Intracellular ATP enhancer

Abstract

The present application provides a pharmaceutical composition for intracellular ATP enhancement comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof. (In the formula, R 1 represents unsubstituted or substituted phenyl, R 2 represents cyano or nitro, R 3 represents hydrogen atom or hydroxy, X represents oxygen atom or -S(O) n -, n represents an integer of 0 to 2, and Y represents oxygen atom or sulfur atom). The present application provides a pharmaceutical composition for intracellular ATP enhancement comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof. (In the formula, R 1 represents unsubstituted or substituted phenyl, R 2 represents cyano or nitro, R 3 represents hydrogen atom or hydroxy, X represents oxygen atom or -S(O) n -, n represents an integer of 0 to 2, and Y represents oxygen atom or sulfur atom).

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition for enhancing intracellular ATP.

[0002] This application claims priority based on Japanese Patent Application No. 2020-203725, filed in Japan on December 8, 2020, the contents of which are incorporated herein by reference. Background Technology

[0003] ATP (also known as adenosine triphosphate) is an important substance involved in the storage and supply of energy in living organisms. In normal individuals, its production and consumption are kept in balance due to its high degree of constancy, so that the concentration in cells is maintained within a certain range.

[0004] However, it is known that in certain diseases, lesions, or syndromes, the intracellular ATP concentration is reduced compared to normal levels, and it is hoped that increasing the amount of intracellular ATP can effectively treat or prevent these diseases, lesions, or syndromes.

[0005] However, it is known that ATP in organisms is sequentially converted into ADP (also known as adenosine diphosphate), AMP (also known as adenosine monophosphate), IMP (inosine monophosphate), inosine, hypoxanthine, xanthine, and uric acid. It is also known that within these metabolic pathways, if the amount of hypoxanthine increases, a pathway exists where hypoxanthine produces IMP, which in turn produces AMP, ADP, and ATP (sometimes referred to as the intracellular purine salvage synthesis pathway).

[0006] Xanthine oxidoreductase (XOR) inhibitors, known to be effective in treating gout, reduce uric acid production by inhibiting the XOR pathway, which acts on the conversion of hypoxanthine to xanthine and xanthine to uric acid. Furthermore, it is hoped that by using XOR inhibitors to inhibit the conversion of hypoxanthine to xanthine and subsequently to uric acid, intracellular hypoxanthine will accumulate, thereby increasing intracellular ATP levels by activating the aforementioned intracellular purine salvage pathway.

[0007] Currently, XOR inhibitors used to treat hyperuricemia include, for example, allopurinol and febuxostat.

[0008] Patent documents 1-5 describe the effectiveness of XOR inhibitors such as allopurinol and febuxostat in treating conditions such as hemolytic anemia, sickle cell disease, pyruvate kinase deficiency, spherocytosis, elliptic polycythemia, stomatocytosis, thalassemia, ischemic heart disease, heart failure, cardiovascular disease, hypertension, tachycardia, arrhythmia, chronic progressive extraocular muscle palsy syndrome, broken red fibers, myoclonic epilepsy syndrome, mitochondrial encephalomyopathy, lactic acidosis, stroke-like syndrome, Leigh encephalopathy, mitochondrial cardiomyopathy, Leber disease, mitochondrial diabetes, Pearson's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, adenosine monosuccinate lyase deficiency, Alzheimer's disease, Lewy body dementia, or frontotemporal dementia. However, it has been disclosed that the intracellular ATP-enhancing effect of allopurinol or febuxostat alone is insufficient and requires co-administration with inosine, inosine monophosphate, hypoxanthine, or their salts.

[0009] Existing technical documents

[0010] Patent documents

[0011] Patent Document 1: Japanese Patent No. 6153281

[0012] Patent Document 2: Japanese Patent Application Publication No. 2018-80135

[0013] Patent Document 3: International Publication No. 2018 / 092911

[0014] Patent Document 4: Japanese Patent Application Publication No. 2018-118914

[0015] Patent Document 5: Japanese Patent Application Publication No. 2018-135278 Summary of the Invention

[0016] The inventors conducted research on pharmaceuticals that enhance intracellular ATP and found that there is still room for improvement in the enhancement of intracellular ATP brought about by pharmaceuticals with XOR inhibitory activity.

[0017] The object of this invention is to provide a pharmaceutical product that enhances intracellular ATP more effectively than previously known pharmaceutical products. Furthermore, the object of this invention is to provide a pharmaceutical product that has XOR inhibitory activity and enhances intracellular ATP without the use of inosine, inosine acid, hypoxanthine, or their salts.

[0018] The inventors conducted various studies on pharmaceuticals with XOR inhibitory activity and found that pharmaceutical compositions containing compounds represented by general formula (I) or pharmaceutically acceptable salts thereof are effective as pharmaceuticals that enhance intracellular ATP, thus completing the present invention.

[0019] That is, the present invention is as follows:

[0020] [1] A pharmaceutical composition for enhancing intracellular ATP, comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

[0021]

[0022] (where R is in the formula) 1 This indicates an unsubstituted phenyl or a substituted phenyl, wherein the substituent is selected from at least one group chosen from alkyl groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with a halogen atom, alkoxy groups having 1 to 8 carbon atoms, alkoxycarbonyl groups having 2 to 8 carbon atoms, formyl groups, carboxyl groups, halogen atoms, phenyl groups, and phenoxy groups. R 2 Indicates cyano or nitro, R 3 X represents a hydrogen atom or a hydroxyl group, and X represents an oxygen atom or -S(O). n -, n represents an integer from 0 to 2, and Y represents an oxygen atom or a sulfur atom;

[0023] [2] The pharmaceutical composition according to [1] is characterized in that the above-mentioned intracellular ATP enhancement effect is carried out through the intracellular purine salvage synthesis pathway;

[0024] [3] The pharmaceutical composition according to [1] or [2] is characterized in that the above-mentioned intracellular ATP-enhancing effect can be sustained even in the presence of an uncoupling agent;

[0025] [4] The pharmaceutical composition according to any one of [1] to [3] is characterized in that the above-mentioned intracellular ATP enhancement effect improves the state in which the balance between ATP production and consumption is tilted towards the consumption side;

[0026] [5] The pharmaceutical composition according to any one of [1] to [4] is characterized in that the above-mentioned intracellular ATP enhancement effect is achieved under hypoxic conditions;

[0027] [6] The pharmaceutical composition according to any one of [1] to [5] is characterized in that the above-mentioned intracellular ATP enhancement effect is carried out under a state of absolute or relative ATP deficiency;

[0028] [7] According to the pharmaceutical composition described in [6], the absolute or relative deficiency of ATP is circulatory failure, abnormal protein accumulation or tissue damage (tissue disorder);

[0029] [8] The pharmaceutical composition according to any one of [1] to [7], wherein the above-mentioned intracellular ATP-enhancing pharmaceutical composition is for the treatment or prevention of ATP-related eye diseases;

[0030] [9] The pharmaceutical composition according to [8], wherein the above-mentioned ATP-related ophthalmopathy is a disease that causes damage to the retina or optic nerve;

[0031]

[10] The pharmaceutical composition according to any one of [1] to [7], wherein the above-mentioned ATP-related ophthalmopathy is retinitis pigmentosa, cone-rod dystrophy, microstomia, punctate fundus, pigmented perivenous choroidal atrophy, Leber congenital amaurosis, cone dystrophy, Stargardt disease, Best disease, familial exudative vitreoretinopathy, Wagner syndrome, Stickler syndrome, central halo choroidal dystrophy, choroidal atrophy, cycloplegic choroidal dystrophy, retinal degeneration caused by uveitis, retinal degeneration including drug-induced (including chloroquine) retinal damage, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, diabetes. Pathological retinopathy, renal retinopathy, age-related macular degeneration, central serous chorioretinopathy, white spot syndrome, retinal vascular streaks, rhegmatogenous retinal detachment involving the macula, macular hole, retinoschisis, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment due to high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, rhinogenic optic neuropathy, demyelinating optic neuropathy (including multiple sclerosis), or toxic optic neuropathy (including ethambutol, methanol, and diluents);

[0032]

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

[10] , wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is used to administer 10 to 320 mg orally once a day to a patient who requires enhancement of intracellular ATP, and to continue the above oral administration for at least 7 days as needed;

[0033]

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

[11] , wherein R 1 It is an unsubstituted phenyl or a phenyl substituted with a halogen atom;

[0034]

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

[12] , wherein X is an oxygen atom;

[0035]

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

[13] , wherein Y is a sulfur atom;

[0036]

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

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

[14] comprises its amorphous content, wherein the content of the amorphous content is 80% by weight or more relative to the total weight of the compound or pharmaceutically acceptable salt of any one of [1] to

[14] ;

[0037]

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

[15] , wherein the pharmaceutical composition is an enteric-coated formulation;

[0038]

[17] The pharmaceutical composition according to

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

[0039]

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

[17] , wherein it comprises a solid dispersion further containing a hydroxypropyl methylcellulose derivative;

[0040]

[19] The pharmaceutical composition according to

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

[0041]

[20] The pharmaceutical composition according to

[18] or

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

[0042]

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

[20] , wherein the pharmaceutical composition is a solid dosage form;

[0043]

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

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

[0044]

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

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

[0045]

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

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

[0046]

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

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

[0047]

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

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

[0048]

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

[26] , wherein, 12 hours after administration on the first day of administration, the blood uric acid concentration is reduced by 0.5 to 2.0 mg / dL (e.g., 0.5 to 1.5 mg / dL) compared with that before administration;

[0049]

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

[27] , wherein by administering the drug once a day for 7 consecutive days, the blood uric acid concentration 12 hours after administration on the 7th day of administration is reduced by 1.5 to 3.0 mg / dL (e.g., 1.5 to 2.5 mg / dL) compared with that before administration;

[0050]

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

[28] , wherein, from the start of administration until 3 weeks after administration, the daily dose of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is not increased;

[0051]

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

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

[0052]

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

[30] , wherein the maximum reduction rate of serum uric acid level on the first day of administration ([(uric acid level before administration - minimum uric acid level after administration on the first day of administration) / uric acid level before administration] × 100) is 10 to 25%;

[0053]

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

[31] , wherein the maximum reduction rate of serum uric acid level on the 7th day of administration ([(uric acid level before administration - minimum uric acid level after administration on the 7th day of administration) / uric acid level before administration] × 100) is 20 to 45%;

[0054]

[33] The 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-hydroxythiazo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof;

[0055]

[34] A package containing the pharmaceutical composition described in any one of [1] to

[33] , comprising the amount of the pharmaceutical composition required for continuous administration for 5 to 15 days.

[0056]

[35] Enhancers of ATP, ADP, GTP or GDP in tissues, organs or cells where the expression of the target enzyme XOR is not substantially visible or low, containing XOR inhibitors as active ingredients.

[0057]

[36] According to the enhancer described in

[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.

[0058]

[37] According to the enhancer described in

[35] or

[36] , the organ in which the expression of the target enzyme XOR is substantially not visible or is poorly expressed is the eyeball.

[0059]

[38] The enhancer according to any one of

[35] to

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

[0060]

[39] The enhancer according to any one of

[35] to

[37] , wherein the tissue in which the expression of the target enzyme XOR is substantially not visible or is poorly expressed is the optic nerve.

[0061]

[40] The enhancer according to any one of

[35] to

[39] , wherein it further comprises an ATP precursor.

[0062]

[41] The enhancer according to

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

[0063]

[42] A treatment and / or preventive agent for ATP-related diseases in tissues, organs, viscera or cells where the expression of the target enzyme XOR is not substantially visible in the cells or is low, containing an XOR inhibitor as an active ingredient.

[0064]

[43] The treatment and / or preventive agent according to

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

[0065]

[44] The treatment and / or preventive agent according to

[42] or

[43] , wherein the organ in which the expression of the target enzyme XOR is substantially not seen or is poorly expressed is the eyeball.

[0066]

[45] The treatment and / or preventive agent according to any one of

[42] to

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

[0067]

[46] The treatment and / or preventive agent according to any one of

[42] to

[44] , wherein the tissue in which the expression of the target enzyme XOR is substantially not visible or is poorly expressed is the optic nerve.

[0068]

[47] The treatment and / or preventive agent according to any one of

[42] to

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

[0069]

[48] ​​According to the treatment and / or preventive agents described in

[47] , wherein the above-mentioned ATP-related eye diseases are retinitis pigmentosa, cone-rod dystrophy, microstomia, punctate fundus, paravenous retinal choroidal atrophy, Leber congenital amaurosis, cone dystrophy, Stargardt disease, Best disease, familial exudative vitreoretinopathy, Wagner syndrome, Stickler syndrome, central halo choroidal dystrophy, choroidal atrophy, cycloplegic choroidal dystrophy, retinal degeneration caused by uveitis, retinal degeneration including drug-induced (including chloroquine) retinal damage, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, diabetic retinopathy, etc. Retinopathy, renal retinopathy, age-related macular degeneration, central serous chorioretinopathy, white spot syndrome, retinal vascular streaks, rhegmatogenous retinal detachment involving the macula, macular hole, retinoschisis, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment due to high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, rhinogenic optic neuropathy, demyelinating optic neuropathy (including multiple sclerosis), or toxic optic neuropathy (including ethambutol, methanol, and diluents).

[0070]

[49] A pharmaceutical composition for the treatment and / or prevention of ATP-related diseases in tissues, organs, viscera or cells where the expression of the target enzyme XOR is not substantially visible in the cells or is low, comprising an XOR inhibitor as an active ingredient.

[0071]

[50] The pharmaceutical composition according to

[49] further comprises an ATP precursor.

[0072]

[51] The pharmaceutical composition according to

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

[0073]

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

[0074]

[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.

[0075]

[54] The pharmaceutical composition according to

[52] or

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

[0076]

[55] According to the pharmaceutical composition described in

[54] , wherein the above-mentioned ATP-related ophthalmopathy is retinitis pigmentosa, cone-rod dystrophy, microstomia, punctate fundus, paravenous retinal choroidal atrophy, Leber congenital amaurosis, cone dystrophy, Stargardt disease, Best disease, familial exudative vitreoretinopathy, Wagner syndrome, Stickler syndrome, central halo choroidal dystrophy, choroidal atrophy, cycloplegic choroidal dystrophy, retinal degeneration caused by uveitis, retinal degeneration including drug-induced (including chloroquine) retinal damage, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, diabetic retinopathy. Membrane disease, renal retinopathy, age-related macular degeneration, central serous chorioretinopathy, white spot syndrome, retinal vascular streaks, rhegmatogenous retinal detachment involving the macula, macular hole, retinoschisis, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment due to high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, rhinogenic optic neuropathy, demyelinating optic neuropathy (including multiple sclerosis), or toxic optic neuropathy (including ethambutol, methanol, and diluents).

[0077] The pharmaceutical compositions provided by this invention are useful as intracellular ATP-enhancing pharmaceutical compositions. In particular, even pharmaceutical compositions provided by this invention containing only compounds represented by general formula (I) or their pharmaceutically acceptable salts as active ingredients, without the use of inosine, inosine acid, hypoxanthine, or their salts, are useful as intracellular ATP-enhancing pharmaceutical compositions. Furthermore, pharmaceutical compositions provided by this invention containing XOR inhibitors as active ingredients also exert ATP-enhancing effects on tissues, organs, viscera, or cells where the expression of the target enzyme XOR is substantially absent or low, for example, they are effective for ATP-related eye diseases. Attached Figure Description

[0078] Figure 1 This is a diagram showing the particle size distribution of the amorphous compound 14 obtained by wet laser diffraction.

[0079] Figure 2 This is a graph showing the blood drug concentration-time curves when the capsules of Reference Example 1a and the capsules of Comparative Reference Example 1a were administered to dogs.

[0080] Figure 3 This is a diagram showing the powder X-ray diffraction pattern of crystals of compound 14.

[0081] Figure 4 The figures shown are powder X-ray diffraction patterns of the amorphous compound 14. (a) shows the powder X-ray diffraction pattern before storage, (b) shows the powder X-ray diffraction pattern after storage for 1 week under light-proof, airtight, and room temperature conditions, (c) shows the powder X-ray diffraction pattern after storage for 2 weeks under light-proof, airtight, and room temperature conditions, and (d) shows the powder X-ray diffraction pattern after storage for 4 weeks under light-proof, airtight, and room temperature conditions.

[0082] Figure 5 These are 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.

[0083] Figure 6 These are 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.

[0084] Figure 7 These are 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.

[0085] Figure 8This is a graph showing the effect of the solid dispersion of Reference Example 11b on reducing serum uric acid levels in rats.

[0086] Figure 9 This is a graph showing the decrease in serum uric acid levels when compound 14 and febuxostat, as a control drug, were orally administered to healthy adult males in Reference Example 14.

[0087] Figure 10 The graph shows the rate of change in serum uric acid levels in rats with hyperuricemia induced by compound 14 and febuxostat xenocyanate as a control drug, as described in Reference Example 15, after repeated oral administration once a day for 28 days.

[0088] Figure 11 This is a diagram illustrating the ATP-enhancing effect under hypoxic conditions in Example 1.

[0089] Figure 12 The diagram shows the ATP-enhancing effect under hypoxic conditions in Example 1, and also shows the significant differences between compound 14 and febuxostat when used in combination with hypoxanthine.

[0090] Figure 13 This is a diagram illustrating the ATP-enhancing effect in the presence of the uncoupling agent in Example 2.

[0091] Figure 14 This is a sagittal ocular tissue specimen (HE stained) containing the optic nerve from a 5-week-old male RCS rat. 1–4 represent the distance from the center of the macula, the thickness of the retina, the thickness of the outer nuclear layer, and the thickness of the cone and rod layers, respectively, which are 1011 μm, 128 μm, 13 μm, and 27 μm.

[0092] Figure 15 These are cross-sectional views of the retina after treatment with the control and compound 14 in Example 3, and graphs showing the thickness of the outer nuclear layer and the cone and rod layers. Detailed Implementation

[0093] <Pharmaceutical Compositions>

[0094] The present invention will now be described in more detail. The intracellular ATP-enhancing pharmaceutical composition of the present invention contains a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0095] In compounds represented by general formula (I), R 1 This indicates an unsubstituted phenyl or a substituted phenyl.

[0096] As R 1Examples of alkyl groups representing phenyl substituents that are "alkyl groups having 1 to 8 carbon atoms" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc., with methyl and ethyl being preferred.

[0097] As R 1 Examples of substituents for phenyl groups that are "alkyl groups having 1 to 8 carbon atoms substituted by halogen atoms" include fluoromethyl, trifluoromethyl, 1,1-difluoroethyl, pentafluoroethyl, etc., with fluoromethyl and trifluoromethyl being preferred.

[0098] As R 1 Examples of alkoxy groups representing phenyl substituents that have 1 to 8 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, etc., with methoxy being a preferred example.

[0099] As R 1 Examples of substituents for phenyl groups that are "alkoxycarbonyl groups with 2 to 8 carbon atoms" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, etc., with methoxycarbonyl and ethoxycarbonyl being preferred.

[0100] As R 1 Examples of "halogen atoms" representing substituents of phenyl groups include fluorine, chlorine, bromine, and iodine atoms, with fluorine and chlorine atoms being preferred.

[0101] As R 1 Preferably, it is an unsubstituted phenyl group.

[0102] In compounds represented by general formula (I), R 2 It indicates cyano or nitro, with cyano being preferred.

[0103] In compounds represented by general formula (I), R 3 It represents a hydrogen atom or a hydroxyl group, preferably a hydrogen atom.

[0104] In compounds represented by general formula (I), X represents an oxygen atom or -S(O). n - Oxygen atoms are preferred.

[0105] In compounds represented by general formula (I), Y represents an oxygen atom or a sulfur atom, preferably a sulfur atom.

[0106] Pharmaceutically acceptable salts of compounds represented by general formula (I) include, for example, alkali metal salts such as sodium, potassium, or lithium salts, with potassium salts being preferred.

[0107] As an embodiment of the present invention, the compound of general formula (I) contained in the pharmaceutical composition for enhancing intracellular ATP can be obtained, for example, by the synthesis method described in International Publication No. 2005 / 121153 or International Publication No. 2019 / 208635.

[0108] Among the compounds of general formula (I) contained in the intracellular ATP-enhancing pharmaceutical composition of the present invention, the compounds listed in Table 1 are preferred examples. In the table, Me represents methyl.

[0109] [Table 1]

[0110]

[0111] Compounds 1 to 15 can form pharmaceutically acceptable salts, wherein compounds 3 to 5, 8 to 10, 13 to 14, or pharmaceutically acceptable salts of these compounds are preferred.

[0112] In the pharmaceutical composition for enhancing intracellular ATP of the present invention, preferably, part or all of the compound represented by general formula (I) or its pharmaceutically acceptable salt exists in an amorphous form. Here, amorphous refers to a substance in which the compounds represented by general formula (I) or its pharmaceutically acceptable salts have short-range order between atoms or molecules but not long-range order like that of crystals.

[0113] In this invention, amorphous materials can be determined by observing halo peaks in X-ray diffraction.

[0114] In this invention, relative to the total weight of the compound represented by general formula (I) or its pharmaceutically acceptable salt, it is preferable that it exists in an amorphous form of 50% or more, more preferably 80% or more, more preferably 90% or more, and even more preferably 95% or more, or 100% by weight. Furthermore, the pharmaceutically acceptable salt of the compound represented by general formula (I) may also be crystalline. In this case, relative to the total weight, it may be less than 50% by weight of amorphous material, less than 40% by weight, less than 30% by weight, less than 20% by weight, less than 10% by weight, or completely absent. The presence rate of the aforementioned amorphous material can be determined using X-ray diffraction. The remaining portion of the aforementioned amorphous material is crystalline. That is, in the respective presence rate descriptions, the total presence rate of amorphous and crystalline materials is 100% by weight.

[0115] A method for producing an amorphous compound of formula (I) or a pharmaceutically acceptable salt thereof can, for example, be by spray drying (also known as spray-drying) the compound of formula (I) or a pharmaceutically acceptable salt thereof. More specifically, by adding the compound of formula (I) or a pharmaceutically acceptable salt thereof and, if desired, a pharmaceutically acceptable additive to a solvent described below to form a solution or suspension, the solution or suspension is atomized into a fine mist using centrifugal spraying based on a rotating disk or pressurized spraying based on a pressure nozzle, and then sprayed into a drying medium (e.g., heated air or nitrogen), thereby obtaining an amorphous powdery dried product. In the spray drying method, the temperature of the drying medium is, for example, 50–120°C, preferably 50–90°C. The drying medium can flow in a constant direction, for example, at a flow rate of 0.1–0.6 m. 3 The airflow is carried out at a rate of / min.

[0116] Examples of solvents used in spray drying include alcohols with 1 to 6 carbon atoms such as methanol, ethanol, 1-propanol, 2-propanol, and tert-butanol, ethers such as tetrahydrofuran (THF), acetonitrile, and water. These solvents can be used individually or as a mixture of two or more solvents. Ethanol, tetrahydrofuran, and mixtures of these solvents with water are preferred.

[0117] Another method for manufacturing amorphous compounds of general formula (I) or pharmaceutically acceptable salts thereof is freeze-drying. More specifically, it can also be manufactured by dissolving the compound of general formula (I) or a pharmaceutically acceptable salt thereof in a solvent and then freeze-drying the solution.

[0118] Examples of solvents used in freeze-drying include alcohols with 1 to 6 carbon atoms, such as methanol, ethanol, 1-propanol, 2-propanol, and tert-butanol; ethers such as tetrahydrofuran; nitriles such as acetonitrile; and water. These solvents can be used alone or as a mixture of two or more solvents.

[0119] There is no particular limitation on the amorphous particle size of the compound represented by general formula (I) or its pharmaceutically acceptable salt. From the viewpoint of the invention effect and formulation, for example, as the volume average particle size (D50), 20 μm or less can be mentioned, 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.

[0120] It should be noted that the above-mentioned volume average particle size (D50) can typically be determined by dispersing the test sample in a solvent such as water or ethanol and then measuring the particle size distribution using laser diffraction. The test sample can be dispersed in a solvent by irradiation with ultrasound or similar methods. The particle size distribution can be measured using a particle size distribution measuring device (e.g., the Shimadzu SALD-2200 laser diffraction particle size distribution measuring device). The volume average particle size (D50) can be calculated based on the obtained particle size distribution results. Furthermore, commercially available software (e.g., Shimadzu WingSALD-2200 version 1.02) can be used for data collection and analysis.

[0121] The pharmaceutical compositions of the present invention may be formulated with pharmaceutically acceptable additives as needed. For example, the pharmaceutical compositions of the present invention may be manufactured by appropriately combining and adjusting the required amounts of binders, disintegrants, excipients, lubricants, etc.

[0122] Examples of such adhesives include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, agar, alginate, sodium alginate, partially saponified polyvinyl alcohol, amylopectin, partially α-starch, dextrin, xanthan gum, and gum arabic powder. They can be used individually or as a mixture of two or more. Hydroxypropylcellulose, hydroxypropyl methylcellulose, or polyvinylpyrrolidone are preferred.

[0123] Examples of disintegrants include crystalline cellulose, carboxymethyl cellulose (also known as Carmellose), croscarmellose sodium, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, croscarmellose, hydroxypropyl starch, starch, partially α-substituted starch, and sodium starch glycolate. They can be used individually or as a mixture of two or more. Croscarmellose sodium, sodium starch glycolate, or croscarmellose are preferred, and croscarmellose is more preferred. The amount of disintegrant used is preferably 5 to 30% by weight, more preferably 5 to 15% by weight, relative to the total weight of the particles containing the active ingredient. Furthermore, when formulated in tablets, the amount is preferably 1 to 10% by weight, more preferably 2 to 6% by weight, relative to the total weight of the tableting granules containing the active ingredient.

[0124] The aforementioned excipients can be incorporated into any step of the pharmaceutical preparation process, including the kneading process, the granulation process, or subsequent granulation steps. Examples of such excipients include celluloses such as crystalline cellulose, ethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and hydroxypropyl methyl cellulose (also known as hydroxypropyl methyl cellulose); starches such as corn starch, potato starch, wheat starch, rice starch, partially α-substituted starch, and hydroxypropyl starch; sugars such as glucose, lactose, white sugar, refined white sugar, powdered sugar, trehalose, dextran, and dextrin; sugar alcohols such as D-mannitol, xylitol, sorbitol, and erythritol; glycerol fatty acid esters; magnesium aluminate metasilicate; synthetic hydrotalcite; anhydrous calcium phosphate; precipitated calcium carbonate; calcium silicate; calcium hydrogen phosphate hydrate; and sodium bicarbonate, among other inorganic salts, with crystalline cellulose being preferred.

[0125] Examples of such lubricants include stearic acid, sodium stearate fumarate, magnesium stearate, calcium stearate, sucrose fatty acid esters, polyethylene glycol, light anhydrous silicate, hydrogenated oil, glycerol fatty acid esters, and talc. They can be used individually or in mixtures of two or more. Among these, sodium stearate fumarate, magnesium stearate, calcium stearate, or sucrose fatty acid esters are preferred.

[0126] Furthermore, by using a mixture of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof with an enteric polymer in the above-described pharmaceutical composition, recrystallization of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof from a supersaturated solution can be suppressed. When mixing the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof with the enteric polymer, it is preferable to mix them uniformly. The weight ratio of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to the enteric polymer may be 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.

[0127] Examples of enteric polymers used for coating include cellulose polymers, and more preferably hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose acetate succinate.

[0128] It should be noted that when compounds represented by general formula (I) or their pharmaceutically acceptable salts are mixed with enteric polymers, the aforementioned pharmaceutically acceptable additives may be appropriately combined.

[0129] <Enteric-coated preparations>

[0130] The pharmaceutical composition of the present invention is preferably an enteric-coated formulation.

[0131] The "enteric-coated formulation" of this invention refers to a formulation designed to prevent the active ingredient from being broken down in the stomach or to prevent the release of the active ingredient from the stomach and release it mainly in the small intestine. Enteric-coated formulations are themselves described in the Japanese Pharmacopoeia. As enteric-coated formulations, dosage forms such as tablets, granules, fine granules, and capsules are known. As methods for manufacturing these dosage forms, examples include: (i) manufacturing enteric-coated granules obtained by coating the active ingredient or the active ingredient and pharmaceutically acceptable additives with an enteric polymer and preparing tablets, granules, fine granules, or capsules containing the enteric-coated granules; (ii) manufacturing tablets, granules, fine granules, or capsules containing the active ingredient and pharmaceutically acceptable additives and coating these formulations with an enteric polymer; or (iii) containing the active ingredient or the active ingredient and pharmaceutically acceptable additives in a hard capsule made of an enteric base, etc.

[0132] That is, examples of enteric-coated formulations of the present invention include: (i) tablets, granules, fine granules, or capsules containing enteric-coated granules obtained by coating an active ingredient, or an active ingredient and a pharmaceutically acceptable additive, 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, encapsulated in a hard capsule made of an enteric base, etc.

[0133] The aforementioned enteric-coating base agent refers to a base agent composed of an enteric-coating polymer that is known in itself. Examples of such enteric-coating polymers include the enteric-coating polymers for coating described later.

[0134] Examples of enteric-coating polymers used in this invention include 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), and methyl acrylate-methyl methacrylate-methacrylic acid copolymer (e.g., Eudragit FS30D, manufactured by Evonik), etc. Enteric-coated cellulose polymers such as methacrylic acid copolymers, hydroxypropyl methylcellulose (also known as hydroxypropyl methylcellulose), hydroxypropyl methylcellulose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd., sometimes abbreviated as HPMCAS), hydroxypropyl methylcellulose phthalate (manufactured by Shin-Etsu Chemical Co., Ltd., sometimes abbreviated as HPMCP), carboxymethyl ethyl cellulose (manufactured by Freund Sangyo Co., Ltd., sometimes abbreviated as CMEC), and cellulofate (also known as cellulose acetate phthalate), as well as enteric-coated vinyl alcohol polymers such as polyvinyl alcohol acetate phthalate (manufactured by Colorcon), are preferred, with enteric-coated cellulose polymers being the most preferred. Among these, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate are preferred.

[0135] The aforementioned enteric-coated granules can be manufactured using known methods. For example, they can be manufactured by using fluidized bed granulation or fluidized bed granulation, centrifugal rotary granulation or stirring granulation, etc., followed by coating with an enteric coating solution and drying.

[0136] The above-mentioned enteric coating solution can be prepared by adding the above-mentioned enteric polymer to a solvent and concentrating the solvent as needed. Examples of solvents used in the preparation of the enteric coating solution include alcoholic solvents such as water, methanol, and ethanol, or mixtures thereof. Pharmaceutically acceptable additives such as binders, plasticizers, coating agents, surfactants, and excipients can be appropriately added as needed. There is no particular limitation on the amount of solvent; it can be used in amounts of 3 to 10 times the total weight of the dissolved substances (i.e., the total weight of the above-mentioned enteric polymer and pharmaceutically acceptable additives).

[0137] Tablets, granules, fine granules, or capsules containing active ingredients and pharmaceutically acceptable additives coated with the above-mentioned enteric polymer can be manufactured by manufacturing tablets, granules, fine granules, or capsules containing active ingredients and pharmaceutically acceptable additives according to known methods, coating the resulting formulations with the above-mentioned enteric coating solution, and drying them.

[0138] As a hard capsule made of an enteric-coated base, commercially available hard capsules can be used, such as hard capsules made of an enteric-coated base containing hydroxypropyl methylcellulose or hydroxypropyl methylcellulose acetate succinate, or more specifically, Vcaps (registered trademark) Enteric (manufactured by Capsugel).

[0139] The enteric-coated formulation of the present invention may include pharmaceutically acceptable additives as needed. For example, the pharmaceutical composition of the present invention can be manufactured by appropriately combining and adjusting the required amounts of binders, disintegrants, excipients, lubricants, etc. Examples of pharmaceutically acceptable additives described in the above-described pharmaceutical compositions can be cited as examples of such "pharmaceutically acceptable additives".

[0140] The enteric-coated formulation provided by this invention exhibits high absorption in vivo.

[0141] <Solid Dispersions>

[0142] The pharmaceutical compositions of the present invention may also be pharmaceutical compositions comprising a solid dispersion further containing a hydroxypropyl methylcellulose derivative.

[0143] The "hydroxypropyl methylcellulose derivative" of this invention refers to hydroxypropyl methylcellulose itself (sometimes abbreviated as HPMC) and organic esters of hydroxypropyl methylcellulose. Hydroxypropyl methylcellulose, also known as hydroxypropyl methylcellulose, is a mixed ether of cellulose with methyl and hydroxypropyl groups. Examples of organic acids that can form esters with hydroxypropyl methylcellulose include acetic acid, succinic acid, or phthalic acid. The hydroxypropyl methylcellulose of this invention can also form esters with one or more organic acids selected from the above-mentioned organic acids.

[0144] Examples of hydroxypropyl methylcellulose derivatives used in this invention include hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate (sometimes abbreviated as HPMCAS), and hydroxypropyl methylcellulose phthalate (sometimes abbreviated as HPMCP), with hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate being preferred.

[0145] As an example of the hydroxypropyl methylcellulose of the present invention, hydroxypropyl methylcellulose with a substitution ratio of 28-30% for methoxy groups and 7-12% for hydroxypropoxy groups per monomer unit can be described.

[0146] Examples of hydroxypropyl methylcellulose acetate succinates of the present invention include hydroxypropyl methylcellulose acetate succinates with a substitution ratio of 20-26%, preferably 21-25%, for methoxy groups, 5-10%, preferably 5-9%, for hydroxypropoxy groups, 5-14%, preferably 7-11%, for acetyl groups, and 4-18%, preferably 10-14%, for succinyl groups. Examples of hydroxypropyl methylcellulose phthalates of the present invention include hydroxypropyl methylcellulose phthalates with a substitution ratio of 18-24%, for hydroxypropoxy groups, 5-10%, and for carboxybenzoyl groups, and 21-35%, for each monomer unit.

[0147] The contents of methoxy, hydroxypropoxy, acetyl, succinyl or carboxybenzoyl groups in the above-mentioned hydroxypropyl methylcellulose derivatives can be determined by the method for determining the degree of substitution of hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate as specified in the 17th revised edition of the Japanese Pharmacopoeia.

[0148] The viscosity of the hydroxypropyl methylcellulose derivative of the present invention is not particularly limited as long as it has the effects of the present invention. For example, 2.4 to 204 mPa·s can be cited, and 2.4 to 3.6 mPa·s is preferred.

[0149] The viscosity of the hydroxypropyl methylcellulose derivative of the present invention can be determined using the method for determining the viscosity of hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate as specified in the 17th revised edition of the Japanese Pharmacopoeia.

[0150] The weight ratio of the compound represented by general formula (I) or its pharmaceutically acceptable salt to a hydroxypropyl methylcellulose 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 its pharmaceutically acceptable salt to a hydroxypropyl methylcellulose 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.

[0151] As one embodiment of the present invention, a solid dispersion of 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof in a weight ratio of 1:0.1 to 1:25 to a hydroxypropyl methylcellulose derivative can be cited. As another embodiment, a solid dispersion in a weight ratio of 1:0.1 to 1:10 can be cited. As yet another embodiment, a solid dispersion in a weight ratio of 1:0.1 to 1:4 can be cited. As yet another embodiment, a solid dispersion in a weight ratio of 1:1 to 1:10 can be cited. As yet another embodiment, a solid dispersion in a weight ratio of 1:2 to 1:5 can be cited. As yet another embodiment, a solid dispersion in a weight ratio of 1:3 to 1:4 can be cited.

[0152] A "solid dispersion" refers to a solid system containing at least two components, and is a solid composition that forms a system in which the at least two components are uniformly mixed. Furthermore, in the aforementioned solid dispersion, at least one component is typically dispersed throughout the entire system.

[0153] Therefore, one embodiment of the "solid dispersion" of the present invention is a solid composition comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a hydroxypropyl methylcellulose derivative thereof, and forming a system in which the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a hydroxypropyl methylcellulose derivative are uniformly mixed.

[0154] Another embodiment of the "solid dispersion" of the present invention is a solid composition in which a compound of general formula (I) or a pharmaceutically acceptable salt thereof is dispersed throughout the hydroxypropyl methylcellulose derivative. In this case, the compound of general formula (I) or a pharmaceutically acceptable salt thereof constitutes the dispersed phase as the dispersed phase, and the hydroxypropyl methylcellulose derivative constitutes the continuous phase as the dispersion medium.

[0155] The "solid dispersion" of the present invention comprises a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, a hydroxypropyl methylcellulose derivative, and a pharmaceutically acceptable additive as desired. Examples of pharmaceutically acceptable additives as desired include, for example, additives selected from surfactants, pH adjusters, sugars, and plasticizers. They can be suitably combined and formulated in the solid dispersion of the present invention in the desired amount.

[0156] Examples of usable surfactants include cationic surfactants such as sodium bis-(2-ethylhexyl)sulfosuccinate (sodium docusate) and alkyltrimethylammonium bromide (e.g., hexadecyltrimethylammonium bromide (bromobrowntrimethylammonium)), anionic surfactants such as sodium lauryl sulfate, and polyoxyethylene sorbitan anhydride (e.g., Tween). TM 20, 40, 60, 80 or 85), sorbitan fatty acid esters (e.g., SpanTM Nonionic surfactants such as 20, 40, 60, 80 or 85.

[0157] As a usable pH adjuster, acids such as succinic acid, maleic acid, tartaric acid, citric acid, and aspartic acid, and bases such as sodium hydroxide, magnesium oxide, silicon dioxide, sodium bicarbonate, and L-arginine can be used.

[0158] Examples of usable sugars include lactose, white sugar, glucose, fructose, sucrose, maltose, reduced maltose, maltitol, mannitol, erythritol, sorbitol, and xylitol.

[0159] Examples of usable plasticizers include triethyl citrate, polyethylene glycol, and triacetin.

[0160] The "solid dispersion" of the present invention may be free of the pharmaceutically acceptable additives described above. When it contains them, for example, the weight ratio of the compound represented by general formula (I) or its pharmaceutically acceptable salt 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 its pharmaceutically acceptable salt to the pH adjuster is 1:0. The weight ratio of the compound represented by general formula (I) to the above-mentioned sugar is 1:0.02 to 1:2, more preferably 1:0.02 to 1:1.5, even more preferably 1:0.03 to 1:1.2, the weight ratio of the compound represented by general formula (I) or its pharmaceutically acceptable salt to the above-mentioned plasticizer is 1:0.02 to 1:20, more preferably 1:0.15 to 1:10.

[0161] In the "solid dispersion" of the present invention, the pharmaceutically acceptable additives described above can constitute the dispersed phase of the solid dispersion or the continuous phase.

[0162] In the "solid dispersion" of the present invention, the compound represented by general formula (I) or its pharmaceutically acceptable salt preferably exists in part or all of its amorphous form.

[0163] The solid dispersion of the present invention can be manufactured by methods known to them, such as mixing and pulverizing (mechanical-chemical method), solvent method, melting method, heating and mixing melting method, etc.

[0164] Here, the mixing and pulverizing method can be carried out using conventional methods by mixing a compound represented by general formula (I) or its pharmaceutically acceptable salt, hydroxypropyl methylcellulose derivative, and pharmaceutically acceptable additives as needed, and then using a mixer and pulverizer such as a ball mill or hammer mill. The solvent method refers to dissolving or suspending a compound represented by general formula (I) or its pharmaceutically acceptable salt and hydroxypropyl methylcellulose derivative, and pharmaceutically acceptable additives as needed, in a solvent (organic solvent, water, or a mixture thereof), and then removing the solvent to precipitate a solid dispersion, or precipitating a solid dispersion in the solvent.

[0165] Solvents can be removed by methods such as spraying (which, depending on the implementation, can be classified as fluidized bed method, spray drying method (also known as spray-dry method), rotating layer method, stirring method, or supercritical method, etc.), filtration method, evaporation method, freeze drying method, etc. Spraying method is preferred, and spray drying method is particularly preferred.

[0166] The solvents that can be used in manufacturing the solid dispersions of the present invention are preferably pharmaceutically acceptable solvents, such as ethanol, methanol, 2-propanol, acetone, 2-butanone, methyl isobutanone, tetrahydrofuran (THF), tetrahydropyran, 1,4-di(2 ... Alkane, diethyl ether, toluene, acetonitrile, dichloromethane, chloroform, methyl acetate, ethyl acetate, butyl acetate, acetic acid, formic acid, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc.

[0167] Among these solvents, those preferred are those that dissolve compounds represented by general formula (I) or their pharmaceutically acceptable salts and pharmaceutically acceptable additives as required.

[0168] In spray drying, solid dispersions can be manufactured using methods known to the public. For example, a solution or suspension can be prepared by adding a compound of general formula (I) or its pharmaceutically acceptable salt and hydroxypropyl methylcellulose derivative, along with pharmaceutically acceptable additives as needed, to the solvent. The solution or suspension can then be atomized into a fine mist using centrifugal spraying based on a rotating disk or pressurized spraying based on a pressure nozzle and sprayed into a drying medium (heated air or nitrogen) to obtain a powdered dried product and thus a solid dispersion.

[0169] In spray drying, the temperature of the drying medium is, for example, 50–120°C, preferably 50–90°C. The drying medium can flow in a constant direction, for example, at a speed of 0.1–0.6 m. 3 / min airflow.

[0170] The preferred method for precipitation in solvent methods is co-precipitation, which can be achieved by dissolving or suspending the compound represented by general formula (I) or its pharmaceutically acceptable salt and hydroxypropyl methylcellulose derivative, and pharmaceutically acceptable additives as needed, in a solvent, adding the dissolved compound (I) or its pharmaceutically acceptable salt and hydroxypropyl methylcellulose derivative, and pharmaceutically acceptable additives as needed, in an insoluble solvent, or by lowering the temperature, thereby reducing the concentration to induce precipitation and obtain a solid dispersion.

[0171] The melt method refers to a method in which the compound represented by general formula (I) or its pharmaceutically acceptable salt and hydroxypropyl methylcellulose derivative, along with pharmaceutically acceptable additives as needed, are heated to above the melting or softening point of the hydroxypropyl methylcellulose derivative and stirred to dissolve or disperse the compound represented by general formula (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable additives as needed in the hydroxypropyl methylcellulose derivative, followed by rapid cooling. At this time, plasticizers such as triethyl citrate, polyethylene glycol, and triacetin, as well as surfactants, can be further added as needed. Manufacturing can be carried out using a stirred granulator equipped with a heating device.

[0172] The heated mixing and melting method refers to a method of mixing a compound represented by general formula (I) or its pharmaceutically acceptable salt and hydroxypropyl methylcellulose derivative, as well as pharmaceutically acceptable additives as needed, under heating and pressure using an extruder equipped with a heating device, such as a twin-shaft extruder, to obtain a solid dispersion. The obtained plastic-like solid dispersion can be pulverized using a pulverizer to obtain a powder of the solid dispersion.

[0173] The solid dispersion of the present invention manufactured by the above manufacturing method can be used to produce particles of solid dispersion with arbitrary particle size by known methods, and the particles of the above solid dispersion can be used directly as powders or granules.

[0174] Pharmaceutical compositions containing the solid dispersion of the present invention comprise the aforementioned solid dispersion and pharmaceutically acceptable additives. The pharmaceutical compositions of the present invention can be manufactured by appropriately combining and adjusting the required amounts of pharmaceutically acceptable additives such as binders, disintegrants, excipients, and lubricants. Examples of pharmaceutically acceptable additives described above in the pharmaceutical compositions can be cited as examples of such additives.

[0175] Pharmaceutical compositions containing the solid dispersions of the present invention can be formulated into solid dosage forms such as tablets, capsules, granules, and powders, or liquid dosage forms such as injections, through well-known formulation processes. It should be noted that the aforementioned injections can also be provided as solid dosage forms and prepared as injections for use.

[0176] Since the present invention also has the effect of inhibiting tableting obstacles, tablets are particularly preferred as the solid dosage form. Furthermore, these solid dosage forms can be coated as needed.

[0177] The content of the solid dispersion in the pharmaceutical composition containing the solid dispersion of the present invention can be 10 to 95% by weight, preferably 30 to 90% by weight, and more preferably 60 to 85% by weight relative to the total weight of the pharmaceutical composition.

[0178] The solid dispersion provided by this invention can exhibit high absorption and storage stability in living organisms.

[0179] The pharmaceutical compositions of the present invention can be manufactured into appropriate dosage forms such as tablets, capsules, granules, powders, eye drops, lozenges, creams, ointments, gels, wet wipes, patches, liniments, adhesive tapes, poultices, injections, or suppositories, according to conventional methods in the field of pharmaceutical technology.

[0180] In the aforementioned formulations, for example, creams can be manufactured using formulas known to the public. For instance, one or more active ingredients can be ground or melted into a base. The ointment base is selected from ointment bases known to the public. For example, one or more base agents selected from higher fatty acids or higher fatty acid esters (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipate ester, myristic acid ester, palmitic acid ester, stearate ester, oleate ester, etc.), waxes (e.g., beeswax, cetearyl wax, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphate, etc.), higher alcohols (e.g., cetyl alcohol, stearyl alcohol, cetearyl alcohol, etc.), silicone oils (e.g., dimethyl polysiloxane, etc.), hydrocarbons (e.g., hydrophilic petrolatum, white petrolatum, refined lanolin, liquid paraffin, etc.), glycols (e.g., ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, PEG, etc.), vegetable oils (e.g., castor oil, olive oil, sesame oil, turpentine, etc.), animal oils (e.g., mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancers, or antifouling agents can be used in combination. It may further include humectants, preservatives, stabilizers, antioxidants, or fragrances.

[0181] The pharmaceutical composition provided by this invention can be administered orally or non-orally to patients who require increased intracellular ATP, and more specifically to individuals or other mammals who have or may have ATP-related eye diseases. In this invention, "ATP-related eye disease" refers to a disease that can be treated or prevented by increasing the concentration of ATP within the eyeball. Examples of such diseases include those causing damage to the retina or optic nerve. Examples of retinal damage include retinal dystrophy (retinitis pigmentosa, cone-rod dystrophy, microstomia, punctate retina, perivenous retinal choroidal atrophy, and Leber congenital amaurosis, etc.), macular dystrophy (cone-rod dystrophy, Stargardt's disease, and Best's disease, etc.), vitreoretinal dystrophy (familial exudative vitreoretinopathy, Wagner syndrome, and Stickler syndrome, etc.), choroidal dystrophy (central halo choroidal dystrophy, choroidal agenesis, and cycloplegic choroidal dystrophy, etc.), retinal degeneration caused by uveitis, and retinal degenerative diseases including drug-induced (chloroquine, etc.) retinopathy; and retinal diseases accompanied by retinal blood flow obstruction (retinal venous dystrophy). Retinal artery occlusion, hypertensive retinopathy, diabetic retinopathy, and renal retinopathy, etc.; damage to retinal pigment epithelial cells (age-related macular degeneration, central serous chorioretinopathy, retinal white spot syndrome, and retinal vascular streaks, etc.); retinopathy accompanied by retinal detachment (rhegmatogenous retinal detachment involving the macula, macular hole, retinoschisis, exudative retinal detachment, proliferative vitreoretinopathy, and retinal detachment caused by high myopia, etc.); and optic nerve damage, including glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, rhinogenic optic neuropathy, demyelinating diseases (represented by multiple sclerosis), and toxic optic neuropathy (ethambutol, methanol, diluents, etc.). In addition, this includes retinitis pigmentosa complicated with Usher syndrome (with deafness), retinitis pigmentosa complicated with Bardet-Biedl syndrome (with polydactyly, obesity, diabetes, and renal malformation), retinitis pigmentosa complicated with Kearns-Sayre syndrome (with ptosis and oculomotor dysfunction), and retinitis pigmentosa complicated with Refsum syndrome (with polyneuritis and cerebellar ataxia). The method of administration can be appropriately selected for each disease. For example, oral administration, such as tablets, is preferred for ATP-related ophthalmopathy, but is not limited thereto. This is because it has been shown that when the XOR inhibitor is administered orally according to the present invention, the levels of hypoxanthine and inosine increase in vivo. These hypoxanthine and inosine cross the blood-retinal barrier, thereby increasing ATP levels in the eye. Furthermore, it is preferred to administer the pharmaceutical composition provided by the present invention to humans.The pharmaceutical composition provided by this invention is useful as a pharmaceutical composition for enhancing intracellular ATP.

[0182] One embodiment of the present invention is a pharmaceutical composition for enhancing intracellular ATP, comprising enteric particles obtained by coating a compound of general formula (I) or a pharmaceutically acceptable salt thereof with an enteric polymer. The pharmaceutical composition is used in a manner in which the compound of general formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a patient requiring enhancement of intracellular ATP at a dose of 10-320 mg, preferably 20-320 mg, more preferably 40-280 mg, more preferably 40-240 mg, more preferably 40-180 mg, more preferably 60-140 mg, and even more preferably 60-120 mg per day, and the oral administration is continued for at least 7 days as needed.

[0183] Another embodiment of the present invention is an intracellular ATP-enhancing tablet, granule, fine granule, or capsule containing enteric particles obtained by coating a compound of general formula (I) or a pharmaceutically acceptable salt thereof with an enteric polymer. The tablet, granule, fine granule, or capsule is used to orally administer 10–320 mg, preferably 20–320 mg, more preferably 40–280 mg, more preferably 40–240 mg, more preferably 40–180 mg, more preferably 60–140 mg, and even more preferably 60–120 mg daily to patients requiring enhanced intracellular ATP, and the oral administration is continued for at least 7 days as needed.

[0184] Another embodiment of the present invention is a pharmaceutical composition comprising enteric-coated particles obtained by coating a compound of general formula (I) or a pharmaceutically acceptable salt thereof with an enteric polymer, and wherein, if necessary, the compound of general formula (I) or a pharmaceutically acceptable salt thereof in the enteric-coated particles is further mixed with the enteric polymer. The pharmaceutical composition is used in a manner in which the compound of general formula (I) or a pharmaceutically acceptable salt thereof is administered orally to patients requiring enhanced intracellular ATP at a dose of 10–320 mg, preferably 20–320 mg, more preferably 40–280 mg, more preferably 40–240 mg, more preferably 40–180 mg, more preferably 60–140 mg, and even more preferably 60–120 mg per day, and the oral administration is continued for at least 7 days if necessary.

[0185] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule for enhancing intracellular ATP, comprising an enteric-coated granule obtained by coating a compound of general formula (I) or a pharmaceutically acceptable salt thereof with an enteric polymer, and wherein, if necessary, the compound of general formula (I) or a pharmaceutically acceptable salt thereof in the enteric-coated granule is further mixed with the enteric polymer. The tablet, granule, fine granule, or capsule is used to orally administer 10-320 mg, preferably 20-320 mg, more preferably 40-280 mg, more preferably 40-240 mg, more preferably 40-180 mg, more preferably 60-140 mg, and even more preferably 60-120 mg of the compound of general formula (I) or a pharmaceutically acceptable salt thereof to a patient requiring enhancement of intracellular ATP for at least 7 days.

[0186] Another embodiment of the present invention is a pharmaceutical composition for enhancing intracellular ATP, comprising enteric particles obtained by coating a compound of general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof with an enteric polymer. The pharmaceutical composition is used in a manner in which the compound of general formula (I) or a pharmaceutically acceptable salt thereof is administered orally to a patient requiring enhancement of intracellular ATP at a dose of 10-320 mg, preferably 20-320 mg, more preferably 40-280 mg, more preferably 40-240 mg, more preferably 40-180 mg, more preferably 60-140 mg, and even more preferably 60-120 mg per day, and the oral administration is continued for at least 7 days as needed.

[0187] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule for enhancing intracellular ATP, comprising enteric granules obtained by coating a compound of general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof with an enteric polymer. The tablet, granule, fine granule, or capsule is used to orally administer 10–320 mg, preferably 20–320 mg, more preferably 40–280 mg, more preferably 40–240 mg, more preferably 40–180 mg, more preferably 60–140 mg, and even more preferably 60–120 mg daily to patients requiring enhanced intracellular ATP, and the oral administration is continued for at least 7 days as needed.

[0188] Another embodiment of the present invention is a pharmaceutical composition for enhancing intracellular ATP, comprising enteric-coated particles obtained by coating a compound of general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof with an enteric polymer, and further mixing the compound of general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof in the enteric-coated particles with the enteric polymer. The pharmaceutical composition is used in a manner in which the compound of general formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a patient requiring enhancement of intracellular ATP at a dose of 10-320 mg, preferably 20-320 mg, more preferably 40-280 mg, more preferably 40-240 mg, more preferably 40-180 mg, more preferably 60-140 mg, and even more preferably 60-120 mg per day, and the oral administration is continued for at least 7 days as needed.

[0189] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule for enhancing intracellular ATP, comprising an enteric-coated granule obtained by coating a compound of general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof with an enteric polymer, and further mixing the compound of general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof in the enteric-coated granule with the enteric polymer. The tablet, granule, fine granule, or capsule is used to orally administer 10-320 mg, preferably 20-320 mg, more preferably 40-280 mg, more preferably 40-240 mg, more preferably 40-180 mg, more preferably 60-140 mg, and more preferably 60-120 mg of the compound of general formula (I) or a pharmaceutically acceptable salt thereof to patients who require enhancement of intracellular ATP for at least 7 days as needed.

[0190] Another embodiment of the present invention is an intracellular ATP-enhancing pharmaceutical composition containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof, which is coated with an enteric polymer and is used to orally administer 10-320 mg, preferably 20-320 mg, more preferably 40-280 mg, more preferably 40-240 mg, more preferably 40-180 mg, more preferably 60-140 mg, and even more preferably 60-120 mg per day to a patient who needs to enhance intracellular ATP, and to continue the above oral administration for at least 7 days as needed.

[0191] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule containing a compound of general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof, coated with an enteric polymer, for enhancing intracellular ATP. The tablet, granule, fine granule, or capsule is used to orally administer 10–320 mg, preferably 20–320 mg, more preferably 40–280 mg, more preferably 40–240 mg, more preferably 40–180 mg, more preferably 60–140 mg, and even more preferably 60–120 mg daily to a patient requiring enhanced intracellular ATP, and the oral administration is continued for at least 7 days as needed.

[0192] Another embodiment of the present invention is a pharmaceutical composition for enhancing intracellular ATP, comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof, coated with an enteric polymer, and further mixed with the enteric polymer. The pharmaceutical composition is used to orally administer 10–320 mg, preferably 20–320 mg, more preferably 40–280 mg, more preferably 40–240 mg, more preferably 40–180 mg, more preferably 60–140 mg, and even more preferably 60–120 mg daily to patients requiring enhanced intracellular ATP. The oral administration is continued for at least 7 days as needed.

[0193] Another embodiment of the present invention is a tablet, granule, fine granule, or capsule for enhancing intracellular ATP, which is coated with an enteric polymer containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof, and further mixed with an enteric polymer. The tablet, granule, fine granule, or capsule is used to orally administer 10–320 mg, preferably 20–320 mg, more preferably 40–280 mg, more preferably 40–240 mg, more preferably 40–180 mg, more preferably 60–140 mg, and even more preferably 60–120 mg daily to patients requiring enhanced intracellular ATP, and the oral administration is continued for at least 7 days as needed.

[0194] Another embodiment of the present invention is a hard capsule for enhancing intracellular ATP, which is obtained by containing a compound of general formula (I) or a pharmaceutically acceptable salt thereof in a hard capsule made of an enteric-coated base. The hard capsule is used to administer 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 orally to patients who need to enhance intracellular ATP for at least 7 days as needed.

[0195] Another embodiment of the present invention is a hard capsule for enhancing intracellular ATP, which is obtained by encapsulating a compound of general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof in a hard capsule made of an enteric-coated base. The hard capsule is used to administer 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 orally to patients who need to enhance intracellular ATP for 1 day. The oral administration is continued for at least 7 days as needed. Another embodiment of the present invention is a hard capsule formulation for enhancing intracellular ATP, comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof contained in a hard capsule made of an enteric-coated base, and further mixed with an enteric-coated polymer. The hard capsule formulation is used to orally administer 10-320 mg, preferably 20-320 mg, more preferably 40-280 mg, more preferably 40-240 mg, more preferably 40-180 mg, more preferably 60-140 mg, and even more preferably 60-120 mg daily to patients requiring enhanced intracellular ATP, and to continue the oral administration for at least 7 days as needed.

[0196] Another embodiment of the present invention is a hard capsule formulation for enhancing intracellular ATP, comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof contained in a hard capsule made of an enteric-coated base, and further mixed with an enteric-coated polymer. The hard capsule formulation is used to orally administer 10–320 mg, preferably 20–320 mg, more preferably 40–280 mg, more preferably 40–240 mg, more preferably 40–180 mg, more preferably 60–140 mg, and even more preferably 60–120 mg daily to patients requiring enhanced intracellular ATP, and to continue the oral administration for at least 7 days as needed.

[0197] Another embodiment of the present invention is a compound of general formula (I) or a pharmaceutically acceptable salt thereof for enhancing intracellular ATP, wherein the compound of general formula (I) or a pharmaceutically acceptable salt thereof is used to orally administer 10-320 mg, preferably 20-320 mg, more preferably 40-280 mg, more preferably 40-240 mg, more preferably 40-180 mg, more preferably 60-140 mg, and even more preferably 60-120 mg per day to a patient requiring enhancement of intracellular ATP, and the oral administration is continued for at least 7 days as needed.

[0198] Another embodiment of the present invention is a pharmaceutical composition containing a compound of general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive for enhancing intracellular ATP, wherein the pharmaceutical composition is used by orally administering 10-320 mg, preferably 20-320 mg, more preferably 40-280 mg, more preferably 40-240 mg, more preferably 40-180 mg, more preferably 60-140 mg, and even more preferably 60-120 mg daily to a patient requiring enhancement of intracellular ATP, and continuing the above oral administration for at least 7 days as needed.

[0199] Another embodiment of the present invention is a solid dispersion of the present invention or a pharmaceutical composition containing the solid dispersion for enhancing intracellular ATP, wherein the solid dispersion or pharmaceutical composition containing the solid dispersion is used to orally administer 10-320 mg, preferably 20-320 mg, more preferably 40-280 mg, more preferably 40-240 mg, more preferably 40-180 mg, more preferably 60-140 mg, and further preferably 60-120 mg per day to a patient requiring enhancement of intracellular ATP, and the oral administration is continued for at least 7 days as needed.

[0200] Another embodiment of the present invention is the use of a compound of general formula (I) or a pharmaceutically acceptable salt thereof for manufacturing a pharmaceutical composition for enhancing intracellular ATP, wherein the use is to administer orally to a patient requiring enhancement of intracellular ATP at a dose of 10-320 mg, preferably 20-320 mg, more preferably 40-280 mg, more preferably 40-240 mg, more preferably 40-180 mg, more preferably 60-140 mg, and even more preferably 60-120 mg per day, and to continue the oral administration for at least 7 days as needed.

[0201] Another embodiment of the present invention is a method for enhancing intracellular ATP by administering the pharmaceutical composition of the present invention orally to a subject requiring enhanced intracellular ATP at a dose of 10-320 mg, preferably 20-320 mg, more preferably 40-280 mg, more preferably 40-240 mg, more preferably 40-180 mg, more preferably 60-140 mg, and even more preferably 60-120 mg for at least 7 days as needed.

[0202] Another embodiment of the present invention is a method for enhancing intracellular ATP by administering, to a subject requiring enhanced intracellular ATP, 10-320 mg, preferably 20-320 mg, more preferably 40-280 mg, more preferably 40-240 mg, more preferably 40-180 mg, more preferably 60-140 mg, and even more preferably 60-120 mg orally for one day, and continuing the oral administration for at least 7 days as needed.

[0203] The dosage of the pharmaceutical composition of the present invention can be adjusted by the content of the compound represented by general formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition according to the present invention. Furthermore, it can be appropriately determined based on the method of administration, the age, weight, sex, symptoms, and sensitivity to the drug, and the dosage can also be adjusted according to the improvement of symptoms. In the present invention, it is preferable to continuously administer a constant dosage.

[0204] For the dosage of the enteric-coated formulation of the present invention, for example, for adults, it can be converted into the content of the compound represented by general formula (I) or its pharmaceutically acceptable salt. Generally, the oral administration is 10-320 mg per day, preferably 20-320 mg, more preferably 40-280 mg, more preferably 40-240 mg, more preferably 40-180 mg, more preferably 60-140 mg, further preferably 60-120 mg, and particularly preferably 60-100 mg. The above oral administration is continued for at least 7 days as needed, but can be increased or decreased according to age, symptoms, etc. In addition, as for the frequency of administration, for example, 1-3 times a day, preferably 1-2 times, more preferably once a day.

[0205] In one aspect of the present invention, since the pharmaceutical composition of the present invention preferably has a state of continuous or constant increase in intracellular ATP, the above-mentioned dosage and frequency of administration of the pharmaceutical composition of the present invention can be appropriately determined in order to achieve the above-mentioned state. For example, the frequency of administration can be twice or three times a day.

[0206] The following explanation uses neurodegenerative diseases as an example to illustrate the relationship between increased intracellular ATP and the treatment or prevention of diseases, lesions, or syndromes.

[0207] Neurodegenerative diseases are a general term for diseases in which certain groups of nerve cells (such as nerve cells related to cognitive function and cells related to motor function) in the brain and spinal cord are slowly damaged and shed for unknown reasons. Currently, treatment focuses on symptomatic relief, targeting disease-modifying drugs that do not yet address the underlying processes causing symptoms or inhibit disease progression.

[0208] The location of detached nerve cells varies depending on the disease, and various symptoms such as dementia, ataxia, and muscle weakness may appear depending on the site of degeneration. The pathogenesis of neurodegenerative diseases remains largely unclear, but a common phenomenon in many diseases is the aggregation of abnormal intracellular proteins and the subsequent cell death. Furthermore, the removal of denatured proteins in diseased nerve tissue via the ubiquitin-proteasome system consumes a large amount of ATP. When ATP consumption is excessive (e.g., due to stress-induced repair processes from the accumulation of the aforementioned abnormal proteins) or when ATP production is insufficient (e.g., due to ischemia), resulting in decreased ATP concentration, AMP breakdown is increased to maintain energy charge (EC) levels, and AMP is rapidly metabolized into uric acid via hypoxanthine.

[0209] XOR inhibitors increase blood levels of hypoxanthine and inosine by utilizing hypoxanthine to inhibit AMP breakdown, causing it to flow into nerve cells. There, purine nucleotides produced by the intracellular purine salvage pathway are regenerated into ATP. As a result, cell death is inhibited by either increasing intracellular ATP concentration or delaying its decrease. Therefore, enhancing intracellular ATP can treat or prevent the aforementioned neurodegenerative diseases. Specific examples of such neurodegenerative diseases, particularly optic neuropathy, include glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, rhinogenic optic neuropathy, demyelinating diseases (represented by multiple sclerosis), and toxic optic neuropathy (ethambutol, methanol, diluents, etc.).

[0210] In addition, in diseases, lesions, or syndromes caused by insufficient intracellular ATP, these diseases, lesions, or syndromes can be treated or prevented by increasing intracellular ATP and utilizing the same mechanism of action.

[0211] As one embodiment of the present invention, the compound represented by general formula (I) or its pharmaceutically acceptable salt has XOR inhibitory activity and is therefore useful as an active ingredient in pharmaceutical compositions for enhancing intracellular ATP.

[0212] In another embodiment of the present invention, the intracellular ATP enhancement effect is preferably achieved through the intracellular purine salvage synthesis pathway.

[0213] In another embodiment of the present invention, it is preferable that the intracellular ATP enhancement effect can be sustained even in the presence of an uncoupling agent. Here, the uncoupling agent is an agent that inhibits mitochondrial function, reduces the efficiency of respiration-based ATP production, and causes intracellular ATP to become deficient. Therefore, "the intracellular ATP enhancement effect can be sustained even in the presence of an uncoupling agent" means that the intracellular ATP enhancement effect can be sustained even in a state where intracellular ATP is deficient, i.e., in a state of circulatory failure, reduced mitochondrial function, and in a state of hypoxia caused by various other reasons (anemia, abnormal hemoglobin, etc.). Examples of uncoupling agents include the carbonyl cyanide m-chlorophenylhydrazone (sometimes abbreviated as CCCP in this specification).

[0214] As another embodiment of the present invention, the intracellular ATP enhancement effect is preferably an improvement in the balance between ATP production and consumption, which is tilted towards the consumption side.

[0215] As another embodiment of the present invention, it is preferred that the intracellular ATP enhancement effect is carried out under hypoxic conditions.

[0216] In another embodiment of the present invention, it is preferred that the intracellular ATP enhancement effect is carried out in a state of absolute or relative ATP deficiency. Here, an absolute ATP deficiency refers to a state of ATP deficiency due to insufficient oxygen required for ATP synthesis; a specific example is circulatory failure. A relative ATP deficiency refers to a state of ATP deficiency due to increased ATP consumption; a specific example is the accumulation of abnormal proteins (a state of ATP deficiency used to remove accumulated abnormal proteins).

[0217] As another embodiment of the present invention, the preferred state of absolute or relative ATP deficiency is circulatory failure, abnormal protein accumulation, or tissue damage (e.g., tissue damage caused by chemicals, trauma, etc.).

[0218] In this specification, "enhancement" of the ATP-enhancing effect refers to a significant increase in the total amount of ATP and its metabolites, namely adenosine monophosphate or adenosine monophosphate, relative to the control group (the non-dosed group of the active ingredient). Preferably, "enhancement" of the ATP-enhancing effect refers to a significant increase in ATP and / or ADP relative to the control group (the non-dosed group of the active ingredient). More preferably, "enhancement" of the ATP-enhancing effect refers to a significant increase in ATP and / or ADP and a significant decrease in AMP and / or IMP relative to the control group (the non-dosed group of the active ingredient).

[0219] Furthermore, the aforementioned "enhancement" in another embodiment refers to changing the state where the intracellular ATP level of a specific organ, tissue, etc., in a healthy person is set to 100, from a state where the ATP level is less than 100 due to disease, etc., to a level close to 100 or more, or increasing to 100 or more. For example, in patients whose intracellular ATP level is reduced due to disease, etc., this means restoring the intracellular ATP concentration to 0.5% or more by mass relative to the intracellular ATP concentration before administration of the pharmaceutical composition of the present invention, preferably restoring it to 1% or more by mass, more preferably restoring it to 2% or more by mass, further preferably restoring it to 3% or more by mass, and even more preferably restoring it to 5% or more by mass. The aforementioned "state in which the balance between ATP production and consumption is tilted towards the consumption side" refers to a disease state (e.g., in the presence of an uncoupling agent, in a hypoxic state, or in a state of abnormal protein accumulation). Furthermore, the aforementioned "state where the balance between ATP production and consumption is tilted towards the consumption side" refers to a situation where, if the intracellular ATP level in a specific organ or tissue of a healthy person is set to 100, and due to disease or other reasons, the ATP level becomes less than 100, then to further indicate that this state is more inclined towards the consumption side, the ATP level becomes 95 or less; to further indicate that this state is more inclined towards the consumption side, the ATP level becomes 90 or less; and to further indicate that this state is more inclined towards the consumption side, the ATP level becomes 80 or less. "Hypoxia" in other words refers to a state of hypoxia, a state in which blood flow to a biological tissue is reduced for some reason, failing to adequately supply oxygen to the tissue, and specifically a state in which intracellular ATP levels are reduced. Examples of diseases caused by hypoxia include circulatory failure (heart failure, cerebral infarction, etc.). "ATP enhancement under hypoxia" as an implementation means, as an example, restoring the reduced ATP levels in the aforementioned diseases of circulatory failure. "Circulatory failure" refers to a disease in which blood flow to a biological tissue is reduced for some reason, failing to adequately supply oxygen to the tissue. Examples of such diseases include chronic heart failure, cerebral infarction, and cardiomyopathy. "Abnormal protein accumulation" refers to the state in which proteins with abnormal conformations aggregate and accumulate in tissues, such as the accumulation of abnormal proteins within nerve cells. Diseases characterized by this state include neurodegenerative diseases, retinitis pigmentosa, and age-related macular degeneration.

[0220] In one embodiment of the present invention, the pharmaceutical composition for enhancing intracellular ATP is effective in treating or preventing diseases, lesions, or syndromes (also referred to collectively as "ATP-related diseases" in this specification), such as hemolytic anemia, sickle cell disease, pyruvate kinase deficiency, spherocytosis, elliptic polycythemia, stomatocytosis, thalassemia, ischemic heart disease, heart failure, cardiovascular disease, hypertension, tachycardia, arrhythmia, chronic progressive extraocular muscle palsy syndrome, fragmented red fibers, and myoclonic 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, adenosine monophosphate lyase deficiency, Alzheimer's disease, Lewy body dementia, frontotemporal dementia, retinitis pigmentosa, cone-rod dystrophy, microstomia, scleral lentigines, paravenous choroidal atrophy, Leber congenital amaurosis, cone dystrophy, Stargardt's disease, Best's disease, familial exudative vitiligo Vitreoretinal diseases, Wagner syndrome, Stickler syndrome, central halo choroidal dystrophy, choroidal agenesis, cycloplegic choroidal dystrophy, retinal degeneration caused by uveitis, retinal degenerative diseases including drug-induced (chloroquine, etc.) retinopathy, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, diabetic retinopathy, renal retinopathy, age-related macular degeneration, central serous chorioretinopathy, retinal white spot syndrome, retinal vascular streaks, rhegmatogenous retinopathy involving the macula. Retinal detachment, macular hole, retinoschisis, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment due to high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, rhinogenic optic neuropathy, demyelinating optic neuropathy (represented by multiple sclerosis), and toxic optic neuropathy (caused by ethambutol, methanol, diluents, etc.). Among these, retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, Leber congenital amaurosis, or glaucoma are preferred. Furthermore, retinitis pigmentosa, age-related macular degeneration, or glaucoma are most preferred. That is, the intracellular ATP-enhancing pharmaceutical composition of one embodiment of the present invention can be used for the treatment or prevention of the above-mentioned diseases, lesions, or syndromes.

[0221] In one embodiment of the present invention, the active ingredient of the pharmaceutical composition for enhancing intracellular ATP preferably contains only the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, without the use of inosine, inosine acid, hypoxanthine or their salts.

[0222] In another embodiment of the present invention, the active ingredient of the pharmaceutical composition for enhancing intracellular ATP may contain inosine, inosine acid, hypoxanthine or salts thereof, and compounds represented by general formula (I) or pharmaceutically acceptable salts thereof.

[0223] However, hyperuricemia is a condition characterized by abnormally high levels of uric acid in the blood. In hyperuricemia, some uric acid does not completely dissolve and crystallizes. If this crystallized uric acid accumulates in the joints and causes inflammation, it can develop into gouty arthritis, manifesting as a gout attack with severe pain. Hyperuricemia can present with the clinical symptoms of gouty arthritis or asymptomatic hyperuricemia without these symptoms.

[0224] The pharmaceutical composition provided by the present invention can be administered to patients who need to enhance intracellular ATP, but since the pharmaceutical composition provided by the present invention can exhibit the effect of lowering the blood uric acid level, it is preferred to use it for patients with gouty arthritis (e.g., patients with gouty arthritis who have symptoms of hyperuricemia), or patients with hyperuricemia who have symptoms of gout attacks, and patients with asymptomatic hyperuricemia.

[0225] In this specification, when the terms "suppressing gout attacks," "suppressing the induction of gout attacks," or "suppressing the manifestation of gout attacks" are used, for example, it means, compared with the control group or placebo group of conventional uric acid-lowering drugs such as allopurinol or febuxostat, that the frequency or severity (e.g., pain level) of "gout attacks" is reduced, preferably with reduced frequency, and preferably includes no "gout attacks."

[0226] Generally, when treating gouty arthritis patients to lower serum uric acid levels, uric acid-lowering drugs are administered after the gout attack has subsided (pain relief). The dosage should start low and be gradually increased to slowly lower the serum uric acid level to the target value. This is because a rapid decrease in serum uric acid levels caused by uric acid-lowering drugs leads to a rapid redissolution of urate crystals attached to the joint, making them easier to detach and triggering a gout attack. It is known that gout attacks caused by a rapid decrease in uric acid levels due to uric acid-lowering drugs are mobilization flare-ups.

[0227] The pharmaceutical composition provided by this invention can exhibit the effect of slowly reducing the concentration of uric acid in the blood, and thus can suppress acute gout attacks such as mobilization flare-up caused by uric acid transfer in a manner that does not gradually increase or increases less gradually.

[0228] On the other hand, when febuxostat, as an XOR inhibitor, is used to treat gout, in Japan, in order to suppress the induction of gout attacks caused by a sharp drop in blood uric acid levels (mobilization flare-up), it is recommended to start with 10 mg once a day, then 20 mg once a day after 2 weeks of starting medication, and then 40 mg once a day after 6 weeks of starting medication, and so on, with a slow increase in dose.

[0229] In one embodiment, the pharmaceutical composition provided by the present invention does not require a gradual increase in the daily dosage to suppress the symptoms of gout attacks (mobilization flare-up) that accompany the start of administration, and the daily dosage can be maintained for 3 weeks from the start of administration without increasing the daily dosage.

[0230] In one embodiment, the pharmaceutical composition provided by the present invention does not require a gradual increase in the daily dosage to suppress the symptoms of gout attacks (mobilization flare-up) that accompany the start of administration. Instead, the daily dosage can be maintained for no more than 7 weeks from the start of administration, or the daily dosage can be increased less than once.

[0231] The effect of slowly lowering blood uric acid levels that can be achieved by administering the pharmaceutical composition provided by the present invention can be manifested, for example, by administering 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 mg, 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg) of a compound of general formula (I) or a pharmaceutically acceptable salt thereof orally for one day. Alternatively, serum uric acid levels can be slowly reduced by administering 10–320 mg (e.g., 10–160 mg, 20–160 mg, 40–160 mg, 80–160 mg, 10–80 mg, 20–80 mg, 40–80 mg, 10–40 mg, 20–40 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg) of a compound of general formula (I) or a pharmaceutically acceptable salt thereof for one day, for example, by administering it for more than 7 days (e.g., 1 month, 2 months, or 3 months).

[0232] In one embodiment, the pharmaceutical composition of the present invention containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is used to administer 10 to 320 mg orally once daily to a patient requiring treatment, and the oral administration is continued for at least 7 days as needed. According to this embodiment, the patient's uric acid level decreases slowly rather than abruptly, thus reducing the induction or severity of gout attacks and being beneficial for enhancing intracellular ATP.

[0233] The effect of the pharmaceutical composition provided by the present invention in slowly lowering serum uric acid levels can be confirmed, for example, by administering the pharmaceutical composition provided by the present invention to healthy adults (e.g., males) for 7 consecutive days, measuring serum uric acid levels before and after administration, and finding that the maximum reduction rate of serum 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 approximately 35% or less (e.g., a reduction of 1% to 35%). Low, 10-30%, 10-25%, 10-20%, 15-25% reduction); and / or, the maximum reduction rate of serum uric acid 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 approximately 55% or less (e.g., 1-55%, 10-50%, 15-45%, 20-45%, 20-40%, 20-35%).

[0234] Blood uric acid levels (blood uric acid concentration) can be measured using the well-known uricase-peroxidase method.

[0235] In this instruction manual, the time or period expressed as "from the start of administration" can be calculated, for example, from the first administration of a compound of general formula (I) or a pharmaceutically acceptable salt thereof in a treatment regimen. Thus, for example, "3 weeks after the start of administration" refers to the time corresponding to 3 weeks after the first administration, and "7 weeks after the start of administration" refers to the time corresponding to 7 weeks after the first administration.

[0236] When the term "administration" is expressed in terms of time or period, it refers to the duration of time or the elapsed period starting from the time of administration. For example, "12 hours after administration" means 12 hours after the time of administration, and "7 days after administration" means 7 days after the time of administration. In this specification, the term "period" is generally used for times specified with "day," "month," or "year."

[0237] In this instruction manual, when expressed as "day X of administration," its meaning is to be determined from the context. For example, "day 1 of administration" sometimes refers to the point in a treatment plan after 1 day (24 hours) from the first administration, sometimes it refers to the period from the first administration to the point before the point after 1 day (24 hours), or sometimes it refers to the time before or after the point after 1 day (24 hours) from the first administration, for example, ±12 hours, preferably ±6 hours, more preferably ±2 hours.

[0238] In this specification, "minimum uric acid value after administration on day 1" refers to, for example, the minimum uric acid value measured by blood samples taken from the subject every hour from the time of the first administration until one day later (after 24 hours) in a treatment plan, using a method known to the author. Similarly, "minimum uric acid value after administration on day 7" refers to, for example, the minimum uric acid value measured by blood samples taken from the subject every hour from the time of the first administration until seven days later (after 144 hours) in a treatment plan, using a method known to the author. As "before administration," it is preferably 12 hours before the first administration in a treatment plan, more preferably 6 hours before the first administration, further preferably 2 hours before the first administration, and particularly preferably 1 hour before the first administration. Therefore, "uric acid value before administration" refers to, for example, the uric acid value measured by blood samples taken from the subject 12 hours, preferably 6 hours, more preferably 2 hours, and further preferably 1 hour before the first administration in a treatment plan, using a method known to the author.

[0239] The content of the compound represented by general formula (I) or its pharmaceutically acceptable salt contained in the pharmaceutical composition provided by the present invention can be appropriately set by those skilled in the art. For example, the content of the compound represented by general formula (I) or its pharmaceutically acceptable salt contained in the pharmaceutical composition provided by the present invention can be 10-320 mg (e.g., 10-160 mg, 20-160 mg, 40-160 mg, 80-160 mg, 10-80 mg, 20-80 mg, 40-80 mg, 10-40 mg, 20-40 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 140 mg or 160 mg).

[0240] The pharmaceutical composition provided by this invention can be a single dosing unit. The content of the compound represented by general formula (I) or its pharmaceutically acceptable salt in each dosing unit can 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).

[0241] The packaging form of the pharmaceutical composition provided by this invention can be appropriately determined by those skilled in the art. Examples of packaging forms include plastic containers, glass containers, PTP tablets, etc. The pharmaceutical composition provided by this invention can be provided in the form of a pharmaceutical composition containing a number of dosing units required for continuous administration for 5 to 15 days. For example, the pharmaceutical composition provided by this invention can be provided in the form of a PTP tablet containing 5 to 15 (e.g., 6, 7, 8, 10, 12, or 14) dosing units.

[0242] In this instruction manual, "drug administration unit" refers to a unit of the formulation, and "one drug administration unit" refers to the smallest unit of the formulation. Therefore, for example, if it is a tablet, the drug administration unit is each tablet, and one drug administration unit represents one tablet. If it is an injection, the drug administration unit is the injection obtained by filling a sealed container such as an ampoule or vial, and one drug administration unit represents the injection obtained by filling one sealed container such as an ampoule or vial.

[0243] When the pharmaceutical composition provided by the present invention is administered to humans or other mammals, one or more of the above-mentioned administration units may be given at one time, or the above-mentioned administration unit may be divided and administered.

[0244] The following can be cited as examples of other embodiments of the present invention.

[0245] <1-1> A pharmaceutical composition containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof for enhancing intracellular ATP.

[0246] <1-2> A pharmaceutical composition comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, for the treatment or prevention of hemolytic anemia, sickle cell disease, pyruvate kinase deficiency, spherocytosis, elliptic polycythemia, stomatocytosis, thalassemia, ischemic heart disease, heart failure, cardiovascular disease, hypertension, tachycardia, arrhythmia, chronic progressive extraocular muscle palsy syndrome, broken red fibers, myoclonic epilepsy syndrome, mitochondrial encephalomyopathy, lactic acidosis, stroke-like syndrome, L... Eigh encephalopathy, mitochondrial cardiomyopathy, mitochondrial diabetes, Pearson's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, adenosine monophosphate lyase deficiency, Alzheimer's disease, Lewy body dementia, frontotemporal dementia, retinitis pigmentosa, cone-rod dystrophy, microstomia, punctate fundus, paravenous choroidal atrophy, Leber congenital amaurosis, cone dystrophy, Stargardt's disease, Best's disease, familial exudative vitreoretinopathy, Wagner's syndrome This includes conditions such as: retinal degeneration caused by uveitis, retinal degenerative diseases including drug-induced (chloroquine, etc.) retinopathy, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, diabetic retinopathy, renal retinopathy, age-related macular degeneration, central serous chorioretinopathy, white spot syndrome, retinal vascular streaks, rhegmatogenous retinal detachment involving the macula, and macular degeneration. Retinal detachment, retinoschisis, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment due to high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, rhinogenic optic neuropathy, demyelinating optic neuropathy (represented by multiple sclerosis), or toxic optic neuropathy (caused by ethambutol, methanol, diluents, etc.).

[0247] <1-3> A pharmaceutical composition for the use described in <1-1> or <1-2>, wherein the symptoms of a gout attack accompanying the initiation of the above treatment or prevention are suppressed.

[0248] <1-4> A pharmaceutical composition for use according to any one of <1-1> to <1-3>, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is administered orally to a patient requiring enhanced intracellular ATP at a dose of 10 to 320 mg per day and, if necessary, the oral administration is continued for at least 7 days.

[0249] <1-5> A pharmaceutical composition for use according to any one of <1-1> to <1-4>, wherein R 1 It is an unsubstituted phenyl or a phenyl substituted with a halogen atom.

[0250] <1-6> A pharmaceutical composition for use according to any one of <1-1> to <1-5>, wherein X is an oxygen atom.

[0251] <1-7> A pharmaceutical composition for use according to any one of <1-1> to <1-6>, wherein Y is a sulfur atom.

[0252] <1-8> A pharmaceutical composition for use according to any one of <1-1> to <1-7>, wherein the compound or pharmaceutically acceptable salt thereof described in any one of <1-1> to <1-7> comprises its amorphous content, wherein the amorphous content is 80% by weight or more relative to the total weight of the compound or pharmaceutically acceptable salt thereof described in any one of <1-1> to <1-7>.

[0253] <1-9> A pharmaceutical composition for use according to any one of <1-1> to <1-8>, wherein the pharmaceutical composition is an enteric-coated preparation.

[0254] <1-10> A pharmaceutical composition for the use described in <1-9>, wherein the above-mentioned enteric-coated preparation is a hard capsule.

[0255] <1-11> A pharmaceutical composition for use according to any one of <1-1> to <1-10>, wherein the composition further comprises a solid dispersion containing a hydroxypropyl methylcellulose derivative.

[0256] <1-12> A pharmaceutical composition for the use described in <1-11>, wherein the weight ratio of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to a hydroxypropyl methylcellulose derivative is 1:0.1 to 1:25.

[0257] <1-13> A pharmaceutical composition for use according to <1-11> or <1-12>, wherein the hydroxypropyl methylcellulose derivative is hydroxypropyl methylcellulose acetate succinate or hydroxypropyl methylcellulose phthalate.

[0258] <1-14> A pharmaceutical composition for use according to any one of <1-1> to <1-13>, wherein the pharmaceutical composition is a solid dosage form.

[0259] <1-15> A pharmaceutical composition for use according to any one of <1-1> to <1-14>, wherein the content of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is 10 mg to 320 mg.

[0260] <1-16> A pharmaceutical composition for use according to any one of <1-1> to <1-15>, wherein the content of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dosing unit is 10 mg to 320 mg.

[0261] <1-17> A pharmaceutical composition for use according to any one of <1-1> to <1-16>, wherein the content of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dosing unit is 10 mg to 160 mg.

[0262] <1-18> A pharmaceutical composition for use according to any one of <1-1> to <1-17>, wherein the content of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dosing unit is 10 mg to 80 mg.

[0263] <1-19> A pharmaceutical composition for use according to any one of <1-1> to <1-18>, wherein the content of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof per dosing unit is 20 mg to 80 mg.

[0264] <1-20> A pharmaceutical composition for use according to any one of <1-1> to <1-19>, wherein, 12 hours after administration on the first day of administration, the blood uric acid concentration is reduced by 0.5 to 2.0 mg / dL (e.g., 0.5 to 1.5 mg / dL) compared to before administration.

[0265] <1-21> A pharmaceutical composition for use according to any one of <1-1> to <1-20>, wherein, by administering once daily for 7 consecutive days, the blood uric acid concentration 12 hours after administration on the 7th day of administration is reduced by 1.5 to 3.0 mg / dL (e.g., 1.5 to 2.5 mg / dL) compared to before administration.

[0266] <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 continuously from the start of administration until 3 weeks after administration, without increasing the daily dose of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

[0267] <1-23> A pharmaceutical composition for use according to any one of <1-1> to <1-22>, wherein the pharmaceutical composition is administered once daily continuously from the start of administration until 7 weeks after administration without increasing or increasing the daily dose of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

[0268] <1-24> A pharmaceutical composition for use according to any one of <1-1> to <1-23>, wherein, when the pharmaceutical composition is administered once a day continuously, the maximum reduction rate of serum uric acid level on the first day of administration ([(uric acid level before administration - minimum uric acid level after administration on the first day of administration) / uric acid level before administration]×100) is 10-25%.

[0269] <1-25> A pharmaceutical composition for use according to any one of <1-1> to <1-24>, wherein, when the pharmaceutical composition is administered continuously once a day, the maximum reduction rate of serum uric acid level on the 7th day of administration ([(uric acid level before administration - minimum uric acid level after administration on the 7th day of administration) / uric acid level before administration]×100) is 20-45%.

[0270] <1-26> 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-hydroxythiazo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof.

[0271] <1-27> A packaging body is a packaging body containing a pharmaceutical composition for any one of <1-1> to <1-26>, the packaging body containing the amount of the pharmaceutical composition required for continuous administration for 5 to 15 days.

[0272] <1-28> An enhancer containing an XOR inhibitor as an active ingredient, used to enhance ATP, ADP, GTP or GDP in tissues, organs, viscera or cells where the expression of the target enzyme XOR is not substantially visible or is low.

[0273] <1-29> An enhancer for use according to <1-28>, wherein the XOR inhibitor is a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, allopurinol, topiroxostat or febuxostat.

[0274] <1-30> Enhancers for the purposes described in <1-28> or <1-29>, wherein the organ in which the expression of the target enzyme XOR is substantially not seen or is poorly expressed is the eyeball.

[0275] <1-31> An enhancer for use according to any one of <1-28> to <1-30>, wherein the tissue in which the expression of the target enzyme XOR is substantially not seen or is poorly expressed is the retina.

[0276] <1-32> An enhancer for use according to any one of <1-28> to <1-30>, wherein the tissue in which the expression of the target enzyme XOR is substantially not visible or is poorly expressed is the optic nerve.

[0277] <1-33> An enhancer for use according to any one of <1-28> to <1-32>, wherein the enhancer further comprises an ATP precursor.

[0278] <1-34> Enhancers for the use described in <1-33>, wherein the aforementioned ATP precursor is inosine and / or hypoxanthine.

[0279] <1-35> A therapeutic and / or preventive agent comprising an XOR inhibitor as an active ingredient, for the treatment and / or prevention of ATP-related diseases in tissues, organs, viscera or cells in which the expression of the target enzyme XOR is substantially not visible or is poorly expressed.

[0280] <1-36> A therapeutic and / or preventive agent for the use described in <1-35>, wherein the XOR inhibitor is a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, allopurinol, topiroxostat or febuxostat.

[0281] <1-37> A therapeutic and / or preventive agent for the purpose described in <1-35> or <1-36>, wherein the organ in which the expression of the target enzyme XOR is substantially not seen or is poorly expressed is the eyeball.

[0282] <1-38> A therapeutic and / or preventive agent for any of the uses described in any one of <1-35> to <1-37>, wherein the tissue in which the expression of the target enzyme XOR is substantially not seen or is poorly expressed is the retina.

[0283] <1-39> A therapeutic and / or preventive agent for any of the uses described in any one of <1-35> to <1-37>, wherein the tissue in which the expression of the target enzyme XOR is substantially not seen or is poorly expressed is the optic nerve.

[0284] <1-40> A treatment and / or preventive agent for use according to any one of <1-35> to <1-39>, wherein the above-mentioned ATP-related disease is an ATP-related eye disease.

[0285] <1-41> A treatment and / or preventative agent according to the uses described in <1-40>, wherein the aforementioned ATP-related eye diseases are retinitis pigmentosa, cone-rod dystrophy, microstomia, punctate fundus, perivenous retinal choroidal atrophy, Leber congenital amaurosis, cone dystrophy, Stargardt's disease, Best's disease, familial exudative vitreoretinopathy, Wagner syndrome, Stickler syndrome, central halo choroidal dystrophy, achoroidemia, cycloplegic choroidal dystrophy, retinal degeneration caused by uveitis, retinal degeneration including drug-induced (including chloroquine) retinal damage, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, and diabetes. Diabetic retinopathy, renal retinopathy, age-related macular degeneration, central serous chorioretinopathy, white spot syndrome, retinal vascular streaks, rhegmatogenous retinal detachment involving the macula, macular hole, retinoschisis, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment due to high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, rhinogenic optic neuropathy, demyelinating optic neuropathy (including multiple sclerosis), or toxic optic neuropathy (including ethambutol, methanol, and diluents).

[0286] <1-42> A pharmaceutical composition comprising an XOR inhibitor as an active ingredient for the treatment and / or prevention of ATP-related diseases in tissues, organs, viscera or cells in which the expression of the target enzyme XOR is substantially not visible or is poorly expressed.

[0287] <1-43> A pharmaceutical composition for use according to <1-42>, wherein the pharmaceutical composition further comprises an ATP precursor.

[0288] <1-44> A pharmaceutical composition for use according to <1-43>, wherein the ATP precursor is inosine and / or hypoxanthine.

[0289] <2-1> The use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for enhancing intracellular ATP.

[0290] <2-2> The use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of hemolytic anemia, sickle cell disease, pyruvate kinase deficiency, spherocytosis, elliptic polycythemia, stomatocytosis, thalassemia, ischemic heart disease, heart failure, cardiovascular disease, hypertension, tachycardia, arrhythmia, chronic progressive extraocular muscle palsy syndrome, broken red fibers, myoclonic epilepsy syndrome, mitochondrial encephalomyopathy, lactic acidosis, stroke-like syndrome, Leigh encephalopathy, mitochondrial heart disease. Myopathy, Leber disease, mitochondrial diabetes, Pearson's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, adenosine monophosphate lyase deficiency, Alzheimer's disease, Lewy body dementia, frontotemporal dementia, retinitis pigmentosa, cone-rod dystrophy, microstomia, white spot fundus, paravenous retinal choroidal atrophy, Leber congenital amaurosis, cone dystrophy, Stargardt's disease, Best's disease, familial exudative vitreoretinopathy, Wagner syndrome, Stic Kler syndrome, central halo choroidal dystrophy, choroidal agenesis, cycloplegic choroidal dystrophy, retinal degeneration caused by uveitis, drug-induced (chloroquine, etc.) retinopathy, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, diabetic retinopathy, renal retinopathy, age-related macular degeneration, central serous chorioretinopathy, white spot syndrome, retinal vascular streaks, rhegmatogenous retinal detachment involving the macula, macular hole, retinal schisis. Pharmaceutical compositions for the treatment or prevention of exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment due to high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, rhinogenic optic neuropathy, demyelinating optic neuropathy (represented by multiple sclerosis), or toxic optic neuropathy (caused by ethambutol, methanol, diluents, etc.).

[0291] <2-3> As described in <2-1> or <2-2>, the symptoms of a gout attack accompanied by the initiation of the above treatment or prevention are suppressed.

[0292] <2-4> Use according to any one of <2-1> to <2-3>, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is used in such a manner as to administer 10 to 320 mg orally once a day to a patient who requires enhancement of intracellular ATP and to continue such oral administration for at least 7 days as needed.

[0293] <2-5> Use according to any one of <2-1> to <2-4>, wherein R 1 It is an unsubstituted phenyl or a phenyl substituted with a halogen atom.

[0294] <2-6> Use according to any one of <2-1> to <2-5>, wherein X is an oxygen atom.

[0295] <2-7> Use according to any one of <2-1> to <2-6>, wherein Y is a sulfur atom.

[0296] <2-8> Use according to any one of <2-1> to <2-7>, wherein the compound or pharmaceutically acceptable salt of any one of <2-1> to <2-7> comprises its amorphous content, wherein the amorphous content is 80% by weight or more relative to the total weight of the compound or pharmaceutically acceptable salt of any one of <2-1> to <2-7>.

[0297] <2-9> Use according to any one of <2-1> to <2-8>, wherein the pharmaceutical composition is an enteric-coated preparation.

[0298] <2-10> The use according to <2-9>, wherein the above enteric-coated preparation is a hard capsule.

[0299] <2-11> Use according to any one of <2-1> to <2-10>, wherein the pharmaceutical composition comprises a solid dispersion further comprising a hydroxypropyl methylcellulose derivative.

[0300] <2-12> According to the use described in <2-11>, wherein the weight ratio of the compound represented by general formula (I) or its pharmaceutically acceptable salt to the hydroxypropyl methylcellulose derivative is 1:0.1 to 1:25.

[0301] <2-13> Used according to <2-11> or <2-12>, wherein the hydroxypropyl methylcellulose derivative is hydroxypropyl methylcellulose acetate succinate or hydroxypropyl methylcellulose phthalate.

[0302] <2-14> Use according to any one of <2-1> to <2-13>, wherein the pharmaceutical composition is a solid dosage form.

[0303] <2-15> Use according to any one of <2-1> to <2-14>, wherein the content of the compound represented by general formula (I) or its pharmaceutically acceptable salt is 10 mg to 320 mg.

[0304] <2-16> Use according to 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 in each dosing unit of the pharmaceutical composition is 10 mg to 320 mg.

[0305] <2-17> Use according to any one of <2-1> to <2-16>, wherein the content of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof in each dosing unit of the pharmaceutical composition is 10 mg to 160 mg.

[0306] <2-18> Use according to 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 in each dosing unit of the pharmaceutical composition is 10 mg to 80 mg.

[0307] <2-19> Use according to any one of <2-1> to <2-18>, wherein the content of the compound represented by general formula (I) or its pharmaceutically acceptable salt in each dosing unit of the pharmaceutical composition is 20 mg to 80 mg.

[0308] <2-20> Use according to 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 (e.g., 0.5 to 1.5 mg / dL) 12 hours after administration on the first day of administration compared with before administration.

[0309] <2-21> Use according to any one of <2-1> to <2-20>, wherein the pharmaceutical composition is administered once daily for 7 consecutive days, and the blood uric acid concentration 12 hours after administration on the 7th day of administration is reduced by 1.5 to 3.0 mg / dL (e.g., 1.5 to 2.5 mg / dL) compared with that before administration.

[0310] <2-22> Use according to any one of <2-1> to <2-21>, wherein the pharmaceutical composition is administered once daily continuously from the start of administration until 3 weeks after administration without increasing the daily dose of the compound represented by general formula (I) or its pharmaceutically acceptable salt.

[0311] <2-23> Use according to any one of <2-1> to <2-22>, wherein the pharmaceutical composition is administered once daily continuously from the start of administration until 7 weeks after administration, without increasing or increasing the daily dose of the compound represented by general formula (I) or its pharmaceutically acceptable salt.

[0312] <2-24> According to any one of <2-1> to <2-23>, wherein the pharmaceutical composition is administered once a day continuously, and the maximum reduction rate of serum uric acid level on the first day of administration ([(uric acid level before administration - minimum uric acid level after administration on the first day of administration) / uric acid level before administration]×100) is 10-25%.

[0313] <2-25> According to any one of <2-1> to <2-24>, wherein the pharmaceutical composition is administered once a day continuously, and the maximum reduction rate of serum uric acid level on the 7th day of administration ([(uric acid level before administration - minimum uric acid level after administration on the 7th day of administration) / uric acid level before administration]×100) is 20-45%.

[0314] <2-26> Use according to 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-hydroxythiazo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof.

[0315] <2-27> The use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof for manufacturing a package containing any one of <2-1> to <2-26> and a package containing the amount of a pharmaceutical composition required for continuous administration for 5 to 15 days.

[0316] <2-28> The use of an XOR inhibitor to produce an enhancer of ATP, ADP, GTP, or GDP in tissues, organs, viscera, or cells where the expression of the target enzyme XOR is substantially invisible or minimal.

[0317] <2-29> According to the use described in <2-28>, the XOR inhibitor is a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, allopurinol, topiroxostat or febuxostat.

[0318] <2-30> According to the use described in <2-28> or <2-29>, the organ in which the expression of the target enzyme XOR is not substantially visible or is poorly expressed is the eyeball.

[0319] <2-31> Use according to any one of <2-28> to <2-30>, wherein the tissue in which the expression of the target enzyme XOR is substantially not seen or is poorly expressed is the retina.

[0320] <2-32> Use according to any one of <2-28> to <2-30>, wherein the tissue in which the expression of the target enzyme XOR is not substantially visible or is poorly expressed is the optic nerve.

[0321] <2-33> Use according to any one of <2-28> to <2-32>, wherein the above-mentioned enhancer further comprises an ATP precursor.

[0322] <2-34> The use according to <2-33>, wherein the above-mentioned ATP precursor is inosine and / or hypoxanthine.

[0323] <2-35> The use of an XOR inhibitor for the manufacture of a therapeutic and / or preventative agent for ATP-related diseases in tissues, organs, viscera or cells where the expression of the target enzyme XOR is substantially not visible or is minimal.

[0324] <2-36> According to the use described in <2-35>, the XOR inhibitor is a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, allopurinol, topiroxostat or febuxostat.

[0325] <2-37> According to the use described in <2-35> or <2-36>, the organ in which the expression of the target enzyme XOR is not substantially visible or is poorly expressed is the eyeball.

[0326] <2-38> Use according to any one of <2-35> to <2-37>, wherein the tissue in which the expression of the target enzyme XOR is substantially not seen or is poorly expressed is the retina.

[0327] <2-39> Use according to any one of <2-35> to <2-37>, wherein the tissue in which the expression of the target enzyme XOR is not substantially visible or is poorly expressed is the optic nerve.

[0328] <2-40> Use according to any one of <2-35> to <2-39>, wherein the above-mentioned ATP-related diseases are ATP-related eye diseases.

[0329] <2-41> According to the use described in <2-40>, the aforementioned ATP-related eye diseases include retinitis pigmentosa, cone-rod dystrophy, microstomia, punctate fundus, perivenous retinal choroidal atrophy, Leber congenital amaurosis, cone dystrophy, Stargardt's disease, Best's disease, familial exudative vitreoretinopathy, Wagner syndrome, Stickler syndrome, central halo choroidal dystrophy, achoroidemia, cycloplegic choroidal dystrophy, retinal degeneration caused by uveitis, retinal degenerative diseases including drug-induced (including chloroquine) retinal damage, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, and diabetic retinopathy. Retinopathy, renal retinopathy, age-related macular degeneration, central serous chorioretinopathy, white spot syndrome, retinal vascular streaks, rhegmatogenous retinal detachment involving the macula, macular hole, retinoschisis, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment due to high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, rhinogenic optic neuropathy, demyelinating optic neuropathy (including multiple sclerosis), or toxic optic neuropathy (including ethambutol, methanol, and diluents).

[0330] <2-42> The use of an XOR inhibitor for the manufacture of pharmaceutical compositions for the treatment and / or prevention of ATP-related diseases in tissues, organs, viscera or cells where the expression of the target enzyme XOR is substantially not visible or is low.

[0331] <2-43> The use according to <2-42>, wherein the above-mentioned pharmaceutical composition further comprises an ATP precursor.

[0332] <2-44> The use according to <2-43>, wherein the above-mentioned ATP precursor is inosine and / or hypoxanthine.

[0333] As another example of embodiments of the present invention, an enhancer of ATP, ADP, GTP, or GDP in tissues, organs, viscera, or cells containing an XOR inhibitor as an active ingredient, wherein the expression of the target enzyme XOR is substantially absent or minimal in cells. The XOR inhibitor can improve cell viability and inhibit cell death by also enhancing ATP, ADP, GTP, or GDP and increasing energy charge (EC) in the tissue, organ, viscera, or cells.

[0334] Here, the expression of XOR is not actually observed, or its expression is rarely investigated using known techniques, such as genetic engineering methods (RT-PCR, Northern blotting, microarray), as well as the immunohistochemical methods and biochemical methods (enzyme activity assays) shown in the embodiments of this application. In this invention, "substantially invisible XOR expression" means that the expression level of XOR cannot be detected using the above methods, and "very low XOR expression" means, for example, that the enzyme activity in the lysate is less than 0.1 nmole urate / min / mg protein or less than 0.05 nmole urate / min / mg protein, or that, based on the expression level of RNA under the known database "THE HUMAN PROTEIN ATLAS" for xanthine dehydrogenase (XDH) (https: / / www.proteinatlas.org / ENSG00000158125-XDH / tissue), the GTEx value is less than 1, 0.8, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 nTPN, or the FANTOM5 value is less than 1, 0.8, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 Scaled Tags Per Million. Examples of organs where the expression of the target enzyme XOR is virtually invisible or minimal within cells include the eyeball. Examples of tissues where the expression of the target enzyme XOR is virtually invisible or minimal within cells include the retina and the optic nerve.

[0335] In this invention, "XOR inhibitor" refers to a compound that inhibits XOR as a target enzyme. Examples of XOR inhibitors include compounds represented by general formula (I) or pharmaceutically acceptable salts thereof, allopurinol, topiroxostat, and febuxostat.

[0336] The ATP, ADP, GTP, or GDP enhancer of the present invention may further include an ATP precursor. The ATP precursor can act directly or indirectly on the purine salvage pathway, enhancing the effect of the XOR inhibitor as an enhancer. Examples of ATP precursors include inosine and inosine, which can act separately with the aforementioned XOR inhibitors.

[0337] As another example of the present invention, a therapeutic and / or preventive agent for ATP-related diseases in tissues, organs, viscera or cells containing an XOR inhibitor as an active ingredient, wherein the expression of the target enzyme XOR is substantially not visible or is minimal in the cells.

[0338] As an example of an embodiment of the present invention, a treatment and / or preventive agent for ATP-related eye diseases containing an XOR inhibitor as an active ingredient may be cited. Examples of ATP-related eye diseases include diseases that cause damage to the retina or optic nerve, specifically, examples include retinitis pigmentosa, cone-rod dystrophy, microstomia, punctate fundus, paravenous retinal choroidal atrophy, Leber congenital amaurosis, cone dystrophy, Stargardt's disease, Best's disease, familial exudative vitreoretinopathy, Wagner syndrome, Stickler syndrome, central halo choroidal dystrophy, choroidal atrophy, cycloplegic choroidal dystrophy, retinal degeneration caused by uveitis, retinal degenerative diseases including drug-induced (including chloroquine) retinal damage, retinal vein occlusion, retinal artery occlusion, hypertensive retinopathy, and diabetes. Pathological retinopathy, renal retinopathy, age-related macular degeneration, central serous chorioretinopathy, white spot syndrome, retinal vascular streaks, rhegmatogenous retinal detachment involving the macula, macular hole, retinoschisis, exudative retinal detachment, proliferative vitreoretinopathy, retinal detachment due to high myopia, Usher syndrome, Bardet-Biedl syndrome, Kearns-Sayre syndrome, Refsum syndrome, glaucoma, optic neuritis, ischemic optic neuropathy, compressive optic neuropathy, rhinogenic optic neuropathy, demyelinating optic neuropathy (including multiple sclerosis), and toxic optic neuropathy (containing ethambutol, methanol, and diluents).

[0339] The method of administration of the XOR inhibitor of the present invention can be appropriately selected for various diseases. For example, oral administration, such as tablets, is preferred for ATP-related ophthalmopathy, but it is not limited thereto. This is because the present invention shows that when the XOR inhibitor is administered orally, the amount of hypoxanthine and inosine increases in organisms such as the liver. The hypoxanthine and inosine transferred to the blood cross the blood-retinal barrier and increase ATP in the eye.

[0340] The XOR inhibitor of the present invention can be a pharmaceutical composition, which can be combined with pharmaceutically acceptable additives as needed. For example, the pharmaceutical composition of the present invention containing the XOR inhibitor as an active ingredient can be manufactured by appropriately combining and adding the required amounts of binders, disintegrants, excipients, lubricants, etc. The pharmaceutical composition can be manufactured into appropriate dosage forms such as tablets, capsules, granules, powders, eye drops, lozenges, ointments, creams, gels, wet wipes, patches, liniments, tapes, poultices, injections, or suppositories according to conventional methods in the field of pharmaceutical formulation.

[0341] Examples of adhesives mentioned above include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, agar, alginate, sodium alginate, partially saponified polyvinyl alcohol, amylopectin, partially α-starch, dextrin, xanthan gum, and gum arabic powder. They can be used individually or in mixtures of two or more. Hydroxypropylcellulose, hydroxypropyl methylcellulose, or polyvinylpyrrolidone are preferred.

[0342] Examples of such disintegrants include crystalline cellulose, carboxymethyl cellulose (also known as Carmellose), croscarmellose sodium, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, croscarmellose, hydroxypropyl starch, starch, partially α-substituted starch, and sodium starch glycolate. They can be used individually or in mixtures of two or more.

[0343] The aforementioned excipients can be incorporated into any of the kneading, granulation, or post-granulation processes in pharmaceutical preparations. Examples of such excipients include cellulose derivatives such as crystalline cellulose, ethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and hydroxypropyl methylcellulose (also known as hydroxypropyl methylcellulose); starch derivatives such as corn starch, potato starch, wheat starch, rice starch, partially α-substituted starch, and hydroxypropyl starch; sugar derivatives such as glucose, lactose, white sugar, refined white sugar, powdered sugar, trehalose, dextran, and dextrin; sugar alcohols such as D-mannitol, xylitol, sorbitol, and erythritol; glycerol fatty acid esters; magnesium aluminate metasilicate; synthetic hydrotalcite; anhydrous calcium phosphate; precipitated calcium carbonate; calcium silicate; calcium hydrogen phosphate hydrate; and inorganic salts such as sodium bicarbonate.

[0344] Examples of such lubricants include stearic acid, sodium fumarate stearate, magnesium stearate, calcium stearate, sucrose fatty acid esters, polyethylene glycol, light anhydrous silica, hydrogenated oil, glycerol fatty acid esters, and talc. They can be used alone or as a mixture of two or more.

[0345] The dosage of XOR inhibitors need only be an effective amount, administered orally or non-orally at a dose of 10–320 mg of a compound of 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, for one day. The above administration should be continued for at least 7, 10, 18 days, 1 month, 3 months, 6 months, or 1 year as needed.

[0346] Pharmaceutical compositions containing the aforementioned XOR inhibitors may further include an ATP precursor, such as inosine or hypoxanthine. The dosage of the ATP precursor is only required to be an effective amount; for example, it can be administered orally or non-orally at a dose of 0.5–4.0 g per day. Alternatively, the ATP precursor may be administered separately from the aforementioned XOR inhibitors.

[0347] Example

[0348] The present invention will be described in more detail below through examples, reference examples, comparative reference examples and test examples, but the present invention is not limited thereto.

[0349] <Reference Example 1a and Comparative Reference Example 1a, Manufacturing of Enteric-Coated Capsules>

[0350] 9 g of compound 14 (2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazo[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) (after slight heating to dissolve). The solution was then pumped into a spray dryer at approximately 5 mL / min using a peristaltic pump and discharged through a two-fluid nozzle (508 μm diameter) at an inlet temperature of 80 °C, an outlet temperature of approximately 60 °C, and a drying air flow rate of 0.30 m³ / min. 3 / min and nozzle spray air pressure 1.0 kgf / cm 2 The mixture was spray-dried and granulated under specific conditions. The resulting dried material was left to stand at room temperature overnight to obtain 100% amorphous compound 14.

[0351] The volume average particle size (D50) of the amorphous compound 14 was determined by dispersing approximately 2 mg of the sample in a 0.2% Aerosol OT aqueous solution and irradiating it with ultrasound for 30 seconds. The dispersion was then measured using a Shimadzu SALD-2200 laser diffraction particle size distribution analyzer. Shimadzu Wing SALD-2200 version 1.02 software was used for data collection and analysis. The particle size distribution results of the amorphous compound 14 are shown below. Figure 1 The volume average particle size (D50) of the amorphous compound 14, determined from the above particle size distribution, is 2.949 μm.

[0352] The amorphous form of compound 14 was filled into capsules as shown in Table 2A, with each capsule containing 40 mg of the amorphous compound 14.

[0353] [Table 2A]

[0354]

[0355] <Experimental Example 1a, Absorption of the Amorphous Compound 14 in Dogs>

[0356] Beagle dogs (1–5 years old, KITAYAMALABES (strain)) that had been fasting since the evening of the day before administration were given a single oral dose of one capsule (40 mg / individual, representing compound 14) using a crossover method with a 1-week dosing interval. Sampling was performed before administration and at 0.5, 1, 3, 5, 8, and 24 hours after administration, via the radial cutaneous vein. The obtained blood was centrifuged at 10000 × g at 4°C for 5 minutes to obtain plasma. The concentration of compound 14 in the plasma was determined using HPLC (OSAKASODA (strain)). It should be noted that, due to the generally high pH in the stomach of dogs, pentagastrin, a gastric acid secretion stimulant, was administered intramuscularly at a dose of 0.01 mg / kg 30 minutes before and immediately before capsule administration. The pH of the gastric solution was then measured; if a low gastric pH was confirmed, the capsule sample was administered. A blood drug concentration-time curve was constructed from the obtained measurements. The results are presented as follows: Figure 2 It should be noted that the drug concentrations in the figure are shown as the mean ± standard deviation of four examples.

[0357] Since the enteric-coated capsule of Reference Example 1a showed a higher drug concentration compared with the conventional gastric-coated capsule of Comparative Reference Example 1a which is not enteric-coated, this indicates that absorption is improved by making the amorphous form of compound 14 enteric-coated.

[0358] <Evaluation of the amorphous state of compound 14 in Experimental Example 2a (Powder X-ray Diffraction)>

[0359] Since it is crucial for amorphous materials to retain their amorphous properties even after prolonged storage, the amorphous state of compound 14 (Reference Example 1a) was evaluated using X-ray diffraction (D2 Phaser, Bruker) under light-shielding, gas-tight conditions at room temperature. The results are presented below. Figure 4 (a) to (d) in the text. Figure 3 The powder X-ray diffraction of the crystals of compound 14 is shown in the figure for comparison.

[0360] When the capsules of Reference Example 1a were stored in a light-proof, airtight environment at room temperature, no changes were observed in the powder X-ray diffraction pattern of compound 14 during the storage period of up to 4 weeks in which the study was conducted.

[0361] <Reference Example 1b and Comparative Reference Examples 1b-9b. Preparation of solid dispersions (polymer, 25 times the amount)>

[0362] 250 mg of compound 14 was dissolved in tetrahydrofuran to prepare 100 mL. 125 mg of each of the polymers shown in Table 2B were 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, and 5 mL of the polymer solution was added. The mixture was then vortexed until homogeneous. Alternatively, a sample without polymer was prepared (for comparison, see Example 9b). These samples were dried under reduced pressure overnight after distilling off the solvent by blowing a stream of nitrogen onto them to obtain a solid dispersion of compound 14.

[0363] The HPMCAS used in Reference Example 1b is of the MF type (i.e., the substitution ratio of each monomer unit is methoxy: 21.0-25.0%, hydroxypropoxy: 5.0-9.0%, acetyl: 7.0-11.0%, succinyl: 10.0-14.0%, viscosity: 2.4-3.6 mPa·s).

[0364] [Table 2B]

[0365]

[0366] <Experimental Example 1b. Solubility Test>

[0367] Add 5 mL of the Japanese Pharmacopoeia Dissolution Test Reagent 1 (pH 1.2) or 5 mL of the Japanese Pharmacopoeia Reagent 2 (pH 6.8) to the solid dispersions of Reference Example 1b and Comparative Reference Examples 1b-8b, and to the sample of Comparative Reference Example 9b. After pulverizing the solid dispersions with a glass rod or spatula, shake at 37°C for 2 hours. Immediately add 400 μL of a mixed solution (acetonitrile / water = 3 / 2) to 600 μL of the sample solution obtained by filtration through a 0.45 μm filter. Determine the concentration of compound 14 in the sample solution using HPLC (Shimadzu Corporation). The results are shown in Table 3B. It should be noted that the values ​​in the table are the average of two replicates.

[0368] [Table 3B]

[0369]

[0370] The solubility of compound 14 in Comparative Example 9b was 0.39 μg / mL in reagent 1 and 0.49 μg / mL in reagent 2. In Comparative Examples 1b, 3b, and 4b, the solubility increased to over 5.0 μg / mL. In particular, Eudragit E-100 (a basic polymer in Comparative Example 3b) under acidic conditions and HPMCAS (an acidic polymer in Comparative Example 1b) under neutral conditions significantly improved the solubility of compound 14.

[0371] <Refer to Example 2b, and compare with Reference Examples 10b and 11b. Preparation of solid dispersions (polymer, 25 times the amount)>

[0372] Compound 14 was dissolved in tetrahydrofuran to prepare a concentration of 2.5 mg / mL. The polymers shown in Table 4B were dissolved in a mixed solvent (methanol / dichloromethane = 3 / 4) to prepare a concentration of approximately 45 mg / mL. The compound 14 solution was added to the polymer solution while stirring, at a weight ratio of 1:25 (compound 14 to polymer). A sample without polymer was also prepared. The solutions were immediately transferred to flasks and the organic solvent was distilled off using a rotary evaporator (N-1100, Tokyo Rika Kiki Co., Ltd.). The flasks were then 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 using an agate mortar or a portable high-speed pulverizer (LM-PLUS, Osaka Chemical Co., Ltd.) and then sieved (mesh size: 150 μm).

[0373] [Table 4B]

[0374] polymer type polymer weight ratio Manufacturer See Example 2b HPMCAS MF 25 times the amount Shin-Etsu Chemical Co., Ltd. Compare with Example 10b Eudragit E-100 25 times the amount Evonik Degussa Japan Co., Ltd. Compare with Example 11b none - - -

[0375] <Experimental Example 2b. Absorption of Compound 14 in Rats as a Solid Dispersion>

[0376] Under fasting conditions, male rats (8 weeks old, Cr1:CD (SD), Charles River Co., Ltd., Japan) were administered a single oral dose of a solid dispersion of Reference Example 2b and Comparative Reference Example 10b suspended in a 1% carboxymethyl cellulose aqueous solution, and a sample of Comparative Reference Example 11b, at a dose of 10 mg / kg or 30 mg / kg of compound 14. As a control, the crystalline original drug of compound 14 (Comparative Reference Example 12b) was used. Sampling was performed at 0.5, 1, 2, 4, 8, and 24 hours after administration, with approximately 300 μL of blood 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 the plasma was determined by HPLC (Shiseido Co., Ltd. and Hitachi High Technology Co., Ltd.). The time to peak concentration (Tc) was calculated based on the observed plasma concentration. max ), maximum blood concentration (C max The values ​​were calculated as follows: (1) and (2) the area under the plasma concentration-time curve (AUC). The results are shown in Table 5B. It should be noted that the values ​​in the table are the mean ± standard deviation of three examples.

[0377] The solid dispersions of Reference Example 2b and Comparative Reference Example 10b, and the sample of Comparative Reference Example 11b, compared with the original drug, exhibited C maxThe high absorption improvement effect of both AUC indicates that compound 14 enhances absorbability through amorphization and subsequent solid dispersion. Furthermore, the solid dispersion with HPMCAS exhibits a higher absorption improvement effect compared to the solid dispersion with Eudragit.

[0378] [Table 5B]

[0379]

[0380] AUC last The area under the blood concentration-time curve up to the final observation point.

[0381] <Refer to Examples 3b, 4b and 5b. Preparation of solid dispersions (polymer, 25 times the amount)>

[0382] Compound 14 was dissolved in tetrahydrofuran to prepare a concentration of 2.5 mg / mL. The polymers shown in Table 6B were dissolved in a mixed solvent (methanol / dichloromethane = 3 / 4) to prepare a concentration of approximately 45 mg / mL. Compound 14 and the polymers were mixed at a weight ratio of 1:25, and the solvent was removed by distillation under reduced pressure at approximately 50°C using a rotary evaporator (N-1100, Tokyo Rika Kiki Co., Ltd.). The resulting first-dry product was further dried a second time using a vacuum pump (room temperature / overnight). The second-dry product was then appropriately pulverized using a portable high-speed pulverizer (LM-PLUS, Osaka Chemical Co., Ltd.) and sieved (mesh size: 300 μm).

[0383] The HPMCAS used in Reference Example 3b is of the LG type (i.e., the substitution ratio of each monomer unit is methoxy: 20.0-24.0%, hydroxypropoxy: 5.0-9.0%, acetyl: 5.0-9.0%, succinyl: 14.0-18.0%, viscosity: 2.4-3.6 mPa·s).

[0384] The HPMCAS used in Reference Example 4b is of the MG type (i.e., the substitution ratio of each monomer unit is methoxy: 21.0-25.0%, hydroxypropoxy: 5.0-9.0%, acetyl: 7.0-11.0%, succinyl: 10.0-14.0%, viscosity: 2.4-3.6 mPa·s).

[0385] The HPMCAS used in Reference Example 5b is of type HG (i.e., the substitution ratio of each monomer unit is methoxy: 22.0-26.0%, hydroxypropoxy: 6.0-10.0%, acetyl: 10.0-14.0%, succinyl: 4.0-8.0%, viscosity: 2.4-3.6 mPa·s).

[0386] [Table 6B]

[0387] polymer type polymer weight ratio Manufacturer See Example 3b HPMCAS LG 25 times the amount Shin-Etsu Chemical Co., Ltd. See Example 4b HPMCAS MG 25 times the amount Shin-Etsu Chemical Co., Ltd. Reference example 5b HPMCAS HG 25 times the amount Shin-Etsu Chemical Co., Ltd.

[0388] <Experimental Example 3b. Absorption of Compound 14 in Rats as a Solid Dispersion>

[0389] Under fasting conditions, male rats (7-9 weeks old, Cr1:CD (SD), Charles River Co., Ltd., Japan) were administered a single oral dose of 10 mg / kg of solid dispersions of Reference Examples 3b, 4b, and 5b suspended in 1% carboxymethyl cellulose aqueous solution. Sampling was performed at 0.5, 1, 2, 4, 8, and 24 hours post-administration, with approximately 300 μL of blood 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 the plasma was determined using HPLC (Shiseido Co., Ltd. and Hitachi High Technology Co., Ltd.). The time to peak concentration (T0) was calculated from the obtained plasma concentration. max ), maximum blood concentration (C max The values ​​were calculated as follows: (1) and (2) the area under the plasma concentration-time curve (AUC). The results are shown in Table 7B. It should be noted that the values ​​in the table are the mean ± standard deviation of three examples.

[0390] In the solid dispersion of Reference Example 4b, C is exhibited max Both AUC and AUC represent the highest blood drug concentrations.

[0391] [Table 7B]

[0392]

[0393] AUC last Area under the blood drug concentration-time curve up to the final observation point

[0394] <Refer to Examples 6b-12b. Preparation of solid dispersions (HPMCAS-MG, 1 to 10 times the amount)>

[0395] 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 was mixed with the polymers shown in Table 8B at a weight ratio of 1:1 to 1:10, and then pumped by a peristaltic pump at a rate of approximately 5 mL / min into a spray dryer (GB22, Yamato Scientific Co., Ltd.). The dryer was operated from 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 drying air flow rate of 0.32–0.47 m³ / min. 3 / min, nozzle spray air pressure 1.0~3.1kgf / cm 2Spray drying and granulation were started under the specified conditions. The resulting first-dry product was further dried twice using a vacuum pump (room temperature / overnight or room temperature / overnight and 40°C / 1 day), and then sieved (mesh size: 300 μm).

[0396] [Table 8B]

[0397] polymer type polymer weight ratio Manufacturer See Example 6b HPMCAS MG 1 times the amount Shin-Etsu Chemical Co., Ltd. See Example 7b HPMCAS MG 2 times the amount Shin-Etsu Chemical Co., Ltd. See Example 8b HPMCAS MG 3 times the amount Shin-Etsu Chemical Co., Ltd. See Example 9b HPMCAS MG 3.5 times the amount Shin-Etsu Chemical Co., Ltd. See Example 10b HPMCAS MG 4 times the amount Shin-Etsu Chemical Co., Ltd. See Example 11b HPMCAS MG 5 times the amount Shin-Etsu Chemical Co., Ltd. Reference example 12b HPMCAS MG 10 times the amount Shin-Etsu Chemical Co., Ltd.

[0398] <Experimental Example 4b. Absorption of Compound 14 in Rats as a Solid Dispersion>

[0399] Under fasting conditions, male rats (7-9 weeks old, Cr1:CD (SD), Charles River Co., Ltd., Japan) were administered a single oral dose of 10 mg / kg of solid dispersions of Reference Examples 6b-8b and 10b-12b suspended in 1% carboxymethyl cellulose aqueous solution. Sampling was performed at 0.5, 1, 2, 4, 8, and 24 hours post-administration, with approximately 300 μL of blood 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 the plasma was determined using HPLC (Shiseido Co., Ltd. and Hitachi High Technology Co., Ltd.). The time to peak concentration (T0) was calculated from the obtained plasma concentration. max ), maximum blood concentration (C max The values ​​were calculated as follows: (1) and (2) area under the plasma concentration-time curve (AUC). The results are shown in Table 9B. It should be noted that the values ​​in the table are the mean ± standard deviation of three examples.

[0400] In the solid dispersions of Reference Examples 6b–8b and 10b–12b, the blood drug concentration increased in a weight ratio of HPMCAS-MG to compound 14 of 1, 2, and 3, but no difference in blood drug concentration in a weight ratio was observed in the range of 4, 5, and 10.

[0401] [Table 9B]

[0402]

[0403] AUC last Area under the blood drug concentration-time curve up to the final observation point

[0404] <Experimental Example 5b. Evaluation of the amorphous state of the solid dispersion of compound 14 (powder X-ray diffraction)>

[0405] Since it is crucial for solid dispersions to retain their amorphous properties even after prolonged storage, the solid dispersions of Reference Examples 9b-11b were stored at 40°C / 75% RH under open conditions, and the changes in the amorphous state were evaluated using an X-ray diffraction apparatus (D2 Phaser, Bruker). The results are presented below. Figures 5-7 .

[0406] When the solid dispersions of Reference Examples 9b to 11b were stored at 40°C / 75% RH under open conditions, no changes were observed in the powder X-ray diffraction patterns over the course of the study, up to 7 weeks.

[0407] <Example 6b. Evaluation of the amorphous state of the solid dispersion of compound 14 (absorption in rats)>

[0408] The solid dispersions of Reference Examples 9b-11b were stored at 40°C / 75% RH under open conditions, and the changes in the amorphous state were evaluated by rat absorption.

[0409] Under fasting conditions, male rats (7-9 weeks old, Cr1:CD (SD), Charles River Co., Ltd., Japan) were administered a single oral dose of a solid dispersion of Reference Examples 9b-11b suspended in a 1% carboxymethyl cellulose aqueous solution at doses of 10 and 30 mg / kg, calculated as compound 14. Sampling was performed at 0.5, 1, 2, 4, 8, and 24 hours post-administration, with approximately 300 μL of blood 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 the plasma was determined using HPLC (Shiseido Co., Ltd. and Hitachi High Technology Co., Ltd.). The time to peak concentration (T0) was calculated from the obtained plasma concentration. max ), maximum blood concentration (C max The values ​​were calculated as follows: ) and area under the plasma concentration-time curve (AUC). The results are shown in Table 10B. It should be noted that the values ​​in the table are the mean ± standard deviation of three examples. When the solid dispersions of Reference Examples 9b–11b were openly stored at 40°C / 75% RH, no daily decrease in plasma concentration was observed during the 7-week storage period studied.

[0410] [Table 10B]

[0411]

[0412] AUC last Area under the blood drug concentration-time curve up to the final observation point

[0413] <Experimental Example 7b. The effect of compound 14 solid dispersion on reducing serum uric acid levels in rats>

[0414] Under fasting conditions, male rats (8 weeks old, Cr1:CD (SD), Charles River Co., Ltd., Japan) were administered a single oral dose of a solid dispersion of Reference Example 11b suspended in a 1% carboxymethyl cellulose aqueous solution at a dose of 30 mg / kg, calculated as compound 14. A 1% carboxymethyl cellulose aqueous solution was used as a control. Sampling was performed before administration (0), and at 2, 6, 12, and 24 hours after administration, with approximately 300 μL of blood collected from the tail vein at each time point (n = 5). The obtained blood was centrifuged at 1500 × g at 4°C for 15 minutes to obtain plasma. The concentration of uric acid in the plasma was determined using HPLC (Hitachi High Technology Co., Ltd.). Welch's t-test was performed on the serum uric acid values ​​at each time point for the control group and Reference Example 11b. The significance level was p < 0.05 (two sides). The results are shown below. Figure 8 .

[0415] The serum uric acid level after administration of the solid dispersion in Reference Example 11b was significantly lower than that in the control group, and the uric acid-lowering effect was sustained.

[0416] <Refer to Examples 13b and 14b. Preparation of solid dispersions (3 times the amount of HPMCAS-MG, 0.03 times the amount of surfactant)>

[0417] 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 was mixed with the polymer and surfactant (Tween 80: Tween 80, sodium lauryl sulfate: SLS) shown in Table 11B at a weight ratio of 1:3:0.03. The mixture was then pumped into a spray dryer (GB22, Yamato Scientific Co., Ltd.) at a rate of approximately 5 mL / min using a peristaltic pump. The dryer operated from 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 drying air flow rate of 0.32–0.47 m³ / min. 3 / min, nozzle spray air pressure 1.0~3.1kgf / cm 2 Spray drying and granulation were started under the specified conditions. The resulting first-dry product was further dried twice using a vacuum pump (room temperature / overnight or room temperature / overnight and 40°C / 1 day), and then sieved (mesh size: 300 μm).

[0418] [Table 11B]

[0419]

[0420] <Experimental Example 8b. Absorption of Compound 14 in Rats as a Solid Dispersion>

[0421] Under fasting conditions, male rats (7–9 weeks old, Cr1:CD (SD), Charles River Co., Ltd., Japan) were administered a single oral dose of 10 mg / kg of solid dispersions of Reference Examples 13b and 14b suspended in 1% carboxymethyl cellulose aqueous solution. Sampling was performed at 0.5, 1, 2, 4, 8, and 24 hours post-administration, with approximately 300 μL of blood 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 the plasma was determined using HPLC (Shiseido Co., Ltd. and Hitachi High Technology Co., Ltd.). The time to peak concentration (T0) was calculated from the obtained plasma concentration. max ), maximum blood concentration (C max The values ​​are calculated as follows: (1) and (2) the area under the plasma concentration-time curve (AUC). The results are presented in Table 12B, together with Reference Example 8b. It should be noted that the values ​​in the table are the mean ± standard deviation of the three examples.

[0422] In the solid dispersions of Reference Examples 13b and 14b, no difference in blood drug concentration was observed compared to Reference Example 8b, which did not contain a surfactant.

[0423] [Table 12B]

[0424]

[0425] Area under the blood drug concentration-time curve up to the final observation point

[0426] <Reference Example 14>

[0427] The effect of compound 14 on reducing serum uric acid levels was studied in six healthy adult males by repeatedly administering compound 14 at a dose of 80 mg once daily for 7 days using the solid dispersion capsules of formulation example 1. Results are presented in conjunction with an example using febuxostat (40 mg) as described in non-patent literature 3 as a comparative reference. Figure 9 .

[0428] As a result, with febuxostat, the maximum reduction rate of serum uric acid levels reached approximately 35% on day 1 of administration (approximately 15 hours after administration), demonstrating a sharp decrease in serum uric acid levels. In contrast, compound 14 showed a maximum reduction rate of approximately 17% on day 1 of administration (12 hours after administration), resulting in a moderate decrease in serum uric acid levels. Subsequently, serum uric acid levels decreased slowly over time throughout the administration period, reaching a maximum reduction rate of approximately 30% on day 7 (approximately 8 hours after administration). Based on these results, compound 14 can be expected to prevent gout attacks or reduce the frequency of gout attacks.

[0429] In addition, when compound 14 was repeatedly administered at 20 mg once a day for 7 days using the solid dispersion capsule of formulation example 1, the serum uric acid level decreased slowly over time throughout the administration period, similar to the results of the above-mentioned 80 mg once a day administration. Finally, the serum uric acid level 24 hours after administration was reduced by about 10-20% compared with the serum uric acid level before administration (initial value).

[0430] In addition, when compound 14 was repeatedly administered at a dose of 40 mg once a day for 7 days using capsules containing micronized compound 14 (not solid dispersion capsules), the serum uric acid level decreased slowly over time throughout the administration period, just as it did when using the solid dispersion capsules.

[0431] <Reference Example 15>

[0432] In rats with paraoxonic acid-induced hyperuricemia, compound 14, suspended in a 1% methylcellulose aqueous solution, was administered orally 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.

[0433] (Preparation of rats with oxazine-induced hyperuricemia)

[0434] Male Cr1:CD (SD) rats (manufactured in Charles River, Japan) were used. These rats were purchased at 6 weeks of age and started treatment at 7 weeks of age.

[0435] Potassium oxonate was prepared by suspending 10 g of potassium oxonate (Sigma-Aldrich Corp., Lot No. 03810HD) in 200 mL of 1% methylcellulose (1% MC) using a mixer. After suspension, the solution was kept in a water bath at approximately 37°C until administration. It should be noted that the above preparation was made immediately before use.

[0436] The oxazine-induced hyperuricemia rats were prepared by subcutaneously administering potassium oxazine (suspended in 1% methylcellulose aqueous solution) at a dose of 250 mg / kg 2.5 hours before blood was collected on days 1, 7, 14, 21 and 28.

[0437] (Experimental Methods)

[0438] Sampling was conducted on days 1, 7, 14, 21, and 28 before (1 hour before) administration, and 2 and 6 hours after administration. Approximately 300 μL of blood was collected from the tail vein at each time point (n = 7). The obtained blood was centrifuged at 1500 × g at 4°C for 15 minutes to obtain plasma. The concentration of uric acid in the plasma was determined using HPLC (Shiseido Co., Ltd., now OSAKASODA Co., Ltd.).

[0439] It should be noted that, in order to obtain pre-drug values ​​and data for grouping, all rats were orally administered a 1% methylcellulose aqueous solution 5 days prior to the start of administration, and plasma uric acid concentrations were measured according to the aforementioned methods, such as subcutaneous administration of potassium oxonate. The mean and standard deviation were calculated for the area under the concentration-time curve (AUC(−1) to 6hr) of serum uric acid values ​​up to 6 hours after administration. Additionally, the rate of change (%) of each individual in the compound 14 and febuxostat administration groups relative to the control group's mean was calculated for the serum uric acid values ​​AUC(−1) to 6hr on each administration day, and the mean and standard deviation were calculated. Furthermore, paired t-tests were performed on the rate of change from day 1 to day 7 onwards in each group.

[0440] (result)

[0441] The results are shown in Figure 10 In the compound 14 administration group, the rate of change of serum uric acid AUC(-1) to 6 relative to the control group increased with repeated administration, but no significant increase was observed in the febuxostat administration group, supporting the fact that compound 14 continuously inhibits xanthine oxidoreductase compared to febuxostat.

[0442] <Example 1: ATP-enhancing effect under hypoxic conditions>

[0443] In this study, MOVAS-1 cells with XOR activity were used. Additionally, the number of samples for each study was n=3. The culture medium (with D-MEM / low glucose / 10% FBS / 100 μM Oxionate) of confluent MOVAS-1 cells was divided into hypoxanthine-added and hypoxanthine-unadded groups. The hypoxanthine-added groups received 50 μM hypoxanthine, 6 μM compound 14, 10 μM febuxostat, or 100 μM allopurinol in the culture medium, respectively. The hypoxanthine-unadded groups received 6 μM compound 14, 10 μM febuxostat, or 100 μM allopurinol in the culture medium, respectively. It should be noted that the controls for each group were as follows: the hypoxanthine-added groups received only 50 μM hypoxanthine, while the hypoxanthine-unadded groups received no added hypoxanthine. The cells were then incubated for 4 hours under a mixed atmosphere of 1% oxygen, 5% carbon dioxide, and 94% nitrogen. After protein removal with PCA, the concentrations of ATP, ADP, and AMP were determined by HPLC. The results are shown in Figure 11 and Figure 12 Compound 14 showed efficacy at lower doses than febuxostat and allopurinol.

[0444] <Example 2: ATP Enhancement in the Presence of Uncoupling Agents>

[0445] The examples used MOVAS-1 cells with XOR activity. Additionally, the sample size for each group was n=3. The culture medium (with D-MEM / low glucose / 10% FBS / 100 μM Oxionate) of confluent MOVAS-1 cells was divided into a CCCP-added group and a CCCP-unadded group, with 6 μM of compound 14 added to the medium. It should be noted that no additives were added to the controls in each group. Then, CCCP was added to the CCCP-added group to reach a final concentration of 10 μM. After standing for 30 minutes, protein was removed with PCA, and the concentrations of ATP, ADP, and AMP were determined by HPLC. The results are presented below. Figure 13 The results of the control group showed that the total adenosine concentration was reduced by adding CCCP. Furthermore, the total adenosine concentration in the CCCP-added group (containing compound 14) was higher than that in the control group (containing CCCP).

[0446] <Example 3: Inhibitory effect on retinal degeneration>

[0447] Three-week-old male RCS rats (CLEA Japan) were purchased and randomly divided into a control group and a compound 14 administration group. From 3.5 weeks of age, both groups were orally administered once daily for 18 consecutive days. The control group received 1% methylcellulose (Shin-Etsu Chemical Co., Ltd., Metalose (SM-15)). The compound 14 administration group received the formulation described in "Formulation Example 1" (described later), which involved suspending the solid dispersion of compound 14 in 1% methylcellulose, at a dose of 5 mg / 100 g body weight (1 mg / 100 g body weight for compound 14). Furthermore, rodents are prone to xanthine stones due to XOR inhibition; therefore, to prevent / reduce xanthine stones, both groups were administered Uralyt-U compound powder (Nippon Chemiphar Co., Ltd.) at a concentration of 1% (w / v) via drinking water. After 18 days of medication, on day 19, two eyeballs were removed from each of the two groups, and tissue images were confirmed using one eyeball.

[0448] It should be noted that, in order to compare the thickness of the retinal layers, such as Figure 14 As shown, the thickness of the retina (2), the thickness of the outer nuclear layer (3), and the thickness of the cone and rod layer (4) were measured at a certain distance (1000 μm) from the center of the optic disc.

[0449] The results are shown in Figure 15 As a result, compared with the control group, the compound 14 administration group significantly inhibited the thinning of the outer nuclear layer and cone-rod layer of the retinal tissue (p < 0.05; n = 4).

[0450] It should be noted that the other eyeball was used for the concentration determination of various factors within the eyeball in Example 4.

[0451] <Refer to Example 16: Confirmation of XOR in the Eye>

[0452] Retinas were isolated from excised rat eyeballs and frozen in liquid nitrogen at -80°C until enzyme activity assays were performed. The retina was homogenized in a solution containing 0.25 M sucrose, 1 mM salicylic acid, 0.3 mM EDTA, and a complete protease inhibitor (Roche Applied Science; complete protease inhibitor cocktail) in 50 mM potassium phosphate buffer (pH 7.4), and then centrifuged at 15000 x g to prepare the supernatant. Protein concentration in the supernatant was determined (Thermo Fisher Scientific; Coomassie (Bradford) Protein Assay Regent). The XOR enzyme reaction was performed at 25°C in a solution containing 0.4 mM EDTA, 0.15 mM xanthine, and 500 μM NAD. + The experiment was conducted in a 50 mM potassium phosphate buffer solution (pH 7.8). The concentration of uric acid as a product was determined by absorbance at a wavelength of 295 nM.

[0453] The XOR activity in rat retinal lysate was below the detection limit (0.01 nmole uric acid / min / mg protein).

[0454] <Example 4: Determination of the concentration of various molecules in the eyeball>

[0455] The concentrations of various molecules in the single eyeballs extracted in Example 3 were determined. Eyeballs stored at -80°C were frozen and pulverized, and treated with a vortex mixer with twice the volume (w / w) of 5% perchloric acid. The supernatant obtained by centrifugation at 15,000 rpm at 4°C for 5 minutes was neutralized with 3M potassium carbonate solution. The supernatant was then centrifuged again at 15,000 rpm at 4°C for 5 minutes and equilibrated with 0.5M sodium phosphate buffer to prepare the eyeball extraction solution. ATP, ADP, AMP, IMP, inosine, hypoxanthine, xanthine, uric acid, GTP, GDP, and GMP in the solution were determined using 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])).

[0456] The results are shown in Tables 13–15. It can be seen that compound 14 significantly increases the intraocular energy charge by increasing ATP, ADP, GTP, and GDP, and decreasing AMP and IMP. It should be noted that GTP represents guanosine triphosphate, GDP represents guanosine diphosphate, and GMP represents guanosine monophosphate.

[0457] [Table 13]

[0458] Drug administration group ATP ADP AMP IMP Comparison 138.757±8.746 33.438±5.891 46.245±5.126 22.149±7.090 Compound 14 175.809±25.506 55.134±7.253 27.828±8.547 3.640±1.122 Significant difference# *p＝0.033 **p＝0.004 *p＝0.010 **p＝0.002

[0459] #: Tests based on Student's t-test: *: p < 0.05, **: p < 0.01

[0460] [Table 14]

[0461] Drug administration group Inosine hypoxanthine xanthine uric acid Comparison 25.283±8.646 13.434±3.479 3.625±1.814 3.238±1.224 Compound 14 13.063±4.690 8.450±3.244 1.739±0.590 1.344±0.444 Significant difference# *p＝0.047 NS p = 0.081 NS p = 0.095 *p＝0.027

[0462] # Tests based on Student's t-test: *: p < 0.05, **: p < 0.01

[0463] [Table 15]

[0464] Drug administration group GTP GDP GMP Energy load Comparison 43.428±2.764 5.754±1.229 21.020±3.441 0.712±0.021 Compound 14 53.157±8.352 8.115±1.245 2.458±1.898 0.786±0.030 Significant differences NS p = 0.069 *p＝0.036 **p＝0.000 **p＝0.007

[0465] #: Tests based on Student's t-test: *: p < 0.05, **: p < 0.01

[0466] <Example 5: Determination of hypoxanthine and inosine concentrations in serum>

[0467] Similar to Example 3, RCS rats were orally administered either the control or compound 14 for 10 consecutive days, and also given Uralyt-U compound powder (manufactured by Nippon Chemiphar) in drinking water. After the 10-day administration period, blood samples were collected from both groups on day 11, and serum was prepared. As shown in Table 16, the concentrations of inosine and hypoxanthine in the serum were significantly increased by approximately 38-fold and approximately 7-fold, respectively, by compound 14 (p < 0.05; n = 4).

[0468] [Table 16]

[0469]

[0470] #: Test based on Student's t-test: *: p < 0.05

[0471] Based on the results of Reference Example 16, it was concluded that XOR enzymes were almost absent in the retina. This result is consistent with the low RNA expression values ​​in humans, pigs, and mice found in the well-known database "THE HUMAN PROTEIN ATLAS" (https: / / www.proteinatlas.org / ENSG00000158125-XDH / tissue). On the other hand, according to Table 13, oral administration of compound 14 significantly increased the intraocular ATP concentration compared to the control group. Furthermore, Table 16 showed a significant increase in serum inosine and hypoxanthine concentrations.

[0472] Based on the above results, it is believed that oral administration of compound 14 inhibits xanthine oxidoreductase (XOR) present in the liver or vascular endothelium, thereby halting the breakdown of AMP in these tissues using hypoxanthine. This increases the levels of hypoxanthine and inosine in the blood. The hypoxanthine and inosine in the blood cross the blood-retinal barrier, allowing them to flow into the retina. There, they are regenerated into ATP via the purine salvage synthesis pathway within the retina, thus increasing the ATP concentration in the eye. Furthermore, it is believed that the increased ATP promotes the repair of retinal tissue damage, protects against retinal cell degeneration, and inhibits the thinning of the outer nuclear layer and cone-rod layers of the retina. It should be noted that the indirect effect of compound 14 on the eye is also supported by the fact that compound 14 administered to rats is almost entirely absent from the eye.

[0473] In addition, since increasing the concentration of ATP in the eyeball can also treat age-related macular degeneration, glaucoma, etc. (Maruoka et al., Heliyon 4(2018)e00624; Nakano et al., Heliyon 2(2016)e00096), it is believed that XOR inhibitors such as compound 14 also play a therapeutic role in these diseases.

[0474] <Formulation Example 1: Manufacturing of Solid Dispersion Capsules>

[0475] Compound 14 (2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazo[5,4-d]pyrimidine) was dissolved in 38.72 kg of a mixed solvent of tetrahydrofuran (sometimes abbreviated as THF), anhydrous ethanol, and purified water (weight ratio: 32.01 / 5.09 / 1.62) under heating. Then, 0.72 kg of HPMCAS-MG was added and stirred to prepare a feed solution. Next, spray drying was performed using a spray dryer at an inlet heat temperature of 100°C, an exhaust heat temperature of 60°C, a feed rate of 100 g / min, and a nitrogen spray pressure of 0.30 MPa using a two-fluid nozzle. The resulting spray-dried product was vacuum dried at 25°C for 16 hours and then vacuum dried at 40°C for 24 hours. Finally, it was naturally dried at room temperature for 24 hours to obtain a solid dispersion of compound 14.

[0476] After sieving the solid dispersion of compound 14 through a sieve (300 μm mesh), 50 g of sodium starch glycolate was added to 250 g of the mixture and mixed to obtain a solid dispersion powder of compound 14.

[0477] The solid dispersion of compound 14 was mixed and filled into white gelatin capsules No. 2 with 60 mg or 120 mg of the mixture to obtain solid dispersion capsules of compound 14.

[0478] Industrial availability

[0479] The pharmaceutical compositions provided by this invention are useful as pharmaceutical compositions for enhancing intracellular ATP. In particular, even pharmaceutical compositions provided by this invention that do not contain inosine, inosine acid, hypoxanthine or their salts, but only contain compounds represented by general formula (I) or their pharmaceutically acceptable salts as active ingredients, are useful as pharmaceutical compositions for enhancing intracellular ATP.

Claims

1. Use of 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for the treatment or prevention of an ATP-related eye disease, the ATP-related eye disease is retinitis pigmentosa, diabetic retinopathy, age-related macular degeneration, or glaucoma.

2. The use according to claim 1, wherein, 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof is orally administered to a patient in need of enhancement of intracellular ATP at 10 to 320 mg per 1 day, and the oral administration is continued for at least 7 days as necessary.

3. The use according to claim 1, wherein, 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof contains a non-crystal thereof at a content of 80% by weight or more relative to the total weight of 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof.

4. The use according to claim 1, wherein, The pharmaceutical composition is an enteric preparation.

5. Use according to claim 4, wherein, The enteric preparation is a hard capsule.

6. The use according to claim 1, wherein, The pharmaceutical composition includes a solid dispersion, The solid dispersion contains 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof, and hypromellose, hypromellose acetate succinate, or hypromellose phthalate.

7. Use according to claim 6, wherein, The weight ratio of 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof to hypromellose, hypromellose acetate succinate, or hypromellose phthalate is 1:0.1 to 1:

25.

8. The use according to claim 1, wherein, The pharmaceutical composition includes a solid dispersion, The solid dispersion contains 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof, and hypromellose acetate succinate or hypromellose phthalate.

9. The use according to claim 1, wherein, The pharmaceutical composition is a solid preparation.

10. The use according to claim 1, wherein, The content of 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof is 10 mg to 320 mg.

11. The use according to claim 1, wherein, The content of 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof per 1 administration unit is 10 mg to 320 mg.

12. The use according to claim 1, wherein, The content of 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof per 1 administration unit is 10 mg to 160 mg.

13. The use according to claim 1, wherein, The content of 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof per 1 administration unit is 10 mg to 80 mg.

14. The use according to claim 1, wherein, The content of 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof per 1 administration unit is 20 mg to 80 mg.

Images