(R)-2-[3-[[N-(BENZOXAZOL-2-YL)-N-3-(4-METOXYPHENOXY)PROPYL]AMINOMETHYL]PHENOXY]BUTYRIC ACID, BLOOD CARNITINE INCREASING AGENT, PHARMACEUTICALS AND PREVENTIVE AND / OR TREATMENTS CONTAINING THIS COMPOUND

Abstract

The invention relates to (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a blood carnitine-increasing agent and a preventative and / or therapeutic agent useful for the prevention and / or treatment of carnitine deficiency, or disease for which carnitine supplementation may be effective. The invention relates to a drug for the prevention and / or treatment of carnitine deficiency, or disease for which carnitine supplementation may be effective, which includes a therapeutically effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salts, or its solvates.

Description

Blood carnitine increaser

[0001] The present invention relates to a blood carnitine increaser.

[0002] Carnitine (3-hydroxy-4-trimethylammoniobutanoic acid) exhibits various physiological effects, with its L-form (L-carnitine; generic name: levocarnitine) as the active ingredient. Carnitine's known functions include transporting long-chain fatty acids into the mitochondrial matrix, maintaining the free CoA pool important for various metabolic processes, acting as an endogenous detoxifier by binding to the acyl group of harmful acyl-CoA and excreting it extracellularly and in the urine, as well as antioxidant, anti-inflammatory, biomembrane stabilizing, and anti-fibrotic effects. Approximately 75% of the carnitine required by adults is supplied through diet, with the remainder biosynthesized in the body (liver, kidney, and brain) and present primarily in tissues such as skeletal muscle, heart, and liver (Non-Patent Document 1).

[0003] Carnitine deficiency occurs when the body lacks carnitine due to factors such as decreased intake or absorption of carnitine, decreased synthesis of carnitine in the body, excessive loss of carnitine, increased excretion of free carnitine, or increased excretion of acylcarnitines in the urine. Carnitine deficiency is known to occur in a variety of conditions, including congenital metabolic disorders; patients receiving valproic acid (e.g., epilepsy patients, psychiatric patients, and post-neurosurgery patients); patients receiving peritoneal dialysis or hemodialysis due to renal failure; patients with Fanconi disease; patients receiving continuous renal replacement therapy (CRRT); patients receiving nutritional management via tube feeding, total parenteral nutrition (TPN), or some cow's milk allergen-free formula; patients receiving pivoxil-containing antibiotics; patients receiving anticancer drugs (e.g., platinum agents, anthracyclines, alkylating agents); patients with liver cirrhosis or liver failure; and patients with muscular dystrophy and amyotrophic lateral sclerosis. These include patients with neuromuscular diseases such as ALS; severely physically and mentally disabled children (and adults); patients with anorexia; elderly people; patients with serious illnesses; patients with malnutrition; and others who are suspected of having carnitine deficiency based on their age, underlying disease or condition, muscle mass, prescribed medications, nutritional form, dietary content, etc. (Non-Patent Document 1).

[0004] Carnitine deficiency is broadly divided into primary carnitine deficiency, which occurs due to reduced carnitine uptake in muscle cells and renal tubules, mainly due to genetic abnormalities in the carnitine transporter (OCTN2), and secondary carnitine deficiency, which occurs due to other causes. Primary carnitine deficiency, also known as systemic carnitine deficiency, is a severe form of carnitine deficiency in which the metabolism of long-chain fatty acids necessary for ATP production is impaired, resulting in sudden infant death syndrome, hypoketotic hypoglycemia, cardiomyopathy, etc. (Non-Patent Document 1).

[0005] Clinical symptoms and signs that may indicate carnitine deficiency include impaired consciousness, convulsions, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, retarded mental and motor development, poor weight gain, respiratory abnormalities, cardiac hypertrophy, cardiomyopathy, functional decline, and sudden death (or a family history of these), recurrent Reye-like syndrome, etc. Also, hypoketotic blood glucose, metabolic acidosis, hyperammonemia, liver dysfunction (elevated AST and ALT), fatty liver, and abnormal blood gas analysis (pH, HCO ). ３－ Carnitine deficiency is suspected when general clinical test findings such as abnormalities in blood sugar (Na, K, Ca, Cl), electrolytes (Na, K, Ca, Cl), and treatment-resistant anemia are present and no other clear causes are found. Carnitine deficiency is diagnosed when these symptoms, signs, and findings are combined with results of a blood carnitine two-fraction test or when improvement is observed with carnitine supplementation (Non-Patent Document 1).

[0006] Carnitine replacement therapy using levocarnitine preparations is known as a pharmacotherapy for carnitine deficiency. The administration method, dosage, route, and duration of carnitine replacement therapy are determined by various factors. Such factors include the continuity of the underlying disease or cause of carnitine deficiency, whether it is acute or chronic, its severity, individual patient factors, and the urgency of treatment. Depending on each factor, the optimal dosage form of levocarnitine is selected from tablets, oral liquids, intravenous liquids, etc. (Non-Patent Document 1). However, levocarnitine preparations have a high dosage of 1.5 g to 3 g per day for adults. High-dose oral administration can lead to problems such as the accumulation of harmful metabolites such as trimethylamine through metabolism by intestinal flora, and gastrointestinal side effects such as nausea, vomiting, and diarrhea. Therefore, there is a need for a method of carnitine replacement other than high-dose administration of levocarnitine preparations, as well as new therapeutic agents that promote the absorption of levocarnitine preparations.

[0007] In addition to carnitine deficiency, carnitine supplementation is also known to be effective in treating a variety of diseases. For example, diseases associated with mitochondrial dysfunction due to abnormalities in carnitine metabolism and diseases whose symptoms are alleviated by increasing blood carnitine levels are examples of such diseases. In recent years, the potential for improving sarcopenia and frailty through carnitine supplementation of skeletal muscle has been suggested (Non-Patent Documents 2-4). While carnitine supplementation through the administration of levocarnitine preparations is expected to be effective in treating these diseases, the emergence of new drugs is still desirable.

[0008] On the other hand, Patent Document 1 discloses the following formula (1):

[0009]

[0010] (In the formula, R １ and R ２ are the same or different and represent a hydrogen atom, a methyl group, or an ethyl group; R ３ａ , R ３ｂ , R ４ａ and R ４ｂ are the same or different and are a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, C １－４ Alkyl group, trifluoromethyl group, C １－４ Alkoxy group, C １－４ Alkylcarbonyloxy group, di-C １－４ Alkylamino group, C １－４ Alkylsulfonyloxy group, C １－４ Alkylsulfonyl group, C １－４ alkylsulfinyl group, or C １－４ represents an alkylthio group, or R ３ａ and R ３ｂ Or R ４ａ and R ４ｂ are bonded to form an alkylenedioxy group; X is an oxygen atom, a sulfur atom, or N—R ５ (R ５ is a hydrogen atom, C １－４ Alkyl group, C １－４ Alkylsulfonyl group, C １－４ represents an alkyloxycarbonyl group; Y represents an oxygen atom, S(O) ｌIt has been disclosed that compounds represented by the following formula (I) (I represents a group (I represents a number from 0 to 2), a carbonyl group, a carbonylamino group, an aminocarbonyl group, a sulfonylamino group, an aminosulfonyl group, or an NH group; Z represents CH or N; n represents a number from 1 to 6; and m represents a number from 2 to 6), their salts, or solvates thereof have a selective PPARα activation effect and are useful as prophylactic and / or therapeutic agents for hyperlipidemia, arteriosclerosis, diabetes, diabetic complications (diabetic nephropathy, etc.), inflammation, heart disease, etc., without causing weight gain or obesity in mammals, including humans. However, there is no description or suggestion as to the effects of these compounds on carnitine deficiency or diseases for which carnitine supplementation is expected to have a therapeutic effect.

[0011] International Publication No. 2005 / 023777

[0012] "Carnitine", [online], March 29, 2021, US Department of Health & Human Services National Institutes of Health, [Retrieved April 26, 2021], Internet <URL: https: / / ods.od.nih.gov / factsheets / Carnitine-HealthProfessional / > Hepatol Commun. 2 (8) pp. 906-918 (2018) Clinical Nutrition 38 (4) pp. 523-31 (1983) Clinical Interventions in Aging pp. 1675-1686 (2016)

[0013] An object of the present invention is to provide a novel therapeutic agent useful for treating carnitine deficiency or diseases for which carnitine supplementation is expected to have a therapeutic effect.

[0014] In order to achieve the above-mentioned object, the present inventors have conducted extensive research and have surprisingly found that the compound disclosed as Example 85 in the above-mentioned Patent Document 1, namely, (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid (hereinafter, sometimes referred to as "Compound A" or "pemafibrate"), increases the concentration of free carnitine in the blood by promoting carnitine synthesis and carnitine absorption, and is useful for the prevention and / or treatment of carnitine deficiency or diseases for which carnitine supplementation is expected to have a therapeutic effect, and have completed the present invention.

[0015] That is, the present invention provides the following [1] to

[41] . [1] A blood carnitine-increasing agent containing (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof as an active ingredient. [2] The blood carnitine-increasing agent according to [1], further containing levocarnitine as an active ingredient. [3] A method for increasing blood carnitine, comprising administering an effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof to a subject in need thereof. [4] The method for increasing blood carnitine according to [3], further comprising administering an effective amount of levocarnitine. [5] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for the manufacture of an agent for increasing blood carnitine. [6] The use according to [5] in combination with levocarnitine. [7] (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for use in increasing blood carnitine. [8] (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof according to [7] in combination with levocarnitine. [9] A pharmaceutical composition for preventing and / or treating carnitine deficiency, comprising a therapeutically effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof.

[10] The pharmaceutical composition according to [9], further comprising levocarnitine as an active ingredient.

[11] An agent for preventing and / or treating carnitine deficiency, comprising (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof as an active ingredient.

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

[11] , further comprising levocarnitine as an active ingredient.

[13] A method for preventing and / or treating carnitine deficiency, comprising administering an effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof to a patient in need thereof.

[14] The prophylactic and / or therapeutic method according to

[13] , further comprising administering an effective amount of levocarnitine.

[15] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for preventing and / or treating carnitine deficiency.

[16] The use according to

[15] , in combination with levocarnitine.

[17] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for the manufacture of a pharmaceutical composition for preventing and / or treating carnitine deficiency.

[18] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for the manufacture of a pharmaceutical composition for preventing and / or treating carnitine deficiency in combination with levocarnitine.

[19] (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for use in the prevention and / or treatment of carnitine deficiency.

[20] A combination of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof with levocarnitine for use in the prevention and / or treatment of carnitine deficiency.

[21] A preventive and / or therapeutic agent for diseases associated with mitochondrial dysfunction, comprising (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof as an active ingredient.

[22] A preventive and / or therapeutic agent for sarcopenia, comprising (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof as an active ingredient.

[23] The preventive and / or therapeutic agent according to

[21] or

[22] , further comprising levocarnitine as an active ingredient.

[24] A method for preventing and / or treating a disease associated with mitochondrial dysfunction, comprising administering an effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof to a patient in need thereof.

[25] A method for preventing and / or treating sarcopenia, comprising administering an effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof to a patient in need thereof.

[26] The method for preventing and / or treating according to

[24] or

[25] , further comprising administering an effective amount of levocarnitine.

[27] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for the manufacture of an agent for the prevention and / or treatment of diseases associated with mitochondrial dysfunction.

[28] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for the manufacture of an agent for the prevention and / or treatment of sarcopenia.

[29] The use according to

[27] or

[28] , in combination with levocarnitine.

[30] (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for use in the prevention and / or treatment of diseases associated with mitochondrial dysfunction.

[31] (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for use in the prevention and / or treatment of sarcopenia.

[32] (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof according to

[30] or

[31] , in combination with levocarnitine.

[33] A preventive and / or therapeutic agent for diseases whose symptoms are alleviated by elevated blood carnitine levels, comprising (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof as an active ingredient.

[34] The preventive and / or therapeutic agent according to

[33] , which further comprises levocarnitine as an active ingredient.

[35] A preventive and / or therapeutic method for diseases whose symptoms are alleviated by elevated blood carnitine levels, comprising administering an effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof to a patient in need thereof.

[36] The method for preventing and / or treating according to

[35] , further comprising administering an effective amount of levocarnitine.

[37] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for the manufacture of an agent for preventing and / or treating a disease whose symptoms are alleviated by an increase in blood carnitine levels.

[38] The use according to

[37] , in combination with levocarnitine.

[39] (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for use in the prevention and / or treatment of a disease whose symptoms are alleviated by an increase in blood carnitine levels.

[40] (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof according to

[39] , in combination with levocarnitine.

[41] The blood carnitine-increasing agent according to [1] or [2], the prophylactic and / or therapeutic agent according to any one of

[11] ,

[12] , and

[21] to

[23] , or the pharmaceutical composition according to [9] or

[10] , in the form of a kit comprising a preparation containing (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof, and a preparation containing levocarnitine.

[0016] The present invention provides a novel drug useful for the prevention and / or treatment of carnitine deficiency or diseases for which carnitine supplementation is expected to have a therapeutic effect. According to the present invention, it is possible to provide a new option for prevention and / or treatment for patients with carnitine deficiency or diseases for which carnitine supplementation is expected to have a therapeutic effect.

[0017] Figure 1 shows the change in fasting blood free carnitine concentration (μmol / L) when Compound A (0.2-0.8 mg per day) was administered to dyslipidemic patients. Figure 2 shows the change in postprandial blood free carnitine concentration (μmol / L) when Compound A (0.2-0.8 mg per day) was administered to dyslipidemic patients. Figure 3 shows the change in fasting blood free carnitine concentration (μmol / L) when Compound A (0.4 mg per day) or placebo was administered to NAFLD patients.

[0018] The (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid (Compound A) used in the present invention has the following chemical formula (A):

[0019]

[0020] The compound A can be produced, for example, according to the method described in the pamphlet of International Publication No. 2005 / 023777 or the like. It can also be formulated according to the method described in the literature. Furthermore, a preparation containing compound A has been approved in Japan as a hyperlipidemia treatment agent "Palmodia (registered trademark) Tablets," and these "Palmodia Tablets" can also be used.

[0021] In one embodiment of the present invention, a salt or solvate of Compound A can also be used. Salts and solvates can be prepared by conventional methods. The salt of Compound A is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; organic base salts such as ammonium salt and trialkylamine salt; mineral acid salts such as hydrochloride and sulfate; and organic acid salts such as acetate. Solvates of Compound A or its salts include hydrates, alcoholates (e.g., ethanolates), and the like.

[0022] In one aspect of the present invention, from the viewpoint of increasing blood carnitine levels, Compound A, a salt thereof, or a solvate thereof may be administered in combination with levocarnitine, which is used in carnitine replacement therapy. Specifically, Compound A, a salt thereof, or a solvate thereof can be administered in place of or in combination with levocarnitine to patients with levocarnitine-resistant carnitine deficiency that shows no improvement even when administered with levocarnitine or patients with diseases for which carnitine replacement is expected to be effective.

[0023] As used herein, "levocarnitine" refers to L-carnitine, and commercially available preparations can be used. Examples of preparations containing levocarnitine include L-carnitine (registered trademark) FF tablets 100 mg, L-carnitine FF tablets 250 mg, L-carnitine FF oral solution 10%, L-carnitine FF oral solution 10%, L-carnitine FF oral solution 10% (5 mL sachets), L-carnitine FF oral solution 10% (10 mL sachets), and L-carnitine FF intravenous injection 1000 mg (all from Otsuka Pharmaceutical Co., Ltd.), as well as "levocarnitine chloride tablets 100 mg and 300 mg" sold by various companies as generic drugs. Preparations approved overseas, such as CARNITOR Tablets and CARNITOR Oral Solution, can also be used.

[0024] As shown in the Examples below, Compound A increases the free carnitine concentration in blood. Since the administration of Compound A increased the free carnitine concentration in blood both in the fasting state and after a meal, Compound A is considered to have the effect of enhancing carnitine synthesis in the body and promoting carnitine absorption from food. Therefore, Compound A, its salt, or a solvate thereof can be an active ingredient of a blood carnitine increaser. Furthermore, Compound A, its salt, or a solvate thereof is useful for preventing and / or treating carnitine deficiency or diseases for which carnitine supplementation can be expected to have a therapeutic effect, through the increase in free carnitine concentration in blood. Diseases for which carnitine supplementation can be expected to have a therapeutic effect include diseases associated with mitochondrial dysfunction related to abnormal carnitine metabolism and diseases for which an increase in blood carnitine levels alleviates symptoms.

[0025] In this specification, unless otherwise specified, the term "blood carnitine increaser" refers to a drug that increases blood carnitine levels through its administration, thereby alleviating or improving symptoms of, for example, carnitine deficiency, diseases associated with mitochondrial dysfunction, or diseases whose symptoms are alleviated by increased blood carnitine levels.

[0026] Unless otherwise specified, the term "carnitine deficiency" used herein refers to a condition in which the body lacks the carnitine required for its function. The presence or absence of the condition is usually determined according to diagnostic criteria, and examples of such conditions include a condition in which the free carnitine concentration in a blood carnitine test is less than 20 μmol / L, or a condition in which symptoms are alleviated or improved by carnitine replacement therapy. In the present invention, those who are "highly likely to develop carnitine deficiency" are also candidates for the prevention and / or treatment of "carnitine deficiency."

[0027] Diagnosis of carnitine deficiency is made by combining "blood carnitine testing" with "clinical symptoms and signs" and "general clinical test findings" commonly seen in carnitine deficiency. When unavoidable, "therapeutic diagnosis" is also performed. In "blood carnitine testing," the standard value is a free carnitine concentration of 36 μmol / L or more and 74 μmol / L or less. If the free carnitine concentration is less than 20 μmol / L (<20 μmol / L), it is diagnosed as "carnitine deficiency has developed" or "a condition in which carnitine deficiency may develop at any time." If the free carnitine concentration is between 20 μmol / L and 36 μmol / L (20≦blood free carnitine concentration<36 μmol / L) (i.e., a borderline state where the free carnitine value is below the standard value but not extremely low), or if the acylcarnitine / free carnitine ratio is greater than 0.4 (>0.4), the patient is diagnosed with "highly likely to develop carnitine deficiency."

[0028] In this specification, the term "prevention and / or treatment of carnitine deficiency" refers to, for example, improving or promoting decreased carnitine intake or absorption, improving or increasing decreased carnitine synthesis in the body, suppressing excessive carnitine loss, suppressing increased free carnitine excretion, suppressing increased urinary excretion of acylcarnitines, etc., thereby restoring deficient carnitine to or bringing it close to the standard value (36 μmol / L≦blood free carnitine concentration≦74 μmol / L), thereby ensuring free carnitine, which is a transporter of long-chain fatty acids, and accepting the acyl group of accumulated toxic acyl-CoA and excreting it outside the mitochondria, cells, and body as acylcarnitine, thereby maintaining the free CoA pool necessary for various metabolisms.

[0029] As used herein, the term "diseases associated with mitochondrial dysfunction" refers to pathological conditions resulting from decreased energy production due to mitochondrial dysfunction. Examples of such pathological conditions include central nervous system diseases such as convulsions, myoclonus, ataxia, stroke-like symptoms, intellectual disability, migraine, psychiatric symptoms, dystonia, and myelopathy; skeletal muscle diseases such as muscle weakness, fatigue, hyperkalemia, myopathy, and sarcopenia; heart diseases such as conduction disorders, Wolff-Parkinson-White syndrome, cardiomyopathy, and pulmonary hypertension; eye diseases such as optic atrophy, external ophthalmoplegia, and retinitis pigmentosa; liver diseases such as hepatic dysfunction and hepatic failure; kidney diseases such as Fanconi syndrome, renal tubular dysfunction, glomerular lesions, and myoglobinuria; pancreatic diseases such as diabetes and exocrine insufficiency; blood diseases such as sideroblastic anemia and pancytopenia; inner ear diseases such as sensorineural hearing loss; intestinal diseases such as diarrhea and constipation; skin diseases such as hypohidrosis and hirsutism; and endocrine gland diseases such as short stature and hypocalcemia.

[0030] As used herein, "prevention and / or treatment of diseases associated with mitochondrial dysfunction" refers to, for example, alleviating, relieving, or curing symptoms in the above-mentioned "diseases associated with mitochondrial dysfunction" by restoring deficient carnitine to or bringing it close to the standard value (36 μmol / L≦blood free carnitine concentration≦74 μmol / L). However, as long as findings of alleviating, relieving, or curing symptoms are obtained or a diagnosis is made, the standard value is not necessarily the limiting factor.

[0031] In this specification, "diseases whose symptoms are alleviated by increasing blood carnitine levels" refers to pathological conditions caused by decreased blood carnitine levels, such as impaired consciousness, convulsions, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, retarded mental and motor development, poor weight gain, respiratory abnormalities, cardiac hypertrophy, cardiomyopathy, functional impairment, and sudden death (or a family history thereof), recurrent Reye-like syndrome, etc.

[0032] As used herein, "prevention and / or treatment of diseases whose symptoms are alleviated by an increase in blood carnitine levels" refers to, for example, alleviating, relieving, or curing symptoms in the above-mentioned "diseases whose symptoms are alleviated by an increase in blood carnitine levels" by restoring deficient carnitine to or bringing it close to the standard value (36 μmol / L≦blood free carnitine concentration≦74 μmol / L). However, as long as findings that show alleviation, remission, or cure of symptoms are obtained or a diagnosis is made, the standard value is not necessarily the limiting factor.

[0033] In one aspect of the present invention, when Compound A, its salt, or solvate thereof, and further levocarnitine are used as pharmaceuticals, they can be formulated into dosage forms such as tablets, capsules, granules, powders, lotions, ointments, injections, and suppositories using other pharmaceutically acceptable carriers as needed. These preparations can be produced by known methods. Examples of pharmaceutically acceptable carriers include excipients, disintegrants, binders, lubricants, plasticizers, fluidizing agents, diluents, solubilizers, suspending agents, isotonicity agents, pH adjusters, buffers, stabilizers, coating agents, colorants, flavoring agents, and odor-correcting agents.

[0034] When compound A, a salt thereof, or a solvate thereof is used in combination with levocarnitine, compound A, a salt thereof, a solvate thereof, and levocarnitine may be formulated together in a single dosage form (i.e., formulated as a combination drug). Alternatively, a kit may be prepared in which a formulation containing compound A, a salt thereof, or a solvate thereof and a formulation containing levocarnitine can be used simultaneously or separately with an interval between them. When each is administered individually, it does not matter which one is administered first.

[0035] When Compound A, a salt thereof, or a solvate thereof is used in combination with levocarnitine, the administration or mixing ratio is not particularly limited as long as it is within the effective range. For example, the mass ratio of Compound A (free form) to levocarnitine may be in the range of 1:1,000,000 to 1:100.

[0036] In one aspect of the present invention, Compound A, a salt thereof, or a solvate thereof can be administered orally or parenterally, with oral administration being preferred. The therapeutically effective amount and frequency of administration of Compound A, a salt thereof, or a solvate thereof vary depending on the patient's weight, age, sex, symptoms, etc., but can be appropriately determined by one skilled in the art. For example, for a typical adult, Compound A can be administered at a dose of 0.05 to 0.8 mg per day in one to three divided doses, preferably 0.1 to 0.4 mg per day in one to two divided doses, and more preferably 0.2 to 0.4 mg per day in one or two divided doses.

[0037] The dosage of levocarnitine for adults is usually prescribed in the package insert as 1.5 to 3 g of levocarnitine per day, to be orally administered in three divided doses.

[0038] The target population for administration of the pharmaceutical of the present invention is humans who require increased carnitine levels, preferably patients with carnitine deficiency or patients with diseases for which carnitine supplementation is expected to be effective (e.g., patients with diseases associated with mitochondrial dysfunction, patients with diseases for which elevated blood carnitine levels alleviate symptoms). Furthermore, the pharmaceutical can also be administered to patients receiving drugs that cause carnitine deficiency, such as patients receiving valproic acid, pivoxil-containing antibiotics, or anticancer drugs. For these applications, levocarnitine may be added to Compound A, its salt, or a solvate thereof, as described above.

[0039] The present invention will be described in more detail below with reference to examples, but these examples do not limit the present invention.

[0040] Example 1: Study of the effect of Compound A on blood carnitine (patients with dyslipidemia) The effect of Compound A on blood carnitine was studied in patients with dyslipidemia when orally administered at 0.2 to 0.8 mg per day for 4 weeks. Compound A was administered using an IR formulation (0.2 mg / day, twice a day), a CR formulation 0.4 mg (once a day), and a CR formulation 0.8 mg (once a day), and was administered before or after meals.

[0041] Example 2: Study of the effect of Compound A on blood carnitine (NAFLD patients) The effect of Compound A on blood carnitine was studied in patients with nonalcoholic fatty liver disease (NAFLD) when 0.4 mg of Compound A was orally administered per day for 48 weeks. Compound A was administered in an IR formulation (0.4 mg / day, twice a day) under fasting conditions. The results were compared with placebo administration.

[0042] The percentage change in fasting blood free carnitine concentration from the pre-administration value (week 0) when Compound A was administered for 4 weeks to patients with dyslipidemia in Example 1 is shown in Table 1 and Figure 1. Administration of Compound A showed a dose-dependent increase in blood free carnitine concentration, demonstrating that Compound A has the effect of increasing fasting blood free carnitine concentration.

[0043]

[0044] Table 2 and Figure 2 show the change in blood free carnitine levels after meals (after ingestion of a high-fat meal) relative to pre-meal levels when Compound A was administered for 4 weeks to patients with dyslipidemia in Example 1. Administration of Compound A increased the post-meal blood free carnitine level relative to pre-meal levels, demonstrating that Compound A has the effect of increasing post-meal blood free carnitine levels.

[0045]

[0046] Table 3 and Figure 3 show the change rate over time of fasting blood free carnitine concentration from the pre-administration value (week 0) when compound A (IR 0.4 mg / day) was administered to NAFLD patients in Example 2 for 48 weeks. Compared to placebo administration, administration of compound A increased the fasting blood free carnitine concentration, and it was revealed that administration of compound A increased the blood free carnitine concentration, with the increasing effect reaching a maximum at 12 weeks of administration.

[0047]

[0048] As can be seen from Tables 1 to 3 and Figures 1 to 3, administration of Compound A increased the free carnitine concentration in blood both in the fasting state and after a meal, suggesting that Compound A has the effect of enhancing carnitine synthesis in the body and promoting carnitine absorption from food, etc. Therefore, Compound A was found to be useful as a preventive and / or therapeutic agent for carnitine deficiency or diseases for which carnitine supplementation can be expected to have a therapeutic effect.

[0049] The present invention was completed based on the first discovery that Compound A has the effect of increasing free carnitine concentrations in blood in fasting and postprandial states, and is useful as a pharmaceutical for preventing and / or treating carnitine deficiency or diseases for which carnitine supplementation can be expected to have a therapeutic effect.

Claims

1. A blood carnitine increaser having as its active ingredient (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salt, or a solvate thereof.

2. The blood carnitine-increasing agent according to claim 1, further comprising levocarnitine as an active ingredient.

3. A pharmaceutical composition for preventing and / or treating carnitine deficiency, comprising a therapeutically effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof.

4. The pharmaceutical composition according to claim 2, further comprising levocarnitine as an active ingredient.

5. A preventive and / or therapeutic agent for diseases associated with decreased mitochondrial function, comprising (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof as an active ingredient.

6. A preventive and / or therapeutic agent for sarcopenia, comprising (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof as an active ingredient.

7. A preventive and / or therapeutic agent according to claim 5 or 6, further comprising levocarnitine as an active ingredient.

8. Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for the production of an agent for increasing blood carnitine.

9. Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for producing a pharmaceutical composition for preventing and / or treating carnitine deficiency.

10. Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for the manufacture of an agent for the prevention and / or treatment of a disease associated with decreased mitochondrial function.

11. Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for the manufacture of an agent for the prevention and / or treatment of sarcopenia.

12. Use according to any one of claims 8 to 11 in combination with levocarnitine.

13. (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for use in increasing blood carnitine.

14. (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for use in the prevention and / or treatment of carnitine deficiency.

15. (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for use in the prevention and / or treatment of a disease associated with decreased mitochondrial function.

16. (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for use in the prevention and / or treatment of sarcopenia.

17. The (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof according to any one of claims 13 to 16, in combination with levocarnitine.

18. A method for increasing blood carnitine, comprising administering an effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof to a subject in need thereof.

19. A method for preventing and / or treating carnitine deficiency, which comprises administering an effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof to a patient in need thereof.

20. A method for preventing and / or treating a disease associated with decreased mitochondrial function, comprising administering an effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof to a patient in need thereof.

21. A method for preventing and / or treating sarcopenia, comprising administering an effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof to a patient in need thereof.

22. The method of any one of claims 18 to 21, further comprising administering an effective amount of levocarnitine.

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