Therapeutic or prophylactic agents for peripheral neuropathy

Abstract

An object of the present application is to provide a compound for treatment or prevention of peripheral neuropathy. The present application provides a therapeutic or preventive agent for peripheral neuropathy, which contains a cyclic amine derivative represented by the following formula or a pharmacologically acceptable salt thereof as an effective ingredient. [Chem. 1]

Description

[0001] This application is a divisional application of PCT application with an international filing date of March 30, 2018, international application number PCT / JP2018 / 013536, Chinese national phase application number 201880022139.2, and invention title "Therapeutic or preventive agent for peripheral neuropathy". Technical Field

[0002] This invention relates to therapeutic or preventative agents for peripheral neuropathy. Background Technology

[0003] Peripheral neuropathy is caused by damage to the nerve cells (axons or cell bodies) or myelin sheaths (Schwan cells) that make up the peripheral nerves. Pathologically, axonal degeneration and myelin degeneration are observed, while physiologically, functional abnormalities such as decreased nerve conduction velocity occur.

[0004] Peripheral neuropathy is considered to be caused by damage to the nerve cells or myelin sheath of peripheral nerves, resulting in symptoms such as limb numbness (dullness of sensation), paresthesia, decreased sensation, pain or hearing impairment; motor ... muscle weakness or atrophy, flaccid paralysis or decreased or absent deep tendon reflexes; or autonomic neuropathy is considered to be caused by damage to the nerve cells or myelin sheath of peripheral nerves, resulting in symptoms such as constipation, abdominal pain, sweating disorders, dysuria or orthostatic hypotension (Non-Patent Literature 1).

[0005] Although most of these symptoms of peripheral neuropathy are not life-threatening, they greatly affect patients' daily lives and significantly reduce their quality of life (Non-Patent Literature 1).

[0006] Peripheral neuropathy can be classified according to the cause of nerve damage. Typical examples include: drug-induced peripheral neuropathy, autoimmune peripheral neuropathy, metabolic peripheral neuropathy, and hereditary peripheral neuropathy.

[0007] Drugs that can cause drug-induced peripheral neuropathy include: anticancer agents, antiviral drugs, antibacterial drugs, antituberculosis drugs, antiarrhythmic drugs, drugs for treating hyperlipidemia, immunosuppressants, and drugs for treating gout. Drug-induced peripheral neuropathy is mostly characterized by sensory disturbances such as pain, and sometimes the disturbances remain even after the drug is discontinued (Non-Patent Literature 2).

[0008] In particular, the problem with anticancer agents is the high incidence of peripheral neuropathy, making cancer treatment difficult to continue. To alleviate the symptoms of anticancer agent-induced peripheral neuropathy, analgesics (e.g., pregabalin, gabapentin, or ketamine), antiepileptic drugs (e.g., lamotrigine, carbamazepine, phenytoin, valproic acid, or clonazepam), antidepressants (e.g., amitriptyline, imipramine, clomipramine, or duloxetine), traditional Chinese medicine (e.g., Niuche Shenqi Wan or Shaoyao Gancao Tang), and vitamin B preparations (e.g., B6 or B12) have been administered, but an effective method for treating or preventing anticancer agent-induced peripheral neuropathy remains unestablished (Non-Patent Literature 1).

[0009] Of the aforementioned drugs, duloxetine alone has a high level of evidence in clinical trials and is recommended for use in the American Society of Clinical Oncology's guidelines for the treatment of chemotherapy-induced peripheral neuropathy (Non-Patent Literature 3). On the other hand, among the drugs recommended for the treatment of neuropathic pain in the respective guidelines of the International Association for the Study of Pain and the European Society of Neurology (Non-Patent Literature 4-5), there is no clear evidence that pregabalin, gabapentin, nortriptyline, or amitriptyline, in addition to duloxetine, are effective against anticancer drug-induced neuropathic pain (Non-Patent Literature 6-7).

[0010] Autoimmune peripheral neuropathy is a neuropathy caused by autoimmunity of the components of peripheral nerves. It is a diverse group of diseases including Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN), and paraproteinamic neuropathy (PPN) (Non-Patent Literature 8).

[0011] GBS is believed to be triggered by infection with pathogenic microorganisms such as viruses and bacteria, and sometimes these pathogens can cause the disease even after vaccination. Its main characteristics are numbness in the limbs, loss of deep reflexes, and often accompanied by sensory disturbances such as pain and hypoesthesia. In severe cases, there have been cases of death due to respiratory failure and autonomic neuropathy. GBS has many subtypes, including acute inflammatory demyelinating neuritis, acute motor axonal neuritis, acute motor-sensory axonal neuritis, and Fisher syndrome (Non-Patent Literature 9). CIDP differs from GBS; it is a chronic or relapsing / remittent autoimmune peripheral neuropathy causing muscle weakness and sensory disturbances. MMN and PPN are diseases similar to CIDP. MMN is characterized by myopathy without sensory disturbances (Non-Patent Literature 10). PPN is caused by the abnormal proliferation of a single immunoglobulin and is characterized by a slowly progressive sensory neuropathy (Non-Patent Literature 11).

[0012] As treatments for autoimmune peripheral neuropathy, intravenous immunoglobulin therapy and plasma exchange alone have been reported to be effective (Non-Patent Literature 12). However, plasma exchange alone has drawbacks, such as requiring specialized facilities and equipment, and being unsuitable for elderly patients or those with poor circulation. On the other hand, intravenous immunoglobulin therapy needs to be administered cautiously to patients with a history of shock or allergies. In view of the above, there is an urgent need in medical practice for treatments that are simple to administer and have fewer side effects.

[0013] Metabolic peripheral neuropathy occurs due to various metabolic abnormalities, and the underlying diseases involved include diabetes, uremia, collagen diseases, vitamin deficiencies, hypothyroidism, and many others.

[0014] In particular, diabetes is the most common cause of peripheral neuropathy, and the number of patients is expected to increase further in the future. One of the mechanisms of diabetic peripheral neuropathy is the hyperactivity of the polyol pathway, which metabolizes glucose into sorbitol. It is believed that excessive accumulation of sorbitol leads to nerve cell damage (Non-Patent Literature 13). Therefore, inhibitors of aldose reductase, which involves the polyol pathway, are considered effective for diabetic peripheral neuropathy. Epalrestat has only recently been approved in Japan and has only shown efficacy in patients with milder symptoms. It is often ineffective in patients with severe symptoms or a long history of the disease (Non-Patent Literature 14). In addition, pregabalin, duloxetine, and other drugs are used to treat pain caused by diabetic peripheral neuropathy, but there are currently no drugs specifically for peripheral neuropathy. Therefore, new drugs that show significant efficacy against diabetic peripheral neuropathy are anticipated.

[0015] Hereditary peripheral neuropathy includes Charcot-Marie-Tooth disease, familial amyloid polyneuropathy, hereditary compression-predisposing neuropathy, and hereditary neuropathic amyotrophic lateral sclerosis. Charcot-Marie-Tooth disease is the most typical. At least 50 genes are known to be associated with Charcot-Marie-Tooth disease, with mutations in genes related to myelination, nerve cell formation and maintenance, and multiple heterologous genes present. Typically, motor and sensory nerves are damaged, and motor dysfunction is significant. Clinically, physical therapy and occupational therapy are sometimes used to maintain muscle strength, but currently there are no effective treatments or drugs for hereditary peripheral neuropathy, including Charcot-Marie-Tooth disease (Non-Patent Literature 15).

[0016] In peripheral neuropathy caused by various reasons, there are patients for whom there are no effective drugs or where drugs are ineffective. Therefore, there is a desire to develop new drugs for peripheral neuropathy.

[0017] Furthermore, in clinical practice, detailed examinations are required to identify the cause of peripheral neuropathy, leading to cases where idiopathic peripheral neuropathy is diagnosed (Non-Patent Literature 16). Therefore, drugs that are universally effective against peripheral neuropathy regardless of the cause of the disorder are highly desirable, but such drugs do not currently exist. Nevertheless, it is believed that drugs universally effective against peripheral neuropathy can be developed. As mentioned above, peripheral neuropathy is classified into many types with diverse clinical symptoms, but the commonality lies in the fact that it causes disease by damaging the cells that make up the peripheral nerves, regardless of the cause. Therefore, it is predicted that drugs based on in vivo molecules related to the survival, proliferation, or maintenance of nerve cells, such as neurotrophic factors, will be widely effective against peripheral neuropathy (Non-Patent Literature 17). However, even drugs based on neurotrophic factors have not shown effectiveness in clinical trials of anticancer drug-induced peripheral neuropathy and diabetic peripheral neuropathy (Non-Patent Literature 18-19), indicating that developing drugs universally effective against peripheral neuropathy is very difficult.

[0018] Patent document 1 discloses that cyclic amine derivatives have analgesic effects, but there is no report suggesting any effect on peripheral neuropathy.

[0019] Existing technical documents Patent documents Patent Document 1: International Publication No. 2016 / 136944 Non-patent literature Non-patent literature 1: Shizuoka Prefectural Shizuoka Cancer Center, "Anticancer Drug Therapy and Peripheral Neuropathy (3rd Edition)", 2016, pp. 1-36 Non-patent literature 2: Vilholm et al., Basic & Clinical Pharmacology & Toxicology, 2014, Vol. 115, pp. 185-192 Non-patent literature 3: Hershman et al., Journal of Oncology Practice, 2014, Vol. 10, pp. e421-e424 Non-patent literature 4: Attal et al., Pain: Clinical Updates, 2010, Vol. 18 Non-patent literature 5: Attal et al., European Journal of Neurology, 2010, Vol. 17, pp. 1113-1123 Non-patent literature 6: Shinde et al., Support Care Cancer, 2016, Vol. 24, pp. 547-553 Non-patent literature 7: Gewandter et al., Pain, 2017, Vol. 158, pp. 30-33 Non-patent literature 8: Nan, Clinical Neurology, 2009, Vol. 49, pp. 956-958 Non-patent literature 9: Hughes et al., The Lancet, 2005, Vol. 366, pp. 1653-1666 Non-patent literature 10: Nan, Journal of the Japanese Society of Internal Medicine, 2013, Vol. 102, pp. 1965-1970 Non-patent literature 11: Rison et al., BioMed Central Neurology, 2016, Vol. 16, No. 13 Non-patent literature 12: Hughes et al., The Lancet, 1997, Vol. 349, pp. 225-230 Non-patent literature 13: Singh et al., Pharmacological Research, 2014, Vol. 80, pp. 21-35 Non-patent literature 14: Schemmel et al., Journal of Diabetes and Its Complication, 2010, Vol. 24, pp. 354-360 Non-patent literature 15: Saporta et al., Neurologic Clinics, 2013, Vol. 31, pp. 597-619 Non-patent literature 16: Azhary et al., American Family Physician, 2010, Vol. 81, pp. 887-892 Non-patent literature 17: McMahon et al., Current Opinion in Neurobiology, 1995, Vol. 5, pp. 616-624 Non-patent literature 18: Argyriou et al., Critical Reviews in Oncology / Hematology, 2012, Vol. 82, pp. 51-77 Non-patent literature 19: Apfel et al., JAMA, 2000, Vol. 284, pp. 2215-2221. Summary of the Invention

[0020] The technical problem that the invention aims to solve The purpose of this invention is to provide a therapeutic or preventative agent for peripheral neuropathy.

[0021] Means for solving technical problems In order to solve the above-mentioned problems, the inventors conducted in-depth research and found that specific cyclic amine derivatives or their pharmacologically acceptable salts have a significant inhibitory effect on peripheral neuropathy.

[0022] That is, the present invention provides a therapeutic or preventive agent for peripheral neuropathy, which contains a cyclic amine derivative of the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. [Chemistry 1] In the formula, the carbon atom marked with * is an asymmetric carbon, and A represents the group represented by general formula (IIa), (IIb), or (IIc). [Chemistry 2] R 1 R indicates a methyl or ethyl group that can be substituted with a halogen atom. 2 R represents an alkyl carbonyl group having 2 to 5 hydrogen atoms or carbon atoms. 3 Each can be used independently to represent methyl or ethyl, and n represents 1 or 2.

[0023] In the above-mentioned cyclic amine derivatives, A is preferably a group represented by general formula (IIa), and R is more preferably a group represented by general formula (IIa). 1 The methyl or ethyl group can be substituted with a fluorine atom, and R is further preferred. 1 It can be methyl, ethyl, difluoromethyl or 2,2,2-trifluoroethyl.

[0024] Furthermore, in the above-mentioned cyclic amine derivatives, A is preferably a group represented by general formula (IIb) or (IIc), and R is more preferably a group represented by general formula (IIb). 1 The methyl or ethyl group can be substituted with a fluorine atom, and R is further preferred. 1 It can be methyl, ethyl, difluoromethyl or 2,2,2-trifluoroethyl.

[0025] Furthermore, in the aforementioned cyclic amine derivatives, it is preferable that A is a group represented by general formula (IIa), and the stereochemistry of the asymmetric carbon with * is S configuration; in this case, R is more preferred. 1 The methyl or ethyl group can be substituted with a fluorine atom, and R is further preferred. 1 It can be methyl, ethyl, difluoromethyl or 2,2,2-trifluoroethyl.

[0026] Furthermore, the present invention provides a pharmaceutical composition for treating or preventing peripheral neuropathy, comprising a cyclic amine derivative of the above general formula (I) or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient, etc.

[0027] Furthermore, the present invention provides a cyclic amine derivative of the above general formula (I) or a pharmacologically acceptable salt thereof for use in the treatment or prevention of peripheral neuropathy.

[0028] Furthermore, the present invention provides the use of the cyclic amine derivative of the above-described general formula (I) or a pharmacologically acceptable salt thereof for the treatment or prevention of peripheral neuropathy.

[0029] Furthermore, the present invention provides the use of the cyclic amine derivative of the above general formula (I) or a pharmacologically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of peripheral neuropathy.

[0030] Furthermore, the present invention provides a method for treating or preventing peripheral neuropathy, the method comprising administering to a patient requiring treatment a therapeutically effective amount of the cyclic amine derivative of the above general formula (I) or a pharmacologically acceptable salt thereof.

[0031] In various embodiments of the present invention, the aforementioned peripheral neuropathy is preferably drug-induced peripheral neuropathy, autoimmune peripheral neuropathy, metabolic peripheral neuropathy, hereditary peripheral neuropathy, vasculitic peripheral neuropathy, toxic peripheral neuropathy, infectious peripheral neuropathy, or peripheral neuropathy associated with malignant tumors; more preferably, it is drug-induced peripheral neuropathy, autoimmune peripheral neuropathy, metabolic peripheral neuropathy, or hereditary peripheral neuropathy; even more preferably, it is drug-induced peripheral neuropathy, autoimmune peripheral neuropathy, or metabolic peripheral neuropathy. The aforementioned drug-induced peripheral neuropathy is preferably anticancer agent-induced peripheral neuropathy. The aforementioned autoimmune peripheral neuropathy is preferably selected from at least one of Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculopathy (CIDP), multifocal motor neuropathy (MMN), and neuropathy with abnormal proteinemia (PPN). The aforementioned metabolic peripheral neuropathy is preferably diabetic peripheral neuropathy. The aforementioned hereditary peripheral neuropathy is preferably Chuck-Maley-Duss disease.

[0032] Invention Effects The cyclic amine derivatives of the present invention, or their pharmacologically acceptable salts, can treat or prevent peripheral neuropathy. The aforementioned peripheral neuropathy includes, for example, drug-induced peripheral neuropathy, autoimmune peripheral neuropathy, or metabolic peripheral neuropathy. Specifically, the aforementioned drug-induced peripheral neuropathy is anticancer agent-induced peripheral neuropathy. Specifically, the aforementioned autoimmune peripheral neuropathy is selected from at least one of Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculopathy (CIDP), multifocal motor neuropathy (MMN), and neuropathy with abnormal proteinemia (PPN). Specifically, the aforementioned metabolic peripheral neuropathy is diabetic peripheral neuropathy. Specifically, the aforementioned hereditary peripheral neuropathy is Chuck-Maley-Duss disease.

[0033] This specification contains the contents described in the specification and / or drawings of Japanese Patent Application No. 2017-071329 and Japanese Patent Application No. 2017-071339, which form the basis of the priority of this application. Attached Figure Description

[0034] Figure 1 Figure : This figure shows the protective effect of compound 1 against cell damage in rat dorsal root ganglion-derived neural cell lines.

[0035] Figure 2 Figure : This figure shows the repair effect of compound 1 on cell damage in rat dorsal root ganglion-derived neural cell lines.

[0036] Figure 3Figure showing the effect of compound 1 on myelin formation in rat dorsal root ganglion nerve cells co-cultured with Schwann cells.

[0037] Figure 4 Figure : This figure shows the effect of compound 1 on the expression level of myelin basic protein in rat dorsal root ganglion nerve cells co-cultured with Schwann cells.

[0038] Figure 5 Figure : This figure shows the effect of repeated administration of compound 1 on cold abnormal pain in a rat model of oxaliplatin-induced peripheral neuropathy.

[0039] Figure 6 Figure : This figure shows the effect of repeated administration of compound 1 on mechanical abnormal pain in a rat model of oxaliplatin-induced peripheral neuropathy.

[0040] Figure 7 Figure : This figure shows the effect of a single dose of compound 1 on mechanical abnormal pain in a rat model of cisplatin-induced peripheral neuropathy.

[0041] Figure 8 Figure : This figure shows the effect of a single dose of compound 1 on mechanical abnormal pain in a rat model of paclitaxel-induced peripheral neuropathy.

[0042] Figure 9 Figure : This figure shows the effect of a single dose of compound 1 on mechanical abnormal pain in a rat model of bortezomib-induced peripheral neuropathy.

[0043] Figure 10 Figure : This figure shows the effect of compound 1 on the clinical scores of a rat model of experimental autoimmune neuritis.

[0044] Figure 11 Figure : This shows the effect of compound 1 on weight loss in a rat model of experimental autoimmune neuritis.

[0045] Figure 12 Figure : This figure shows the effect of compound 1 on mechanical abnormal pain in a rat model of experimental autoimmune neuritis.

[0046] Figure 13 Figure : This figure shows the effect of compound 1 on reducing nerve conduction velocity in a rat streptozotocin-induced diabetes model.

[0047] Figure 14 Figure : This figure shows the effect of compound 1 on mechanical abnormal pain in a rat streptozotocin-induced diabetic model. Detailed Implementation

[0048] Unless otherwise specified, the following terms used in this specification are defined as follows.

[0049] An embodiment of the present invention relates to a cyclic amine derivative characterized by having the following general formula (I). [Chemistry 3] In the formula, Carbons marked with an asterisk (*) are asymmetric carbons, and A represents a group represented by general formula (IIa), (IIb), or (IIc). [Chemistry 4] R 1 R indicates a methyl or ethyl group that can be substituted with a halogen atom. 2 R represents an alkyl carbonyl group having 2 to 5 hydrogen atoms or carbon atoms. 3 Each can be used independently to represent methyl or ethyl, and n represents 1 or 2.

[0050] In the above-mentioned cyclic amine derivatives, A is preferably a group represented by general formula (IIa), and R is preferably a group represented by general formula (IIa). 1 It is a methyl or ethyl group that can be substituted with a fluorine atom, more preferably R. 1 It can be methyl, ethyl, difluoromethyl or 2,2,2-trifluoroethyl.

[0051] Furthermore, in the above-mentioned cyclic amine derivatives, A is preferably a group represented by general formula (IIb) or (IIc), and R is preferably a group represented by general formula (IIb) or (IIc). 1 It is a methyl or ethyl group that can be substituted with a fluorine atom, more preferably R. 1 It can be methyl, ethyl, difluoromethyl or 2,2,2-trifluoroethyl.

[0052] Furthermore, in the above-mentioned cyclic amine derivatives, A is preferably a group represented by general formula (IIa), and the stereochemistry of the asymmetric carbon with * is preferably S-configuration. In this case, R is preferred. 1 The methyl or ethyl group can be substituted with a fluorine atom, and R is further preferred. 1 It can be methyl, ethyl, difluoromethyl or 2,2,2-trifluoroethyl.

[0053] In one embodiment of the above-mentioned cyclic amine derivative, A is a group represented by general formula (IIa), and R... 1 Indicates methyl, ethyl, difluoromethyl, or 2,2,2-trifluoroethyl, R 2 R represents an alkyl carbonyl group having 2 to 5 hydrogen atoms or carbon atoms. 3 Each can be represented independently as methyl or ethyl. In this embodiment, the stereochemistry of the asymmetric carbon with an asterisk (*) is preferably S-configuration.

[0054] In one embodiment of the above-mentioned cyclic amine derivative, A is a group represented by general formula (IIa), and R... 1R represents methyl or 2,2,2-trifluoroethyl. 2 R represents an alkyl carbonyl group having 2 hydrogen atoms or 2 carbon atoms. 3 This indicates a methyl group. In this embodiment, the stereochemistry of the asymmetric carbon with an asterisk (*) is preferably S-configuration.

[0055] In one embodiment of the above-mentioned cyclic amine derivative, A is a group represented by general formula (IIb), and R... 1 R indicates a methyl or ethyl group that can be substituted with a fluorine atom. 2 R represents an alkyl carbonyl group having 2 to 5 hydrogen atoms or carbon atoms. 3 Each can be independently represented as methyl or ethyl, and n represents 1 or 2. In this embodiment, the stereochemistry of the asymmetric carbon with * is preferably S configuration.

[0056] In one embodiment of the above-mentioned cyclic amine derivative, A is a group represented by general formula (IIb), and R... 1 Indicates methyl, ethyl, difluoromethyl, or 2,2,2-trifluoroethyl, R 2 R represents an alkyl carbonyl group having 2 to 5 hydrogen atoms or carbon atoms. 3 Each can be independently represented as methyl or ethyl, and n represents 1 or 2. In this embodiment, the stereochemistry of the asymmetric carbon with * is preferably S configuration.

[0057] In one embodiment of the above-mentioned cyclic amine derivative, A is a group represented by general formula (IIb), and R... 1 R represents methyl or 2,2,2-trifluoroethyl. 2 R represents an alkyl carbonyl group having 2 hydrogen atoms or 2 carbon atoms. 3 The symbol represents a methyl group, and n represents 1 or 2. In this embodiment, the stereochemistry of the asymmetric carbon with an asterisk (*) is preferably S-configuration.

[0058] In one embodiment of the above-mentioned cyclic amine derivative, A is a group represented by general formula (IIc), and R... 1 R indicates a methyl or ethyl group that can be substituted with a fluorine atom. 2 R represents an alkyl carbonyl group having 2 to 5 hydrogen atoms or carbon atoms. 3 This indicates methyl or ethyl. In this embodiment, the stereochemistry of the asymmetric carbon with an asterisk (*) is preferably S-configuration.

[0059] In one embodiment of the above-mentioned cyclic amine derivative, A is a group represented by general formula (IIc), and R... 1 Indicates methyl, ethyl, difluoromethyl, or 2,2,2-trifluoroethyl, R 2 R represents an alkyl carbonyl group having 2 to 5 hydrogen atoms or carbon atoms. 3 This indicates methyl or ethyl. In this embodiment, the stereochemistry of the asymmetric carbon with an asterisk (*) is preferably S-configuration.

[0060] In one embodiment of the above-mentioned cyclic amine derivative, A is a group represented by general formula (IIc), and R... 1 R represents methyl or 2,2,2-trifluoroethyl. 2 R represents an alkyl carbonyl group having 2 hydrogen atoms or 2 carbon atoms. 3 This indicates a methyl group. In this embodiment, the stereochemistry of the asymmetric carbon with an asterisk (*) is preferably S-configuration.

[0061] "Halogen atom" refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom.

[0062] "Methyl or ethyl that can be substituted by a halogen atom" means that each hydrogen atom can be independently substituted by the aforementioned halogen atom. Examples include: methyl or ethyl, or difluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl.

[0063] "Alkyl carbonyl with 2 to 5 carbon atoms" refers to a group formed by the bonding of a straight-chain, branched, or cyclic saturated hydrocarbon group with 1 to 4 carbon atoms to a carbonyl group. Examples include acetyl, n-propionyl, n-butyryl, isobutyryl, or valeryl.

[0064] Preferred examples of the cyclic amine derivatives (hereinafter, cyclic amine derivatives (I)) represented by the above general formula (I) are shown in Tables 1-1 and 1-2, but the present invention is not limited thereto.

[0065] It should be noted that when the cyclic amine derivative (I) contains enantiomers, stereoisomers, or other isomers, any one of these isomers and mixtures thereof are included in the cyclic amine derivative (I). Furthermore, when the cyclic amine derivative (I) contains enantiomers, stereoisomers, or other isomers, any one of these isomers and mixtures thereof are included in the cyclic amine derivative (I). Additionally, conformational isomers may sometimes be generated, but such isomers and mixtures thereof are also included in the cyclic amine derivative (I). The target isomer can be obtained by known methods or similar methods. For example, when the cyclic amine derivative (I) contains enantiomers, the enantiomers resolved from the cyclic amine derivative (I) are also included in the cyclic amine derivative (I).

[0066] The target enantiomer can be obtained by known means (e.g., using optically active synthetic intermediates, or using known methods or similar methods (e.g., optical resolution) on racemic mixtures of the final product).

[0067] Furthermore, the present invention comprises a prodrug of a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof. The prodrug of the cyclic amine derivative (I) is a compound that is enzymatically or chemically converted into the cyclic amine derivative (I) in vivo. The active form of the prodrug of the cyclic amine derivative (I) is the cyclic amine derivative (I), but the prodrug of the cyclic amine derivative (I) itself may also be active.

[0068] Examples of prodrugs for cyclic amine derivatives (I) include compounds formed by alkylation, phosphorylation, or boronization of the hydroxyl group of the cyclic amine derivative (I). These compounds can be synthesized from cyclic amine derivatives (I) using known methods.

[0069] In addition, the prodrug of the cyclic amine derivative (I) can also be a substance that is converted into the cyclic amine derivative (I) under the physiological conditions described in well-known literature ("Development of Pharmaceuticals", Hirokawa Shoten, 1990, Vol. 7, pp. 163-198 and Progress in Medicine, Vol. 5, 1985, pp. 2157-2161).

[0070] Cyclic amine derivatives (I) can be isotopically labeled. Examples of labeled isotopes include, for instance, 2 H, 3 H, 13 C 14 C 15 N、 15 O、 18 O and / or 125 I.

[0071] Pharmacologically acceptable salts of cyclic amine derivatives (I) include, for example, inorganic acid salts such as hydrochloride, sulfate, phosphate, or hydrobromide, or organic acid salts such as oxalate, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, salicylate, hydroxynaphthylcarboxylate, palmitate, ascorbate, adipate, methanesulfonate, p-toluenesulfonate, or cinnamate. Furthermore, these salts can form hydrates, solvates, or polymorphs.

[0072] Cyclic amine derivatives (I) or their pharmacologically acceptable salts can be synthesized according to methods described, for example, in well-known literature (International Publication No. 2016 / 136944).

[0073] As peripheral nerves, examples include sensory nerves, motor nerves, and autonomic nerves.

[0074] Peripheral neuropathy is caused by damage to at least one of the nerve cells and myelin sheath (Schwan cells) that make up the peripheral nerves.

[0075] Peripheral neuropathy is not limited to the following examples, but may include drug-induced peripheral neuropathy, autoimmune peripheral neuropathy, metabolic peripheral neuropathy, hereditary peripheral neuropathy, vasculitic peripheral neuropathy, toxic peripheral neuropathy, infectious peripheral neuropathy, and peripheral neuropathy associated with malignant tumors.

[0076] Symptoms of peripheral neuropathy are not limited to those listed below. For example, when the damaged nerve is a sensory nerve, symptoms may include numbness (dullness of sensation), paresthesia, decreased sensation, pain, and hearing impairment. When the damaged nerve is a motor nerve, symptoms may include muscle weakness / atrophy, flaccid paralysis, and decreased / absent deep tendon reflexes. When the damaged nerve is an autonomic nerve, symptoms may include constipation, abdominal pain, sweating disorders, difficulty urinating, and orthostatic hypotension.

[0077] Examples of drug-induced peripheral neuropathy include peripheral neuropathy caused by anticancer drugs, antiviral drugs, antibiotics, antituberculosis drugs, antiarrhythmic drugs, drugs for treating hyperlipidemia, immunosuppressants, drugs for treating gout, and other drugs.

[0078] Examples of anticancer agents include, for example, nucleic acid metabolism inhibitors, microtubule polymerization or depolymerization inhibitors, hormone antagonists, intracellular signal transduction inhibitors, malignant tumor-specific molecularly targeted drugs, and non-specific immune activators.

[0079] Examples of nucleic acid metabolism inhibitors include alkylating agents, antitumor antibiotics, topoisomerase inhibitors, platinum preparations, pyrimidine metabolism inhibitors, purine metabolism inhibitors, and folic acid synthesis inhibitors.

[0080] Examples of inhibitors of microtubule polymerization or depolymerization include vinca alkaloid-based anticancer agents and taxane-based anticancer agents.

[0081] Examples of hormone antagonists include anti-estrogens and anti-androgens.

[0082] Examples of intracellular signal transduction inhibitors include protein body inhibitors and hydroxycerebroside inhibitors.

[0083] Examples of specific molecularly targeted drugs for malignant tumors include tyrosine kinase inhibitors, antibody preparations, and arsenic preparations.

[0084] Examples of non-specific immune activators include hemolytic streptococcal preparations and Coriolus versicolor polysaccharide preparations.

[0085] Not limited to the specific anticancer agents listed below, examples of nucleic acid metabolism inhibitors include oxaliplatin, cisplatin, carboplatin, nedaplatin, cytarabine, nelabine, etoposide, and teniposide; examples of microtubule polymerization or depolymerization inhibitors include paclitaxel, docetaxel, cabazitaxel, vincristine, vinblastine, vinorelbine, vindesin, eribulin, vinflunine, epothilone, and ixapril; examples of intracellular signal transduction inhibitors include bortezomib and carfilzomib; and examples of malignant tumor-specific molecularly targeted drugs include belenutuzumab-vitoline, trastuzumab-mettansine, thalidomide, pomalidomide, or lenalidomide.

[0086] Antiviral drugs are not limited to those listed below, but may include, for example, efavirenz, emtricitabine, emtricitabine-tenofovir disoproxil fumarate, saquinavir, shanivudine, zalcitabine, doxorinosine, stavudine, zidovudine, darunavir, deravirin mesylate, nevirapine, tenofovir disoproxil fumarate, foscarnet sodium hydrate, lamivudine, lamivudine-abacavir sulfate, ritonavir, ribavirin, lopinavir-ritonavir, atazanavir, indinavir, etc.

[0087] Antibacterial drugs are not limited to those listed below, but may include, for example, chloramphenicol, nitrofurantoin, metronidazole, dapsone, ethambutol, and fluoroquinolones (levofloxacin, ciprofloxacin, moxifloxacin, norfloxacin, ofloxacin, etc.).

[0088] Anti-tuberculosis drugs are not limited to those listed below; examples include isoniazid and ethambutol.

[0089] Antiarrhythmic drugs are not limited to those listed below; examples include amiodarone and procainamide.

[0090] Drugs used to treat hyperlipidemia are not limited to those listed below; examples include pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin, etc.

[0091] Immunosuppressive drugs are not limited to those listed below; examples include tacrolimus, cyclosporine, mycophenolate mofetil, leflunomide, chloroquine, interferon-alpha, and gold preparations.

[0092] Other examples of drugs include, but are not limited to, those listed below, such as colchicine or allopurinol for gout treatment, phenytoin for antiepileptic drugs, nitrous oxide for anesthetics, pyridoxine for vitamins, disulfiram for anti-alcohol drugs, and hydralazine for antihypertensive drugs.

[0093] Drugs that cause drug-induced peripheral neuropathy include not only those drugs discovered to date based on the above classification, but also those discovered in the future.

[0094] Autoimmune peripheral neuropathy includes, but is not limited to, the following examples: Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculopathy, multifocal motor neuropathy, and neuropathy with abnormal proteinemia. Subtypes of Guillain-Barré syndrome include, for example, acute inflammatory demyelinating neuritis, acute motor axonal neuritis, acute motor-sensory axonal neuritis, and Fisher syndrome.

[0095] Metabolic peripheral neuropathy is not limited to the following examples; other examples include diabetic peripheral neuropathy, uremic peripheral neuropathy, collagen neuropathy, vitamin deficiency peripheral neuropathy, and hypothyroid peripheral neuropathy.

[0096] Hereditary peripheral neuropathy is not limited to the following examples; other examples include Chuck-Maley-Duss disease, familial amyloid polyneuropathy, hereditary compression-susceptible neuropathy, and hereditary neuropathic amyotrophic lateral sclerosis.

[0097] The inhibitory effects of cyclic amine derivatives (I) or their pharmacologically acceptable salts on peripheral nerve cell dysfunction can be evaluated using rat dorsal root ganglion-derived nerve cell lines. Specifically, cell viability was induced by treating rat dorsal root ganglion-derived nerve cell lines with cytotoxic substances, and the inhibitory effect on this reduction in cell viability was evaluated.

[0098] The myelination-promoting effects of cyclic amine derivatives (I) or their pharmacologically acceptable salts can be evaluated using co-culture of rat dorsal root ganglion neurons and Schwann cells. Specifically, rat dorsal root ganglion neurons and Schwann cells are co-cultured, myelination is induced by ascorbic acid treatment, and the promotion of myelination is evaluated.

[0099] The aforementioned inhibitory effects on cell activity reduction and myelin formation promotion are considered effective in the prevention and treatment of peripheral neuropathy. It should be noted that this embodiment is not limited to this conjecture.

[0100] Cyclic amine derivatives (I) or their pharmacologically acceptable salts are effective for the treatment or prevention of drug-induced peripheral neuropathy, particularly anticancer drug-induced peripheral neuropathy, and can be evaluated using peripheral neuropathy models induced by various drugs, particularly various anticancer drugs (Hoeke et al., ILAR Journal, 2014, Vol. 54, pp. 273-281).

[0101] The efficacy of cyclic amine derivatives (I) or their pharmacologically acceptable salts for the treatment or prevention of autoimmune peripheral neuropathy can be evaluated using an experimental autoimmune neuritis (EAN) model (Soliven, ILAR Journal, 1994, Vol. 54, pp. 282-290).

[0102] The efficacy of cyclic amine derivatives (I) or their pharmacologically acceptable salts for the treatment or prevention of metabolic peripheral neuropathy, particularly diabetic peripheral neuropathy, can be evaluated using a streptozotocin-induced diabetes model (O'Brien et al., ILAR Journal, 2014, Vol. 54, pp. 259-272).

[0103] The efficacy of cyclic amine derivatives (I) or their pharmacologically acceptable salts for the treatment or prevention of hereditary peripheral neuropathy, particularly Chuck-Mally-Duss disease, can be evaluated using PMP22 Trembler-J mice (Nicks et al., Neurobiology of Disease, 2014, Vol. 70, pp. 224-236).

[0104] Cyclic amine derivatives (I) or their pharmacologically acceptable salts can be used as excellent medicines useful for the treatment or prevention of peripheral neuropathy in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, or humans), especially humans.

[0105] When a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof is used as a drug, the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof may be administered orally or non-orally, either directly or in combination with a pharmaceutically acceptable carrier.

[0106] Examples of dosage forms for oral administration of drugs containing a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as the active ingredient include, for example, tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules and microcapsules), syrups, emulsions, or suspensions. Furthermore, examples of dosage forms for non-oral administration of drugs containing a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as the active ingredient include, for example, injections, infusions, drips, suppositories, ointments, or patches. Further, formulations combining with a suitable base (e.g., polymers of butyric acid, polymers of glycolic acid, copolymers of butyric acid and glycolic acid, mixtures of polymers of butyric acid and glycolic acid, or polyglycerol fatty acid esters) to form sustained-release formulations are also effective.

[0107] The preparation of the above-mentioned dosage form can be carried out according to well-known manufacturing methods commonly used in the pharmaceutical industry. In this case, it can be manufactured with excipients, binders, lubricants, disintegrants, sweeteners, surfactants, suspending agents, or emulsifiers commonly used in the pharmaceutical industry, as needed.

[0108] The preparation of tablets may include, for example, excipients, binders, disintegrants, or lubricants. The preparation of pills and granules may include, for example, excipients, binders, or disintegrants. Furthermore, the preparation of powders and capsules may include, for example, excipients. The preparation of syrups may include, for example, sweeteners. The preparation of emulsions or suspensions may include, for example, surfactants, suspending agents, or emulsifiers.

[0109] Examples of excipients include lactose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, or calcium sulfate.

[0110] Examples of adhesives include starch paste solutions, gum arabic solutions, gelatin solutions, tragacanth solutions, carboxymethyl cellulose solutions, sodium alginate solutions, or glycerin.

[0111] Examples of disintegrants include starch or calcium carbonate.

[0112] Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, or purified talc.

[0113] Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerol, or simple syrup.

[0114] Examples of surfactants include sodium lauryl sulfate, polysorbate 80, sorbitol monofatty acid ester, or stearate polyoxyethylene (40) ester.

[0115] Examples of suspending agents include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, or bentonite.

[0116] Examples of emulsifiers include gum arabic, gum tragali, gelatin, or polysorbate 80.

[0117] Furthermore, when preparing a drug containing a cyclic amine derivative (I) or its pharmacologically acceptable salt as an active ingredient into the above dosage form, colorants, preservatives, flavoring agents, tasters, stabilizers or thickeners commonly used in the pharmaceutical field can be added.

[0118] The daily dosage of a drug containing a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient varies depending on the patient's condition or weight, the type of compound, or the route of administration. For example, when administering orally to an adult (weighing approximately 60 kg), it is preferable to administer the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof in an active ingredient amount ranging from 1 to 1000 mg, divided into 1 to 3 doses. When administering non-orally to an adult (weighing approximately 60 kg), if it is an injectable drug, it is preferable to administer the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof in an active ingredient amount equivalent to 0.01 to 100 mg per kg of body weight via intravenous injection.

[0119] To supplement or enhance therapeutic or preventative effects, or to reduce dosage, cyclic amine derivatives (I) or their pharmacologically acceptable salts may be used in combination with other drugs in appropriate amounts. For example, they may be used in combination with drugs that relieve symptoms of peripheral neuropathy. Example

[0120] The present invention will now be described in detail based on specific embodiments, but the present invention is not limited thereto.

[0121] As the test compound, (S)-1-(4-(dimethylamino)piperidin-1-yl)-3-hydroxy-3-(1-methyl-1H-imidazol-2-yl)prop-1-one (hereinafter referred to as compound 1) was synthesized according to the method described in the publicly known document (International Publication No. 2016 / 136944).

[0122] [Chemistry 5] (Example 1) Protective effect of cyclic amine derivative (I) or its pharmacologically acceptable salt against cell damage in rat dorsal root ganglion-derived neural cell lines: This study investigated the protective effect of cyclic amine derivatives (I) or their pharmacologically acceptable salts against cell damage in rat dorsal root ganglion-derived neural cell lines.

[0123] The rat fetal dorsal root ganglion-derived cell line ND15 was cultured in DMEM medium containing 10% FBS. On the second day, it was cultured for 8 days in DMEM medium containing 10% FBS and EC23 (10 μM, Reinner) to differentiate into nerve cells.

[0124] The medium was replaced with DMEM / F12 containing cisplatin (final concentration 50 μM), and cultured for 4 hours to induce cell damage. Compound 1 was treated in the same medium as cisplatin (final concentration 0.5, 5, or 50 μM). The treatment groups were: no treatment, 50 μM compound 1 treatment, cisplatin treatment, 0.5 μM cisplatin and compound 1 treatment, 5 μM cisplatin and compound 1 treatment, and 50 μM cisplatin and compound 1 treatment, totaling 6 groups.

[0125] To determine cell viability, the medium was replaced with DMEM / F12 containing Alamar Blue (Invitrogen). After culturing for 2 hours, absorbance was measured at 570 nm and 595 nm. Cell viability was calculated as the ratio of absorbance at 570 nm to absorbance at 595 nm, with the untreated group set as 100%.

[0126] The evaluation results of the effect of compound 1 on cell activity are shown in Figure 1 . Figure 1 The vertical axis represents cell viability (%) (mean ± standard error; 6 cases per group). The horizontal axis, from left to right, represents the untreated group, the 150 μM compound treatment group, the cisplatin treatment group, the cisplatin and 10.5 μM compound treatment group, the cisplatin and 15 μM compound treatment group, and the cisplatin and 150 μM compound treatment group. "#" in the figure indicates a statistically significant difference compared to the untreated group (#: p < 0.05, Student's t-test), and "*" indicates a statistically significant difference compared to the cisplatin treatment group (*: p < 0.025, Williams' multiple comparisons, one-sided).

[0127] Cisplatin treatment resulted in decreased cell activity in rat dorsal root ganglion-derived neural cell lines, which was subsequently inhibited by co-treatment with compound 1. This indicates that compound 1 protects rat dorsal root ganglion-derived neural cell lines from damage.

[0128] (Example 2) The repair effect of cyclic amine derivative (I) or its pharmacologically acceptable salt on cell damage in rat dorsal root ganglion-derived neural cell lines: This study investigated the effects of cyclic amine derivatives (I) or their pharmacologically acceptable salts on the repair of cell damage in rat dorsal root ganglion-derived neural cell lines.

[0129] Cell damage was induced in the rat fetal dorsal root ganglion-derived cell line ND15 by cisplatin using the same method as in Example 1, and cell viability was measured. Compound 1 was treated with cisplatin for 24 hours followed by a 2-hour treatment in culture medium (final concentration 0.5, 5, or 50 μM). The groups consisted of six groups: no treatment, 50 μM compound 1 treatment, cisplatin treatment, 0.5 μM cisplatin and compound 1 treatment, 5 μM cisplatin and compound 1 treatment, and 50 μM cisplatin and compound 1 treatment.

[0130] The evaluation results of the effect of compound 1 on cell activity are shown in Figure 2 . Figure 2 The vertical axis represents cell viability (%) (mean ± standard error; 6 cases per group). The horizontal axis, from left to right, represents the untreated group, the 150 μM compound treatment group, the cisplatin treatment group, the cisplatin and 10.5 μM compound treatment group, the cisplatin and 15 μM compound treatment group, and the cisplatin and 150 μM compound treatment group. "#" in the figure indicates a statistically significant difference compared to the untreated group (#: p < 0.05, Student's t-test), and "*" indicates a statistically significant difference compared to the cisplatin treatment group (*: p < 0.025, Williams' multiple comparisons, one-sided).

[0131] Cisplatin treatment resulted in decreased cell activity in rat dorsal root ganglion-derived neural cell lines, which was subsequently inhibited by post-treatment with compound 1. This indicates that compound 1 repairs damage to rat dorsal root ganglion-derived neural cell lines.

[0132] (Example 3) Effects of cyclic amine derivatives (I) or their pharmacologically acceptable salts on myelination in rat dorsal root ganglion neurons co-cultured with Schwann cells: This study investigated the promoting effect of cyclic amine derivatives (I) or their pharmacologically acceptable salts on myelin formation in rat dorsal root ganglion cells co-cultured with Schwann cells.

[0133] Dorsal root ganglia were extracted from fetuses of female SD rats on day 15 of gestation and separated into nerve cells and Schwann precursor cells for culture (cell culture start day was set as day 1). On day 19 (day 19) from the start of cell culture, Schwann precursor cells were added to the nerve cell culture medium, thus initiating co-culture. Myelination was induced by ascorbic acid treatment from day 26 to 40 (days 26 to 40) (combined with 2 to 3 medium changes, for a total of 4 to 5 times).

[0134] Compound 1 (final concentration 30 μM) dissolved in sterile distilled water was treated a total of 4 to 5 times in conjunction with ascorbic acid treatment. As a control, sterile distilled water was treated instead of the compound 1 solution. The groups consisted of two groups: a sterile distilled water treatment group (vehicle treatment group) and a 30 μM compound 1 treatment group (compound 1 treatment group).

[0135] For cell immunostaining, cells were washed with phosphate-buffered saline and fixed with 4% paraformaldehyde-phosphate buffer on days 40–43 of the cell culture start date. After methanol treatment and blocking, myelin basic protein (MBP), a marker protein for myelin sheathing, was subjected to fluorescent immunostaining.

[0136] Fluorescence images of MBP were captured using a fluorescence microscope (DMI4000B, Leica), and the number of myelin fragments (≥25 μm) was analyzed based on the images. It should be noted that the region of interest (ROI) was defined as the area in which the co-culture was divided into four regions, and the region in which the fibrous staining of MBP was most frequently observed.

[0137] The evaluation results of the effect of compound 1 on myelin formation are shown in Figure 3 . Figure 3 The vertical axis represents the number of myelin fragments in each ROI (mean ± standard error; 8–12 cases per group). The horizontal axis represents the number of days of cell culture.

[0138] (Example 4) Effect of cyclic amine derivative (I) or a pharmacologically acceptable salt thereof on the expression level of MBP in rat dorsal root ganglion neurons-Schwann cells co-culture: This study investigated the effect of a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof on the expression level of MBP in rat dorsal root ganglion cells-Schwann cells co-culture.

[0139] Rat dorsal root ganglion neurons and Schwann cells were co-cultured using the same method as in Example 3, and myelination was induced and the cells were treated with Compound 1. The groups consisted of two groups: a sterile distilled water treatment group (Vehicle treatment group) and a 30 μM Compound 1 treatment group (Compound 1 treatment group).

[0140] To perform Western blotting, co-cultures were dissolved in RIPA cell lysate on day 43 of cell culture initiation, and the cell lysates were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Proteins were then transferred to a PVDF membrane, and MBP bands were detected by antibody reaction. Quantification of the detected bands was performed using Image Lab software (BIO-RAD).

[0141] The evaluation results of the effect of compound 1 on MBP expression levels are shown in Figure 4. Figure 4 The vertical axis represents the relative expression level of MBP (mean ± standard error; 4 cases in each group) when the mean of the Vehicle group is set to 1. The horizontal axis represents the Vehicle treatment group and the compound 1 treatment group from left to right. The "*" in the figure indicates a statistically significant difference compared to the Vehicle treatment group (*: p < 0.05, Student's t-test).

[0142] Treatment with compound 1 resulted in an increase in the number of myelin fragments and an increase in MBP, a myelin marker protein. This indicates that compound 1 promotes myelin formation in rat dorsal root ganglion neurons co-cultured with Schwann cells.

[0143] According to Examples 1, 2, 3 and 4, it is known that cyclic amine derivatives (I) or their pharmacologically acceptable salts are effective against impairment of nerve cells and myelin sheaths in the peripheral nerves.

[0144] (Example 5) Effects of repeated administration of a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof on a rat model of oxaliplatin-induced peripheral neuropathy for atypical pain in response to cold stimulation (cold atypical pain) and atypical pain in response to tactile stimulation (mechanical atypical pain): The effects of cyclic amine derivatives (I) or their pharmacologically acceptable salts on cold and mechanical abnormal pain caused by oxaliplatin administration were investigated.

[0145] Oxaliplatin (4 mg / kg, Elplat intravenous infusion 200 g; Yakult) was administered to 7-week-old male SD rats (CHARLES RIVER LABORATORIES JAPAN, INC.) for 2 or 3 weeks in a 1-week cycle (2 intraperitoneal administrations for 2 consecutive days per week) to establish an oxaliplatin-induced peripheral neuropathy model. As a control (sham induction), 5% glucose solution (Otsuka Pharmaceutical Factory, Inc.) was administered, with the first administration day designated as day 0 of disease induction.

[0146] Starting from day 0 of disease induction, rats were orally administered a solution containing compound 1 (3 or 10 mg / kg) or its solvent (water for injection; Otsuka Pharmaceutical Factory, Inc.) twice daily for 18 days (the second dose was administered 8 hours after the first). Day 0 of disease induction was the first dose administered before oxaliplatin administration, and the day of abnormal pain evaluation was the first dose administered after evaluation. The groups consisted of four groups: sham-solvent administration group (Sham group), disease induction-solvent administration group (Vehicle group), disease induction-3 mg / kg compound 1 administration group (3 mg / kg compound 1 administration group), and disease induction-10 mg / kg compound 1 administration group (10 mg / kg compound 1 administration group).

[0147] The efficacy of the drug for cold parapain was evaluated before and on day 12 of the onset of the disease (before the first administration of compound 1). The efficacy for cold parapain was evaluated using the Cold Plate test. The test used a Cold Plate apparatus (UgoBasile). Animals were placed on a plate maintained at a constant temperature (8°C), and the escape latency was measured until pain-associated behaviors (raising hind paws, shaking hind paws, licking hind paws, standing, jumping) were confirmed. It should be noted that the cutoff time was set at 180 seconds.

[0148] The efficacy of the drug for mechanical analgesia was evaluated before disease induction and on day 18 after disease induction (before the first administration of compound 1). The efficacy for mechanical analgesia was evaluated using the von Frey test. It should be noted that the test was performed using a von Frey filament (North Coast Medical) according to the method described in the prior art (Chaplan et al., Journal of Neuroscience Methods, 1994, Vol. 53, pp. 55-63), and the 50% response threshold was calculated.

[0149] The evaluation results of the effect of compound 1 on cold abnormal pain are shown in Figure 5 . Figure 5The vertical axis represents the escape latency in the ColdPlate test; a higher value indicates a greater improvement in cold abnormal pain (mean ± standard error; 10 cases per group). The horizontal axis, from left to right, represents the treatment groups before symptom induction ("Day 0 (before symptom induction)" in the figure) and on day 12 after symptom induction ("Day 12 (after symptom induction)" in the figure). "#" in the figure indicates a statistically significant difference compared to the Sham group (#: p < 0.05, Student's t-test), and "*" in the figure indicates a statistically significant difference compared to the Vehicle group (*: p < 0.025, Williams' multiple comparisons, one-sided).

[0150] On day 12 of symptom onset, a significant shortening of the escape latency was observed in the Vehicle group compared to the Sham group. This confirmed the onset of oxaliplatin-induced peripheral neuropathy, specifically cold abnormal pain.

[0151] By administering compound 1 orally twice daily on day 12 of symptom induction, a significant prolongation of the escape latency was observed in the 10 mg / kg compound 1 group compared to the vehicle group. This indicates that compound 1 inhibits cold abnormal pain in an oxaliplatin-induced peripheral neuropathy model.

[0152] The evaluation results of the effect of compound 1 on mechanical abnormal pain are shown in Figure 6 . Figure 6 The vertical axis represents the 50% response threshold in the von Frey test; a higher value indicates greater improvement in mechanical paradoxical pain (mean ± standard error; 10 cases per group). The horizontal axis, from left to right, represents the treatment groups before disease induction ("Day 0 (before disease induction)" in the figure) and on day 18 after disease induction ("Day 18 (after disease induction)" in the figure). "#" in the figure indicates a statistically significant difference compared to the Sham group (#: p < 0.05, Welch's t-test), and "*" in the figure indicates a statistically significant difference compared to the Vehicle group (*: p < 0.025, Shirley-Williams multiple comparisons, one-sided).

[0153] On day 18 of symptom onset, a significant decrease in the 50% response threshold was observed in the Vehicle group compared to the Sham group. This confirmed the pathogenesis of oxaliplatin-induced peripheral neuropathy, i.e., mechanical abnormal pain.

[0154] By administering compound 1 orally twice daily on day 18 after disease induction, a significant increase in the 50% response threshold was observed in the 3 mg / kg and 10 mg / kg compound 1 groups compared to the Vehicle group. This indicates that compound 1 inhibits oxaliplatin-induced mechanical abnormal pain in the peripheral neuropathy model.

[0155] As can be seen from the above, cyclic amine derivatives (I) or their pharmacologically acceptable salts show a significant inhibitory effect on oxaliplatin-induced peripheral neuropathy.

[0156] (Example 6) The therapeutic effect of a single dose of a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof on mechanical abnormal pain in a rat model of cisplatin-induced peripheral neuropathy: Investigate the effects of cyclic amine derivatives (I) or pharmacologically acceptable salts thereof on mechanical abnormal pain caused by cisplatin administration.

[0157] A cisplatin-induced peripheral neuropathy model was established in 6-week-old male SD rats (CHARLES RIVER LABORATORIES JAPAN, INC.) by intraperitoneal administration of cisplatin (Wako Pure Chemical Industries, Ltd.) twice weekly (1 or 2 mg / kg) for 5 weeks. Cisplatin was dissolved in physiological saline to a concentration of 10 mg / mL for administration. Physiological saline was administered as a control (sham induction). The day of initial administration was designated as day 1 of symptom induction.

[0158] On day 34 of disease induction, rats were orally administered a solution containing compound 1 (10 mg / kg) or its solvent (water for injection). The groups consisted of three groups: a sham-induced solvent administration group (Sham group), a disease induction-solvent administration group (Vehicle group), and a disease induction-10 mg / kg compound 1 administration group (10 mg / kg compound 1 administration group).

[0159] The efficacy of compound 1 for mechanical abnormal pain was evaluated using the same method as in Example 5, before administration and 2 hours after administration on day 34 of the onset of the condition.

[0160] The evaluation results of the effect of compound 1 on mechanical abnormal pain are shown in Figure 7 . Figure 7The vertical axis represents the 50% response threshold in the von Frey test; a higher value indicates greater improvement in mechanical paralysis pain (mean ± standard error; 4–6 cases per group). The horizontal axis, from left to right, represents the treatment groups before compound 1 administration ("Day 34 (before administration)" in the figure) and 2 hours after compound administration ("Day 34 (2 hours after administration)" in the figure). "#" in the figure indicates a statistically significant difference compared to the Sham group (#: p < 0.05, Student's t-test), and "*" in the figure indicates a statistically significant difference compared to the Vehicle group (*: p < 0.05, Student's t-test).

[0161] Two hours after administration of compound 1, a significant increase in the 50% response threshold was observed in the 10 mg / kg compound 1 group compared to the vehicle group. This indicates that compound 1 inhibits cisplatin-induced mechanical abnormal pain in the peripheral neuropathy model.

[0162] As can be seen from the above, cyclic amine derivatives (I) or their pharmacologically acceptable salts show a significant inhibitory effect on cisplatin-induced peripheral neuropathy.

[0163] (Example 7) Effect of a single dose of a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof on mechanical abnormal pain in a rat model of paclitaxel-induced peripheral neuropathy: Investigate the effects of cyclic amine derivatives (I) or pharmacologically acceptable salts thereof on mechanical abnormal pain caused by administration of paclitaxel.

[0164] A paclitaxel-induced peripheral neuropathy model was established in 6-week-old male SD rats (CHARLES RIVER LABORATORIES JAPAN, INC.) by intraperitoneal administration of paclitaxel (4 mg / kg, ChromaDex) four times every other day. Paclitaxel was dissolved in a 1:1 mixture of Cremophor EL and ethanol (Wako PureChemical Industries, Ltd.) to prepare a 6 mg / mL solution, which was then diluted with physiological saline to 4 mg / mL for administration. The day of the first administration was designated as day 0 of disease induction.

[0165] On day 14 of disease induction, rats were orally administered a solution containing compound 1 (10 mg / kg) or its solvent (water for injection). The groups consisted of two groups: a solvent administration group (Vehicle group) and a 10 mg / kg compound 1 administration group.

[0166] The efficacy of the drug for mechanical abnormal pain was evaluated using the same method as in Example 5, before and on day 14 after the onset of symptoms (3 hours after administration of compound 1).

[0167] The evaluation results of the effect of compound 1 on mechanical abnormal pain are shown in Figure 8 . Figure 8 The vertical axis represents the 50% response threshold in the von Frey test; a higher value indicates greater improvement in mechanical paralysis pain (mean ± standard error; 8 cases per group). The horizontal axis, from left to right, represents the treatment groups before disease induction and 3 hours after administration of compound 1 on day 14 of disease induction (in the figure, "Day 14 (3 hours after administration)"). "*" in the figure indicates a statistically significant difference compared to the Vehicle group (*: p < 0.05, Student's t-test, both sides).

[0168] On day 14 of symptom induction (3 hours after administration of compound 1), a significant increase in the 50% response threshold was observed in the 10 mg / kg compound 1 group compared to the vehicle group. This indicates that compound 1 inhibits paclitaxel-induced abnormal mechanical pain in the peripheral neuropathy model.

[0169] As can be seen from the above, cyclic amine derivatives (I) or their pharmacologically acceptable salts show a significant inhibitory effect on paclitaxel-induced peripheral neuropathy.

[0170] (Example 8) Effect of a single dose of a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof on mechanical abnormal pain in a rat model of bortezomib-induced peripheral neuropathy: This study investigates the therapeutic effects of cyclic amine derivatives (I) or pharmacologically acceptable salts thereof on mechanical abnormal pain caused by bortezomib administration.

[0171] In 6-week-old male SD rats (CHARLES RIVER LABORATORIES JAPAN, INC.), bortezomib (0.2 mg / kg, AdooQ BioScience) was administered intraperitoneally four times on days 1, 4, 8, and 11 of disease induction, with the day of initial administration considered as day 1 of disease induction. Bortezomib was dissolved in dimethyl sulfoxide (DMSO) and then Tween 80 was added. Water for injection was then added to prepare a concentration of 0.2 mg / mL, bringing the final concentrations of DMSO and Tween 80 to 5% each.

[0172] On day 15 of disease induction, rats were orally administered a solution containing compound 1 (20 mg / kg) or its solvent (water for injection). The groups consisted of two groups: a solvent administration group (Vehicle group) and a 20 mg / kg compound 1 administration group.

[0173] The efficacy of the drug for mechanical abnormal pain was evaluated using the same method as in Example 5, before the onset of symptoms and on day 15 after the onset of symptoms (3 hours after administration of compound 1).

[0174] The evaluation results of the effect of compound 1 on mechanical abnormal pain are shown in Figure 9 . Figure 9 The vertical axis represents the 50% response threshold in the von Frey test; a higher value indicates greater improvement in mechanical paralysis pain (mean ± standard error; 8 cases per group). The horizontal axis, from left to right, represents the treatment groups before disease onset and 3 hours after administration of compound 1 on day 15 of disease onset (in the figure, "Day 15 (3 hours after administration)"). "*" in the figure indicates a statistically significant difference compared to the Vehicle group (*: p < 0.05, Student's t-test, both sides).

[0175] On day 15 of symptom induction (3 hours after administration of compound 1), a significant increase in the 50% response threshold was observed in the 20 mg / kg compound 1 group compared to the vehicle group. This indicates that compound 1 inhibits mechanopathic pain induced by bortezomib in the peripheral neuropathy model.

[0176] As can be seen from the above, cyclic amine derivatives (I) or their pharmacologically acceptable salts show a significant inhibitory effect on bortezomib-induced peripheral neuropathy.

[0177] Therefore, it can be seen that cyclic amine derivatives (I) or their pharmacologically acceptable salts show significant inhibitory effects on peripheral neuropathy induced by drugs, especially anticancer agents.

[0178] (Example 9) Effects of cyclic amine derivatives (I) or their pharmacologically acceptable salts on an experimental autoimmune neuritis (EAN) model in rats: This study investigated the inhibitory effects of cyclic amine derivatives (I) or their pharmacologically acceptable salts on a rat EAN model.

[0179] This describes the method for establishing an EAN model in rats. A partial peptide of peripheral myelin P2, P2(57-81) (synthesized by Toray Research Center, Inc.), was dissolved in physiological saline (Otsuka Pharmaceutical Factory, Inc.) to prepare a 2 mg / mL solution. This solution was then mixed with an equal volume of 2 mg / mL Freund's complete adjuvant (Difco Laboratories) containing dead tuberculosis bacteria H37Ra to create an emulsion-like peptide administration solution. In Lewis rats (6-7 weeks old, male; CHARLES RIVERLABORATORIES JAPAN, INC.), 200 μL of the peptide administration solution was administered subcutaneously via the base of the tail under anesthesia, thus establishing the EAN model. The day of peptide administration was designated as day 0 of disease induction.

[0180] The clinical score is evaluated as follows: 0 = asymptomatic, 1 = tail or hind limb weakness, 2 = tail and hind limb weakness, 3 = partial hind limb paralysis, 4 = complete hind limb paralysis, 5 = near death or death. In addition, body weight is measured.

[0181] Compound 1 (20 mg / kg) was dissolved in distilled water (Otsuka Pharmaceutical Factory, Inc.) and administered orally twice daily to EAN models (starting from day 10 of disease induction). As a control, EAN models were administered distilled water orally. The groups consisted of two groups: a solvent administration group (Vehicle group) and a compound 1 administration group.

[0182] For histopathological evaluation, the sciatic and tibial nerves were isolated on day 17 of disease induction and immersed in 10% formalin neutral buffer. After sectioning, hematoxylin-eosin staining, Klüver-Barrera staining (double staining with Luxol Fast Blue and Nissl staining), and immunostaining (Iba1, CD3, NFP, and MBP) were performed. The specimens were observed under a light microscope to evaluate the infiltration of T cells and macrophages, and the presence or absence of myelin and axonal degeneration.

[0183] The evaluation results of the effect of compound 1 on clinical scores are shown in Figure 10 . Figure 10 The vertical axis represents the clinical score, with lower values ​​indicating greater symptom improvement (mean ± standard error, n = 6–7). Compared to the Vehicle group, the increase in clinical score was inhibited in the compound 1 treatment group.

[0184] The evaluation results of the effect of compound 1 on weight loss are shown in Figure 11 . Figure 11The vertical axis represents the body weight of the rats (mean ± standard error, 6–7 rats per group). Weight loss occurred in the Vehicle group, but not in the 20 mg / kg compound 1 administration group.

[0185] The histopathological evaluation results of compound 1 are shown in Table 2. Table 2 shows the number of individuals (3 cases in each group) showing histological changes in the sciatic and tibial nerves. Infiltration of T cells and macrophages, myelin and axonal degeneration were observed in the Vehicle group, but were virtually not observed in the 20 mg / kg compound 1 administration group.

[0186] As can be seen from the above, cyclic amine derivatives (I) or their pharmacologically acceptable salts are effective for autoimmune peripheral neuropathy.

[0187] (Example 10) Effects of cyclic amine derivatives (I) or pharmacologically acceptable salts thereof on mechanical abnormal pain in an experimental autoimmune neuritis (EAN) model in rats: This study investigated the inhibitory effects of cyclic amine derivatives (I) or their pharmacologically acceptable salts on mechanical abnormal pain in a rat EAN model.

[0188] EAN model rats were created using the same method as in Example 9. Additionally, sham-induced animals were designed to be administered saline (Otsuka Pharmaceutical Factory, Inc.) instead of the peptide administration solution. The day of administration of either the peptide administration solution or saline was designated as day 0 of disease induction.

[0189] On day 14 of disease induction, compound 1 (5 or 10 mg / kg) or its solvent (water for injection) was orally administered to rats. The groups consisted of four groups: sham-solvent administration group (Sham group), disease induction-solvent administration group (Vehicle group), disease induction-5 mg / kg compound 1 administration group (5 mg / kg compound 1 administration group), and disease induction-10 mg / kg compound 1 administration group (10 mg / kg compound 1 administration group).

[0190] The efficacy of the drug for mechanical abnormal pain was evaluated using the same method as in Example 5, 3 hours after administration of compound 1 on day 14 of the onset of the condition.

[0191] The evaluation results of the effect of compound 1 on mechanical abnormal pain are shown in Figure 12 . Figure 12The vertical axis represents the 50% response threshold in the von Frey test; a higher value indicates a greater improvement in mechanical abnormal pain (mean ± standard error, 4-10 cases in each group). In the figure, "#" indicates a statistically significant difference compared to the Sham group (#: p < 0.05, Student's t-test), and "*" indicates a statistically significant difference compared to the Vehicle group (*: p < 0.025, Williams' multiple comparisons, one-sided).

[0192] Compared with the Sham group, a significant decrease in the 50% response threshold was observed in the Vehicle group. That is, the pathogenesis of mechanical abnormal pain in the EAN model was confirmed.

[0193] Compared with the Vehicle group, the 5 mg / kg and 10 mg / kg compound 1 groups showed a significant increase in the 50% response threshold. This indicates that compound 1 inhibits mechanical abnormal pain in the EAN model.

[0194] The results indicate that cyclic amine derivatives (I) or their pharmacologically acceptable salts are effective for mechanical abnormal pain in autoimmune peripheral neuropathy.

[0195] (Example 11) Effects of cyclic amine derivatives (I) or their pharmacologically acceptable salts on decreased nerve conduction velocity in a rat streptozotocin-induced diabetes model: This study investigated the inhibitory effect of cyclic amine derivatives (I) or their pharmacologically acceptable salts on mechanical abnormal pain in a rat streptozotocin-induced diabetes model.

[0196] A streptozotocin-induced diabetes model was established by intravenous administration of streptozotocin (50 mg / kg, Sigma-Aldrich) into the tail vein of 6-week-old male SD rats. The streptozotocin was dissolved in citrate buffer to prepare a concentration of 25 mg / mL for administration. Additionally, non-induced disease animals were included without streptozotocin administration. The day of the first administration was designated as day 1 of disease induction.

[0197] From day 14 of disease induction, for 28 days, rats were orally administered a solution containing compound 1 (3 or 10 mg / kg) or its solvent (water for injection) twice daily. The groups consisted of four subgroups: a non-inducible disease-solvent administration group (Normal group), a disease-inducible disease-solvent administration group (Vehicle group), a disease-inducible disease-3 mg / kg compound 1 administration group (3 mg / kg compound 1 administration group), and a disease-inducible disease-10 mg / kg compound 1 administration group (10 mg / kg compound 1 administration group).

[0198] Nerve conduction velocity was measured three days from day 2 of final drug administration. Two single-needle electrodes (A and B) were inserted into the thigh to contact the sciatic nerve, and a third single-needle electrode (C) was inserted into the lower end of the gastrocnemius muscle (Achilles tendon). A lead-out electrode was placed on the footpad. Stimuli between A and B and between B and C were used as distal and proximal stimuli, respectively, and the conduction time of the stimuli was analyzed from the respective lead-out waveforms obtained from the electrodes on the footpad. Nerve conduction velocity was calculated based on the difference in conduction time between the distal and proximal stimuli and the distance between the electrodes.

[0199] The evaluation results of the effect of compound 1 on reducing nerve conduction velocity are shown in Figure 13 . Figure 13 The vertical axis represents nerve conduction velocity (mean ± standard error; 5–6 cases in each group). "#" in the figure indicates a statistically significant difference compared to the Normal group (#: p < 0.05, Student's t-test), and "*" indicates a statistically significant difference compared to the Vehicle group (*: p < 0.025, Williams' multiple comparisons, one-sided).

[0200] By repeatedly administering compound 1, a significant increase in nerve conduction velocity was observed in the 10 mg / kg compound 1 group compared to the vehicle group. This indicates that compound 1 inhibits the decrease in nerve conduction velocity in the streptozotocin-induced diabetes model.

[0201] (Example 12) Effects of cyclic amine derivatives (I) or their pharmacologically acceptable salts on mechanical abnormal pain in a rat streptozotocin-induced diabetic model: This study investigated the inhibitory effect of cyclic amine derivatives (I) or their pharmacologically acceptable salts on mechanical abnormal pain in a rat streptozotocin-induced diabetes model.

[0202] A streptozotocin-induced diabetes model was established by intravenous administration of streptozotocin (50 mg / kg, Sigma-Aldrich) into the tail vein of 6-week-old male SD rats. The streptozotocin was dissolved in physiological saline (Otsuka Pharmaceutical Factory, Inc.) to prepare a concentration of 25 mg / mL for administration. Additionally, sham-induced animals were designed to be administered physiological saline instead of the streptozotocin solution. The day of the first administration was designated as day 0 of disease induction.

[0203] On day 28 of disease induction, rats were orally administered a solution containing compound 1 (3 or 10 mg / kg) or its solvent (water for injection). The groups consisted of four groups: sham-solvent administration group (Sham group), disease induction-solvent administration group (Vehicle group), disease induction-10 mg / kg compound 1 administration group (3 mg / kg compound 1 administration group), and disease induction-30 mg / kg compound 1 administration group (10 mg / kg compound 1 administration group).

[0204] The efficacy of the drug for mechanical abnormal pain was evaluated using the same method as in Example 5, 3 hours after administration of compound 1 on day 28 of the onset of the condition.

[0205] The evaluation results of the effect of compound 1 on mechanical abnormal pain are shown in Figure 14 . Figure 14 The vertical axis represents the 50% response threshold in the von Frey test; a higher value indicates a greater improvement in mechanical abnormal pain (mean ± standard error; 8 cases in each group). "*" in the figure indicates a statistically significant difference compared to the Vehicle group (*: p < 0.025, Shirley-Williams multiple comparisons, one-sided).

[0206] On day 28 of disease induction (3 hours after administration of compound 1), a significant increase in the 50% response threshold was observed in the 10 mg / kg and 30 mg / kg compound 1 groups compared to the vehicle group. This indicates that compound 1 inhibits mechanical abnormal pain induced by streptozotocin in a diabetes model.

[0207] As can be seen from the above, cyclic amine derivatives (I) or their pharmacologically acceptable salts are effective for metabolic peripheral neuropathy, especially diabetic peripheral neuropathy.

[0208] Industrial practicality The cyclic amine derivatives of the present invention or their pharmacologically acceptable salts have protective and repairing effects on peripheral nerve cells and promote myelination, and significantly inhibit the symptoms of various peripheral neuropathy, and therefore can be used as therapeutic or preventive agents for peripheral neuropathy.

[0209] All publications, patents, and patent applications referenced in this specification are incorporated herein by reference.

Claims

1. A therapeutic or preventative agent for peripheral neuropathy, comprising a cyclic amine derivative of general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. [Chemistry 1] In the formula, Carbon atoms marked with an asterisk (*) are asymmetric carbons. A represents a group represented by the general formula (IIa), (IIb) or (IIc). [Chemistry 2] R 1 This indicates methyl or ethyl groups that can be substituted by halogen atoms. R 2 This indicates an alkyl carbonyl group having 2 to 5 hydrogen atoms or carbon atoms. R 3 Each can independently represent methyl or ethyl. n represents 1 or 2.

2. The therapeutic or preventative agent according to claim 1, wherein, A is a group represented by general formula (IIa); and / or A is a group represented by general formula (IIb) or (IIc); and / or A is a group represented by general formula (IIa), and the stereochemistry of the asymmetric carbon with an asterisk (*) is S configuration; and / or R 1 Methyl or ethyl groups that can be substituted with fluorine atoms; and / or R 1 It can be methyl, ethyl, difluoromethyl or 2,2,2-trifluoroethyl.

3. A therapeutic or preventative agent for drug-induced peripheral neuropathy, comprising a cyclic amine derivative of general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. [Chemistry 3] In the formula, Carbon atoms marked with an asterisk (*) are asymmetric carbons. A represents a group represented by the general formula (IIa), (IIb) or (IIc). [Chemistry 4] R 1 This indicates methyl or ethyl groups that can be substituted by halogen atoms. R 2 This indicates an alkyl carbonyl group having 2 to 5 hydrogen atoms or carbon atoms. R 3 Each can independently represent methyl or ethyl. n represents 1 or 2.

4. The therapeutic or preventative agent according to claim 3, wherein, A is a group represented by general formula (IIa); and / or A is a group represented by general formula (IIb) or (IIc); and / or A is a group represented by general formula (IIa), and the stereochemistry of the asymmetric carbon with an asterisk (*) is S configuration; and / or R 1 Methyl or ethyl groups that can be substituted with fluorine atoms; and / or R 1 It is methyl, ethyl, difluoromethyl or 2,2,2-trifluoroethyl; and / or Drug-induced peripheral neuropathy is selected from at least one of the following: peripheral neuropathy caused by anticancer agents, peripheral neuropathy caused by antiviral drugs, peripheral neuropathy caused by antibacterial drugs, peripheral neuropathy caused by antituberculosis drugs, peripheral neuropathy caused by antiarrhythmic drugs, peripheral neuropathy caused by hyperlipidemia treatment drugs, peripheral neuropathy caused by immunosuppressive drugs, peripheral neuropathy caused by gout treatment drugs, and peripheral neuropathy caused by other drugs.

5. A therapeutic or preventative agent for autoimmune peripheral neuropathy, comprising a cyclic amine derivative of general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. [Chemistry 5] In the formula, Carbon atoms marked with an asterisk (*) are asymmetric carbons. A represents a group represented by the general formula (IIa), (IIb) or (IIc). [Chemistry 6] R 1 This indicates methyl or ethyl groups that can be substituted by halogen atoms. R 2 This indicates an alkyl carbonyl group having 2 to 5 hydrogen atoms or carbon atoms. R 3 Each can independently represent methyl or ethyl. n represents 1 or 2.

6. The therapeutic or preventative agent according to claim 5, wherein, A is a group represented by general formula (IIa); and / or A is a group represented by general formula (IIb) or (IIc); and / or A is a group represented by general formula (IIa), and the stereochemistry of the asymmetric carbon with an asterisk (*) is S configuration; and / or R 1 Methyl or ethyl groups that can be substituted with fluorine atoms; and / or R 1 It is methyl, ethyl, difluoromethyl or 2,2,2-trifluoroethyl; and / or Autoimmune peripheral neuropathy is selected from at least one of Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and neuropathy with abnormal proteinemia.

7. A therapeutic or preventative agent for metabolic peripheral neuropathy, comprising a cyclic amine derivative of general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. [Chemistry 7] In the formula, Carbon atoms marked with an asterisk (*) are asymmetric carbons. A represents a group represented by the general formula (IIa), (IIb) or (IIc). [Chemistry 8] R 1 This indicates methyl or ethyl groups that can be substituted by halogen atoms. R 2 This indicates an alkyl carbonyl group having 2 to 5 hydrogen atoms or carbon atoms. R 3 Each can independently represent methyl or ethyl. n represents 1 or 2.

8. The therapeutic or preventative agent according to claim 7, wherein, A is a group represented by general formula (IIa); and / or A is a group represented by general formula (IIb) or (IIc); and / or A is a group represented by general formula (IIa), and the stereochemistry of the asymmetric carbon with an asterisk (*) is S configuration; and / or R 1 Methyl or ethyl groups that can be substituted with fluorine atoms; and / or R 1 It is methyl, ethyl, difluoromethyl or 2,2,2-trifluoroethyl; and / or Metabolic peripheral neuropathy is selected from at least one of diabetic peripheral neuropathy, uremic peripheral neuropathy, collagenous peripheral neuropathy, and vitamin deficiency peripheral neuropathy.

9. A therapeutic or preventative agent for hereditary peripheral neuropathy, comprising a cyclic amine derivative of general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. [Chemistry 9] In the formula, Carbon atoms marked with an asterisk (*) are asymmetric carbons. A represents a group represented by the general formula (IIa), (IIb) or (IIc). [Chemistry 10] R 1 This indicates methyl or ethyl groups that can be substituted by halogen atoms. R 2 This indicates an alkyl carbonyl group having 2 to 5 hydrogen atoms or carbon atoms. R 3 Each can independently represent methyl or ethyl. n represents 1 or 2.

10. The therapeutic or preventative agent according to claim 9, wherein, A is a group represented by general formula (IIa); and / or A is a group represented by general formula (IIb) or (IIc); and / or A is a group represented by general formula (IIa), and the stereochemistry of the asymmetric carbon with an asterisk (*) is S configuration; and / or R 1 Methyl or ethyl groups that can be substituted with fluorine atoms; and / or R 1 It is methyl, ethyl, difluoromethyl or 2,2,2-trifluoroethyl; and / or Hereditary peripheral neuropathy is selected from at least one of Chuck-Maley-Duss disease, familial amyloid polyneuropathy, hereditary compression-susceptible neuropathy, and hereditary neuropathic amyotrophic lateral sclerosis.

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