wherein administration once daily for seven consecutive days reduces the blood uric acid concentration 12 hours after administration on the seventh day of administration by 1.5 to 3.0 mg / dL (e.g., 1.5 to 2.5 mg / dL) compared to before administration;

[29] A pharmaceutical composition according to any one of [1] to

[28] , wherein the daily dose of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is not increased from the start of administration to three weeks after administration;

[30] The pharmaceutical composition according to any one of [1] to

[29] , in which the daily dose of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is not increased, or increased once, within 7 weeks from the start of administration;

[31] A pharmaceutical composition according to any one of [1] to

[30] , wherein the maximum reduction rate of blood uric acid levels on day 1 of administration ([(pre-administration uric acid level - minimum post-administration uric acid level on day 1 of administration) / pre-administration uric acid level] × 100) is 10 to 25%;

[32] A pharmaceutical composition according to any one of [1] to

[31] , wherein the maximum rate of reduction in blood uric acid levels on day 7 of administration ([(pre-administration uric acid level - minimum post-administration uric acid level on day 7 of administration) / pre-administration uric acid level] × 100) is 20-45%;

[33] A pharmaceutical composition according to any one of [1] to

[32] , wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof; The present invention relates to a package containing a pharmaceutical composition described in any one of

[34] [1] to

[33] , wherein the package contains a number of dosage units of the pharmaceutical composition necessary for continuous administration for 5 to 15 days.

[35] An ATP, ADP, GTP, or GDP enhancer containing an XOR inhibitor as an active ingredient, wherein intracellular expression of the target enzyme XOR is substantially absent or low.

[36] The enhancer according to

[35] , wherein the XOR inhibitor is a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, allopurinol, topiroxostat, or febuxostat.

[37] The enhancer according to

[35] or

[36] , wherein the organ in which the expression of the target enzyme XOR is substantially absent or low is the eyeball.

[38] The enhancer according to any one of

[35] to

[37] , wherein the tissue in which the target enzyme XOR is substantially not expressed or is of low expression is the retina.

[39] The enhancer according to any one of

[35] to

[37] , wherein the tissue in which the target enzyme XOR is substantially absent or has little expression is the optic nerve.

[40] An enhancer according to any one of

[35] to

[39] , further comprising an ATP precursor.

[41] The enhancer according to

[40] , wherein the ATP precursor is inosine and / or hypoxanthine.

[42] A therapeutic and / or prophylactic agent for ATP-related diseases in tissues, organs, tissues or cells in which the expression of the target enzyme XOR is substantially absent or faintly observed within the cell, comprising an XOR inhibitor as an active ingredient.

[43] The therapeutic and / or prophylactic agent according to

[42] , wherein the XOR inhibitor is a compound represented by the earlier general formula (I) or a pharmaceutically acceptable salt thereof, allopurinol, topiroxostat, or febuxostat.

[44] The therapeutic and / or prophylactic agent according to

[42] or

[43] , wherein the organ in which the expression of the target enzyme XOR is substantially absent or reduced is the eyeball.

[45] The therapeutic and / or prophylactic agent according to any one of

[42] to

[44] , wherein the tissue in which the target enzyme XOR is substantially absent or has little expression is the retina.

[46] The therapeutic and / or prophylactic agent according to any one of

[42] to

[44] , wherein the tissue in which the target enzyme XOR is substantially absent or has little expression is the optic nerve.

[47] The therapeutic and / or prophylactic agent according to any one of

[42] to

[46] , wherein the ATP-related disease is an ATP-related eye disease.

[48] ​​The ATP-related eye diseases include retinitis pigmentosa, cone-rod dystrophy, Oguchi disease, punctate fundus, paravenoretinal retinal atrophy, Leber congenital blindness, cone dystrophy, Stargardt disease, Best's disease, familial exudative vitreoretinopathy, Wagner syndrome, Stickler syndrome, central ossicular choroidal dystrophy, choroideremia, gyral choroidal dystrophy, retinal degeneration secondary to uveitis, drug-induced (including chloroquine) retinal disorders, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, diabetic retinopathy, renal retinopathy, age-related macular degeneration, A treatment and / or prophylactic agent for central serous chorioretinopathy, retinal white spot syndrome, retinal pigment streaks, rhegmatogenous retinal detachment extending to the macula, macular hole, retinal schizophrenia, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment associated with high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, nasal optic neuropathy, demyelinating optic neuropathy (including multiple sclerosis), or toxic optic neuropathy (including ethambutol, methanol, and thinner), as described in

[47] .

[49] A pharmaceutical composition for the treatment and / or prevention of ATP-related diseases in tissues, organs, tissues or cells in which the expression of the target enzyme XOR is substantially absent or low, comprising an XOR inhibitor as an active ingredient.

[50] The pharmaceutical composition according to

[49] , further comprising an ATP precursor.

[51] The pharmaceutical composition according to

[50] , wherein the ATP precursor is inosine and / or hypoxanthine.

[52] A pharmaceutical composition for the treatment and / or prevention of ATP-related diseases, comprising an XOR inhibitor as an active ingredient.

[53] The pharmaceutical composition according to

[52] , wherein the XOR inhibitor is a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, allopurinol, topiroxostat, or febuxostat.

[54] The pharmaceutical composition according to

[52] or

[53] , wherein the ATP-related disease is an ATP-related eye disease.

[55] The ATP-related eye diseases include retinitis pigmentosa, cone-rod dystrophy, Oguchi disease, pitted retina, paravenoretinal retinal atrophy, Leber congenital blindness, cone dystrophy, Stargardt disease, Best's disease, familial exudative vitreoretinopathy, Wagner syndrome, Stickler syndrome, central ossicular choroidal dystrophy, choroideremia, gyral choroidal dystrophy, retinal degeneration secondary to uveitis, drug-induced (including chloroquine) retinal disorders, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, diabetic retinopathy, renal retinopathy, and age-related macular degeneration. The pharmaceutical composition described in

[54] is for the following conditions: central serous chorioretinopathy, retinal white spot syndrome, retinal pigment streaks, rhegmatogenous retinal detachment extending to the macula, macular hole, retinal schizophrenia, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment associated with high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, nasal optic neuropathy, demyelinating optic neuropathy (including multiple sclerosis), or toxic optic neuropathy (including ethambutol, methanol, and thinner). [Effects of the Invention]

[0008] The pharmaceutical compositions provided by the present invention are useful as pharmaceutical compositions for enhancing intracellular ATP. In particular, the pharmaceutical compositions provided by the present invention are useful as pharmaceutical compositions for enhancing intracellular ATP even if they contain only the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, without the use of inosine, inosinic acid, hypoxanthine, or salts thereof as active ingredients. Furthermore, the pharmaceutical compositions provided by the present invention that contain an XOR inhibitor as an active ingredient exert an ATP-enhancing effect even in tissues, organs, tissues, or cells in which the expression of the target enzyme XOR is substantially absent or low, and are effective, for example, for ATP-related eye diseases. [Brief explanation of the drawing]

[0009] [Figure 1] This figure shows the particle size distribution of compound 14 obtained by wet laser diffraction of the amorphous material. [Figure 2] This figure shows the plasma drug concentration-time curve when the capsule formulation of Reference Example 1a was administered to dogs. [Figure 3] This figure shows the crystalline powder X-ray diffraction pattern of compound 14. [Figure 4] The figures show the amorphous powder X-ray diffraction patterns of compound 14, with (a) showing the pattern before storage, (b) showing the pattern after 1 week of storage under light-shielded, airtight, and room temperature conditions, (c) showing the pattern after 2 weeks of storage under light-shielded, airtight, and room temperature conditions, and (d) showing the pattern after 4 weeks of storage under light-shielded, airtight, and room temperature conditions. [Figure 5] This figure shows the powder X-ray diffraction patterns of the solid dispersion of Reference Example 9b before storage and after storage at 40°C / 75%RH under open conditions for 1 week, 3 weeks, and 7 weeks, respectively. [Figure 6] This figure shows the powder X-ray diffraction patterns of the solid dispersion of Reference Example 10b before storage and after storage at 40°C / 75%RH under open conditions for 1 week, 3 weeks, and 7 weeks, respectively. [Figure 7] This figure shows the powder X-ray diffraction patterns of the solid dispersion of Reference Example 11b before storage and after storage at 40°C / 75%RH under open conditions for 1 week, 3 weeks, and 7 weeks, respectively. [Figure 8] This graph shows the effect of the solid dispersion of Reference Example 11b on lowering plasma uric acid levels in rats. [Figure 9] Reference Example 14 shows the decrease in serum uric acid levels when compound 14 and febuxostat (as a control drug) were orally administered to healthy adult males. [Figure 10] Reference Example 15 shows the percentage change in plasma uric acid levels when oxonate-induced hyperuricemia rats were repeatedly administered compound 14 and febuxostat as a control drug once daily for 28 days. [Figure 11] This figure shows the ATP-enhancing effect under hypoxic conditions in Example 1. [Figure 12] This figure shows the ATP-enhancing effect in a hypoxic state in Example 1, illustrating the significant difference between compound 14 and febuxostat when hypoxanthine was administered concomitantly. [Figure 13] This figure shows the ATP-enhancing effect in the presence of an uncoupling agent in Example 2. [Figure 14] These are sagittal section eye tissue specimens (HE stained) including the optic nerve from a 5-week-old male RCS rat. Numbers 1-4 represent the distance from the center of the macula, the thickness of the retina, the thickness of the outer granular layer, and the thickness of the cone-rod layer, respectively, which are 1011 μm, 128 μm, 13 μm, and 27 μm. [Figure 15] The image shows cross-sectional views of the retina after administration of the control and compound 14 in Example 3, as well as graphs representing the thickness of the outer granular layer and the cone-rod layer. [Modes for carrying out the invention]

[0010] <Pharmaceutical composition> The present invention will be described in further detail below. The pharmaceutical composition for enhancing intracellular ATP of the present invention contains a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. In compounds represented by general formula (I), R 1represents an unsubstituted phenyl group or a phenyl group substituted with a substituent. R 1 Examples of the "alkyl group having 1 to 8 carbon atoms" as the substituent in the phenyl group represented by 1 include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, etc., and preferably a methyl group, an ethyl group, etc.

[0011] R 1 Examples of the "alkyl group having 1 to 8 carbon atoms substituted with a halogen atom" as the substituent in the phenyl group represented by 1 include a fluoromethyl group, a trifluoromethyl group, a 1,1-difluoroethyl group, a pentafluoroethyl group, etc., and preferably a fluoromethyl group, a trifluoromethyl group, etc.

[0012] R 1 Examples of the "alkoxy group having 1 to 8 carbon atoms" as the substituent in the phenyl group represented by 1 include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, etc., and preferably a methoxy group, etc.

[0013] R 1 Examples of the "alkoxycarbonyl group having 2 to 8 carbon atoms" as the substituent in the phenyl group represented by 1 include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group, etc., and preferably a methoxycarbonyl group, an ethoxycarbonyl group, etc.

[0014] R 1 Examples of the "halogen atom" as the substituent in the phenyl group represented by 1 include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and preferably a fluorine atom, a chlorine atom, etc.

[0015] R 1 is preferably an unsubstituted phenyl group.

[0016] In the compound represented by the general formula (I), R2 The symbol represents either a cyano group or a nitro group, but a cyano group is preferred.

[0017] In compounds represented by general formula (I), R 3 The symbol represents either a hydrogen atom or a hydroxyl group, but a hydrogen atom is preferred.

[0018] In compounds represented by general formula (I), X is an oxygen atom or -S(O) n It represents a -, but an oxygen atom is preferred.

[0019] In the compound represented by general formula (I), Y represents either an oxygen atom or a sulfur atom, but a sulfur atom is preferred.

[0020] Examples of pharmaceutically acceptable salts of the compound represented by general formula (I) include alkali metal salts such as sodium salts, potassium salts, or lithium salts, with potassium salts being preferred.

[0021] The compound of general formula (I) contained in a pharmaceutical composition for intracellular ATP enhancement, which is one embodiment of the present invention, can be obtained, for example, by the synthesis method described in International Publication No. 2005 / 121153 or International Publication No. 2019 / 208635.

[0022] In the pharmaceutical composition for enhancing intracellular ATP according to the present invention, preferred compounds of general formula (I) are those listed in Table 1. In the table, Me represents a methyl group.

[0023] [Table 1] Compounds 1 to 15 may form pharmaceutically acceptable salts, with compounds 3 to 5, compounds 8 to 10, compounds 13 to 14, or pharmaceutically acceptable salts of these compounds being preferred.

[0024] In the pharmaceutical composition for intracellular ATP enhancement of the present invention, it is preferable that the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof exists in an amorphous state, either partially or entirely. Here, amorphous means a substance in which the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof has short-range order between atoms or molecules, but does not have long-range order like a crystal. In this invention, amorphous materials can be identified by the presence of a halo peak in X-ray diffraction. In the present invention, it is preferable that 50% by weight or more of the total weight of the compound represented by general formula (I) or its pharmaceutically acceptable salt is amorphous, more preferably 80% by weight or more, more preferably 90% by weight or more, even more preferably 95% by weight or more, and it may be 100% by weight amorphous. The pharmaceutically acceptable salt of the compound represented by general formula (I) may also be crystalline, in which case less than 50% by weight of amorphous material may be present, 40% by weight or less may be amorphous, 30% by weight or less may be amorphous, 20% by weight or less may be amorphous, 10% by weight may be amorphous, or there may be no amorphous material at all. The above amorphous content can be determined by X-ray diffraction. In the above amorphous content, the remainder is crystalline. That is, in each description of content, the sum of the amorphous and crystalline content is 100% by weight.

[0025] A method for producing amorphous compounds represented by general formula (I) or pharmaceutically acceptable salts thereof can be obtained, for example, by subjecting the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to spray drying. More specifically, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable additive are added to a solvent described later to form a solution or suspension, the solution or suspension is atomized into a fine mist by centrifugal spraying with a rotating disk or pressurized spraying with a pressure nozzle, and this is sprayed into a drying medium (e.g., heated air or nitrogen gas) to obtain an amorphous powdery dry product. In the spray drying method, the temperature of the drying medium is, for example, 50 to 120°C, preferably 50 to 90°C. The drying medium may be flowing in a constant direction, for example, 0.1 to 0.6 m 3 It can be flowed at an airflow rate of / min. Solvents used in spray drying include methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol and other alcohols containing 1 to 6 carbon atoms, ethers such as tetrahydrofuran (THF), acetonitrile, and water. These solvents can be used individually or as a mixture of two or more. Among these, ethanol, tetrahydrofuran, and mixed solvents of these solvents with water are preferred. Another method for producing amorphous compounds of the compound represented by general formula (I) or its pharmaceutically acceptable salts is freeze-drying. More specifically, the compound represented by general formula (I) or its pharmaceutically acceptable salts can be dissolved in a solvent, and then the solution can be freeze-dried. Solvents used in freeze-drying include alcohols containing 1 to 6 carbon atoms, such as methanol, ethanol, 1-propanol, 2-propanol, and tert-butyl alcohol; ethers such as tetrahydrofuran; nitriles such as acetonitrile; and water. These solvents can be used individually or as a mixture of two or more solvents. The amorphous particle size of the compound represented by general formula (I) or its pharmaceutically acceptable salt is not particularly limited, but from the viewpoint of the effects of the invention and formulation, for example, a volume average particle size (D50) of 20 μm or less, preferably 1 to 15 μm, more preferably 1 to 10 μm, even more preferably 1.5 to 5 μm, and most preferably 2 to 5 μm is given. The volume-average particle diameter (D50) can usually be measured by dispersing the sample in a solvent such as water or ethanol and measuring the particle size distribution by laser diffraction. The sample may also be dispersed in the solvent by irradiating it with ultrasound. The particle size distribution can be measured using a particle size distribution analyzer (for example, the Shimadzu SALD-2200 laser diffraction particle size distribution analyzer). The volume-average particle diameter (D50) can be determined from the obtained particle size distribution. In addition, commercially available software (for example, Shimadzu WingSALD-2200 version 1.02) can be used for data collection and analysis.

[0026] The pharmaceutical composition of the present invention may contain pharmaceutically acceptable additives as needed. For example, the pharmaceutical composition of the present invention can be manufactured by appropriately combining and adding the required amounts of binders, disintegrants, excipients, lubricants, etc.

[0027] Examples of the binders include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, gelatin, agar, alginic acid, sodium alginate, partially saponified polyvinyl alcohol, pullulan, partially pregelatinized starch, dextrin, xanthan gum, and acacia powder. These may be used individually or as a mixture of two or more. Among these, hydroxypropylcellulose, hypromellose, or polyvinylpyrrolidone are preferred.

[0028] Examples of the disintegrants include crystalline cellulose, carboxymethylcellulose (also known as carmellose), croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, crospovidone, hydroxypropyl starch, starch, partially pregelatinized starch, and sodium starch glycolate. These may be used individually or as a mixture of two or more. Among these, croscarmellose sodium, sodium starch glycolate, or crospovidone are preferred, with crospovidone being more preferred. The amount of disintegrant used is preferably 5 to 30% by weight, and more preferably 5 to 15% by weight, relative to the total weight of the particles containing the active ingredient. When incorporated into tablets, the amount is preferably 1 to 10% by weight, and more preferably 2 to 6% by weight, relative to the total weight of the tablet granules containing the active ingredient.

[0029] The excipient can be incorporated into any of the following processes of the pharmaceutical preparation: the mixing process, the granulation process, or the post-granulation finishing process. Examples of the excipient include celluloses such as crystalline cellulose, ethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and hydroxypropyl methylcellulose (also known as hypromellose); starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, and hydroxypropyl starch; sugars such as glucose, lactose, sucrose, refined sucrose, powdered sugar, trehalose, dextran, and dextrin; sugar alcohols such as D-mannitol, xylitol, sorbitol, and erythritol; inorganic salts such as glycerin fatty acid esters, magnesium aluminometasilicate, synthetic hydrotalcite, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium hydrogen phosphate hydrate, and sodium bicarbonate, with crystalline cellulose being preferred.

[0030] Examples of the lubricant include stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, light anhydrous silicic acid, hydrogenated oil, glycerin fatty acid ester, and talc. These may be used individually or as a mixture of two or more. Among these, sodium stearyl fumarate, magnesium stearate, calcium stearate, or sucrose fatty acid ester are preferred.

[0031] Furthermore, in the pharmaceutical composition, by mixing the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof with an enteric polymer, recrystallization of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof from a supersaturated solution can be suppressed. When the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and the enteric polymer are mixed, it is preferable that they are uniformly mixed. The weight ratio of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to the enteric polymer can be exemplified as 1:0.5 to 1:10, preferably 1:1 to 1:5, more preferably 1:2 to 1:5, and even more preferably 1:1 to 1:4. Examples of the enteric polymer include the enteric polymer for coating, with cellulose-based polymers being preferred, and hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose acetate succinate being more preferred. Furthermore, when mixing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof with an enteric polymer, the aforementioned pharmaceutically acceptable additives may be appropriately incorporated.

[0032] <Enteric-coated preparation> The pharmaceutical composition according to the present invention is preferably an enteric-coated preparation. The "enteric-coated preparation" according to the present invention is a preparation designed to prevent the breakdown of the active ingredient in the stomach, or to prevent the release of the active ingredient in the stomach, and instead release it mainly in the small intestine. Enteric-coated preparations themselves are described in the Japanese Pharmacopoeia. Enteric-coated preparations are known in dosage forms such as tablets, granules, fine granules, and capsules. Methods for producing these dosage forms include (i) producing enteric-coated granules in which the active ingredient, or the active ingredient and a pharmaceutically acceptable additive, is coated with an enteric polymer, and then producing tablets, granules, fine granules, or capsules containing these; (ii) producing tablets, granules, fine granules, or capsules containing the active ingredient and a pharmaceutically acceptable additive, and then coating these preparations with an enteric polymer; or (iii) encapsulating the active ingredient, or the active ingredient and a pharmaceutically acceptable additive, in a hard capsule made of an enteric-coated base. In other words, examples of enteric-coated preparations according to the present invention include (i) tablets, granules, fine granules, or capsules containing an active ingredient, or an active ingredient and a pharmaceutically acceptable additive, coated with an enteric polymer; (ii) tablets, granules, fine granules, or capsules containing an active ingredient and a pharmaceutically acceptable additive, coated with an enteric polymer; or (iii) hard capsules containing an active ingredient, or an active ingredient and a pharmaceutically acceptable additive, in a hard capsule made of an enteric-coated base. The enteric-coated base refers to a base composed of an enteric-coated polymer that is known in itself, and examples of such enteric-coated polymers include the enteric-coated polymers exemplified later as enteric-coated polymers for coating.

[0033] Enteric polymers for coating used in the present invention include enteric methacrylic acid copolymers such as methacrylic acid copolymer L, methacrylic acid copolymer S (e.g., Eudragit® L100, Eudragit® S100, manufactured by Evonik), methacrylic acid copolymer LD (e.g., Eudragit® L100-55, Eudragit® L30D-55, manufactured by Evonik), methyl acrylate / methyl methacrylate / methacrylic acid copolymer (e.g., Eudragit® FS30D, manufactured by Evonik), and hypromellose (Hyd Examples include enteric-coated cellulose polymers such as hydroxypropyl methylcellulose (also known as roxypropyl methylcellulose), hypromellose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd., sometimes abbreviated as HPMCAS), hypromellose phthalate (manufactured by Shin-Etsu Chemical Co., Ltd., sometimes abbreviated as HPMCP), carboxymethyl ethylcellulose (manufactured by Freund Industrial Co., Ltd., sometimes abbreviated as CMEC), and ceracephate (also known as cellulose acetate phthalate), as well as enteric-coated vinyl alcohol polymers such as polyvinyl alcohol acetate phthalate (manufactured by Karakon Co., Ltd.), but enteric-coated cellulose polymers are preferred. Among these, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate are preferred. The enteric-coated granules can be manufactured according to known methods. For example, they can be manufactured by producing granules using a fluid granulation method such as rolling fluid bed granulation and fluid granulation, a rolling granulation method such as centrifugal rolling granulation, or agitation granulation, and then coating them with an enteric coating solution and drying. The enteric coating solution can be prepared by adding the enteric polymer to a solvent and concentrating the solvent as needed. Examples of solvents used in preparing the enteric coating solution include water, alcohol-based solvents such as methanol and ethanol, or mixtures thereof. Medicinalally acceptable additives such as binders, plasticizers, coating agents, surfactants, and excipients may be added as needed. The amount of solvent is not particularly limited, but it can be used in an amount of 3 to 10 times the total weight of the dissolved product (i.e., the total weight of the enteric polymer and the medicamentally acceptable additives).

[0034] Tablets, granules, fine granules, or capsules containing an active ingredient and pharmaceutically acceptable additives, coated with the aforementioned enteric polymer, can be manufactured by producing tablets, granules, fine granules, or capsules containing an active ingredient and pharmaceutically acceptable additives according to a known method, and then coating these resulting preparations with the aforementioned enteric coating solution and drying them.

[0035] Commercially available hard capsules consisting of an enteric-coated base can be used. For example, hard capsules consisting of an enteric-coated base containing hydroxypropyl methylcellulose or hydroxypropyl methylcellulose acetate succinate can be used. More specifically, Vcaps® Enteric (manufactured by Capsugel Corporation) can be used. The enteric-coated preparation according to the present invention may contain pharmaceutically acceptable additives as needed. For example, the pharmaceutical composition of the present invention can be manufactured by appropriately combining and adding in the required amounts binders, disintegrants, excipients, lubricants, etc. Examples of "pharmaceutically acceptable additives" include the pharmaceutically acceptable additives exemplified in the pharmaceutical composition. The enteric-coated formulation provided by the present invention may exhibit high absorption in vivo.

[0036] <Solid dispersion> The pharmaceutical composition of the present invention may further include a solid dispersion containing a hypromellose derivative. The term "hypromellose derivative" according to the present invention refers to hypromellose itself (sometimes abbreviated as HPMC) and organic acid esters of hypromellose. Hypromellose is also called hydroxypropyl methylcellulose and is a mixed ether of cellulose with methyl and hydroxypropyl groups. Examples of organic acids that form esters with hypromellose include acetic acid, succinic acid, or phthalic acid. The hypromellose according to the present invention may form esters with one or more organic acids selected from the above organic acids. Examples of hypromellose derivatives used in the present invention include hypromellose, hypromellose acetate succinate (sometimes abbreviated as HPMCAS), and hypromellose phthalate (sometimes abbreviated as HPMCP), with hypromellose acetate succinate and hypromellose phthalate being preferred.

[0037] An example of hypromellose according to the present invention is hypromellose in which the substitution ratio per monomer unit is 28-30% for methoxy groups and 7-12% for hydroxypropoxy groups. An example of the hypromellose acetate succinate according to the present invention is a hypromellose acetate succinate in which the substitution ratio per monomer unit is 20-26%, preferably 21-25%, for methoxy groups, 5-10%, preferably 5-9%, for hydroxypropoxyl groups, 5-14%, preferably 7-11%, for acetyl groups, and 4-18%, preferably 10-14%, for succinoyl groups. An example of the hypromellose phthalate according to the present invention is a hypromellose phthalate in which the substitution ratio per monomer unit is 18-24%, for methoxy groups, 5-10%, for hydroxypropoxy groups, and 21-35%, for carboxybenzoyl groups. The content of methoxy groups, hydroxypropoxy groups, acetyl groups, succinoyl groups, or carboxybenzoyl groups in the above-mentioned hypromellose derivatives can be measured by a method in accordance with the method for measuring the degree of substitution of hypromellose, hypromellose acetate succinate, and hypromellose phthalate as specified in the 17th edition of the Japanese Pharmacopoeia.

[0038] The viscosity of the hypromellose derivative according to the present invention is not particularly limited as long as it has the effects of the present invention, but for example, it can be 2.4 to 204 mPa·s, and preferably 2.4 to 3.6 mPa·s. The viscosity of the hypromellose derivative according to the present invention can be measured by a method in accordance with the method for measuring the viscosity of hypromellose, hypromellose acetate succinate, and hypromellose phthalate as specified in the 17th edition of the Japanese Pharmacopoeia.

[0039] The weight ratio of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to the hypromellose derivative can be appropriately adjusted within the range of 1:0.1 to 1:25. One example of the weight ratio of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to the hypromellose derivative is 1:0.1 to 1:10, another example is 1:0.1 to 1:4, yet another example is 1:1 to 1:10, yet another example is 1:2 to 1:5, and yet another example is 1:3 to 1:4. One embodiment of the present invention is a solid dispersion in which the weight ratio of 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof to a hypromellose derivative is 1:0.1 to 1:25; another embodiment is 1:0.1 to 1:10; yet another embodiment is 1:0.1 to 1:4; yet another embodiment is 1:1 to 1:10; yet another embodiment is 1:2 to 1:5; and yet another embodiment is 1:3 to 1:4.

[0040] A "solid dispersion" means a solid composition comprising a system of at least two components, wherein the at least two components are uniformly mixed to form a system. In such a solid dispersion, at least one component is typically dispersed throughout the entire system. Accordingly, one embodiment of the "solid dispersion" according to the present invention is a solid composition comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a hypromellose derivative, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and the hypromellose derivative form a system in which they are uniformly mixed. Another embodiment of the "solid dispersion" according to the present invention is a solid composition in which a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof forms a system in which a hypromellose derivative is dispersed throughout the hypromellose derivative. In this case, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof constitutes the dispersed phase as the dispersed phase, and the hypromellose derivative constitutes the continuous phase as the dispersion medium.

[0041] The "solid dispersion" according to the present invention is composed of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, a hypromellose derivative, and optionally a pharmaceutically acceptable additive. Examples of optionally included pharmaceutically acceptable additives include those selected from surfactants, pH adjusters, sugars, and plasticizers. These can be combined as appropriate and incorporated in the required amounts into the solid dispersion according to the present invention. Suitable surfactants include cationic surfactants such as sodium bis-(2-ethylhexyl) sulfosuccinate (sodium doxate), alkyltrimethylammonium bromide (e.g., cetyltrimethylammonium bromide (cetrimid)), anionic surfactants such as sodium lauryl sulfate, and polyoxyethylene sorbitan (e.g., Tween). TM 20, 40, 60, 80 or 85)), sorbitan fatty acid esters (e.g., Span TM Examples of nonionic surfactants include those such as 20, 40, 60, 80, or 85. Suitable pH adjusters include acids such as succinic acid, maleic acid, tartaric acid, citric acid, and aspartic acid, as well as alkalis such as sodium hydroxide, magnesium oxide, silicon dioxide, sodium bicarbonate, and L-arginine. Examples of sugars that can be used include lactose, sucrose, glucose, fructose, sucrose, maltose, reduced maltose, maltitol, mannitol, erythritol, sorbitol, and xylitol. Examples of plasticizers that can be used include triethyl citrate, polyethylene glycol, and triacetin. The "solid dispersion" according to the present invention does not necessarily contain the pharmaceutically acceptable additives, but if it does, for example, the weight ratio of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to the surfactant is 1:0.01 to 1:2, more preferably 1:0.02 to 1:1.5, and even more preferably 1:0.03 to 1:1.2, and the weight ratio of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to the pH adjusting agent is 1: The weight ratio of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to the sugars is 0.01 to 1:2, more preferably 1:0.02 to 1:1.5, and even more preferably 1:0.03 to 1:1.2, and the weight ratio of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to the plasticizer is 1:0.02 to 1:20, more preferably 1:0.15 to 1:10. In the "solid dispersion" according to the present invention, the pharmaceutically acceptable additive may constitute the dispersed phase of the solid dispersion or the continuous phase.

[0042] In the "solid dispersion" according to the present invention, it is preferable that the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof exists in part or all as amorphous material.

[0043] The solid dispersion according to the present invention can be manufactured by known methods, such as the mixing and grinding method (mechanochemical method), solvent method, melting method, and heated kneading and melting method. Here, the mixed-and-ground method refers to a method in which a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, a hypromellose derivative, and optionally a pharmaceutically acceptable additive are mixed, and then ground using a conventional method with a mixer such as a ball mill or hammer mill and a grinder. The solvent method refers to a method in which a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, a hypromellose derivative, and optionally a pharmaceutically acceptable additive are dissolved or suspended in a solvent (organic solvent, water, or a mixture thereof), and then the solvent is removed to precipitate a solid dispersion, or a solid dispersion is precipitated in the solvent. The solvent can be removed by methods such as spraying (which can be classified into fluidized bed method, spray drying method (also called spray drying method), rolling bed method, stirring method, or supercritical method depending on the embodiment), filtration method, evaporation method, or freeze-drying method, with spraying method being preferred, and spray drying method being particularly preferred. The solvents that can be used to produce the solid dispersion according to the present invention are preferably pharmaceutically acceptable solvents, such as ethanol, methanol, 2-propanol, acetone, 2-butanone, methyl isobutyl ketone, tetrahydrofuran (THF), tetrahydropyran, 1,4-dioxane, diethyl ether, toluene, acetonitrile, methylene chloride, chloroform, methyl acetate, ethyl acetate, butyl acetate, acetic acid, formic acid, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide. In these solvents, it is preferable that the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, and optionally added pharmaceutically acceptable additives, be dissolved. In the spray drying method, a solid dispersion can be produced by a method known in itself. For example, a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a hypromellose derivative, and optionally a pharmaceutically acceptable additive, can be added to the solvent to form a solution or suspension. This solution or suspension can be atomized into a fine mist by centrifugal spraying using a rotating disk or pressurized spraying using a pressure nozzle, and this mist can be ejected into a drying medium (heated air or nitrogen gas) to obtain a solid dispersion as a powdery dry product. In the spray drying method, the temperature of the drying medium is, for example, 50 to 120°C, preferably 50 to 90°C. The drying medium may be flowed in a constant direction, for example, 0.1 to 0.6 m 3 It can be flowed at an airflow rate of / min. In the solvent method, the coprecipitation method is preferred. A compound represented by general formula (I) or its pharmaceutically acceptable salt and hypromellose derivative, and optionally a pharmaceutically acceptable additive, are dissolved or suspended in a solvent. A solid dispersion can be obtained by precipitating the dissolved compound (I) or its pharmaceutically acceptable salt and hypromellose derivative, and optionally the pharmaceutically acceptable additive, by adding a solvent in which they are insoluble or by lowering the temperature to reduce the solubility. The melting method refers to a method in which a compound represented by general formula (I) or its pharmaceutically acceptable salt and hypromellose derivative, and optionally a pharmaceutically acceptable additive, are heated to a temperature above the melting or softening point of the hypromellose derivative and stirred, thereby dissolving or dispersing the compound represented by general formula (I) or its pharmaceutically acceptable salt and optionally added pharmaceutically acceptable additive in the hypromellose derivative, and then rapidly cooling. At this time, additives such as plasticizers such as triethyl citrate, polyethylene glycol, and triacetin, and surfactants may be added as desired. The manufacturing can be carried out using a stirring granulator equipped with a heating device. The heated mixing and melting method is a method of obtaining a solid dispersion by mixing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a hypromellose derivative, as well as optionally a pharmaceutically acceptable additive, under heat and pressure using an extruder equipped with a heating device, such as a twin-screw extruder. The resulting plastic-like solid dispersion can then be pulverized using a pulverizer to obtain a powder of the solid dispersion.

[0044] The solid dispersion according to the present invention, produced by the above manufacturing method, can be formed into particles of the solid dispersion having any particle size by known methods, and these particles of the solid dispersion can be used as is as a powder or granule.

[0045] The pharmaceutical composition containing the solid dispersion according to the present invention comprises the solid dispersion and a pharmaceutically acceptable additive. The pharmaceutical composition of the present invention can be manufactured by appropriately combining and adding in the required amount a pharmaceutically acceptable additive such as a binder, disintegrant, excipient, lubricant, etc. The pharmaceutically acceptable additives are examples of those exemplified in the pharmaceutical composition.

[0046] The pharmaceutical composition containing the solid dispersion according to the present invention can be formulated into solid dosage forms such as tablets, capsules, granules, or powders, or into liquid dosage forms such as injections, by subjecting it to a known formulation process. The injection may be provided in the form of a solid dosage form of the pharmaceutical composition of the present invention, which is then prepared as an injection at the time of use. Since the present invention also has the effect of suppressing tableting disorders, it is particularly preferable that the solid dosage form be a tablet. Furthermore, these solid dosage forms can be coated as desired.

[0047] The content of the solid dispersion in the pharmaceutical composition containing the solid dispersion according to the present invention may be 10 to 95% by weight, preferably 30 to 90% by weight, and more preferably 60 to 85% by weight, based on the total weight of the pharmaceutical composition. The solid dispersion provided by the present invention may exhibit high absorption in living organisms and storage stability. The pharmaceutical composition according to the present invention can be manufactured as a pharmaceutical in a suitable dosage form such as tablets, capsules, granules, powders, eye drops, mouthwashes, ointments, creams, gels, patches, liniments, tapes, poultices, injections, or suppositories, according to conventional methods in the pharmaceutical technology. Of the above preparations, for example, ointments can be manufactured by formulations that are known in themselves. For example, they can be manufactured by grinding or melting one or more active ingredients into a base. The ointment base is selected from ointment bases that are known in themselves. For example, higher fatty acids or higher fatty acid esters (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes (e.g., beeswax, whale wax, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphate ester, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., di One or more bases selected from methylpolysiloxane, hydrocarbons (e.g., hydrophilic petrolatum, white petrolatum, refined lanolin, liquid paraffin, etc.), glycols (e.g., ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oils (e.g., castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oils (e.g., mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancers, or anti-rash agents may be mixed together. Furthermore, humectants, preservatives, stabilizers, antioxidants, or fragrances may also be included.

[0048] The pharmaceutical compositions provided by the present invention can be administered orally or parenterally to patients who require enhancement of intracellular ATP, more specifically, to humans or other mammals suffering from or at risk of suffering from ATP-related eye diseases. In the present invention, "ATP-related eye diseases" means diseases that can be treated or prevented by increasing the ATP concentration in the eyeball. Examples of such diseases include diseases that cause damage to the retina or optic nerve. Retinal disorders include retinal dystrophy (retinitis pigmentosa, cone-rod dystrophy, Oguchi disease, white punctate fundus, paravenoretinal-choroidal atrophy of the pigment, and Leber congenital blindness, etc.), macular dystrophy (cone dystrophy, Stargardt disease, and Best's disease, etc.), vitreoretinal dystrophy (familial exudative vitreoretinopathy, Wagner syndrome, and Stickler syndrome, etc.), choroidal dystrophy (central albopictal choroidal dystrophy, choroideremia, and gyral choroidal dystrophy, etc.), retinal degeneration secondary to uveitis, and retinal degenerative diseases including drug-induced (chloroquine, etc.) retinal disorders; Retinal disorders associated with impaired blood flow (retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, diabetic retinopathy, and renal retinopathy, etc.); disorders of the retinal pigment epithelium (age-related macular degeneration, central serous chorioretinopathy, retinal white spot syndrome, and retinal pigment streaks, etc.); retinal disorders associated with retinal detachment (rhegmatogenous retinal detachment extending to the macula, macular hole, retinal schizophrenia, exudative retinal detachment, proliferative vitreoretinopathy, and retinal detachment associated with high myopia, etc.); and disorders of the optic nerve include glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, nasal optic neuropathy, demyelinating diseases (such as multiple sclerosis), and toxic optic neuropathy (ethambutol, methanol, paint thinner, etc.). Furthermore, this includes retinitis pigmentosa associated with Usher syndrome accompanied by hearing loss, retinitis pigmentosa associated with Bardet-Biedl syndrome accompanied by polydactyly, obesity, diabetes, and renal malformations, retinitis pigmentosa associated with Kearns-Sayre syndrome accompanied by ptosis and oculomotor disorders, and retinitis pigmentosa associated with Refsum syndrome, which is accompanied by polyoptic neuritis and cerebellar ataxia. The method of administration can be appropriately selected for each disease. For example, for ATP-related eye diseases, oral administration, such as tablets, is preferred, but is not limited to this.In the present invention, it has been shown that when an XOR inhibitor is administered orally, the amount of hypoxanthine and inosine in the body increases, and that the hypoxanthine and inosine cross the blood-retinal barrier, thereby increasing ATP in the eyeball. Preferably, the pharmaceutical composition provided by the present invention is administered to humans. The pharmaceutical composition provided by the present invention is useful as a pharmaceutical composition for enhancing intracellular ATP.

[0049] One embodiment of the present invention is a pharmaceutical composition for intracellular ATP enhancement containing enteric granules coated with an enteric polymer in which a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is administered orally to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration may be continued for at least 7 days if desired.

[0050] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule for intracellular ATP enhancement, comprising enteric granules coated with an enteric polymer containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration may be continued for at least 7 days if desired.

[0051] Another embodiment of the present invention is a pharmaceutical composition for intracellular ATP enhancement, comprising enteric granules coated with an enteric polymer in which a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is optionally mixed with an enteric polymer, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof in the enteric granules is optionally mixed with an enteric polymer, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg per day, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg, and optionally the oral administration is continued for at least 7 days.

[0052] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule for intracellular ATP enhancement, comprising enteric granules coated with an enteric polymer containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, and optionally the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof in the enteric granules being further mixed with an enteric polymer, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg per day, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg, and optionally the oral administration is continued for at least 7 days.

[0053] Another embodiment of the present invention is a pharmaceutical composition for intracellular ATP enhancement comprising enteric granules coated with an enteric polymer containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is administered orally to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is optionally continued for at least 7 days.

[0054] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule for intracellular ATP enhancement, comprising enteric granules coated with an enteric polymer containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration may be continued for at least 7 days if desired.

[0055] Another embodiment of the present invention is a pharmaceutical composition for intracellular ATP enhancement, comprising enteric granules coated with an enteric polymer containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive in the enteric granules is further mixed with an enteric polymer, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is optionally continued for at least 7 days.

[0056] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule for intracellular ATP enhancement, comprising enteric granules coated with an enteric polymer containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive in the enteric granules is further mixed with an enteric polymer, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration may be continued for at least 7 days if desired.

[0057] Another embodiment of the present invention is a pharmaceutical composition for intracellular ATP enhancement comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive coated with an enteric polymer, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is administered orally to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is optionally continued for at least 7 days.

[0058] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule for intracellular ATP enhancement, comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, coated with an enteric polymer, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration may be continued for at least 7 days if desired.

[0059] Another embodiment of the present invention is a pharmaceutical composition for intracellular ATP enhancement comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive coated with an enteric polymer, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive are further mixed with the enteric polymer, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is administered orally to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg per day, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg, and the oral administration is optionally continued for at least 7 days.

[0060] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule for intracellular ATP enhancement, comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive coated with an enteric polymer, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive are further mixed with the enteric polymer, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration may be continued for at least 7 days if desired.

[0061] Another embodiment of the present invention is a hard capsule for intracellular ATP enhancement, comprising a hard capsule made of an enteric-coated base containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg per day, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg, and the oral administration is optionally continued for at least 7 days.

[0062] Another embodiment of the present invention is a hard capsule for intracellular ATP enhancement, comprising a hard capsule made of an enteric-coated base containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is administered orally to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg per day, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg, and the oral administration is optionally continued for at least 7 days. Another embodiment of the present invention is a hard capsule for intracellular ATP enhancement, comprising a hard capsule made of an enteric-coated base containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, and the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof further mixed with an enteric-coated polymer, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is administered orally to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg per day, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg, and the oral administration is optionally continued for at least 7 days.

[0063] Another embodiment of the present invention is a hard capsule for intracellular ATP enhancement, comprising a hard capsule made of an enteric-coated base, containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, and wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive are further mixed with an enteric-coated polymer, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is administered orally to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg per day, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg, and the oral administration is optionally continued for at least 7 days.

[0064] Another embodiment of the present invention relates to a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof for use in intracellular ATP enhancement, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is used to administer orally to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg per day, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg, and optionally the oral administration is continued for at least 7 days.

[0065] Another embodiment of the present invention is a pharmaceutical composition for use in intracellular ATP enhancement, comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is administered orally to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg per day, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg, and the oral administration is optionally continued for at least 7 days.

[0066] Another embodiment of the present invention is a solid dispersion or a pharmaceutical composition comprising the solid dispersion according to the present invention for use in intracellular ATP enhancement, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is administered orally to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and the oral administration is optionally continued for at least 7 days.

[0067] Another embodiment of the present invention relates to the use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for intracellular ATP enhancement, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a patient requiring intracellular ATP enhancement at a dose of 10 to 320 mg per day, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg, and the oral administration is optionally continued for at least 7 days.

[0068] Another embodiment of the present invention is a method for enhancing intracellular ATP, comprising orally administering the pharmaceutical composition of the present invention to a subject requiring intracellular ATP enhancement at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and optionally continuing the oral administration for at least 7 days. A further embodiment of the present invention is a method for enhancing intracellular ATP, comprising orally administering a solid dispersion or a pharmaceutical composition containing the solid dispersion according to the present invention to a subject requiring intracellular ATP enhancement at a dose of 10 to 320 mg, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, and even more preferably 60 to 120 mg per day, and optionally continuing the oral administration for at least 7 days.

[0069] The dosage of the pharmaceutical composition of the present invention can be adjusted according to the content of the compound represented by general formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition of the present invention. Furthermore, the dosage may be appropriately determined according to the method of administration, the age, weight, sex, symptoms, and sensitivity to the drug of the recipient, but the dosage may be adjusted according to the improvement of symptoms. In the present invention, it is preferable to administer a constant dosage continuously. The dosage of the enteric-coated preparation of the present invention is, for example, in adults, typically 10 to 320 mg per day, preferably 20 to 320 mg, more preferably 40 to 280 mg, more preferably 40 to 240 mg, more preferably 40 to 180 mg, more preferably 60 to 140 mg, even more preferably 60 to 120 mg, and particularly preferably 60 to 100 mg, orally, calculated in terms of the content of the compound represented by general formula (I) or its pharmaceutically acceptable salt. If desired, the oral administration can be continued for at least 7 days, but the dosage may be increased or decreased depending on age, symptoms, etc. The number of administrations can also be, for example, 1 to 3 times per day, preferably 1 to 2 times, and more preferably 1 time. In one aspect of the present invention, since the pharmaceutical composition of the present invention is preferred to be in a state in which intracellular ATP is sustained or constitutively enhanced, the dosage and frequency of administration of the pharmaceutical composition according to the present invention can be appropriately determined in order to achieve the above state. For example, the frequency of administration may be two or three times per day.

[0070] The relationship between the enhancement of intracellular ATP and the treatment or prevention of diseases, disorders, or syndromes will be explained below, using neurodegenerative diseases as an example. Neurodegenerative diseases are a general term for diseases of unknown cause in which certain groups of nerve cells in the brain and spinal cord (for example, nerve cells involved in cognitive function or cells involved in motor function) are gradually damaged and lost. Currently, there are no disease-modifying drugs that act on the essential processes of these diseases to suppress disease progression, and treatment is symptomatic. The locations of nerve cells lost vary depending on the disease, and the affected areas result in a variety of symptoms, including dementia, ataxia, and muscle weakness. While the mechanisms by which neurodegenerative diseases develop are largely unknown, a common phenomenon across many diseases is the intracellular aggregation of abnormal proteins followed by cell death. Furthermore, in diseased nerve tissue, a large amount of ATP is consumed to remove denatured proteins by the ubiquitin-proteasome system. When the ATP concentration decreases due to increased ATP consumption in the tissue (e.g., the repair process from stress such as the accumulation of abnormal proteins mentioned above) or insufficient ATP production (e.g., ischemia), the breakdown of AMP is accelerated to maintain the energy charge (EC) value, and it is rapidly metabolized to uric acid via hypoxanthine. XOR inhibitors inhibit AMP degradation with hypoxanthine, increasing the levels of hypoxanthine and inosine in the blood. These then flow into nerve cells, where purine nucleotides produced by the intracellular purine salvage cycle are regenerated into ATP. As a result, intracellular ATP concentration can be increased or its decline can be delayed, thereby suppressing cell death. Therefore, by enhancing intracellular ATP, the aforementioned neurodegenerative diseases can be treated or prevented. Specific examples of such neurodegenerative diseases, particularly optic nerve disorders, include glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, nasal optic neuropathy, demyelinating diseases (such as multiple sclerosis), and toxic optic neuropathy (e.g., ethambutol, methanol, paint thinner). Furthermore, in diseases, disorders, or syndromes involving intracellular ATP deficiency, enhancing intracellular ATP may enable the treatment or prevention of such diseases, disorders, or syndromes through a similar mechanism of action. As one embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof has XOR inhibitory activity and is therefore useful as an active ingredient in a pharmaceutical composition for enhancing intracellular ATP. In another embodiment of the present invention, it is preferable that the intracellular ATP enhancement effect is achieved by the intracellular purine salvage cycle. In another embodiment of the present invention, it is preferable that the intracellular ATP-enhancing effect can be sustained even in the presence of an uncoupling agent. Here, an uncoupling agent is a drug that inhibits mitochondrial function, reduces the efficiency of ATP production by respiration, and causes a state of intracellular ATP deficiency. Therefore, "the intracellular ATP-enhancing effect can be sustained even in the presence of an uncoupling agent" means that the intracellular ATP-enhancing effect can be sustained even in a state of intracellular ATP deficiency, that is, in circulatory failure, a state of reduced mitochondrial function, or a state of oxygen deficiency due to various other reasons (anemia, hemoglobin abnormalities, etc.). An example of an uncoupling agent is carbonylcyanide-m-chlorophenylhydrazone (sometimes abbreviated as CCCP in this specification). In another embodiment of the present invention, it is preferable that the intracellular ATP-enhancing effect is the improvement of a state in which the balance of ATP production and consumption is skewed towards consumption. In another embodiment of the present invention, it is preferable that the intracellular ATP enhancement effect is performed under hypoxic conditions. In another embodiment of the present invention, it is preferable that the intracellular ATP enhancement effect is performed in a state of absolute or relative ATP deficiency. Here, an absolute ATP deficiency means a state in which ATP is deficient because there is insufficient oxygen necessary for ATP synthesis, and a specific example of such a state is circulatory failure. A relative ATP deficiency means a state in which ATP is deficient because ATP consumption is high, and a specific example of such a state is the accumulation of abnormal proteins (a state in which there is insufficient ATP to remove the accumulated abnormal proteins). In another embodiment of the present invention, it is preferable that the absolute or relative deficiency of ATP is due to circulatory failure, abnormal protein accumulation, or tissue damage (for example, tissue damage caused by chemicals, trauma, etc.). In this specification, "enhancement" of ATP enhancement means a state in which the total amount of ATP and its metabolites, adenylate or adenylic acid, is significantly increased compared to the control group (group not administered the active ingredient). Preferably, "enhancement" of ATP enhancement means a state in which ATP and / or ADP are significantly increased compared to the control group (group not administered the active ingredient), and more preferably, "enhancement" of ATP enhancement means a state in which ATP and / or ADP are significantly increased compared to the control group (group not administered the active ingredient), and AMP and / or IMP are significantly decreased. Furthermore, the term "enhancement" as described above, in another embodiment, refers to raising the intracellular ATP amount of a specific organ or tissue in a healthy person from a state where the ATP amount has fallen below 100 due to disease, etc., to approximately 100, or increasing it to 100 or more. For example, in a patient whose intracellular ATP amount has decreased due to disease, etc., it means restoring the intracellular ATP concentration to 0.5% by mass or more compared to the intracellular ATP concentration before administration of the pharmaceutical composition according to the present invention, preferably to 1% by mass or more, more preferably to 2% by mass or more, even more preferably to 3% by mass or more, and even more preferably to 5% by mass or more. The term "a state in which the balance of ATP production and consumption is tilted towards consumption" refers to a pathological state (for example, in the presence of an uncoupling agent or in a hypoxic state, or in a state of accumulation of abnormal proteins). Furthermore, the "state in which the balance of ATP production and consumption is tilted towards consumption" refers to a state in which, if the intracellular ATP amount of a specific organ or tissue in a healthy person is set to 100, the ATP amount falls below 100 due to disease, etc. To express that this state is more tilted towards consumption, the ATP amount is 95 or less, to express that this state is more tilted towards consumption, the ATP amount is 90 or less, and to express that it is even more tilted towards consumption, the ATP amount is 80 or less. "Hypoxia" is another way of saying a state of oxygen deficiency, which refers to a state in which blood flow to the tissues of a living organism decreases for some reason, and oxygen is not sufficiently supplied to the tissues, and the intracellular ATP amount is also decreased. Diseases caused by the hypoxic state include circulatory failure (heart failure, cerebral infarction, etc.). "ATP enhancement effect performed in a hypoxic state" refers, as one embodiment, to restoring the decreased ATP amount in each of the aforementioned circulatory failure diseases. "Circulatory failure" is a disease in which blood flow to the tissues of a living organism decreases for some reason, and oxygen is not sufficiently supplied to the tissues. Examples of the aforementioned diseases include chronic heart failure, cerebral infarction, and cardiomyopathy. "Abnormal protein accumulation" refers to a condition in which proteins with abnormal conformations aggregate and accumulate in tissues, such as the accumulation of abnormal proteins within nerve cells.Diseases characterized by the aforementioned condition include, for example, neurodegenerative diseases, retinitis pigmentosa, and age-related macular degeneration. In one embodiment of the present invention, a pharmaceutical composition for intracellular ATP enhancement is effective in treating or preventing diseases, disorders, or syndromes (collectively referred to herein as "ATP-related diseases") such as hemolytic anemia, sickle cell disease, piruvate kinase deficiency, spherocytosis, ellipticosis, labial cell carcinoma, thalassemia, ischemic heart disease, heart failure, cardiovascular disorders, hypertension, tachycardia, arrhythmia, chronic progressive ophthalmoplegia syndrome, red ragweed, myoclonus. Epilepsy syndrome, mitochondrial encephalomyopathy, lactic acidosis, stroke-like syndrome, Leigh encephalopathy, mitochondrial cardiomyopathy, mitochondrial diabetes, Pearson's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, adenylosuccinate lyase deficiency, Alzheimer's disease, Lewy body dementia, frontotemporal dementia, retinitis pigmentosa, cone-rod dystrophy, Oguchi disease, white punctate fundus, paravenoretinal-choroidal atrophy, Leigh congenital blindness, cone dystrophy, Stargardt disease, Best's disease, familial exudative vitreoretinopathy, Wagner syndrome, Stickler syndrome, central ring-shaped choroidal dystrophy, choroideremia, gyral choroidal dystrophy, retinal degeneration secondary to uveitis, drug-induced (chloroquine, etc.) retinal damage, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, diabetic retinopathy, renal retinopathy, age-related macular degeneration, central serous chorioretinopathy, retinal white spot syndrome, retinal pigment streaks, and macular involvement. Examples include rhegmatogenous retinal detachment, macular hole, retinal schizophrenia, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment associated with high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, nasal optic neuropathy, demyelinating optic neuropathy (represented by multiple sclerosis), and toxic optic neuropathy (caused by ethambutol, methanol, thinner, etc.). Among these, retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, Leber's congenital blindness, or glaucoma are preferred. Furthermore, retinitis pigmentosa or age-related macular degeneration and glaucoma are optimal. In other words, one embodiment of the present invention, a pharmaceutical composition for intracellular ATP enhancement, can be applied to the treatment or prevention of the aforementioned diseases, disorders, or syndromes. In one embodiment of the present invention, it is preferable that the active ingredient of the pharmaceutical composition for enhancing intracellular ATP contains only a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, without the use of inosine, inosinic acid, hypoxanthine, or salts thereof. In another embodiment of the present invention, the active ingredient of the pharmaceutical composition for enhancing intracellular ATP may include inosine, inosinic acid, hypoxanthine, or salts thereof, and a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. By the way, hyperuricemia is a condition in which the level of uric acid in the blood is abnormally high. In hyperuricemia, some of the uric acid becomes undissolved and crystallizes. When this crystallized uric acid accumulates in the joints and causes inflammation, it becomes gouty arthritis, presenting with symptoms known as gout attacks, which are accompanied by severe pain. There are two types of hyperuricemia: hyperuricemia that presents with clinical symptoms such as gouty arthritis, and asymptomatic hyperuricemia that does not present with clinical symptoms such as gouty arthritis. The pharmaceutical compositions provided by the present invention may be administered to patients who need to enhance intracellular ATP, but since administration of the pharmaceutical compositions provided by the present invention may produce an effect of lowering uric acid levels in the blood, it is preferable to exercise caution when applying them to patients with gouty arthritis (for example, patients with gouty arthritis who have developed hyperuricemia), or patients with hyperuricemia who have experienced gout attacks, and even to asymptomatic patients with hyperuricemia. In this specification, when the terms “suppression of gout attacks,” “suppression of induction of gout attacks,” or “suppression of the occurrence of gout attacks” are used, for example, compared to a group receiving conventional uric acid-lowering drugs such as allopurinol or febuxostat or a placebo group, it means that the frequency or severity (e.g., the degree of pain, etc.) of “gout attacks” is reduced, preferably the frequency is reduced, and preferably includes the absence of “gout attacks.” Generally, when treating gouty arthritis patients to lower blood uric acid levels, uric acid-lowering drugs are administered after the gout attack has subsided (after the pain has stopped). However, administration should begin at a low dose and be gradually increased to slowly lower blood uric acid levels to the target level. This is because a rapid decrease in blood uric acid levels due to the administration of uric acid-lowering drugs accelerates the redissolution of urate crystals attached to the joint, making them more prone to detachment and thus inducing a gout attack. Gout attacks caused by a rapid decrease in uric acid levels due to uric acid-lowering drugs are known as mobilization flare-ups. The pharmaceutical composition provided by the present invention can exert an effect of gradually lowering blood uric acid concentration, and therefore can suppress acute gout attacks such as mobilization flare-ups caused by uric acid movement with no or less gradual increase in dosage. On the other hand, when using febuxostat, an XOR inhibitor, to treat gout, in Japan, it is recommended to start with 10 mg once daily, gradually increasing the dose to 20 mg once daily after 2 weeks, and then to 40 mg once daily after 6 weeks, in order to suppress the induction of gout attacks (mobilization flare-ups) caused by a rapid decrease in blood uric acid levels. In one embodiment, the pharmaceutical composition provided by the present invention does not require a gradual increase in the daily dose to suppress the occurrence of gout attacks (attacks caused by uric acid movement (mobilization flare-up)) associated with the start of administration, and the daily dose does not need to be increased for the first three weeks after the start of administration. In one embodiment, the pharmaceutical composition provided by the present invention does not require a gradual increase in the daily dose to suppress the occurrence of gout attacks (attacks caused by uric acid movement (mobilization flare-up)) associated with the start of administration. In fact, the daily dose may not be increased at all during the first seven weeks of administration, or the daily dose may be increased only once or less. The effect of gradually lowering blood uric acid levels, which can be achieved by administering the pharmaceutical composition provided by the present invention, can be achieved, for example, by orally administering a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof in an amount of 10 to 320 mg per day (e.g., 10 to 160 mg, 20 to 160 mg, 40 to 160 mg, 80 to 160 mg, 10 to 80 mg, 20 to 80 mg, 40 to 80 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg). Furthermore, blood uric acid levels may be gradually lowered by administering 10 to 320 mg per day (for example, 10 to 160 mg, 20 to 160 mg, 40 to 160 mg, 80 to 160 mg, 10 to 80 mg, 20 to 80 mg, 40 to 80 mg, 10 to 40 mg, 20 to 40 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg) of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof on a daily basis. For example, blood uric acid levels may be gradually lowered by administering it daily for 7 days or more (for example, 1 month, 2 months, or 3 months). In one embodiment, a pharmaceutical composition containing the compound represented by general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is administered orally to a patient in need of treatment at a dose of 10 to 320 mg per day, and optionally, the oral administration is continued for at least 7 days. Such an embodiment may gradually lower the patient's uric acid level without causing a rapid decrease, and thus may be useful in enhancing intracellular ATP while reducing the induction or severity of gout attacks. The effect of gradually lowering blood uric acid levels that can be achieved by administering the pharmaceutical composition provided by the present invention can be demonstrated, for example, by administering the pharmaceutical composition provided by the present invention to a healthy adult (e.g., male) for 7 consecutive days, measuring blood uric acid levels before and after administration, and finding that the maximum percentage decrease in blood uric acid level on day 1 of administration ([(pre-administration uric acid level - minimum post-administration uric acid level on day 1 of administration) / pre-administration uric acid level] × 100) is approximately 35% or less (e.g., a decrease of 1-35%, 10-30%). This can also be confirmed by the following: a decrease of 10-25%, a decrease of 10-20%, a decrease of 15-25%; and / or by the maximum percentage decrease in blood uric acid levels on day 7 of administration ([(pre-administration uric acid level - minimum post-administration uric acid level on day 7) / pre-administration uric acid level] × 100) being approximately 55% or less (for example, a decrease of 1-55%, a decrease of 10-50%, a decrease of 15-45%, a decrease of 20-45%, a decrease of 20-40%, a decrease of 20-35%). Blood uric acid levels (blood uric acid concentration) may be measured by a known uricase peroxidase method. In this specification, the time or period expressed as "from the start of administration" may be calculated starting from, for example, the time of the first administration of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof in a single treatment plan. Therefore, for example, "3 weeks after the start of administration" means the corresponding time 3 weeks after the first administration, and "7 weeks after the start of administration" means the corresponding time 7 weeks after the first administration. When the term "administration" is followed by a time or period, it refers to a point in time after the time or period has elapsed, with the time of administration as the starting point. For example, "12 hours after administration" means 12 hours after administration, and "7 days after administration" means 7 days after administration. In this specification, the term "period" is usually used for times defined in "days," "months," or "years." In this specification, the meaning of "day X of administration" can be determined from the context. For example, "day 1 of administration" may mean one day (24 hours) after the first administration in a treatment plan, the period immediately preceding one day (24 hours) after the first administration, or the period before and after one day (24 hours) after the first administration, for example, ±12 hours, preferably ±6 hours, more preferably ±2 hours. In this specification, "minimum post-administration uric acid level on day 1 of administration" means, for example, the lowest uric acid level measured by a known method when blood is collected from the subject every hour from the time of the first administration until 1 day (24 hours) after the first administration in one treatment plan. Also, "minimum post-administration uric acid level on day 7 of administration" means, for example, the lowest uric acid level measured by a known method when blood is collected from the subject every hour from 6 days (144 hours) after the first administration until 7 days after the first administration in one treatment plan. "Before administration" is preferably 12 hours before the first administration in one treatment plan, more preferably 6 hours before the first administration, even more preferably 2 hours before the first administration, and particularly preferably 1 hour before the first administration. Therefore, "pre-administration uric acid level" means, for example, the uric acid level measured by a known method after blood has been collected from the subject 12 hours before the first administration, preferably 6 hours before the first administration, more preferably 2 hours before the first administration, and even more preferably 1 hour before the first administration, in a single treatment plan. The content of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition provided by the present invention can be appropriately determined by those skilled in the art. For example, the content of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition provided by the present invention may be 10 to 320 mg (for example, 10 to 160 mg, 20 to 160 mg, 40 to 160 mg, 80 to 160 mg, 10 to 80 mg, 20 to 80 mg, 40 to 80 mg, 10 to 40 mg, 20 to 40 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg). The pharmaceutical composition provided by the present invention may be one dose unit. The content of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit may be, for example, 10 to 320 mg (e.g., 10 to 160 mg, 20 to 160 mg, 40 to 160 mg, 80 to 160 mg, 10 to 80 mg, 20 to 80 mg, 40 to 80 mg, 10 to 40 mg, 20 to 40 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg). The packaging form of the pharmaceutical composition provided by the present invention can be appropriately determined by those skilled in the art. Examples of packaging forms include plastic containers, glass containers, PTP sheets, etc. The pharmaceutical composition provided by the present invention may be provided as a package containing the number of dosage units of the pharmaceutical composition necessary for continuous administration for 5 to 15 days. For example, the pharmaceutical composition provided by the present invention may be provided as a PTP sheet containing 5 to 15 (e.g., 6, 7, 8, 10, 12, or 14) dosage units.

[0071] In this specification, "dosage unit" refers to a unit of the preparation, and "1 dose unit" refers to the smallest unit of the preparation. Therefore, for example, in the case of tablets, the dose unit is each tablet, and 1 dose unit represents one tablet. In the case of injectable preparations, the dose unit is the injectable preparation contained in a sealed container such as an ampoule or vial, and 1 dose unit represents the injectable preparation contained in a sealed container such as an ampoule or vial. When the pharmaceutical composition provided by the present invention is administered to a human or other mammal, one or more of the aforementioned administration units may be administered at a time, or one of the aforementioned administration units may be divided and administered in parts.

[0072] Other examples of embodiments of the present invention include the following. <1-1> A pharmaceutical composition containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof for use in enhancing intracellular ATP. <1-2> Hemolytic anemia, sickle cell disease, pirubate kinase deficiency, spherocytosis, ellipticosis, labial cell carcinoma, thalassemia, ischemic heart disease, heart failure, cardiovascular disorders, hypertension, tachycardia, arrhythmia, chronic progressive ophthalmoplegia syndrome, red ragweed, myoclonus epilepsy syndrome, mitochondrial encephalomyopathy, lactic acidosis, stroke-like syndrome, Leigh encephalopathy, mitochondrial cardiomyopathy, mitochondrial diabetes, Pearson's disease, amyotrophic lateral sclerosis Dementia palsy, Parkinson's disease, multiple sclerosis, adenylosuccinate lyase deficiency, Alzheimer's disease, Lewy body dementia, frontotemporal dementia, retinitis pigmentosa, cone-rod dystrophy, Oguchi disease, white punctate fundus, paravenoretinal atrophy of the retina pigmentosa, Leber congenital blindness, cone dystrophy, Stargardt disease, Best's disease, familial exudative vitreoretinopathy, Wagner syndrome, Stickler syndrome, central serous choroidal dystrophy, choroide Mia, gyrocotyleminal dystrophy, retinal degeneration secondary to uveitis, drug-induced (chloroquine, etc.) retinal damage, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, diabetic retinopathy, renal retinopathy, age-related macular degeneration, central serous chorioretinopathy, retinal white spot syndrome, retinal pigment streaks, rhegmatogenous retinal detachment extending to the macula, macular hole, retinal schizophrenia, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment associated with high myopia, Usher A pharmaceutical composition containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of ) syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, nasal optic neuropathy, demyelinating optic neuropathy (represented by multiple sclerosis), or toxic optic neuropathy (caused by ethambutol, methanol, thinner, etc.). <1-3> A pharmaceutical composition for use according to <1-1> or <1-2>, which suppresses the occurrence of a gout attack associated with the initiation of the aforementioned treatment or prevention. <1-4> A pharmaceutical composition for use according to any one of <1-1> to <1-3>, wherein a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is administered orally at a dose of 10 to 320 mg per day to a patient requiring enhancement of intracellular ATP, and the oral administration is optionally continued for at least 7 days. <1-5>R 1 A pharmaceutical composition for use as described in any one of <1-1> to <1-4>, wherein the phenyl group is either unsubstituted or phenyl group substituted with a halogen atom. A pharmaceutical composition for use as described in any one of <1-1> to <1-5>, wherein X is an oxygen atom. A pharmaceutical composition for use as described in any one of <1-1> to <1-6>, wherein Y is a sulfur atom. A pharmaceutical composition for use according to any one of <1-1> to <1-7>, wherein the compound or a pharmaceutically acceptable salt thereof described in any one of <1-8> to <1-1> to <1-7> contains an amorphous form, and the content of the amorphous form is 80% by weight or more of the total weight of the compound or a pharmaceutically acceptable salt thereof described in any one of <1-1> to <1-7>. A pharmaceutical composition for use according to any one of <1-1> to <1-8>, which is an enteric-coated preparation. <1-10> The pharmaceutical composition for use according to <1-9>, wherein the enteric-coated preparation is a hard capsule. <1-11>A pharmaceutical composition for use according to any one of <1-1> to <1-10>, further comprising a solid dispersion containing a hypromellose derivative. A pharmaceutical composition for use as described in <1-11>, wherein the weight ratio of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to a hypromellose derivative is 1:0.1 to 1:25. <1-13> A pharmaceutical composition for use according to <1-11> or <1-12>, wherein the hypromellose derivative is hypromellose acetate succinate or hypromellose phthalate. <1-14> A pharmaceutical composition for use as described in any one of <1-1> to <1-13>, which is a solid dosage form. A pharmaceutical composition for use as described in any one of <1-1> to <1-14>, wherein the content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is 10 mg to 320 mg. <1-16> A pharmaceutical composition for use as described in any one of <1-1> to <1-15>, wherein the content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit is 10 mg to 320 mg. <1-17> A pharmaceutical composition for use as described in any one of <1-1> to <1-16>, wherein the content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit is 10 mg to 160 mg. A pharmaceutical composition for use as described in any one of <1-1> to <1-17>, wherein the content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit is 10 mg to 80 mg. <1-19> A pharmaceutical composition for use as described in any one of <1-1> to <1-18>, wherein the content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit is 20 mg to 80 mg. A pharmaceutical composition for use as described in any one of <1-1> to <1-19>, which reduces the blood uric acid concentration by 0.5 to 2.0 mg / dL (e.g., 0.5 to 1.5 mg / dL) 12 hours after administration on the first day of administration compared to before administration. A pharmaceutical composition for use as described in any one of <1-1> to <1-20>, wherein continuous administration once a day for 7 days reduces the blood uric acid concentration 12 hours after administration on the 7th day of administration by 1.5 to 3.0 mg / dL (e.g., 1.5 to 2.5 mg / dL) compared to before administration. <1-22> A pharmaceutical composition for use according to any one of <1-1> to <1-21>, wherein the pharmaceutical composition is administered once daily in a continuous manner, and the daily dose of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is not increased from the start of administration to three weeks after administration. <1-23> A pharmaceutical composition for use according to any one of <1-1> to <1-22>, wherein the pharmaceutical composition is administered continuously once a day, and the daily dose of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is not increased or is increased once within 7 weeks from the start of administration. <1-24> A pharmaceutical composition for use as described in any one of <1-1> to <1-23>, wherein the pharmaceutical composition is administered continuously once a day, and the maximum reduction rate of blood uric acid levels on day 1 of administration ([(uric acid level before administration - minimum uric acid level after administration on day 1 of administration) / uric acid level before administration] × 100) is 10 to 25%. <1-25> A pharmaceutical composition for use as described in any one of <1-1> to <1-24>, wherein the pharmaceutical composition is administered once daily in a continuous manner, and the maximum reduction rate of blood uric acid levels on day 7 of administration ([(pre-administration uric acid level - minimum post-administration uric acid level on day 7 of administration) / pre-administration uric acid level] × 100) is 20-45%. A pharmaceutical composition for use according to any one of <1-1> to <1-25>, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof. A package comprising a pharmaceutical composition for use as described in any one of <1-27>, <1-1> to <1-26>, wherein the package contains a number of dosage units of the pharmaceutical composition necessary for continuous administration for 5 to 15 days. <1-28> An enhancer containing an XOR inhibitor as an active ingredient for use in enhancing ATP, ADP, GTP, or GDP in tissues, organs, or cells where the expression of the target enzyme XOR is substantially absent or low within the cell. <1-29> The enhancer for use according to <1-28>, wherein the XOR inhibitor is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, allopurinol, topiroxostat, or febuxostat. <1-30> The eyeball is an auger for use as described in <1-28> or <1-29>, wherein the expression of the target enzyme XOR is substantially absent or minimal in the eye. <1-31> The retina is a tissue in which the expression of the target enzyme XOR is substantially absent or in small amounts, and is an enhancer for use according to any one of <1-28> to <1-30>. <1-32> The optic nerve is a tissue in which the expression of the target enzyme XOR is substantially absent or low, and is an enhancer for use as described in any one of <1-28> to <1-30>. <1-33> An enhancer for use according to any one of <1-28> to <1-32>, wherein the enhancer further comprises an ATP precursor. <1-34> The enhancer for use according to <1-33>, wherein the ATP precursor is inosine and / or hypoxanthine. <1-35> A therapeutic and / or prophylactic agent containing an XOR inhibitor as an active ingredient for use in the treatment and / or prevention of ATP-related diseases in tissues, organs, tissues, or cells in which the expression of the target enzyme XOR is substantially absent or low within the cell. <1-36> The therapeutic and / or prophylactic agent for use according to <1-35>, wherein the XOR inhibitor is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, allopurinol, topiroxostat, or febuxostat. <1-37> Therapeutic and / or prophylactic agent for use as described in <1-35> or <1-36>, wherein the organ in which the expression of the target enzyme XOR is substantially absent or reduced is the eyeball. <1-38> Therapeutic and / or prophylactic agent for use according to any one of <1-35> to <1-37>, wherein the retina is a tissue in which the expression of the target enzyme XOR is substantially absent or low. <1-39> Therapeutic and / or prophylactic agent for use according to any one of <1-35> to <1-37>, wherein the optic nerve is a tissue in which the expression of the target enzyme XOR is substantially absent or low. <1-40> Therapeutic and / or prophylactic agent for use according to any one of <1-35> to <1-39>, wherein the ATP-related disease is an ATP-related eye disease. <1-41> The ATP-related eye diseases mentioned above include retinitis pigmentosa, cone-rod dystrophy, Oguchi disease, punctate fundus, paravenoretinal retinal atrophy, Leber congenital blindness, cone dystrophy, Stargardt disease, Best's disease, familial exudative vitreoretinopathy, Wagner syndrome, Stickler syndrome, central serous choroidal dystrophy, choroideremia, gyral choroidal dystrophy, retinal degeneration secondary to uveitis, drug-induced (including chloroquine) retinal disorders, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, diabetic retinopathy, renal retinopathy, age-related macular degeneration, and central serous A therapeutic and / or prophylactic agent for use as described in <1-40> for serous chorioretinopathy, retinal white spot syndrome, retinal pigment streaks, rhegmatogenous retinal detachment extending to the macula, macular hole, retinal schizophrenia, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment associated with high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, nasal optic neuropathy, demyelinating optic neuropathy (including multiple sclerosis), or toxic optic neuropathy (including ethambutol, methanol, and thinner). <1-42> A pharmaceutical composition containing an XOR inhibitor as an active ingredient for use in the treatment and / or prevention of ATP-related diseases in tissues, organs, tissues, or cells in which the expression of the target enzyme XOR is substantially absent or low within the cell. <1-43> The pharmaceutical composition for use according to <1-42>, wherein the pharmaceutical composition further comprises an ATP precursor. <1-44> A pharmaceutical composition for use according to <1-43>, wherein the ATP precursor is inosine and / or hypoxanthine.

[0073] <2-1> Use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof for the production of a pharmaceutical composition for enhancing intracellular ATP. <2-2> Hemolytic anemia, sickle cell disease, pirubate kinase deficiency, spherocytosis, ellipticosis, labial cell carcinoma, thalassemia, ischemic heart disease, heart failure, cardiovascular disorders, hypertension, tachycardia, arrhythmia, chronic progressive ophthalmoplegia syndrome, red ragweed, myoclonus epilepsy syndrome, mitochondrial encephalomyopathy, lactic acidosis, stroke-like syndrome, Leigh encephalopathy, mitochondrial cardiomyopathy, Leber's disease, mitochondrial diabetes, Pearson's disease, muscle Atrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, adenylosuccinate lyase deficiency, Alzheimer's disease, Lewy body dementia, frontotemporal dementia, retinitis pigmentosa, cone-rod dystrophy, Oguchi disease, white punctate fundus, paravenoretinal atrophy of the retina pigmentosa, Leber congenital blindness, cone dystrophy, Stargardt disease, Best's disease, familial exudative vitreoretinopathy, Wagner syndrome, Stickler syndrome, central serous choroidal dystrophy, Reederemia, gyrocotylemrine dystrophy, retinal degeneration secondary to uveitis, drug-induced (chloroquine, etc.) retinal damage, including retinal degenerative diseases, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, diabetic retinopathy, renal retinopathy, age-related macular degeneration, central serous chorioretinopathy, retinal white spot syndrome, retinal pigment streaks, rhegmatogenous retinal detachment extending to the macula, macular hole, retinal schizophrenia, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment associated with high myopia, Usher (Ah Use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of pharmaceutical compositions for the treatment or prevention of Shah syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, nasal optic neuropathy, demyelinating optic neuropathy (represented by multiple sclerosis), or toxic optic neuropathy (caused by ethambutol, methanol, thinner, etc.). <2-3> The use described in <2-1> or <2-2> to suppress the occurrence of a gout attack associated with the initiation of the aforementioned treatment or prevention. <2-4> The use described in any one of <2-1> to <2-3>, wherein a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is administered orally at a dose of 10 to 320 mg per day to a patient requiring enhancement of intracellular ATP, and the oral administration is continued for at least 7 days if desired. <2-5>R 1 However, the use described in any one of <2-1> to <2-4> is either an unsubstituted phenyl group or a phenyl group substituted with a halogen atom. <2-6> The use described in any one of <2-1> to <2-5>, wherein X is an oxygen atom. <2-7> The use described in any one of <2-1> to <2-6>, wherein Y is a sulfur atom. <2-8> The use described in any one of <2-1> to <2-7>, wherein the compound or pharmaceutically acceptable salt thereof described in any one of <2-1> to <2-7> contains amorphous material, and the content of said amorphous material is 80% by weight or more of the total weight of the compound or pharmaceutically acceptable salt thereof described in any one of <2-1> to <2-7>. <2-9> The use described in any one of <2-1> to <2-8>, wherein the pharmaceutical composition is an enteric-coated preparation. <2-10> The use described in <2-9>, wherein the enteric-coated preparation is a hard capsule. <2-11> The use according to any one of <2-1> to <2-10>, wherein the pharmaceutical composition further comprises a solid dispersion containing a hypromellose derivative. <2-12> The use described in <2-11>, wherein the weight ratio of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to the hypromellose derivative is 1:0.1 to 1:25. <2-13> Use according to <2-11> or <2-12>, wherein the hypromellose derivative is hypromellose acetate succinate or hypromellose phthalate. <2-14> Use according to any one of <2-1> to <2-13>, wherein the pharmaceutical composition is a solid dosage form. <2-15> Use as described in any one of <2-1> to <2-14>, wherein the content of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is 10 mg to 320 mg. <2-16> Use as described in any one of <2-1> to <2-15>, wherein the content of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit of the pharmaceutical composition is 10 mg to 320 mg. <2-17> The use described in any one of <2-1> to <2-16>, wherein the amount of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit of the pharmaceutical composition is 10 mg to 160 mg. <2-18> The use described in any one of <2-1> to <2-17>, wherein the content of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit of the pharmaceutical composition is 10 mg to 80 mg. <2-19> The use described in any one of <2-1> to <2-18>, wherein the amount of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit of the pharmaceutical composition is 20 mg to 80 mg. <2-20> The use described in any one of <2-1> to <2-19>, wherein the pharmaceutical composition reduces the blood uric acid concentration by 0.5 to 2.0 mg / dL (for example, 0.5 to 1.5 mg / dL) 12 hours after administration on the first day of administration compared to before administration. <2-21> The use described in any one of <2-1> to <2-20>, wherein the pharmaceutical composition is administered once a day for seven consecutive days, and the blood uric acid concentration 12 hours after administration on the seventh day of administration decreases by 1.5 to 3.0 mg / dL (for example, 1.5 to 2.5 mg / dL) compared to before administration. <2-22> The use described in any one of <2-1> to <2-21>, wherein the pharmaceutical composition is administered once a day on a continuous basis, and the daily dose of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is not increased from the start of administration until three weeks after administration. <2-23> The use according to any one of <2-1> to <2-22>, wherein the pharmaceutical composition is administered once daily in a continuous course, and the daily dose of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is not increased or is increased once within 7 weeks from the start of administration. <2-24> The use according to any one of <2-1> to <2-23>, wherein the pharmaceutical composition is administered once daily in a continuous course, and the maximum reduction rate of blood uric acid levels on day 1 of administration ([(pre-administration uric acid level - minimum post-administration uric acid level on day 1 of administration) / pre-administration uric acid level] × 100) is 10-25%. <2-25> The use described in any one of <2-1> to <2-24>, wherein the pharmaceutical composition is administered continuously once a day, and the maximum reduction rate of blood uric acid levels on day 7 of administration ([(uric acid level before administration - minimum uric acid level after administration on day 7 of administration) / uric acid level before administration] × 100) is 20-45%. The use described in any one of <2-1> to <2-25>, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof. Use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof for manufacturing a package containing a pharmaceutical composition described in any one of <2-27>, <2-1> to <2-26>, wherein the package contains a number of dose units of the pharmaceutical composition necessary for continuous administration for 5 to 15 days. <2-28> Use of XOR inhibitors to produce ATP, ADP, GTP, or GDP enhancers in tissues, organs, tissues, or cells in which the expression of the target enzyme XOR is substantially absent or faint. <2-29> The use according to <2-28>, wherein the XOR inhibitor is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, allopurinol, topiroxostat, or febuxostat. <2-30> The use described in <2-28> or <2-29>, wherein the organ in which the expression of the target enzyme XOR is substantially absent or low is the eyeball. <2-31> The use described in any one of <2-28> to <2-30>, wherein the retina is a tissue in which the expression of the target enzyme XOR is substantially absent or minimal. <2-32> The use described in any one of <2-28> to <2-30>, wherein the optic nerve is a tissue in which the expression of the target enzyme XOR is substantially absent or low. <2-33> The use according to any one of <2-28> to <2-32>, wherein the enhancer further comprises an ATP precursor. <2-34> The use according to <2-33>, wherein the ATP precursor is inosine and / or hypoxanthine. <2-35> Use of XOR inhibitors for the production of therapeutic and / or prophylactic agents for ATP-related diseases in tissues, organs, tissues, or cells in which the expression of the target enzyme XOR is substantially absent or faint. <2-36> The use according to <2-35>, wherein the XOR inhibitor is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, allopurinol, topiroxostat, or febuxostat. <2-37> The use described in <2-35> or <2-36>, wherein the organ in which the expression of the target enzyme XOR is substantially absent or low is the eyeball. <2-38> The use described in any one of <2-35> to <2-37>, wherein the retina is a tissue in which the expression of the target enzyme XOR is substantially absent or low. <2-39> The use described in any one of <2-35> to <2-37>, wherein the optic nerve is a tissue in which the expression of the target enzyme XOR is substantially absent or low. <2-40> The use described in any one of <2-35> to <2-39>, wherein the ATP-related disease is an ATP-related eye disease. <2-41> The ATP-related eye diseases include retinitis pigmentosa, cone-rod dystrophy, Oguchi disease, punctate fundus, paravenoretinal retinal atrophy, Leber congenital blindness, cone dystrophy, Stargardt disease, Best's disease, familial exudative vitreoretinopathy, Wagner syndrome, Stickler syndrome, central ossicular choroidal dystrophy, choroideremia, gyral choroidal dystrophy, retinal degeneration secondary to uveitis, drug-induced (including chloroquine) retinal disorders, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, diabetic retinopathy, renal retinopathy, and age-related jaundice. Use as described in <2-40> for macula degeneration, central serous chorioretinopathy, retinal white spot syndrome, retinal pigment streaks, rhegmatogenous retinal detachment extending to the macula, macular hole, retinal schizophrenia, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment associated with high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, nasal optic neuropathy, demyelinating optic neuropathy (including multiple sclerosis), or toxic optic neuropathy (including ethambutol, methanol, and thinner). <2-42> Use of XOR inhibitors for the manufacture of pharmaceutical compositions for the treatment and / or prevention of ATP-related diseases in tissues, organs, tissues, or cells in which the expression of the target enzyme XOR is substantially absent or faint. <2-43> The use according to <2-42>, wherein the pharmaceutical composition further comprises an ATP precursor. <2-44> The use according to <2-43>, wherein the ATP precursor is inosine and / or hypoxanthine.

[0074] Other examples of the embodiment of the present invention include ATP, ADP, GTP, or GDP enhancers containing an XOR inhibitor as an active ingredient in tissues, organs, tissues, or cells in which the expression of the target enzyme XOR is substantially absent or low. The XOR inhibitor can enhance ATP, ADP, GTP, or GDP in such tissues, organs, tissues, or cells, thereby increasing the energy charge (EC) value, and thereby increasing the cell viability and suppressing cell death in such tissues, organs, tissues, or cells.

[0075] The fact that XOR expression is substantially absent or low can be investigated using known techniques, such as genetic engineering methods (RT-PCR, Northern blotting, microarray), as well as immunohistochemical methods and biochemical methods (measurement of enzyme activity) as shown in the examples of this application. In the present invention, "substantially no XOR expression is observed" means that the amount of XOR expression cannot be detected by the method described above, and "low XOR expression" means, for example, that the enzyme activity in the lysate is 0.1 nmole uric acid / min / mg protein or less, or 0.05 nmole uric acid / min / mg protein or less, or that the RNA expression level at the Xanthine dehydrogenase (XDH) site of the known database "THE HUMAN PROTEIN ATLAS" (https: / / www.proteinatlas.org / ENSG00000158125-XDH / tissue) is GTEx value 1, 0.8, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 nTPN or less, or that the FANTOM5 value 1, 0.8, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 Scaled Tags Per Million or less. The eyeball is an example of an organ in which the expression of the target enzyme XOR is virtually absent or minimal within the cell. The retina and optic nerve are examples of tissues in which the expression of the target enzyme XOR is virtually absent or minimal within the cell.

[0076] In the present invention, "XOR inhibitor" means a compound that inhibits the target enzyme XOR. Examples of XOR inhibitors include the compound represented by general formula (I) or its pharmaceutically acceptable salt, allopurinol, topiroxostat, and febuxostat.

[0077] The ATP, ADP, GTP, or GDP enhancers of the present invention may further contain an ATP precursor. The ATP precursor can be used directly or indirectly in the purine salvage pathway to enhance the effect of the XOR inhibitor as an enhancer. Examples of ATP precursors include hypoxanthine and inosine, and the ATP precursor may act separately from the XOR inhibitor.

[0078] Other examples of the embodiment of the present invention include therapeutic and / or prophylactic agents for ATP-related diseases in tissues, organs, tissues, or cells in which the expression of the target enzyme XOR is substantially absent or faint, and which contain an XOR inhibitor as an active ingredient.

[0079] Examples of embodiments of the present invention include a therapeutic and / or prophylactic agent for ATP-related eye diseases containing an XOR inhibitor as an active ingredient. Examples of ATP-related eye diseases include diseases that cause damage to the retina or optic nerve, specifically, retinitis pigmentosa, cone-rod dystrophy, Oguchi disease, white punctate fundus, paravenopleural retinal atrophy, Leber congenital blindness, cone dystrophy, Stargardt disease, Best's disease, familial exudative vitreoretinopathy, Wagner syndrome, Stickler syndrome, centrally serous choroidal dystrophy, choroideremia, gyral choroidal dystrophy, retinal degeneration secondary to uveitis, retinal degenerative diseases including drug-induced (including chloroquine) retinal damage, retinal vein occlusion, retinal artery occlusion, and hypertensive network Examples include optic neuropathy, diabetic retinopathy, renal retinopathy, age-related macular degeneration, central serous chorioretinopathy, retinal white spot syndrome, retinal pigment streaks, rhegmatogenous retinal detachment extending to the macula, macular holes, retinal schizophrenia, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment associated with high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, nasal optic neuropathy, demyelinating optic neuropathy (including multiple sclerosis), and toxic optic neuropathy (including ethambutol, methanol, and paint thinner).

[0080] The method of administering the XOR inhibitor of the present invention can be appropriately selected for each disease. For example, for ATP-related eye diseases, oral administration, such as in tablet form, is preferred, but the invention is not limited thereto. In the present invention, it has been found that oral administration of the XOR inhibitor increases the amount of hypoxanthine and inosine in the body, such as in the liver, and that the hypoxanthine and inosine that have entered the bloodstream cross the blood-retinal barrier and increase ATP in the eyeball.

[0081] The XOR inhibitor of the present invention may be a pharmaceutical composition, and pharmaceutically acceptable additives may be added as needed. For example, a pharmaceutical composition containing the XOR inhibitor of the present invention as an active ingredient can be produced by appropriately combining and adding the required amount of binders, disintegrants, excipients, lubricants, etc. The pharmaceutical composition can be produced as a pharmaceutical in an appropriate dosage form such as tablets, capsules, granules, powders, eye drops, mouthwashes, ointments, creams, gels, patches, liniments, tapes, poultices, injections, or suppositories, according to conventional methods in the pharmaceutical art.

[0082] Examples of the binders include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, gelatin, agar, alginic acid, sodium alginate, partially saponified polyvinyl alcohol, pullulan, partially pregelatinized starch, dextrin, xanthan gum, and acacia powder. These may be used individually or as a mixture of two or more. Among these, hydroxypropylcellulose, hypromellose, or polyvinylpyrrolidone are preferred.

[0083] Examples of the disintegrants include crystalline cellulose, carboxymethylcellulose (also known as carmellose), croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, crospovidone, hydroxypropyl starch, starch, partially pregelatinized starch, and sodium starch glycolate. These may be used individually or as a mixture of two or more.

[0084] The excipient can be incorporated into any of the following processes of the pharmaceutical preparation: the mixing process, the granulation process, or the post-granulation finishing process. Examples of the excipient include celluloses such as crystalline cellulose, ethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and hydroxypropyl methylcellulose (also known as hypromellose); starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, and hydroxypropyl starch; sugars such as glucose, lactose, sucrose, refined sucrose, powdered sugar, trehalose, dextran, and dextrin; sugar alcohols such as D-mannitol, xylitol, sorbitol, and erythritol; inorganic salts such as glycerin fatty acid esters, magnesium aluminometasilicate, synthetic hydrotalcite, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium hydrogen phosphate hydrate, and sodium bicarbonate.

[0085] Examples of the lubricant include stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, light anhydrous silicic acid, hydrogenated oil, glycerin fatty acid ester, and talc, which may be used individually or as a mixture of two or more.

[0086] The dose of the XOR inhibitor should be an effective dose, and may be 10-320 mg per day of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, 50-800 mg of allopurinol, 40-160 mg of topiroxostat, or 10-80 mg of febuxostat, administered orally or parenterally. If desired, the administration may be continued for at least 7 days, 10 days, 18 days, 1 month, 3 months, 6 months, or 1 year.

[0087] The pharmaceutical composition containing the XOR inhibitor may further contain an ATP precursor, such as hypoxanthine and inosine. The dose of the ATP precursor can be any effective amount, for example, 0.5 to 4.0 g per day, administered orally or parenterally. The ATP precursor may also be administered separately from the XOR inhibitor. [Examples]

[0088] The present invention will be described in more detail below with reference to examples, reference examples, comparative reference examples, and test examples, but the present invention is not limited thereto. <Reference Example 1a and Comparative Reference Example 1a: Manufacturing of Enteric-Coated Capsules> 9 g of compound 14 (2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine) was dissolved in 1936 g of a mixed solvent of tetrahydrofuran (sometimes abbreviated as THF), ethanol, and water (weight ratio: THF / ethanol / water = 1600.5 / 254.5 / 81) (dissolved by slightly warming). This mixture was then pumped into a spray dryer at a rate of approximately 5 mL / min via a peristaltic pump, and dispensed through a two-fluid nozzle (diameter 508 μm) at an inlet temperature of 80°C, an outlet temperature of approximately 60°C, and a dry air volume of 0.30 m³. 3 / min, and nozzle spray air pressure of 1.0 kgf / cm². 2 The material was spray-dried and granulated under the specified conditions. The resulting dried material was left at room temperature overnight to obtain 100% amorphous compound 14. The amorphous volume-average particle size (D50) of compound 14 was measured by adding approximately 2 mg of the sample to a 0.2% Aerosol OT aqueous solution, dispersing it by irradiating it with ultrasound for 30 seconds, and then measuring the dispersion using a Shimadzu SALD-2200 laser diffraction particle size distribution analyzer. Shimadzu WingSALD-2200 version 1.02 software was used for data acquisition and analysis. The amorphous particle size distribution of compound 14 is shown in Figure 1. The amorphous volume-average particle size (D50) of compound 14, determined from the particle size distribution, was 2.949 μm. The amorphous form of compound 14 was filled into 40 mg of each capsule shown in Table 2A to obtain amorphous capsules of compound 14. [Table 2A]

[0089] <Test Example 1a: Absorption of Amorphous Compound 14 in Dogs> Beagle dogs (1-5 years old, Kitayama Labes Co., Ltd.) that had fasted from the evening before administration were given one capsule each (40 mg / body as compound 14) as a single oral dose in a crossover design with a one-week interval between administrations, using the capsule formulations of Reference Example 1a and Comparative Reference Example 1a. Blood samples were collected from the cephalic vein on the lateral side of the leg at pre-administration, and 0.5, 1, 3, 5, 8, and 24 hours after administration. The obtained blood was centrifuged at 10000 × g at 4°C for 5 minutes to obtain plasma. The concentration of compound 14 in this plasma was measured by HPLC (Osaka Soda Co., Ltd.). Since dogs generally have a high gastric pH, the gastric acid secretion stimulant pentagastrin was administered intramuscularly at a dose of 0.01 mg / kg 30 minutes and immediately before capsule administration. Subsequently, the pH of the gastric solution was measured to confirm that the gastric pH was low before administering the capsule samples. A plasma drug concentration-time curve was created from the obtained measurements. The results are shown in Figure 2. The drug concentrations in the figure represent the mean ± standard deviation of the four samples. When the enteric-coated capsule of Reference Example 1a was used, a higher drug concentration was observed compared to when the ordinary gastric-soluble capsule without enteric coating of Comparative Reference Example 1a was used. This indicates that the absorption of the amorphous compound 14 is improved by making it enteric-coated.

[0090] <Test Example 2a: Evaluation of the amorphous state of compound 14 (powder X-ray diffraction)> Since it is extremely important that amorphous materials retain their amorphous properties even after storage over time, the amorphous state of compound 14 from Reference Example 1a was stored at room temperature in a light-shielded and airtight container, and the change in the amorphous state of compound 14 was evaluated using an X-ray diffractometer (D2 Phaser, Bruker). The results are shown in Figures 4(a) to (d). For comparison, Figure 3 shows the powder X-ray diffraction of the crystalline compound 14. When the capsule formulation of Reference Example 1a was stored at room temperature in a light-shielded and airtight container, no change in the daily powder X-ray diffraction pattern of compound 14 was observed during the four-week storage period.

[0091] <Reference Example 1b and Comparative Reference Examples 1b-9b. Preparation of Solid Dispersion (Polymer, 25x Amount)> 250 mg of compound 14 was dissolved in tetrahydrofuran to make 100 mL. 125 mg of each polymer shown in Table 2B was dissolved in 5 mL of a mixed solution (dichloromethane / methanol = 50 / 15). 2 mL of the compound 14 solution was placed in a test tube, 5 mL of the above polymer solution was added, and the mixture was homogenized using a vortex mixer. Samples without added polymer were also prepared (Comparative Reference Example 9b). After removing the solvent from these samples by blowing a nitrogen stream, the samples were dried under reduced pressure overnight to obtain solid dispersion samples of compound 14. The HPMCAS used in Reference Example 1b is of the MF type (i.e., the substitution ratio per monomer unit is methoxy group: 21.0-25.0%, hydroxypropoxyl group: 5.0-9.0%, acetyl group: 7.0-11.0%, succinoyl group: 10.0-14.0%, viscosity: 2.4-3.6 mPa·s).

[0092] [Table 2B]

[0093] <Test Example 1b. Solubility Test> To the solid dispersions of Reference Example 1b and Comparative Reference Examples 1b-8b, and the sample of Comparative Reference Example 9b, 5 mL of either Solution 1 (pH 1.2) or Solution 2 (pH 6.8) of the Japanese Pharmacopoeia Dissolution Test was added. The solid dispersions were then pulverized with a glass rod or spatula and shaken at 37°C for 2 hours. 600 μL of the sample solution filtered through a 0.45 μm filter was immediately mixed with 400 μL of a mixed solution (acetonitrile / water = 3 / 2), and the concentration of compound 14 in the sample solution was measured by HPLC (Shimadzu Corporation). The results are shown in Table 3B. The values ​​in the table are the average of two repeated measurements.

[0094] [Table 3B] In comparative reference example 9b, the solubility of compound 14 was 0.39 μg / mL in the first solution and 0.49 μg / mL in the second solution. However, in reference example 1b, comparative reference examples 3b and 4b, the solubility increased to 5.0 μg / mL or higher. In particular, in the first solution under acidic conditions, Eudragit E-100, a basic polymer from comparative reference example 3b, was highly effective in improving the solubility of compound 14, while in the second solution under neutral conditions, HPMCAS, an acidic polymer from reference example 1b, was highly effective in improving the solubility of compound 14.

[0095] <Reference Example 2b, Comparative Reference Examples 10b and 11b. Production of Solid Dispersion (Polymer, 25x Quantity)> Compound 14 was dissolved in tetrahydrofuran to prepare a concentration of 2.5 mg / mL. Each polymer shown in Table 4B was dissolved in a mixed solvent (methanol / dichloromethane = 3 / 4) to prepare a concentration of approximately 45 mg / mL. Compound 14 solution was added to the polymer solution while stirring so that the weight ratio of compound 14 to polymer was 1:25. Samples without added polymer were also prepared. The samples were immediately transferred to round-bottom flasks, and the organic solvent was removed using a rotary evaporator (N-1100, Tokyo Rikakikai Co., Ltd.). The round-bottom flasks were transferred to a desiccator and dried under reduced pressure using a vacuum pump for approximately 16 hours to obtain a solid dispersion of compound 14. After drying, the solid dispersion was pulverized in an agate mortar or a portable high-speed grinder (LM-PLUS, Osaka Chemical Co., Ltd.), and then sieved (mesh size: 150 μm).

[0096] [Table 4B]

[0097] <Test Example 2b. Absorption of a solid dispersion of compound 14 in rats> Under fasting conditions, male rats (8 weeks old, Crl:CD(SD), Charles River Co., Ltd.) were orally administered a single dose of compound 14 at a dose of 10 mg / kg or 30 mg / kg using solid dispersions of Reference Example 2b and Comparative Reference Example 10b suspended in 1% carboxymethylcellulose aqueous solution, and the sample of Comparative Reference Example 11b. As a control, the crystalline active pharmaceutical ingredient of compound 14 was used (Comparative Reference Example 12b). Blood samples were collected at 0.5, 1, 2, 4, 8, and 24 hours after administration, with approximately 300 μL collected from the tail vein at each time point (n=3). The obtained blood was centrifuged at 1500 × g at 4°C for 15 minutes to obtain plasma. The concentration of compound 14 in this plasma was measured by HPLC (Shiseido Co., Ltd. and Hitachi High-Technologies Corporation). From the obtained plasma concentration profile, the time to reach peak plasma concentration (T) was calculated. max ), maximum plasma concentration (C max The area under the plasma concentration-time curve (AUC) was calculated. The results are shown in Table 5B. The values ​​in the table are the mean ± standard deviation of the three cases. The solid dispersions of Reference Example 2b and Comparative Reference Example 10b, and the sample of Comparative Reference Example 11b, have a C content compared to the active pharmaceutical ingredient. max Compound 14 showed high absorption improvement effects in both AUC, indicating that its absorption properties can be improved by amorphous and further by solid dispersion. Furthermore, the solid dispersion with HPMCAS showed a higher absorption improvement effect than the solid dispersion with Eudragit.

[0098] [Table 5B]

[0099] <Reference Examples 3b, 4b, and 5b. Production of Solid Dispersion (Polymer, 25x Quantity)> Compound 14 was dissolved in tetrahydrofuran to prepare a concentration of 2.5 mg / mL. Each polymer shown in Table 6B was dissolved in a mixed solvent (methanol / dichloromethane = 3 / 4) to prepare a concentration of approximately 45 mg / mL. After mixing compound 14 and the polymers in a weight ratio of 1:25, the solvent was removed by distillation at approximately 50°C under reduced pressure using a rotary evaporator (N-1100, Tokyo Rikakikai Co., Ltd.). The resulting primary dried product was further dried secondary using a vacuum pump (room temperature / overnight), and the secondary dried product was pulverized as appropriate using a portable high-speed pulverizer (LM-PLUS, Osaka Chemical Co., Ltd.) and then sieved (mesh opening: 300 μm). The HPMCAS used in Reference Example 3b is of the LG type (i.e., the substitution ratio per monomer unit is methoxy group: 20.0-24.0%, hydroxypropoxyl group: 5.0-9.0%, acetyl group: 5.0-9.0%, succinoyl group: 14.0-18.0%, viscosity: 2.4-3.6 mPa·s). The HPMCAS used in Reference Example 4b is of the MG type (i.e., the substitution ratio per monomer unit is methoxy group: 21.0-25.0%, hydroxypropoxyl group: 5.0-9.0%, acetyl group: 7.0-11.0%, succinoyl group: 10.0-14.0%, viscosity: 2.4-3.6 mPa·s). The HPMCAS used in Reference Example 5b is of the HG type (i.e., the substitution ratio per monomer unit is methoxy group: 22.0-26.0%, hydroxypropoxyl group: 6.0-10.0%, acetyl group: 10.0-14.0%, succinoyl group: 4.0-8.0%, viscosity: 2.4-3.6 mPa·s).

[0100] [Table 6B]

[0101] <Test Example 3b. Absorption of a solid dispersion of compound 14 in rats> Under fasting conditions, male rats (7-9 weeks old, Crl:CD(SD), Charles River Japan Co., Ltd.) were orally administered a single dose of 10 mg / kg of solid dispersions of Reference Examples 3b, 4b, and 5b, suspended in a 1% carboxymethylcellulose aqueous solution, as compound 14. Blood samples were collected at 0.5, 1, 2, 4, 8, and 24 hours after administration, with approximately 300 μL collected from the tail vein at each time point (n=3). The obtained blood was centrifuged at 1500 × g at 4°C for 15 minutes to obtain plasma. The concentration of compound 14 in this plasma was measured by HPLC (Shiseido Co., Ltd. and Hitachi High-Technologies Corporation). From the obtained plasma concentration profiles, the time to reach peak plasma concentration (T) was calculated. max ), maximum plasma concentration (C max The area under the plasma concentration-time curve (AUC) was calculated. The results are shown in Table 7B. The values ​​in the table are the mean ± standard deviation of the three cases. In the solid dispersion of Reference Example 4b, C max Both AUC and γ showed the highest plasma concentrations.

[0102] [Table 7B]

[0103] <Reference Examples 6b-12b. Preparation of Solid Dispersion (HPMCAS-MG, 1-10 times the amount)> Compound 14 was dissolved in tetrahydrofuran to prepare a concentration of 2.5 mg / mL. HPMCAS-MG was dissolved in a mixed solvent (ethanol / water = 4 / 1) to prepare a concentration of approximately 45 mg / mL. Compound 14 and the polymer shown in Table 8B were mixed so that the weight ratio was 1:1 to 1:10. The mixture was then pumped through a peristaltic pump at a rate of approximately 5 mL / min into a spray dryer (GB22, Yamato Scientific Co., Ltd.), and dispensed through a two-fluid nozzle (diameter 406 or 508 μm) at an inlet temperature of 80°C, an outlet temperature of approximately 60°C, and a dry air volume of 0.32 to 0.47 m³. 3 / min, nozzle spray air pressure 1.0 to 3.1 kgf / cm² 2 Spray drying and granulation were initiated under these conditions. The obtained primary dried material was further subjected to secondary drying using a vacuum pump (room temperature / overnight or room temperature / overnight - 40°C / 1 day) and sieved (mesh size: 300 μm).

[0104] [Table 8B]

[0105] <Test Example 4b. Absorption of a solid dispersion of compound 14 in rats> Under fasting conditions, male rats (7-9 weeks old, Crl:CD(SD), Charles River Japan Co., Ltd.) were orally administered a single dose of 10 mg / kg of the solid dispersions of Reference Examples 6b-8b and 10b-12b, suspended in a 1% carboxymethylcellulose aqueous solution, as compound 14. Blood samples were collected at 0.5, 1, 2, 4, 8, and 24 hours after administration, with approximately 300 μL collected from the tail vein at each time point (n=3). The obtained blood was centrifuged at 1500 × g at 4°C for 15 minutes to obtain plasma. The concentration of compound 14 in this plasma was measured by HPLC (Shiseido Co., Ltd. and Hitachi High-Technologies Corporation). From the obtained plasma concentration profiles, the time to reach peak plasma concentration (T) was calculated. max ), maximum plasma concentration (C max The area under the plasma concentration-time curve (AUC) was calculated. The results are shown in Table 9B. The values ​​in the table are the mean ± standard deviation of the three cases. In the solid dispersions of Reference Examples 6b-8b and 10b-12b, plasma concentrations increased in a weight-ratio-dependent manner when the weight ratio of HPMCAS-MG to compound 14 was 1, 2, and 3 times, but no weight-ratio-dependent differences in plasma concentrations were observed in the range of 4, 5, and 10 times.

[0106] [Table 9B]

[0107] <Test Example 5b. Evaluation of the amorphous state of the solid dispersion of compound 14 (powder X-ray diffraction)> Since it is extremely important that solid dispersions retain their amorphous properties even after storage over time, the solid dispersions of Reference Examples 9b to 11b were stored at 40°C / 75%RH under open conditions, and the change in the amorphous state was evaluated using an X-ray diffractometer (D2 Phaser, Bruker). The results are shown in Figures 5 to 7. When the solid dispersions of Reference Examples 9b to 11b were stored at 40°C / 75%RH under open conditions, no changes in the powder X-ray diffraction pattern over time were observed during the 7-week storage period.

[0108] <Test Example 6b. Evaluation of the amorphous state of the solid dispersion of compound 14 (absorption in rats)> The solid dispersions of Reference Examples 9b to 11b were stored at 40°C / 75%RH under open conditions, and the change in amorphous state was evaluated by rat absorption. Under fasting conditions, male rats (7-9 weeks old, Crl:CD(SD), Charles River Co., Ltd.) were orally administered a single dose of compound 14 at doses of 10 and 30 mg / kg, consisting of the solid dispersions of Reference Examples 9b-11b suspended in a 1% carboxymethylcellulose aqueous solution. Blood samples were collected from the tail vein at 0.5, 1, 2, 4, 8, and 24 hours after administration, with approximately 300 μL collected at each time point (n=3). The obtained blood was centrifuged at 1500 × g at 4°C for 15 minutes to obtain plasma. The concentration of compound 14 in this plasma was measured by HPLC (Shiseido Co., Ltd. and Hitachi High-Technologies Corporation). From the obtained plasma concentration profiles, the time to reach peak plasma concentration (T) was calculated. max ), maximum plasma concentration (C max The area under the plasma concentration-time curve (AUC) was calculated. The results are shown in Table 10B. The values ​​in the table are the mean ± standard deviation of the three cases. When the solid dispersions of Reference Examples 9b to 11b were stored open at 40°C / 75%RH, no decrease in plasma concentration over the course of the 7 weeks of storage examined was observed.

[0109] [Table 10B]

[0110] <Test Example 7b. Effect of Solid Dispersion of Compound 14 on Lowering Plasma Uric Acid Levels in Rats> Under fasting conditions, male rats (8 weeks old, Crl:CD(SD), Charles River Japan Co., Ltd.) were orally administered a single dose of 30 mg / kg of a solid dispersion of Reference Example 11b suspended in a 1% carboxymethylcellulose aqueous solution as compound 14. A 1% carboxymethylcellulose aqueous solution was used as a control. Blood samples were collected from the tail vein at 0 (before administration) and 2, 6, 12, and 24 hours (24 hours after administration), with approximately 300 μL collected at each time point (n=5). The obtained blood was centrifuged at 1500 × g at 4°C for 15 minutes to obtain plasma. The uric acid concentration in this plasma was measured by HPLC (Hitachi High-Technologies Corporation). Welch's t-test was performed on the plasma uric acid levels at each time point for the control group and Reference Example 11b. The significance level was set at p<0.05 (two-sided). The results are shown in Figure 8. The plasma uric acid levels after administration of the solid dispersion in Reference Example 11b were significantly lower compared to the control group, and its uric acid-lowering effect was sustained.

[0111] <Reference Examples 13b and 14b. Production of Solid Dispersion (3x HPMCAS-MG, 0.03x surfactant)> Compound 14 was dissolved in tetrahydrofuran to prepare a concentration of 2.5 mg / mL. HPMCAS-MG was dissolved in a mixed solvent (ethanol / water = 4 / 1) to prepare a concentration of approximately 45 mg / mL. Compound 14, the polymer shown in Table 11B, and the surfactant (polysorbate 80: Tween 80, sodium lauryl sulfate: SLS) were mixed in a weight ratio of 1:3:0.03. The mixture was then pumped via a peristaltic pump at a rate of approximately 5 mL / min into a spray dryer (GB22, Yamato Scientific Co., Ltd.), and dispensed through a two-fluid nozzle (diameter 406 or 508 μm) at an inlet temperature of 80°C, an outlet temperature of approximately 60°C, and a dry air volume of 0.32 to 0.47 m³. 3 / min, nozzle spray air pressure 1.0 to 3.1 kgf / cm² 2 Spray drying and granulation were initiated under these conditions. The obtained primary dried material was further subjected to secondary drying using a vacuum pump (room temperature / overnight or room temperature / overnight - 40°C / 1 day) and sieved (mesh size: 300 μm).

[0112] [Table 11B]

[0113] <Test Example 8b. Absorption of a solid dispersion of compound 14 in rats> Under fasting conditions, male rats (7-9 weeks old, Crl:CD(SD), Charles River Co., Ltd.) were orally administered a single dose of 10 mg / kg of solid dispersions of Reference Examples 13b and 14b, suspended in a 1% carboxymethylcellulose aqueous solution, as compound 14. Blood samples were collected at 0.5, 1, 2, 4, 8, and 24 hours after administration, with approximately 300 μL collected from the tail vein at each time point (n=3). The obtained blood was centrifuged at 1500 × g at 4°C for 15 minutes to obtain plasma. The concentration of compound 14 in this plasma was measured by HPLC (Shiseido Co., Ltd. and Hitachi High-Technologies Corporation). From the obtained plasma concentration profiles, the time to reach peak plasma concentration (T) was calculated. max ), maximum plasma concentration (C max The area under the plasma concentration-time curve (AUC) was calculated. The results, along with Reference Example 8b, are shown in Table 12B. The values ​​in the table are the mean ± standard deviation of the three cases. In the solid dispersions of Reference Examples 13b and 14b, no difference was observed compared to the plasma concentration of Reference Example 8b, which did not contain a surfactant.

[0114] [Table 12B]

[0115] <Reference example 14> Six healthy adult males were repeatedly administered compound 14 at a dose of 80 mg once daily for 7 days using the solid dispersion capsule formulation example 1, and the effect of reducing serum uric acid levels was examined. For comparison, the results are shown in Figure 9, along with an example using febuxostat (40 mg) described in Non-Patent Literature 3. As a result, with febuxostat, the maximum reduction in serum uric acid levels reached approximately 35% on day 1 (approximately 15 hours after administration), showing a rapid decrease in serum uric acid levels. In contrast, with compound 14, the maximum reduction in serum uric acid levels on day 1 was approximately 17% (12 hours after administration), indicating a milder reduction in serum uric acid levels. Subsequently, serum uric acid levels gradually decreased over time throughout the administration period, reaching a maximum reduction of approximately 30% on day 7 (approximately 8 hours after administration). Based on these results, compound 14 is expected to prevent gout attacks or reduce the frequency of gout attacks. Furthermore, when compound 14 was repeatedly administered at a dose of 20 mg once daily for 7 days using the solid dispersion capsule of formulation example 1, serum uric acid levels gradually decreased over time throughout the administration period, similar to the results for 80 mg once daily as described above. Serum uric acid levels 24 hours after the final administration were approximately 10-20% lower than the serum uric acid levels before administration (initial value). Furthermore, when compound 14 was administered repeatedly at a dose of 40 mg once daily for 7 days using capsules containing the finely powdered compound 14 (not solid dispersion capsules), serum uric acid levels gradually decreased over time throughout the administration period, similar to the results obtained when using the solid dispersion capsules described above.

[0116] <Reference example 15> Oxonic acid-induced hyperuricemia rats were repeatedly administered compound 14, suspended in a 1% methylcellulose aqueous solution, at a dose of 0.3 mg / kg once daily for 28 days under non-fasting conditions. A 1% methylcellulose aqueous solution was used as a control, and febuxostat was used as a positive control. (Creation of oxonate-induced hyperuricemia rats) Male Crl:CD(SD) rats (manufactured by Charles River Japan) were used. The rats were purchased at 6 weeks of age, and treatment was started at 7 weeks of age. Potassium oxonate was prepared by adding 10 g of potassium oxonate (Sigma-Aldrich Corp., Lot No. 03810HD) to 200 mL of 1% methylcellulose (1% MC) and suspending it in a mixer. After suspension, the solution was kept warm in a water bath at approximately 37°C until immediately before administration. The above preparation was performed fresh for each use. Oxonate-induced hyperuricemia rats were prepared by subcutaneously administering potassium oxonate (suspended in 1% methylcellulose aqueous solution) at a dose of 250 mg / kg 2.5 hours before each blood collection on days 1, 7, 14, 21, and 28 of administration. (Test method) Blood samples were collected from the tail vein at approximately 300 μL per time point on days 1, 7, 14, 21, and 28 of administration, one hour prior to administration and two and six hours after administration (n=7). The collected blood was centrifuged at 1500 × g at 4°C for 15 minutes to obtain plasma. The uric acid concentration in this plasma was measured by HPLC (Shiseido Co., Ltd., now Osaka Soda Co., Ltd.). Furthermore, in order to obtain data for Predose values ​​and group classification, all rats were orally administered a 1% methylcellulose aqueous solution 5 days before the start of administration, and plasma uric acid concentrations were measured according to the aforementioned method, including subcutaneous administration of potassium oxonate. The mean and standard deviation of plasma uric acid levels and the area under the concentration-time curve of plasma uric acid levels up to 6 hours after administration (plasma uric acid AUC(-1) to 6hr) were calculated. Furthermore, for each administration day, the percentage change (%) of plasma uric acid levels from AUC(-1) to 6hr in each individual group treated with compound 14 and febuxostat relative to the mean of the control group was determined, and the mean and standard deviation were calculated. In addition, paired t-tests were performed for the percentage change on day 1 and from day 7 onwards in each group. (result) The results are shown in Figure 10. In the compound 14 administration group, the rate of change in plasma uric acid level AUC(-1) to 6 compared to the control group increased with repeated administration, but no clear increase was observed in the febuxostat administration group. This supports the idea that compound 14 sustainably inhibits xanthine oxidoreductase compared to febuxostat.

[0117] <Example 1: ATP-enhancing effect under hypoxic conditions> The examples used MOVAS-1 cells exhibiting XOR activity. Each study consisted of n=3 cells. The culture medium (with D-MEM / low glucose / 10% FBS / 100 μM Oxionate) of confluent MOVAS-1 cells was divided into a hypoxanthine-supplemented group and a hypoxanthine-free group. The hypoxanthine-supplemented group was supplemented with 50 μM hypoxanthine and either 6 μM compound 14, 10 μM febuxostat, or 100 μM allopurinol, while the hypoxanthine-free group was supplemented with either 6 μM compound 14, 10 μM febuxostat, or 100 μM allopurinol. For the control groups, the hypoxanthine-supplemented group received only 50 μM hypoxanthine, while the hypoxanthine-free group received no supplements. Subsequently, the mixture was allowed to stand for 4 hours under a mixed gas condition of 1% oxygen, 5% carbon dioxide, and 94% nitrogen. After deproteinization by PCA, ATP, ADP, and AMP concentrations were measured using HPLC. The results are shown in Figures 11 and 12. Compound 14 showed efficacy at lower doses than febuxostat and allopurinol. <Example 2: ATP-enhancing effect in the presence of an uncoupling agent> The examples used MOVAS-1 cells exhibiting XOR activity. Each sample size was n=3. The culture medium for confluent MOVAS-1 cells (with D-MEM / low glucose / 10% FBS / 100uM Oxionate) was divided into a CCCP-added group and a CCCP-free group, and 6 μM of compound 14 was added to the medium. Nothing was added to the control groups. Subsequently, CCCP was added to the CCCP-added group to a final concentration of 10 μM. After standing for 30 minutes, deproteinization was performed by PCA, and ATP, ADP, and AMP concentrations were measured using HPLC. The results are shown in Figure 13. The control results showed that the total adenylate concentration decreased with the addition of CCCP. Furthermore, the total adenylate concentration in the CCCP-added group (with compound 14 added) was higher than that of the control group.

[0118] <Example 3: Inhibitory effect on retinal degeneration> Three-week-old RCS rats (Claire Japan, male) were purchased and randomly assigned to either a control group or a group receiving compound 14. From 3.5 weeks of age, the control group and compound 14 were administered orally once daily for 18 days. The control group was administered 1% methylcellulose (Shin-Etsu Chemical Co., Ltd., Metroze (SM-15)), while the compound 14 group was administered a formulation of compound 14 solid dispersion suspended in 1% methylcellulose, as described in "Formulation Example 1" below, at a dose of 5 mg / 100g body weight (1 mg / 100g body weight as compound 14) per dose. In addition, since rodents are prone to xanthine stones due to XOR inhibition, both groups were given 1% (w / v) Uralit-U powder (Nippon Chemiphar Co., Ltd.) in drinking water to prevent / reduce xanthine stones. After 18 days of administration, on the 19th day, eyeballs were collected from both eyes of each group, and the histological features were examined in one eyeball. To compare the thickness of the retinal layers, the measurements were taken at a point a certain distance (1000 μm) from the center of the optic nerve head: the thickness of the retina (2), the thickness of the outer granular layer (3), and the thickness of the cone-rod layer (4), as shown in Figure 14. The results are shown in Figure 15. Compared to the control group, the group administered compound 14 significantly suppressed thinning of the outer granular layer and cone-rod layer in retinal tissue (p<0.05; n=4). The other eyeball was used for measuring the concentrations of various factors within the eyeball, as described in Example 4.

[0119] <Reference Example 16: Confirmation of XOR in the eyeball> The retina was isolated from collected rat eyeballs, frozen in liquid nitrogen, and stored at -80°C until enzyme activity measurement. The retina was homogenized in a solution of [0.25M sucrose, 1 mM salicylic acid, 0.3 mM MEDTA, and a protease inhibitor (Roche Applied Science; complete protease inhibitor cocktail) in 50 mM potassium phosphate buffer (pH 7.4)], then centrifuged at 15000xg to prepare the supernatant. The protein concentration in the supernatant was measured (Thermo Fisher Scientific; Coomassie (Bradford) Protein Assay Regent). The XOR enzyme reaction was performed at 25°C using [0.4 mM MEDTA, 0.15 mM xanthine, 500 μM NAD]. + The procedure was performed in a 50 mM potassium phosphate buffer (pH 7.8) solution containing [the substance]. The concentration of the product, uric acid, was measured by absorbance at a wavelength of 295 nM. XOR activity in rat retinal lysate was below the detection limit (0.01 nmole uric acid / min / mg protein).

[0120] <Example 4: Measurement of the concentration of various molecules in the eyeball> The concentrations of various molecules in one eyeball collected in Example 3 were measured. The eyeball, stored at -80°C, was freeze-dried and pulverized, and treated with 2 times the volume (w / w) of 5% perchloric acid solution using a vortex mixer. The supernatant obtained by centrifugation at 15000 rpm at 4°C for 5 minutes was neutralized with 3M potassium carbonate solution. The supernatant was again centrifuged at 15000 rpm at 4°C for 5 minutes, and the supernatant was equilibrated with 0.5M sodium phosphate buffer to prepare an eyeball extract solution. ATP, ADP, AMP, IMP, inosine, hypoxanthine, xanthine, uric acid, GTP, GDP, and GMP in the solution were measured by HPLC (HPLC: Shimadzu LC-20AD, diode array detector: Shimadzu SPD-M20A), and the energy charge was calculated (calculation formula: ([ATP] + 1 / 2[ADP]) / ([ATP] + [ADP] + [AMP])). The results are shown in Tables 13-15. Compound 14 was found to significantly enhance the energy charge within the eyeball by increasing ATP, ADP, GTP, and GDP, and decreasing AMP and IMP. Note that GTP represents guanosine triphosphate, GDP represents guanosine diphosphate, and GMP represents guanosine monophosphate.

[0121] [Table 13]

[0122] [Table 14]

[0123] [Table 15]

[0124] <Example 5: Measurement of hypoxane and inosine concentrations in serum> Similar to Example 3, RCS rats were orally administered either the control or compound 14 daily for 10 days, and Uralit-U compound powder (manufactured by Nippon Chemiphar Co., Ltd.) was administered via drinking water. After the completion of the 10-day administration, blood samples were collected from both groups on the 11th day and serum was prepared. As shown in Table 16, the concentrations of inosine and hypoxanthine in the serum were significantly increased by approximately 38 times and approximately 7 times, respectively, by compound 14 (p<0.05; n=4).

[0125] [Table 16]

[0126] According to the results of Reference Example 16, the XOR enzyme appears to be almost nonexistent in the retina. This is consistent with the low RNA expression levels in humans, pigs, and mice in the publicly known database "THE HUMAN PROTEIN ATLAS" (https: / / www.proteinatlas.org / ENSG00000158125-XDH / tissue). On the other hand, as shown in Table 13, oral administration of compound 14 significantly increased intraocular ATP concentration compared to the control group, and as shown in Table 16, serum inosine and hypoxanthine concentrations increased dramatically. Based on these results, it is thought that when compound 14 is administered orally, it inhibits xanthine oxidoreductase (XOR) present in the liver or vascular endothelium, thereby stopping AMP degradation in these tissues with hypoxanthine, increasing the amount of hypoxanthine and inosine in the blood. When hypoxanthine and inosine in the blood cross the blood-retinal barrier, they flow into the retina and are regenerated into ATP via the purine salvage cycle in the retina, thereby increasing the ATP concentration in the eyeball. It is thought that the increased ATP promotes the repair of damage in retinal tissue and protects against retinal cell degeneration, thereby suppressing the thinning of the outer granular layer and cone-rod layer in the retinal tissue. Furthermore, the fact that compound 14 acts indirectly on the eyeball is supported by the fact that compound 14 administered to rats was hardly distributed in the eyeball. Furthermore, since age-related macular degeneration and glaucoma can be treated by increasing the concentration of ATP in the eyeball (Maruoka et al., Heliyon 4 (2018)e00624; Nakano et al., Heliyon 2 (2016)e00096), XOR inhibitors such as compound 14 were thought to have therapeutic effects in these diseases as well.

[0127] <Example of formulation 1: Manufacturing of solid dispersion capsules> 0.18 kg of compound 14 (2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine) was dissolved in 38.72 kg of a mixed solvent (weight ratio: 32.01 / 5.09 / 1.62) of tetrahydrofuran (sometimes abbreviated as THF), anhydrous ethanol, and purified water while being heated. Then, 0.72 kg of HPMCAS-MG was added and stirred to prepare the feed solution. Next, the mixture was spray-dried in a spray dryer under the conditions of an input temperature of 100°C, an exhaust temperature of 60°C, a feed solution volume of 100 g / min, and a two-fluid nozzle nitrogen spray pressure of 0.30 MPa. The resulting spray-dried product was vacuum-dried at a drying temperature of 25°C for 16 hours and then at 40°C for 24 hours. After that, it was air-dried at room temperature for 24 hours to obtain a solid dispersion of compound 14. The obtained solid dispersion of compound 14 was sieved using a sieve (mesh size 300 μm), and then 250 g of the dispersion was mixed with 50 g of sodium starch glycolate to obtain a mixed powder of the solid dispersion of compound 14. The obtained solid dispersion powder of compound 14 was filled into capsules No. 2 (white gelatin) at a dose of 60 mg or 120 mg each to obtain solid dispersion capsules of compound 14. [Industrial applicability]

[0128] The pharmaceutical compositions provided by the present invention are useful as pharmaceutical compositions for enhancing intracellular ATP. In particular, even if the pharmaceutical compositions provided by the present invention contain only the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, without using inosine, inosinic acid, hypoxanthine, or salts thereof as active ingredients, they are still useful as pharmaceutical compositions for enhancing intracellular ATP.

Claims

1. General formula (I) 【Chemistry 1】 (In the formula, R １ R represents an unsubstituted phenyl group or a phenyl group substituted with a substituent, wherein the substituent represents at least one group selected from the group consisting of C1-C8 alkyl groups, C1-C8 alkyl groups substituted with a halogen atom, C1-C8 alkoxy groups, C2-C8 alkoxycarbonyl groups, formyl groups, carboxyl groups, halogen atoms, phenyl groups, and phenoxy groups, ２ R represents a cyano group or a nitro group. ３ represents a hydrogen atom or hydroxyl group, and X represents an oxygen atom or -S(O) ｎ A pharmaceutical composition for enhancing intracellular ATP, comprising a compound represented by (where - represents a negative number, n represents an integer between 0 and 2, and Y represents an oxygen atom or a sulfur atom) or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, characterized in that the intracellular ATP-enhancing effect is achieved by the intracellular purine salvage pathway.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that the intracellular ATP-enhancing effect can be sustained even in the presence of an uncoupling agent.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that the intracellular ATP-enhancing effect improves a state in which the balance of ATP production and consumption is skewed towards consumption.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that the intracellular ATP-enhancing effect is achieved under hypoxic conditions.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that the intracellular ATP-enhancing effect is achieved in a state of absolute or relative ATP deficiency.

7. The pharmaceutical composition according to claim 6, wherein the absolute or relative deficiency of ATP is circulatory failure, abnormal protein accumulation, or tissue damage.

8. The pharmaceutical composition for enhancing intracellular ATP, wherein the pharmaceutical composition is for the treatment or prevention of ATP-related eye diseases, according to any one of claims 1 to 7.

9. The pharmaceutical composition according to claim 8, wherein the eye disease is a disease involving damage to the retina or optic nerve.

10. The aforementioned ATP-related eye diseases include retinitis pigmentosa, cone-rod dystrophy, Oguchi disease, punctate fundus, paravenoretinal-choroidal atrophy, Leber congenital blindness, cone dystrophy, Stargardt disease, Best's disease, familial exudative vitreoretinopathy, Wagner syndrome, Stickler syndrome, central ossicular choroidal dystrophy, choroideremia, gyral choroidal dystrophy, retinal degeneration secondary to uveitis, drug-induced (including chloroquine) retinal disorders, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, diabetic retinopathy, renal retinopathy, age-related macular degeneration, and central serosal dystrophy. A pharmaceutical composition according to any one of claims 1 to 7, wherein the condition is humoral chorioretinopathy, retinal white spot syndrome, retinal pigment streaks, rhegmatogenous retinal detachment extending to the macula, macular hole, retinal schizophrenia, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment associated with high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, nasal optic neuropathy, demyelinating optic neuropathy (including multiple sclerosis), or toxic optic neuropathy (including ethambutol, methanol, and thinner).

11. A pharmaceutical composition according to any one of claims 1 to 10, wherein a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is administered orally to a patient requiring enhancement of intracellular ATP at a dose of 10 to 320 mg per day, and the oral administration is optionally continued for at least 7 days.

12. R １ The pharmaceutical composition according to any one of claims 1 to 11, wherein the phenyl group is unsubstituted or phenyl group substituted with a halogen atom.

13. A pharmaceutical composition according to any one of claims 1 to 12, wherein X is an oxygen atom.

14. A pharmaceutical composition according to any one of claims 1 to 13, wherein Y is a sulfur atom.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof includes an amorphous form, and the content of the amorphous form is 80% by weight or more of the total weight of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition according to any one of claims 1 to 15, which is an enteric-coated preparation.

17. The pharmaceutical composition according to claim 16, wherein the enteric-coated preparation is a hard capsule.

18. The pharmaceutical composition according to any one of claims 1 to 17, further comprising a solid dispersion containing a hypromellose derivative.

19. The pharmaceutical composition according to claim 18, wherein the weight ratio of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to a hypromellose derivative is 1:0.1 to 1:

25.

20. The pharmaceutical composition according to claim 18 or 19, wherein the hypromellose derivative is hypromellose acetate succinate or hypromellose phthalate.

21. A pharmaceutical composition according to any one of claims 1 to 20, which is a solid dosage form.

22. A pharmaceutical composition according to any one of claims 1 to 21, wherein the content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is 10 mg to 320 mg.

23. A pharmaceutical composition according to any one of claims 1 to 22, wherein the content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit is 10 mg to 320 mg.

24. A pharmaceutical composition according to any one of claims 1 to 23, wherein the content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit is 10 mg to 160 mg.

25. A pharmaceutical composition according to any one of claims 1 to 24, wherein the content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit is 10 mg to 80 mg.

26. A pharmaceutical composition according to any one of claims 1 to 25, wherein the content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dose unit is 20 mg to 80 mg.

27. The pharmaceutical composition according to any one of claims 1 to 26, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof.

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