Pharmaceuticals for the prevention or treatment of fibular muscle atrophy.

Abstract

The invention proposes a pharmaceutical preparation for the prevention or treatment of Charcot-Marie-Tooth (CMT) muscular atrophy of the peripheral nervous system, comprising the compound represented by formula I, its optical isomers or pharmaceutical salts as the active ingredient.

Description

[0001] Specification Title Compositions for preventing or treating Charcot-Marie-Tooth disease (CMT) Technical Field The present disclosure relates to a pharmaceutical composition for preventing or treating Charcot-Marie-Tooth disease associated with a peripheral nervous system, comprising a compound represented by formula I, optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient, a method for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system using the compound, a use of the compound for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system, and a use of the compound in preparing a medicament for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system. Background Charcot-Marie-Tooth (CMT, hereditary motor and sensory neuropathy: HMSN) disease is the most common type of hereditary peripheral nerve disorder caused by a mutation of proteins that constitute nerves. More than 1,000 mutations have been identified from about 90 genes so far (Timmerman et al., (2014) Genes 5:13-32). Upon the development of Charcot- Marie-Tooth disease, progressive degeneration of peripheral nerves leads to atrophy of muscles affected by neural distribution, and thus patients show gradual atrophy in their muscles of hands and feet as well a symptom of deformed hands and feet. The CMT is genetically and clinically very diverse and complicated, and it is known that symptoms thereof vary ranging from a close- to-normal state to a wheelchair-bound state depending on mutation types. The CMT emerges mainly in teen years and occurs to one for every 2,500 people (Krajewski et al., (2000) Brain 123:1516). The CMT belongs to rare diseases such as hereditary peripheral nerve disorder. However, a prevalence rate thereof amounts to one for every 2,500 people. There are about 20,000 patients in South Korea and 2,800,000 ones worldwide. Until now, a therapy for the CMT is limited only to rehabilitation, aids, pain control, surgical therapy, etc., but a successful therapeutic agent has not been developed yet. Thus, there is a great need for developing a therapeutic agent for the CMT. For example, concerning the CMT, which is the most common type of hereditary motor and sensory neuropathy, a large-scale clinical trial was conducted on ascorbic acid, which had been proven as an essential material for myelination in the peripheral nervous system through an experiment on culturing lemmocytes and dorsal root ganglion cells together, but such trial was failed in proving efficacy (Pareyson et al., (2011) 10(4):3205).

Related Art Reference

[0002] In example embodiment of the present invention, the pharmaceutical composition including a compound of Table A, optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient may prevent or treat Charcot-Marie-Tooth (CMT) disease associated with the peripheral nervous systems (PNS). In the pharmaceutical composition according to the disclosure, the compounds represented by formula I may be shown in Table B below: [Table B] In example embodiment of the present invention, the pharmaceutical composition including a compound of Table B, optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient may prevent or treat Charcot-Marie-Tooth (CMT) disease associated with the peripheral nervous systems (PNS). In the present disclosure, the compound represented by above formula I may be prepared by a method disclosed in Korean Unexamined Patent Application Publication No.10- 2017-0017792, but is not limited thereto. In the present disclosure, the compound represented by the above formula I may contain at least one asymmetric carbon, and thus may be present as a racemic mixture, a single enantiomer (optical isomer), a mixture of diastereomers, and a single diastereomer. Such isomer may be separated by being split according to the prior art, for example, column chromatography, HPLC or the like. Alternatively, the isomer may be stereospecifically synthesized with a known array of optically pure starting materials and / or reagents. Particularly, said isomer may be an optical isomer(enantiomer). In the present disclosure, the term “pharmaceutically acceptable” may refer to the one which is physiologically acceptable and does not conventionally cause gastrointestinal disturbance, an allergic response such as dizziness or other responses similar thereto, when being administered to an individual. The pharmaceutically acceptable salts according to the embodiments of the present invention may be prepared by a conventional method known to those skilled in the art. The pharmaceutically acceptable salts according to the embodiment of the present invention may include, for example, inorganic ion salts prepared from calcium, potassium, sodium, magnesium, etc.; inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, hydroiodic acid, etc.; organic acid salts prepared from acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, etc.; sulfonic acid salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, naphthalene sulfonic acid, etc.; amino acid salts prepared from glycine, arginine, lysine, etc.; amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc.; and the like, but are not limited thereto. In the embodiments of the present invention, salts may include hydrochloric acid, trifluoroacetic acid, citric acid, bromic acid, maleic acid, phosphoric acid, sulfuric acid, tartaric acid or a mixture thereof. In the present disclosure, the term "Charcot-Marie-Tooth (CMT) disease" may refer to a degenerative peripheral neuropathy that causes dysfunction and death of peripheral nerve cells due to various genetic factors, indicating a disease, of which the main etiological cause is an axonal transport defect. In the present disclosure, Charcot-Marie-Tooth disease associated with the peripheral nervous system may be at least one selected from the group consisting of CMT1 type, CMT2 type, CMT4 type, degerine-sottas syndrome (DSN), congenital hypomyelination (CH), hereditary neuropathy with liability to pressure palsy (HNPP) and giant axonal neuropathy (GAN), but is not limited thereto. The CMT1 type may be at least one selected from the group consisting of CMT1A, CMT1B, CMT1C, CMT1D and CMTX, and the CMT2 type may be at least one selected from the group consisting of CMT2A, CMT2B, CMT2C, CMT2D, CMT2E and CMT2F, and the CMT4 type may be at least one selected from the group consisting of CMT4A, CMT4B1, CMT4B2, CMT4C, CMT4D, CMT4E and CMT4F. In the present disclosure, said Charcot-Marie-Tooth disease associated with the peripheral nervous system may be at least one selected from the group consisting of CMT1A, CMT2D and CMT2F, but is not limited thereto. In example embodiments of the present invention, the compound according to the present disclosure may prevent or treat the symptom associated with degeneration of the peripheral nervous systems in a subject with Charcot-Marie-Tooth disease. In example embodiments of the present invention, the compound according to the present disclosure may prevent or treat the symptom associated with dysfunction and / or death of peripheral nerve cells in a subject with Charcot-Marie-Tooth disease. In example embodiments of the present invention, the compound according to the present disclosure may prevent or treat a degenerative peripheral neuropathy that is caused by dysfunction and / or death of peripheral nerve cells in a subject with Charcot-Marie-Tooth disease. In the present disclosure, the term “prevention” may refer to all the acts, which inhibit or delay the occurrence of a disease by administering the compound of formula I of the present disclosure, optical isomers thereof or pharmaceutically acceptable salts thereof. In the present disclosure, the term “treatment” may refer to all the acts, by which a symptom of an individual likely to develop or suffering from a disease gets better or takes a favorable turn by administering the compound of formula I of the present disclosure, optical isomers thereof or pharmaceutically acceptable salts thereof. The compound represented by formula I of the present disclosure, optical isomers thereof or pharmaceutically acceptable salts thereof may be advantageously used in preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system. A pharmaceutical composition including the compound represented by formula I of the present disclosure, optical isomers thereof, or pharmaceutically acceptable salts thereof as an active ingredient may be advantageously used in preventing or treating Charcot-Marie- Tooth disease associated with the peripheral nervous system. In example embodiments of the present invention, the pharmaceutical composition including the compound according to the present disclosure may prevent or treat the symptom associated with degeneration of the peripheral nervous systems in a subject with Charcot- Marie-Tooth disease. In example embodiments of the present invention, the pharmaceutical composition including the compound according to the present disclosure may prevent or treat the symptom associated with dysfunction and / or death of peripheral nerve cells in a subject with Charcot- Marie-Tooth disease. In example embodiments of the present invention, the pharmaceutical composition including the compound according to the present disclosure may prevent or treat a degenerative peripheral neuropathy that is caused by dysfunction and / or death of peripheral nerve cells in a subject with Charcot-Marie-Tooth disease. In this regard, in one particular embodiment of the present invention, it was confirmed that the compound represented by formula I of the present disclosure, optical isomers thereof, or pharmaceutically acceptable salts thereof improve and restore an axonal mitochondrial movement velocity (tables 1 and 2, FIGS. 1 and 2) and suppress the induced PMP22 protein expression (FIG.3). In addition, it was confirmed that the compound represented by formula I of the present disclosure, optical isomers thereof, or pharmaceutically acceptable salts thereof enhance a motor function (CRT, GST, BBT) of a mouse (FIGS.4 to 8), and a nerve conduction velocity of the mouse (FIGS. 9 and 10). Furthermore, it was confirmed that the compound represented by formula I of the present disclosure, optical isomers thereof, or pharmaceutically acceptable salts thereof improved and restored the size of the axon is (FIG.11). In other words, the compound represented by formula I, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present disclosure may effectively treat or alleviate symptoms shown in Charcot-Marie-Tooth disease associated with the peripheral nervous system, such as a decrease in motor nerve conduction velocity, a decrease in compound muscle action potential, progressive degeneration of nerve cells, muscle weakness, abnormal sense, axonal atrophy, etc., and may inhibit or delay an expression of such symptoms. In one particular embodiment of the present invention, the compound represented by formula I of the present disclosure, optical isomers thereof, or pharmaceutically acceptable salts thereof may adjust the genetic properties of patients with Charcot Marie Tooth disease to a normal level or to a level similar thereto, suggesting that the compound represented by formula I, optical isomers thereof or pharmaceutically acceptable salts thereof may ameliorate or treat the symptoms of Charcot Marie Tooth disease (FIGS.13 to 15). In one particular embodiment of the present invention, the compound represented by formula I of the present disclosure, optical isomers thereof, or pharmaceutically acceptable salts thereof may raise the proportion of atrophic muscle fibers and increase the cross-sectional area of muscle fibers in patients with Charcot Marie Tooth disease (FIGS.16 and 17). In one particular embodiment of the present invention, the compound represented by formula I of the present disclosure, optical isomers thereof, or pharmaceutically acceptable salts thereof may increase fully innervated neuromuscular junctions in patients with Charcot Marie Tooth disease (FIGS.19 and 20). In one particular embodiment of the present invention, the compound represented by formula I of the present disclosure, optical isomers thereof, or pharmaceutically acceptable salts thereof may increase a diameter of axons and / or a thickness of myelin sheaths in sensory nerves, decrease abnormal myelination, and increase the proportion of axons with a large diameter in patients with Charcot Marie Tooth disease (FIGS.21 to 23). In one particular embodiment of the present invention, the compound represented by formula I of the present disclosure, optical isomers thereof, or pharmaceutically acceptable salts thereof may increase a sensory nerve conduction velocity (SNCV) and an amplitude of a sensory nerve action potential (SNAP) in patients with Charcot Marie Tooth disease (FIGS.24 and 25). The compound represented by formula I of the present disclosure, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present disclosure may show an effect of preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system at a level that is similar to or substantially the same as or superior to a conventionally known drug for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system. The pharmaceutical composition of the present disclosure may further include at least one pharmaceutically acceptable carrier, in addition to the compound represented by above formula I, optical isomers thereof or pharmaceutically acceptable salts thereof. The pharmaceutically acceptable carrier may be the one which is conventionally used in the art, specifically including, but not limited thereto, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidine, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral, or oil. The pharmaceutical composition of the present invention may further include lubricants, humectants, sweetening agents, flavoring agents, emulsifiers, suspending agents, preservatives, dispersing agents, stabilizing agents, etc., in addition to the above ingredients. In addition, the pharmaceutical composition of the present invention may be formulated into an oral dosage form such as a tablet, powder, granule, pill, capsule, suspension, emulsion, liquid for internal use, oiling agent, syrup, etc., as well as a form of external application, suppository or sterile solution for injection, by using pharmaceutically acceptable carriers and excipients and thus may be prepared in a unit dose form or prepared by being inserted into a multi-dose container. Such preparations may be prepared according to a conventional method used for formulation in the art or a method disclosed in Remington's Pharmaceutical Science (19thed., 1995), and may be formulated into various preparations depending on each disease or ingredient. A non-limiting example of preparations for oral administration using the pharmaceutical composition of the present invention may include tablets, troches, lozenges, water-soluble suspensions, oil suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups, elixirs or the like. To formulate the pharmaceutical composition according to the embodiments of the present invention into preparation for oral administration, the followings may be used: binders such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose, gelatin or the like; excipients such as dicalcium phosphate, etc.; disintegrants such as maize starch, sweet potato starch or the like; lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol wax, or the like; etc., in which sweetening agents, flavoring agents, syrups, etc. may also be used. Furthermore, in the case of the capsules, liquid carriers such as fatty oil, etc. may be further used in addition to the above-mentioned materials. A non-limiting example of parenteral preparations using the pharmaceutical composition according to the embodiments of the present invention may include injectable solutions, suppositories, powders for respiratory inhalation, aerosols for spray, ointments, powders for application, oils, creams, etc. To formulate the pharmaceutical composition according to the embodiments of the present invention into preparation for parenteral administration, the following may be used: sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, external preparations, etc. As said non- aqueous solvents and suspensions, the following may be used, but without limitation thereto: propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. The pharmaceutical composition according to the embodiments of the present invention may be subjected to oral administration or parenteral administration according to a targeted method, for example, intravenous, subcutaneous, intraperitoneal or local administration, particularly oral administration, but is not limited thereto. A daily dosage of the compound represented by formula I, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present disclosure may be particularly about 0.1 to about 10,000 mg / kg, about 1 to about 8,000 mg / kg, about 5 to about 6,000 mg / kg, or about 10 to about 4,000 mg / kg, and more particularly about 50 to about 2,000 mg / kg, but is not limited thereto and may be also administered once a day or several times a day by dividing the daily dosage of the compound. A pharmaceutically effective dose and an effective dosage of the pharmaceutical composition according to the embodiments of the present invention may vary depending on a method for formulating the pharmaceutical composition, an administration mode, an administration time, an administration route, and / or the like, and may be diversified according to various factors including a type and degree of reaction to be achieved by administration of the pharmaceutical composition, a type of an individual for administration, the individual’s age, weight, general health condition, disease symptom or severity, gender, diet and excretion, ingredients of other drug compositions to be used for the corresponding individual at the same time or different times, etc., as well as other similar factors well known in a pharmaceutical field, and those skilled in the art may easily determine and prescribe an effective dosage for the intended treatment. The pharmaceutical composition according to the embodiments of the present invention may be administered once a day or several times a day by dividing the daily dosage of the composition. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with a conventional therapeutic agent. Considering all the above factors, the pharmaceutical composition of the present invention may be administered in such an amount that a maximum effect may be achieved by a minimum amount without a side effect, and such amount may be easily determined by those skilled in the art to which the present invention pertains. The pharmaceutical composition according to the embodiments of the present invention may show an excellent effect even when solely used, but may be further used in combination with various methods such as hormone therapy, drug treatment, etc. to increase therapeutic efficiency. The present disclosure may provide a method for preventing or treating Charcot- Marie-Tooth disease associated with the peripheral nervous system, including administering a compound represented by above formula I, optical isomers thereof or pharmaceutically acceptable salts thereof into an individual. The present disclosure may provide a method for preventing or treating Charcot- Marie-Tooth disease associated with the peripheral nervous system, including administering a compound of the above Table A, optical isomers thereof or pharmaceutically acceptable salts thereof into an individual. The present disclosure may provide a method for preventing or treating Charcot- Marie-Tooth disease associated with the peripheral nervous system, including administering a compound of the above Table B, optical isomers thereof or pharmaceutically acceptable salts thereof into an individual. Said terms "Charcot-Marie-Tooth disease," "prevention" and "treatment" may be the same as described above. In the present disclosure, the term “administration” may refer to introducing a predetermined substance into an individual by an appropriate method. In the present disclosure, the term “individual” may refer to all the animals such as rats, mice, livestock, etc., including humans, who have developed or are likely to develop Charcot-Marie-Tooth disease associated with the peripheral nervous system, and may be particularly mammals including humans, but is not limited thereto. The method for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system according to the embodiments of the present invention may include administering a therapeutically effective amount of the compound represented by above formula I, optical isomers thereof or pharmaceutically acceptable salts thereof. In the present disclosure, the term “therapeutically effective amount” may refer to an amount enough to treat a disease at a reasonable risk / benefit ratio applicable to medical treatment and not to cause a side effect, and may be determined by those skilled in the art according to factors including a patient’s gender, age, weight and health condition, a type of disease, severity, the activity of a drug, sensitivity to a drug, an administration method, an administration time, an administration route, an excretion rate, a treatment period, a drug combined or concurrently used, as well as other factors well known in a pharmaceutical field. It is preferable to differently apply a particular therapeutically effective amount for a certain patient depending on various factors including a type and degree of reaction to be achieved therefrom, a particular composition including a presence of other preparations used in some cases, a patient’s age, weight, general health condition, gender and diet, an administration time, an administration route, a secretion rate of the composition, a treatment period and a drug used together with the particular composition or simultaneously therewith, as well as other similar factors well known in a pharmaceutical field. The method for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system of the present invention may include not only dealing with the disease per se before expression of its symptoms, but also inhibiting or avoiding such symptoms by administering the compound represented by above formula I, isomers thereof or pharmaceutically acceptable salts thereof. In managing the disease, a preventive or therapeutic dose of a certain active ingredient may vary depending on the characteristics and severity of the disease or conditions, and a route in which the active ingredient is administered. A dose and a frequency thereof may vary depending on an individual patient’s age, weight and reactions. A suitable dose and usage may be easily selected by those skilled in the art, naturally considering such factors. In addition, the method for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system of the present invention may further include administering a therapeutically effective amount of an additional active agent, which helps prevent or treat the disease, along with the compound represented by above formula I, optical isomers thereof or pharmaceutically acceptable salts thereof, and the additional active agent may show a synergy effect or an additive effect together with the compound represented by above formula I, optical isomers thereof or pharmaceutically acceptable salts thereof. The present disclosure may provide a use of the compound represented by the above formula I, optical isomers thereof or pharmaceutically acceptable salts thereof for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system. The present disclosure may provide a use of the compound of the above Table A, optical isomers thereof or pharmaceutically acceptable salts thereof for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system. The present disclosure may provide a use of the compound of the above Table B, optical isomers thereof or pharmaceutically acceptable salts thereof for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system. The present disclosure may provide a use of the compound represented by above formula I, optical isomers thereof or pharmaceutically acceptable salts thereof in preparing a medicament for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system. The present disclosure may provide a use of the compound of the above Table A, optical isomers thereof or pharmaceutically acceptable salts thereof in preparing a medicament for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system. The present disclosure may provide a use of the compound of the above Table B, optical isomers thereof or pharmaceutically acceptable salts thereof in preparing a medicament for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system. Said terms "Charcot-Marie-Tooth disease," "prevention" and "treatment" may be the same as described above. For the preparation of the medicament, the compound represented by above formula I, optical isomers thereof or pharmaceutically acceptable salts thereof may be mixed with pharmaceutically acceptable adjuvants, diluents, carriers, etc., and may be prepared into a complex preparation together with other active agents, thus providing a synergy action. Matters mentioned in the pharmaceutical composition, treatment method and use of the present disclosure are applied the same, if not contradictory to each other.

Advantageous Effects

Brief Description of the Drawings

Mode for Invention

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

[0003] From above table 9, it was confirmed that the compound of the present disclosure exhibits an effect of increasing and restoring the axon size. <Experimental Example 6> Genetic analysis This experiment was made to evaluate the efficacy of the compound of the present disclosure through a genetic analysis of animals. Ten-week-old C3 CMT1A mice were provided with a standard diet (Central Lab Animal, Inc.) and water ad libitum and were housed in a controlled environment with a temperature of 22 ± 2°C, a humidity of 44-56% and a 12-hour light-dark cycle. All experimental procedures were approved and performed according to the Institutional Animal Care and Use Committee (IACUC) of the Korea CKD Laboratory Animal Center (with an approved number: S-17_033). Each group was classified as shown in table 10 below.

Table 10

[0004] Vehicle was 0.5% methylene chloride (MC), and each group was administered vehicle or compound 43 for eight weeks. TG or C3 refers to C3 CMT1A mice; a wild type (WT) is a group in which only vehicle is administered to normal mice; Vehicle(C3) or C3 group is a group in which only vehicle is administered to C3 CMT1A mice; and compound 43 is a group in which compound 43 is administered to C3 CMT1A mice with five animals in each group. After the last administration of vehicle or compound 43, the sciatic nerves were collected at 0.5 hours, from which RNA was extracted with a kit (RNeasy Kit, Qiagen, Venlo, Netherlands), and then RNA quantification and integrity evaluation was carried out evaluate through Quant-IT RiboGreen (Invitrogen) and apeStation RNA screentape (Agilent, Santa Clara, CA, USA). Then, the corresponding RNA was quantified at a gene level through RNA sequencing using more than 24 million leads. A gene set enrichment analysis was performed from a quantified gene level to confirm various biological effects (gene sets) among WT, TG(C3), and drug administration groups (compound 43), and then the significance of the results was analyzed and confirmed with a threshold value set to nominal p < 0.05, false detection rate (FDR) q < 0.25. The gene set, of which significance was finally confirmed, was graphed through Prism 9, and the results are shown in FIGS.12 to 15. As confirmed above in FIG.12, it was shown that the group dosed with compound 43 shows genetic properties close to those of normal mice (WT) compared with the C3 group, when divided into the groups of WT, C3 group, and compound 43 group on the basis of specific criteria (three PC values) of the gene module. In addition, as confirmed in FIGS. 13 to 15, it was understood that compound 43 raises gene levels associated with myogenesis, postsynaptic density, postsynaptic specialization, neuromuscular junction, synaptic cleft, EGR2_SOX10 myelination, Schwann cell myelination / development, Schwann cell differentiation, lipid metabolism, lipogenesis, etc., which were down-regulated in mice with CMT disease (TG, C3 CMT1A mice). It can be confirmed from FIG. 13 that the genes associated with myogenesis, postsynaptic density, postsynaptic specialization, neuromuscular junction, synaptic cleft, EGR2_SOX10 myelination, Schwann cell myelination / development, Schwann cell differentiation, lipid metabolism, lipogenesis, etc. are remarkably up-regulated in the group dosed with compound 43 compared with in mice with CMT disease (TG, C3 CMT1A mice). In particular, it can be understood from FIG. 14 that the expression of individual genes included in the gene set varies according to the administration of compound 43; it was confirmed from FIG. 15 that genes associated with PM22 aggregates, myelination, nerotransmission, and lipid metabolism, which appear to be related to CMT disease, vary according to the administration of compound 43; and it could be seen that the transcription of genes involved in increasing neurotransmission and myelination and controlling PM22 aggregations and lipid metabolism is up-regulated according to the administration of compound 43. <Experimental Example 7> Analysis of muscle fiber atrophy amelioration This experiment was made to evaluate the efficacy of the compound of the present disclosure by confirming the effect of the compound of the present disclosure on the myofibrillar atrophic neuromuscular junctions in CMT mice. <Experimental Example 7-1> 10-week-old CMT1A mouse model Ten-week-old C3 CMT1A mice were provided with a standard diet (Central Lab Animal, Inc.) and water ad libitum and were housed in a controlled environment with a temperature of 22 ± 2°C, a humidity of 44-56% and a 12-hour light-dark cycle. All experimental procedures were approved and performed according to the Institutional Animal Care and Use Committee (IACUC) of the Korea CKD Laboratory Animal Center (with an approved number: S-17_033). Each group was classified as shown in table 11 below.

Table 11

Table 12

Claims

Claims 1. A pharmaceutical composition for preventing or treating Charcot-Marie- Tooth (CMT) disease associated with peripheral nervous systems (PNS), comprising a compound represented by formula I below, optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient: [Formula I]in formula I,wherein L1, L2or L3are each independently a bond or -(C1-C2alkylene)-; R1 is -CX2H or -CX3;-(C1-C4alkyl), -CF3, -CF2H, -CN, -aryl, -heteroaryl, -(C1-C4alkyl)-aryl or -(C1-C4alkyl)- heteroaryl, [wherein at least one H of the -aryl, -heteroaryl, -(C1-C4alkyl)-aryl or -(C1-C4alkyl)-heteroaryl may be substituted with -X, -OH, -CF3or -CF2H]}; R3is -H, -(C1-C4alkyl), -(C1-C4alkyl)-O(C1-C4alkyl), -(C1-C4alkyl)-C(=O)-O(C1- C4 alkyl), -(C3-C7cycloalkyl), -(C2-C6cycloheteroalkyl), -aryl, -heteroaryl, -adamantyl,{wherein, at least one H of -(C1-C4alkyl) may be substituted with -X or -OH, at least one H of -aryl or -heteroaryl each independently may be substituted with -X, -OH, -O(C1-C4alkyl), -OCF3, -O-aryl, -NRDRE, -(C1-C4alkyl), -CF3, -CF2H, -C(=O)-(C1-C4alkyl), -C(=O)-O(C1-C4alkyl), -C(=O)-NRDRE, -S(=O)2-(C1-C4alkyl), aryl, heteroaryl,[wherein, at least one H of may be subsD Etituted with -X, -(C1-C4alkyl), -NR R , -CF3or -CF2H], at least one H of -(C3-C7cycloalkyl), -(C2-C6cycloheteroalkyl), adamantyl, may be each independently substituted with -X, -OH or-(C1-C4alkyl)}; Y1, Y2and Y4are each independently -CH2-, -NRF-, -O-, -C(=O)- or -S(=O)2-; Y3is -CH- or -N-; Z1to Z4are each independently N or CRZ, {wherein at least three of Z1to Z4may not be simultaneously N, and RZis -H, -X or -O(C1-C4alkyl)}; Z5and Z6are each independently -CH2- or -O-; Z7and Z8are each independently =CH- or =N-; Z9is -NRG- or -S-; RAand RBare each independently -H, -(C1-C4alkyl), -(C1-C4alkyl)-OH, -(C1-C4alkyl)-NRDRE, -aryl, -(C1-C4alkyl)-aryl, -heteroaryl, -(C1-C4aryl)-heteroaryl, -(C3-C7cycloalkyl), -(C2-C6heterocycloalkyl) or {wherein, at least one H of the -(C1-C4alkyl), -(C1-C4alkyl)-OH or -(C1-C4alkyl)-NRDREmay be substituted with -X, at least one H of the -aryl, -(C1-C4alkyl)-aryl, -heteroaryl, -(C1-C4alkyl)-heteroaryl, -(C3-C7cycloalkyl) or -(C2-C6heterocycloalkyl) may be substituted with -X, -OH, -O(C1-C4alkyl), -(C1-C4alkyl), -CF3, -CF2H or -CN, at t least onemay be substituted with n-X, -OH, -O(C1-C4alkyl), -(C1-C4alkyl), -CF3, -CF2H, -CN, -(C2-C6heterocycloalkyl), -aryl, -(C1-C4alkyl)-aryl, - heteroaryl or -heteroaryl-(C1-C4alkyl)}; RCis -(C1-C4alkyl), -aryl, -(C1-C4alkyl)-aryl, -heteroaryl or -(C1-C4alkyl)- heteroaryl, {wherein, at least one H of -(C1-C4alkyl) may be substituted with -X or -OH, at least one H of -aryl, -(C1-C4alkyl)-aryl, -heteroaryl or -(C1-C4alkyl)-heteroaryl may be substituted with -X, -OH, -CF3or -CF2H}; RDand REare each independently -H, -(C1-C4alkyl), -aryl or -(C1-C4alkyl)-aryl, {wherein, at least one H of -(C1-C4alkyl) may be substituted with -X or -OH, at least one H of -aryl or -(C1-C4alkyl)-aryl may be substituted with -X, -OH, -CF3or -CF2H}; RFis -H, -(C1-C6alkyl), -(C1-C4alkyl)-OH, -(C1-C4alkyl)-O-(C1-C4alkyl), -C(=O)- (C1-C4alkyl), -C(=O)-0(C1-C4alkyl), -(C1-C4alkyl)-C(=O)-O(C1-C4alkyl), -(C1-C4alkyl)- NRDRE, -S(=O)2-(C1-C4alkyl), -aryl, -(C1-C4alkyl)-aryl, -(C2-C4alkenyl)-aryl, -heteroaryl, - (C1-C4alkyl)-heteroaryl, -C(=O)-(C3-C7cycloalkyl), -(C2-C6heterocycloalkyl) or -(C1-C4alkyl)-C(=O)-(C2-C6heterocycloalkyl) {wherein at least one H of -(C1-C4alkyl), -(C1-C4alkyl)-OH, -(C1-C4alkyl)-O-(C1- C4 alkyl), -C(=O)-(C1-C4alkyl), -C(=O)-O(C1-C4alkyl), -(C1-C4alkyl)-C(=O)-O(C1-C4alkyl), -(C1-C4alkyl)-NRDREor -S(=O)2-(C1-C4alkyl) may be substituted with -X, at least one H of -aryl, -(C1-C4alkyl)-aryl, -(C2-C4alkenyl)-aryl, -heteroaryl, -(C1-C4alkyl)-heteroaryl, -C(=O)-(C3-C7cycloalkyl), -C2-C6heterocycloalkyl or -(C1-C4alkyl)-C(=O)- (C2-C6heterocycloalkyl) may be substituted with -X, -OH, -CF3or -CF2H}; RGis -H or -(C1-C4alkyl); Q is -O- or a bond; is a single bond or double bond, {provided that, is a double bond, Y1is =CH-}; a to e are each independently an integer of 0, 1, 2, 3 or 4 {provided that, a and bmay not be simultaneously 0, and c and d may not be simultaneously 0}; X is each independently F, Cl, Br or I.

2. The pharmaceutical composition of claim 1, wherein in the compound represented by formula I, L1, L2or L3are each independently a bond or -(C1-C2alkylene)-; R1is -CX2H or -CX3; R2is -NRARB, -ORC,{wherein at least one of H ofmay be substituted with -X, -OH, -NRDRE, -(C1-C4alkyl)}; R3is -(C1-C4alkyl), -(C3-C7cycloalkyl), -aryl, -heteroaryl, -adamantyl,{wherein at least one H of -aryl or -heteroaryl may be each independently substituted with -X, -O(C1-C4alkyl), -OCF3, -O-aryl, -NRDRE, -(C1-C4alkyl), -CF3, -S(=O)2-(C1-C4alkyl), -aryl, -heteroaryl,[wherein, at least one H of may be substituted with -NRDREor -(C1-C4alkyl)],at least one H ofmaybe each independently substituted with -(C1-C4alkyl)}; Y1, Y2and Y4are each independently -CH2-, -NRF-, -O-, -C(=O)- or -S(=O)2-; Y3is -CH- or -N-; Z1to Z4is each independently N or CRZ{wherein at least three of Z1to Z4may not be simultaneously N, and RZis -H, -X or -O(C1-C4alkyl)}; Z5and Z6are each independently -CH2- or -O-; Z7and Z8are each independently =CH- or =N-; Z9is -NRG- or -S-; RAand RBare each independently -H, -(C1-C4alkyl), -(C1-C4alkyl)-OH, -(C1-C4alkyl)-NRDRE, -aryl, -(C1-C4alkyl)-aryl, -(C3-C7cycloalkyl) or{wherein, at least one H of may be substituted with -X, -(C1-C4alkyl), -CF3, -(C2-C6heterocycloalkyl), -(C1-C4alkyl)-aryl, -heteroaryl or heteroaryl- (C1-C4alkyl)}; RCis -(C1-C4alkyl) or -aryl; RDand REare each independently -H, -(C1-C4alkyl) or -(C1-C4alkyl)-aryl; RFis -H, -(C1-C6alkyl), -(C1-C4alkyl)-OH, -(C1-C4alkyl)-O-(C1-C4alkyl), -C(=O)- (C1-C4alkyl), -C(=O)-O(C1-C4alkyl), -(C1-C4alkyl)-C(=O)-O(C1-C4alkyl), -(C1-C4alkyl)- NRDRE, -S(=O)2-(C1-C4alkyl), -aryl, -(C1-C4alkyl)-aryl, -(C2-C4alkenyl)-aryl, -heteroaryl, - (C1-C4alkyl)-heteroaryl, -C(=O)-(C3-C7cycloalkyl), -(C2-C6heterocycloalkyl) or -(C1-C4alkyl)-C(=O)-(C2-C6heterocycloalkyl) {wherein at least one H of -(C1-C4alkyl) or -C(=O)-O(C1-C4alkyl) may be substituted with -X, at least one H of -aryl may be substituted with -X}; RGis -(C1-C4alkyl);Q is -O- or a bond; is a single bond or a double bond {provided that is a double bond, Y1is - CH-}; a to e are each independently an integer of 0, 1, 2, 3 or 4 {provided that a and b may not be simultaneously 0, and c and d may not be simultaneously 0}; X is each independently F, Cl, Br or I.

3. The pharmaceutical composition of claim 1, wherein the compound represented by formula I is the compound represented by formula Ia: [Formula Ia]in formula Ia, wherein,R2isR3is -aryl {wherein, at least one H of -aryl may be each independently substituted with -X}; Y1is -O- or -S(=O)2-; Z1is N or CRZ{wherein, RZis -X}; a and b are each independently an integer of 0, 1, 2, 3 or 4 {wherein, a and b may not be simultaneously 0}; X is each independently F, Cl, Br or I.

4. The pharmaceutical composition of claim 3, wherein in the compound represented by formula Ia,R2isR3is -phenyl {wherein, at least one H of -phenyl each independently is substituted with -F or -Cl}; Y1is -O- or -S(=O)2-; Z1is N or CF.

5. A pharmaceutical composition for preventing or treating Charcot-Marie- Tooth (CMT) disease associated with peripheral nervous systems (PNS), comprising a compound, optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient, wherein the compound has the following structure:91949698991186. A pharmaceutical composition for preventing or treating Charcot-Marie- Tooth (CMT) disease associated with peripheral nervous systems (PNS), comprising acompound, optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient, wherein the compound has the following structure:

7. The pharmaceutical composition of claim 1, wherein the Charcot-Marie- Tooth disease associated with the peripheral nervous system is at least one selected from the group consisting of CMT1 type, CMT2 type, CMT4 type, CMTX, degerine-sottas syndrome (DSN), congenital hypomyelination (CH), hereditary neuropathy with liability to pressure palsy (HNPP) and giant axonal neuropathy (GAN).

8. The pharmaceutical composition of claim 1, wherein the Charcot-Marie- Tooth disease associated with the peripheral nervous system PNS is at least one selected from the group consisting of CMT1A, CMT2D and CMT2F.

9. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is orally administered.

10. A method for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system, including administering a compound represented by formula I, optical isomers thereof or pharmaceutically acceptable salts thereof into anindividual, wherein the formula I is the same as in claim 1.

11. A method for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system, including administering a compound, optical isomers thereof or pharmaceutically acceptable salts thereof into an individual, wherein the compound has the following structure:

12. A use of a compound represented by the above formula I, optical isomers thereof or pharmaceutically acceptable salts thereof for preventing or treating Charcot-Marie- Tooth disease associated with the peripheral nervous system, wherein the formula I is the same as in claim 1.

13. A use of a compound, optical isomers thereof or pharmaceutically acceptable salts thereof for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system, wherein the compound has the following structure:

14. A use of the compound represented by above formula I, optical isomers thereof or pharmaceutically acceptable salts thereof in preparing a medicament for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system, wherein the formula I is the same as in claim 1.

15. A use of a compound, optical isomers thereof or pharmaceutically acceptable salts thereof in preparing a medicament for preventing or treating Charcot-Marie-Tooth disease associated with the peripheral nervous system, wherein the compound has the following structure:

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