Entitled peripheral neuropathy therapeutic or prophylactic agent

Technical field

[0001]

　The present invention relates to a therapeutic agent or preventive agent for peripheral neuropathy.

BACKGROUND

[0002]

　Peripheral neuropathy, nerve cells that make up the peripheral nerves (axonal or nerve cell bodies) or myelin sheath (Schwann cells) is caused by injured. Histopathologically, the axonal degeneration and demyelination degeneration observed in the physiological such as reduction of nerve conduction velocity dysfunction occurs.

[0003]

　By giving damage to neurons or the myelin sheath of the peripheral nerves, numbness of the extremities (abnormal sensations), paresthesia, sensory Donma, sensory neuropathy exhibiting symptoms such as pain or hearing loss, muscle weakness, atrophy, flaccid paralysis or motor neuropathy showing symptoms of reduced or lost, etc. of deep tendon reflexes, or constipation, abdominal pain, sweating disorders, the causes of peripheral neuropathy, such as autonomic neuropathy exhibiting symptoms such as dysuria or orthostatic hypotension considered It is (non-patent document 1).

[0004]

　These symptoms of peripheral neuropathy is rarely fatal, a major impact on the daily life of the patient, significantly reduces the quality of life (Non-patent Document 1).

[0005]

　Peripheral neuropathy, nerve can be divided by cause of injury, and as a typical, drug-induced peripheral neuropathy, autoimmune neuropathy, metabolic peripheral neuropathy include hereditary peripheral neuropathies like.

[0006]

　Agents that cause drug-induced peripheral neuropathy, an anticancer agent, an antiviral agent, antibacterial agents, anti-tuberculosis drugs, antiarrhythmic drugs, antihyperlipidemic agents, immunosuppressive agents, gout therapeutic agent or the like. The drug peripheral neuropathy, many, sometimes after washout remains even failure that sensory disorders such as pain is mainly (Non-Patent Document 2).

[0007]

　In particular anticancer agent has a high incidence of peripheral neuropathy, it is also a problem which becomes thereby difficult to continue the treatment of cancer. To relieve the symptoms of peripheral neuropathy induced by anticancer agents, analgesics (e.g., pregabalin, gabapentin or ketamine), antiepileptics (e.g., lamotrigine, carbamazepine, phenytoin, valproate or clonazepam), antidepressants (e.g., amitriptyline, imipramine, clomipramine or duloxetine), Chinese medicine (e.g., goshajinkigan or shakuyakukanzoto), vitamin B preparations (e.g., B6 or B12) but like is administered, induced by anti-cancer agents It is an effective method of treating or preventing peripheral neuropathy that is not established (non-patent document 1).

[0008]

　Among the above agents, duloxetine only high level of evidence in clinical trials, American Clinical Cancer Society has developed, has been recommended used in chemotherapy-induced peripheral neuropathy treatment guidelines (Non-Patent Document 3). On the other hand, the International Pain Society and European Society of Neurology has developed respectively, among the agents used in neuropathic pain treatment guidelines (Non-Patent Documents 4-5) is recommended, with the exception of duloxetine, pregabalin, gabapentin, nortriptyline, any amitriptyline, no evidence exists to clearly indicate that it is effective in neuropathic pain induced by anticancer agents (non-Patent documents 6-7).

[0009]

　Autoimmune peripheral neuropathy is a neuropathy by autoimmunity to components of peripheral nerves, Guillain-Barre syndrome (Guillain-Barre syndrome: GBS), chronic inflammatory demyelinating polyneuropathy (chronic inflammatory demyelinating polyradiculoneuropathy : CIDP), multifocal motor neuropathy (multifocal motor neuropathy: MMN), and abnormal protein viremia in associated neuropathy (paraproteinamic neuropathy: PPN) are a diverse group of diseases including (non-Patent Document 8).

[0010]

　GBS is believed to be caused as a trigger infection of pathogenic microorganisms such as viruses and bacteria, it is sometimes develop after vaccination infection thereof pathogenic microorganisms. The disappearance of the paralysis and deep reflection of the extremities as the main symptom, it is also often accompanied by sensory disorders such as pain or abnormal sensation. In the case of severe, there is also an example of death by respiratory failure or autonomic neuropathy. The GBS has many subtypes, acute inflammatory demyelinating neuritis, acute motor axonal neuritis, acute motor and sensory axonal neuritis, such as in a Fisher syndrome is known (Non-Patent Documents 9). CIDP is different from the GBS, is an autoimmune peripheral neuropathy of chronic or relapsing-remitting, leading to muscle weakness and sensory disturbance. MMN and the PPN is a disease that is similar to CIDP. MMN is characterized myopathy without sensory impairment (Non-patent Document 10). PPN is due overgrowth of a single immunoglobulin, and wherein the sensory neuropathy indolent (Non-Patent Document 11).

[0011]

　The treatment of autoimmune peripheral neuropathy, intravenous immunoglobulin therapy and simple plasma exchange therapy is said to be effective (12). However, the simple plasma exchange therapy is special facilities, equipment is required, there is a drawback, such as there are patients who can not enforce the elderly and circulatory failure, such as a patient. On the other hand, the immune globulin intravenous therapy patients with a history of shock and hypersensitivity will be carefully administered. From the above, it is simple and less treatment side effects are coveted used in the medical field.

[0012]

　Metabolic peripheral nerve disorder is one which is caused by a variety of metabolic abnormalities, diabetes as a disease caused by, over uremia, collagen diseases, vitamin deficiencies, etc. variety hypothyroidism.

[0013]

　In particular, diabetes is the most frequent cause of peripheral neuropathy, it is expected that future further increase number of patients. One of the pathogenesis of diabetic peripheral neuropathy, metabolizes glucose to sorbitol, has increased polyol pathway, the nerve cells are believed to be injured by the excessive accumulated sorbitol (Non-patent Document 13 ). Therefore, in diabetic peripheral neuropathy, but inhibitor of aldose reductase enzyme involved in the polyol pathway is to be effective, Epalrestat merely have been approved only in Japan, the patient condition is relatively mild only shown the effect, in many cases it is ineffective in the long patients critically ill or diseased winning (non-Patent Document 14). Further, for the pain from diabetic peripheral neuropathy, but like pregabalin and duloxetine is used, not a drug for peripheral neuropathy, is desired drug showing a marked effect on diabetic peripheral neuropathy ing.

[0014]

　The hereditary peripheral neuropathy, there is Charcot-and Marie-Tooth disease, familial amyloid polyneuropathy, hereditary fragility neuropathy, and the like hereditary neuralgia muscle atrophy. The most typical is the Charcot-Marie-Tooth disease. Gene that has been implicated in Charcot-Marie-Tooth disease is known at least 50 species, there is a mutation in a gene involved in the formation and maintenance, etc. of myelination and nerve cells, atypical is wide present. Normally, the motor nerve and sensory nerve disorder, is in many cases a remarkable movement disorder. Clinically be done physical and occupational therapy for muscle maintenance, but including Charcot-Marie-Tooth disease, effective treatment-agent hereditary peripheral neuropathies are currently no (non-patent document 15) .

[0015]

　In peripheral neuropathy various causes, since the patient is even with effective drugs is not patient or drug invalid is present, creation of new drugs for peripheral neuropathy is expected.

[0016]

　Further, since the clinical practice to distinguish the causes of peripheral neuropathy are necessary detailed examination, further that in some cases it is diagnosed with idiopathic peripheral neuropathy (Non-Patent Document 16) or the like, failure irrespective of the cause of, but the drug is effective for peripheral neuropathy in general is a very useful, such agents does not currently exist. Nevertheless a certain, creation of a drug is effective for peripheral neuropathy in general is considered to be possible. As described above, peripheral neuropathy is classified into many types, although clinical symptoms are diverse, that develops in the cells constituting the peripheral nerve is injured, the common without depending on the pathogenesis is is because. Thus, for example, neural cell survival, drug was based on neurotrophic factors is a biological molecule involved in the growth or maintenance is expected to be widely effective against peripheral neuropathy (Non-Patent Document 17) . However, even drugs was based on neurotrophic factors, as indicated that the efficacy was not observed in clinical trials of peripheral neuropathy or diabetic peripheral neuropathy caused by anticancer agents (Non-Patent Document 18 to 19), the creation of effective drugs to peripheral neuropathy in general is extremely difficult.

[0017]

　Patent Document 1 discloses that cyclic amine derivatives have an analgesic effect, reports suggesting an effect on peripheral neuropathy is not all.

CITATION

Patent Document

[0018]

Patent Document 1: International Publication No. WO 2016/136944

Non-patent literature

[0019]

Non-Patent Document 1: Shizuoka Cancer Center, "an anti-cancer agent therapy and peripheral neuropathy (Third Printing)", 2016, p. 1-36
Non-Patent Document 2: Vilholm et al., Basic & Clinical Pharmacology & Toxicology, 2014 year, the first 115 Volume, p. 185-192
Non-Patent Document 3: Hershman et al., Journal of Oncology Practice, 2014 years, Vol. 10, p. e421-e424
Non-Patent Document 4: Attal et al., Pain: Clinical Updates, 2010 years, Vol. 18
Non-Patent Document 5: Attal et al., European Journal of Neurology, 2010 years, Vol. 17, p. 1113-1123
Non-Patent Document 6: Shinde et al, Support Care Cancer, 2016 years, Vol. 24, p. 547-553
Non-Patent Document 7: Gewandter et, Pain, 2017 years, 158 vol, p. 30-33
Non-Patent Document 8: camphor tree, clinical neurological, 2009, Vol. 49, p. 956-958
Non-Patent Document 9: Hughes et al., The Lancet, 2005 years, Vol. 366, p. 1653-1666
Non-Patent Document 10: Camphor, Japanese Society of Internal Medicine Journal, 2013, No. 102 Vol, p. 1965-1970
Non-Patent Document 11: Rison et, BioMed Central Neurology, 2016 years, Vol. 16, No. 13
Non-Patent Document 12: Hughes et al., The Lancet, 1997 years, 349 vol, p. 225-230
Non-patent Document 13: Singh et al., Pharmacological Research, 2014 years, Vol. 80, p. 21-35
Non-Patent Document 14: Schemmel, et al., Journal of Diabetes and Its Complication, 2010 years, Vol. 24, p. 354-360
Non-Patent Document 15: Saporta et al, Neurologic Clinics, 2013 year, vol. 31, p. 597-619
Non-Patent Document 16: Azhary et al., American Family Physician, 2010 years, Vol. 81, p. 887-892
Non-Patent Document 17: McMahon et al., Current Opinion in Neurobiology, 1995 years, Vol. 5, p. 616-624
Non-Patent Document 18: Argyriou et al., Critical Reviews in Oncology / Hematology, 2012 years, the first 82 vol., P. 51-77
Non-Patent Document 19: Apfel, et al., JAMA, 2000 year, the first 284 Volume, p. 2215-2221

Summary of the Invention

Problems that the Invention is to Solve

[0020]

　The present invention aims at providing a therapeutic agent or preventive agent for peripheral neuropathy.

Means for Solving the Problems

[0021]

　The present inventors have result of intensive studies to solve the above problems, is acceptable salts specific cyclic amine derivative or a pharmacologically, to have a significant inhibitory effect against peripheral neuropathy It led to the finding.

[0022]

　That is, the present invention contains the formula cyclic amine derivative or a pharmacologically acceptable salt thereof represented by the general formula (I) below as an active ingredient provides therapeutic or preventive agent for peripheral neuropathy.
[Chemical formula 1]

wherein the carbon marked with * is an asymmetric carbon, A is of the general formula (IIa), a group represented by (IIb) or (IIc),
[Formula

　2] R 1 is , may be substituted with a halogen atom, a methyl group or an ethyl group, R 2 represents a hydrogen atom or an alkyl group having a carbon number of 2 ~ 5, R 3 are each independently a methyl group or an ethyl radical, n represents 1 or 2. ]

[0023]

　In cyclic amine derivative described above, it is preferable that A is a group represented by the general formula (IIa), at that time, R 1 may be substituted with a fluorine atom, a methyl group or an ethyl group more preferably, R 1 is a methyl group, an ethyl group, more preferably a difluoromethyl group or a 2,2,2-trifluoroethyl group.

[0024]

　Further, the cyclic amine derivatives of the above, it is preferred that A is a group represented by the general formula (IIb) or (IIc), when its, R 1 is a fluorine atom may be substituted, methyl group, or more preferably an ethyl a group, R 1 is a methyl group, an ethyl group, more preferably a difluoromethyl group or a 2,2,2-trifluoroethyl group.

[0025]

　Further, the cyclic amine derivatives of the above, A is a group represented by the general formula (IIa), the stereochemistry of the asymmetric carbon is the marked *, is preferably S-configuration, in which, R 1 is a fluorine atom may be substituted, more preferably a methyl group or an ethyl group, R 1 is a methyl group, an ethyl group, to be a difluoromethyl group or a 2,2,2-trifluoroethyl group A further preferred.

[0026]

　Further, the present invention, the above general formula cyclic amine derivative or a pharmacologically acceptable salt thereof represented by (I), and containing pharmacologically acceptable excipient or the like, a peripheral neuropathy It provides a pharmaceutical composition for treating or preventing.

[0027]

　The present invention also provides for use in the treatment or prevention of peripheral neuropathy, a cyclic amine derivative or a pharmacologically acceptable salt thereof represented by the general formula (I).

[0028]

　Further, the present invention provides a method for treating or preventing peripheral neuropathy, provides for the use of salts cyclic amine derivative or a pharmacologically acceptable represented by the above general formula (I).

[0029]

　Further, the present invention is in the manufacture of a medicament for the treatment or prevention of peripheral neuropathy, provides for the use of salts cyclic amine derivative or a pharmacologically acceptable represented by the above general formula (I).

[0030]

　Further, the present invention provides a method of treating or preventing peripheral neuropathy, therapeutically effective amount of a cyclic amine derivative or a pharmacologically acceptable represented by the above general formula (I) to a patient in need of treatment which method comprises administering to salts.

[0031]

　In the embodiments of the present invention, the above-mentioned peripheral neuropathy, drug-induced peripheral neuropathy, autoimmune neuropathy, metabolic peripheral neuropathy, hereditary peripheral neuropathy, vasculitic peripheral neuropathy, toxic peripheral it is preferable, drug-induced peripheral neuropathy, autoimmune neuropathy, metabolic peripheral neuropathy, or hereditary peripheral neuropathy neuropathy is a peripheral neuropathy associated with infectious peripheral neuropathy or malignancy, more preferably, drug-induced peripheral neuropathy, and more preferably autoimmune peripheral neuropathy, or metabolic peripheral neuropathy. The above drug-induced peripheral neuropathy is preferably an anti-cancer agent induced peripheral neuropathy. Additional autoimmune peripheral neuropathy, nerve caused by Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating root neuritis (CIDP), multifocal motor neuropathy (MMN), and abnormal protein viremia is preferably at least one selected from the failure (PPN). Additional metabolic peripheral neuropathy is preferably a diabetic peripheral neuropathy. Additional hereditary peripheral neuropathy is preferably Charcot-Marie-Tooth disease.

The invention's effect

[0032]

　Cyclic amine derivative or a pharmacologically acceptable salt thereof of the present invention can be used to treat or prevent peripheral neuropathy. Additional peripheral neuropathy, for example, drug-induced peripheral neuropathy, autoimmune peripheral neuropathy, or metabolic peripheral neuropathy. The above drug-induced peripheral neuropathy, particularly anti-cancer agents induced peripheral neuropathy. Additional autoimmune peripheral neuropathy, particularly, Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating root neuritis (CIDP), multifocal motor neuropathy (MMN), and abnormal protein viremia it is at least one selected from the accompanying neuropathy (PPN). Additional metabolic peripheral neuropathy, particularly diabetic peripheral neuropathy. The hereditary peripheral neuropathy, in particular, is Charcot-Marie-Tooth disease.

[0033]

　This specification includes the contents as disclosed in the description and / or drawings of a priority document of the present application Japanese Patent Application No. 2017-071329 and Japanese Patent Application No. 2017-071339.

BRIEF DESCRIPTION OF THE DRAWINGS

[0034]

FIG. 1 is a diagram showing a protective effect of Compound 1 on cell injury in root ganglia from strain of neurons after rat.
2 is a diagram showing a repair effect of Compound 1 on cell injury in root ganglia from strain of neurons after rat.
3 is a diagram showing the effect of Compound 1 on myelination rat dorsal root ganglion neurons, Schwann cell co-culture.
4 is a diagram showing the effect of Compound 1 on the expression level of Myelin Basic Protein in rats dorsal root ganglion neurons, Schwann cell co-culture.
5 is a diagram showing the effect of repeated administration of Compound 1 on cold allodynia in rats oxaliplatin-induced peripheral neuropathy model.
6 is a diagram showing the effect of repeated administration of Compound 1 on mechanical allodynia in the rat oxaliplatin-induced peripheral neuropathy model.
7 is a diagram showing an effect of a single dose of Compound 1 on mechanical allodynia in rats cisplatin-induced peripheral neuropathy model.
8 is a diagram showing an effect of a single dose of Compound 1 on mechanical allodynia in the rat paclitaxel-induced peripheral neuropathy model.
9 is a diagram showing an effect of a single dose of Compound 1 on mechanical allodynia in the rat bortezomib induced peripheral neuropathy model.
Shows the effect of Compound 1 on the clinical score [Figure 10] rat experimental autoimmune neuritis model.
11 is a diagram showing the effect of Compound 1 on body weight loss in rats Experimental autoimmune neuritis model.
12 is a diagram showing the effect of Compound 1 on mechanical allodynia in the rat experimental autoimmune neuritis model.
13 is a diagram showing the effect of Compound 1 on nerve conduction velocity reduction in the rat streptozotocin-induced diabetes model.
14 is a diagram showing the effect of Compound 1 on mechanical allodynia of rats with streptozotocin-induced diabetes model.

DESCRIPTION OF THE INVENTION

[0035]

　The following terms used herein, unless otherwise specified, as defined below.

[0036]

　Cyclic amine derivative according to an embodiment of the present invention is characterized in that represented by the following general formula (I).
[Chemical Formula 3]

wherein
　a subjected carbon is an asymmetric carbon *, A of the general formula (IIa), a group represented by (IIb) or (IIc),
Formula

　4] R 1 is , may be substituted with a halogen atom, a methyl group or an ethyl group, R 2 represents a hydrogen atom or an alkyl group having a carbon number of 2 ~ 5, R 3 are each independently a methyl group or an ethyl radical, n represents 1 or 2. ]

[0037]

　In cyclic amine derivatives of the above, A is preferably a group represented by the general formula (IIa), R 1 is a fluorine atom may be substituted, preferably a methyl group or an ethyl group, R 1 is a methyl group, an ethyl group, more preferably a difluoromethyl group or a 2,2,2-trifluoroethyl group.

[0038]

　Further, the cyclic amine derivatives of the above, A is preferably a group represented by the general formula (IIb) or (IIc), R 1 may be substituted with a fluorine atom, a methyl group or an ethyl group it is preferably, R 1 is methyl group, an ethyl group, more preferably a difluoromethyl group or a 2,2,2-trifluoroethyl group.

[0039]

　Further, the cyclic amine derivatives of the above, it is preferred that A is a group represented by the general formula (IIa), it is preferably the stereochemistry of the asymmetric carbon S configuration asterisked, in which, R 1 but fluorine atoms may be substituted is preferably a methyl group or an ethyl group, R 1 is a methyl group, an ethyl group, difluoromethyl group or a 2,2,2-trifluoroethyl group but more preferable.

[0040]

　In one embodiment of the above cyclic amine derivative, A is a group represented by the general formula (IIa), R 1 is a methyl group, an ethyl group, difluoromethyl group or a 2,2,2-trifluoroethyl group the stands, R 2 represents a hydrogen atom or an alkyl group having a carbon number of 2 ~ 5, R 3 each independently represents a methyl group or an ethyl group. In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0041]

　In one embodiment of the above cyclic amine derivative, A is a group represented by the general formula (IIa), R 1 represents a methyl group or a 2,2,2-trifluoroethyl group, R 2 is represents a hydrogen atom or an alkyl group having 2 carbon atoms, R 3 represents a methyl group. In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0042]

　In one embodiment of the above cyclic amine derivative, A is a group represented by the general formula (IIb), R 1 may be substituted with a fluorine atom, a methyl group or an ethyl group, R 2 represents a hydrogen atom or an alkyl group having a carbon number of 2 ~ 5, R 3 each independently represents a methyl group or an ethyl radical, n represents 1 or 2. In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0043]

　In one embodiment of the above cyclic amine derivative, A is a group represented by the general formula (IIb), R 1 is a methyl group, an ethyl group, difluoromethyl group or a 2,2,2-trifluoroethyl group the stands, R 2 represents a hydrogen atom or an alkyl group having a carbon number of 2 ~ 5, R 3 each independently represents a methyl group or an ethyl radical, n represents 1 or 2. In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0044]

　In one embodiment of the above cyclic amine derivative, A is a group represented by the general formula (IIb), R 1 represents a methyl group or a 2,2,2-trifluoroethyl group, R 2 is represents a hydrogen atom or an alkyl group having 2 carbon atoms, R 3 represents a methyl radical, n represents 1 or 2. In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0045]

　In one embodiment of the above cyclic amine derivative, A is a group represented by the general formula (IIc), R 1 may be substituted with a fluorine atom, a methyl group or an ethyl group, R 2 represents a hydrogen atom or an alkyl group having a carbon number of 2 ~ 5, R 3 represents a methyl group or an ethyl group. In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0046]

　In one embodiment of the above cyclic amine derivative, A is a group represented by the general formula (IIc), R 1 is a methyl group, an ethyl group, difluoromethyl group or a 2,2,2-trifluoroethyl group the stands, R 2 represents a hydrogen atom or an alkyl group having a carbon number of 2 ~ 5, R 3 represents a methyl group or an ethyl group. In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0047]

　In one embodiment of the above cyclic amine derivative, A is a group represented by the general formula (IIc), R 1 represents a methyl group or a 2,2,2-trifluoroethyl group, R 2 is represents a hydrogen atom or an alkyl group having 2 carbon atoms, R 3 represents a methyl group. In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0048]

　The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0049]

　"Optionally substituted with a halogen atom, a methyl group or an ethyl group" and the hydrogen atom, independently, may be substituted by halogen atoms as mentioned above, it means a methyl group or an ethyl group. For example, a methyl group or an ethyl group or a difluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2,2-difluoroethyl group or 2,2,2-trifluoroethyl group.

[0050]

　The "alkylcarbonyl group having 2 to 5 carbon atoms" means a straight chain, branched chain or cyclic groups saturated hydrocarbon group is bonded to a carbonyl group having 1 to 4 carbon atoms, e.g., acetyl group, n- propionyl group, n- butyryl group, and isobutyryl group or valeryl group.

[0051]

　The above general formula (I) a cyclic amine derivative (hereinafter, a cyclic amine derivative (I)) represented as a preferred embodiment of is shown in Table 1-1 and Table 1-2, the present invention is to be limited thereto is not.

[0052]

[Table 1-1]

[0053]

[Table 1-2]

[0054]

　Incidentally, the cyclic amine derivative (I), enantiomers, when isomers such as stereoisomers are present, any isomers and mixtures thereof are encompassed cyclic amine derivative (I). Further, a cyclic amine derivative (I) is, enantiomers, when containing isomers such as stereoisomers, any isomers and mixtures thereof are also included in the cyclic amine derivative (I). Also, there are cases where isomers by conformation to produce even such isomers and mixtures thereof are included in the cyclic amine derivative (I). Isomer of interest can be obtained by known methods or methods analogous thereto. For example, if there are enantiomers cyclic amine derivative (I) is the enantiomer divided from cyclic amine derivative (I) are also encompassed by the cyclic amine derivative (I).

[0055]

　Enantiomer of interest, known means (e.g., using an optically active synthetic intermediate, or with respect to the racemic mixture of the final product, using known methods or methods analogous thereto (e.g., optical resolution)) it can be obtained by.

[0056]

　Further, the present invention includes prodrug thereof, or a pharmaceutically acceptable salt of the cyclic amine derivative (I). Prodrugs of a cyclic amine derivative (I), enzymatically or chemically in vivo, is a compound which is converted to the cyclic amine derivative (I). Active principle of the prodrug cyclic amine derivative (I) is a cyclic amine derivative (I), a prodrug itself cyclic amine derivative (I) may have activity.

[0057]

　Examples of the prodrug of a cyclic amine derivative (I), for example, hydroxyl group of the cyclic amine derivative (I) is alkylated, compounds phosphorylated or borated and the like. These compounds according to known methods, can be synthesized from cyclic amine derivative (I).

[0058]

　In addition, the prodrug of the cyclic amine derivative (I), known in the literature ( "Development of Pharmaceuticals", Hirokawa Shoten, 1990, Vol. 7, p.163 ~ 198 and Progress in Medicine, Vol. 5, 1985, p under physiological conditions described in .2157 ~ 2161), or may be changed to a cyclic amine derivative (I).

[0059]

　Cyclic amine derivative (I) may be labeled with isotope, the isotope labeled, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 15 O, 18 O and / or 125 include I.

[0060]

　Examples of the pharmaceutically acceptable salt of the cyclic amine derivative (I), for example, hydrochloride, sulfate, inorganic salts such as phosphate or hydrobromide, or oxalate, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, salicylate, xinafoate, pamoic , ascorbate, adipate, methanesulfonate, and organic acid salts such as p- toluenesulfonate or cinnamate. In addition these salts, hydrates may form solvates or polymorphs.

[0061]

　Cyclic amine derivative (I) or a pharmaceutically acceptable salt thereof pharmacologically, for example, can be synthesized according to the method described in a known literature (WO 2016/136944).

[0062]

　The peripheral nerves, sensory nerves include motor nerves and autonomic nerves.

[0063]

　Peripheral neuropathy, at least one is caused by the injury of neuronal cells and myelin sheath constituting a peripheral nerve (Schwann cells).

[0064]

　The peripheral neuropathy, but are not limited to those listed below, for example, drug-induced peripheral neuropathy, autoimmune neuropathy, metabolic peripheral neuropathy, hereditary peripheral neuropathy, vasculitic peripheral neuropathy, toxic neuropathy, infectious peripheral neuropathy, peripheral neuropathy, etc. of malignancy and the like.

[0065]

　Symptoms of peripheral neuropathy include, but are not limited to those listed below, for example, when the nerve is injury in sensory nerve, numbness of the extremities (abnormal sensations), paresthesia, sensory Donma, pain and hearing loss, and the like, when the nerve is injury motor neurons, muscle weakness, atrophy, flaccid paralysis, and reduced or lost, etc. of deep tendon reflexes, and the like, when the nerve is injury autonomic constipation, abdominal pain, sweating disorders, dysuria, and orthostatic hypotension, and the like.

[0066]

　The drug-induced peripheral neuropathy, e.g., peripheral neuropathy caused by anticancer agents, peripheral neuropathy with anti-viral drugs, peripheral neuropathy caused by antibiotic, peripheral neuropathy with anti-tuberculosis drugs, peripheral neuropathy with anti-arrhythmic drugs, peripheral neuropathy caused by lipid lowering agents, peripheral neuropathy with immunosuppressive drugs, peripheral neuropathy caused by gout therapeutics, and peripheral neuropathy due other agents and the like.

[0067]

　The anticancer agent, e.g., nucleic acid metabolism inhibitor, microtubule polymerization or depolymerization inhibitors, hormone antagonists, intracellular signal transduction inhibitors, malignant tumor-specific molecular target drug, nonspecific immunostimulants such and the like.

[0068]

　The nucleic acid metabolism inhibitor, for example, alkylating agents, antitumor antibiotics, topoisomerase inhibitors, platinum agents, pyrimidine antimetabolites, purine antimetabolites, folate synthesis inhibitors, and the like.

[0069]

　The microtubule polymerization or depolymerization inhibitor, for example, vinca alkaloid anticancer agents include taxane anticancer agents and the like.

[0070]

　The hormone antagonists, for example, an antiestrogen, antiandrogen agents.

[0071]

　The intracellular signaling inhibitors, for example, proteosome inhibitors, cerebronic inhibitors, and the like.

[0072]

　The malignant tumor-specific molecular target drug, e.g., a tyrosine kinase inhibitor, antibody formulation, arsenic preparations, and the like.

[0073]

　The non-specific immunostimulant, e.g., hemolytic streptococcus formulations include Coriolus versicolor polysaccharide preparations like.

[0074]

But is not limited to the specific anti-cancer agents listed below, the nucleic acid metabolism inhibitor e.g., oxaliplatin, cisplatin, carboplatin, nedaplatin, cytarabine, nelarabine, etoposide, teniposide and the like, microtubule the polymerization or depolymerization inhibitors such as paclitaxel, docetaxel, cabazitaxel, vincristine, vinblastine, vinorelbine, vindesine, eribulin, vinflunine, epothilones, ixabepilone, and examples of the intracellular signaling inhibitor e.g., bortezomib, carfilzomib etc. and examples of the malignant tumor-specific molecular target drug, e.g., brentuximab Bedochin, trastuzumab Emutanshin, thalidomide, or the like pomalidomide or lenalidomide and the like.

[0075]

　Antiviral agents include, but are not limited to those listed below, for example, efavirenz, emtricitabine, emtricitabine, phthalic acid tenofovir disoproxil, saquinavir, sanilvudine, zalcitabine, didanosine, stavudine, Jidopujin, darunavir, delavirdine mesylate salt, nevirapine, fumarate tenofovir disoproxil, foscarnet sodium hydrate, lamivudine, lamivudine, abacavir sulfate, ritonavir, ribavirin, lopinavir, ritonavir, atazanavir, indinavir, and the like.

[0076]

　Antimicrobial agents include, but are not limited to those listed below, for example, chloramphenicol, nitrofurantoin, metronidazole, dapsone, ethambutol, fluoroquinolones (levofloxacin, ciprofloxacin, Mokishifurokisa Shin, norfloxacin, include ofloxacin, etc.), and the like.

[0077]

　The antituberculous agents include, but are not limited to those listed below, for example, isoniazid, ethambutol, and the like.

[0078]

　The antiarrhythmic agents include, but are not limited to those listed below, for example, amiodarone, procainamide, and the like.

[0079]

　The hypolipidemic agent, but are not limited to those listed below, for example, pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin and the like.

[0080]

　Immunosuppressive agents include, but are not limited to those listed below, for example, tacrolimus, cyclosporine, mycophenolate mofetil, leflunomide, chloroquine, interferon alpha, gold preparations and the like.

[0081]

　Other agents include, but are not limited to those listed below, for example, colchicine or allopurinol gout therapeutics, phenytoin antiepileptic drugs, nitrous oxide anesthetic pyridoxine vitamins, anti be a vicious drinker agents disulfiram, hydralazine, etc. antihypertensive drugs.

[0082]

　Drugs that cause drug-induced peripheral neuropathy, based on the classification, not only those which have so far been found, also include those which will be found.

[0083]

　Autoimmune peripheral neuropathy, but are not limited to those listed below, for example, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and abnormal protein blood They include neurological disorders associated with the disease. As subtype contained in Guillain-Barre syndrome, for example, acute inflammatory demyelinating neuritis, acute motor axonal neuritis, acute motor and sensory axonal neuritis, Fisher syndrome, and the like.

[0084]

　Metabolic peripheral neuropathy, but are not limited to those listed below, for example, diabetic peripheral neuropathy, uremic peripheral neuropathy, collagen disease peripheral neuropathy, vitamin deficiency peripheral neuropathy, hypothyroidism peripheral neuropathy, and the like.

[0085]

　The hereditary peripheral neuropathy, but are not limited to those listed below, for example, Charcot-Marie-Tooth disease, familial amyloid polyneuropathy, hereditary fragility neuropathy, hereditary neuralgia muscular atrophy disease and the like.

[0086]

　The cyclic amine derivative (I) or a salt thereof pharmacologically acceptable has an inhibitory effect on disorders of the peripheral nerve cell can be evaluated using root ganglia from strain of neurons after rat. Specifically, inducing a slow down cell activity by the root ganglia from strain of neurons after rat treating cytotoxic agent, to assess the inhibitory effect on the cell activity reduction.

[0087]

　The cyclic amine derivative (I) or a pharmacologically acceptable salt thereof has myelination promoting effect can be evaluated using the rat dorsal root ganglion neurons, Schwann cell co-culture. Specifically, a root ganglion neurons and Schwann cells after rats were cultured together, to induce myelination by ascorbic acid treatment, to assess whether the myelination is promoted.

[0088]

　That it has the above cell activity reduction suppressing action and myelination promoting action is considered to be effective in the prevention and treatment of peripheral neuropathy. Incidentally, but the present embodiment is limited by this assumption.

[0089]

　It cyclic amine derivative (I) or a salt thereof pharmacologically acceptable is effective in treating or preventing drug-induced peripheral neuropathy, particularly anti-cancer agents induced peripheral neuropathy, various drugs, particularly various anti can be evaluated using a peripheral neuropathy model was induced by'm agent (Hoeke, et al., ILAR Journal, 2014 years, Vol. 54, p.273-281).

[0090]

　It cyclic amine derivative (I) or a pharmacologically acceptable salt thereof is effective for the treatment or prevention of autoimmune peripheral neuropathy, experimental autoimmune neuritis (Experimental autoimmune neuritis: EAN) Model It can be evaluated using (Soliven, ILAR Journal, 1994 years, Vol. 54, p.282-290).

[0091]

　It cyclic amine derivative (I) or a pharmacologically acceptable salt thereof is effective for the treatment or prevention of metabolic peripheral neuropathy, particularly diabetic peripheral neuropathy can be evaluated using the streptozotocin-induced diabetes model ( O'Brien et al., ILAR Journal, 2014 years, Vol. 54, p.259-272).

[0092]

　It cyclic amine derivative (I) or a pharmacologically acceptable salt thereof is effective in treating or preventing inherited peripheral neuropathies, particularly Charcot-Marie-Tooth disease, assessed using PMP22 Trembler-J mice can (Nicks et al., Neurobiology of Disease, 2014 years, Vol. 70, p.224-236).

[0093]

　Peripheral cyclic amine derivative (I) or a pharmaceutically acceptable salt thereof pharmacologically a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey or human), particularly excellent to human it can be used as pharmaceuticals useful in the treatment or prevention of neurological disorders.

[0094]

　When using a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as a pharmaceutical, compounding a carrier and a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, it is acceptable as it is or a pharmaceutical to, may be administered orally or parenterally.

[0095]

　A medicament comprising as an active ingredient a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as dosage forms for oral administration include, for example, tablets (including dragees and film-coated tablets), pills, granules, powders, (including soft capsules and micro capsules) capsules, syrups, emulsions or suspensions. As the dosage form for parenteral administration of a medicament comprising as an active ingredient a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, for example, injections, infusions, drip infusions, suppositories include liniments or patches. Furthermore, a suitable base (e.g., polymer of butyric acid, polymer of glycolic acid, butyric acid - copolymers of glycolic acid, a mixture of the polymers of glycolic acid acid or polyglycerol fatty acid ester) and combination, it is also effective to sustained release formulations.

[0096]

　Preparation of the dosage form of the preparation can be carried out according to a known production method generally used in the pharmaceutical field. In this case, if necessary, commonly used excipients in the pharmaceutical field, binders, lubricants, disintegrating agents, sweetening agents, surfactants, prepared by incorporating a suspending agent or emulsifier such as be able to.

[0097]

　Preparation of a tablet, for example, excipients, binders, can be carried out by incorporating a disintegrating agent or lubricant. Preparation of pills and granules, for example, can be carried out by incorporating an excipient, a binder or disintegrant. Further, the preparation of powders and capsules, for example, can be carried out by incorporating an excipient. Preparation of syrups are, for example, can be carried out by incorporating the sweeteners. Preparation of emulsions or suspensions, for example, can be carried out by containing a surfactant, suspending agent or emulsifying agent.

[0098]

　Examples of the excipient include lactose, glucose, starch, sucrose, microcrystalline cellulose, powdered glycyrrhiza, mannitol, sodium hydrogen carbonate, and calcium phosphate or calcium sulfate.

[0099]

　As the binder, for example, starch paste solution, gum arabic solution, gelatin solution, tragacanth solution, carboxymethylcellulose solution, sodium alginate solution, or glycerol.

[0100]

　Examples of the disintegrant include starch, or calcium carbonate.

[0101]

　Examples of the lubricant include magnesium stearate, stearic acid, calcium or purification talc stearate.

[0102]

　Sweetening agents, for example, glucose, fructose, invert sugar, sorbitol, xylitol, glycerine, or simple syrup.

[0103]

　As the surfactant, for example, sodium lauryl sulfate, polysorbate 80, and a sorbitan mono fatty acid ester or stearic acid polyoxyl 40.

[0104]

　Suspending agents, such as gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose or bentonite.

[0105]

　Emulsifiers, such as gum arabic, tragacanth and gelatin or polysorbate 80.

[0106]

　Furthermore, a medicament comprising as an active ingredient a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, in preparing the above dosage forms may contain coloring agents generally used in the pharmaceutical field, storage agents, fragrances, flavoring agents, may be added stabilizers or thickeners, and the like.

[0107]

　The daily dose of a pharmaceutical containing a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient, the patient's condition or body weight, depending on the kind of the compound or the administration route and the like, for example, , in the case of oral administration to an adult (body weight about 60kg) is in the range of 1 ~ 1000 mg of a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient amount, in 1-3 divided doses preferably administered, adult when administered parenterally (weighing about 60kg), if injection, body weight 1kg cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient amount it is preferably administered intravenously in a range of around 0.01 ~ 100 mg.

[0108]

　Cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, complement or enhance the therapeutic or prophylactic effect, or to reduce the dosage, it may also be appropriate amount, or combination with other agents. For example, it can also be used in combination with drugs that relieve the symptoms of peripheral neuropathy.
Example

[0109]

　Is specifically described below based on the present invention embodiment, the present invention is not limited thereto.

[0110]

　The test compound, represented by the following chemical formula, (S) -1- (4-(dimethylamino) piperidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazol-2-yl ) propan-1-one (hereinafter compound 1) used was synthesized according to the method described in a known literature (WO 2016/136944).
[Of 5]

[0111]

(Example 1) a cyclic amine derivative for cell injury in root ganglia from strain of neurons after rat (I) or a pharmacologically acceptable protective effect of salt:
　cyclic amine derivative (I) or a pharmaceutically It was examined the protective effect against cell injury in rat dorsal root ganglion-derived strains of neurons acceptable salt.

[0112]

　The fetal rat dorsal root ganglion-derived cell lines ND15, were cultured in DMEM medium containing 10% FBS. The next day, and cultured for 8 days in 10% FBS-containing DMEM medium containing EC23 (10μM, Reinner), it was differentiated into neural cells.

[0113]

　It was replaced with DMEM / F12 medium containing cisplatin (final concentration 50 [mu] M), by culturing for 4 hours, to induce cytotoxicity. Compound 1 is similar to cisplatin, it was treated by including in the medium (final concentration 0.5, 5 or 50 [mu] M). Group configuration, the non-treatment group, Compound 1 50 [mu] M treatment group, cisplatin treatment group, cisplatin and compound 1 0.5 [mu] M treatment group, cisplatin and compound 1 5 [mu] M treatment group, was 6 group of cisplatin and compound 1 50 [mu] M treatment group.

[0114]

　To measure cellular activity, was replaced with DMEM / F12 medium containing Alamar Blue (Invitrogen), after 2 hours incubation, the absorbance was measured 570nm and 595 nm. Cell activity was calculated as the ratio of 570nm absorbance to the absorbance of 595 nm, a non-treatment group was defined as 100%.

[0115]

　The results of the evaluation of the effects on cellular activity of Compound 1 is shown in FIG. The vertical axis of FIG. 1 shows a cell activity (%) (mean ± standard error; 6 cases in each group). The horizontal axis indicates the non-treated group from the left, Compound 1 50 [mu] M treatment group, cisplatin treatment group, cisplatin and compound 1 0.5 [mu] M treatment group, cisplatin and compound 1 5 [mu] M treatment group and cisplatin and compound 1 50 [mu] M treatment group. "#" In the figure, compared with statistically significant to the untreated group (#: p <0.05, t-test Student) indicates a difference, in the figure "*" is compared to cisplatin treatment groups statistically significant (*: p <0.025, multiple comparisons of Williams, one side) indicates a difference.

[0116]

　Whereas reduction of cell activity of rat dorsal root ganglion-derived strains of neuronal cells by cisplatin treatment was observed, by the simultaneous treatment of Compound 1, inhibit the decrease were observed. That is, Compound 1 was found to protect the injury to root ganglia from strain of neurons after rat.

[0117]

(Example 2) cyclic amine derivatives on cell injury in root ganglia from strain of neurons after rat (I) or a pharmacologically acceptable salt thereof repaired Effect:
　cyclic amine derivative (I) or a pharmaceutically It was examined repair effects on cell injury in rat dorsal root ganglion-derived strains of neurons acceptable salt.

[0118]

　Induced cytotoxicity with cisplatin for Examples 1 Rat fetuses dorsal root ganglion-derived cell line ND15 in the same manner as was determined cell activity. After compound 1 of cisplatin treatment for 24 hours, it was treated for 2 hours while contained in the culture medium (final concentration 0.5, 5 or 50 [mu] M). Group configuration, the non-treatment group, Compound 1 50 [mu] M treatment group, cisplatin treatment group, cisplatin and compound 1 0.5 [mu] M treatment group, cisplatin and compound 1 5 [mu] M treatment group, was 6 group of cisplatin and compound 1 50 [mu] M treatment group.

[0119]

　The results of the evaluation of the effects on cellular activity of Compound 1 is shown in FIG. The vertical axis of FIG. 2 shows the cell activity (%) (mean ± standard error; 6 cases in each group). The horizontal axis indicates the non-treated group from the left, Compound 1 50 [mu] M treatment group, cisplatin treatment group, cisplatin and compound 1 0.5 [mu] M treatment group, cisplatin and compound 1 5 [mu] M treatment group and cisplatin and compound 1 50 [mu] M treatment group. "#" In the figure, compared with statistically significant to the untreated group (#: p <0.05, t-test Student) indicates a difference, in the figure "*" is compared to cisplatin treatment groups statistically significant (*: p <0.025, multiple comparisons of Williams, one side) indicates a difference.

[0120]

　Whereas reduction of cell activity of rat dorsal root ganglion-derived strains of neuronal cells was observed by cisplatin treatment, treatment after Compound 1, inhibit the decrease were observed. That is, Compound 1 was found to repair injuries to root ganglia from strain of neurons after rat.

[0121]

(Example 3) Rat dorsal root ganglion neurons, Schwann cell co-cyclic amine derivatives on myelination culture (I) or a pharmacologically acceptable effect of salt:
　cyclic amine derivative (I) or a drug was examined effect of promoting myelination pharmacologically acceptable rat dorsal root ganglion cells, Schwann cell co-culture of salt.

[0122]

　Were excised dorsal root ganglia from the fetus of pregnant day 15 of the female SD rats were cultured separately in the nerve cells and Schwann precursor cells (the cell culture start the first day was Day1). On day 19 from the cell culture the first day (Day19), was initiated co-culture by the addition of Schwann precursor cells to the culture medium of neurons. Myelination was induced by treating ascorbic acid (in accordance with the medium change medium 2-3 in total 4-5 times) in 26-40 days after the cell culture the first day (Day26 ~ 40).

[0123]

　Together with ascorbic acid treatment, compounds were dissolved in sterile distilled water 1 (final concentration 30 [mu] M) were treated in total 4-5 times. As a control, we were treated with sterile distilled water instead of compound 1 solution. Group configuration, sterile distilled water treated group (Vehicle treated group), was two groups of 30μM Compound 1 treated group (Compound 1 treatment group).

[0124]

　To perform immunocytochemistry, the cells were washed with phosphate buffered saline to 40-43 days from cell culture first day (Day40 ~ 43), fixed with 4% paraformaldehyde-phosphate buffer. Methanol treatment, was subjected to blocking, a myelin marker protein Myelin Basic Protein to (MBP) were fluorescently immunostained.

[0125]

　Fluorescence microscopy (DMI4000B, Leica), the captured fluorescence image of MBP, were analyzed myelin segments (≧ 25 [mu] m) number from the image. Incidentally, the analysis region (ROI) is divided into four co-culture, fibrous stained images of MBP among each partition has been the most frequently observed region.

[0126]

　The results of the evaluation of the effects on myelination of Compound 1 shown in FIG. The vertical axis of FIG. 3 shows the number of myelin segments per ROI (mean ± standard error; each group 8-12 cases). The horizontal axis indicates the cell culture days.

[0127]

(Example 4) rat dorsal root ganglion neurons, Schwann cell co-cyclic amine derivatives on the expression of MBP in culture (I) or a pharmacologically acceptable effect of salt:
　cyclic amine derivative (I) or a was studied the effect on the expression of MBP in pharmacologically acceptable rat dorsal root ganglion cells, Schwann cell co-culture of salt.

[0128]

　To prepare a rat dorsal root ganglion neurons, Schwann cell co-cultured in the same manner as in Example 3, was subjected to induction and treatment of Compound 1 of myelination. Group configuration, sterile distilled water treated group (Vehicle treated group), was two groups of 30μM Compound 1 treated group (Compound 1 treatment group).

[0129]

　To perform Western blotting, the 43 days after the cell culture the first day, was dissolved cocultured RIPA cell lysate was subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis for cell lysates. Thereafter, the proteins were transferred to a PVDF membrane and detected a band of MBP by antibody reaction. Using Image Lab software (BIO-RAD) for quantification of detected bands.

[0130]

　The results of the evaluation of the effect on the expression of MBP of Compound 1 shown in FIG. The vertical axis was 1 an average value of the Vehicle group, showing the relative expression levels of MBP in FIG. 4 (mean ± standard error; 4 cases in each group). The horizontal axis shows the Vehicle treated group and Compound 1-treated groups left. "*" In the figure, compared with statistically significant and Vehicle treated group (*: p <0.05, t-test Student) indicates a difference.

[0131]

　Treatment of compound 1, increase in MBP is increased and myelin marker protein number myelinated segments was observed. That is, Compound 1 was found to promote myelination in the rat dorsal root ganglion neurons, Schwann cell co-culture.

[0132]

　From Examples 1, 2, 3 and 4, a cyclic amine derivative (I) or a pharmaceutically acceptable salt thereof pharmacologically it is found to be effective against disorders of the peripheral nerve neurons and myelin It was.

[0133]

(Example 5) Rat oxaliplatin-induced peripheral neuropathy allodynia for cold stimuli in the model (cold allodynia) and tactile allodynia to stimulation cyclic amine derivative for (mechanical allodynia) (I) or a pharmacologically acceptable salt thereof effect of repeated administration:
　was studied oxaliplatin cold allodynia and effects of the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof for mechanical allodynia develops by administration of.

[0134]

　SD rats (7-week-old, male; Charles River Japan) to oxaliplatin (4mg / kg, El Prat intravenous infusion solution 200g; Yakult) twice in the abdominal cavity in two days every day to a 1-week cycle (1 weeks ) in to administer two or three weeks to prepare oxaliplatin-induced peripheral neuropathy model. As a control (sham-induced), administered 5% glucose solution (Otsuka Pharmaceutical Factory), it was the day of administration for the first time in the pathology-induced day 0.

[0135]

　From pathology induced day 0, Compound 1 (3 or 10 mg / kg) solution or the solvent containing the (water for injection; Otsuka Pharmaceutical Factory) for 18 days to rats, twice daily administration of daily oral administration (second 1 administration from the administration of times day after 8 hours) was. Pathology-induced day 0 performs the first dose prior to administration oxaliplatin, is allodynia valuation date was administered for the first time after the evaluation. Group configuration, false induced - solvent administered group (Sham group), conditions induced - solvent administered group (Vehicle group), pathology induced -3mg / kg Compound 1 administration group (3 mg / kg Compound 1 administration group), pathology induced -10mg / was 4 groups kg compound 1 administration group (10 mg / kg compound 1 administration group).

[0136]

　Efficacy evaluation of cold allodynia was carried out in the pathology before induction and pathogenesis-induced 12 days (1 before administration first compound). Efficacy against the cold allodynia was evaluated by Cold Plate test. Using Cold Plate apparatus (Ugo Basile) in the test. The animals are placed kept on plates at a constant temperature (8 ℃), pain-related behavior (raise the leg, shake a leg, licking the feet, stand up, to jump) measuring the escape latency of until it is confirmed did. It should be noted that, cut off time was 180 seconds.

[0137]

　Efficacy evaluation of mechanical allodynia was carried out in the pathology before induction and pathogenesis-induced 18 days (1 before administration first compound). Efficacy against mechanical allodynia was evaluated by the von Frey test. The test method is known in the literature (Chaplan et al., Journal of Neuroscience Methods, 1994 years, Vol. 53, P.55-63) according to the method described in, carried out using von Frey filaments (North Coast Medical), 50% to calculate the reaction threshold.

[0138]

　The results of the evaluation of the effects on cold allodynia of Compound 1 shown in FIG. The vertical axis of FIG. 5 shows the escape latency in the Cold Plate test, indicating that the numerical values ​​is improved, the higher cold allodynia (mean ± standard error; 10 patients for each group). Horizontal axis (in the figure, "Day 0 (pre-condition induced)") conditions before induction from the left, pathology induced 12 days (in the figure, "day 12 (after pathology induction)") indicates each administration group at. "#" In the figure, statistically compared to the Sham group significantly (#: p <0.05, t-test Student) indicates a difference, in the figure "*" is Vehicle compared with statistically significant with group (*: p <0.025, multiple comparisons of Williams, one side) indicates a difference.

[0139]

　In pathology induced 12 days, Vehicle group, as compared with the Sham group, a significant shortening of the escape latency was observed. That is, the onset of cold allodynia is peripheral neuropathy induced by oxaliplatin was confirmed.

[0140]

　The daily orally twice daily Compound 1, in pathologies induced 12 days, 10 mg / kg Compound 1 administered group, compared to the Vehicle group, a significant prolongation of the escape latency was observed. That is, Compound 1 was found to inhibit cold allodynia in the oxaliplatin-induced peripheral neuropathy model.

[0141]

　The results of the evaluation of the effects on mechanical allodynia of Compound 1 shown in FIG. The vertical axis of FIG. 6 shows a 50% reaction threshold in the von Frey test, indicating that the number is mechanical allodynia higher are improved (mean ± standard error; 10 patients for each group). Horizontal axis (in the figure, "Day 0 (pre-condition induced)") conditions before induction from the left, pathology induced 18 days (in the figure, "Day18 (after pathology induction)") indicates each administration group at. "#" Is in the figure, compared with statistically significant and Sham group (#: p <0.05, t-test Welch) indicates a difference, in the figure "*" is, Vehicle compared with statistically significant with group (*: p <0.025, multiple comparison Shirley-Williams, one side) indicates a difference.

[0142]

　In pathology induced 18 days, Vehicle group, as compared with the Sham group, a significant decrease of 50% reaction threshold value was observed. That is, the development of mechanical allodynia is peripheral neuropathy induced by oxaliplatin was confirmed.

[0143]

　The daily oral administration twice daily of compound 1, in pathologies induced 18 days, 3 mg / kg Compound 1 administration group and 10 mg / kg Compound 1 administered group, compared to the Vehicle group, a significant 50% response threshold increase was observed. That is, Compound 1 was found to inhibit the mechanical allodynia in oxaliplatin-induced peripheral neuropathy model.

[0144]

　From the above, cyclic amine derivative (I) or a pharmaceutically acceptable salt thereof pharmacologically was proved to exhibit a significant suppression effect against peripheral neuropathy induced by oxaliplatin.

[0145]

(Example 6) rats cisplatin-induced peripheral neuropathy cyclic amine derivative to mechanical allodynia in a model (I) or a pharmacologically acceptable single dose of treatment effect of the salt:
　mechanical allodynia develops by administration of cisplatin It was studied the effect of cyclic amine derivative (I) or a pharmacologically acceptable salt thereof for.

[0146]

　SD rats (6-week-old, male; Charles River Japan) to cisplatin (Wako Pure Chemical Industries, Ltd.) twice a week intraperitoneally (1 or 2mg / kg), to be administered 5 weeks intermittent, cisplatin-induced peripheral neuropathy the model was produced. Cisplatin was administered prepared in 10 mg / mL dissolved in physiological saline. As a control (mock-induced) were administered saline. The initial day of administration was in the pathology induce the first day.

[0147]

　Pathologies induced 34 days compound 1 (10 mg / kg) solution or the solvent containing the (water for injection) was administered orally to rats. Group configuration, false induced - solvent administered group (Sham group), conditions induced - solvent administered group (Vehicle group), and a third group of pathologies induced -10mg / kg Compound 1 administration group (10 mg / kg Compound 1 administration group) .

[0148]

　Efficacy evaluation of mechanical Arodenyia is evaluated in the same manner as in Example 5 was performed after pathology induction 34 days of Compound 1 prior to administration and administered two hours.

[0149]

　The results of the evaluation of the effects on mechanical allodynia of Compound 1 shown in FIG. The vertical axis of FIG. 7, von Frey showed 50% reaction threshold in the test, the numerical indicate that has been improved, the higher the mechanical allodynia (mean ± standard error; each group 4-6 cases). Horizontal axis (in the figure, "Day34 (predose)") Compound 1 prior to administration from the left, (in the figure, "Day34 (administered 2 hours after)") compound administration 2 hours after showing each administration group at. "#" In the figure, statistically compared to the Sham group significantly (#: p <0.05, t-test Student) indicates a difference, in the figure "*" is Vehicle compared to the group statistically significant (*: p <0.05, t-test Student) indicates a difference.

[0150]

　In Compound 1 administration two hours after, 10 mg / kg Compound 1 administered group, compared to the Vehicle group, significant increase of 50% reaction threshold value was observed. That is, Compound 1 was found to inhibit the mechanical allodynia in cisplatin-induced peripheral neuropathy model.

[0151]

　From the above, cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, to the peripheral neuropathy induced by cisplatin, were proved to exhibit a significant suppression effect.

[0152]

(Example 7) Rat paclitaxel-induced peripheral neuropathy cyclic amine derivative to mechanical allodynia in a model (I) or a pharmacologically acceptable effect by single administration of a salt:
　to mechanical allodynia develops by administration of paclitaxel It was studied the effect of cyclic amine derivative (I) or a pharmacologically acceptable salt thereof.

[0153]

　SD rats (6 weeks old, male; Japan Charles River) paclitaxel (4 mg / kg, ChromaDex) to be administered four times intraperitoneally every other day, to prepare a paclitaxel-induced peripheral neuropathy model. Paclitaxel, 1: 1 was dissolved in mixed Cremophor EL (Nacalai Tesque) and ethanol (Wako Pure Chemical) in and prepared to 6 mg / mL, was administered was diluted to 4 mg / mL with physiological saline. The initial day of administration was in the pathology-induced day 0.

[0154]

　Pathologies induced day 14 Compound 1 (10 mg / kg) solution or the solvent containing the (water for injection) was administered orally to rats. Group configuration, and the solvent administration group and (Vehicle group) and two groups of 10 mg / kg Compound 1 administration group.

[0155]

　Efficacy evaluation of mechanical Arodenyia is evaluated in the same manner as in Example 5 were carried out in the pathology induced before and pathologies induced 14 days (Compound 1 administered three hours after).

[0156]

　The results of the evaluation of the effects on mechanical allodynia of Compound 1 shown in FIG. The vertical axis of FIG. 8 shows a 50% reaction threshold in the von Frey test, indicating that the number is mechanical allodynia higher are improved (mean ± standard error; example each group 8). The horizontal axis, before pathologies induced from the left, pathology induced 14 days of compound 1 administration 3 hours (in the figure, "Day 14 (post-dose 3 hours)") indicates each administration group at. "*" In the figure, compared with statistically significant and Vehicle group (*: p <0.05, t-test Student, both sides) indicates a difference.

[0157]

　In pathology induced 14 days (Compound 1 administered three hours after), 10 mg / kg Compound 1 administered group, compared to the Vehicle group, significant increase of 50% reaction threshold value was observed. That is, Compound 1 was found to inhibit the mechanical allodynia in paclitaxel-induced peripheral neuropathy model.

[0158]

　From the above, cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, to the peripheral neuropathy induced by paclitaxel was found to exhibit a significant suppression effect.

[0159]

(Example 8) Rat bortezomib induced peripheral neuropathy cyclic amine derivative to mechanical allodynia in a model (I) or a pharmacologically acceptable effect by single administration of a salt:
to mechanical allodynia develops by the administration of bortezomib It was examined the therapeutic effects of cyclic amine derivative (I) or a pharmacologically acceptable salt thereof.

[0160]

　SD rats (6-week-old, male; Charles River Japan) as to bortezomib (0.2mg / kg, AdooQ BioScience) condition inducing the first day of the first of the administration date (Day1), pathology-induced 1, 4, 8 and by administering the four times intraperitoneally on day 11, was prepared bortezomib-induced peripheral neuropathy model. Bortezomib was dissolved in dimethyl sulfoxide, was added Tween 80. Then, water for injection, was prepared in 0.2 mg / mL. The final concentration of dimethyl sulfoxide and Tween80 was 5% each.

[0161]

　Pathologies induced 15 days compound 1 (20 mg / kg) solution or the solvent containing the (water for injection) was administered orally to rats. Group configuration, and the solvent administration group and (Vehicle group) and two groups of 20 mg / kg Compound 1 administration group.

[0162]

　Efficacy evaluation of mechanical Arodenyia is evaluated in the same manner as in Example 5 were carried out in the pathology induced before and pathologies induced 15 days (Compound 1 administered three hours after).

[0163]

　The results of the evaluation of the effects on mechanical allodynia of Compound 1 shown in FIG. The vertical axis of FIG. 9 shows a 50% reaction threshold in the von Frey test, indicating that the number is mechanical allodynia higher are improved (mean ± standard error; example each group 8). The horizontal axis, before pathologies induced from the left, pathology induced 15 days of compound 1 administration 3 hours (in the figure, "Day15 (post-dose 3 hours)") indicates each administration group at. "*" In the figure, compared with statistically significant and Vehicle group (*: p <0.05, t-test Student, both sides) indicates a difference.

[0164]

　In pathology induced 15 days (Compound 1 administered three hours after), 20 mg / kg Compound 1 administered group, compared to the Vehicle group, significant increase of 50% reaction threshold value was observed. That is, Compound 1 was found to inhibit the mechanical allodynia in Borutezomimibu induced peripheral neuropathy model.

[0165]

　From the above, cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, to the peripheral neuropathy induced by bortezomib, were proved to exhibit a significant suppression effect.

[0166]

　Therefore, the cyclic amine derivative (I) or a pharmacologically acceptable salt, pharmaceutical, against peripheral neuropathy induced particularly by anticancer agents, were proved to exhibit a significant suppression effect.

[0167]

(Example 9) a rat experimental autoimmune neuritis (EAN) a cyclic amine derivative to the model (I) or a pharmacologically acceptable effect of salt:
　cyclic amine derivative (I) or a pharmaceutically It was examined inhibitory effect on rat EAN model acceptable salt thereof.

[0168]

　Illustrating a method for manufacturing a EAN model rats. Partial peptide P2 of peripheral myelin protein P2 (57-81) peptide (synthesized by Toray Research Center) was dissolved in physiological saline (Otsuka Pharmaceutical Factory) was prepared in 2 mg / mL, including killed Mycobacterium tuberculosis H37Ra 2 mg / mL complete Freund's adjuvant (Difco Laboratories) and by mixing equal amounts, was a peptide administered liquid emulsions. Lewis rats (6-7 weeks old, male; Japan Charles River) under anesthesia, the peptide administration was subcutaneously ridge portion by 200μL administration, to prepare a EAN model. The peptide administration date was in the pathology-induced day 0.

[0169]

　The clinical score was evaluated as follows. 0 = no symptoms, 1 = tail or hind limb weakness, 2 = tail and hind limb weakness, 3 = hind limb portions paralysis, 4 = complete hind limb paralysis, 5 = moribund or death. Also, I went also to body weight measurement.

[0170]

　Compound 1 (20 mg / kg) is distilled water (Otsuka Pharmaceutical Factory) was orally administered twice daily EAN model dissolved in (starting administered pathology induced 10 days). As a control, it was orally administered distilled water EAN model. Group configuration, a solvent-administered group (Vehicle group), and the two groups of compounds 1 administration group.

[0171]

　To perform histopathological evaluation, sciatic nerve and tibial nerve pathologies induced 17 days were isolated and immersed in 10% neutral buffered formalin. After sliced, hematoxylin and eosin staining, were carried out Kluver-Barrera staining (Luxol fast blue staining and Nissl staining of double staining) and immunostaining (Iba1, CD3, NFP and MBP). Observing the sample with an optical microscope, infiltration of T cells and macrophages, to evaluate the presence or absence of denaturation of myelin and axons.

[0172]

　The results of the evaluation of the effects on clinical scores of Compound 1 shown in FIG. 10. The vertical axis of FIG. 10 shows clinical scores, indicating that the numerical value symptoms The lower is improved (mean ± standard error, n = 6 ~ 7). Compound 1 administered group as compared to the Vehicle group, increase in clinical score was suppressed.

[0173]

　The results of the evaluation of the effects on weight loss of Compound 1 shown in FIG. 11. The vertical axis indicates the weight of the rats (mean ± standard error, each group 6-7 cases) of FIG. 11. Weight loss is a Vehicle group occurred, but did not cause weight loss in 20 mg / kg Compound 1 administration group.

[0174]

　The results of the histopathological evaluation of Compound 1 shown in Table 2. Table 2 shows the number of individuals showed histological changes in the sciatic nerve and tibial nerve (3 cases in each group). The Vehicle group, infiltration of T cells and macrophages, degeneration of myelin and axons were observed, it was hardly observed in the 20 mg / kg Compound 1 administration group.

[0175]

[Table 2]

[0176]

　From the above, cyclic amine derivative (I) or a pharmacologically acceptable salt thereof was found to be effective against autoimmune peripheral neuropathy.

[0177]

(Example 10) rats Experimental autoimmune neuritis (EAN) Model mechanical cyclic amine derivatives on allodynia (I) or a pharmacologically acceptable effect of salt:
　cyclic amine derivative (I) or a It was examined inhibitory effect on mechanical allodynia rat EAN model pharmacologically acceptable salt thereof.

[0178]

　It was prepared EAN model rats in the same manner as in Example 9. It was also administered saline solution (Otsuka Pharmaceutical Factory) instead of peptide administration solution, provided false induced animals. The dosing day of peptide administration solution or physiological saline was pathology induced on Day 0.

[0179]

　Pathologies induced 14 days compound 1 (5 or 10 mg / kg) or a solvent (water for injection) was administered orally to rats. Group configuration, false induced - solvent administered group (Sham group), conditions induced - solvent administered group (Vehicle group), pathology induced -5mg / kg Compound 1 administration group (5 mg / kg Compound 1 administration group), pathology induced -10mg / was 4 groups kg compound 1 administration group (10 mg / kg compound 1 administration group)

[0180]

　Efficacy evaluation of mechanical Arodenyia is evaluated in the same manner as in Example 5 were carried out in the pathology induced 14 days of compound 1 administration 3 hours.

[0181]

　The results of the evaluation of the effects on mechanical allodynia of Compound 1 shown in FIG. 12. The vertical axis of FIG. 12, von Frey showed 50% reaction threshold in the test, the numerical indicate that has been improved, the higher the mechanical allodynia (mean ± standard error, 4-10 cases per group). "#" In the figure, statistically compared to the Sham group significantly (#: p <0.05, t-test Student) to be a difference, in the figure "*" is Vehicle group statistically significant compared to (*: p <0.025, multiple comparisons of Williams, one side) indicates a difference.

[0182]

　Vehicle group, as compared with the Sham group, a significant decrease of 50% reaction threshold value was observed. That is, the development of mechanical allodynia in the EAN model was confirmed.

[0183]

　5 mg / kg Compound 1 administration group and 10 mg / kg Compound 1 administered group, compared to the Vehicle group, significant increase of 50% reaction threshold value was observed. That is, Compound 1 was found to inhibit the mechanical allodynia in EAN model.

[0184]

　From this result, a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof was found to be effective against mechanical allodynia in autoimmune peripheral neuropathy.

[0185]

(Example 11) rats streptozotocin-induced diabetic model of cyclic amine derivatives on nerve conduction velocity reduction (I) or a pharmacologically acceptable Effect of Salts:
　acceptable cyclic amine derivative (I) or a pharmaceutically It was examined inhibitory effect on mechanical allodynia of rats with streptozotocin-induced diabetes model salts.

[0186]

　SD rats (6 weeks old, male; Japan Charles River) in streptozotocin (50mg / kg, Sigma-Aldrich) to to be administered into the tail vein, to produce a streptozotocin-induced diabetes model. Streptozotocin was administered prepared in 25 mg / mL dissolved in citrate buffer. Moreover, not administered streptozotocin solution, provided conditions non-induced animals. The initial day of administration was in the pathology induce the first day.

[0187]

　Pathologies induced 14 days after 28 days, a solution or a solvent containing the compound 1 (3 or 10 mg / kg) a (water for injection) was administered orally twice daily to rats. Group configuration condition uninduced - solvent administered group (Normal group), conditions induced - solvent administered group (Vehicle group), pathology induced -3mg / kg Compound 1 administration group (3 mg / kg Compound 1 administration group), pathology induced - was four groups of 10 mg / kg compound 1 administration group (10 mg / kg compound 1 administration group).

[0188]

　Measurement of nerve conduction velocity was performed the day following the final administration in 3 days. The two single-needle electrodes (A, B) is brought into contact with the inserted sciatic nerve thigh, further one single needle electrode (C) is inserted into the lower end portion of the gastrocnemius (Achilles tendon), derived footpad the electrode of use was installed. Stimulation between and between B-C A-B respectively as the distal stimulation and proximal stimulation was analyzed transmission time of stimulation in each derived waveform obtained from the electrodes of the footpad. Nerve conduction velocity, and the difference in transmission time of a distal stimulation and proximal stimulation was calculated based on the distance between the electrodes.

[0189]

　The results of the evaluation of the effect of Compound 1 on nerve conduction velocity reduction shown in Fig. The vertical axis shows the nerve conduction velocity in FIG. 13 (mean ± standard error; each group 5-6 cases). "#" In the figure, statistically compared to the Normal group significant (#: p <0.05, t-test Student) indicates a difference, in the figure "*" is Vehicle compared with statistically significant with group (*: p <0.025, multiple comparisons of Williams, one side) indicates a difference.

[0190]

　By repeated administration of Compound 1, 10 mg / kg Compound 1 administered group, compared to the Vehicle group, a significant increase in nerve conduction velocity were observed. That is, Compound 1 was found to suppress a decrease nerve conduction velocity in streptozotocin-induced diabetes model.

[0191]

(Example 12) rats streptozotocin induced diabetic cyclic amine derivatives for mechanical allodynia model (I) or a pharmacologically acceptable effect of salt:
　cyclic amine derivative (I) or a pharmacologically acceptable salt thereof inhibitory effect on mechanical allodynia of rats with streptozotocin-induced diabetes model was studied.

[0192]

　SD rats (6 weeks old, male; Japan Charles River) in streptozotocin (50mg / kg, Sigma-Aldrich) to to be administered into the tail vein, to produce a streptozotocin-induced diabetes model. Streptozotocin was administered prepared in 25 mg / mL dissolved in physiological saline (Otsuka Pharmaceutical Factory). Further, Saline was administered in place of streptozotocin solution was provided false induced animals. The initial day of administration was in the pathology-induced day 0.

[0193]

　Pathologies induced 28 days Compound 1 (3 or 10 mg / kg) solution or the solvent containing the (water for injection) was administered orally to rats. Group configuration, false induced - solvent administered group (Sham group), conditions induced - solvent administered group (Vehicle group), pathology induced -10mg / kg Compound 1 administration group (3 mg / kg Compound 1 administration group), pathology induced -30mg / was 4 groups kg compound 1 administration group (10 mg / kg compound 1 administration group).

[0194]

　Efficacy evaluation of mechanical Arodenyia is evaluated in the same manner as in Example 5 were carried out in the pathology induced 28 days of compound 1 administration 3 hours.

[0195]

　The results of the evaluation of the effects on mechanical allodynia of Compound 1 shown in FIG. 14. The vertical axis of FIG. 14 shows a 50% reaction threshold in the von Frey test, indicating that the number is mechanical allodynia higher are improved (mean ± standard error; example each group 8). "*" In the figure, compared with statistically significant and Vehicle group (*: p <0.025, multiple comparison Shirley-Williams, one side) indicates a difference.

[0196]

　In pathology induced 28 days (Compound 1 administered three hours after), 10 mg / kg Compound 1 administration group and 30 mg / kg Compound 1 administered group, compared to the Vehicle group, significant increase of 50% reaction threshold was observed It was. That is, Compound 1 was found to inhibit the mechanical allodynia in streptozotocin-induced diabetes model.

[0197]

　From the above, cyclic amine derivative (I) or a pharmaceutically acceptable salt thereof pharmacologically, the metabolite peripheral neuropathy, it has been revealed to be particularly effective against diabetic peripheral neuropathy.

Industrial Applicability

[0198]

　Cyclic amine derivative or salt thereof pharmacologically acceptable of the present invention has a protection and restoration effect and myelination promoting effects of peripheral nerve cells, it can be significantly inhibited such symptoms of various peripheral neuropathies from available as a therapeutic or preventive agent for peripheral neuropathy.

[0199]

　All publications cited herein shall be incorporated herein patents and patent applications as reference.

The scope of the claims

[Requested item 1]

　Cyclic amine derivative or a pharmacologically acceptable salt thereof represented by the general formula (I)
[Chemical formula 1]

wherein
　the carbon marked with * is an asymmetric carbon,
　A is represented by the general formula (IIa), represents a group represented by (IIb) or (IIc),
[of 2]

　R 1 may be substituted with a halogen atom, a methyl group or an ethyl group,
　R 2 is a hydrogen atom or 2 carbon atoms represents an alkylcarbonyl group of ~ 5,
　R 3 each independently represents a methyl group or an ethyl group,
　n represents 1 or 2. ]
The containing as an active ingredient, the therapeutic agent or prophylactic agent for peripheral neuropathy.

[Requested item 2]

　A is a group represented by the general formula (IIa), the therapeutic agent or prophylactic agent according to claim 1.

[Requested item 3]

　A is a group represented by the general formula (IIb) or (IIc), the therapeutic agent or prophylactic agent according to claim 1.

[Requested item 4]

　A is a group represented by the general formula (IIa), the stereochemistry of the asymmetric carbon marked with * is in the S configuration, the therapeutic agent or prophylactic agent according to claim 1.

[Requested item 5]

　R 1 is a fluorine atom may be substituted, a methyl group or an ethyl group, a therapeutic agent or prophylactic agent according to any one of claims 1-4.

[Requested item 6]

　R 1 is a methyl group, an ethyl group, a difluoromethyl group or a 2,2,2-trifluoroethyl group, a therapeutic agent or prophylactic agent according to any one of claims 1-4.

[Requested item 7]

　Cyclic amine derivative or a pharmacologically acceptable salt thereof represented by the general formula (I)
[Chemical Formula 3]

wherein
　the carbon marked with * is an asymmetric carbon,
　A is represented by the general formula (IIa), represents a group represented by (IIb) or (IIc),
[of 4]

　R 1 may be substituted with a halogen atom, a methyl group or an ethyl group,
　R 2 is a hydrogen atom or 2 carbon atoms represents an alkylcarbonyl group of ~ 5,
　R 3 each independently represents a methyl group or an ethyl group,
　n represents 1 or 2. ]
The containing as an active ingredient, a therapeutic agent or prophylactic agent for a drug peripheral neuropathy.

[Requested item 8]

　A, the therapeutic agent or prophylactic agent for a group, according to claim 7, wherein the general formula (IIa).

[Requested item 9]

　A, the therapeutic agent or prophylactic agent for a group, according to claim 7, wherein the general formula (IIb) or (IIc).

[Requested item 10]

　A is a group represented by the general formula (IIa), * the stereochemistry of the asymmetric carbon marked with a S configuration, the therapeutic agent or prophylactic agent according to claim 7.

[Requested item 11]

　R 1 is a fluorine atom may be substituted, a methyl group or an ethyl group, a therapeutic agent or prophylactic agent according to any one of claims 7-10.

[Requested item 12]

　R 1 is a methyl group, an ethyl group, a difluoromethyl group or a 2,2,2-trifluoroethyl group, a therapeutic agent or prophylactic agent according to any one of claims 7-10.

[Requested item 13]

　Drug resistance peripheral neuropathy, peripheral neuropathy caused by anticancer agents, peripheral neuropathy with anti-viral drugs, peripheral neuropathy caused by antibiotic, peripheral neuropathy with anti-tuberculosis drugs, peripheral neuropathy with anti-arrhythmic drugs, hyperlipemia lowering agents by peripheral neuropathy, which is at least one selected from peripheral neuropathy due peripheral neuropathy and other agents by peripheral neuropathy, gout treatment with immunosuppressive drugs, claim 7-12 therapeutic agent or prophylactic agent according Section scratch.

[Requested item 14]

　Cyclic amine derivative or a pharmacologically acceptable salt thereof represented by the general formula (I)
[Chemical Formula 5]

[wherein,
　the carbon marked with * is an asymmetric carbon,
　A is represented by the general formula (IIa), represents a group represented by (IIb) or (IIc),
[of 6]

　R 1 may be substituted with a halogen atom, a methyl group or an ethyl group,
　R 2 is a hydrogen atom or 2 carbon atoms represents an alkylcarbonyl group of ~ 5,
　R 3 each independently represents a methyl group or an ethyl group,
　n represents 1 or 2. ]
The containing as an active ingredient, the therapeutic agent or prophylactic agent for autoimmune peripheral neuropathy.

[Requested item 15]

　A is a group represented by the general formula (IIa), the therapeutic agent or prophylactic agent according to claim 14, wherein.

[Requested item 16]

　A is a group represented by the general formula (IIb) or (IIc), the therapeutic agent or prophylactic agent according to claim 14, wherein.

[Requested item 17]

　A is a group represented by the general formula (IIa), * the stereochemistry of the asymmetric carbon marked with a S configuration, the therapeutic agent or prophylactic agent according to claim 14, wherein.

[Requested item 18]

　R 1 is a fluorine atom may be substituted, a methyl group or an ethyl group, a therapeutic agent or prophylactic agent according to any one of claims 14-17.

[Requested item 19]

　R 1 is a methyl group, an ethyl group, a difluoromethyl group or a 2,2,2-trifluoroethyl group, a therapeutic agent or prophylactic agent according to any one of claims 14-17.

[Requested item 20]

　Autoimmune peripheral neuropathy is at least one selected from Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and neuropathy caused by abnormal protein hypertriglyceridemia, wherein therapeutic agent or prophylactic agent according to any one claim of claim 14-19.

[Requested item 21]

　Cyclic amine derivative or a pharmacologically acceptable salt thereof represented by the general formula (I)
[Chemical Formula 7]

wherein
　the carbon marked with * is an asymmetric carbon,
　A is represented by the general formula (IIa), represents a group represented by (IIb) or (IIc),
[of 8]

　R 1 may be substituted with a halogen atom, a methyl group or an ethyl group,
　R 2 is a hydrogen atom or 2 carbon atoms represents an alkylcarbonyl group of ~ 5,
　R 3 each independently represents a methyl group or an ethyl group,
　n represents 1 or 2. ]
The containing as an active ingredient, the therapeutic agent or prophylactic agent for metabolic peripheral neuropathy.

[Requested item 22]

　A is a group represented by the general formula (IIa), the therapeutic agent or prophylactic agent according to claim 21.

[Requested item 23]

　A, the therapeutic agent or prophylactic agent for a group, according to claim 21, wherein the general formula (IIb) or (IIc).

[Requested item 24]

　A is a group represented by the general formula (IIa), * the stereochemistry of the asymmetric carbon marked with a S configuration, the therapeutic agent or prophylactic agent according to claim 21.

[Requested item 25]

　R 1 is a fluorine atom may be substituted, a methyl group or an ethyl group, a therapeutic agent or prophylactic agent according to any one of claims 21-24.

[Requested item 26]

　R 1 is a methyl group, an ethyl group, a difluoromethyl group or a 2,2,2-trifluoroethyl group, a therapeutic agent or prophylactic agent according to any one of claims 21-24.

[Requested item 27]

　Metabolic peripheral neuropathy, diabetic peripheral neuropathy, is at least one selected from uremic peripheral neuropathy, collagen disease peripheral neuropathy and vitamin deficiency peripheral neuropathy, one of the claims 21 to 26 therapeutic agent or prophylactic agent according one paragraph or.

[Requested item 28]

　Cyclic amine derivative or a pharmacologically acceptable salt thereof represented by the general formula (I)
[Chemical Formula 9]

[wherein,
　the carbon marked with * is an asymmetric carbon,
　A is represented by the general formula (IIa), represents a group represented by (IIb) or (IIc),
[of 10]

　R 1 may be substituted with a halogen atom, a methyl group or an ethyl group,
　R 2 is a hydrogen atom or 2 carbon atoms represents an alkylcarbonyl group of ~ 5,
　R 3 each independently represents a methyl group or an ethyl group,
　n represents 1 or 2. ]
The containing as an active ingredient, the therapeutic agent or prophylactic agent for hereditary peripheral neuropathies.

[Requested item 29]

　A is a group represented by the general formula (IIa), the therapeutic agent or prophylactic agent according to claim 28.

[Requested item 30]

　A is a group represented by the general formula (IIb) or (IIc), the therapeutic agent or prophylactic agent according to claim 28.

[Requested item 31]

　A is a group represented by the general formula (IIa), the stereochemistry of the asymmetric carbon marked with * is in the S configuration, the therapeutic agent or prophylactic agent according to claim 28.

[Requested item 32]

　R 1 is a fluorine atom may be substituted, a methyl group or an ethyl group, a therapeutic agent or prophylactic agent according to any one of claims 28-31.

[Requested item 33]

　R 1 is a methyl group, an ethyl group, a difluoromethyl group or a 2,2,2-trifluoroethyl group, a therapeutic agent or prophylactic agent according to any one of claims 28-31.

[Requested item 34]

　Hereditary peripheral neuropathies is at least one selected Charcot-Marie-Tooth disease, familial amyloid polyneuropathy, hereditary fragility neuropathy and hereditary neuralgia muscular atrophy, claims 28-33 therapeutic agent or prophylactic agent according to any one claim of.