Agent for reducing blood myostatin level

Abstract

The purpose of the present invention is to provide a new prophylactic and / or therapeutic agent that is useful in the prevention and / or treatment of diseases in which symptoms are alleviated or ameliorated by inhibiting myostatin.　The present invention relates to a medicine for preventing and / or treating diseases in which symptoms are alleviated or ameliorated by inhibiting myostatin, the medicine containing 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 of these.

Description

Blood myostatin lowering agents

[0001] The present invention relates to a blood myostatin lowering agent.

[0002] Myostatin (also known as Growth Differentiation Factor-8 (GDF8)) is a secreted protein produced by skeletal muscle cells that inhibits skeletal muscle growth and belongs to the TGF-β superfamily. Phenotypes of myostatin gene abnormalities in animals and humans, as well as observations in animal models, have shown that myostatin inhibition leads to muscle hypertrophy.

[0003] Focusing on the function of myostatin, its inhibition is expected to be applied to the treatment of muscle-wasting diseases such as muscular dystrophy. However, although attempts have been made to develop drugs that have shown muscle hypertrophy in animal models, such as myostatin-neutralizing antibodies, myostatin antagonists such as soluble activin IIB receptors, and analogs of follistatin, a physiological antagonist of the TGF-β superfamily, none have been put into practical use as therapeutic agents for humans.

[0004] Another approach has been reported in which fenofibrate, a known PPARα agonist, suppresses myostatin expression (Non-Patent Document 1), and its effects on Duchenne muscular dystrophy animal models have been investigated (Non-Patent Document 2). However, these studies were conducted on rodent animal models, and the clinical effects in humans are unclear.

[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 1-4Alkyl 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 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 myostatin.

[0008] International Publication No. 2005 / 023777

[0009] Am J Physiol-Endoclinol Metab. (2011) 300, E790-E799Br J Pharmacol. (2021) 179, 1237-1250

[0010] An object of the present invention is to provide a novel preventive and / or therapeutic agent that is useful for the prevention and / or treatment of diseases for which the therapeutic effect can be expected to be achieved by inhibiting myostatin.

[0011] 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 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"), reduces blood myostatin levels and is useful for the prevention and / or treatment of diseases for which inhibition of myostatin is expected to have a therapeutic effect, and have completed the present invention.

[0012] That is, the present invention provides the following [1] to

[28] . [1] A blood myostatin level lowering agent 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] A myostatin inhibitor 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 preventive and / or therapeutic agent for muscle wasting diseases 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. [4] The prophylactic and / or therapeutic agent according to [3], wherein the muscle-wasting disease is Duchenne muscular dystrophy. [5] The prophylactic and / or therapeutic agent according to [3], wherein the muscle-wasting disease is sarcopenia. [6] A pharmaceutical composition for preventing and / or treating muscle-wasting disease, 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. [7] The pharmaceutical composition according to [6], wherein the muscle-wasting disease is Duchenne muscular dystrophy. [8] The pharmaceutical composition according to [6], wherein the muscle-wasting disease is sarcopenia. [9] A method for lowering blood myostatin 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.

[10] A method for inhibiting myostatin, 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.

[11] A method for preventing and / or treating a muscle-wasting disease, 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.

[12] The method for preventing and / or treating the muscle-wasting disease according to

[11] , wherein the muscle-wasting disease is Duchenne muscular dystrophy.

[13] The method for preventing and / or treating the muscle-wasting disease according to

[11] , wherein the muscle-wasting disease is sarcopenia.

[14] 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 lowering blood myostatin levels.

[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 inhibiting myostatin.

[16] 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 muscle-wasting disease.

[17] The use according to

[16] , wherein the muscle-wasting disease is Duchenne muscular dystrophy.

[18] The use according to

[16] , wherein the muscle-wasting disease is sarcopenia.

[19] 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 blood myostatin level lowering agent.

[20] 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 myostatin inhibitor.

[21] 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 the prevention and / or treatment of muscle wasting diseases.

[22] The use according to

[21] , wherein the muscle-wasting disease is Duchenne muscular dystrophy.

[23] The use according to

[21] , wherein the muscle-wasting disease is sarcopenia.

[24] (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for lowering blood myostatin levels.

[25] (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for inhibiting myostatin.

[26] (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 muscle-wasting disease.

[27] (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

[26] , wherein the muscle-wasting disease is Duchenne muscular dystrophy.

[28] (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

[26] , wherein the muscle-wasting disease is sarcopenia.

[0013] The present invention provides a novel agent useful for the prevention and / or treatment of diseases for which myostatin inhibition 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 myostatin inhibition is expected to have a therapeutic effect.

[0014] FIG. 1 shows the change in fasting blood myostatin concentration (pg / mL) when Compound A (0.4 mg per day) was administered to patients with non-alcoholic fatty liver disease.

[0015] 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):

[0016]

[0017] 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.

[0018] 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.

[0019] As shown in the Examples below, Compound A reduces myostatin levels in the blood. Since administration of Compound A reduced myostatin levels in the blood, Compound A is thought to have the effect of suppressing myostatin synthesis in the body or promoting myostatin excretion. Therefore, Compound A, its salts, or solvates thereof can be used as active ingredients in blood myostatin-lowering agents. Furthermore, Compound A, its salts, or solvates thereof are useful for the prevention and / or treatment of diseases whose symptoms are alleviated or improved by myostatin inhibition, via their reduction in blood myostatin levels.

[0020] In this specification, unless otherwise specified, the term "blood myostatin lowering agent" refers to a drug that, when administered, lowers blood myostatin levels and alleviates or improves the symptoms of diseases in which the symptoms are alleviated or improved by myostatin inhibition.

[0021] Unless otherwise specified, the term "myostatin inhibitor" as used herein refers to a drug that inhibits the function of myostatin in the body, thereby alleviating or ameliorating the symptoms of diseases and the like whose symptoms are alleviated or improved by myostatin inhibition. The manner in which myostatin function is inhibited is not particularly limited, and examples include suppression or inhibition of myostatin expression, inhibition of binding to myostatin receptors, competitive inhibition of myostatin receptors, and degradation of myostatin.

[0022] As used herein, "diseases whose symptoms are alleviated or improved by the inhibition of myostatin" include, for example, muscle atrophy, cancer cachexia, etc. Inhibition of myostatin is also expected to reduce body fat.

[0023] Examples of muscular atrophy diseases include those caused by myogenic muscular atrophy such as muscular dystrophy, those caused by neurogenic muscular atrophy such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal-bulbar muscular atrophy, as well as sarcopenia, etc. Of these, muscular dystrophy and sarcopenia are preferred in the present invention.

[0024] Muscular dystrophy is a general term for hereditary muscle diseases in which muscle fibers undergo repeated destruction, degeneration (myonecrosis), and regeneration, gradually leading to progressive muscle atrophy and muscle weakness. These diseases are characterized by variations in muscle fiber size, circularization, an increase in central nuclei, increased connective tissue, and fatty changes, resulting in a loss of muscle fiber bundle structure, a phenomenon known as dystrophic changes.

[0025] Examples of muscular dystrophies include chromosomally recessive muscular dystrophies such as Duchenne muscular dystrophy and Becker muscular dystrophy, congenital muscular dystrophies such as Fukuyama, Ullrich, merosin deficiency, integrin deficiency, and Walker-Warburg syndrome, limb-girdle muscular dystrophy, Miyoshi muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy, etc. Of these, in the present invention, chromosomally recessive muscular dystrophies such as Duchenne muscular dystrophy and Becker muscular dystrophy are preferred, and Duchenne muscular dystrophy is more preferred.

[0026] 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.

[0027] 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.

[0028] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0029] Example 1: Examination of the effect of Compound A on blood myostatin levels Patients with non-alcoholic fatty liver disease (NAFLD) were orally administered 0.4 mg of Compound A per day (0.2 mg Compound A tablets administered twice daily in the fasting state) for 72 weeks, and the effect on blood myostatin levels was compared with placebo administration.

[0030] Figure 1 shows the change (pg / mL) in blood myostatin concentration from baseline at 12 and 72 weeks after the start of administration. The baseline values ​​are shown in Table 1.

[0031]

[0032] As shown in Figure 1, fasting blood myostatin levels were gradually reduced by Compound A at 12 and 72 weeks of administration compared to placebo administration. Therefore, Compound A was found to be useful as a preventive and / or therapeutic agent for diseases whose symptoms are alleviated or improved by inhibiting myostatin.

[0033] The present invention was completed based on the first discovery that compound A has the effect of lowering fasting blood myostatin levels, and is useful as a pharmaceutical for preventing and / or treating diseases whose symptoms are alleviated or improved by inhibiting myostatin.

Claims

1. A blood myostatin-lowering agent comprising (R)-2-[3-[[N-(benzoxazole-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salt, or a solvate thereof as an active ingredient.

2. A myostatin inhibitor 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 prophylactic and / or therapeutic agent for muscular atrophy 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.

4. The preventive and / or therapeutic agent according to claim 3, wherein the muscular atrophy is Duchenne muscular dystrophy.

5. The preventive and / or therapeutic agent according to claim 3, wherein the muscular atrophy is sarcopenia.

6. Use of (R)-2-[3-[[N-(benzoxazole-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salts, or solvates thereof for the manufacture of blood myostatin-lowering agents.

7. Use of (R)-2-[3-[[N-(benzoxazole-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salts, or solvates thereof for the manufacture of myostatin inhibitors.

8. Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salts, or solvates thereof for the manufacture of pharmaceutical compositions for the prevention and / or treatment of muscular atrophy.

9. The use according to claim 8, wherein the muscular atrophy is Duchenne muscular dystrophy.

10. The use according to claim 8, wherein the muscular atrophy is sarcopenia.