Schwann cell differentiation promoter and / or dedifferentiation inhibitor

Abstract

To provide a drug that treats or improves a disease in which symptoms are improved or alleviated by a Schwann-cell-differentiation-promoting action or a dedifferentiation-inhibiting action. The present invention provides a drug that treats or improves a disease in which symptoms are improved or alleviated by a Schwann-cell-differentiation-promoting action or a dedifferentiation-inhibiting action, the drug containing a vitamin D derivative represented by formula (1) or a pharmaceutically acceptable salt or solvate thereof.

Description

Agents for promoting differentiation and / or inhibiting dedifferentiation of Schwann cells

[0001] The present invention relates to a therapeutic or ameliorating drug containing a vitamin D derivative, which is a therapeutic or ameliorating drug for diseases whose symptoms are improved or alleviated by promoting differentiation of immature Schwann cells, inhibiting dedifferentiation of mature Schwann cells, and / or promoting differentiation of dedifferentiated Schwann cells. More specifically, the vitamin D derivative used in the present invention is a vitamin D derivative having a cyclic tertiary amine in the side chain, and includes pharmaceutically acceptable salts and solvates thereof. Pharmaceuticals that can be clinically applied as therapeutic agents or ameliorating agents for diseases whose symptoms are improved or alleviated by promoting Schwann cell differentiation or inhibiting dedifferentiation include therapeutic agents or ameliorating agents for chemotherapy-induced peripheral neuropathy (CIPN), diabetic peripheral neuropathy (DN), myasthenia gravis (MG), and amyotrophic lateral sclerosis (ALS).

[0002] Schwann cells are glial cells that form the myelin sheath in peripheral nerves. When peripheral nerve myelin is damaged by hyperglycemia, anticancer drugs, etc., Schwann cells dedifferentiate and demyelinate, causing various neuropathies. Although such peripheral nerve disorders are seen in various pathologies, there are no effective treatments. Therefore, it is necessary to develop a fundamental treatment that inhibits dedifferentiation and promotes differentiation of Schwann cells.

[0003] Patent documents 1 to 3 disclose compounds having neuroprotective and / or restorative effects. All of them are based on their effects on Schwann cells, and Patent document 1 shows promotion of Schwann cell differentiation, neurite outgrowth, and an increase in neuromuscular junctions. Patent documents 2 and 3 show inhibition of dedifferentiation.

[0004] On the other hand, although the vitamin D derivatives of the present invention are disclosed in Patent Documents 4 and 5, it is not known that the vitamin D derivatives have an effect of promoting Schwann cell differentiation or inhibiting dedifferentiation.

[0005] WO2021 / 241504WO2020 / 027150WO2021 / 15369WO2022 / 059684WO2023 / 171736

[0006] The problem to be solved by the present invention is to provide a therapeutic or ameliorating agent for diseases whose symptoms are improved or alleviated by a differentiation-promoting effect on immature Schwann cells, a dedifferentiation-inhibiting effect on mature Schwann cells, and / or a differentiation-promoting effect on dedifferentiated Schwann cells (hereinafter sometimes simply referred to as "Schwann cell differentiation-promoting effect or dedifferentiation-inhibiting effect").

[0007] As a result of extensive research, the present inventors have found that a vitamin D derivative represented by the following formula (1), or a pharmaceutically acceptable salt or solvate thereof, has the effect of promoting Schwann cell differentiation and / or inhibiting dedifferentiation, and have completed the present invention.

[0008]

[0009] That is, the gist of the present invention relates to, for example, the following.

[0010] [Item 1] The following formula (1): [In the formula, R represents any one of the structures Ra, Rb, Rc, Rd, and Re in the following formula.

[0011] R １ , R ３ , R ８ , and R １０ each independently represents a C optionally substituted with 1 to 3 halogen atoms; １ ~C ６ Alkyl group, C ３ ~C ６ a cycloalkyl group, a C group optionally substituted with 1 to 3 halogen atoms; １ ~C ６ R represents an alkoxy group, a halogen atom, or a hydrogen atom. ２ , R４ , R ９ , and R １１ each independently represents a hydrogen atom, a hydroxy group, or a C optionally substituted with 1 to 3 halogen atoms; １ ~C ６ represents an alkyl group. １ , R ３ , R ８ , and R １０ each independently represents a C optionally substituted with 1 to 3 halogen atoms; １ ~C ６ When R represents an alkoxy group or a halogen atom, １ , R ３ , R ８ , R １０ R substituted on the same carbon atom as ２ , R ４ , R ９ , R １１ is not a hydroxy group. ６ , R ７ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , and R ２３ are each independently a hydrogen atom or a C optionally substituted with 1 to 3 halogen atoms. １ ~C ６ alkyl group, or C ３ ~C ６ represents a cycloalkyl group. １ and R ２ , R ３ and R ４ , R ６ and R ７ , R ８ and R ９ , R １０ and R １１ , R １２ and R １３ , R １４ and R １５ , R １６ and R １７ , R１８ and R １９ , R ２０ and R ２１ , R ２２ and R ２３ can be bonded to each other to form a ring structure having 3 to 5 members. ５ represents a hydrogen atom, one -OR ５０１ C optionally substituted with a group １ ~C ６ an alkyl group or one -OR ５０１ C optionally substituted with a group ３ ~C ６ represents a cycloalkyl group, R ５０１ is a hydrogen atom, or C １ ~C ６ represents an alkyl group. ２４ is a hydrogen atom, C １ ~C ３ alkyl group, or C １ ~C ３ The stereochemistry at the 2-position of the pyrrolidine ring (Rb) is either the (R) or (S) configuration. X １ , and X ２ are each independently a hydrogen atom or C １ ~C ３ represents an alkyl group, or X １ and X ２ together represent a methylidene group, or -(CH ２ ) ｍ - (where m is an integer of 2 to 5). ３ is CH ２ group, or C=CH ２ group (wherein X １ and X ２ When X ３ is C=CH ２) represents an integer of 1 to 3. The stereochemistry of the hydroxyl group at position 1 is either the (R) or (S) configuration. The stereochemistry of the methyl group at position 20 is either the (R) or (S) configuration. ], or a pharmaceutically acceptable salt or solvate thereof, for a disease whose symptoms are improved or alleviated by the effect of promoting Schwann cell differentiation or inhibiting dedifferentiation, the drug comprising the vitamin D derivative represented by the formula (I):

[0012] [Item 2] The vitamin D derivative represented by formula (1) is represented by the following formula (1A): [n represents an integer of 1 to 3. ３ C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl group, C ３ ~C ６ a cycloalkyl group or a C group optionally substituted with 1 to 3 halogen atoms; １ ~C ６ represents an alkoxy group. １ , and X ２ are each independently a hydrogen atom or C １ ~C ３ represents an alkyl group, or X １ and X ２ together represent a methylidene group, or -(CH ２ ) ｍ - (where m is an integer of 2 to 5). ３ is CH ２ group, or C=CH ２ group (wherein X １ and X ２ When X ３ is C=CH ２ Item 3. The therapeutic or ameliorating agent according to Item 1, wherein the therapeutic or ameliorating agent is represented by the formula:

[0013] [Item 3] n represents 1, R ３ C optionally substituted with 1 to 3 halogen atoms ２ ~C ６ C optionally substituted with an alkyl group or 1 to 3 halogen atoms １ ~C ６Item 3. The therapeutic or ameliorating agent according to Item 2, wherein the compound represents an alkoxy group.

[0014] [Item 4] The vitamin D derivative represented by formula (1) is represented by the following formula (1B): [n represents an integer of 1 to 3. １２ , R １３ , R １４ , R １５ are each independently a hydrogen atom or a C optionally substituted with 1 to 3 halogen atoms. １ ~C ６ alkyl group, or C ３ ~C ６ represents a cycloalkyl group. 12 and R 13 , R 14 and R 15 can be bonded to each other to form a ring structure having 3 to 5 members. １ , and X ２ are each independently a hydrogen atom or C １ ~C ３ represents an alkyl group, or X １ and X ２ together represent a methylidene group, or -(CH ２ ) ｍ - (where m is an integer of 2 to 5). ３ is CH ２ group, or C=CH ２ group (wherein X １ and X ２ When X ３ is C=CH ２ Item 3. The therapeutic or ameliorating agent according to Item 1, wherein the therapeutic or ameliorating agent is represented by the formula:

[0015] [Item 5] n represents 1, R １２ and R １３ are bonded together to form a cyclopropyl group, or R １４ , R １５ [Item 6] The therapeutic agent or ameliorating agent according to Item 4, wherein X simultaneously represents a methyl group. １ and X ２ is a hydrogen atom, and X ３ is CH ２[Item 7] The therapeutic agent or ameliorating agent according to any one of Items 1 to 5, wherein X is a group. １ and X ２ is a hydrogen atom, and X ３ is C=CH ２ [Item 8] The therapeutic agent or ameliorating agent according to any one of Items 1 to 5, wherein X １ and X ２ together form a methylidene group, and X ３ is CH ２[Item 9] The therapeutic agent or ameliorating agent according to any one of items 1 to 5, wherein n is a group. [Item 10] The therapeutic agent or ameliorating agent according to any one of items 1 to 9, wherein the vitamin D derivative represented by formula (1) is any one of the following vitamin D derivatives or pharmaceutically acceptable salts or solvates thereof: (1) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-ethylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B005) (2) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-ethylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B006) (3) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B030) (4) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B034) (5) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B042) (6) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-Difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B043) (7) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B051) (8) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B052) (9) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B057) (10) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(2,2-difluoroethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B058) (11) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(3,3-difluoropropyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B063) (12) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(3,3-difluoropropyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B064) (13) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-3-(difluoromethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B080) (14) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-(difluoromethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B081) (15) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B082) (16) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B083) (17) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-3-(difluoromethoxy)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B086) (18) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-(difluoromethoxy)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B087) (19) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-oxa-7-azaspiro[2.5]octan-7-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound D019) (20) (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-7a-Methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound D022) (21) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D023) (22) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D024) (23) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((S)-2-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D025) (24) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(4-oxa-7-azaspiro[2.5]octan-7-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D030) (25) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-2-(difluoromethyl)morpholino)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D034) (26) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((S)-2-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D041) (27) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((R)-3-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-Diol (Compound D042) (28) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((S)-3-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D043) (29) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-5-morpholinopentan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D044) (30) (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3,3-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (compound F006) (31) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3,3-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound G006),

[0016] [Item 11] The therapeutic agent or improving agent according to any one of Items 1 to 10, wherein the disease whose symptoms are improved or alleviated by the Schwann cell differentiation-promoting effect or dedifferentiation-inhibiting effect is chemotherapy-induced peripheral neuropathy (CIPN). [Item 12] The therapeutic agent or improving agent according to any one of Items 1 to 10, wherein the disease whose symptoms are improved or alleviated by the Schwann cell differentiation-promoting effect or dedifferentiation-inhibiting effect is diabetic peripheral neuropathy (DN). [Item 13] The therapeutic agent or improving agent according to any one of Items 1 to 10, wherein the disease whose symptoms are improved or alleviated by the Schwann cell differentiation-promoting effect or dedifferentiation-inhibiting effect is myasthenia gravis (MG). [Item 14] The therapeutic or ameliorating agent according to any one of Items 1 to 10, wherein the disease whose symptoms are improved or alleviated by the Schwann cell differentiation promoting effect or dedifferentiation inhibiting effect is amyotrophic lateral sclerosis (ALS).

[0017] According to the present invention, a therapeutic or ameliorating agent for a disease whose symptoms are improved or alleviated by a differentiation-promoting effect on immature Schwann cells, a dedifferentiation-inhibiting effect on mature Schwann cells, and / or a differentiation-promoting effect on dedifferentiated Schwann cells is provided.

[0018] Graph showing the differentiation-promoting effect of the vitamin D derivative of the present invention on immature Schwann cells. Graph showing the dedifferentiation-inhibiting and differentiation-promoting effect of the vitamin D derivative of the present invention on paclitaxel-induced Schwann cell dedifferentiation. Graph showing the dedifferentiation-inhibiting and differentiation-promoting effect of the vitamin D derivative of the present invention on paclitaxel-induced Schwann cell dedifferentiation. Graph showing the dedifferentiation-inhibiting and differentiation-promoting effect of the vitamin D derivative of the present invention on high glucose-induced Schwann cell dedifferentiation. The effects of the vitamin D derivative D023 of the present invention, eldecalcitol, and 1α,25-dihydroxyvitamin D on high glucose-induced Schwann cell dedifferentiation. ３1 is a graph showing the results of a comparison of the dedifferentiation-inhibiting and differentiation-promoting effects of the vitamin D derivative of the present invention with those of the present invention, using streptozotocin (STZ)-induced diabetic rats.

[0019] Terms used alone or in combination in this specification are explained below. Unless otherwise specified, the explanation of each substituent is the same for each site. When any variable exists in any component, its definition is independent for each component. Furthermore, combinations of substituents and variables are permitted only if such combinations result in chemically stable compounds. When a substituent itself is substituted with two or more groups, these multiple groups may be present on the same carbon or different carbons as long as a stable structure is produced.

[0020] In the present invention, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0021] In the present invention, the term "C1-C6 alkyl group" means a monovalent saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an isopropyl group, an isobutyl group, an s-butyl group, a t-butyl group, an isopentyl group, a 2-methylbutyl group, a neopentyl group, a 1-ethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl group, a 3,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, a t-pentyl group, and an isohexyl group.

[0022] In the present invention, the term "methylidene group" refers to a =CH2 group.

[0023] In the present invention, the term "C3-C6 cycloalkyl group" refers to a cycloalkyl group having 3 to 6 carbon atoms, including, but not limited to, cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0024] In the present invention, the term "C1 to C6 alkoxy group" refers to a group consisting of an alkyl group having 1 to 6 carbon atoms, selected from the above-mentioned "C1 to C6 alkyl groups," and an oxy group. Examples include a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group, an n-butoxy group, an s-butoxy group, a 2-methylpropoxy group, an n-pentyloxy group, an isopentyloxy group, a 2-methylbutoxy group, a 1-ethylpropoxy group, a 2,2-dimethylpropoxy group, an n-hexyloxy group, a 4-methylpentoxy group, a 3-methylpentoxy group, a 2-methylpentoxy group, a 3,3-dimethylbutoxy group, a 2,2-dimethylbutoxy group, a 1,1-dimethylbutoxy group, and a t-butoxy group.

[0025] In the present invention, the term "C1-C6 alkylsulfonyl group" refers to a group consisting of the above-mentioned "C1-C6 alkyl group" and a sulfonyl group. Examples include a methylsulfonyl group, an ethylsulfonyl group, and an isopropylsulfonyl group.

[0026] In the above definitions, for example, "C" in "C1" represents a carbon atom, and the number following it represents the number of carbon atoms. For example, "C1-C6" represents a range of carbon atoms from 1 to 6. Of course, in the present invention, if the number of carbon atoms is different, it means the group having that number of carbon atoms. For example, "C1-C3 alkyl group" means an alkyl group defined as "C1-C6 alkyl group" having 1 to 3 carbon atoms. The number of carbon atoms in other groups is treated in the same way.

[0027] In the present invention, a "C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms" means a C1-C6 alkyl group optionally having 1 to 3 halogen atoms at substitutable positions. When a C1-C6 alkyl group is substituted with multiple halogen atoms, the C1-C6 alkyl groups may be substituted with the same halogen atoms or different halogen atoms. A "C1-C6 alkoxy group optionally substituted with 1 to 3 halogen atoms" has a similar meaning.

[0028] In the present invention, the term "vitamin D derivative" refers to a compound having a secosteroid structure (ie, 4-(2-cyclohexylideneethylidene)octahydro-1H-indene).

[0029] In the above formula (1), X 1 and X 2 each independently represents a hydrogen atom or a C1-C3 alkyl group, or X 1 and X 2 together represent a methylidene group, or -(CH2) m - (where m is an integer of 2 to 5). 1 and X 2 each independently represents a hydrogen atom, or X 1 and X 2 and preferably together form a methylidene group.

[0030] In the above formula (1), X 3 is a CH2 or C=CH2 group (where X 1 and X 2 When X 3 represents a C=CH2 group.

[0031] X 1 , X 2 , and X 3 Preferred examples of the combination of (i) X 1 and X 2 is a hydrogen atom, X 3 represents a CH group, (ii) X 1 and X 2 is a hydrogen atom, X 3represents a C=CH group, and (iii) X 1 and X 2 together form a methylidene group, X 3 represents a CH2 group.

[0032] In the above formula (1), n ​​represents an integer of 1 to 3. The stereochemistry of the methyl group at the 20th position in the above formula (1) may be either the (R) configuration or the (S) configuration. The stereochemistry of the hydroxyl group at the 1st position in the above formula (1) may be either the (R) configuration or the (S) configuration. In the above formula (1), R represents the structures Ra to Re described above. Of these, a pyrrolidine ring (Rb) and a morpholine ring (Rd) are particularly preferred structures. The stereochemistry at the 2nd position of the pyrrolidine ring (Rb) may be either the (R) configuration or the (S) configuration.

[0033] R 1 , R 3 , R 8 , and R 10 R each independently represents a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group optionally substituted with 1 to 3 halogen atoms, a halogen atom, or a hydrogen atom. 1 , R 3 , R 8 , and R 10 Preferred groups include a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group optionally substituted with 1 to 3 halogen atoms, a fluorine atom, or a hydrogen atom, and more preferred groups include a methyl group, an ethyl group, a methoxy group, an ethoxy group, a difluoromethyl group, a 1,1-difluoroethyl group, a 2,2-difluoroethyl group, a difluoromethoxy group, a 2,2-difluoroethoxy group, a 3,3-difluoropropyl group, a 2,2-difluoropropyl group, and the like.

[0034] R 2 , R 4 , R 9 , and R 11each independently represents a hydrogen atom, a hydroxy group, or a C1-C3 alkyl group which may be substituted with 1 to 3 halogen atoms. Among these, a hydrogen atom, a hydroxy group, or a C1-C3 alkyl group which may be substituted with 1 to 3 fluorine atoms is preferred, and a hydrogen atom or a hydroxy group is more preferred. 1 , R 3 , R 8 , and R 10 are each independently a C1-C3 alkoxy group optionally substituted with 1 to 3 halogen atoms, or a halogen atom, then R 1 , R 3 , R 8 , R 10 R substituted on the same carbon atom as 2 , R 4 , R 9 , R 11 is preferably not a hydroxy group but a hydrogen atom in this case.

[0035] R 6 , R 7 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , and R 23 each independently represents a hydrogen atom, a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms, or a C3-C6 cycloalkyl group. Among these, a hydrogen atom, a C1-C6 alkyl group optionally substituted with 1 to 3 fluorine atoms, or a C3-C6 cycloalkyl group is preferred, and more preferred groups include a hydrogen atom, a methyl group, and a difluoromethyl group.

[0036] Also, R 1 and R 2 , R 3 and R 4 , R 6 and R 7 , R 8 and R 9 , R10 and R 11 , R 12 and R 13 , R 14 and R 15 , R 16 and R 17 , R 18 and R 19 , R 20 and R 21 , R 22 and R 23 can be bonded to each other to form a 3- to 5-membered ring structure. Here, the 3- to 5-membered ring structure is a hydrocarbon ring, and R 1 and R 2 , R 3 and R 4 , R 6 and R 7 , R 8 and R 9 , R 10 and R 11 , R 12 and R 13 , R 14 and R 15 , R 16 and R 17 , R 18 and R 19 , R 20 and R 21 , R 22 and R 23 together with the carbon atom on which it is substituted, can form a cyclopropyl ring, a cyclobutyl ring, or a cyclopentyl ring.

[0037] R 5 represents a hydrogen atom, one -OR 501 a C1-C6 alkyl group optionally substituted with a group, or one -OR 501 represents a C3-C6 cycloalkyl group optionally substituted by a group, R 501 represents a hydrogen atom or a C1-C6 alkyl group. 5 is a hydrogen atom or -C(CH3)2-OR 501 is preferred.

[0038] R 24 represents a hydrogen atom, a C1-C3 alkyl group, or a C1-C3 alkylsulfonyl group, with methylsulfonyl being particularly preferred.

[0039] Furthermore, among the vitamin D derivatives represented by formula (1) or pharmaceutically acceptable salts or solvates thereof, preferred specific examples of the present invention include vitamin D derivatives represented by formulas (1A) and (1B) or pharmaceutically acceptable salts or solvates thereof.

[0040] A vitamin D derivative represented by formula (1A) or a pharmaceutically acceptable salt or solvate thereof [n represents an integer of 1 to 3. ３ is C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl group, C ３ ~C ６ a cycloalkyl group or a C group optionally substituted with 1 to 3 halogen atoms; １ ~C ６ represents an alkoxy group. １ , and X ２ are each independently a hydrogen atom or C １ ~C ３ represents an alkyl group, or X １ and X ２ together represent a methylidene group, or -(CH ２ ) ｍ - (where m is an integer of 2 to 5). ３ is CH ２ group, or C=CH ２ group (wherein X １ and X ２ When X ３ is C=CH ２ It is not a group.)

[0041] In formula (1A), n preferably represents 1 or 2. When n represents 1, R ３ C optionally substituted with 1 to 3 halogen atoms ２ ~C ６ C optionally substituted with an alkyl group or 1 to 3 halogen atoms １ ~C ６ It preferably represents an alkoxy group.

[0042] In formula (1A), X 1 , X2 , and X 3 Preferred examples of the combination of (i) X 1 and X 2 is a hydrogen atom, X 3 represents a CH group, (ii) X 1 and X 2 is a hydrogen atom, X 3 represents a C=CH group, and (iii) X 1 and X 2 together form a methylidene group, X 3 represents a CH2 group.

[0043] A vitamin D derivative represented by formula (1B) or a pharmaceutically acceptable salt or solvate thereof [n represents an integer of 1 to 3. １２ , R １３ , R １４ , R １５ are each independently a hydrogen atom or a C optionally substituted with 1 to 3 halogen atoms. １ ~C ６ alkyl group, or C ３ ~C ６ represents a cycloalkyl group. 12 and R 13 , R 14 and R 15 can be bonded to each other to form a 3- to 5-membered ring structure. Here, the 3- to 5-membered ring structure is a hydrocarbon ring, and R 12 and R 13 , R 14 and R 15 Together with the carbon atom on which it is substituted, X can form a cyclopropyl ring, a cyclobutyl ring, or a cyclopentyl ring. １ , and X ２ are each independently a hydrogen atom or C １ ~C ３ represents an alkyl group, or X １ and X ２ together represent a methylidene group, or -(CH ２ ) ｍ - (where m is an integer of 2 to 5). ３ is CH ２ group, or C=CH２ group (wherein X １ and X ２ When X ３ is C=CH ２ It is not a group.)

[0044] In formula (1B), n preferably represents 1 or 2. When n represents 1, R １２ and R １３ are bonded together to form a cyclopropyl group, or R １４ , R １５ Preferably, simultaneously represent a methyl group.

[0045] In formula (1B), X 1 , X 2 , and X 3 Preferred examples of the combination of (i) X 1 and X 2 is a hydrogen atom, X 3 represents a CH group, (ii) X 1 and X 2 is a hydrogen atom, X 3 represents a C=CH group, and (iii) X 1 and X 2 together form a methylidene group, X 3 represents a CH2 group.

[0046] Specific preferred examples of the vitamin D derivatives represented by formula (1) of the present invention include the following compounds: (1) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-ethylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B005) (2) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-ethylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B006) (3) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B030) (4) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B034) (5) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B042) (6) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B043) (7) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B051) (8) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B052) (9) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B057) (10) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(2,2-difluoroethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B058) (11) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(3,3-difluoropropyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B063) (12) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(3,3-difluoropropyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B064) (13) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-3-(difluoromethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B080) (14) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-(difluoromethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B081) (15) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B082) (16) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B083) (17) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-3-(difluoromethoxy)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B086) (18) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-(difluoromethoxy)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B087) (19) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-oxa-7-azaspiro[2.5]octan-7-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D019) (20) (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound D022) (21) (1R,3R)-5-(2-((1R,(3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D023) (22) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D024) (23) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((S)-2-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D025) (24) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(4-oxa-7-azaspiro[2.5]octan-7-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D030) (25) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-2-(difluoromethyl)morpholino)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D034) (26) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((S)-2-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D041) (27) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((R)-3-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound D042) (28) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-Methyl-1-((R)-4-((S)-3-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D043) (29) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-5-morpholinopentan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D044) (30) (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3,3-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (compound F006) (31) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3,3-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound G006),

[0047] The vitamin D derivative of the present invention can be converted into its pharmaceutically acceptable salt as needed. Such salts include hydrochloride, hydrobromide, methanesulfonate, paratoluenesulfonate, acetate, trifluoroacetate, fumarate, maleate, malate, succinate, oxalate, citrate, and benzoate. Particularly preferred are hydrochloride, acetate, fumarate, maleate, malate, and succinate.

[0048] Furthermore, the vitamin D derivatives of the present invention can be converted into their pharmaceutically acceptable solvates, if necessary. Examples of such solvents include water, methanol, ethanol, 1-propanol, 2-propanol, butanol, acetonitrile, acetone, methyl ethyl ketone, methyl acetate, and ethyl acetate. Water, methanol, ethanol, and acetonitrile are particularly preferred.

[0049] The vitamin D derivative represented by formula (1), or a pharmaceutically acceptable salt or solvate thereof, has an excellent effect of promoting differentiation of immature Schwann cells, inhibiting dedifferentiation of mature Schwann cells, and / or promoting differentiation of dedifferentiated Schwann cells. Because of its excellent effect of promoting differentiation of immature Schwann cells, inhibiting dedifferentiation of mature Schwann cells, and / or promoting differentiation of dedifferentiated Schwann cells, it is useful as a therapeutic or ameliorating agent for diseases whose symptoms are improved or alleviated by the effect of promoting differentiation of immature Schwann cells, inhibiting dedifferentiation of mature Schwann cells, or promoting differentiation of dedifferentiated Schwann cells. More specifically, it can be clinically applied as a therapeutic or improving agent for chemotherapy-induced peripheral neuropathy (CIPN), diabetic peripheral neuropathy (DN), myasthenia gravis (MG), and amyotrophic lateral sclerosis (ALS).

[0050] A therapeutic agent or ameliorator for a disease whose symptoms are improved or alleviated by promoting Schwann cell differentiation or inhibiting dedifferentiation, containing a vitamin D derivative represented by formula (1) or a pharmaceutically acceptable salt or solvate thereof, is prepared into a pharmaceutical composition using carriers, bases, excipients, and other additives commonly used in formulations. The carriers, bases, and excipients used in pharmaceutical compositions may be solid or liquid, and examples include lactose, magnesium stearate starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, medium-chain fatty acid triglycerides, and other commonly used carriers. Administration may be oral, such as in the form of tablets, pills, capsules, soft capsules, granules, powders, or liquids, or parenterally, such as intravenous or intramuscular injections, suppositories, transdermal routes, or intranasal routes.

[0051] The therapeutically effective amount of the active ingredient in the therapeutic agent of the present invention varies depending on the route of administration, the age and sex of the patient, and the severity of the disease, but is usually about 0.1 to 10,000 μg / day, and the frequency of administration is usually 1 to 3 times / day or 1 to 3 times / week, and it is preferable to prepare a formulation that satisfies these conditions. However, since the dosage varies depending on various conditions, a dosage less than the above-mentioned dosage may be sufficient in some cases, and a dosage exceeding the above-mentioned range may also be required in other cases.

[0052] The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. The vitamin D derivative of the present invention can be obtained by the method described in WO2022 / 059684.

[0053] Example 1 Evaluation of the Differentiation-Promoting Effect of the Vitamin D Derivative of the Present Invention on Immature Schwann Cells 1) Preparation of Rat Schwann Cells Primary rat Schwann cells were obtained as follows: Sciatic nerves were collected from Wistar / ST rats (1-day-old, Japan SLC) in a medium containing 250 U / mL hyaluronidase type IS (Sigma-Aldrich #H3506) and 160 U / mL collagenase type I (Merck Millipore #SCR103) (2 mM GlutaMAX (Gibco #35050-061) / 1% penicillin-streptomycin (Gibco #15140-122) / serum-free Advanced DMEM / F-12 (Gibco #12634-010)) and incubated at 37°C for 2 hours. After pipetting, the mixture was centrifuged (300 × g, 5 min, room temperature), and the pellet was resuspended in maintenance medium (2 μM forskolin (Sigma-Aldrich #6886) / 20 ng / mL heregulin β-1 (Sigma-Aldrich #H7660) in 5% D-(+)-trehalose dihydrate (Nacalai Tesque #11667-34) / 2 mM GlutaMAX (Gibco #35050-061) / 1% Penicillin-Streptomycin (Gibco #15140-122) / Serum-free Advanced DMEM / F-12 (Gibco #12634-010)) and transferred to a 6-well plate coated with poly-L-lysine (Sigma-Aldrich #P4707). The entire volume was seeded onto a well-plate and cultured in a CO2 incubator under conditions of 5% CO2 and 37°C. After 4 days of culture, the medium was replaced with a maintenance medium containing 10% heat-inactivated fetal bovine serum.Four days after the medium change, cells were harvested and resuspended in removing fibroblast medium (0.1% mouse anti-CD90 / Thy1 antibody (BIO-RAD #MCA04GT) / 3% bovine serum albumin (Sigma-Aldrich #A7906-50G) / 2 mM GlutaMAX (Gibco #35050-061) / 1% penicillin-streptomycin (Gibco #15140-122) / serum-free Advanced DMEM / F-12 (Gibco #12634-010)) and incubated on ice for 2 hours. After centrifugation (300 × g, 5 min, room temperature), the pellet was treated with rabbit complement medium (20% rabbit complement (CEDARLANE #CL3441-S50-R) / 3% bovine serum albumin (Sigma-Aldrich #A7906-50G) / 2 mM GlutaMAX (Gibco #35050-061) / 1% penicillin-streptomycin (Gibco #15140-122) / serum-free Advanced DMEM / F-12 (Gibco #12634-010)) for 1 h at 37°C to remove fibroblasts. After centrifugation (300 × g, 5 minutes, room temperature), the pellet was resuspended in maintenance medium and seeded onto 10 cm dishes coated with poly-L-lysine (Sigma-Aldrich #P4707) at a density of 5.0 × 10^5 cells / 10 mL / dish. Cells obtained by expansion were defined as primary rat Schwann cells and used in the experiments. 2) Evaluation of the Vitamin D Derivatives of the Present Invention: Evaluation of the vitamin D derivatives of the present invention was performed according to the following schedule. The harvested primary rat Schwann cells were suspended in maintenance medium and seeded onto 10 cm dishes coated with poly-L-lysine (Sigma-Aldrich #P4707) and cultured at 37°C and 5.0% CO2. Subconfluent cells were washed with PBS, detached with 0.05% Trypsin / EDTA (Gibco #25300-054), and centrifuged (300 × g, 5 minutes, room temperature).After removing the supernatant, the cells were suspended in maintenance medium to prepare a cell suspension. The cell suspension was diluted to 2.0 x 10 cells. 4 Cells were seeded onto Poly-D-lysine 96-well plates, Black Clear (CORNING, 254640) at a density of 100 cells / well and cultured at 37°C under 5.0% CO2. After confirming cell adhesion, maintenance medium containing various concentrations of vitamin D derivatives or 0.1% DMSO was added at 100 μL / well for a total of 200 μL / well for 2 days. After culture, MAG immunostaining and image analysis were performed as described below. After removing the supernatant and washing with PBS, the cells were fixed by adding 4% paraformaldehyde (Fujifilm Wako Pure Chemical #163-20145) and incubating at room temperature for 15 minutes. After removing the supernatant, 0.1% Tween-20-containing skim milk solution was added and the cells were incubated at room temperature for 30 minutes. After washing three times with PBS, a PBS solution containing 2.5 μg / mL anti-MAG antibody (Millipore #MAB1567) was added and the cells were incubated overnight at 4°C. After washing three times with PBS, a PBS solution containing 5 μg / mL Alexa fluor 488 anti-mouse IgG (Invitrogen, A11029) was added and the cells were incubated at room temperature for 60 minutes. After washing three times with PBS, a PBS solution containing 1 μg / mL Hoechst 33342 (DOJINDO #NU043) was added and the cells were incubated at room temperature for 15 minutes in the dark. Fluorescence images were then captured using a fluorescence microscope (KEYENCE #BZ-X800) with six fields of view per well. The MAG-positive areas of the captured fluorescence images were measured using an image analysis application (KEYENCE #BZ-X800 Analyzer), and the sum of the six fields of view was calculated for each well. 3) Results: The differentiation-promoting effect of the vitamin D derivatives of the present invention on immature Schwann cells is shown in Figure 1. The vitamin D derivative group of the present invention significantly promoted the differentiation of immature Schwann cells compared to the DMSO group.

[0054] Example 2: Evaluation of the inhibitory and differentiation-promoting effects of the vitamin D derivatives of the present invention on paclitaxel-induced Schwann cell dedifferentiation. In this example, the inhibitory and differentiation-promoting effects of the vitamin D derivatives of the present invention on paclitaxel-induced Schwann cell dedifferentiation were evaluated. 1) Method: Primary rat Schwann cells were collected as in Example 1, and the effects of vitamin D derivatives were evaluated according to the following schedule. The collected primary rat Schwann cells were suspended in maintenance medium and seeded on 10 cm dishes coated with poly-L-lysine (Sigma-Aldrich #P4707) and cultured at 37°C and 5.0% CO2. Subconfluent cells were washed with PBS, detached with 0.05% trypsin / EDTA (Gibco #25300-054), and centrifuged (300 × g, 5 minutes, room temperature). After removing the supernatant, the cells were suspended in differentiation medium (20 μM forskolin (Sigma-Aldrich #6886), 20 ng / mL heregulin β-1 (Sigma-Aldrich #H7660), 5% D-(+)-trehalose dihydrate (Nacalai Tesque #11667-34), 2 mM GlutaMAX (Gibco #35050-061), 1% penicillin-streptomycin (Gibco #15140-122), and serum-free Advanced DMEM / F-12 (Gibco #12634-010)). The cell suspension was seeded at a density of 1.0 × 10^4 cells / 100 μL / well onto a 96-well plate containing Poly-D-lysine, Black Clear (Corning #354640). Because at least two days of differentiation culture is required for the maturation of immature Schwann cells, the cells were cultured for three days at 37°C in 5.0% CO. Then, 100 μL of sample was added per well, and the cells were cultured for two days at a total volume of 200 μL per well.The samples were divided into the Pac(-) group (differentiation medium containing 0.2% DMSO), the DMSO group (differentiation medium containing 0.1% 2 μM paclitaxel in DMSO and 0.2% DMSO), the amorolfine group (differentiation medium containing 0.1% 2 μM paclitaxel in DMSO and 0.1% 2 mM amorolfine in DMSO), and the vitamin D derivative group (differentiation medium containing 0.1% 2 μM paclitaxel in DMSO and 0.1% 2 mM vitamin D derivative in DMSO). After incubation, MAG immunostaining and image analysis were performed as follows. After removing the supernatant and washing with PBS, the cells were fixed by adding 4% paraformaldehyde (Fujifilm Wako Pure Chemical #163-20145) and incubating at room temperature for 15 minutes. After removing the supernatant, 0.1% Tween-20-containing skim milk solution was added and incubated at room temperature for 30 minutes. After washing three times with PBS, 2.5 μg / mL anti-MAG antibody (Millipore #MAB1567) in PBS was added and incubated overnight at 4°C. After washing three times with PBS, 5 μg / mL Alexa fluor 488 anti-mouse IgG (Invitrogen, A11029) in PBS was added and incubated at room temperature for 60 minutes. After washing three times with PBS, 1 μg / mL Hoechst 33342 (DOJINDO #NU043) in PBS was added and incubated at room temperature for 15 minutes in the dark. Fluorescence images were then captured using a fluorescence microscope (KEYENCE #BZ-X800) from six fields per well. The MAG-positive area of ​​the acquired fluorescent images was measured using an image analysis application (KEYENCE #BZ-X800 Analyzer), and the sum of the six fields of view for each well was calculated. 2) Results The inhibitory and differentiation-promoting effects of the vitamin D derivative of the present invention on paclitaxel-induced Schwann cell dedifferentiation are shown in Figures 2 and 3. In this experiment, treatment with the anticancer drug paclitaxel caused dedifferentiation of mature Schwann cells (comparison between the DMSO group and the paclitaxel-untreated group (Pac(-) group)).The vitamin D derivatives of the present invention exhibited dedifferentiation-inhibiting and differentiation-promoting effects to the same extent as the positive control compound, amorolfin.

[0055] Example 3 Evaluation of the effects of the vitamin D derivative of the present invention on inhibiting dedifferentiation and promoting differentiation of Schwann cells induced by high glucose In this example, the effects of the vitamin D derivative of the present invention on inhibiting dedifferentiation and promoting differentiation of Schwann cells induced by high glucose were evaluated, and the effects of the vitamin D derivative of the present invention, D023, and known vitamin D derivatives, eldecalcitol and 1α,25-dihydroxyvitamin D ３ (1α,25-(OH) ２ D ３1) Method Primary rat Schwann cells were collected in the same manner as in Example 1, and the vitamin D derivatives were evaluated according to the following schedule. The harvested primary rat Schwann cells were suspended in maintenance medium (2 μM forskolin (Sigma-Aldrich #6886) / 20 ng / mL heregulin β-1 (Sigma-Aldrich #H7660) in 5% D-(+)-trehalose dihydrate (Nacalai Tesque #11667-34) / 2 mM GlutaMAX (Gibco #35050-061) / 1% penicillin-streptomycin (Gibco #15140-122) / serum-free Advanced DMEM / F-12 (Gibco #12634-010)) and seeded onto poly-L-lysine (Sigma-Aldrich #P4707)-coated 10-cm dishes and cultured at 37°C in 5.0% CO2. Subconfluent cells were washed with PBS, detached with 0.05% Trypsin / EDTA (Gibco #25300-054), and centrifuged at 300 × g for 5 minutes at room temperature. After removing the supernatant, the cells were suspended in differentiation medium (20 μM forskolin (Sigma-Aldrich #6886), 20 ng / mL heregulin β-1 (Sigma-Aldrich #H7660), 5% D-(+)-trehalose dihydrate (Nacalai Tesque #11667-34), 2 mM GlutaMAX (Gibco #35050-061), 1% Penicillin-Streptomycin (Gibco #15140-122), and Serum-free Advanced DMEM / F-12 (Gibco #12634-010)). The cell suspension was seeded at a density of 1.0 x 10^4 cells / 100 μL / well onto a 96-well, black clear Poly-D-lysine plate (CORNING #354640). Because at least two days of differentiation culture is required for immature Schwann cell maturation, the cells were cultured for four days at 37°C and 5.0% CO2. Then, 100 μL / well of the sample was added, and the cells were cultured for four days at a total volume of 200 μL / well.The samples were: glucose (-) group (differentiation medium containing distilled water (Invitrogen #10977015) at 2% and DMSO at 0.1%); DMSO group (differentiation medium containing 2.5 M glucose solution (Sigma-Aldrich #G8769-100ML) at 2% and DMSO at 0.1%); amorolfine group (differentiation medium containing 2.5 M glucose solution (Sigma-Aldrich #G8769-100ML) at 2% and 2 mM amorolfine (DMSO solution) at 0.1%); vitamin D derivative group (differentiation medium containing 2.5 M glucose solution (Sigma-Aldrich #G8769-100ML) at 2% and 0.1% vitamin D derivative (DMSO solution) prepared at 2000 times the final concentration); eldecalcitol group (differentiation medium containing 2.5 M glucose solution (Sigma-Aldrich #G8769-100ML) at 0.1%). #G8769-100ML) at 2%, 2 mM eldecalcitol (DMSO solution) at 0.1%, and 1α,25-dihydroxyvitamin D. ３ Group (differentiation medium containing 2% 2.5 M glucose solution (Sigma-Aldrich #G8769-100ML) and 2 mM 1α,25-dihydroxyvitamin D ３ (DMSO solution) was added to a concentration of 0.1%. After culturing, MAG immunostaining and image analysis were performed as in Example 1. 2) Results Figures 4 and 5 show the inhibitory effect of the vitamin D derivatives of the present invention on the dedifferentiation and promotion of differentiation of mature Schwann cells in response to high glucose-induced Schwann cell dedifferentiation. The vitamin D derivatives of the present invention exhibited the same inhibitory effect on dedifferentiation and promotion of differentiation of mature Schwann cells as the positive control compound amorolfin, even under high glucose loading conditions. Compound D023, which is classified as a vitamin D derivative, concentration-dependently inhibited high glucose-induced Schwann cell dedifferentiation and promoted differentiation. Furthermore, the effects were significant at 100 nM and 1000 nM. On the other hand, the vitamin D derivatives eldecalcitol and 1α,25-dihydroxyvitamin D ３In this experiment, the vitamin D derivative of the present invention did not exhibit any dedifferentiation-inhibiting or differentiation-promoting effects. This also confirmed that the vitamin D derivative of the present invention is superior to known vitamin D derivatives.

[0056] Example 4: Evaluation of pain suppression effect using streptozotocin (STZ)-induced diabetic rats 1) Method: STZ dissolved in citrate buffer (pH 4.5) was administered intravenously to the tail vein of SD rats (7 weeks old, male) at a dose of 55 mg / kg to induce pathology. Two, three, and four weeks after the induction of pathology, the 50% pain thresholds of both hind paws were measured using the von Frey test, and the sum of these values ​​(maximum 30 g) was used as the pain threshold. Four weeks after the induction of pathology, the rats were divided into groups based on the pain threshold (4 weeks after the induction of pathology), the mean pain threshold (mean value at 2, 3, and 4 weeks after the induction of pathology), and body weight. The day after grouping, administration of a vitamin D derivative (20 μg / kg), duloxetine (30 mg / kg), or vehicle was initiated. The administration solution was a 0.5 w / v% MC solution prepared by dissolving methylcellulose (MC) 400 (Fujifilm Wako Pure Chemical Industries, #132-05055) in water for injection (Fuso Pharmaceutical Industries), where the vitamin D derivative or duloxetine was suspended. Oral administration was performed once daily for a total of seven doses. Two hours after the final administration, 50% pain thresholds were measured using the von Frey test on both hind paws. The sham group was a non-pathological group administered only citrate buffer (pH 4.5) instead of STZ. 2) Results: The pain-inhibitory effect of the vitamin D derivative of the present invention on STZ-induced diabetic rats is shown in Figure 6. The vitamin D derivative D023 of the present invention exhibited pain-inhibitory effects at a low dose of 20 μg / kg that were equal to or better than those of duloxetine (30 mg / kg), which is used to treat diabetic peripheral neuropathy.

Claims

1. The following formula (1): [In the formula, R represents any one of the structures Ra, Rb, Rc, Rd, and Re in the following formula. R １ , R ３ , R ８ , and R １０ each independently represents a C optionally substituted with 1 to 3 halogen atoms; １ ~C ６ Alkyl group, C ３ ~C ６ a cycloalkyl group, a C group optionally substituted with 1 to 3 halogen atoms; １ ~C ６ R represents an alkoxy group, a halogen atom, or a hydrogen atom. ２ , R ４ , R ９ , and R １１ each independently represents a hydrogen atom, a hydroxy group, or a C optionally substituted with 1 to 3 halogen atoms; １ ~C ６ represents an alkyl group. １ , R ３ , R ８ , and R １０ each independently represents a C optionally substituted with 1 to 3 halogen atoms; １ ~C ６ When R represents an alkoxy group or a halogen atom, １ , R ３ , R ８ , R １０ R substituted on the same carbon atom as ２ , R ４ , R ９ , R １１ is not a hydroxy group. ６ , R ７ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , and R ２３ are each independently a hydrogen atom or a C optionally substituted with 1 to 3 halogen atoms. １ ~C ６ alkyl group, or C ３ ~C ６ represents a cycloalkyl group. １ and R ２ , R ３ and R ４ , R ６ and R ７ , R ８ and R ９ , R １０ and R １１ , R １２ and R １３ , R １４ and R １５ , R １６ and R １７ , R １８ and R １９ , R ２０ and R ２１ , R ２２ and R ２３ can be bonded to each other to form a ring structure having 3 to 5 members. ５ represents a hydrogen atom, one -OR ５０１ C optionally substituted with a group １ ~C ６ an alkyl group or one -OR ５０１ C optionally substituted with a group ３ ~C ６ represents a cycloalkyl group, R ５０１ is a hydrogen atom, or C １ ~C ６ represents an alkyl group. ２４ is a hydrogen atom, C １ ~C ３ alkyl group, or C １ ~C ３ The stereochemistry at the 2-position of the pyrrolidine ring (Rb) is either the (R) or (S) configuration. X １ , and X ２ are each independently a hydrogen atom or C １ ~C ３ represents an alkyl group, or X １ and X ２ together represent a methylidene group, or -(CH ２ ) ｍ - (where m is an integer of 2 to 5). ３ is CH ２ group, or C=CH ２ group (wherein X １ and X ２ When X ３ is C=CH ２ ) represents an integer of 1 to 3. The stereochemistry of the hydroxyl group at position 1 is either the (R) or (S) configuration. The stereochemistry of the methyl group at position 20 is either the (R) or (S) configuration. ], or a pharmaceutically acceptable salt or solvate thereof, for a disease whose symptoms are improved or alleviated by the effect of promoting Schwann cell differentiation or inhibiting dedifferentiation, the drug comprising the vitamin D derivative represented by the formula (I):

2. The vitamin D derivative represented by formula (1) is represented by the following formula (1A): [n represents an integer of 1 to 3. ３ C optionally substituted with 1 to 3 halogen atoms １ ~C ６ Alkyl group, C ３ ~C ６ a cycloalkyl group or a C group optionally substituted with 1 to 3 halogen atoms; １ ~C ６ represents an alkoxy group. １ , and X ２ are each independently a hydrogen atom or C １ ~C ３ represents an alkyl group, or X １ and X ２ together represent a methylidene group, or -(CH ２ ) ｍ - (where m is an integer of 2 to 5). ３ is CH ２ group, or C=CH ２ group (wherein X １ and X ２ When X ３ is C=CH ２ The therapeutic or ameliorating agent according to claim 1 , wherein the medicament is represented by the formula:

3. n represents 1, and R ３ C optionally substituted with 1 to 3 halogen atoms ２ ~C ６ C optionally substituted with an alkyl group or 1 to 3 halogen atoms １ ~C ６ The therapeutic or ameliorating agent according to claim 2, which represents an alkoxy group.

4. The vitamin D derivative represented by formula (1) is a compound represented by the following formula (1B): [n represents an integer of 1 to 3. １２ , R １３ , R １４ , R １５ are each independently a hydrogen atom or a C optionally substituted with 1 to 3 halogen atoms. １ ~C ６ alkyl group, or C ３ ~C ６ represents a cycloalkyl group. 12 and R 13 , R 14 and R 15 can be bonded to each other to form a ring structure having 3 to 5 members.] X １ , and X ２ are each independently a hydrogen atom or C １ ~C ３ represents an alkyl group, or X １ and X ２ together represent a methylidene group, or -(CH ２ ) ｍ - (where m is an integer of 2 to 5). ３ is CH ２ group, or C=CH ２ group (wherein X １ and X ２ When X ３ is C=CH ２ The therapeutic or ameliorating agent according to claim 1 , wherein the medicament is represented by the formula:

5. n represents 1, and R １２ and R １３ are bonded together to form a cyclopropyl group, or R １４ , R １５ The therapeutic or ameliorating agent according to claim 4 , wherein simultaneously represents a methyl group.

6. X １ and X ２ is a hydrogen atom, and X ３ is CH ２ The therapeutic or improving agent according to any one of claims 1 to 5, wherein the therapeutic or improving agent is a group.

7. X １ and X ２ is a hydrogen atom, and X ３ is C=CH ２ The therapeutic or improving agent according to any one of claims 1 to 5, wherein the therapeutic or improving agent is a group.

8. X １ and X ２ together form a methylidene group, and X ３ is CH ２ The therapeutic or improving agent according to any one of claims 1 to 5, which is a group.

9. A therapeutic or improving agent according to any one of claims 1, 2, 4, or 6 to 8, wherein n represents 2.

10. The therapeutic or improving agent according to any one of claims 1 to 9, wherein the vitamin D derivative represented by formula (1) is any one of the following vitamin D derivatives, or a pharmaceutically acceptable salt or solvate thereof: (1) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-ethylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (compound B005) (2) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-ethylpyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound B006) (3) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B030) (4) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B034) (5) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B042) (6) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B043) (7) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(difluoromethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B051) (8) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(difluoromethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B052) (9) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(2,2-difluoroethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B057) (10) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(2,2-difluoroethoxy)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B058) (11) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((S)-3-(3,3-difluoropropyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B063) (12) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-((R)-3-(3,3-difluoropropyl)pyrrolidin-1-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B064) (13) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-3-(difluoromethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B080) (14) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-(difluoromethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B081) (15) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-(2,2-difluoroethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B082) (16) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-3-(1,1-difluoroethyl)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B083) (17) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-3-(difluoromethoxy)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B086) (18) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((R)-3-(difluoromethoxy)pyrrolidin-1-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound B087) (19) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(4-oxa-7-azaspiro[2.5]octan-7-yl)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D019) (20) (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (Compound D022) (21) (1R,3R)-5-(2-((1R,(3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D023) (22) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-morpholinobutan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D024) (23) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((S)-2-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol (Compound D025) (24) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-(4-oxa-7-azaspiro[2.5]octan-7-yl)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D030) (25) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((R)-4-((S)-2-(difluoromethyl)morpholino)butan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D034) (26) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((S)-2-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D041) (27) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-4-((R)-3-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound D042) (28) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-Methyl-1-((R)-4-((S)-3-methylmorpholino)butan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D043) (29) (1R,3R)-5-(2-((1R,3aS,7aR,E)-7a-methyl-1-((R)-5-morpholinopentan-2-yl)octahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (Compound D044) (30) (1R,3S,Z)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3,3-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol (compound F006) (31) (1R,3R)-5-(2-((1R,3aS,7aR,E)-1-((S)-1-(3,3-dimethylmorpholino)propan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene)cyclohexane-1,3-diol (compound G006), 11. The therapeutic or ameliorating agent according to any one of claims 1 to 10, wherein the disease whose symptoms are improved or alleviated by the Schwann cell differentiation-promoting effect or dedifferentiation-inhibiting effect is chemotherapy-induced peripheral neuropathy (CIPN).

12. A therapeutic or ameliorating agent according to any one of claims 1 to 10, wherein the disease whose symptoms are improved or alleviated by the Schwann cell differentiation-promoting effect or dedifferentiation-inhibiting effect is diabetic peripheral neuropathy (DN).

13. The therapeutic or ameliorating agent according to any one of claims 1 to 10, wherein the disease whose symptoms are improved or alleviated by the Schwann cell differentiation-promoting effect or dedifferentiation-inhibiting effect is myasthenia gravis (MG).

14. A therapeutic or ameliorating agent according to any one of claims 1 to 10, wherein the disease whose symptoms are improved or alleviated by the Schwann cell differentiation-promoting effect or dedifferentiation-inhibiting effect is amyotrophic lateral sclerosis (ALS).

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