Drug for treating or preventing charcot-marie-tooth disease

Abstract

The present invention provides a drug for treating or preventing Charcot-Marie-Tooth disease, said drug comprising a compound represented by formula (I) (in formula (I), the symbols are as defined in the attached description) or formula (II) (in formula (II), the symbols are as defined in the attached description), or a salt of the compound.

Description

Drugs for treating or preventing Charcot-Marie-Tooth disease

[0001] The present invention relates to a therapeutic or preventive agent for Charcot-Marie-Tooth disease. More specifically, the present invention relates to a therapeutic or preventive agent for Charcot-Marie-Tooth disease, comprising clofazimine or an analog thereof, or methylergometrine or an analog thereof.

[0002] Charcot-Marie-Tooth disease (CMT), first described in 1886 by Charcot, Marie, and Tooth, is the most common peripheral neuropathy, primarily caused by genetic abnormalities. CMT affects approximately 1 in 2,500 to 10,000 people worldwide. CMT causes gradually progressive muscle atrophy, weakness, sensory impairment, and foot deformities. Currently, there is no cure for CMT.

[0003] CMT is broadly classified into axonopathic (approximately 12%) and demyelinating (approximately 75%) types based on the lesion site. The most common causative gene for the axonopathic type is the mitochondrial protein mitofusin 2 (MFN2) (see, for example, Non-Patent Document 1). Mitofusin isoforms include not only MFN2 but also mitofusin 1 (MFN1). It has been reported that overexpression of MFN1 in transgenic mice expressing the human MFN2 mutant (R94Q mutant) specifically in neurons improves the symptoms of CMT (see, for example, Non-Patent Document 2).

[0004] It is also believed that pathological conditions can be reproduced in vitro by establishing induced pluripotent stem cells (iPS cells) from patient-derived cells using reprogramming technology and inducing differentiation of these iPS cells into disease-causing cells. The present inventors previously generated iPS cells from CMT patients with mutations in the gene encoding MFN2, differentiated them into neurons, including motor neurons, and created a model for evaluating the neurotoxicity of test substances (Patent Document 1, Non-Patent Document 3). Using this model, we compared the phenotypes of CMT patient iPS cell-derived neurons (CMT-N) with those of healthy individuals (controls) and found that mitochondria in neurites were morphologically shorter and less mobile than those in controls.

[0005] In this way, a neurotoxicity evaluation system using iPS cell-derived neurons has been developed, and promising candidate substances (therapeutic drug seeds) are being identified, but it is expected that there is still a considerable distance to go before they can be put into practical use as pharmaceuticals.

[0006] Meanwhile, a new research concept called drug repositioning (DR) is being discussed as a way to break through the recent impasse in new drug development research. The idea is to discover new pharmacological effects from existing drugs whose safety and pharmacokinetics have already been confirmed in humans, and then to put them to practical use. Since a large amount of existing data can be used, development costs can be kept low, and there is also the added advantage of the existence of accumulated know-how and materials (such as related compounds).

[0007] International Publication No. 2018 / 207789

[0008] Abe A. et al., J Hum Genet., 56(5):364-368 (2011)Zhou Y. et al, J Clin Invest., 129(4):1756-1771 (2019)Ohara R. et al., Clin Pharmacol Ther., 101(6):754-762 (2017)

[0009] Therefore, an object of the present invention is to provide, through drug repositioning, drugs having therapeutic or preventive activity for CMT and to accelerate the development of practical pharmaceutical agents for the treatment or prevention of CMT.

[0010] The present inventors induced the differentiation of motor neurons from iPS cells established from patients with mutations in the gene encoding MFN2 using the method described in Non-Patent Document 3, and then screened a known compound library, including drugs already on the market, for compounds that increase the expression level of the MFN1 gene or the MFN2 gene, using the survival of the motor neurons as an indicator. Through this screening, they succeeded in identifying compounds that increase the expression level of the MFN1 gene or the MFN2 gene. Based on these findings, the present inventors conducted further research, which led to the completion of the present invention.

[0011] That is, the present invention is as follows: [1] A compound represented by the following formula (I):

[0012]

[0013] [In formula (I), R １ represents a group selected from the group consisting of aliphatic groups having 1 to 6 carbon atoms and alicyclic hydrocarbon groups having 3 to 7 carbon atoms, in which each hydrogen atom may be substituted and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ２ and R ３ are independently selected from the group consisting of alicyclic hydrocarbon groups having 3 to 7 carbon atoms and 6 to 10-membered monocyclic or bicyclic aromatic groups, each hydrogen atom of which may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, n and m are independently integers of 0 to 2, and each R ４ and each R ５ R independently represent a halogen atom, CN, or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted, ６ represents a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted], or a group represented by the following formula (II):

[0014]

[0015] [In formula (II), R １ represents a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted, R ２ may or may not be present, and when present, represents a hydrogen atom; R ３ and R ４ are independently selected from the group consisting of aliphatic groups having 1 to 6 carbon atoms and alicyclic hydrocarbon groups having 3 to 7 carbon atoms, each hydrogen atom of which may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, n is an integer of 0 to 2, X is a nitrogen atom or CZ (Z is a hydrogen atom, a halogen atom, CN, or an aliphatic group having 1 to 3 carbon atoms, each hydrogen atom of which may be substituted), and a dotted line indicates the presence of a double bond at any position), or a salt thereof. [2-1] A therapeutic or preventive agent for Charcot-Marie-Tooth disease, comprising a compound represented by the formula (I), ２ and R ３ is independently a 6- to 10-membered monocyclic aromatic group in which each hydrogen atom may be substituted and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. ２ and R ３ and each of R is a 6- to 10-membered monocyclic aromatic group optionally substituted with a hydrogen atom. ２ and R ３ and each of R and R in formula (I) are a 6-membered monocyclic aromatic group optionally substituted with a hydrogen atom. ２ and R ３[2-5] The therapeutic or prophylactic agent according to [2-4], wherein at least one of the aromatic groups in formula (I) is an aromatic group in which at least one of the hydrogen atoms is substituted with a halogen atom. [3-1] The therapeutic or prophylactic agent according to [2-4], wherein the halogen atom is a chlorine atom. [3-2] The therapeutic or prophylactic agent according to [2-2], wherein at least one of the aromatic groups in formula (I) is an aromatic group in which at least one of the hydrogen atoms is substituted with a halogen atom. １ is an aliphatic group having 1 to 6 carbon atoms or an alicyclic hydrocarbon group having 3 to 7 carbon atoms, each hydrogen atom of which may be substituted and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [3-2] The therapeutic or prophylactic agent according to any one of [1] to [2-5], １ is an aliphatic group having 1 to 6 carbon atoms, each hydrogen atom of which may be substituted. [3-3] R of formula (I) １ is an aliphatic group in which each hydrogen atom is substituted with an aliphatic group having 1 to 3 carbon atoms. [3-4] The therapeutic or prophylactic drug according to [3-3], wherein the aliphatic group having 1 to 3 carbon atoms is an alkyl group having 1 to 3 carbon atoms. [4-1] The therapeutic or prophylactic drug according to any one of [1] to [2-3] and [3-1], wherein formula (I) is represented by the following formulas (I-1) to (I-10):

[0016]

[0017] [4-2] The therapeutic or prophylactic agent according to any one of [1] to [3-2], wherein formula (I) is represented by the following formula (I-1):

[0018]

[0019] [5-1] The therapeutic or prophylactic agent according to [1], wherein X in formula (II) is CZ (Z represents a hydrogen atom, a halogen atom, or CN). [5-2] The therapeutic or prophylactic agent according to [5-1], wherein Z is a hydrogen atom. [6-1] The therapeutic or prophylactic agent according to [6-2], wherein R in formula (II) is CZ (Z represents a hydrogen atom, a halogen atom, or CN). ３ and R ４are independently a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted. [6-2] The therapeutic or prophylactic agent according to [1], [5-1] or [5-2], ３ [6-3] The therapeutic or prophylactic agent according to [6-1] or [6-2], wherein at least one of the aliphatic groups is an alkyl group. [6-4] The therapeutic or prophylactic agent according to any one of [1] and [5-1] to [6-1], wherein R in formula (II) is an aliphatic group having 1 to 3 carbon atoms. [6-4] The therapeutic or prophylactic agent according to [6-1] or [6-2], wherein R in formula (II) is an aliphatic group having 1 to 3 carbon atoms. ４ is a hydrogen atom. [7] The therapeutic or prophylactic agent according to any one of [1] and [5-1] to [6-4], wherein formula (II) is represented by the following formula (II-1):

[0020]

[0021] [8] The therapeutic or prophylactic agent according to any one of [1] to [7], wherein the Charcot-Marie-Tooth disease is Charcot-Marie-Tooth disease type 2. [9] A compound represented by the following formula (I):

[0022]

[0023] [In formula (I), R １ represents a group selected from the group consisting of aliphatic groups having 1 to 6 carbon atoms and alicyclic hydrocarbon groups having 3 to 7 carbon atoms, in which each hydrogen atom may be substituted and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ２ and R ３ are independently selected from the group consisting of alicyclic hydrocarbon groups having 3 to 7 carbon atoms and 6 to 10-membered monocyclic or bicyclic aromatic groups, each hydrogen atom of which may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, n and m are independently integers of 0 to 2, and each R ４ and each R ５ R independently represent a halogen atom, CN, or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted, ６represents a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted], or a group represented by the following formula (II):

[0024]

[0025] [In formula (II), R １ represents a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted, R ２ may or may not be present, and when present, represents a hydrogen atom; R ３ and R ４ are independently selected from the group consisting of aliphatic groups having 1 to 6 carbon atoms and alicyclic hydrocarbon groups having 3 to 7 carbon atoms, each hydrogen atom of which may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, n is an integer of 0 to 2, X is a nitrogen atom or CZ (Z is a hydrogen atom, a halogen atom, CN, or an aliphatic group having 1 to 3 carbon atoms, each hydrogen atom of which may be substituted), and a dotted line indicates the presence of a double bond at any position), or a salt thereof.

[10] An agent for promoting the expression of the mitofusin 1 gene, comprising a compound represented by the following formula (I):

[0026]

[0027] [In formula (I), R １ represents a group selected from the group consisting of aliphatic groups having 1 to 6 carbon atoms and alicyclic hydrocarbon groups having 3 to 7 carbon atoms, in which each hydrogen atom may be substituted and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ２ and R ３ are independently selected from the group consisting of alicyclic hydrocarbon groups having 3 to 7 carbon atoms and 6 to 10-membered monocyclic or bicyclic aromatic groups, each hydrogen atom of which may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, n and m are independently integers of 0 to 2, and each R ４ and each R ５R independently represent a halogen atom, CN, or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted, ６ represents a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted], or a group represented by the following formula (II):

[0028]

[0029] [In formula (II), R １ represents a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted, R ２ may or may not be present, and when present, represents a hydrogen atom; R ３ and R ４ are independently selected from the group consisting of aliphatic groups having 1 to 6 carbon atoms and alicyclic hydrocarbon groups having 3 to 7 carbon atoms, each hydrogen atom of which may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, n is an integer of 0 to 2, X is a nitrogen atom or CZ (Z is a hydrogen atom, a halogen atom, CN, or an aliphatic group having 1 to 3 carbon atoms, each hydrogen atom of which may be substituted), and a dotted line indicates the presence of a double bond at any position), or a salt thereof, for use in treating or preventing Charcot-Marie-Tooth disease.

[11] A method for treating or preventing Charcot-Marie-Tooth disease in a mammal, comprising administering an effective amount of a compound represented by the following formula (I):

[0030]

[0031] [In formula (I), R １ represents a group selected from the group consisting of aliphatic groups having 1 to 6 carbon atoms and alicyclic hydrocarbon groups having 3 to 7 carbon atoms, in which each hydrogen atom may be substituted and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ２ and R ３are independently selected from the group consisting of alicyclic hydrocarbon groups having 3 to 7 carbon atoms and 6 to 10-membered monocyclic or bicyclic aromatic groups, each hydrogen atom of which may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, n and m are independently integers of 0 to 2, and each R ４ and each R ５ R independently represent a halogen atom, CN, or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted, ６ represents a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted], or a group represented by the following formula (II):

[0032]

[0033] [In formula (II), R １ represents a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted, R ２ may or may not be present, and when present, represents a hydrogen atom; R ３ and R ４ are independently selected from the group consisting of aliphatic groups having 1 to 6 carbon atoms and alicyclic hydrocarbon groups having 3 to 7 carbon atoms, each hydrogen atom of which may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, n is an integer of 0 to 2, X is a nitrogen atom or CZ (Z is a hydrogen atom, a halogen atom, CN, or an aliphatic group having 1 to 3 carbon atoms, each hydrogen atom of which may be substituted), and a dotted line indicates the presence of a double bond at any position), or a salt thereof.

[12] A compound represented by the following formula (I):

[0034]

[0035] [In formula (I), R １ represents a group selected from the group consisting of aliphatic groups having 1 to 6 carbon atoms and alicyclic hydrocarbon groups having 3 to 7 carbon atoms, in which each hydrogen atom may be substituted and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R２ and R ３ are independently selected from the group consisting of alicyclic hydrocarbon groups having 3 to 7 carbon atoms and 6 to 10-membered monocyclic or bicyclic aromatic groups, each hydrogen atom of which may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, n and m are independently integers of 0 to 2, and each R ４ and each R ５ R independently represent a halogen atom, CN, or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted, ６ represents a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted], or a group represented by the following formula (II):

[0036]

[0037] [In formula (II), R １ represents a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted, R ２ may or may not be present, and when present, represents a hydrogen atom; R ３ and R ４ are independently selected from the group consisting of aliphatic groups having 1 to 6 carbon atoms and alicyclic hydrocarbon groups having 3 to 7 carbon atoms, each hydrogen atom of which may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, n is an integer of 0 to 2, X is a nitrogen atom or CZ (Z is a hydrogen atom, a halogen atom, CN, or an aliphatic group having 1 to 3 carbon atoms, each hydrogen atom of which may be substituted), and a dotted line indicates the presence of a double bond at any position), or a salt thereof.

[0038] The present invention makes it possible to treat or prevent CMT. In particular, because the present invention uses an existing drug whose safety has been confirmed as an active ingredient, it is expected that the development period for clinical application can be shortened.

[0039] These figures show the results of measuring the mRNA expression levels of MFN1 and MFN2 in iPS cells from healthy individuals, iPS cells from CMT patients with MFN2 mutations, iPS cell-derived neural stem cells, and iPS cell-derived motor neurons. Total MFN2 mRNA expression was lower in motor neurons derived from CMT patient iPS cells compared to motor neurons derived from iPS cells from healthy individuals. Error bars: standard error; *: p<0.05, N=3 for each. A schematic diagram and results of screening for compounds that increase MFN1 or MFN2 mRNA expression using motor neurons derived from CMT patient iPS cells with MFN2 mutations are shown.

[0040] As shown in the Examples below, the present inventors have discovered that administering clofazimine or methylergometrine maleate to cells increases the expression level of the mitofusin 1 (MFN1) gene in the cells. Since increasing the expression level of the MFN1 gene in vivo can improve the symptoms of Charcot-Marie-Tooth disease (CMT), clofazimine or its analogs and methylergometrine or its analogs can be used to treat or prevent CMT. Therefore, the present invention provides a therapeutic or preventive agent for CMT (hereinafter sometimes referred to as the "medicine of the present invention") comprising clofazimine or its analog or methylergometrine or its analog (hereinafter sometimes referred to as the "compound of the present invention"). Furthermore, unless otherwise specified, the therapeutic or preventive agent (or method) for CMT also encompasses a pharmaceutical agent (or method) capable of treating and preventing the disease.

[0041] As used herein, the term "therapeutic drug" encompasses not only drugs intended to cure CMT but also drugs intended to inhibit the progression of CMT, alleviate symptoms (e.g., improvement to minimal manifestations (MM) that do not interfere with daily life or work), or alleviate sequelae. For example, because CMT is a disease that progresses over a long period of time (usually years), early initiation of treatment can prevent the progression of symptoms. Furthermore, as used herein, the term "prophylactic drug" encompasses not only drugs intended to reduce the risk of developing CMT in subjects who have not yet developed CMT, but also drugs intended to reduce the risk of CMT recurrence in subjects who have developed CMT. For example, the onset of CMT can be prevented by administering the drug of the present invention to patients with a genetic background potentially predisposed to CMT before the onset of CMT symptoms. The same applies to "therapeutic method" and "prophylactic method."

[0042] The pharmaceutical composition of the present invention can be administered orally or parenterally as an appropriate pharmaceutical composition containing the compound of the present invention as an active ingredient, either alone or mixed with a pharmacologically acceptable carrier, excipient, diluent, etc. Furthermore, the pharmaceutical composition of the present invention can be administered to mammals (e.g., humans, rats, mice, guinea pigs, rabbits, sheep, horses, pigs, cattle, dogs, cats, and monkeys). Therefore, a method for treating or preventing CMT in a mammal is also provided, which comprises administering an effective amount of the compound of the present invention to the mammal.

[0043] CMT is a general term for diseases that cause hereditary peripheral neuropathy, both motor and sensory. In the present invention, the CMT to be treated or prevented may be demyelinating type (type 1) (also referred to as "CMT1"), axonal type (type 2) (also referred to as "CMT2"), or other CMTs, but is preferably CMT2. Examples of CMT1 include CMT type 1A (CMT1A) (causative gene: PMP22 gene), CMT type 1B (CMT1B) (causative gene: MPZ gene), CMT type 1C (CMT1C) (causative gene: LITAF gene), CMT type 1D (CMT1D) (causative gene: EGR2 gene), and CMT type 1E (CMT1E) (causative gene: PMP22 gene). CMT2 includes CMT type 2A (CMT2A) (causative genes: MFN2 gene, KIF 1B gene), CMT type 2A2 (CMT2A2) (causative gene: MFN2 gene), CMT type 2B (CMT2B) (causative gene: RAB7 gene), CMT type 2C (CMT2C) (causative gene: TRPV4 gene), CMT type 2D (CMT2D) (causative gene: GARS gene), CMT type 2E (CMT2E) (causative gene: NEFL gene), CMT type 2F (CMT2F) (causative gene: HSPB1 gene), CMT type 2G (CMT2G), CMT type 2H (CMT2H), CMT type 2I (CMT2I) (causative gene: MPZ gene), CMT type 2J (CMT2J) (causative gene: MPZ gene), and CMT type Examples of CMT include CMT type 2K (CMT2K) (causative gene: GDAP1 gene) and CMT type 2L (CMT2L) (causative gene: HSPB8 gene). Other CMTs include CMT type 3 (CMT3), CMT type 4 (CMT4) (causative genes: PRX gene, NF-L gene, dyn2 gene, SOX10 gene, EGR2 gene, etc.), and X-linked (CMTX) (causative gene: GJB1 gene, etc.).

[0044] Among these, CMT2 is preferred as a target for treatment or prevention, with CMT2A and CMT2A2 caused by mutations in the mitofusin 2 (MFN2) gene being more preferred. MFN2 is involved in mitochondrial fusion and axonal transport of mitochondria. While the majority of mutations identified in CMT2A families are located in the GTPase domain, mutations outside this domain may also be present. Specific examples of MFN2 gene mutations include a mutation resulting in a substitution of the histidine at position 128 in the amino acid sequence of MFN2, preferably with another amino acid, preferably tyrosine (H128Y), or a mutation resulting in a substitution of the arginine at position 94, preferably with another amino acid, preferably glutamine (R94Q), a mutation resulting in a substitution with glycine (R94G), or a mutation resulting in a substitution with tryptophan (R94W). Other MFN2 mutations include V69F, L76P, T105M, H165D, I213T, F223L, T236M, V244M, P251A, V273G, R274Q, R280H, F284Y, K357N, R364P, R364W, R418X, E424G, and W740S (ZUchne S, et al. Nature Genet 36: 449-451 (2004); Kijima K, et al. Hum Genet 116: 23-27, (2005); Zhu D, Kennerson ML, et al. Neurology 65: 496-497 (2005); Lawson VH, et al. Neurology 65: 197-204 (2005), Stuppia G, et al. J Neurol Sci 356(1-2):7-18 (2015)).

[0045] The compounds of the present invention can also be used as agents for promoting the expression of the MFN1 gene. Accordingly, in another embodiment of the present invention, there is provided an agent for promoting the expression of the MFN1 gene (hereinafter, sometimes referred to as the "expression promoter of the present invention"), comprising a compound of the present invention. As used herein, the expression promoter of the present invention includes any agent that promotes the expression of the MFN1 gene at the cellular or organismal level. Furthermore, as used herein, the term "gene expression," unless otherwise specified, is used to mean at least "the production of a functional protein encoded by MFN1 mRNA," but also encompasses "the production of MFN1 mRNA." Therefore, promotion of MFN1 gene expression may refer not only to an increase in the amount of the functional protein encoded by the gene in cells, but also to an increase in the amount of mRNA transcribed from the gene in cells, as a result of administration of a compound of the present invention.

[0046] The expression promoters of the present invention are prepared as general pharmaceutical compositions or pharmaceutical preparations, or as cosmetics or foods, and are administered orally or parenterally. The expression promoters of the present invention can also be used as reagents. The expression promoters of the present invention can be administered to subjects, including humans (e.g., mammals, mammalian cells, tissues, organs, etc.). Therefore, a method for promoting the expression of the MFN1 gene in a subject is also provided, which comprises administering a compound of the present invention to the subject.

[0047] Examples of clofazimine or its analogues used in the present invention include the compound represented by the following formula (I) or a salt thereof:

[0048]

[0049] [In formula (I), R １ represents a group selected from the group consisting of aliphatic groups having 1 to 6 carbon atoms and alicyclic hydrocarbon groups having 3 to 7 carbon atoms, in which each hydrogen atom may be substituted and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R ２ and R ３are independently selected from the group consisting of alicyclic hydrocarbon groups having 3 to 7 carbon atoms and 6 to 10-membered monocyclic or bicyclic aromatic groups, each hydrogen atom of which may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, n and m are independently integers of 0 to 2 (preferably both 0), and each R ４ and each R ５ R independently represent a halogen atom, CN, or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted, ６ represents a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted.

[0050] In one embodiment, R in formula (I) above ２ and R ３ are independently a 6- to 10-membered monocyclic aromatic group in which each hydrogen atom may be substituted and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a salt thereof. ２ and R ３ are preferably 6- to 10-membered (preferably 6-membered) monocyclic aromatic groups in which each hydrogen atom may be substituted. ２ and R ３ Also preferred are compounds or salts thereof in which at least one, preferably both, of the aromatic groups in the above are aromatic groups in which at least one (preferably one) of the hydrogen atoms is substituted with a halogen atom (preferably a chlorine atom).

[0051] In another embodiment, R １ However, each hydrogen atom may be substituted, and the compound may have 1 to 4 (preferably 1) heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the compound or its salt is an aliphatic group having 1 to 6 carbon atoms. Such heteroatoms are preferably nitrogen atoms. Furthermore, the substitution of hydrogen atoms with 1 to 3 aliphatic groups (preferably alkyl groups) is preferred. Furthermore, the R １ is 1 to 3 (preferably 2 to 3) aliphatic groups (preferably an alkyl group) or a salt thereof is also preferred.

[0052] Specific examples of clofazimine or its analogs include compounds represented by the following formulas (I-1) to (I-10) or salts thereof. Among them, the compound represented by the following formula (I-1) (i.e., clofazimine; N,5-bis(4-chlorophenyl)-3-propan-2-yliminophenazin-2-amine) or a salt thereof is preferred.

[0053]

[0054] Examples of methylergometrine or its analogues used in the present invention include the compound represented by the following formula (II) or a salt thereof:

[0055]

[0056] [In formula (II), R １ represents a hydrogen atom or an aliphatic group (preferably an alkyl group) having 1 to 3 carbon atoms (preferably 1 carbon atom) in which each hydrogen atom may be substituted, R ２ may or may not be present, and when present, represents a hydrogen atom; R ３ and R ４ are independently selected from the group consisting of aliphatic groups having 1 to 6 carbon atoms and alicyclic hydrocarbon groups having 3 to 7 carbon atoms, each hydrogen atom of which may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, n is an integer of 0 to 2 (preferably 0), X is a nitrogen atom or CZ (Z is a hydrogen atom, a halogen atom, CN, or an aliphatic group having 1 to 3 carbon atoms in which each hydrogen atom may be substituted), and a dotted line indicates the presence of a double bond at any position.

[0057] The above formula (II) can also be shown as the following formula (II-a) or formula (II-b).

[0058]

[0059] [In formula (II-a) and formula (II-b), R １ , R ３ , R ４The definitions of , n, and X are the same as those in formula (II).

[0060] In one embodiment, the compound or salt thereof represented by the formula (II) above is CZ (Z represents a hydrogen atom, a halogen atom, or CN). Among these, the compound or salt thereof represented by the formula (II) above is preferred.

[0061] In another embodiment, R ３ and R ４ are independently a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms which may be substituted at each hydrogen atom, or a salt thereof. ３ is an aliphatic group (preferably an alkyl group) having 1 to 3 carbon atoms (preferably 2), or a salt thereof. ４ is also preferred. ３ is an aliphatic group (preferably an alkyl group) having 1 to 3 carbon atoms (preferably 2), and R ４ is a hydrogen atom, or a salt thereof.

[0062] Specific examples of methylergometrine or its analogs include the compound represented by the following formula (II-1) (i.e., methylergometrine; (6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide). Specific examples of salts of the compound include the salt represented by the following formula (II-2) (i.e., methylergometrine maleate; (6aR,9R)-N-((S)-1-hydroxybutan-2-yl)-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide maleate).

[0063]

[0064]

[0065] As used herein, the term "aliphatic group" refers to a straight or branched hydrocarbon chain that is completely saturated or contains one or more unsaturated bonds. Examples of aliphatic groups include straight or branched alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, 2-butyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 3-pentyl, 3-methylbutyl, hexyl, and 3-hexyl groups), alkenyl groups (e.g., vinyl, allyl, 2-propynyl, 2-butenyl, and 3-methyl-2-butenyl groups), and the like. Examples of such groups include alkynyl groups (e.g., ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl, and the like). Furthermore, the term "alicyclic hydrocarbon group" refers to a monocyclic or bicyclic hydrocarbon group that is completely saturated or contains one or more unsaturated bonds and does not belong to the category of aromatic hydrocarbon groups, or an aliphatic group having such a hydrocarbon group. Examples of alicyclic hydrocarbon groups include cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl groups), cycloalkenyl groups (e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl groups), (cycloalkyl)alkyl groups, (cycloalkenyl)alkyl groups, and (cycloalkyl)alkenyl groups.

[0066] Examples of the monocyclic or bicyclic aromatic group include an aryl group and a heteroaryl group. Examples of the aryl group include aryl groups having 10 or less carbon atoms, such as a phenyl group and a naphthyl group. Examples of heteroaryl groups include 5- to 6-membered monocyclic groups containing 1 or 2 nitrogen atoms, 5- to 6-membered monocyclic groups containing 1 or 2 nitrogen atoms and 1 oxygen atom or 1 sulfur atom, 5-membered monocyclic groups containing 1 oxygen atom or 1 sulfur atom, and bicyclic groups containing 1 to 4 nitrogen atoms in which a 6-membered ring is fused with a 5- or 6-membered ring. Specific examples include a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 2-thienyl group, a 3-thienyl group, a 3-oxadiazolyl group, a 1-imidazolyl group, a 2-imidazolyl group, a 2-thiazolyl group, a 3-isothiazolyl group, a 2-oxazolyl group, a 3-isoxazolyl group, a 2-furyl group, a 3-furyl group, a 3-pyrrolyl group, an 8-quinolyl group, a 2-quinazolinyl group, and an 8-purinyl group.

[0067] Examples of halogen atoms include fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms.

[0068] As used herein, the phrase "each hydrogen atom may be substituted (or has been substituted)" means that at least one hydrogen atom of the group may be substituted (or has been substituted) with another atom or group. In other words, a group in which each hydrogen atom may be substituted (or has been substituted) can be rephrased as a group that may have a substituent (or has a substituent). In this specification, examples of the substituent include a halogen atom, a cyano group, a benzyloxy group, a trifluoromethyl group, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a lower alkylaminocarbonyl group, a di-lower alkylaminocarbonyl group, a lower alkoxycarbonylamino group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkanoylamino group, a lower alkylsulfonamido group, a phthalimido group, a heteroaryl group, an aryl having a substituent (substituted aryl), a heteroaryl having a substituent (substituted heteroaryl), a saturated heterocyclic group, or a group of the formula: -NR ７ R ８ (R ７ and R ８ each independently represents a hydrogen atom, a lower alkoxy group, a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group, or an aralkyl group, or R ７ and R ８are bonded to each other and, together with the nitrogen atom to which they are bonded, represent a saturated cyclic amino group having 4 to 8 carbon atoms constituting the ring. Examples of heteroaryl groups include the same heteroaryl groups as described above. Examples of saturated heterocyclic groups include 5- to 8-membered ring groups having one nitrogen atom, such as 1-piperidinyl and 1-pyrrolidinyl, 6- to 8-membered ring groups having two nitrogen atoms, and 6- to 8-membered ring groups having one nitrogen atom and one oxygen atom. Examples of substituted alkyl groups include alkyl groups having 1 to 6 carbon atoms substituted with a cycloalkyl group or a substituted cycloalkyl, and aralkyl groups or substituted aralkyl groups. Examples of aralkyl groups and substituted aralkyl groups include alkyl groups having 1 to 6 carbon atoms substituted with the above-mentioned aryl group or substituted aryl group, such as benzyl, 1-phenylethyl, 2-phenylethyl, and 2-naphthylmethyl. Unless otherwise specified, in this specification, unless there is a statement that "each hydrogen atom may be substituted," this means an unsubstituted group. In addition, in this specification, the term "lower" means having 5 or less carbon atoms (preferably 3 or less).

[0069] Clofazimine or its analogs, or methylergometrine or its analogs, are commercially available or can be prepared by known methods for each compound. Clofazimine or its analogs can be prepared, for example, by methods described in U.S. Patent Nos. 2,891,062, 2,943,089, 2,946,792, 2,948,726, and 8,669,257, or by methods described in the literature cited therein. Clofazimine is also sold by Sandoz Co., Ltd. as a drug for treating leprosy. Methylergometrine or its analogs can be prepared, for example, by methods described in U.S. Patent Nos. 3,920,664, 4,201,862, and 5,480,885, or by methods described in the literature cited therein. Methylergometrine is also sold as a uterotonic or hemostatic agent by Mochida Pharmaceutical Co., Ltd., Fuji Pharma Co., Ltd., Aska Pharmaceutical Co., Ltd., and others.

[0070] Clofazimine or an analog thereof, or methylergometrine or an analog thereof, encompasses not only the free form but also pharmacologically acceptable salts thereof. While the pharmacologically acceptable salts vary depending on the type of compound, examples include inorganic base salts such as alkali metal salts (e.g., sodium salt, potassium salt), alkaline earth metal salts (e.g., calcium salt, magnesium salt), aluminum salt, and ammonium salt; base addition salts such as organic base salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, and N,N'-dibenzylethylenediamine; inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate; and organic acid salts such as citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, and paratoluenesulfonate.

[0071] When clofazimine or an analog thereof, or methylergometrine or an analog thereof, has isomers such as optical isomers, stereoisomers, positional isomers, or rotational isomers, either one of the isomers or a mixture thereof is encompassed by the compound of the present invention. For example, when clofazimine or an analog thereof, or methylergometrine or an analog thereof, has optical isomers, the optical isomers resolved from the racemate are also encompassed by the compound of the present invention. These isomers can be obtained individually by known synthesis methods, separation methods (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.), optical resolution methods (e.g., fractional recrystallization, chiral column method, diastereomer method, etc.), etc.

[0072] Clofazimine or an analog thereof, or methylergometrine or an analog thereof may be in the form of a crystal, and the compound of the present invention includes both a single crystal form and a mixture of crystal forms. The crystal can be produced by crystallization using a crystallization method known per se.

[0073] Clofazimine or an analog thereof, or methylergometrine or an analog thereof may be a solvate (e.g., a hydrate, etc.) or a non-solvate (e.g., a non-hydrate, etc.), and both are encompassed in the compounds of the present invention.

[0074] Also, isotopes (e.g., 3 H, 14 C, 35 S, 125 Compounds labeled with , for example, I, are also encompassed by the compounds of the present invention.

[0075] Compositions for oral administration include solid or liquid dosage forms, specifically tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules), syrups, emulsions, suspensions, etc. On the other hand, compositions for parenteral administration include, for example, injections, suppositories, etc., and injections may include dosage forms such as intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, and drip injections. These preparations contain excipients (e.g., sugar derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, and dextrin; cellulose derivatives such as crystalline cellulose; organic excipients such as gum arabic; dextran; and pullulan; and inorganic excipients such as silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and magnesium aluminometasilicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate), lubricants (e.g., metal stearates such as stearic acid, calcium stearate, and magnesium stearate; talc; colloidal silica; waxes such as beeswax and Gay's wax; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; and sodium lauryl sulfate). , lauryl sulfates such as magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and the above-mentioned starch derivatives), binders (e.g., hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and compounds similar to the above-mentioned excipients), disintegrants (e.g., cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, and internally crosslinked sodium carboxymethyl cellulose; chemically modified starch / celluloses such as carboxymethyl starch, carboxymethyl starch sodium, and crosslinked polyvinylpyrrolidone), emulsifiers (e.g., colloidal clays such as bentonite and Veegum; metal hydroxides such as magnesium hydroxide and aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate and calcium stearate;The compositions are produced by well-known methods using additives such as cationic surfactants such as benzalkonium chloride; and nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, and sucrose fatty acid esters), stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid), flavoring agents (for example, commonly used sweeteners, acidulants, fragrances, etc.), diluents, etc.;

[0076] The dosage of the compound of the present invention, which is the active ingredient of the medicament or expression promoter of the present invention, can vary depending on various conditions such as the type of compound, the symptoms, age, body weight, and drug tolerance of the subject. However, for oral administration, the lower limit is 0.1 mg (preferably 0.5 mg) and the upper limit is 1000 mg (preferably 500 mg), and for parenteral administration, the lower limit is 0.01 mg (preferably 0.05 mg) and the upper limit is 100 mg (preferably 50 mg), and can be administered 1 to 6 times per day to an adult. The dosage may be increased or decreased depending on the symptoms. In particular, when the compound of the present invention is already marketed as a pharmaceutical for diseases other than those mentioned above, the dosage can be selected appropriately for each compound within the range of confirmed safety.

[0077] The medicaments or expression promoters of the present invention can also be used in combination with physical therapy and / or surgical therapy for CMT, or in combination with therapeutic or preventive agents for CMT (e.g., neurotrophic factors, progesterone inhibitors and stimulants, ascorbic acid, curcumin, etc.). When used as a concomitant drug, such a concomitant drug can be formulated together with the compound of the present invention and administered as a single formulation, or can be formulated separately from the compound of the present invention and administered simultaneously or at different times via the same or a different route as the medicament or expression promoter of the present invention. The dosage of these concomitant drugs may be the amount normally used when the drug is administered alone, or it can be reduced from the amount normally used.

[0078] When the expression promoter of the present invention is administered to cells, the administration can typically be carried out by culturing the cells in a culture medium containing the expression promoter of the present invention. Such culturing can be carried out under conditions commonly used in the art, as long as the conditions are such that the expression of the MFN1 gene can be promoted.

[0079] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples.

[0080] <Materials and Methods> Generation of iPS cells and cell culture iPS cells were established using the method described in Non-Patent Document 3. iPS cells were derived from peripheral blood mononuclear cells (PBMCs) from CMT2 patients with MFN2 gene mutations (CMT1(R94Q) and CMT2(H128Y)) and from healthy individuals without MFN2 mutations. iPS cells were maintained and cultured in feeder-free medium.

[0081] Induction of neural stem cells (NSCs). Human iPS cells were dissociated into single cells and cultured on Matrigel-coated 24-well plates with 5% DFK medium (Dulbecco's modified Eagle's medium / Ham's F12; Thermo Fisher Scientific, Pittsburgh, PA), 5% KSR (Thermo Fisher Scientific), NEAA (Thermo Fisher Scientific), L-glutamine (Sigma-Aldrich), 0.1 M 2-ME (Thermo Fisher Scientific), 2 μM dorsomorphin, and 10 μM SB431542 for 10 days.

[0082] Induction of motor neurons (MNs) by rapid embryoid body aggregation (SFEBq). Human iPS cells were dissociated into single cells and rapidly reaggregated in U-bottom 96-well plates (Greiner Bio-One, Frickenhausen, Germany) for resuspension culture that had been precoated with Pluronic acid (Sigma-Aldrich, St. Louis, MO) adjusted to a concentration of 2% in 100% ethanol. Embryoid body aggregates were cultured for 12 days in 5% DFK medium (Dulbecco's modified Eagle's medium / Ham's F12; Thermo Fisher Scientific, Pittsburgh, PA), 5% KSR (Thermo Fisher Scientific), NEAA (Thermo Fisher Scientific), L-glutamine (Sigma-Aldrich), 0.1 M 2-ME (Thermo Fisher Scientific), and 2 μM dorsomorphin for the neuronal induction stage (P1). After patterning in Neurobasal medium (Thermo Fisher Scientific) supplemented with 2% B27 (Thermo Fisher Scientific) without vitamin A, 100 nM retinoic acid, 500 nM Smoothened agonist (a Sonic Hedgehog signaling activator), and FGF 2 (12.5 ng / ml) (Thermo Fisher Scientific), the aggregates were allowed to attach to Matrigel (Corning, Tewksbury, MA)-coated culture vessels on day 22.

[0083] Adherent embryoid bodies were cultured to the P2 stage in Neurobasal medium supplemented with brain-derived neurotrophic factor (BDNF) (10 ng / ml), glial cell line-derived neurotrophic factor (GDNF) (10 ng / ml), and NT-3 (10 ng / ml). They were detached from the culture vessel and dissociated into small clumps or single cells using Accutase (Innovative Cell Technologies, San Diego, CA). For P3 maturation, they were cultured at 500,000 cells per well on day 35 in Matrigel-coated 24-well culture vessels.

[0084] Measurement of MFN2 gene expression levels mRNA was extracted, and the mRNA expression levels of MFN1 and MFN2 were quantified by qPCR.

[0085] High-Throughput Screening. An overview of the screening method is shown in the upper left of Figure 2. Using a PiggyBac vector, constructs expressing Lhx3, Ngn2, and Isl1 were introduced into iPS cells under tetracycline induction, and stable cell lines were generated. The iPS cells were then treated with doxycycline and cultured in neural differentiation medium for 7 days to generate motor neurons (Imamura et al. Sci Transl Med 2017). Motor neurons generated from iPS cells of a CMT patient carrying an MFN2 mutation were cultured in 96-well plates, and approximately 1,400 compounds were added on Day 10. RNA was extracted on Day 12, and qPCR was performed to evaluate the mRNA levels of MFN1 and MFN2.

[0086] Statistical Analysis. All data are presented as mean ± standard error. Group comparisons were performed using one- or two-way ANOVA followed by post-hoc testing with Scheffe's multiple comparison test. p<0.05 was considered statistically significant.

[0087] Example 1: Analysis of MFN2 gene expression levels in cells carrying a mutant MFN2 gene The relative expression levels of the MFN2 gene were measured in iPS cells, neural stem cells, and motor neurons. The results are shown in Figure 1. Figure 1 shows that the expression level of the MFN2 gene is reduced in motor neurons carrying a mutant MFN2 gene. Therefore, we decided to screen for substances that promote the expression of the MFN2 gene or the MFN1 gene (overexpression of which has been reported to improve CMT symptoms in CMT model mice).

[0088] Example 2: Screening of candidate substances Using motor neurons carrying a mutant MFN2 gene, we screened for existing drugs that increase the expression level of the MFN1 or MFN2 gene. The screening results are shown in the upper right of Figure 2. The classification results of the hit compounds are shown in the lower left of Figure 2. From the hit compounds, drugs that act on the cardiovascular system and anticancer drugs were excluded, and the following two existing drugs used to treat the brain and nervous system were selected. The expression levels of the MFN1 gene and MFN2 gene are shown as relative expression levels, with the mRNA expression level following vehicle (DMSO) administration set to 1.

[0089] (1) Clofazimine Relative expression level of MFN1 gene: 1.888976 Relative expression level of MFN2 gene: 1.196658

[0090] (2) Methylergometrine maleate Relative expression level of MFN1 gene: 2.006676 Relative expression level of MFN2 gene: 3.675887

[0091] These results indicate that clofazimine can promote the expression of the MFN1 gene, and methylergometrine maleate can promote the expression of both the MFN1 and MFN2 genes, strongly suggesting that these compounds may be effective in treating or preventing Charcot-Marie-Tooth disease.

[0092] Clofazimine or its analogs and methylergometrine or its analogs are useful for treating or preventing Charcot-Marie-Tooth disease. In particular, drugs that are already on the market as pharmaceuticals for other diseases have accumulated clinical and non-clinical data on safety, etc., and libraries of related compounds already exist, so it may be possible to develop pharmaceuticals that can treat or prevent Charcot-Marie-Tooth disease quickly and at low cost.

[0093] This application is based on patent application No. 2022-045440 filed in Japan (filing date: March 22, 2022), the contents of which are incorporated in their entirety herein.

Claims

1. Formula (I) below: 【Chemistry 1】 [In formula (I), R １ This represents a group selected from the group consisting of aliphatic groups having 1 to 6 carbon atoms and alicyclic hydrocarbon groups having 3 to 7 carbon atoms, in which each hydrogen atom may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. R ２ and R ３ This independently represents a group selected from the group consisting of alicyclic hydrocarbon groups having 3 to 7 carbon atoms and monocyclic or bicyclic aromatic groups having 6 to 10 members, wherein each hydrogen atom may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. n and m are independent integers between 0 and 2. Each R ４ and each R ５ This independently represents a halogen atom, CN, or a carbon-1 to carbon-3 aliphatic group in which each hydrogen atom may be substituted. R ６ This represents a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms, in which case each hydrogen atom may be substituted. Or formula (II) below: 【Chemistry 2】 [In formula (II), R １ This represents a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms, in which case each hydrogen atom may be substituted. R ２ It may or may not exist; if it exists, it indicates a hydrogen atom. R ３ and R ４ are each independently selected from the group consisting of a hydrogen atom, an aliphatic group having 1 to 6 carbon atoms, and an alicyclic hydrocarbon group having 3 to 7 carbon atoms, each hydrogen atom may be substituted, and having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. n is an integer between 0 and 2. X represents a nitrogen atom or CZ (where Z represents a hydrogen atom, a halogen atom, CN, or an aliphatic group having 1 to 3 carbon atoms, in which case each hydrogen atom may be substituted), The dotted line indicates the presence of a double bond at one of the positions. A therapeutic or prophylactic agent for Charcot-Marie-Tooth disease comprising a compound represented by or a salt thereof.

2. R in equation (I) ２ and R ３ The therapeutic or prophylactic agent according to claim 1, wherein the 6-10 member monocyclic aromatic group may have each hydrogen atom independently substituted and may have 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

3. R in equation (I) １ The therapeutic or prophylactic agent according to claim 1, wherein each hydrogen atom is an aliphatic group having 1 to 6 carbon atoms, in which case each hydrogen atom may be substituted.

4. The therapeutic or prophylactic agent according to claim 1, wherein formula (I) is represented by the following formula (I-1). 【Transformation 3】

5. The therapeutic or prophylactic agent according to claim 1, wherein X in formula (II) is CZ [where Z represents a hydrogen atom, a halogen atom, or CN].

6. R in equation (II) ３ and R ４ The therapeutic or prophylactic agent according to claim 1, wherein each hydrogen atom is independently a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms, in which case each hydrogen atom may be substituted.

7. The therapeutic or prophylactic agent according to claim 1, wherein formula (II) is represented by the following formula (II-1). 【Chemistry 4】

8. A therapeutic or prophylactic agent according to any one of claims 1 to 7, wherein Charcot-Marie-Tooth disease is Charcot-Marie-Tooth disease type 2.

9. Formula (I) below: 【Transformation 5】 [In formula (I), R １ This represents a group selected from the group consisting of aliphatic groups having 1 to 6 carbon atoms and alicyclic hydrocarbon groups having 3 to 7 carbon atoms, in which each hydrogen atom may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. R ２ and R ３ This independently represents a group selected from the group consisting of alicyclic hydrocarbon groups having 3 to 7 carbon atoms and monocyclic or bicyclic aromatic groups having 6 to 10 members, wherein each hydrogen atom may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. n and m are independent integers between 0 and 2. Each R ４ and each R ５ This independently represents a halogen atom, CN, or a carbon-1 to carbon-3 aliphatic group in which each hydrogen atom may be substituted. R ６ This represents a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms, in which case each hydrogen atom may be substituted. Or formula (II) below: 【Transformation 6】 [In formula (II), R １ This represents a hydrogen atom or an aliphatic group having 1 to 3 carbon atoms, in which case each hydrogen atom may be substituted. R ２ It may or may not exist; if it exists, it indicates a hydrogen atom. R ３ and R ４ This independently represents a group selected from the group consisting of a hydrogen atom, or an aliphatic group having 1 to 6 carbon atoms and an alicyclic hydrocarbon group having 3 to 7 carbon atoms, where each hydrogen atom may be substituted, and which may have 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. n is an integer between 0 and 2. X represents a nitrogen atom or CZ (where Z represents a hydrogen atom, a halogen atom, CN, or an aliphatic group having 1 to 3 carbon atoms, in which case each hydrogen atom may be substituted), The dotted line indicates the presence of a double bond at one of the positions. An expression promoter for the mitofusin 1 gene, comprising a compound represented by or a salt thereof.

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