Agent for increasing blood ketone body concentration

Abstract

Provided is a novel prophylactic and / or therapeutic agent useful for preventing and / or treating diseases of which symptoms are relieved or ameliorated by an increase in blood ketone body concentration.　The present invention pertains to a medicine for preventing and / or treating diseases of which symptoms are relieved or ameliorated by an increase in blood ketone body concentration, the medicine 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.

Description

Blood ketone body concentration-increasing agents

[0001] The present invention relates to an agent for increasing blood ketone body levels.

[0002] Ketone bodies are a collective term for acetoacetate, β-hydroxybutyrate, acetone, and other compounds produced in hepatocytes. Their levels remain almost constant before and after meals, but increase during prolonged fasting, starvation, glucose depletion, and other conditions. Acetoacetate and β-hydroxybutyrate are used as alternative energy sources to glucose, especially during starvation. Specifically, acetoacetate and β-hydroxybutyrate are converted to acetoacetyl-CoA and acetyl-CoA in tissues other than the liver and then used to produce ATP in the mitochondrial TCA cycle. Acetyl-CoA provides an acetyl group for acetylation and is involved in histone acetylation and lipid synthesis. β-hydroxybutyrate also inhibits histone deacetylase, promoting histone acetylation and resulting in antioxidant and apoptosis-suppressing effects.

[0003] There have been several reports on the relationship between ketone bodies and pathologies, but one long-standing treatment is the ketogenic diet for epileptic seizures. The ketogenic diet, also known as ketogenic therapy, is a type of dietary therapy that involves consuming sufficient amounts of protein and large amounts of fat and avoiding carbohydrates as much as possible, with the aim of continuously increasing the concentration of ketone bodies in the blood and inducing ketosis.

[0004] However, diabetic coma, a diabetic coma, is known to be caused by a condition called ketoacidosis, in which the blood becomes acidic as a result of a significant increase in ketone bodies. Therefore, the concept of improving the condition by increasing ketone bodies needs to be carefully considered.

[0005] On the other hand, Patent Document 1 discloses the following formula (1):

[0006]

[0007] (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) l It 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., which are not accompanied by weight gain or obesity in mammals including humans. However, there is no description or suggestion as to what effect these compounds have on the dynamics of ketone bodies in the blood.

[0008] International Publication No. 2005 / 023777

[0009] An object of the present invention is to provide a novel preventive and / or therapeutic agent useful for the prevention and / or treatment of diseases for which an increase in blood ketone body concentration is expected to have a therapeutic effect.

[0010] In order to achieve the above-mentioned object, the present inventors have conducted extensive research and have unexpectedly 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 ketone bodies in the blood and is useful for the prevention and / or treatment of diseases for which an increase in the concentration of ketone bodies in the blood is expected to have a therapeutic effect, and have thus completed the present invention.

[0011] That is, the present invention provides the following [1] to [8]. [1] An agent for elevating blood ketone body 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. [2] An agent for preventing and / or treating diseases for which an increase in blood ketone body levels can be expected to have a therapeutic effect, 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. [3] A pharmaceutical composition for preventing and / or treating a disease for which an increase in blood ketone body levels can be expected to have a therapeutic effect, 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] A method for preventing and / or treating a disease for which an increase in blood ketone body levels can be expected to have a therapeutic effect, 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. [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 preventing and / or treating a disease for which an increase in blood ketone body concentration is expected to have a therapeutic effect. [6] 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 an agent for elevating blood ketone body concentrations. [7] 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 a disease for which an increase in blood ketone body concentration is expected to have a therapeutic effect.[8] (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 for which an increase in blood ketone body concentration is expected to have a therapeutic effect.

[0012] The present invention provides a novel drug useful for the prevention and / or treatment of diseases for which an increase in blood ketone body concentration is expected to have a therapeutic effect. According to the present invention, it is possible to provide a novel option for prevention and / or treatment for patients with diseases for which an increase in blood ketone body concentration is expected to have a therapeutic effect.

[0013] Figure 1 shows the change from the pre-administration value (week 0) in fasting serum ketone body (total, acetoacetate, β-hydroxybutyrate) concentrations (μmol / L) when Compound A (0.2-0.4 mg per day) was administered to dyslipidemic patients. Figure 2 shows the time course of change in fasting serum ketone body (total, acetoacetate, β-hydroxybutyrate) concentrations (μmol / L) when Compound A (0.2-0.4 mg per day) was administered to dyslipidemic patients.

[0014] 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):

[0015]

[0016] 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.

[0017] 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.

[0018] As shown in the Examples below, Compound A increases the concentration of ketone bodies (acetoacetic acid and β-hydroxybutyric acid) in the blood. Since the administration of Compound A increased the concentration of ketone bodies in the blood, Compound A is considered to have the effect of promoting the synthesis of ketone bodies in the body or the effect of inhibiting the metabolism of ketone bodies. Therefore, Compound A, its salts, or solvates thereof can be the active ingredient of an agent for increasing the concentration of blood ketone bodies. Furthermore, Compound A, its salts, or solvates thereof are useful, via the increase in the concentration of blood ketone bodies, for the prevention and / or treatment of diseases for which an increase in the concentration of blood ketone bodies is expected to have a therapeutic effect.

[0019] In this specification, unless otherwise specified, the term "blood ketone body concentration elevating agent" refers to a drug that, when administered, increases blood ketone body levels, thereby alleviating or ameliorating the symptoms of diseases, etc., whose symptoms are alleviated or improved by an increase in ketone body concentrations.

[0020] As used herein, "diseases whose symptoms are alleviated or improved by an increase in blood ketone body concentration" include, for example, diseases whose symptoms are alleviated or improved by ATP supply, inflammatory diseases, diseases whose symptoms are alleviated or improved by histone deacetylase (HDAC) inhibition, diseases for which neuroprotective effects are expected, and diseases whose symptoms are alleviated or improved by regulating intracellular glycolipid metabolism or energy production.

[0021] Examples of diseases whose symptoms can be alleviated or improved by ATP supply include glucose uptake disorder-related diseases, glucose utilization disorder-related diseases, and mitochondrial dysfunction. Specific examples of such diseases include glucose transporter 1 (GLUT1) deficiency, mitochondrial disease, pyruvate dehydrogenase (PDHC) deficiency, mitochondrial encephalomyopathies, lactic acidosis, and stroke-like episodes syndrome (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), and chronic progressive external ophthalmoplegia-Kearns-Sayre syndrome. Progressive external ophthalmoplegia / Kearns-Sayre syndrome (CPEO / KSS), Leigh encephalopathy, epilepsy, migraine, mild Alzheimer's disease, Parkinson's disease, frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Huntington's disease, etc.

[0022] Examples of inflammatory diseases include Alzheimer's disease, gout, arteriosclerosis, cryopyrin-associated periodic syndromes (CAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multi-systemic inflammatory disease (NOMID).

[0023] Examples of diseases whose symptoms are alleviated or improved by HDAC inhibition include ischemia-reperfusion injury (heart, kidney), diseases accompanied by age-related changes in tissues and organs, cisplatin-induced nephropathy, cisplatin-induced liver injury, etc. Examples of diseases for which neuroprotective effects are expected include epilepsy, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, oxygen toxicity attacks in the central nervous system, etc.

[0024] Examples of diseases whose symptoms can be alleviated or improved by regulating intracellular glycolipid metabolism or energy production include metabolically associated fatty liver disease (MASLD), metabolically associated steatohepatitis (MASH), heart failure, and cardiac ischemia-reperfusion injury.

[0025] In one embodiment of the present invention, when Compound A, its salt, or a solvate thereof is used as a medicine, it can be made into dosage forms such as tablets, capsules, granules, powders, lotions, ointments, injections, suppositories, etc., using other pharmaceutically acceptable carriers as necessary. These preparations can be produced by known methods. Examples of pharmaceutically acceptable carriers include excipients, disintegrants, binders, lubricants, plasticizers, fluidizing agents, diluents, solubilizing agents, suspending agents, isotonicity agents, pH adjusters, buffers, stabilizers, coating agents, colorants, flavoring agents, and odor-correcting agents.

[0026] 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 or two divided doses, and more preferably 0.2 to 0.4 mg per day in one or two divided doses.

[0027] The present invention will be described in more detail below with reference to examples, but these examples do not limit the present invention.

[0028] Example 1: Study of the effect of Compound A on blood ketone bodies Fasting serum ketone body concentrations were measured in patients with dyslipidemia with high TG levels when they were administered Compound A immediate-release formulation (IR) 0.2 mg / day (twice a day), Compound A sustained-release formulation (XR) 0.2 mg / day (once a day), or 0.4 mg / day (once a day) for 12 weeks (116 cases, 117 cases, and 119 cases, respectively).

[0029] The results are shown in Table 1 and Figures 1 and 2.

[0030]

[0031] In all groups administered Compound A, the blood concentrations of acetoacetic acid, β-hydroxybutyric acid, and the sum of these were significantly increased from the pre-administration values. Therefore, Compound A was found to be useful as a preventive and / or therapeutic agent for diseases whose symptoms are alleviated or improved by an increase in blood ketone body concentrations.

[0032] The present invention was completed based on the first discovery that compound A has the effect of increasing fasting blood ketone body levels, and is useful as a pharmaceutical for preventing and / or treating diseases whose symptoms are alleviated or improved by an increase in blood ketone body levels.

Claims

1. A blood ketone body concentration elevating agent containing (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salt, or a solvate thereof as the active ingredient.

2. A preventive and / or therapeutic agent for diseases for which an increase in blood ketone body concentration is expected to have a therapeutic effect, comprising (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salt, or a solvate thereof as the active ingredient.

3. A method for preventing and / or treating a disease for which an increase in blood ketone body concentration is expected to have a therapeutic effect, 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.

4. 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 ketone body concentrations.

5. Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salt, or a solvate thereof for producing a pharmaceutical composition for preventing and / or treating a disease for which an increase in blood ketone body concentration is expected to have a therapeutic effect.

6. (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salt, or a solvate thereof for use in the prevention and / or treatment of a disease for which an increase in blood ketone body concentration is expected to have a therapeutic effect.

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