Pharmaceutical composition for preventing or treating muscle weakness-related diseases comprising alverine, 4-hydroxyalverine, derivatives thereof or pharmaceutically acceptable salts thereof

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating diseases related to muscle weakness, which comprises alverine, 4-hydroxyalverine, a derivative thereof or a pharmaceutically acceptable salt thereof. When myoblasts are treated with alverine, 4-hydroxyalverine, a derivative thereof or a pharmaceutically acceptable salt thereof of the present invention, differentiation into myotubes is promoted. Therefore, alverine, 4-hydroxyalverine, a derivative thereof or a pharmaceutically acceptable salt thereof according to the present invention can be effectively used to promote differentiation of myoblasts and prevent or treat diseases related to muscle weakness.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for preventing or treating muscle weakness-related diseases, comprising alverine, 4-hydroxyalverine, derivatives thereof or pharmaceutically acceptable salts thereof. Background Art

[0002] Diseases associated with decreased muscle strength include sarcopenia, which progresses with age, and muscular dystrophy, a degenerative myopathy associated with the necrosis of muscle fibers caused by genetic mutations.

[0003] Sarcopenia involves a gradual decrease in muscle strength due to age-related loss of muscle mass. Sarcopenia is accompanied not only by a decrease in muscle mass but also by changes in the type of muscle fibers. Sarcopenia leads to various signs of aging and functional impairments seen in the elderly. Muscular dystrophy is caused by the absence or mutation of muscle-related genes and induces necrosis and degeneration of muscle fibers, leading to disability or death. Cachexia is a disease characterized by decreased muscle strength and is common in cancer patients. Excessive skeletal muscle catabolism due to increased metabolism, resulting in loss of muscle mass and loss of muscle strength, is often observed in cancer patients. Since this disturbed metabolism eventually reaches a stage where it cannot be restored even by eating, more aggressive treatments such as medication are required.

[0004] Since the sarcopenia treatment drugs currently under development are reported to show extremely limited efficacy in clinical trials, it is believed that there is no confirmed sarcopenia candidate drug (Ju Yeon Kwak, Ki-Sun Kwon, Ann Geriatr Med Res.98-104, 2019). Therefore, at present, the supplementary treatment regimen through physical exercise and nutritional intake is the only safe method that produces clear positive results. Physical exercise can have a beneficial effect on skeletal muscle through various mechanisms, such as mTORC1 activation, oxidative stress reduction, inflammation reduction, mitochondrial generation increase, etc. (Jiayu Yin et al., Theranostics, 4019-4029, 2019). Physical exercise and nutritional intake can indeed improve muscle strength, muscle function and muscle mass, but the effect is limited, and it is difficult to benefit the elderly who cannot exercise or have low nutritional absorption due to physical disability.

[0005] However, sarcopenia is a multifactorial disease with diverse causes, and because there are large differences in muscle mass between races, ages, genders, etc., there is no unified diagnostic standard for sarcopenia. In 2019, EWGSOP further divided sarcopenia into the following three groups based on muscle mass, muscle strength and physical performance: possible sarcopenia, confirmed sarcopenia, and severe sarcopenia (AJ Cruz-Jentoft et al., Age Ageing, 601, 2019). Although the molecular biological mechanism of sarcopenia is still unclear, mitochondrial fusion / fission failure, oxidative stress, inflammation, and stem cell exhaustion are considered to be the causes of sarcopenia (Jessica Hiu-tung Lo et al., J Orthop Translat, 38-52, 2020).

[0006] Satellite cells are stem cells found in adult muscles and are necessary for the regeneration of damaged skeletal muscle. In mice, it was found that the number of satellite cells in muscle decreased with aging. In humans, a reduction in satellite cells was observed in type II muscles. The reduction in the number of satellite cells can lead to the development of sarcopenia and is related to the failure of muscle regeneration in elderly animals (Carlson et al., J Gerontol, B224-233, 2001).

[0007] So far, research on skeletal muscle hypertrophy and regeneration has focused on the regulation of myogenic regulatory factors (MRFs) (such as MyoD, Mef2) and myogenin on myoblast differentiation (Sabourin LA and Rudnicki MA., Clin Genet. January 2000; 57 (1): 16-25). Since improving the differentiation and regeneration ability of myoblasts by drug treatment can lead to muscle hypertrophy or improve muscle function, many attempts have been made to use this method to solve the decline in muscle function caused by age (Francesca Riuzzi et al., JCachexia Sarcopenia Muscle, 1255-1268, 2018; Mary F. O'Leary, Sci Rep. 12997, 2017; Jin-A Kim and Seong Min Kim, BMC Complement Altern Med, 287, 2019). In other words, improving the function of satellite cells and increasing the number of satellite cells can be a strategy to inhibit the development of sarcopenia and improve muscle regeneration. Therefore, it is necessary to develop substances that can promote myoblast differentiation.

[0008] [Prior art literature]

[0009] [Non-patent literature]

[0010] (Non-patent document 1) Ju Yeon Kwak, Ki-Sun Kwon, Ann Geriatr Med Res. 98-104, 2019

[0011] (Non-patent document 2) Jiayu Yin, Xiang Lu, Zhiyuan Qian, Weiting Xu and Xiang Zhou, Theranostics, 4019-4029, 2019

[0012] (Non-patent document 3) AJ Cruz-Jentoft et al., Age Ageing, 601, 2019

[0013] (Non-patent document 4) Jessica Hiu-tung Lo, Kin Pong U, Tszlam Yiu, J Orthop Translat, 38-52, 2020

[0014] (Non-patent document 5) Carlson et al., J Gerontol, B224-233, 2001

[0015] (Non-patent document 6) Sabourin LA, Rudnicki MA., Clin Genet. 2000 Jan; 57(1): 16-25.

[0016] (Non-Patent Document 7) Francesca Riuzzi, Guglielmo Sorci, Cataldo Arcuri, J Cachexia Sarcopenia Muscle, 1255-1268, 2018,

[0017] (Non-patent document 8) Mary F. O'Leary, Sci Rep. 12997, 2017,

[0018] (Non-patent document 9) Jin-A Kim, Seong Min Kim, BMC Complement Altern Med, 287, 2019 Summary of the invention

[0019] Technical issues

[0020] The inventor is committed to developing a substance that can promote myoblast differentiation to increase muscle mass and effectively restore muscle function. As a result, the inventor found that alverine, 4-hydroxyalverine, its derivatives and pharmaceutically acceptable salts thereof promote myoblast differentiation and restore muscle strength, thereby completing the present invention.

[0021] Solution to the problem

[0022] In order to solve the above problems, one aspect of the present invention provides a compound represented by Formula 1 and a pharmaceutically acceptable salt thereof.

[0023] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating a disorder related to muscle weakness, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0024] Another aspect of the present invention provides a composition for promoting in vitro myoblast differentiation, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0025] Another aspect of the present invention provides a method for promoting myoblast differentiation, comprising treating isolated myoblasts with a compound or a pharmaceutically acceptable salt thereof.

[0026] Another aspect of the present invention provides a method for producing myotubes, comprising treating isolated myoblasts with a compound or a pharmaceutically acceptable salt thereof, thereby differentiating the myoblasts.

[0027] Another aspect of the present invention provides a food composition for preventing or alleviating muscle weakness-related disorders, comprising a compound represented by Formula 1 or a nutritionally acceptable salt thereof.

[0028] Another aspect of the present invention provides a composition for enhancing muscle strength, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0029] Another aspect of the present invention provides a method for preventing or treating a disorder related to muscle weakness, comprising administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject.

[0030] Another aspect of the present invention provides use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for preventing or treating disorders related to muscle weakness.

[0031] Another aspect of the present invention provides use of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disorder related to muscle weakness.

[0032] Advantageous Effects of the Invention

[0033] When applied to myoblasts, the alverine, 4-hydroxyalverine, its derivatives or pharmaceutically acceptable salts thereof of the present invention promote the differentiation of myoblasts into myotubes. Therefore, the alverine, 4-hydroxyalverine, its derivatives or pharmaceutically acceptable salts thereof of the present invention can be advantageously used to promote the differentiation of myoblasts or prevent or treat the conditions associated with muscle weakness. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 Fluorescence images of myotubes differentiated by treating myoblasts with DMSO, insulin, or alverine citrate are shown.

[0035] Figure 2 Shown are graphs showing the eMyHC fluorescence staining area in myotubes differentiated by treating myoblasts with DMSO, insulin, or alverine citrate.

[0036] Figure 3 Depicts the experimental protocol for determining the muscle strength enhancing effects of alverine citrate using animals.

[0037] Figure 4 is a graph showing the grip strength measurement values ​​of mice according to the administered concentration of alverine citrate.

[0038] Figure 5 The running time of mice in the normal group and the experimental group is shown.

[0039] Figure 6 The graph shows the duration of time that mice in the normal group and the experimental group grasped the rotor-rod.

[0040] Figure 7 The graph shows the muscle mass of the gastrocnemius (GA) muscle and the tibialis anterior (TA) muscle obtained from the normal group mice and the experimental group mice.

[0041] Figure 8 Describes the experimental protocol for determining the muscle strength enhancing effects of alverine citrate using sarcopenia-induced animals.

[0042] Fig. 9 The running time of mice in the normal group, control group, and experimental group is shown.

[0043] Fig.10 Shown are graphs showing the muscle mass of gastrocnemius (GA) muscles and tibialis anterior (TA) muscles obtained from mice in the normal group, the control group, and the experimental group.

[0044] Fig.11 Fluorescence staining images of myotubes differentiated by treating myoblasts with DMSO, insulin, alverine citrate, or 4-hydroxyalverine (4HA) are shown.

[0045] Fig.12 Shown are graphs showing the eMyHC fluorescence staining area in myotubes differentiated by treating myoblasts with DMSO, insulin, alverine citrate, or 4-hydroxyalverine (4HA).

[0046] Fig.13 Shown are fluorescently stained images of myotubes in which atrophy was induced by cancer cell conditioned medium (CM) in alverine citrate (AC) or 4-hydroxyalverine (4HA).

[0047] Fig.14 Diagrams showing the diameter of myotubes in which atrophy was induced by cancer cell conditioned medium (CM) in alverine citrate (AC) or 4-hydroxyalverine (4HA).

[0048] Fig.15 Fluorescence staining images of myotubes differentiated by treating myoblasts with DMSO, alverine, and 27 alverine derivatives, respectively, are shown.

[0049] Fig.16 Shown are graphs showing the areas of myotubes differentiated by treating myoblasts with DMSO, alverine, and 27 alverine derivatives, respectively. DETAILED DESCRIPTION

[0050] Hereinafter, the present invention will be described in more detail.

[0051] One aspect of the present invention provides a compound represented by the following formula 1 and a pharmaceutically acceptable salt thereof:

[0052] [Formula 1]

[0053]

[0054] In formula 1,

[0055] R1, R2, R4 and R5 are each independently hydrogen, halogen, -CF3, hydroxyl, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-4 Haloalkyl, C 1-10 Haloalkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -NHR a 、-NHC(=O)R b 、-NHC(=O)NHR c , amino-C 1-10 Alkoxy, C 1-10 Alkenyloxy or C 6-10 Aryl-C 1-10Alkoxy,

[0056] R3 is C 1-10 Alkyl, C 2-12 Alkenyl, C 1-4 Haloalkyl, C 2-4 Alkenyl or C 2-4 Alkynyl,

[0057] R a To R c are independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 6-10 aryl; and

[0058] n and m are each independently an integer of 1 to 10.

[0059] As used herein, the term "halo" or "halogen" refers to F, Cl, Br or I, unless otherwise indicated.

[0060] Unless otherwise indicated, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon residue. 1-10 "Alkyl" refers to an alkyl group having 1 to 10 carbon atoms in its backbone structure. In particular, C 1-10 Alkyl groups may include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, sec-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl.

[0061] Unless otherwise indicated, the term "alkoxy" refers to a group having an -O-alkyl structure in which the alkyl group as defined above is attached to the parent compound via an oxygen atom. The alkyl portion of the alkoxy group may contain 1 to 20 carbon atoms (i.e., C1-C 20 Alkoxy), 1 to 12 carbon atoms (i.e. C1-C 12 alkoxy), or 1 to 6 carbon atoms (i.e. C1-C6 alkoxy). Examples of suitable alkoxy groups include methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), tert-butoxy (-OC(CH3)3 or -O-tBu), and the like.

[0062] The term "haloalkyl" refers to an alkyl group substituted by one or more halogen atoms. More specifically, the haloalkyl group may be an alkyl group substituted by two or more of the same halogens, or an alkyl group substituted by two or more different halogens.

[0063] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms.

[0064] The term "aminoalkoxy" refers to an alkoxy group substituted with one or more amino groups.

[0065] The term "amino" refers to -NR2, wherein "R" is independently selected from H, alkyl, aryl, etc. Typical amino groups may include but are not limited to -NH2, -N(CH3)2, -NH(CH3), -N(CH2CH3)2, -NH(CH2CH3), -NH(substituted or unsubstituted benzyl), -NH(substituted or unsubstituted phenyl), etc.

[0066] The term "alkenyl" refers to a hydrocarbon having primary, secondary, tertiary or cyclic carbon atoms, which has one or more unsaturated moieties, i.e., a carbon-carbon sp 2 For example, an alkenyl group may contain 2 to 20 carbon atoms (i.e., C2-C 20 alkenyl), 2 to 12 carbon atoms (i.e. C2-C 12 Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0067] Unless otherwise indicated, the term "alkenyloxy" refers to a group having the structure -O-alkenyl, wherein the alkenyl group as defined above is attached to the parent compound through an oxygen atom.

[0068] The term "alkynyl" refers to a hydrocarbon having primary, secondary, tertiary or cyclic carbon atoms, which has one or more unsaturated moieties, i.e., a carbon-carbon triple bond. For example, an alkynyl group can contain 2 to 20 carbon atoms (i.e., C2-C 20 Alkynyl), 2 to 12 carbon atoms (i.e. C2-C 12 Suitable alkynyl groups include, for example, ethynyl (-C≡H), propargyl (-CH2C≡H), and the like, but are not limited thereto.

[0069] As used herein, the term "aryl" refers to an aromatic hydrocarbon group derived by removing one hydrogen atom from the six carbon atoms of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms.

[0070] As used herein, the term "substitution" refers to replacing a hydrogen atom in a molecular structure with a substituent, thereby becoming a chemically stable compound from such substitution without exceeding the valence of a given atom. For example, the phrase "group A is substituted with a substituent B" may refer to a hydrogen atom bonded to an atom (i.e., carbon) constituting the skeleton of group A being substituted with a substituent B, thereby forming a covalent bond between group A and substituent B.

[0071] According to one example, in Formula 1, R1, R2, R4 and R5 can each independently be hydrogen, halogen, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkoxy, -NHR a 、-NHC(=O)R b 、-NHC(=O)NHR c , amino-C 1-10 Alkoxy, C 1-10 Alkenyloxy or C 6-10 Aryl-C 1-10 Alkoxy, R3 can be C 1-10 Alkyl or C 2-12 Alkenyl; R a To R c can be independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 aryl; and n and m may each independently be an integer from 1 to 7.

[0072] According to one example, in Formula 1, R1 and R2 can each independently be hydrogen, halogen, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkoxy, -NHR a , amino-C 1-10 Alkoxy, C 1-10 Alkenyloxy or C 6-10 Aryl-C 1-10 Alkoxy; R3 can be C 1-10 Alkyl, R4 and R5 can each independently be hydrogen, hydroxyl, -NHR a 、-NHC(=O)R b or -NHC(=O)NHR c ; R a To R c can be independently hydrogen, C 1-4 Alkyl, C 1-6 Alkoxy or C 6-10 aryl; and n and m may each independently be an integer from 1 to 5.

[0073] According to another example, in Formula 1, R1 and R2 can each independently be hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NHR a , amino-C 1-10 Alkoxy, C 1-10 Alkenyloxy or C 6-10 Aryl-C 1-6 Alkoxy, R3 can be C 1-6 Alkyl, R4 can be hydrogen, halogen, hydroxyl, -NHR a 、-NHC(=O)R b or -NHC(=O)NHR c , and R5 may be hydrogen; R a It can be hydrogen or C 1-6 Alkoxy; R b It can be hydrogen or C 1-6 Alkyl; R c It can be hydrogen or C 6-10 aryl; and n and m may each independently be an integer from 1 to 3.

[0074] According to another example, in Formula 1, if n and m are each 2, R3 is ethyl, and R1, R4 and R5 are each hydrogen, then R2 is hydrogen or hydroxyl. In this case, the example may be alverine or 4-hydroxyalverine.

[0075] Particularly, alverine has a structure shown in Formula 2 below.

[0076] [Formula 2]

[0077]

[0078] Here, alverine corresponds to the compound of formula 1 when n and m are each 2, R3 is ethyl, and R1, R2, R4 and R5 are all hydrogen.

[0079] As used herein, the term "alverine" refers to a compound with the IUPAC name N-ethyl-3-phenyl-N-(3-phenylpropyl)propan-1-amine and the chemical formula C 20 H 27 N, molecular weight is 281.44 g / mol. Alverine is known to be commonly used as a drug for gastrointestinal diseases, but little is known about its relationship with myoblast differentiation.

[0080] In addition, 4-hydroxyalverine is a metabolite of alverine, and 4-hydroxyalverine has a structure of the following Formula 3.

[0081] [Formula 3]

[0082]

[0083] Here, 4-hydroxyalverine corresponds to the compound of formula 1 when n and m are each 2, R3 is ethyl, and three of R1, R2, R4 and R5 are hydrogen and one is hydroxyl. In particular, the case where three of R1, R2, R4 and R5 are hydrogen and one is hydroxyl can include the following cases: 1) R2, R4 and R5 are each hydrogen, and R1 is hydroxyl; 2) R1, R4 and R5 are each hydrogen, and R2 is hydroxyl; iii) R1, R2 and R5 are each hydrogen, and R4 is hydroxyl; and iv) R1, R2 and R4 are each hydrogen, and R5 is hydroxyl.

[0084] According to specific examples, specific examples of the compound represented by Formula 1 include the following:

[0085] 1) 4-(3-ethyl(3-phenylpropyl)amino)propyl)aniline;

[0086] 2) N-ethyl-3-(4-methoxyphenyl)-N-(3-phenylpropyl)propan-1-amine;

[0087] 3) N-ethyl-3-phenyl-N-(3-(p-tolyl)propyl)propan-1-amine;

[0088] 4) 3-(3-(ethyl(3-phenylpropyl)amino)propyl)phenol;

[0089] 5) N-methyl-3-phenyl-N-(3-phenylpropyl)propan-1-amine;

[0090] 6) 4,4'-((ethylazadiyl))bis(propane-3,1-diyl))diphenol;

[0091] 7) 4-(3-(methyl(3-phenylpropyl)amino)propyl)phenol;

[0092] 8) 4-(3-((3-(4-(benzyloxy)phenyl)propyl)(ethyl)amino)propyl)aniline;

[0093] 9) N-(4-(3-((3-)4-(benzyloxy)phenyl)propyl)(ethyl)amino)propyl)phenyl)acetamide;

[0094] 10) 4-(3-(ethyl(phenethyl)amino)propyl)phenol;

[0095] 11) 4-(3-(ethyl(3-phenylpropyl)amino)propyl)-2-fluorophenol;

[0096] 12) 2-bromo-4-(3-(ethyl(3-phenylpropyl)amino)propyl)phenol;

[0097] 13) 1-(4-(3-((3-(4-(benzyloxy)phenyl)propyl)(ethyl)amino)propyl)phenyl)-3-phenylurea;

[0098] 14) Ethyl (4-phenylbutyl) (3-phenylpropyl) amine;

[0099] 15) Ethylbis(4-phenylbutyl)amine;

[0100] 16)(4-phenylbutyl)(3-phenylpropyl)propylamine;

[0101] 17) 3-(4-Butoxyphenyl)-N-ethyl-N-(3-phenylpropyl)propan-1-amine;

[0102] 18) 3-(4-(but-3-en-1-yloxy)phenyl)-N-ethyl-N-(3-phenylpropyl)propan-1-amine;

[0103] 19) 3-(4-(4-bromobutoxy)phenyl)-N-ethyl-N-(3-phenylpropyl)propan-1-amine;

[0104] 20) 4-(4-(3-(ethyl(3-phenylpropyl)amino)propyl)phenoxy)butan-1-amine;

[0105] 21) 4-(3-(ethyl(3-(4-methoxyphenyl)propyl)amino)propyl)-2-fluorophenol;

[0106] 22) 4-(3-((3-(4-(benzyloxy)-3-fluorophenyl)propyl)(ethyl)amino)propyl)aniline;

[0107] 23) N-(4-(3-((3-(4-(benzyloxy)-3-fluorophenyl)propyl)(ethyl)amino)propyl)phenyl)acetamide;

[0108] 24) 3-(4-(Benzyloxy)-3-fluorophenyl)-N-methyl-N-(3-phenylpropyl)propan-1-amine;

[0109] 25) 4-(3-(ethyl(3-(p-tolyl)propyl)amino)propyl)-2-fluorophenol;

[0110] 26) N-ethyl-3-phenyl-N-(3-(4-(3-phenylpropyl)phenyl)propyl)propan-1-amine;

[0111] 27) N-ethyl-3-phenyl-N-(3-(4-((5-phenylpentyl)oxy)phenyl)propyl)propan-1-amine;

[0112] 28) N-ethyl-3-phenyl-N-(3-phenylpropyl)propan-1-amine (i.e., alverine); and

[0113] 29) 4-[3-[Ethyl(3-phenylpropyl)amino]propyl]phenol (ie, 4-hydroxyalverine).

[0114] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared according to a common method known in the art, and such preparation methods are known to those skilled in the art. In particular, pharmaceutically acceptable salts include pharmacologically or physiologically acceptable salts derived from the following inorganic acids, organic acids and bases, but are not limited thereto. Suitable examples of such acids may include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, p-toluenesulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, etc. Salts derived from suitable bases may include alkali metals such as sodium or potassium, and alkaline earth metals such as magnesium. In particular, a pharmaceutically acceptable salt may be a citrate. In one example of the present invention, a citrate is used as a pharmaceutically acceptable salt.

[0115] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating muscle weakness-related disorders, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. Here, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is the same as described above.

[0116] Muscle weakness-related disorders refer to any and all disorders caused by muscle weakness, especially disorders in which myoblast efficacy is reduced or weakened due to a decrease in muscle cells or reduced satellite cell activity in the body, and thus it is expected to be prevented, alleviated or treated by promoting myoblast differentiation. In particular, muscle weakness-related disorders may be sarcopenia, muscular atrophy, muscular dystrophy or cachexia.

[0117] As used herein, the term "sarcopenia" refers to a symptom characterized by a gradual decrease in muscle mass caused by aging, which leads to a decrease in muscle strength. As the cause of the decrease in muscle mass in sarcopenia, the decrease in satellite cell activity is considered to be the main cause. Satellite cells are activated by stimulation (such as exercise or injury), proliferate into myoblasts, and as differentiation proceeds, fuse with other cells to form multinucleated muscle fibers.

[0118] As used herein, the term "muscular atrophy" refers to a symptom characterized by gradual atrophy of the muscles of the limbs in a nearly symmetrical manner. Muscular atrophy can lead to the progressive degeneration of motor nerve fibers and cells in the spinal cord, and can lead to amyotrophic lateral sclerosis (ALS) and spinal progressive muscular atrophy (SPMA).

[0119] The term "muscular dystrophy" as used herein refers to a degenerative muscle disease characterized by necrosis of muscle fibers, which is unrelated to the central nervous system and peripheral nervous system. There are subtle differences between muscular dystrophy and muscular atrophy clinically. The most common onset of muscular dystrophy is childhood, and the onset of muscular atrophy is usually in adolescence. In addition, muscular dystrophy occurs in proximal muscles and muscular atrophy occurs in distal muscles. Muscle stiffness is present in muscular dystrophy but not in muscular atrophy, and while muscular dystrophy is a clear hereditary disorder, muscular atrophy is rarely inherited.

[0120] The term "cachexia" as used herein refers to the severe systemic weakness that can be seen in the terminal stages of cancer, tuberculosis, hemophilia, etc. In addition, cachexia is considered to be a poisoning state caused by various organ dysfunctions in the body. The symptoms of cachexia include muscle weakness, rapid weight loss, anemia, lethargy, and yellow skin. Some potential conditions that may cause cachexia include malignant tumors, Basedow's disease, and hypopituitarism. It has also been found that bioactive substances (such as tumor necrosis factor (TNF) produced by macrophages) are factors that increase the weight of cachexia.

[0121] In the pharmaceutical composition, the concentration of the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be 10 μg / ml to 180 μg / ml. More particularly, the concentration of the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be 20 μg / ml to 160 μg / ml, 40 μg / ml to 140 μg / ml, or 60 μg / ml to 120 μg / ml.

[0122] In addition, the dosage of the pharmaceutical composition can be determined based on the amount of the active ingredient administered, the active ingredient being the compound of Formula 1 or a pharmaceutically acceptable salt thereof. In particular, the dosage of the compound of Formula 1 or a pharmaceutically acceptable salt thereof can be 60 mg to 240 mg per day, and for high doses, 1 to 3 separate administrations can be performed in one day. Preferably, the dosage of the compound of Formula 1 or a pharmaceutically acceptable salt thereof is 60 mg to 120 mg, and can be administered once or twice a day.

[0123] The pharmaceutical composition may optionally include a pharmaceutically acceptable carrier. The carrier is a carrier commonly used in drug manufacturing, and may include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, etc.

[0124] The pharmaceutical composition may further comprise a pharmaceutically acceptable additive selected from lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, and combinations thereof.

[0125] The pharmaceutical composition can be appropriately administered to a subject according to methods, administration routes and dosages commonly used in the art. In particular, a suitable dosage and a suitable administration frequency of the pharmaceutical composition can be selected according to methods known in the art, and in practice, the dosage and administration frequency of the pharmaceutical composition can be determined by a variety of factors, such as the type of symptoms to be prevented or treated, administration routes, sex, physical condition, diet, age, weight and severity of the disease of the subject, etc.

[0126] Another aspect of the present invention provides a composition for promoting in vitro myoblast differentiation, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. Here, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is as described above.

[0127] As used herein, the term "ex vivo" refers to the state of a part of a living organism (such as a cell or tissue) extracted and separated "outside the living organism". In particular, ex vivo can mean that a part of a living organism is experimented on "in vitro" under artificial conditions.

[0128] Myoblasts refer to muscle cells in an undifferentiated state. During myoblast differentiation, mononuclear myoblasts fuse into multinucleated myotubes. During the terminal differentiation of myoblasts, the expression of myosin heavy chain (MyHC) increases.

[0129] The composition for promoting differentiation can be a DMEM differentiation medium containing serum, but can include any medium or composition capable of promoting myoblast differentiation without limitation. In addition, the composition can further include additional materials required for cell growth or differentiation.

[0130] In the pharmaceutical composition, the concentration of the compound shown in Formula 1 or its pharmaceutically acceptable salt may be 0.01 μM to 100 μM. In particular, the concentration of the compound shown in Formula 1 or its pharmaceutically acceptable salt may be 0.1 μM to 50 μM, 0.1 μM to 25 μM, 0.5 μM to 25 μM, 0.1 μM to 10 μM, 0.5 μM to 10 μM, 1 μM to 10 μM, 0.1 μM to 5 μM, 0.5 μM to 5 μM, 1 μM to 5 μM, 0.1 μM to 2 μM, 0.5 μM to 2 μM, or 1 μM to 2 μM. In one example of the present invention, the compound shown in Formula 1 or its pharmaceutically acceptable salt is administered to mouse-derived myoblast C2C12 cells at a concentration of 1 μM.

[0131] Another aspect of the present invention provides a method for promoting myoblast differentiation, comprising treating in vitro myoblasts with a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. The method for promoting myoblast differentiation can be performed in vitro or in vitro.

[0132] Another aspect of the present invention provides a method for producing myotubes, comprising treating myoblasts in vitro with the compound of Formula 1 or a pharmaceutically acceptable salt thereof, thereby differentiating the myoblasts. The method for producing myotubes can be performed in vitro or in vitro.

[0133] Another aspect of the present invention provides a food composition for preventing or alleviating muscle weakness-related disorders, comprising a compound represented by Formula 1 or a nutritionally acceptable salt thereof. When used as a food additive, the food composition can be added directly, or can be used in combination with other food ingredients, and can be used appropriately according to common methods.

[0134] In order to prevent or alleviate the muscle weakness related conditions, the food composition can be used simultaneously or independently with the medicine for disease treatment before or after the muscle weakness related conditions develop. In particular, the food composition is characterized in that it promotes the differentiation of myoblasts. The muscle weakness related conditions are the same as described in the above-mentioned pharmaceutical composition.

[0135] Another aspect of the present invention provides a composition for enhancing muscle strength, comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a nutritionally acceptable salt thereof as an active ingredient. The composition for enhancing muscle strength can be used as a pharmaceutical composition or a food composition.

[0136] Muscle strength enhancement refers to increased muscle weight, enhanced muscle recovery and reduced muscle fatigue. The composition for muscle strength enhancement can increase muscle mass and subsequently increase overall muscle mass by differentiating myoblasts into muscle cells, thereby reducing muscle fatigue. In addition, the rapid replacement of muscle cells can enable rapid recovery of muscle damage. The composition for muscle strength enhancement of the present invention can be used as feed or feed additive.

[0137] Another aspect of the present invention provides a method for preventing or treating a muscle weakness-related disorder, comprising administering to a subject a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. Here, the compound, the muscle weakness-related disorder and the subject are the same as described above.

[0138] Another aspect of the present invention provides a use of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for preventing or treating a muscle weakness-related disorder. Here, the compound and the muscle weakness-related disorder are the same as described above.

[0139] Another aspect of the present invention provides the use of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a muscle weakness-related disorder. Here, the compound and the muscle weakness-related disorder are the same as described above.

[0140] Invention method

[0141] Hereinafter, the present invention is described in detail by way of examples. The following examples are intended to further illustrate the present invention without limiting its scope.

[0142] Experimental Example 1. Determination of the effect of alverine citrate in promoting myoblast differentiation

[0143] Experimental Example 1.1. Cultivation of myoblast cell line C2Cl2

[0144] C2Cl2 (American Type Culture Collection, CRL-1772 TM ) cells are myoblast cell lines obtained from C3H mice and used for myoblast differentiation studies. C2Cl2 cells were cultured using growth media and then cultured using differentiation media to induce differentiation. Here, DMEM supplemented with 10% fetal bovine serum was used as growth media (GM), and DMEM supplemented with 5% horse serum (HS) was used as differentiation media (DM).

[0145] Experimental Example 1.2. Promotion of myoblast differentiation

[0146] In order to confirm that alverine citrate promotes the effect of myoblast differentiation, C2C12 cells are distributed in the GM of embodiment 1.1 and cultivated for 24 hours, then C2C12 cells are processed with DMSO, insulin or alverine citrate, and differentiation is induced for 3 days. Subsequently, by using the antibody for myosin H chain (hereinafter referred to as MyHC) to carry out fluorescent staining, observe the cell differentiation into myotube and the change of myotube thickness and diameter. Here, the DMSO, insulin and alverine citrate used in the experiment are all purchased from Sigma-Aldrich. The insulin treatment group is used as the positive control group.

[0147] Specifically, C2C12 cells were plated at 5 × 10 5 The concentration of cells was distributed into a 6-well plate treated with GM of Example 1.1. After 24 hours, the DMEM medium supplemented with 5% HS was replaced and differentiation was induced. Then, the cells were treated with DMSO, insulin (1.72 μM) or alverine citrate (0.01 μM, 0.1 μM, 1 μM or 10 μM). After 3 days, after removing the medium, the cells were washed with phosphate buffer solution (1x PBS), treated with paraformaldehyde (4%), and fixed at room temperature for 15 minutes. Then, after washing 3 times with phosphate buffer solution (1x PBS), PBS containing 0.3% triton X-100 was treated with permeabilization buffer and reacted at room temperature for 10 minutes.

[0148] After washing three times with phosphate buffer (1x PBS), PBST containing 2% bovine serum albumin (blocking buffer, PBS containing 0.5% Tween 20) was applied and reacted for 30 minutes to inhibit nonspecific binding of the antibody. After washing three times with phosphate buffer (1X PBS), 100 μL of MYH3 primary antibody (SC-20641, Santa Cruz Biotechnology) diluted to 1:500 was added and reacted at room temperature for 1 hour. Then, after washing three times with phosphate buffer (1X PBS), 100 μL of secondary antibody (goat anti-rabbit IgG-HRP) diluted to 1:5,000 was added and reacted at room temperature for 1 hour. After 1 hour, for nuclear staining, after washing three times with phosphate buffer (1X PBS), the blocking buffer was treated with diluted DAPI dye and reacted at room temperature for 10 minutes. Then, after washing three times with phosphate buffered saline (1X PBS), the absorbance of the washed coverslips at a wavelength of 450 nm was measured, and fluorescent images were taken using a fluorescence microscope. The anti-MyHC antibody-stained area was analyzed using imageJ (a Java-based image processing program).

[0149] The results showed that myoblasts treated with insulin or alverine citrate were more able to differentiate into myotubes than myoblasts treated with DMSO alone. In particular, as the concentration of alverine citrate treatment increased, the diameter of myotubes increased ( Figure 1 and Figure 2 ).

[0150] Experimental Example 2. Determination of the muscle strength enhancing effect of alverine citrate using normal mice

[0151] In order to confirm the muscle strength enhancing effect of alverine citrate, after alverine citrate was administered to mice, the motor function of the mice (such as grip strength, running, balance coordination, etc.) was tested. After the motor function test, the muscle weight was measured. Specifically, each 10-week-old C57BL / 6 male mouse was orally administered with 200 μL of alverine citrate for 4 weeks at a daily dose of 17 mg / kg / day (AC-L), 50 mg / kg / day (AC-M), or 150 mg / kg / day (AC-H). This group of mice was used as the experimental group ( Figure 3 ). 10-week-old C57BL / 6 male mice were purchased from Daehan BioLink.

[0152] Experimental Example 2.1. Grip strength measurement

[0153] Grip strength was measured using a mouse grip dynamometer (Bioseb, USA). Specifically, mice were placed on a metal grid connected to a dashboard through which grip strength could be monitored, and the grip strength of the mice grasping the metal grid was measured while the mice were pulled back by their tails. Here, 5 consecutive repeated measurements were recorded and the average of the 5 measurements was calculated.

[0154] As a result, the grip strength of the experimental group mice was higher than that of the normal group mice. Through the above, it was confirmed that alverine citrate has a muscle strength enhancing effect ( Figure 4 ).

[0155] Experimental Example 2.2. Running ability test

[0156] Running ability was measured using a treadmill designed specifically for this experiment. First, an aversive stimulus was provided by allowing an electrical stimulus to flow at the starting point. Before measurement, the mice were acclimated at 8m / min for 10 minutes. The running time was recorded by having the mice in each group run on different tracks until exhaustion. Exhaustion was defined as when the mouse stayed outside the track for 10 seconds or more without running, and the mouse was determined to be exhausted and the time was recorded. This experiment could not be repeated on the same mouse. The mouse was placed on the treadmill and the test started at 8rpm, with the speed increasing by 2rpm every 10 minutes, with a maximum speed of 20rpm. The slope of the track started at a 0-degree slope and increased to a 5-degree slope 30 minutes after the start.

[0157] The results showed that the running time of the experimental group mice increased compared with the normal group mice. In particular, a significant increase in running time was observed in the experimental group treated with 150 mg / kg / day alverine citrate ( Figure 5 ).

[0158] Experimental Example 2.3. Balance and coordination test

[0159] Balance coordination was measured using the rota-rod test. The rota-rod test apparatus consisted of 4 test areas (3 cm shaft diameter, 9 cm runway width), 5 rotatable circular baffles (60 cm diameter) and a round rod. The test started at a speed of 10 rpm, and the speed was increased to a maximum of 40 rpm over 5 minutes. The duration that the mouse stayed in the rota-rod apparatus and adhered to the round rod without falling was recorded. The mice were allowed to rest for 15 minutes after each test, and a total of 3 tests were performed. The average of the three measurements was calculated.

[0160] The results showed that compared with the normal group of mice, the duration of the experimental group of mice clinging to the round bar increased, and as the dose of alverine citrate increased, the duration of the experimental group of mice clinging to the round bar also increased proportionally ( Figure 6 ).

[0161] Experimental Example 2.4. Muscle weight measurement

[0162] For muscle weight measurement, the gastrocnemius (GA) and tibialis anterior (TA) muscles of the hind limbs of each group of mice were removed and weighed. The results showed that the GA and TA muscle weights of the experimental group mice increased compared with the normal group mice. In particular, as the dose of alverine citrate increased, the GA and TA muscle weights of the experimental group mice also increased ( Figure 7 ).

[0163] Experimental Example 3. Determination of the muscle strength enhancing effect of alverine citrate using sarcopenia-induced mice

[0164] In order to determine the muscle strength enhancing effect of alverine citrate, alverine citrate was administered to sarcopenia-induced mice and running ability was tested. After the treadmill running test, muscle weight was measured. In particular, the hind limbs of 10-week-old C57BL / 6 male mice were fixed using a surgical stapler (Autosuture Royal 35W stapler). The stapler was removed after 5 days and the mice were allowed to re-activate for 3 days. After this, running ability was measured. Mice were orally administered 200 μL of alverine citrate, with each mouse dosed at 17 mg / kg / day (AC-L), 50 mg / kg / day (AC-M) or 150 mg / kg / day (AC-H), and these mice were set as experimental groups. Untreated sarcopenia-induced mice were set as a control group ( Figure 8 ). 10-week-old C57BL / 6 male mice were purchased from Daehan BioLink.

[0165] Experimental Example 3.1. Running ability test

[0166] The running ability was measured by the same method as in Example 2.2. It was found that the running time of the control group mice was reduced by about 10 minutes compared with the normal group mice. On the other hand, the running time of the experimental group mice increased proportionally with the dosage concentration of alverine citrate, and in particular, the running time of the experimental group of oral 150mg / kg / day (AC-H) dosage alverine increased compared with the normal mice.

[0167] Experimental Example 3.2. Muscle weight measurement

[0168] For muscle weight measurement, the GA and TA muscles of the hind limbs of mice in each group were removed and weighed. The results showed that the GA and TA muscle weights of the control group were significantly reduced compared with the normal group. However, in the case of the experimental group, as the dose concentration of alverine citrate increased, the GA and TA muscle weights of the experimental group mice also increased ( Fig.10 ).

[0169] Experimental Example 4. Determination of the effect of 4-hydroxyalverine in promoting myoblast differentiation

[0170] In order to determine the effect of 4-hydroxyalverine in promoting myoblast differentiation, DMSO, insulin (1.72 μM), alverine citrate (0.01 μM, 0.1 μM, 1 μM or 10 μM), 4-hydroxyalverine (0.01 μM, 0.1 μM, 1 μM or 10 μM) were respectively administered according to the same method as in Example 1, and the differentiation of cells into myotubes and the changes in myotube thickness and diameter were observed. Here, alverine and 4-hydroxyalverine are shown in Table 1.

[0171] [Table 1]

[0172]

[0173]

[0174] The results showed that myoblasts treated with alverine citrate or 4-hydroxyalverine were more likely to differentiate into myotubes than myoblasts treated with DMSO or insulin ( Fig.11 and Fig.12 ). When compared at the same concentration, the differentiation-promoting effect of 4-hydroxyalverine was superior to that of alverine.

[0175] Experimental Example 5. Determination of the cachexia therapeutic effects of alverine citrate and 4-hydroxyalverine

[0176] In order to determine the cachexia therapeutic effect of alverine citrate and 4-hydroxyalverine, an experiment was performed as an in vitro method to simulate the tumor growth environment by treating with cancer cell conditioned medium (CM). First, cancer cell CM was prepared using the C26 cancer cell line. Here, RPMI 1640 medium supplemented with 10% fetal bovine serum was used as cancer cell growth medium (GM). The C26 cancer cell line was cultured using a 100mm cell culture plate and cancer cell GM. Here, the medium was removed when the cell fusion reached 90%. Then, after washing with phosphate buffer (1X buffer), the prepared differentiation medium was treated according to the same process as in Example 1. After 24 hours, the C26 cancer cell line CM was obtained and filtered using a bottle top filter (Thermo, PES, 1L) before use.

[0177] C2C12 cells were plated at 5 × 10 5 The concentration of cells was distributed into a 6-well plate treated with GM of Example 1.1. After 24 hours, the DMEM medium supplemented with 5% HS was replaced and differentiation was induced. After 4 days, the differentiated myotubes were treated with differentiation medium supplemented with 33% CM and myotube atrophy was induced for 3 days. Here, the effect of inhibiting myotube atrophy was evaluated by treating the experimental group with 1 μM alverine citrate (AC) and 4-hydroxyalverine (4HA). DMSO was used as a negative control group and ursolic acid (UA) was used as a positive control group. According to the same method as in Example 1.2, the expression level of MyHC was measured by fluorescent staining using an antibody against MyHC.

[0178] As a result, it was found that the myotubes in the negative control group atrophied due to CM. On the other hand, it was found that myotube atrophy was inhibited when treated with alverine citrate or 4-hydroxyalverine ( Fig.13 and Fig.14 ).

[0179] Example 1. Determination of the effect of alverine derivatives in promoting myoblast differentiation

[0180] Example 1.1. Growth of myoblast cell line C2Cl2

[0181] C2Cl2 (American Type Culture Collection, CRL-1772 TM ) cells are myoblast cell lines obtained from C3H mice and used for myoblast differentiation studies. C2Cl2 cells were cultured using growth medium and then cultured using differentiation medium to induce differentiation. Here, DMEM supplemented with 10% fetal bovine serum was used as growth medium (GM), and DMEM supplemented with 5% horse serum (HS) was used as differentiation medium (DM).

[0182] Example 1.2. Acceleration of differentiation of myoblast cell lines

[0183] In order to determine the effect of alverine derivatives in promoting myoblast differentiation, C2C12 cells were distributed in the GM of Example 1.1 and cultured for 24 hours. Then, C2C12 cells were treated with DMSO (Sigma-Aldrich), insulin, alverine (Sigma-Aldrich) or 27 alverine derivatives, each at a concentration of 1 μM, to induce differentiation for 4 days. Then, fluorescent staining was performed using antibodies against MyHC to monitor the differentiation of myotubes and changes in myotube thickness and diameter. Here, 27 alverine derivatives were designed and synthesized by the Korea Institute of Bioscience and Biotechnology and JD Biosciences on request. The alverine and 27 alverine derivatives 1 to 27 used in the experiment are shown in Table 2 below.

[0184] [Table 2]

[0185]

[0186]

[0187]

[0188] Specifically, C2C12 cells were plated at 5 × 10 5The concentration of cells was distributed into a 6-well plate treated with GM of Example 1.1. After 24 hours, the DMEM medium supplemented with 5% HS was replaced and differentiation was induced. Then, the cells were treated with DMSO, alverine or 27 alverine derivatives at a concentration of 1 μM. After 4 days, after removing the medium, the cells were washed with phosphate buffer (1x PBS), treated with paraformaldehyde (4%), and fixed at room temperature for 15 minutes. Then, after washing 3 times with phosphate buffer (1xPBS), PBS containing 0.3% triton X-100 was treated with permeabilization buffer and reacted at room temperature for 10 minutes.

[0189] After washing three times with phosphate buffer (1x PBS), PBST containing 2% bovine serum albumin (blocking buffer, PBS containing 0.5% Tween 20) was applied and reacted for 30 minutes to inhibit nonspecific binding of the antibody. After washing three times with phosphate buffer (1X PBS), 100 μL of MYH3 primary antibody (SC-20641, Santa Cruz Biotechnology) diluted to 1:500 was added and reacted at room temperature for 1 hour. Then, after washing three times with phosphate buffer (1X PBS), 100 μL of secondary antibody (goat anti-rabbit IgG-HRP) diluted to 1:5,000 was added and reacted at room temperature for 1 hour. After 1 hour, for nuclear staining, after washing three times with phosphate buffer (1X PBS), the blocking buffer was treated with diluted DAPI dye and reacted at room temperature for 10 minutes. Then, after washing three times with phosphate buffer (1X PBS), the absorbance of the washed coverslip at a wavelength of 450 nm was measured, and a fluorescence image was taken using a fluorescence microscope.

[0190] The results confirmed that myoblasts treated with each of the 27 alverine derivatives also promoted differentiation into myotubes compared to myoblasts treated with DMSO alone, just as myoblasts treated with alverine did.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, Wherein the compound is selected from: 1) 4-(3-ethyl(3-phenylpropyl)amino)propyl)aniline; 2) N-ethyl-3-(4-methoxyphenyl)-N-(3-phenylpropyl)propan-1-amine; 3) N-ethyl-3-phenyl-N-(3-(p-tolyl)propyl)propan-1-amine; 7) 4-(3-(methyl(3-phenylpropyl)amino)propyl)phenol; 8) 4-(3-((3-(4-(benzyloxy)phenyl)propyl)(ethyl)amino)propyl)aniline; 9) N-(4-(3-((3-)4-(benzyloxy)phenyl)propyl)(ethyl)amino)propyl)phenyl)acetamide; 10) 4-(3-(ethyl(phenethyl)amino)propyl)phenol; 11) 4-(3-(ethyl(3-phenylpropyl)amino)propyl)-2-fluorophenol; 12) 2-bromo-4-(3-(ethyl(3-phenylpropyl)amino)propyl)phenol; 13) 1-(4-(3-((3-(4-(benzyloxy)phenyl)propyl)(ethyl)amino)propyl)phenyl)-3-phenylurea; 16)(4-phenylbutyl)(3-phenylpropyl)propylamine; 17) 3-(4-Butoxyphenyl)-N-ethyl-N-(3-phenylpropyl)propan-1-amine; 18) 3-(4-(but-3-en-1-yloxy)phenyl)-N-ethyl-N-(3-phenylpropyl)propan-1-amine; 19) 3-(4-(4-bromobutoxy)phenyl)-N-ethyl-N-(3-phenylpropyl)propan-1-amine; 20) 4-(4-(3-(ethyl(3-phenylpropyl)amino)propyl)phenoxy)butan-1-amine; and 21) 4-(3-(ethyl(3-(4-methoxyphenyl)propyl)amino)propyl)-2-fluorophenol.

2. A pharmaceutical composition for preventing or treating a muscle weakness-related disorder, comprising a compound or a pharmaceutically acceptable salt thereof, Wherein the compound is selected from: 1) 4-(3-ethyl(3-phenylpropyl)amino)propyl)aniline; 2) N-ethyl-3-(4-methoxyphenyl)-N-(3-phenylpropyl)propan-1-amine; 3) N-ethyl-3-phenyl-N-(3-(p-tolyl)propyl)propan-1-amine; 7) 4-(3-(methyl(3-phenylpropyl)amino)propyl)phenol; 8) 4-(3-((3-(4-(benzyloxy)phenyl)propyl)(ethyl)amino)propyl)aniline; 9) N-(4-(3-((3-)4-(benzyloxy)phenyl)propyl)(ethyl)amino)propyl)phenyl)acetamide; 10) 4-(3-(ethyl(phenethyl)amino)propyl)phenol; 11) 4-(3-(ethyl(3-phenylpropyl)amino)propyl)-2-fluorophenol; 12) 2-bromo-4-(3-(ethyl(3-phenylpropyl)amino)propyl)phenol; 13) 1-(4-(3-((3-(4-(benzyloxy)phenyl)propyl)(ethyl)amino)propyl)phenyl)-3-phenylurea; 16)(4-phenylbutyl)(3-phenylpropyl)propylamine; 17) 3-(4-Butoxyphenyl)-N-ethyl-N-(3-phenylpropyl)propan-1-amine; 18) 3-(4-(but-3-en-1-yloxy)phenyl)-N-ethyl-N-(3-phenylpropyl)propan-1-amine; 19) 3-(4-(4-bromobutoxy)phenyl)-N-ethyl-N-(3-phenylpropyl)propan-1-amine; 20) 4-(4-(3-(ethyl(3-phenylpropyl)amino)propyl)phenoxy)butan-1-amine; and 21) 4-(3-(ethyl(3-(4-methoxyphenyl)propyl)amino)propyl)-2-fluorophenol.

3. The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable salt is citrate.

4. Use of a compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a condition associated with muscle weakness, Wherein the compound is selected from: 1) 4-(3-ethyl(3-phenylpropyl)amino)propyl)aniline; 2) N-ethyl-3-(4-methoxyphenyl)-N-(3-phenylpropyl)propan-1-amine; 3) N-ethyl-3-phenyl-N-(3-(p-tolyl)propyl)propan-1-amine; 4) 3-(3-(ethyl(3-phenylpropyl)amino)propyl)phenol; 5) N-methyl-3-phenyl-N-(3-phenylpropyl)propan-1-amine; 6) 4,4'-((ethylazadiyl))bis(propane-3,1-diyl))diphenol; 7) 4-(3-(methyl(3-phenylpropyl)amino)propyl)phenol; 8) 4-(3-((3-(4-(benzyloxy)phenyl)propyl)(ethyl)amino)propyl)aniline; 9) N-(4-(3-((3-)4-(benzyloxy)phenyl)propyl)(ethyl)amino)propyl)phenyl)acetamide; 10) 4-(3-(ethyl(phenethyl)amino)propyl)phenol; 11) 4-(3-(ethyl(3-phenylpropyl)amino)propyl)-2-fluorophenol; 12) 2-bromo-4-(3-(ethyl(3-phenylpropyl)amino)propyl)phenol; 13) 1-(4-(3-((3-(4-(benzyloxy)phenyl)propyl)(ethyl)amino)propyl)phenyl)-3-phenylurea; 14) Ethyl (4-phenylbutyl) (3-phenylpropyl) amine; 15) Ethylbis(4-phenylbutyl)amine; 16)(4-phenylbutyl)(3-phenylpropyl)propylamine; 17) 3-(4-Butoxyphenyl)-N-ethyl-N-(3-phenylpropyl)propan-1-amine; 18) 3-(4-(but-3-en-1-yloxy)phenyl)-N-ethyl-N-(3-phenylpropyl)propan-1-amine; 19) 3-(4-(4-bromobutoxy)phenyl)-N-ethyl-N-(3-phenylpropyl)propan-1-amine; 20) 4-(4-(3-(ethyl(3-phenylpropyl)amino)propyl)phenoxy)butan-1-amine; 21) 4-(3-(ethyl(3-(4-methoxyphenyl)propyl)amino)propyl)-2-fluorophenol; 28) N-ethyl-3-phenyl-N-(3-phenylpropyl)propan-1-amine; and 29) 4-[3-[Ethyl(3-phenylpropyl)amino]propyl]phenol.

5. The use according to claim 4, wherein the muscle weakness-related disorder is sarcopenia, muscle atrophy, muscular dystrophy or cachexia.

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