Medicament for reducing myostatin in blood

Abstract

Provided is a novel prophylactic and / or therapeutic agent which can be used for the prophylaxis and / or treatment of diseases in which the symptoms can be alleviated or ameliorated by inhibiting myostatin. The present invention relates to a pharmaceutical agent for preventing and / or treating a disease whose symptoms can be alleviated or ameliorated by inhibition of myostatin, 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

Technical Field

[0001] The present invention relates to a pharmaceutical agent for reducing blood myostatin. Background Art

[0002] Myostatin (also known as Growth Differentiation Factor-8 (GDF8)) is a secretory protein produced by skeletal muscle cells that inhibits skeletal muscle proliferation and belongs to the TGF-β superfamily. Through observations of abnormal myostatin gene expression in animals and humans or animal models, it is known that inhibition of myostatin will result in muscle hypertrophy.

[0003] Focusing on the function of myostatin, it is expected that myostatin can be used to treat muscle wasting diseases such as muscular dystrophy by inhibiting it. However, although attempts have been made to develop drugs that have shown muscle hypertrophy in animal models, such as neutralizing antibodies against myostatin, antagonists of myostatin such as soluble activin IIB receptors, and analogs of follistatin, a physiological antagonist of the TGF-β superfamily, no drug has been found that can be put into practical use as a therapeutic drug for humans.

[0004] As another method, a study focusing on the fact that fenofibrate, a PPARα agonist, can inhibit the expression of myostatin (Non-Patent Document 1) and its effect on Duchenne muscular dystrophy model animals (Non-Patent Document 2) was reported. However, these studies were all conducted in rodent models, and the clinical effects on humans are uncertain.

[0005] On the other hand, Patent Document 1 discloses that the compound represented by the following formula (1), its salt or its solvate has a selective PPARα activation effect and is useful as a preventive and / or therapeutic drug for hyperlipidemia, arteriosclerosis, diabetes, diabetic complications (diabetic nephropathy, etc.), inflammation, heart disease, etc., which is not accompanied by weight gain or obesity in mammals including humans.

[0006]

[0007] (Where R 1 and R 2 The same or different, represents a hydrogen atom, a methyl group or an ethyl group; R 3a , R 3b , R 4a and R 4b The same or different, representing hydrogen atoms, halogen atoms, nitro groups, hydroxyl groups, C 1-4 Alkyl, trifluoromethyl, C 1-4 Alkoxy, C 1-4Alkylcarbonyloxy, di-C 1-4 Alkylamino, C 1-4 Alkylsulfonyloxy, C 1-4 Alkylsulfonyl, C 1-4 Alkylsulfinyl or C 1-4 Alkylthio, or R 3a With R 3b or R 4a With R 4b bond, represents an alkylenedioxy group; X represents an oxygen atom, a sulfur atom or NR 5 (R 5 represents hydrogen atom, C 1-4 Alkyl, C 1-4 Alkylsulfonyl, C 1-4 Alkoxycarbonyl); Y represents an oxygen atom, S(O) l yl (l represents a number from 0 to 2), carbonyl, carbonylamino, aminocarbonyl, sulfonylamino, aminosulfonyl or NH group; Z represents CH or N; n represents a number from 1 to 6; m represents a number from 2 to 6).

[0008] However, there is no record or teaching on what effects these compounds have on myostatin.

[0009] Prior art literature

[0010] Patent Literature

[0011] Patent Document 1: International Publication No. 2005 / 023777

[0012] Non-patent literature

[0013] Non-patent document 1: Am J Physiol-Endoclinol Metab. (2011) 300, E790-E799

[0014] Non-patent literature 2: Br J Pharmacol. (2021) 179, 1237-1250 Summary of the invention

[0015] Technical problem to be solved by the invention

[0016] An object of the present invention is to provide a novel preventive and / or therapeutic agent useful for a disease for which a therapeutic effect can be expected by inhibiting myostatin.

[0017] Technical solutions for solving technical problems

[0018] To achieve the above-mentioned object, the inventors of the present invention conducted intensive studies and 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"), can reduce the concentration of myostatin in the blood and is useful for preventing and / or treating diseases for which a therapeutic effect can be expected by inhibiting myostatin, thereby completing the present invention.

[0019] That is, the present invention provides the following [1] to

[28] .

[0020] [1] A drug for reducing blood myostatin, 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.

[0021] [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.

[0022] [3] A preventive and / or therapeutic agent for a muscular dystrophy, 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.

[0023] [4] The preventive and / or therapeutic agent according to [3], wherein the muscle wasting disease is Duchenne muscular dystrophy.

[0024] [5] The preventive and / or therapeutic agent according to [3], wherein the muscle wasting disease is sarcopenia.

[0025] [6] A pharmaceutical composition for preventing and / or treating a muscular dystrophy, 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.

[0026] [7] The pharmaceutical composition according to [6], wherein the muscle wasting disease is Duchenne muscular dystrophy.

[0027] [8] The pharmaceutical composition according to [6], wherein the muscle wasting disease is sarcopenia.

[0028] [9] A method for reducing blood 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.

[0029]

[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.

[0030]

[11] A method for preventing and / or treating a muscular dystrophy, 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.

[0031]

[12] The method for prevention and / or treatment as described in

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

[0032]

[13] The prevention and / or treatment method as described in

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

[0033]

[14] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salt or its solvate for the manufacture of a drug for reducing blood myostatin.

[0034]

[15] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salt or its solvate for the manufacture of a myostatin inhibitor.

[0035]

[16] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salt or its solvate for preventing and / or treating muscle wasting diseases.

[0036]

[17] The use as described in

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

[0037]

[18] The use as described in

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

[0038]

[19] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salt or its solvate for the manufacture of a drug for reducing blood myostatin.

[0039]

[20] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salt or its solvate for the manufacture of a myostatin inhibitor.

[0040]

[21] Use of (R)-2-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salt or its solvate for the manufacture of a pharmaceutical composition for preventing and / or treating muscle wasting diseases.

[0041]

[22] The use as described in

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

[0042]

[23] The use as described in

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

[0043]

[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.

[0044]

[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 use in myostatin inhibition.

[0045]

[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 muscular dystrophy.

[0046]

[27] (R)-2-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof as described in

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

[0047]

[28] (R)-2-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof as described in

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

[0048] Effects of the Invention

[0049] The present invention provides a novel agent useful for preventing and / or treating a disease for which a therapeutic effect can be expected by inhibiting myostatin. According to the present invention, a new prevention and / or treatment option can be provided for patients with a disease for which a therapeutic effect can be expected by inhibiting myostatin. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 The graph shows the change in fasting blood myostatin concentration (pg / mL) when Compound A (0.4 mg per day) was administered to patients with nonalcoholic fatty liver disease. DETAILED DESCRIPTION

[0051] The (R)-2-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid (Compound A) used in the present invention is represented by the following chemical formula (A):

[0052]

[0053] This compound A can be manufactured according to the method described in International Publication No. 2005 / 023777 Gazette, etc., for example. In addition, it can also be formulated according to the method described in the literature. In addition, the preparation containing compound A has been approved as the hyperlipidemia therapeutic agent "PARMODIA (registered trademark) tablets" in Japan, and this "PARMODIA tablets" can also be used.

[0054] In addition, in one embodiment of the present invention, a salt or solvate of compound A may also be used. Salts and solvates may be prepared by conventional methods. As a salt of compound A, there is no particular limitation as long as it is a pharmaceutically acceptable salt, and examples thereof include: alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; organic alkali salts such as ammonium salts and trialkylamine salts; inorganic acid salts such as hydrochlorides and sulfates; organic acid salts such as acetates, etc. As solvates of compound A or its salts, hydrates, alcoholates (such as ethanolates), etc. may be cited.

[0055] As shown in the following examples, compound A reduces the myostatin concentration in the blood. Since the myostatin concentration in the blood is reduced by administering compound A, it is believed that compound A has an effect of inhibiting the synthesis of myostatin in the body or promoting the excretion of myostatin. Therefore, compound A, its salt or its solvate can be an active ingredient of a drug that reduces myostatin in the blood. In addition, compound A, its salt or its solvate is useful for preventing and / or treating diseases whose symptoms are alleviated or improved by inhibiting myostatin by reducing the myostatin concentration in the blood.

[0056] In the present specification, unless otherwise specified, "agents that reduce blood myostatin" refers to, for example, agents that reduce blood myostatin levels by use and that reduce or improve symptoms of diseases whose symptoms are reduced or improved by inhibiting myostatin.

[0057] In the present specification, unless otherwise specified, "myostatin inhibitor" refers to, for example, a drug that reduces or improves the symptoms of a disease or the like whose symptoms are reduced or improved by inhibiting myostatin by inhibiting the function of myostatin in a living body. The method of inhibiting the function of myostatin is not particularly limited, and examples thereof include: inhibition of myostatin expression or inhibition of myostatin expression, inhibition of binding to myostatin receptors, antagonistic inhibition of myostatin receptors, and decomposition of myostatin.

[0058] In the present specification, "diseases whose symptoms are alleviated or improved by inhibiting myostatin" include, for example, muscle wasting diseases, cancer cachexia, etc. In addition, by inhibiting myostatin, a decrease in body fat can also be expected.

[0059] As muscle wasting diseases, for example, in addition to myogenic muscle atrophy such as muscular dystrophy, or neurogenic muscle atrophy such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), or spinal bulbar muscular atrophy, sarcopenia, etc. can also be cited. Among these, muscular dystrophy and sarcopenia are preferred in the present invention.

[0060] Muscular dystrophy is a general term for hereditary muscle diseases characterized by repeated destruction, degeneration (myonecrosis) and regeneration of muscle fibers, and the gradual development of muscle atrophy and decreased muscle strength. It manifests itself in so-called atrophic changes characterized by different sizes of muscle fibers, rounding, increased central nuclei, connective tissue hyperplasia, and fat formation, resulting in loss of the structure of muscle fiber bundles.

[0061] Examples of muscular dystrophy include: chromosomal recessive muscular dystrophy such as Duchenne muscular dystrophy and Becker muscular dystrophy; congenital muscular dystrophy such as Fukuyama type, Ullrich type, merosin deficiency, integrin deficiency, Walker-Warburg syndrome; limb-girdle muscular dystrophy, Miyoshi distal muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy, etc. Among these, in the present invention, chromosomal recessive muscular dystrophy such as Duchenne muscular dystrophy and Becker muscular dystrophy is preferred, and Duchenne muscular dystrophy is more preferred.

[0062] In one embodiment of the present invention, when compound A, its salt or their solvate is used as medicine, other pharmaceutically acceptable carriers may be used as needed to prepare tablets, capsules, granules, powders, lotions, ointments, injections, suppositories and other dosage forms. These preparations can be manufactured by known methods. As pharmaceutically acceptable carriers, examples include: excipients, disintegrants, binders, lubricants, plasticizers, flow agents, diluents, solubilizers, suspending agents, isotonic agents, pH adjusters, buffers, stabilizers, coating agents, colorants, flavoring agents, odor correctors, etc.

[0063] In one embodiment of the present invention, compound A, its salt or their solvate can be administered by oral administration or parenteral administration, preferably oral administration. In addition, the therapeutically effective amount and the number of administrations of compound A, its salt or their solvate vary according to the patient's weight, age, sex, symptoms, etc., and can be appropriately set by those skilled in the art. For example, in the case of an ordinary adult, 0.05-0.8 mg of compound A can be administered 1 to 3 times a day, preferably 0.1-0.4 mg once or twice a day, more preferably 0.2-0.4 mg once or twice a day.

[0064] Example

[0065] Hereinafter, the present invention will be further described in detail by way of examples, but these examples are not intended to limit the present invention.

[0066] Example 1: Study on the effect of compound A on myostatin in blood

[0067] In patients with non-alcoholic fatty liver disease (NAFLD), Compound A was orally administered at a dose of 0.4 mg per day (administered on an empty stomach, 0.2 mg tablets of Compound A were administered twice per day) for 72 weeks, and the effect of myostatin in the blood was compared with that of a placebo.

[0068] Figure 1 The changes (pg / mL) in blood myostatin concentrations from the baseline at 12 weeks and 72 weeks after the start of administration are shown. The baseline values ​​are shown in Table 1.

[0069] [Table 1]

[0070] Baseline (pg / mL)

[0071]

[0072] according to Figure 1 It was clearly observed that the fasting blood myostatin concentration was reduced stepwise at 12 weeks and 72 weeks after administration of compound A compared to the placebo. Therefore, it was found that compound A is useful as a preventive and / or therapeutic agent for diseases whose symptoms are alleviated or improved by inhibiting myostatin.

[0073] Industrial Applicability

[0074] The present invention was accomplished based on the first discovery that Compound A has the effect of reducing the fasting blood myostatin concentration, and is extremely useful as a medicine for preventing and / or treating diseases whose symptoms are alleviated or improved by inhibiting myostatin.

Claims

1. A drug for reducing blood myostatin, characterized in that: The invention contains (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, characterized in that: The invention contains (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 muscular atrophy, characterized in that: The invention contains (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, characterized in that: The muscle wasting disease is Duchenne muscular dystrophy.

5. The preventive and / or therapeutic agent according to claim 3, characterized in that: The muscle-wasting disease is sarcopenia.

6. A method for reducing myostatin in blood, characterized in that: 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 is administered to a patient in need thereof.

7. A method for inhibiting myostatin, characterized in that: 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 is administered to a patient in need thereof.

8. A method for preventing and / or treating a muscular atrophy disease, characterized in that: 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 is administered to a patient in need thereof.

9. The method for prevention and / or treatment according to claim 8, characterized in that: The muscle wasting disease is Duchenne muscular dystrophy.

10. The method for prevention and / or treatment according to claim 8, characterized in that: The muscle-wasting disease is sarcopenia.

11. Use of (R)-2-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salt or its solvate for the manufacture of a pharmaceutical agent for reducing blood myostatin.

12. Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salt or its solvate for the manufacture of a myostatin inhibitor.

13. Use of (R)-2-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salts or their solvates for the manufacture of pharmaceutical compositions for the prevention and / or treatment of muscle wasting diseases.

14. The use according to claim 13, characterized in that: The muscle wasting disease is Duchenne muscular dystrophy.

15. The use according to claim 13, characterized in that: The muscle-wasting disease is sarcopenia.

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 lowering blood myostatin.

17. (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 myostatin inhibition.

18. (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 muscular dystrophy.

19. (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 claim 18, characterized in that: The muscle wasting disease is Duchenne muscular dystrophy.

20. (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 claim 18, characterized in that: The muscle-wasting disease is sarcopenia.

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