Motor function improver and pharmaceutical composition containing same

Abstract

The present invention provides a therapeutic drug for frailty or muscular dystrophy, and particularly for sarcopenia, and a medicinal drug for improving motor function. The present invention provides a motor function improver that contains a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and additionally contains an ATP precursor substance or is used in combination with an ATP precursor substance. The ATP precursor substance is preferably inosine, inosinic acid, or hypoxanthine. This motor function improver is preferably used as a medicinal drug and is used as a therapy or preventive for frailty and sarcopenia and as a therapy or preventive for muscle wasting and muscle loss.

Description

Motor function enhancer and pharmaceutical composition containing same

[0001] The present invention relates to an agent for improving motor function and a pharmaceutical containing the same, particularly to a pharmaceutical composition for treating physical frailty (including sarcopenia and locomotive syndrome), muscular dystrophy, age-related weakness, etc.

[0002] Due to aging, long-term hospitalization, and prolonged restrictions on activities, an increasing number of people are experiencing symptoms such as decreased motor function, decreased stamina, and fatigue. At the same time, an increasing number of people are hoping to further improve their current motor skills and endurance. To improve motor function, it is necessary to improve physical strength in a balanced manner, including muscle strength, balance, walking ability, and multi-motor ability.

[0003] In the process of elderly people becoming dependent on care, they often go through a vulnerable state (an intermediate stage) that is prone to health problems, such as unintentional weakness, decreased muscle strength, decreased activity, and decreased mental activity, and the Japan Geriatrics Society refers to this state as "frailty." The concept of frailty includes the reversibility of returning to a healthy state with appropriate intervention.

[0004] The elements that make up frailty include physical frailty, mental / psychological frailty, and social frailty. Known symptoms of physical frailty include sarcopenia and locomotive syndrome. Sarcopenia refers to the loss of muscle mass and strength due to aging. Locomotive syndrome refers to a state in which the function of the musculoskeletal system declines due to age-related muscle weakness, joint or spinal diseases, osteoporosis, etc., leading to a high risk of becoming dependent on care or bedridden. Sarcopenia and locomotive syndrome are accompanied by a loss of muscle mass and strength, and these symptoms are sometimes called muscle wasting or sarcopenia.

[0005] Thus, there is a demand for means for improving motor function and promoting motor development. Known means for such means include exercise therapy, nutritional management, and drug therapy, and a combination of these is considered preferable (Non-Patent Document 1). Furthermore, components that improve motor function, such as Euglena-derived substances, soybean saponins, butyric acid bacteria, lactic acid bacteria, bifidobacteria, and globin proteolysates, have been reported as nutritional management or drug therapy (Patent Documents 1 to 5).

[0006] However, there are no drugs approved for the treatment of frailty, particularly sarcopenia and locomotive syndrome, or muscle wasting or sarcopenia, and clinical development is limited. For example, 1) bone marrow mesenchymal stem cells have been developed as a stem cell therapy for the treatment of frailty (Non-Patent Document 2), 2) a small molecule compound with selective androgen receptor modulator (SARM) activity called OPK-88004 has been developed for the treatment of frailty and sarcopenia (Non-Patent Document 3), 3) a selective activator of the troponin complex called Reldesemtiv (CK-2127107) has been clinically developed for the treatment of locomotive syndrome (improvement of muscle function) (Non-Patent Document 4), 4) a small molecule compound with troponin activating activity called Tirasemtiv has been clinically developed for the treatment of muscle wasting (Non-Patent Document 5), and 5) a small molecule compound that is an MAS receptor agonist called SARconeos has been clinically developed for the treatment of age-related sarcopenia (Non-Patent Document 6), but none of these have been approved as pharmaceuticals. Therefore, there is a strong need for pharmaceuticals that can effectively treat frailty, particularly sarcopenia, locomotive syndrome, muscle wasting, or sarcopenia.

[0007] Intracellular adenosine phosphate (adenosine triphosphate, ATP, etc.) is known to be an important substance involved in the storage and supply of energy in the body, and in normal individuals, a high degree of homeostasis maintains a balance between its production and consumption, and the intracellular concentration is maintained within a certain range, so obtaining ATP is important for the body to continue moving. In Patent Document 6 and elsewhere, xanthine oxidoreductase (XOR) inhibitors are expected to be drugs that enhance intracellular adenosine phosphate (ATP), and it has been suggested that they are particularly effective when used in combination with ATP precursor substances (inosine, inosinic acid, hypoxanthine, or salts thereof, etc.).

[0008] JP 2019-024481 A, International Publication No. 2019 / 208627, JP 2021-121584 A, JP 2022-164021 A, JP 2023-048160 A, International Publication No. 2022 / 124325

[0009] Sarcopenia and Rehabilitation, The Japanese Journal of Rehabilitation Medicine, Volume 54, Issue 8, p609 - 616, 2017. The Design and Rationale of a Phase 2b, Randomized, Double - Blinded, and Placebo - Controlled Trial to Evaluate the Safety and Efficacy of Lomecel - B in Older Adults with Frailty (J Frailty Aging, 2022; 11(2), 214 - 223) Opko Health Inc (OPK) Q4 2018 Earnings Conference Call Transcript, https: / / www.fool.com / earnings / call - transcripts / 2019 / 02 / 27 / opko - health - inc - opk - q4 - 2018 - earnings - conference - ca.aspx CK - 2127107 AMPLIFIES SKELETAL MUSCLE RESPONSE TO NERVE ACTIVATION IN HUMANS, Muscle Nerve, 2018, 57, 729 - 734. A Double - Blinded, Randomized, Placebo - Controlled Trial to Evaluate Efficacy, Safety, and Tolerability of Single Doses of Tirasemtiv in Patients with Acetylcholine Receptor - Binding Antibody - Positive Myasthenia Gravis, Neurotherapeutics, 2015, 12, 455 - 460.SARA-data: Integrated, real-time ICT Platform for the SARA in terventional Clinical Trial inAge-related SARcopenia, Journal of Cachexia, Sarcopenia and Muscle, 2017, 8, 1001.

[0010] As described above, there is a need for therapeutic agents that can effectively treat frailty or muscular dystrophy, particularly sarcopenia and locomotive syndrome, and the associated muscle wasting or sarcopenia. Furthermore, conventional motor function enhancers containing components that improve motor function are not sufficiently effective, and the development of novel pharmaceuticals that improve motor function is desired. The present invention addresses the need to provide therapeutic agents for frailty, particularly sarcopenia, and the associated muscle wasting or sarcopenia, as well as pharmaceutical compositions that improve motor function.

[0011] That is, the present invention provides the following motor function improver: <1> General formula (I) (In the formula, R １ represents an unsubstituted phenyl group or a phenyl group substituted with a substituent, and the substituent represents at least one group selected from the group consisting of an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, a formyl group, a carboxyl group, a halogen atom, a phenyl group, and a phenoxy group; R ２ represents a cyano group or a nitro group, R ３ represents a hydrogen atom or a hydroxyl group, X represents an oxygen atom or -S(O)n-, n represents an integer of 0 to 2, and Y represents an oxygen atom or a sulfur atom), or a pharmaceutically acceptable salt thereof.

[0012] The present invention preferably relates to the following motor function improvers. <2> The motor function improver according to <1> above, which is used in combination with an ATP precursor substance in the salvage circuit. <3> The motor function improver according to <1> above, further containing an ATP precursor substance in the salvage circuit. <4> The motor function improver according to <2> or <3> above, wherein the ATP precursor substance is inosine, inosinic acid, or hypoxanthine. <5> The motor function improver according to any of <1> to <4> above, for improving walking ability or muscle strength.

[0013] <6> R in the general formula (I) １ is an unsubstituted phenyl group or a phenyl group substituted with a halogen atom. <7> The motor performance improver according to any one of <1> to <6> above, wherein X in general formula (I) is an oxygen atom. <8> The motor performance improver according to any one of <1> to <7> above, wherein Y in general formula (I) is a sulfur atom. <9> The motor performance improver according to any one of <1> to <8> above, wherein the compound represented by general formula (I) is 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine.

[0014] The present invention further relates to the following pharmaceutical compositions. <10> A pharmaceutical composition for treating or preventing physical frailty, muscular dystrophy, or age-related weakness, comprising the motor function improver according to any one of <1> to <9>. <11> The pharmaceutical composition according to <10> for treating or preventing sarcopenia or locomotive syndrome. <12> The pharmaceutical composition according to <10> or <11> for treating or preventing muscle wasting or sarcopenia. <13> The pharmaceutical composition according to any one of <10> to <12> for treating or preventing sarcopenia or locomotive syndrome in combination with exercise therapy. <14> A pharmaceutical composition comprising the motor function improver according to <2>, wherein an ATP precursor in the salvage circuit is administered before, simultaneously with, or after administration of the compound or a salt thereof.

[0015] The present invention also relates to the following therapeutic or preventive methods: <15> A method for treating or preventing frailty, muscular dystrophy, or age-related wasting in a subject in need thereof, comprising administering a compound represented by general formula (I) or a salt thereof to the subject. <16> The method according to <15> above, wherein an ATP precursor in the salvage circuit is administered before, simultaneously with, or after administration of the compound represented by general formula (I) or a salt thereof. <17> The method according to <15> or <16> above, wherein sarcopenia or locomotive syndrome is treated or prevented in the subject. <18> The method according to any of <15> to <17> above, wherein muscle wasting or sarcopenia in the subject is treated or prevented. <19> The method according to any of <15> to <18> above, wherein treatment or prevention is performed in combination with exercise therapy.

[0016] The present invention further relates to the following uses. <20> Use of a compound represented by general formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for treating or preventing physical frailty, muscular dystrophy, or age-related weakness. <21> Use of a compound represented by general formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for treating or preventing sarcopenia or locomotive syndrome. <22> Use of a compound represented by general formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for treating or preventing muscle wasting or sarcopenia. <23> Use of a compound represented by general formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for treating or preventing sarcopenia or locomotive syndrome in combination with exercise therapy. <24> Use in any of the above <20> to <23>, in combination with an ATP precursor in the salvage cycle.

[0017] The motor function improver of the present invention can improve the motor function of humans suffering from symptoms such as decreased motor ability, decreased stamina, and fatigue due to aging, long-term hospitalization, prolonged activity restriction, etc. Furthermore, it is expected to be used as a therapeutic agent for age-related weakness, physical frailty, muscular dystrophy, particularly sarcopenia and locomotive syndrome, or for muscle wasting and sarcopenia. Alternatively, it can also improve the motor function of healthy individuals who wish to further improve their motor function.

[0018] 1 is a graph showing the relationship between the running time (X-axis) and the number of times electrical stimulation was received (Y-axis) for healthy mice administered a single dose of compound 14 (a compound represented by general formula (I)) and inosine and healthy mice administered a single dose of methylcellulose in the treadmill test in Example 1. FIG. 2 is a graph comparing the running distance for healthy mice administered a single dose of compound 14 and inosine and healthy mice administered a single dose of methylcellulose in the treadmill test in Example 1. FIG. 3 is a graph comparing the rate of increase in running distance (relative value) for healthy mice administered successively with compound 14 (a compound represented by general formula (I)) and inosine and healthy mice administered successively with methylcellulose in the treadmill test in Example 2. 4(A) and 4(D) show the plasma inosine concentration ( FIG. 4(A) ), hypoxanthine concentration ( FIG. 4(B) ), xanthine concentration ( FIG. 4(C) ), and uric acid concentration ( FIG. 4(D) ) of healthy mice continuously administered with compound 14 (a compound represented by general formula (I)) and inosine, and healthy mice continuously administered with methylcellulose, in the treadmill test in Example 2. 4(B) and 4(D) show the plasma running time extension rate of sarcopenia model mice (SAMP8 strain mice) continuously administered with compound 14 (a compound represented by general formula (I)) and inosine, and sarcopenia model mice continuously administered with methylcellulose, in the treadmill test in Example 3. FIG. 4(A) shows the individual extension rate for each administration group. 5(B) is a graph showing the running time extension rate of sarcopenia model mice (SAMP8 strain mice) administered compound 14 (a compound represented by general formula (I)) and inosine continuously, and sarcopenia model mice administered methylcellulose continuously, in the treadmill test in Example 3; FIG. 5(B) shows the average extension rate (relative value) for each administration group. FIG. 5(C) is a graph showing the ATP concentration (μM) in the hind limb muscles of healthy mice administered a single dose of compound 14 (a compound represented by general formula (I)) and inosine, and healthy mice administered a single dose of methylcellulose in Example 4. FIG. 5(D) is a graph showing the hypoxanthine concentration (μM) in the hind limb muscles of healthy mice administered a single dose of compound 14 (a compound represented by general formula (I)) and inosine, and healthy mice administered a single dose of methylcellulose in Example 4.

[0019] [1. Composition of the Motor Function Improver] The motor function improver of the present invention comprises a compound represented by general formula (I) or a salt thereof (preferably a pharmaceutically acceptable salt). Furthermore, the motor function improver of the present invention may be used in combination with (used in combination with) an ATP precursor substance in the salvage circuit, or may further comprise (coformulate) an ATP precursor substance in the salvage circuit. Furthermore, the motor function improver of the present invention may contain any component (e.g., an additive).

[0020] [1-1. Compound represented by general formula (I) or salt thereof] The motor function improver of the present invention contains a compound represented by general formula (I) or a salt thereof, preferably as an active ingredient.

[0021] In the compound represented by general formula (I), R １ represents an unsubstituted phenyl group or a phenyl group substituted with a substituent. １ Examples of the "alkyl group having 1 to 8 carbon atoms" as a substituent on the phenyl group represented by the formula (I) include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, etc., and preferably a methyl group, an ethyl group, etc. １ Examples of the "alkyl group having 1 to 8 carbon atoms substituted with a halogen atom" as a substituent in the phenyl group represented by the formula (I) include a fluoromethyl group, a trifluoromethyl group, a 1,1-difluoroethyl group, a pentafluoroethyl group, etc., and preferred are a fluoromethyl group, a trifluoromethyl group, etc. １ Examples of the "alkoxy group having 1 to 8 carbon atoms" as a substituent in the phenyl group represented by the formula (I) include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, etc., and a methoxy group etc. is preferred. １Examples of the "alkoxycarbonyl group having 2 to 8 carbon atoms" as a substituent on the phenyl group represented by the formula (I) include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group, etc., and preferably a methoxycarbonyl group, an ethoxycarbonyl group, etc. １ Examples of the "halogen atom" as a substituent in the phenyl group represented by the formula (I) include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and preferably a fluorine atom, a chlorine atom, etc. １ As the aryl group, an unsubstituted phenyl group is preferred.

[0022] In the compound represented by general formula (I), R ２ represents a cyano group or a nitro group, with a cyano group being preferred. ３ represents a hydrogen atom or a hydroxy group, preferably a hydrogen atom. In the compound represented by general formula (I), X represents an oxygen atom or -S(O)n-, preferably an oxygen atom. In the compound represented by general formula (I), Y represents an oxygen atom or a sulfur atom, preferably a sulfur atom.

[0023] Pharmaceutically acceptable salts of the compound represented by formula (I) include, for example, alkali metal salts such as sodium salts, potassium salts, and lithium salts, with potassium salts being preferred.

[0024] The compound represented by general formula (I) can be obtained, for example, by the synthesis method described in WO 2005 / 121153 or WO 2019 / 208635.

[0025] Of the compounds represented by general formula (I) contained in the motor function improver of the present invention, preferred compounds include the compounds in Table 1. In the table, Me represents a methyl group.

[0026] Compounds 1 to 15 shown in the above table may form salts (preferably pharmaceutically acceptable salts); among these, Compounds 3 to 5, Compounds 8 to 10, Compounds 13 to 14, or pharmaceutically acceptable salts of these compounds are preferred.

[0027] In the motor function improver of the present invention, it is preferable that the compound represented by general formula (I) or its salt is present in part or in whole as amorphous. Amorphous refers to a substance in a state in which the compound represented by general formula (I) or its salt has short-range order between atoms or molecules but does not have long-range order like a crystal. Whether it is amorphous or not can be confirmed by showing a halo peak in X-ray diffraction.

[0028] In the present invention, the compound represented by general formula (I) or its salt preferably exists as amorphous in an amount of 50% by weight or more, more preferably 80% by weight or more, more preferably 90% by weight or more, even more preferably 95% by weight or more, or even 100% by weight. The compound represented by general formula (I) or its salt may be crystalline. In this case, the amorphous content may be less than 50% by weight, 40% by weight or less, 30% by weight or less, 20% by weight or less, 10% by weight or less, or none at all. The amorphous content can be determined by X-ray diffraction. The remainder of the amorphous content is produced as crystalline. That is, in the description of each content, the sum of the amorphous and crystalline content is 100% by weight.

[0029] The amorphous compound represented by general formula (I) or a salt thereof can be obtained, for example, by subjecting the compound represented by general formula (I) or a salt thereof to a spray drying method (also referred to as a spray-drying method). More specifically, the compound represented by general formula (I) or a salt thereof, and optionally a pharmaceutically acceptable additive, are added to a solvent described below to form a solution or suspension, and the solution or suspension is turned into a fine mist by centrifugal atomization using a rotating disk or pressurized atomization using a pressure nozzle, and this is sprayed into a drying medium (e.g., heated air or nitrogen gas), thereby obtaining an amorphous powdery dried product. In the spray-drying method, the temperature of the drying medium is, for example, 50 to 120°C, preferably 50 to 90°C. The drying medium may be flowed in a certain direction, for example, at a rate of 0.1 to 0.6 m ３ The solvent can be made to flow at a rate of 1 / min. Examples of solvents used in spray drying include alcohols containing alcohols having 1 to 6 carbon atoms, such as methanol, ethanol, 1-propanol, 2-propanol, and tert-butyl alcohol; ethers, such as tetrahydrofuran (THF); acetonitrile; and water. These solvents can be used alone or as a mixed solvent of two or more of them. Among these, ethanol, tetrahydrofuran, and mixed solvents of these solvents with water are preferred.

[0030] Another method (a method other than spray drying) for producing an amorphous form of the compound represented by general formula (I) or a salt thereof is freeze-drying. More specifically, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof can be produced by dissolving the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof in a solvent and then freeze-drying the solution. Solvents used in freeze-drying include alcohols containing alcohols having 1 to 6 carbon atoms, such as methanol, ethanol, 1-propanol, 2-propanol, and tert-butyl alcohol; ethers such as tetrahydrofuran; nitriles such as acetonitrile; and water. These solvents can be used alone or as a mixed solvent of two or more.

[0031] The particle size of the amorphous compound represented by general formula (I) or a salt thereof is not particularly limited. However, from the viewpoint of the effects of the invention and formulation, the volume average particle size (D50) is, for example, 20 μm or less, preferably 1 to 15 μm, more preferably 1 to 10 μm, even more preferably 1.5 to 5 μm, and most preferably 2 to 5 μm. The volume average particle size (D50) can usually be measured by dispersing a measurement sample in a solvent such as water or ethanol and measuring the particle size distribution by laser diffraction. The measurement sample may also be dispersed in a solvent by irradiating it with ultrasound. The particle size distribution can be measured using a particle size distribution analyzer (e.g., Shimadzu laser diffraction particle size distribution analyzer SALD-2200, etc.). The volume average particle size (D50) can be calculated from the particle size distribution obtained. Commercially available software (eg, Shimadzu WingSALD-2200 version 1.02) can also be used for data collection and analysis.

[0032] [1-2. ATP Precursor Substance] The motor function enhancer of the present invention can contain, as a constituent, an ATP precursor substance in the salvage circuit (also referred to as the "(purine) salvage pathway"). The phrase "containing an ATP precursor substance as a constituent" includes the use of an ATP precursor substance in combination with a compound represented by general formula (I) or a salt thereof; and the use of a compound represented by general formula (I) or a salt thereof in combination with an ATP precursor substance in the motor function enhancer of the present invention (preparation of a combination preparation). Here, "use in combination" includes the administration or ingestion of an ATP precursor substance before, simultaneously with, or after the administration or ingestion of a compound represented by general formula (I) or a salt thereof. Furthermore, the use of an ATP precursor substance in combination with an ATP precursor substance includes the inclusion of a description in the instruction manual for a composition containing a compound represented by general formula (I) or a salt thereof that the composition is to be used in combination with an ATP precursor substance; or the use of a composition containing a compound represented by general formula (I) or a salt thereof in a kit preparation.

[0033] ATP precursors refer to purine bases, nucleosides, nucleotides, and the like, which serve as raw materials for ATP production in the purine salvage pathway. ATP precursors are used as raw materials for generating intracellular ATP in the salvage pathway, and can enhance the effect of improving motor function as enhancers of XOR inhibitors represented by general formula (I). Examples of ATP precursors include hypoxanthine, inosine, and inosinic acid. Inosine is an N-riboside composed of hypoxanthine and D-ribose. Inosine itself can be produced by known methods and is also commercially available.

[0034] [1-3. Additives] The motor function improver of the present invention can be blended with additives as needed. For example, the motor function improver of the present invention can be produced by blending appropriate combinations of binders, disintegrants, excipients, lubricants, enteric polymers, etc. in required amounts.

[0035] Examples of binders include methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, gelatin, agar, alginic acid, sodium alginate, partially saponified polyvinyl alcohol, pullulan, partially pregelatinized starch, dextrin, xanthan gum, and gum arabic powder. These may be used alone or in combination. Among these, hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, etc. are preferred.

[0036] Examples of disintegrants include crystalline cellulose, carboxymethylcellulose (also known as carmellose), croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, crospovidone, hydroxypropyl starch, starch, partially pregelatinized starch, and sodium starch glycolate. These may be used alone or in combination. Among these, croscarmellose sodium, sodium starch glycolate, and crospovidone are preferred, with crospovidone being more preferred. The amount of disintegrant used is preferably 5 to 30% by weight, more preferably 5 to 15% by weight, based on the total weight of the particles containing the active ingredient. When incorporated into tablets, the amount is preferably 1 to 10% by weight, more preferably 2 to 6% by weight, based on the total weight of the granules for tableting containing the active ingredient.

[0037] The excipient can be added in any of the kneading step, the granulation step, and the post-granulation powdering step of the preparation. Examples of the excipient include celluloses such as crystalline cellulose, ethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and hydroxypropylmethylcellulose (also known as hypromellose), starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, and hydroxypropyl starch, sugars such as glucose, lactose, sucrose, refined sucrose, powdered sugar, trehalose, dextran, and dextrin, sugar alcohols such as D-mannitol, xylitol, sorbitol, and erythritol, and inorganic salts such as glycerin fatty acid esters, magnesium aluminometasilicate, synthetic hydrotalcite, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium hydrogen phosphate hydrate, and sodium bicarbonate, with crystalline cellulose being preferred.

[0038] Examples of lubricants include stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid esters, polyethylene glycol, light anhydrous silicic acid, hardened oils, glycerin fatty acid esters, and talc. These may be used alone or in combination. Among these, sodium stearyl fumarate, magnesium stearate, calcium stearate, and sucrose fatty acid esters are preferred.

[0039] The motor function enhancer of the present invention may contain an enteric polymer. By mixing the compound represented by general formula (I) or a salt thereof with an enteric polymer, recrystallization of the compound represented by general formula (I) or a salt thereof from a supersaturated solution can be suppressed. It is preferred that the compound represented by general formula (I) or a salt thereof and the enteric polymer are uniformly mixed. The weight ratio of the compound represented by general formula (I) or a salt thereof to the enteric polymer is, for example, 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.

[0040] Examples of the enteric polymer include enteric polymers for coating, and are preferably cellulose-based polymers, more preferably hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose acetate succinate. When the compound represented by general formula (I) or a salt thereof is mixed with the enteric polymer, the above-mentioned additives can be appropriately added.

[0041] [1-4. Formulation Design of the Motor Function Enhancer of the Present Invention] The motor function enhancer of the present invention may be formulated in any manner, for example, into an enteric coated preparation or a solid dispersion.

[0042] [1-4-1. Enteric-coated Preparation] The motor function enhancer of the present invention is preferably an enteric-coated preparation. By forming the motor function enhancer of the present invention into an enteric-coated preparation, the compound represented by general formula (I) or a salt thereof can exhibit high in vivo absorbability. An "enteric-coated preparation" is a preparation designed to prevent the active ingredient from being decomposed in the stomach or to release the active ingredient mainly in the small intestine without releasing it in the stomach. Enteric-coated preparations themselves are described in the Japanese Pharmacopoeia. Known dosage forms of enteric-coated preparations include tablets, granules, fine granules, and capsules. Methods for producing these dosage forms include: (i) producing enteric granules in which the active ingredient, or the active ingredient and a pharmaceutically acceptable additive, are coated with an enteric polymer; and then forming the granules into tablets, granules, fine granules, or capsules containing the active ingredient; (ii) producing tablets, granules, fine granules, or capsules containing the active ingredient and a pharmaceutically acceptable additive; and coating these preparations with an enteric polymer; or (iii) encapsulating the active ingredient, or the active ingredient and a pharmaceutically acceptable additive, in a hard capsule made of an enteric base.

[0043] The enteric formulation of the present invention includes (i) tablets, granules, fine granules, or capsules containing enteric granules in which an active ingredient, or an active ingredient and a pharmaceutically acceptable additive, are coated with an enteric polymer; (ii) tablets, granules, fine granules, or capsules coated with an enteric polymer and containing an active ingredient and a pharmaceutically acceptable additive; or (iii) hard capsules in which an active ingredient, or an active ingredient and a pharmaceutically acceptable additive, are housed in a hard capsule made of an enteric base.

[0044] The enteric base means a base composed of a known enteric polymer, and examples of the enteric polymer include enteric polymers exemplified as enteric polymers for coating. Examples of enteric polymers for coating include enteric methacrylic acid copolymers such as methacrylic acid copolymer L, methacrylic acid copolymer S (e.g., Eudragit (registered trademark) L100, Eudragit (registered trademark) S100, manufactured by Evonik), methacrylic acid copolymer LD (e.g., Eudragit (registered trademark) L100-55, Eudragit (registered trademark) L30D-55, manufactured by Evonik), and methyl acrylate-methyl methacrylate-methacrylic acid copolymer (e.g., Eudragit (registered trademark) FS30D, manufactured by Evonik), hypromellose (hydroxypropyl methacrylate), and the like. Examples of such polymers include enteric cellulose polymers such as hydroxypropylmethylcellulose, hypromellose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd., sometimes abbreviated as HPMCAS), hypromellose phthalate (manufactured by Shin-Etsu Chemical Co., Ltd., sometimes abbreviated as HPMCP), carboxymethylethylcellulose (manufactured by Freund Corporation, sometimes abbreviated as CMEC), and ceracephate (also called cellulose acetate phthalate), and enteric vinyl alcohol polymers such as polyvinyl alcohol acetate phthalate (manufactured by Colorcon Corporation), with enteric cellulose polymers being preferred. Among these, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and hydroxypropylmethylcellulose acetate succinate are preferred.

[0045] Enteric-coated granules can be produced according to known methods. For example, they can be produced by producing granules using fluidized bed granulation (e.g., tumbling fluidized bed granulation and fluidized bed granulation), tumbling granulation (e.g., centrifugal tumbling granulation), or agitation granulation, followed by coating with an enteric coating solution and drying. The enteric coating solution can be prepared by adding the enteric polymer to a solvent and, if necessary, concentrating the solvent. Examples of solvents used to prepare the enteric coating solution include water, alcoholic solvents such as methanol and ethanol, and mixtures thereof. Pharmaceutically acceptable additives such as binders, plasticizers, coating bases, surfactants, and excipients can be appropriately blended as needed. The amount of solvent is not particularly limited, but can be 3 to 10 times the total weight of the solution (i.e., the total weight of the enteric polymer and pharmaceutically acceptable additives).

[0046] Tablets, granules, fine granules, or capsules coated with an enteric polymer and containing an active ingredient and pharmaceutically acceptable additives can be produced by producing tablets, granules, fine granules, or capsules containing an active ingredient and pharmaceutically acceptable additives according to a known method, and then coating the resulting preparation with the enteric coating liquid and drying it.

[0047] As the hard capsule shell made of an enteric base, a commercially available product can be used. For example, a hard capsule shell made of an enteric base containing hydroxypropyl methylcellulose or hydroxypropyl methylcellulose acetate succinate can be used. More specifically, Vcaps (registered trademark) Enteric (manufactured by Capsugel) can be used.

[0048] The enteric coated preparation of the present invention can be blended with additives (preferably pharmaceutically acceptable additives) as needed, and the motor function enhancer of the present invention can be produced by blending, for example, a binder, a disintegrant, an excipient, a lubricant, etc. in appropriate combinations in the required amounts. Examples of such additives include the additives described above in [1-3. Additives].

[0049] [1-4-2. Solid Dispersion] A "solid dispersion" refers to a solid system containing at least two components, and is a solid composition in which the at least two components form a uniformly mixed system. In a solid dispersion, at least one component is usually dispersed throughout the system. 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 salt thereof and a hypromellose derivative; the compound represented by general formula (I) or a salt thereof and the hypromellose derivative form a uniformly mixed system. In other words, the motor function improver of the present invention may be a solid dispersion containing a hypromellose derivative.

[0050] The "hypromellose derivative" contained in the solid dispersion refers to hypromellose itself (sometimes abbreviated as HPMC) and organic acid esters of hypromellose. Hypromellose is also called hydroxypropyl methylcellulose and is a mixed ether of a methyl group and a hydroxypropyl group of cellulose. Examples of organic acids that form esters with hypromellose include acetic acid, succinic acid, and phthalic acid. The hypromellose of the present invention may form esters with one or more organic acids selected from organic acids. Examples of hypromellose derivatives include hypromellose, hypromellose acetate succinate (sometimes abbreviated as HPMCAS), and hypromellose phthalate (sometimes abbreviated as HPMCP), with hypromellose acetate succinate and hypromellose phthalate being preferred.

[0051] The hypromellose contained in the solid dispersion is exemplified by hypromellose having a substitution rate per monomer unit of 28 to 30% for methoxy groups and 7 to 12% for hydroxypropoxy groups.

[0052] The hypromellose acetate succinate contained in the solid dispersion is exemplified by hypromellose acetate succinate having a substitution ratio per monomer unit of 20 to 26%, preferably 21 to 25%, for methoxy groups, 5 to 10%, preferably 5 to 9%, for hydroxypropoxyl groups, 5 to 14%, preferably 7 to 11%, for acetyl groups, and 4 to 18%, preferably 10 to 14%, for succinoyl groups. The hypromellose phthalate of the present invention is exemplified by hypromellose phthalate having a substitution ratio per monomer unit of 18 to 24% for methoxy groups, 5 to 10% for hydroxypropoxy groups, and 21 to 35% for carboxybenzoyl groups.

[0053] The content of methoxy groups, hydroxypropoxy groups, acetyl groups, succinoyl groups, carboxybenzoyl groups, etc. in the hypromellose derivative contained in the solid dispersion can be measured by a method in accordance with the method for measuring the degree of substitution of hypromellose, hypromellose acetate succinate, and hypromellose phthalate specified in the 17th Edition of the Japanese Pharmacopoeia.

[0054] The viscosity of the hypromellose derivative contained in the solid dispersion is not particularly limited as long as the effects of the present invention are achieved, but may be, for example, 2.4 to 204 mPa s, preferably 2.4 to 3.6 mPa s. The viscosity of the hypromellose derivative can be measured by a method conforming to the method for measuring the viscosity of hypromellose, hypromellose acetate succinate, and hypromellose phthalate specified in the 17th Edition of the Japanese Pharmacopoeia.

[0055] The weight ratio of the compound represented by general formula (I) or a salt thereof to the hypromellose derivative in the solid dispersion can be appropriately adjusted within the range of 1:0.1 to 1:25. One example of the weight ratio of the compound represented by general formula (I) or a salt thereof to the hypromellose derivative is 1:0.1 to 1:10, another example is 1:0.1 to 1:4, still 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. In one embodiment, the weight ratio of 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine or a pharmaceutically acceptable salt thereof to the hypromellose derivative is 1:0.1 to 1:25, in another embodiment, 1:0.1 to 1:10, in yet another embodiment, 1:0.1 to 1:4, in yet another embodiment, 1:1 to 1:10, in yet another embodiment, 1:2 to 1:5, and in yet another embodiment, 1:3 to 1:4.

[0056] The solid dispersion of the present invention can exhibit high in vivo absorbability and storage stability of the compound represented by general formula (I) or a salt thereof. In the "solid dispersion" of the present invention, it is preferred that the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is present in part or in whole as an amorphous substance.

[0057] Another embodiment of the solid dispersion of the present invention is a solid composition in which the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is dispersed throughout a hypromellose derivative to form a system in which the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof constitutes the dispersed phase as a dispersoid, and the hypromellose derivative constitutes the continuous phase as a dispersion medium.

[0058] The solid dispersion of the present invention comprises a compound represented by general formula (I) or a salt thereof, a hypromellose derivative, and, if desired, pharmaceutically acceptable additives. Examples of the pharmaceutically acceptable additives that may be contained optionally include additives selected from surfactants, pH adjusters, sugars, plasticizers, etc. These may be appropriately combined and incorporated in the required amount into the solid dispersion of the present invention.

[0059] Surfactants that can be used in the solid dispersion include cationic surfactants such as sodium bis-(2-ethylhexyl) sulfosuccinate (docusate sodium), alkyltrimethylammonium bromide (e.g., cetyltrimethylammonium bromide (cetrimide)), anionic surfactants such as sodium lauryl sulfate, polyoxyethylene sorbitan (e.g., Tween TM 20, 40, 60, 80 or 85), sorbitan fatty acid esters (e.g., Span TM 20, 40, 60, 80, or 85. When the solid dispersion contains a surfactant, for example, the weight ratio of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to the surfactant is 1:0.01 to 1:2, more preferably 1:0.02 to 1:1.5, and even more preferably 1:0.03 to 1:1.2.

[0060] Examples of pH adjusters that can be used in the solid dispersion include acids such as succinic acid, maleic acid, tartaric acid, citric acid, and aspartic acid, and alkalis such as sodium hydroxide, magnesium oxide, silicon dioxide, sodium bicarbonate, and L-arginine. When the solid dispersion contains a pH adjuster, the weight ratio of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to the pH adjuster 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.

[0061] Examples of sugars that can be used in the solid dispersion include lactose, sucrose, glucose, fructose, sucrose, maltose (malt sugar), reduced maltose, maltitol, mannitol, erythritol, sorbitol, xylitol, etc. When the solid dispersion contains a sugar, the weight ratio of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to the sugar is 1:0.02 to 1:20, more preferably 1:0.15 to 1:10.

[0062] Examples of plasticizers that can be used in the solid dispersion include triethyl citrate, polyethylene glycol, triacetin, etc. When the solid dispersion contains a saccharide, the weight ratio of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to the plasticizer is 1:0.02 to 1:20, more preferably 1:0.15 to 1:10.

[0063] In the solid dispersion of the present invention, the pharmaceutically acceptable additive may constitute either the dispersed phase or the continuous phase of the solid dispersion.

[0064] The solid dispersion of the present invention can be produced by a method known per se, for example, a mixing and grinding method (mechanochemical method), a solvent method, a melting method, a heat-kneading and melting method, or the like.

[0065] The production by the mixing and grinding method can be carried out by mixing the compound represented by general formula (I) or a salt thereof, a hypromellose derivative, and optionally a pharmaceutically acceptable additive, and then using a mixer and grinder such as a ball mill or a hammer mill in a conventional manner.

[0066] The solvent method refers to a method in which the compound represented by general formula (I) or a salt thereof, the hypromellose derivative, and optionally pharmaceutically acceptable additives are dissolved or suspended in a solvent (organic solvent, water, or a mixture thereof), and then the solvent is removed to precipitate a solid dispersion, or a solid dispersion is precipitated in the solvent. It is preferable that the compound represented by general formula (I) or a salt thereof, and optionally the (pharmaceutically acceptable) additives, are dissolved in these solvents.

[0067] The solvent that can be used in producing a solid dispersion by the solvent method is preferably a pharmaceutically acceptable solvent, and examples thereof include ethanol, methanol, 2-propanol, acetone, 2-butanone, methyl isobutyl ketone, tetrahydrofuran (THF), tetrahydropyran, 1,4-dioxane, diethyl ether, toluene, acetonitrile, methylene chloride, chloroform, methyl acetate, ethyl acetate, butyl acetate, acetic acid, formic acid, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0068] In the production of solid dispersions by the solvent method, the solvent can be removed by methods such as a spray method (which can be classified into a fluidized bed method, a spray drying method (also called a spray-drying method), a tumbling bed method, a stirring method, or a supercritical method depending on the embodiment), a filtration method, an evaporation method, or a freeze-drying method, of which the spray method is preferred, and of which the spray-drying method is particularly preferred.

[0069] Solvent removal by spray drying is known per se, and a solid dispersion can be produced by this method. For example, a compound represented by general formula (I) or a salt thereof, a hypromellose derivative, and optionally pharmaceutically acceptable additives are added to the solvent to form a solution or suspension, and the solution or suspension is then centrifuged with a rotating disk or pressurized sprayed with a pressure nozzle to form a fine mist, which is then sprayed into a drying medium (heated air or nitrogen gas) to obtain a powdery dried product, thereby obtaining a solid dispersion. In the spray drying method, the temperature of the drying medium is, for example, 50 to 120°C, preferably 50 to 90°C. The drying medium may be flowed in a certain direction, for example, at a rate of 0.1 to 0.6 m. ３ The air can be made to flow at a rate of 1 / min.

[0070] In the production of solid dispersions by the solvent method, the method for precipitating the solid dispersion is preferably a coprecipitation method, in which a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, a hypromellose derivative, and optionally pharmaceutically acceptable additives are dissolved or suspended in a solvent, and the dissolved compound (I) or a pharmaceutically acceptable salt thereof, a hypromellose derivative, and optionally pharmaceutically acceptable additives are precipitated by lowering the dissolution concentration by adding a solvent in which the dissolved compound (I) or a pharmaceutically acceptable salt thereof, a hypromellose derivative, and optionally pharmaceutically acceptable additives are insoluble, or by lowering the temperature, to obtain a solid dispersion.

[0071] The production of a solid dispersion by the melting method refers to a method in which a compound represented by general formula (I) or a salt thereof, a hypromellose derivative, and optionally pharmaceutically acceptable additives are heated to a temperature above the melting point or softening point of the hypromellose derivative, followed by stirring, etc., to dissolve or disperse the compound represented by general formula (I) or a salt thereof, and optionally pharmaceutically acceptable additives, in the hypromellose derivative, and then rapidly cooled. In this process, additives such as plasticizers (e.g., triethyl citrate, polyethylene glycol, triacetin), and surfactants can be further added, if desired. The production of a solid dispersion by the melting method can be carried out using a stirring granulator equipped with a heating device.

[0072] The production of a solid dispersion by the heat-kneading melting method is a method in which a compound represented by formula (I) or a salt thereof, a hypromellose derivative, and optionally pharmaceutically acceptable additives are mixed under heat and pressure in an extruder equipped with a heating device, such as a twin-screw 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.

[0073] The solid dispersions produced by these production methods can be converted into solid dispersion particles having any particle size by known methods, and the solid dispersion particles can be used as they are as powders or granules.

[0074] The motor function enhancer of the present invention containing the solid dispersion comprises the solid dispersion and pharmaceutically acceptable additives, and the pharmaceutical composition of the present invention can be produced by blending the required amounts of appropriate combinations of pharmaceutically acceptable additives such as binders, disintegrants, excipients, lubricants, etc. Examples of the additives include those exemplified in [1-3. Additives].

[0075] The motor function enhancer of the present invention containing the solid dispersion can be provided by subjecting it to a formulation process known per se to be formulated into solid preparations such as tablets, capsules, granules, powders, etc., or liquid preparations such as injections. The injections may be in the form of a solid preparation of the motor function enhancer of the present invention, which is prepared and used immediately after administration. Since the motor function enhancer of the present invention also has the effect of suppressing tableting problems, tablets, which are solid preparations, may be particularly preferred. These solid preparations may be coated as desired.

[0076] The content of the solid dispersion in the motor function improver of the present invention may be 10 to 95 wt %, preferably 30 to 90 wt %, and more preferably 60 to 85 wt %, based on the total weight of the motor function improver.

[0077] [1-5. Dosage Form of the Motor Function Enhancer of the Present Invention] The motor function enhancer of the present invention can be manufactured as a pharmaceutical in an appropriate dosage form such as a tablet, capsule, granule, powder, eye drop, mouthwash, ointment, cream, gel, poultice, patch, liniment, tape, cataplasm, injection, or suppository, according to a conventional method in the technical field of pharmaceutical preparations.

[0078] Of these preparations, for example, ointments can be prepared by a known method. For example, they can be prepared by triturating or dissolving one or more active ingredients in a base. The ointment base can be selected from known ointment bases. For example, higher fatty acids or higher fatty acid esters (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipate esters, myristic acid esters, palmitate esters, stearic acid esters, oleate esters, etc.), waxes (e.g., beeswax, spermaceti, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphate esters, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., dimethicone, methylpropional ... The cosmetic composition may contain one or more bases selected from the group consisting of: methylpolysiloxane, etc.; hydrocarbons (e.g., hydrophilic petrolatum, white petrolatum, refined lanolin, liquid paraffin, etc.); glycols (e.g., ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.); vegetable oils (e.g., castor oil, olive oil, sesame oil, turpentine oil, etc.); animal oils (e.g., mink oil, egg yolk oil, squalane, squalene, etc.); water; absorption enhancers; and anti-rash agents. The cosmetic composition may further contain moisturizers, preservatives, stabilizers, antioxidants, fragrances, etc.

[0079] [2. Pharmaceuticals Containing Motor Performance Enhancers] In the present invention, "improvement of motor performance" is not particularly limited to specific embodiments, but includes aspects in which athletic ability is maintained or improved by improving or suppressing a decline in stamina that enables sustained exercise under aerobic or anaerobic exercise, increasing the amount of exercise, improving or suppressing a decline in muscle function (muscle strength), suppressing muscle fatigue, and enhancing muscle contractile force. More typically, it may be an improvement in walking ability or an increase in muscle strength. It also includes aspects in which weight loss or visceral fat mass is achieved by maintaining or improving athletic ability. Improvement of motor function includes aspects obtained as a result of the improvement of motor function, such as improvement of movements in daily life, prevention or improvement of lower back pain, prevention or improvement of muscle or joint stiffness, improvement of muscle or joint mobility, improvement of body flexibility, and prevention of injury.

[0080] The compound represented by general formula (I) or its salt contained in the motor function enhancer of the present invention is known to exhibit XOR (xanthine oxidoreductase) inhibitory effect.In addition, the compound represented by general formula (I) or its salt is known to inhibit ATP metabolism [ATP (adenosine triphosphate) → ADP (adenosine diphosphate) → AMP (adenosine monophosphate) → IMP (inosine monophosphate) → inosine → hypoxanthine → xanthine → metabolism to urea], that is, to inhibit the conversion reaction of hypoxanthine to xanthine, and the conversion reaction of xanthine to urea; as a result, the compound represented by general formula (I) or its salt can accumulate intracellular hypoxanthine, strengthen the function of salvage cycle (hypoxanthine → inosine → IMP → synthesis of AMP, ADP, ATP), and enhance intracellular adenosine phosphate (AMP, ADP, ATP) (see Patent Document 6 mentioned above).

[0081] The motor function improver of the present invention contains a compound represented by general formula (I) or a salt thereof, and may be used in combination with or further contain an ATP precursor substance (e.g., inosine, inosinic acid, or hypoxanthine). Therefore, it is believed that the ATP precursor substance further enhances the enhancement of the salvage pathway function achieved by the compound represented by general formula (I) or a salt thereof.

[0082] The mechanism by which the motor function enhancer of the present invention improves the motor function of a subject is not particularly limited, but it may be thought that by strengthening the function of the salvage circuit, each adenosine phosphate in the cells is increased, thereby increasing the energy consumption of the cells (such as muscle cells).

[0083] In Example 2 described below, it is shown that the plasma inosine concentration, hypoxanthine concentration, and xanthine concentration of mice administered with the motor function enhancer of the present invention are increased. Furthermore, in Example 4 described below, it is shown that the ATP concentration and hypoxanthine concentration are increased in the skeletal muscle (particularly fast muscle) of mice administered with the motor function enhancer of the present invention (compound 14 and inosine). Thus, the motor function enhancer of the present invention may improve motor function by strengthening the function of the salvage circuit, and may particularly be effective in treating sarcopenia.

[0084] Improving motor function includes improving the symptoms of "muscular dystrophy," "age-related weakness," or "frailty," as well as improving symptoms of physical frailty such as "sarcopenia" and "locomotor syndrome," which are components of frailty. It also includes improving muscle wasting and sarcopenia associated with "sarcopenia" and "locomotor syndrome." In other words, the motor function enhancer of the present invention can be used as a pharmaceutical composition for treating these conditions. Treatment includes restoring impaired motor function, suppressing the decline of motor function, maintaining motor function, and improving motor function. "Muscular dystrophy" is a general term for hereditary muscle disorders in which muscle atrophy and muscle weakness progress through repeated destruction, degeneration (myo-necrosis), and regeneration of muscle fibers. Specifically, it refers to a condition in which the main complaint is muscle weakness and muscle atrophy and the following two conditions are met: (1) It is a hereditary disease. (2) Skeletal muscles show dystrophic changes. Dystrophic changes are characterized by loss of muscle fiber structure, including irregularities in muscle fiber size, rounding, increased central nuclei, increased connective tissue, and fatty changes. This definition was based on the pathological findings of Duchenne muscular dystrophy, which was the first reported type of muscular dystrophy.

[0085] "Frailty" refers to a vulnerable state (intermediate stage) in which elderly people are prone to health disorders such as unintentional weakness, decreased muscle strength, decreased activity, and decreased mental activity as they become dependent on care. The evaluation index of Fried et al. is the mainstream index for evaluating frailty, and if three of the following five indexes apply, the person is considered to be "frail." Furthermore, if one or two of the five indexes apply, the person is considered to be "pre-frail." The frailty treated by the pharmaceutical composition of the present invention includes both frailty and pre-frailty, and is preferably frail. 1) Weight loss 2) Decreased walking speed 3) Decreased grip strength 4) Easily fatigued 5) Decreased physical activity level

[0086] "Sarcopenia" refers to a condition in which muscle mass is reduced, resulting in muscle weakness or even decreased physical function due to aging or other factors. According to the AWGS 2019 diagnostic criteria, sarcopenia can be diagnosed based on "grip strength (muscle strength)," "walking speed (physical function)," and "skeletal muscle mass (skeletal muscle mass index)," but the diagnostic criteria are not limited to these. The AWSG 2019 diagnostic criteria define sarcopenia as a condition in which reduced grip strength (less than 28 kg for men and less than 18 kg for women) and reduced walking speed (less than 1.0 m / s) are observed, and the skeletal muscle mass index (SMI) measured by DXA is 7.0 kg / m or less for men. ２ or less than 5.4 kg / m ２ Sarcopenia is diagnosed when the body's overall blood cholesterol level is less than 100%.

[0087] "Locomotive syndrome" refers to a condition in which a disorder of the musculoskeletal system causes a decline in mobility, and as it progresses, the risk of needing nursing care increases. Locomotive syndrome is generally diagnosed using a sit-to-stand test, a two-step test, and a 25-item medical interview (Locomotive 25), and can be rated on a locomotive scale of 1 to 3.

[0088] "Muscle wasting" is sometimes considered synonymous with sarcopenia; however, it refers to the weakening, atrophy, and loss of muscle due to disease or lack of exercise, and is interpreted more broadly than sarcopenia. Muscle wasting leads to a decrease in physical strength and reduced athletic ability. "Sarcopenia" is also sometimes considered synonymous with sarcopenia; however, while sarcopenia primarily involves a decrease in skeletal muscle mass, "sarcopenia" is sometimes considered a broader concept that includes a decrease in muscle mass not only of skeletal muscle but also of smooth muscle and cardiac muscle.

[0089] As shown in Examples 1 and 2 below, administration (single administration) of the motor function improver of the present invention to healthy mice subjected to a treadmill test significantly extended the running distance compared to mice not administered the agent, demonstrating that the motor function improver of the present invention has an effect of improving endurance and athletic performance.

[0090] Furthermore, SAM-P, a strain of senescence-accelerated mouse (SAM), is an animal model that exhibits aging-related diseases similar to those in humans. In particular, SAM-P8 has been observed to exhibit a decrease in skeletal muscle mass and has been reported to be an animal model of sarcopenia. Therefore, by performing a treadmill test using the SAM-P model, the therapeutic effect (improvement effect) of the motor function enhancer of the present invention on sarcopenia and frailty can be confirmed. Example 3 described below demonstrates that administration of the motor function enhancer of the present invention to a sarcopenia model mouse (SAM-P8) improved motor function.

[0091] When the motor function enhancer of the present invention is administered as a pharmaceutical, the route of administration is not particularly limited and may be oral or parenteral. Examples of parenteral administration include injection (including intravenous injection, subcutaneous injection, intramuscular injection, etc.), transdermal administration, eye drops, etc.

[0092] The dosage of the motor function improver of the present invention is determined appropriately depending on the administration method, the age, weight, sex, symptoms (severity, etc.), drug sensitivity, etc. of the subject, and the dosage may be adjusted depending on the state of symptom improvement. In the present invention, it is preferable to administer a constant dosage continuously.

[0093] For example, in the case of oral administration, the dose of the motor function enhancer of the present invention for an adult is typically 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, even more preferably 60 to 120 mg, and particularly preferably 60 to 100 mg per day as the dose of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, and the oral administration can be continued for at least 7 days as desired, although this dose can be increased or decreased depending on age, symptoms, etc.

[0094] The number of times (frequency) of administration of the motor function enhancer of the present invention may be, for example, 1 to 3 times per day, preferably 1 to 2 times per day, and more preferably 1 time per day. Note that, since the motor function enhancer of the present invention preferably continuously enhances motor function, the dosage and the number of times of administration can be appropriately determined to achieve the above-mentioned state, and for example, the number of times of administration may be 2 or 3 times per day.

[0095] The dose of the ATP precursor substance constituting the motor function improver of the present invention is also determined appropriately depending on the administration method, the age, weight, sex, symptoms, drug sensitivity of the subject, etc. The mass ratio of the dose of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof to the dose of the ATP precursor substance is preferably 1:0.05 to 1:20, and more preferably 1:0.1 to 1:10.

[0096] The motor function improving agent of the present invention may contain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof in combination with an ATP precursor substance in the salvage cycle; the order of administration may be such that the ATP precursor substance in the salvage cycle is administered before, simultaneously with, or after the administration of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

[0097] The pharmaceutical composition containing the motor function enhancer of the present invention can be administered in combination with exercise therapy. In particular, exercise therapy is often used to maintain muscle mass and prevent muscle weakness in patients with sarcopenia or locomotive syndrome, physical frailty, or muscular dystrophy. By administering the motor function enhancer of the present invention in combination with exercise therapy, it is possible to more effectively improve the motor function of patients. Exercise therapy includes, but is not limited to, stretching, strength training, aerobic exercise, etc. In the examples described below (e.g., Example 3), a motor function enhancer (a compound represented by general formula (I)) was administered to a model mouse and the mouse was subjected to load running, thereby improving the motor function.

[0098] The present invention will now be described in more detail with reference to examples, but the present invention should not be construed as being limited to these examples.

[0099] Compound 14, the drug (compound represented by general formula (I)) used in the following examples, is "Compound 14" listed in Table 1 above, and has the following molecular structure.

[0100] Reference Example: Formulation of Compound 14 (Production of Solid Dispersion Mixed Powder) 0.18 kg of Compound 14 was dissolved in 38.72 kg of a mixed solvent of tetrahydrofuran, absolute ethanol, and purified water (weight ratio: 32.01 / 5.09 / 1.62) while heating, and then 0.72 kg of HPMCAS-MG was added and stirred to prepare a feed solution. The mixture was then spray-dried using a spray dryer under the following conditions: heat input temperature 100°C, heat exhaust temperature 60°C, feed rate 100 g / min, and nitrogen spray pressure of a two-fluid nozzle 0.30 MPa. The resulting spray-dried product was vacuum-dried at 25°C for 16 hours and at 40°C for 24 hours. This was then air-dried at room temperature for 24 hours to obtain a solid dispersion of Compound 14. The obtained solid dispersion of Compound 14 was sieved through a sieve (mesh opening: 300 μm), and 250 g of the sieve was added to and mixed with 50 g of sodium starch glycolate to obtain a solid dispersion mixed powder of Compound 14.

[0101] Example 1. Evaluation of endurance in healthy mice using a treadmill 1 (single administration) Ten C57BL6j mice (13-week-old, male) were prepared and divided into a methylcellulose (MC) administration group (6 mice) and a Compound 14 + inosine administration group (4 mice). Each mouse was orally administered a drug 90 minutes before running on a treadmill. The drug was orally administered by forced administration using a probe (oral administration needle). The drug dose was 1 / 100 volume (v / w) of body weight for both the MC administration group and the Compound 14 + inosine administration group. In the MC group, the drug was a 0.5 w / v% methylcellulose solution (containing sodium bicarbonate (50 mg / ml)); in the Compound 14 + inosine group, Compound 14 and inosine were suspended in a 0.5 w / v% methylcellulose solution (containing sodium bicarbonate (50 mg / ml)) at doses of 5 mg / kg and 25 mg / kg, respectively. Compound 14 is known to be a xanthine oxidoreductase (XOR) inhibitor, and XOR inhibitors can cause kidney stone formation in mice. Therefore, sodium bicarbonate was added to the methylcellulose solution administered to both groups to suppress kidney stone formation.

[0102] Ninety minutes after drug administration, the endurance of the mice was evaluated using a treadmill. A small animal treadmill, model LE8700RTS (BBC Bioresearch Center), was used. An electrode was placed at the rear end of the running lane of the treadmill, and when the mouse touched the electrode during the running test, it received an electrical stimulus. The running speed on the treadmill began at 4 m / min, increased by 4 m / min every 2 minutes, and reached 20 m / min (maximum speed) after 8 minutes, after which the maximum speed was maintained. The number of times the mouse touched the electrode at the rear of the running lane to receive an electrical stimulus was recorded, and the number of times it received an electrical stimulus was used as a measure of fatigue. The running was terminated when the electrical stimulus exceeded 130 times, and the running time and distance were recorded. The maximum running time was 80 minutes.

[0103] The relationship between the running time (X axis) and the number of times electrical stimulation was received (Y axis) for each mouse (MC administration group or Compound 14 + inosine administration group) is shown in the graph in Figure 1. As shown in Figure 1, the mice in the Compound 14 + inosine administration group received fewer electrical stimulations per hour than the mice in the MC administration group. In other words, it can be seen that the mice in the Compound 14 + inosine administration group ran actively in the treadmill test.

[0104] Figure 2 is a graph comparing the average distance traveled by the MC-treated group (6 mice) with the average distance traveled by the Compound 14 + inosine-treated group (4 mice) in a treadmill test. As shown in Figure 2, the mice in the Compound 14 + inosine-treated group ran a longer distance, reaching 2.5 times the distance traveled by the MC-treated group.

[0105] As described above, mice administered with Compound 14 and inosine showed an increased running distance in the treadmill test, suggesting that Compound 14 and inosine reduced the degree of fatigue in the mice and increased their endurance.

[0106] Example 2. Evaluation of endurance in healthy mice using a treadmill 2 (continuous administration) Six C57BL6j mice (14-week-old, male) were prepared and divided into a methylcellulose (MC) administration group (4 mice) and a Compound 14 + inosine administration group (2 mice).

[0107] On test day 1 (Day 1), one day before drug administration, each mouse was run on a treadmill (Pre-run). The treadmill used was the same as in Example 1. The inclination angle of the running lane of the treadmill was set to 0 degrees, and the initial speed was 4 m / min. The speed was increased by 4 m / min every 2 minutes, reaching 20 m / min (maximum speed) after 8 minutes, and the maximum speed was maintained thereafter. The number of times the mouse touched the electrode at the rear of the running lane to receive electrical stimulation was recorded, and the number of times it received electrical stimulation was used as a measure of fatigue. The run was terminated when the electrical stimulation exceeded 130 times, and the running time and running distance were recorded. The running time was limited to a maximum of 80 minutes.

[0108] From the second day (Day 2) to the sixth day (Day 6) of the test, the drug was orally administered once a day. The MC administration group was orally administered with a 0.5 w / v% methylcellulose solution. The Compound 14 + inosine administration group was administered with a liquid preparation prepared by suspending a Compound 14 formulation (see Reference Example) in a 0.5 w / v% methylcellulose solution so that the concentration of Compound 14 was 5 mg / kg and suspending inosine at 25 mg / kg. The dose administered to each mouse was 1 / 100 volume (v / w) of body weight for both the MC administration group and the Compound 14 + inosine administration group. The drug was orally administered by forced administration using a probe (oral administration needle).

[0109] From Day 2 to Day 6, 60 minutes after oral drug administration, each mouse (MC group and Compound 14 + inosine group) was orally administered a 0.5 w / v% methylcellulose solution (50 mg / ml) containing sodium bicarbonate (NaHCO3) at 1 / 100 volume (v / w) of the mouse body weight using a syringe. Compound 14 is known to be a xanthine oxidoreductase (XOR) inhibitor, and XOR inhibitors can cause kidney stone formation in mice. Therefore, sodium bicarbonate was administered 60 minutes after oral drug administration to inhibit kidney stone formation.

[0110] As exercise therapy, from Day 2 to Day 6 of the test, 90 minutes after drug administration (30 minutes after sodium bicarbonate administration), each mouse ran on a treadmill under load. The treadmill used was the same as in Example 1. The inclination angle of the running lane of the treadmill was set to 0 degrees, and the mice were run on the running lane at a speed of 16 m / min for 15 minutes to apply load.

[0111] On Day 7 of the study, as with Days 2 to 6, drugs and sodium bicarbonate were orally administered, and each mouse was run on a treadmill under the same conditions as Day 1 (Post-run). The running distances in the Pre-run and Post-run were compared for the MC-administered group and the Compound 14 + inosine-administered group. As a result, as shown in Figure 3, in the Compound 14 + inosine-administered group, the running distance in the Post-run increased by approximately 5-fold compared to the running distance in the Pre-run, whereas in the MC-administered group that only underwent exercise therapy, the increase was only about 1.5-fold.

[0112] On Day 8, mice were orally administered with the drug and sodium bicarbonate as in Days 2-7. Then, each mouse was dissected and plasma concentrations of (A) inosine, (B) hypoxanthine, (C) xanthine, and (D) uric acid were measured for both the MC-treated group and the Compound 14 + inosine-treated group. As shown in Figures 4(A)-(D), the inosine concentration was significantly elevated in the Compound 14 + inosine-treated group compared with the MC-treated group (Figure 4(A)). Furthermore, the hypoxanthine and xanthine concentrations were significantly elevated in the Compound 14 + inosine-treated group compared with the MC-treated group (Figures 4(B) and (C)). These results suggest that the salvage pathway function was enhanced. Furthermore, the uric acid concentration was significantly reduced in the Compound 14 + inosine-treated group compared with the MC-treated group. This indicates that compound 14 acts as an XOR inhibitor to suppress uric acid production.

[0113] Example 3. Effect on sarcopenia model Eleven SAMP8 mice (43 weeks old) were prepared and divided into a methylcellulose (MC) administration group: 5 mice (average body weight 31.6±6.3 kg) and a Compound 14 + inosine administration group: 6 mice (average body weight 30.9±3.7 kg).

[0114] On the first day of the study (Day 1), each mouse was orally administered a drug. The MC administration group was orally administered a 0.5 w / v% methylcellulose solution. The Compound 14 + inosine administration group was orally administered a liquid obtained by suspending 5 mg of a Compound 14 formulation (see Reference Example) in 4 mL of a 0.5 w / v% methylcellulose solution and sonicating it for 3 minutes. The dose administered to each mouse was 1 / 100 volume (v / w) of the mouse body weight for both the MC administration group and the Compound 14 + inosine administration group, and the dose of Compound 14 was 2.5 mg / kg. Oral administration of the drug was performed by forced administration using a probe (oral administration needle).

[0115] Furthermore, 60 minutes after drug administration, sodium bicarbonate (NaHCO3) and inosine were orally administered to the Compound 14 + inosine administration group. That is, a solution of 1 mg of inosine and 50 mg of sodium bicarbonate dissolved in 1 ml of 0.5 w / v% methylcellulose solution was orally administered. The volume administered to each mouse was 1 / 100 volume (v / w) of the mouse body weight, and the inosine dose was 10 mg / kg. Meanwhile, 60 minutes after drug administration, a methylcellulose solution containing only sodium bicarbonate (without inosine) was orally administered to the MC administration group.

[0116] On Day 1, each mouse was run on a treadmill 90 minutes after drug administration (30 minutes after administration of sodium bicarbonate and inosine) (pre-run). The treadmill used was the same as in Example 1. The inclination angle of the running lane of the treadmill was 10 degrees, and the initial speed was 4 m / min. The speed was increased by 4 m / min every 2 minutes, reaching 20 m / min (maximum speed) after 8 minutes, and the maximum speed was maintained thereafter. The number of times the mouse touched the electrode at the rear of the running lane to receive electrical stimulation was recorded, and the number of times it received electrical stimulation was used as a measure of fatigue. The run was terminated when the electrical stimulation exceeded 130 times, and the running time and running distance were recorded. The running time was limited to a maximum of 150 minutes.

[0117] From test day 2 (Day 2) to test day 6 (Day 6), and from test day 9 (Day 9) to test day 13 (Day 13), each mouse was orally administered with the drug once a day in the same manner as Day 1. That is, the MC administration group was orally administered with 0.5 w / v% methylcellulose solution. The compound 14 + inosine administration group was orally administered with a liquid obtained by suspending 5 mg of compound 14 formulation (see Reference Example) in 4 mL of 0.5 w / v% methylcellulose solution and sonicating for 3 minutes. The dose administered to each mouse was 1 / 100 volume (v / w) of the mouse body weight for both the MC administration group and the compound 14 + inosine administration group, and the dose of compound 14 was 2.5 mg / kg. The drug was orally administered by forced administration using a probe (oral administration needle).

[0118] Furthermore, from test day 2 (Day 2) to test day 6 (Day 6), and from test day 9 (Day 9) to test day 13 (Day 13), the Compound 14 + inosine administration group was orally administered sodium bicarbonate (NaHCO3) and inosine 60 minutes after drug administration, as in Day 1. That is, a solution prepared by dissolving 1 mg of inosine and 50 mg of sodium bicarbonate in 1 ml of 0.5 w / v% methylcellulose solution was orally administered. The dose administered to each mouse was 1 / 100 volume (v / w) of the mouse body weight, and the dose of inosine was 10 mg / kg. On the other hand, the MC administration group was orally administered a methylcellulose solution containing only sodium bicarbonate (without inosine).

[0119] As exercise therapy, from test day 2 (Day 2) to test day 15 (Day 15), each mouse was subjected to load running on a treadmill. The treadmill used was the same as in Example 1. The inclination angle of the running lane of the treadmill was set to 10 degrees, and the mice were subjected to load running on the running lane at a speed of 16 m / min for 15 minutes. Note that the load running from test day 2 (Day 2) to test day 6 (Day 6) and from test day 9 (Day 9) to test day 13 (Day 13) was performed 90 minutes after drug administration (30 minutes after administration of sodium bicarbonate and inosine).

[0120] On Day 16 of the study (Day 16), the drugs and sodium bicarbonate were orally administered to mice as on Days 2 to 6 and 9 to 13. Each mouse was then run on a treadmill under the same conditions as Day 1 (Post-run). Figures 5A and 5B show the results of comparing the running times during Pre-run and Post-run for the MC-treated group and the Compound 14 + inosine-treated group. As shown in Figure 5A, the running time during Post-run was prolonged relative to the running time during Pre-run for all mice in the Compound 14 + inosine-treated group (n = 6) (lower graph in Figure 5A); however, some mice in the MC-treated group showed shortened running times (upper graph in Figure 5A). In the upper graph in Figure 5A, the graphs for MC1 and MC5 overlap. As shown in FIG. 5B, when the average running time of each administration group was compared, it was found that the compound 14 + inosine administration group had a higher extension rate of running time than the MC administration group that received only exercise therapy.

[0121] In Example 3, improvement in motor function was observed in SAMP8 mice, which are known as a sarcopenia model animal, by administering compound 14. This suggests that compound 14 is effective in improving sarcopenia.

[0122] Example 4. Effect on intramuscular ATP levels during exercise Eight C57BL6j mice (14-week-old, male) were prepared and divided into a methylcellulose (MC) administration group (4 mice) and a Compound 14 + inosine administration group (4 mice).

[0123] Each mouse in the MC group was orally administered a 0.5 w / v% methylcellulose solution. Each mouse in the Compound 14 + inosine group was orally administered the following solution: 5 mg of Compound 14 was ground in an agate mortar to form a film, to which 1 ml of a 0.5 w / v% methylcellulose solution containing 50 mg / ml sodium bicarbonate was added, 25 mg of inosine was added to the resulting solution, and the solution was further diluted 10 times with a 0.5 w / v% methylcellulose solution containing 50 mg / ml sodium bicarbonate. The volume (w / v) administered to each mouse was 1 / 100 of the mouse's body weight, and the solution was forcefully administered using a probe (oral administration needle).

[0124] Ninety minutes after drug administration, each mouse was run on a treadmill for 20 minutes. The inclination angle of the running lane of the treadmill was set to 0°, and the initial speed was 4 m / min. The speed was increased by 4 m / min every 2 minutes, reaching 20 m / min (maximum speed) after 8 minutes, and the maximum speed was maintained thereafter.

[0125] After 20 minutes of running, hindlimb muscles (tibialis anterior (mixed muscle), extensor digitorum longus (fast-twitch muscle), and soleus (slow-twitch muscle)) were removed under isoflurane anesthesia and immediately frozen in liquid nitrogen. The weight of the frozen muscles was measured, and the muscles were crushed using a bead shocker. Then, they were extracted with 70% acetonitrile in an amount 10 times the tissue weight. The resulting extracts were analyzed by HPLC, and ATP and its metabolite, hypoxanthine (Hx), were quantitatively evaluated for each muscle site. The results are shown in Figures 6A and 6B.

[0126] As shown in Figure 6A, intramuscular ATP levels increased in all muscles, with the increase in the extensor digitorum longus being particularly significant. Also, as shown in Figure 6B, intramuscular hypoxanthine levels also increased in all muscles, with the increase in the extensor digitorum longus being particularly significant. Sarcopenia is a pathological condition characterized by a decrease in muscle mass and strength with age, and it is known that the muscle mass required for explosive power, known as fast-twitch muscle, is particularly prone to atrophy and decline ( Current Status of Sarcopenia Research and Clinical Applications, Physical Therapy, Vol. 45, No. 5, pp. 332-341, 2018). ATP is known to be the energy source required for muscle contraction, so increasing ATP levels in the fast-twitch extensor digitorum longus muscle is expected to contribute to improving sarcopenia. Furthermore, it is said that muscles that predominantly use the salvage pathway are long-distance slow-twitch muscles, and in the compound 14 + inosine administration group, ATP concentrations also tended to increase in the tibialis anterior muscle, a mixed muscle, and the soleus muscle, a slow-twitch muscle. This suggests that the motor function improver of the present invention activates the salvage pathway and enhances muscle strength.

[0127] The motor function improver provided by the present invention can suppress or restore motor function decline caused by aging, long-term hospitalization, prolonged activity restriction, etc., and is therefore expected to be a pharmaceutical agent for treating frailty, sarcopenia, or muscular dystrophy, or for treating muscle wasting or sarcopenia.

Claims

1. General formula (I): (In the formula, R １ represents an unsubstituted phenyl group or a phenyl group substituted with a substituent, and the substituent represents at least one group selected from the group consisting of an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, a formyl group, a carboxyl group, a halogen atom, a phenyl group, and a phenoxy group; R ２ represents a cyano group or a nitro group, R ３ represents a hydrogen atom or a hydroxyl group, X represents an oxygen atom or -S(O)n-, n represents an integer of 0 to 2, and Y represents an oxygen atom or a sulfur atom) or a salt thereof.

2. The exercise performance enhancer according to claim 1, which is used in combination with an ATP precursor substance in the salvage circuit.

3. The exercise performance enhancer according to claim 1, further comprising an ATP precursor substance in the salvage circuit.

4. The motor function enhancer according to claim 2 or 3, wherein the ATP precursor is inosine, inosinic acid, or hypoxanthine.

5. A motor function enhancer according to any one of claims 1 to 3 for improving walking ability or muscle strength.

6. R in the general formula (I) １ The motor function improver according to any one of claims 1 to 3, wherein is an unsubstituted phenyl group or a phenyl group substituted with a halogen atom.

7. The motor function improver according to any one of claims 1 to 3, wherein X in general formula (I) is an oxygen atom.

8. The motor function improver according to any one of claims 1 to 3, wherein Y in general formula (I) is a sulfur atom.

9. The motor function improver according to any one of claims 1 to 3, wherein the compound represented by general formula (I) is 2-(3-cyano-4-phenoxyphenyl)-7-hydroxythiazolo[5,4-d]pyrimidine.

10. A pharmaceutical composition for treating or preventing physical frailty, muscular dystrophy or age-related weakness, comprising the motor function improving agent according to any one of claims 1 to 3.

11. The pharmaceutical composition according to claim 10 for treating or preventing sarcopenia or locomotive syndrome.

12. The pharmaceutical composition according to claim 10 for treating or preventing muscle wasting or sarcopenia.

13. The pharmaceutical composition according to claim 10 for treating or preventing sarcopenia or locomotive syndrome in combination with exercise therapy.

14. A pharmaceutical composition comprising the motor function enhancer according to claim 2, wherein an ATP precursor substance in the salvage circuit is administered before, simultaneously with, or after administration of the compound or a salt thereof.

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