Novel compound and agent for preventing or improving peripheral neuropathy using the same

Abstract

Heretofore, there has been no medicine or food medicament capable of preventing or ameliorating particularly a peripheral neuropathy induced by an anti-cancer agent such as oxaliplatin among adverse side effects induced by medication.　Provided is a prophylactic or ameliorating agent for a peripheral neuropathy, which comprises at least one compound selected from the compounds represented by formulae (1) to (3) as an active ingredient. The prophylactic or ameliorating agent can ameliorate numbness in the limbs, pain in the limbs, decreased deep tendon reflex, loss in muscle strength, allodynia, hyperalgesia, dysfunction in skilled movements of fingers, disturbance in gait, stumbling, falling, difficulties in bodily flexion (difficulties or inabilities associated with such postures as sitting on the soles, sitting with the legs crossed, sitting with the legs folded sideways, or sitting on a chair), limb paralysis or the like which are induced by drugs such as anticancer agents or induced by diabetes.　[Formula 200] [Formula 201] [Formula 202]

Description

[Technical Field]

[0001] The present invention relates to an agent for preventing or ameliorating peripheral neuropathy, and in particular to an agent for preventing or ameliorating peripheral neuropathy that can be suitably used to prevent or ameliorate peripheral neuropathy caused by anticancer drugs or diabetes. [Background technology]

[0002] Drugs with various mechanisms of action have been developed for use in chemotherapy for malignant tumors. These drugs suppress the survival or proliferation of tumor cells based on a specific mechanism of action. However, these drugs generally do not act only on tumor cells but also have a similar effect on normal cells. Therefore, when drugs used in chemotherapy are taken, in addition to the tumor-suppressing effect, side effects such as peripheral neuropathy, hair loss, vomiting, gastrointestinal disorders, hepatotoxicity, nephrotoxicity, and neurotoxicity occur.

[0003] Among these, peripheral neuropathy includes a hypersensitivity response (allodynia) in which pain is felt in response to stimuli that are insensitive in healthy people. The numbness and tingling sensations that accompany this hypersensitivity response can continue for a long period of time, sometimes forcing the discontinuation of chemotherapy, and is therefore considered a major problem for chemotherapy.

[0004] To date, treatments for peripheral neuropathy, a side effect of chemotherapy, have included anesthetics such as ketamine, antiepileptic drugs such as gabapentin, lamotrigine, and clonazepam, antidepressants such as clomipramine and duloxetine, herbal medicines such as Goshajinkigan and Shakuyakukanzoto, and vitamin B preparations. However, these have not been very effective.

[0005] Therefore, drugs for improving peripheral neuropathy have been proposed. Patent Document 1 proposes a composition containing an amino acid containing serine and a lipid containing n-3 fatty acid.

[0006] Furthermore, Patent Document 2 discloses that certain cyclic amine compounds can be used as therapeutic or preventive agents for peripheral nerve disorders.

[0007] It is also known that peripheral neuropathy, which has similar symptoms, can occur as one of the symptoms of diabetes. This peripheral neuropathy reduces the quality of daily life of patients. Therefore, there is a strong demand for improvement of the symptoms of diabetic peripheral neuropathy.

[0008] Patent Document 3 describes that lactam compounds are effective as sugar transport enhancers and can be used as preventive and / or therapeutic agents for diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic macroangiopathy, impaired glucose tolerance, or obesity. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] Japanese Patent Application Publication No. 2019-182881 [Patent Document 2] International Publication No. 2018 / 181860 [Patent Document 3] Japanese Patent Application Laid-Open No. 2006-213732 Summary of the Invention [Problem to be solved by the invention]

[0010] Patent Document 1 is composed of amino acids and fatty acids, so it can be said to have a relatively good track record of safety for the human body. However, because it is a peptide, further study is thought to be necessary regarding its favorable pharmacokinetic properties. Patent Document 2 is a non-peptide, so it is necessary to verify the side effects of the drug itself.

[0011] Patent Document 3 discloses, including in the examples, that lactam compounds have the ability to transport sugars, but does not specifically mention peripheral neuropathy, and only discloses that they have the effect of lowering blood sugar levels. The cause of diabetic peripheral neuropathy is still unclear. Furthermore, diabetic peripheral neuropathy is a complication of diabetes, and it is considered important to first halt the progression of diabetes. [Means for solving the problem]

[0012] The present invention was conceived in view of the above problems, and provides an agent for preventing or ameliorating peripheral neuropathy that uses components other than peptides and has few side effects. The agent for preventing or ameliorating peripheral neuropathy according to the present invention is effective against both chemotherapy-induced peripheral neuropathy and diabetic peripheral neuropathy. Furthermore, the agent for preventing or ameliorating peripheral neuropathy according to the present invention has the effect of inhibiting the NK1 receptor.

[0013] More specifically, the agent for preventing or improving peripheral neuropathy according to the present invention is characterized by containing at least one compound selected from the group consisting of D-(+)-arabinitol derivatives represented by the following formulas (1), (2), and (3):

[0014] [ka]

[0015] [ka]

[0016] [ka] [Effects of the Invention]

[0017] The present invention provides agents for preventing or ameliorating peripheral neuropathy. Specifically, these agents are three novel substances in which specific functional groups have been added to arabinitol. Administration or ingestion of at least one selected from these three substances improves symptoms such as limb numbness, limb pain, decreased deep tendon reflexes, muscle weakness, allodynia, hyperalgesia, impaired finger dexterity, gait disturbance, stumbling, falls, flexion disorders (difficulty or inability to sit upright, cross-legged, sideways, or in a chair), or limb paralysis induced by cancer chemotherapy or diabetes. Furthermore, the preventive or ameliorating agents of the present invention can also be used to prevent the aforementioned peripheral neuropathy by taking them simultaneously with the initiation of chemotherapy or after being conscious of excessive carbohydrate intake.

[0018] Until now, in order to deal with peripheral neuropathy, it has been necessary to reduce the dosage of anticancer drugs or discontinue cancer chemotherapy, but by using the agent of the present invention, it is possible to continue appropriate cancer treatment, leading to a faster recovery from cancer.

[0019] Furthermore, the provision of a preventive or ameliorating agent for peripheral neuropathy that can be easily administered or ingested at home according to the present invention is extremely useful for patients undergoing cancer treatment at home. Furthermore, the prevention or amelioration of peripheral neuropathy caused by cancer chemotherapy or diabetes also improves the quality of life (QOL) of patients.

[0020] Furthermore, as is well known, arabinitol itself is a sugar alcohol and is known to be safe for the human body. Furthermore, the added functional group is a fatty acid and does not have a significant effect on the human body. Therefore, it is highly expected that arabinitol is highly safe for the human body and does not have any significant side effects.

[0021] Peripheral neuropathy can be caused not only by cancer chemotherapy and diabetes, but also by the administration of other drugs, trauma, infections, etc., and the use of the preventive or ameliorating agent of the present invention can also prevent or ameliorate the symptoms of these peripheral neuropathy. [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 shows the results of a cold plate test in which arabinitol derivatives were administered together with oxaliplatin to mice. [Figure 2] FIG. 1 shows the results of a von Frey test in which arabinitol derivatives were administered together with oxaliplatin to mice. [Figure 3] FIG. 1 shows the results of a cold plate test in which arabinitol derivatives were administered together with paclitaxel to mice. [Figure 4] FIG. 1 shows the results of a von Frey test in which arabinitol derivatives were administered together with paclitaxel to mice. [Figure 5] FIG. 1 shows the results of a cold plate test in which arabinitol derivatives were administered together with vincristine to mice. [Figure 6] FIG. 1 shows the results of a von Frey test in which arabinitol derivatives were administered together with vincristine to mice. [Figure 7] FIG. 1 shows the results of a cold plate test in which arabinitol derivatives were administered together with bortezomib to mice. [Figure 8] FIG. 1 shows the results of a von Frey test in which arabinitol derivatives were administered together with bortezomib to mice. [Figure 9] FIG. 1 shows the results of a cold plate test in which an arabinitol derivative was administered to mice that had developed peripheral neuropathy due to oxaliplatin. [Figure 10] FIG. 1 shows the results of a von Frey test in which arabinitol derivatives were administered to mice that had developed peripheral neuropathy due to oxaliplatin. [Figure 11] FIG. 1 shows the results of a cold plate test in which arabinitol derivatives were administered to mice that had developed peripheral neuropathy due to paclitaxel. [Figure 12] FIG. 1 shows the results of a von Frey test in which arabinitol derivatives were administered to mice that had developed peripheral neuropathy due to paclitaxel. [Figure 13]FIG. 1 shows the results of a cold plate test in which an arabinitol derivative was administered to mice that had developed peripheral neuropathy due to vincristine. [Figure 14] FIG. 1 shows the results of a von Frey test in which arabinitol derivatives were administered to mice that had developed peripheral neuropathy due to vincristine. [Figure 15] FIG. 1 shows the results of a cold plate test in which arabinitol derivatives were administered to mice that had developed peripheral neuropathy due to bortezomib. [Figure 16] FIG. 1 shows the results of a von Frey test in which arabinitol derivatives were administered to mice that had developed peripheral neuropathy due to bortezomib. [Figure 17] FIG. 1 shows the results of a cold plate test in which mice were administered with an arabinitol derivative from the day they were administered streptozotocin. [Figure 18] FIG. 1 shows the results of a von Frey test in which arabinitol derivatives were administered to mice starting from the day streptozotocin was administered. [Figure 19] FIG. 1 shows the results of a cold plate test in which an arabinitol derivative was administered to mice that had been induced to develop diabetes and peripheral neuropathy by the administration of streptozotocin. [Figure 20] FIG. 1 shows the results of a von Frey test in which arabinitol derivatives were administered to mice that had been induced to develop diabetes and peripheral neuropathy by the administration of streptozotocin. [Figure 21] This panel shows the binding of substance P-FAM to the NK1 receptor measured by flow cytometry after adding arabinitol derivatives to U251 cells. (a) shows the results for arabinitol-linoleic acid diester, (b) for arabinitol-linolenic acid diester, and (c) for arabinitol-eicosapentaenoic acid diester. DETAILED DESCRIPTION OF THE INVENTION

[0023] The preventive or ameliorating agent according to the present invention will be explained below with reference to drawings and examples. These preventive or ameliorating agents for peripheral neuropathy are pharmaceutical compositions and also NK1 receptor inhibitors. Note that the following explanation exemplifies one embodiment of the present invention and one example, and the present invention is not limited to the following explanation. The following explanation can be modified within the scope of the present invention.

[0024] In the prophylactic or ameliorating agent of the present invention, "prevention" does not only mean preventing the onset of peripheral neuropathy but also includes the effect of alleviating the severity of symptoms at the time of onset, and "amelioration" does not only mean radical treatment of peripheral neuropathy but also includes the effect of alleviating or mitigating the severity of symptoms of peripheral neuropathy. In this specification, "to" indicates a range of "greater than or equal to, less than or equal to."

[0025] The preventive or ameliorative agent according to the present invention comprises a compound represented by formula (1), (2) or (3) as an active ingredient.

[0026] [ka]

[0027] The substance in formula (1) is a diester compound in which linoleoyl groups (ester bonds with linoleic acid) are attached to both ends of D-(+)-arabinitol (CAS number 488-82-4). This is also called arabinitol-linoleic acid diester.

[0028] [ka]

[0029] The substance in formula (2) is a diester compound in which α-linoleyl groups (ester bonds of linolenic acid) are attached to both ends of D-(+)-arabinitol (CAS number 488-82-4). This is also called arabinitol-linolenic acid diester.

[0030] [ka]

[0031] The substance in formula (3) is a diester compound in which eicosapentanoyl groups (ester bonds of eicosapentaenoic acid) are attached to both ends of D-(+)-arabinitol (CAS number 488-82-4). This is also called arabinitol-eicosapentaenoic acid diester.

[0032] These compounds can also be expressed as (4).

[0033] [ka]

[0034] Here, R is one of the expressions (5), (6), and (7).

[0035] [ka]

[0036] Hereinafter, these will be collectively referred to as "arabinitol derivatives" or "various arabinitol derivatives." Their synthesis methods will be described in detail later, but the raw materials are arabinitol and the respective fatty acids (linoleic acid, linolenic acid, and eicosapentaenoic acid). Each fatty acid is industrially produced and easily available.

[0037] D-(+)-arabinitol can be obtained by conventional methods such as chemical reduction of D-arabinol or by microbial decomposition of glycerol as a carbon source.

[0038] The preventive or ameliorating agent according to the present invention can be provided in the form of a pharmaceutical, food, etc. Furthermore, the ameliorating agent according to the present invention can also be provided with a label indicating that it is for ameliorating peripheral neuropathy or for preventing peripheral neuropathy.

[0039] When the prophylactic or ameliorating agent according to the present invention is used as a pharmaceutical, it can be provided as a therapeutic agent (pharmaceutical composition) for peripheral neuropathy or a preventive agent (pharmaceutical composition) for peripheral neuropathy. The compound of the present invention can also be provided as an NK1 receptor inhibitor.

[0040] When the preventive or ameliorating agent according to the present invention is used as a pharmaceutical, it may be administered by any method, such as orally, transdermally, enterally, intravenously, pulmonary, subcutaneously, transmucosally, or intramuscularly, and the method may be appropriately selected depending on the severity of the peripheral neuropathy to be prevented or ameliorated.

[0041] When the preventive or ameliorating agent according to the present invention is formulated into a pharmaceutical product, the arabinitol derivative may be formulated into a desired dosage form either as is or in combination with other additives, etc. Specific examples of pharmaceutical products include oral preparations such as capsules, granules, powders, pills, tablets, jellies, and syrups; topical preparations such as liquids, ointments, creams, lotions, gelling agents, patches, and aerosols; and injections.

[0042] When the preventive or ameliorating agent according to the present invention is formulated into a pharmaceutical product, additives such as binders, lubricants, disintegrants, colorants, flavoring agents, preservatives, antioxidants, stabilizers, water, lower alcohols, solubilizers, surfactants, emulsion stabilizers, gelling agents, adhesives, fragrances, and pigments may be appropriately selected to obtain the desired dosage form. Furthermore, pharmacological ingredients such as vasodilators, adrenocortical hormones, keratolytic agents, moisturizers, disinfectants, antioxidants, and refreshing agents may also be included, if necessary.

[0043] When the preventive or ameliorating agent according to the present invention is formulated as a pharmaceutical product, the content of the arabinitol derivative in the pharmaceutical product may be appropriately determined depending on the pharmaceutical dosage form, etc., so as to satisfy the daily dosage described below. For example, in the case of an oral formulation, the total amount of the arabinitol derivative is (0.1 to 100) mass%, preferably (15 to 80) mass%, and more preferably (30 to 70) mass%, and in the case of an external formulation, the total amount of the arabinitol derivative is (0.01 to 50) mass%, preferably (0.1 to 40) mass%, and more preferably (0.5 to 30) mass%.

[0044] Furthermore, when the preventive or ameliorating agent according to the present invention is formulated into a food, the food is provided as a food for preventing or ameliorating peripheral neuropathy.

[0045] When the preventive or ameliorating agent according to the present invention is made into a food product, the arabinitol derivative may be prepared in a desired form either as is or in combination with other food materials or additives. Examples of the food product include general processed foods such as luxury foods and health foods, and foods with health claims such as foods for specified health uses, foods with nutrient functions, and foods with functional claims as defined by the Health Claims Food System of the Ministry of Health, Labor and Welfare.

[0046] Specific examples of foods include candy, gum, jelly, biscuits, cookies, rice crackers, bread, yogurt, ice cream, pudding, and other luxury foods; noodles; fish and meat paste products; beverages such as tea, soft drinks, coffee drinks, milk drinks, whey drinks, and lactic acid bacteria drinks; and general processed foods such as capsules (soft capsules, hard capsules), tablets, granules, powders, and jellies. Among these foods and beverages, supplements are preferred.

[0047] When the preventive or ameliorating agent according to the present invention is formulated as a food product, the content of the arabinitol derivatives in the food product may be appropriately determined depending on the type of food product, etc., so as to satisfy the daily intake amount described below. For example, the total amount of the arabinitol derivatives may be (0.05 to 100) mass%, preferably (10 to 80) mass%, and more preferably (20 to 60) mass%.

[0048] The prophylactic or ameliorating agent of the present invention is used for preventing or ameliorating peripheral neuropathy. Examples of symptoms of peripheral neuropathy to which the agent is applied include numbness in the limbs, pain in the limbs, decreased deep tendon reflexes, decreased muscle strength, allodynia, hyperalgesia, dysalgia, impaired dexterity of the fingers, gait disturbance, stumbling, falling, flexion disorder (difficulty or inability to sit upright, cross-legged, sideways, or on a chair), and paralysis of the limbs.

[0049] Furthermore, the prophylactic or ameliorative agent of the present invention is not particularly limited in terms of the factors inducing peripheral neuropathy to which it is applied, and can be applied to any peripheral neuropathy caused by, for example, cancer chemotherapy, administration of other drugs, progression of diabetes, trauma, infection, etc., but is particularly suitable for use in peripheral neuropathy induced by cancer chemotherapy or diabetes.

[0050] When the preventive or ameliorating agent of the present invention is used for peripheral neuropathy induced by various anticancer drugs, the type of anticancer drug is not particularly limited. Examples include platinum compounds, alkylating agents, metabolic antagonists, microtubule-active agents, anticancer antibiotics, topoisomerase inhibitors, proteasome inhibitors, histone deacetylase inhibitors, FLT3 tyrosine kinase inhibitors, antibody drugs, ALK inhibitors, HER2 / EGFR tyrosine kinase inhibitors, ALK / ROS1 tyrosine kinase inhibitors, TRK / ROS1 tyrosine kinase inhibitors, multikinase inhibitors, JAK inhibitors, BCR-ABL inhibitors, FGFR inhibitors, MET inhibitors, BRAF inhibitors, MEK inhibitors, immunomodulators, and immune checkpoint inhibitors. Specific examples of platinum compounds include oxaliplatin, cisplatin, carboplatin, and nedaplatin. Specific examples of alkylating agents include cyclophosphamide, ifosfamide, thiotepa, carboquone, and nimustine hydrochloride. Specific examples of antimetabolites include 5-fluorouracil, methotrexate, doxifluridine, tegafur, cytarabine, and gemcitabine. Specific examples of microtubule-active agents include docetaxel, paclitaxel, vincristine, vinblastine, vindesine, vinorelbine, cabazitaxel, and embrin. Specific examples of anticancer antibiotics include doxorubicin hydrochloride, mitomycin, amrubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, aclarubicin hydrochloride, mitoxantrone hydrochloride, bleomycin hydrochloride, and peplomycin sulfate. Specific examples of topoisomerase inhibitors include irinotecan and nogitecan hydrochloride. Specific examples of proteasome inhibitors include bortezomib, carfilzomib, and ixazomib. Specific examples of histone deacetylase inhibitors include romidepsin, etc. Specific examples of FLT3 tyrosine kinase inhibitors include gilteritinib, etc. Specific examples of antibody drugs include pertuzumab, trastuzumab emtansine, brentuximab vedotin, polatuzumab vedotin, rituximab, obinutuzumab, blinatumomab, and bevacizumab.Specific examples of ALK inhibitors include alectinib and brigutinib. Specific examples of HER2 / EGFR tyrosine kinase inhibitors include lapatinib. Specific examples of ALK / ROS1 tyrosine kinase inhibitors include crizotinib and lorlatinib. Specific examples of TRK / ROS1 tyrosine kinase inhibitors include larotrectinib and entrectinib. Specific examples of multikinase inhibitors include sorafenib, sunitinib, vandetanib, axitinib, regorafenib, cabozantinib, and the like. Specific examples of JAK inhibitors include ruxolitinib. Specific examples of BCR-ABL inhibitors include ponatinib. Specific examples of FGFR inhibitors include pemigatinib. Specific examples of MET inhibitors include tepotinib. Specific examples of BRAF inhibitors include vemurafenib and encorafenib. Specific examples of MEK inhibitors include binimetinib. Specific examples of immunomodulatory drugs include thalidomide, lenalidomide, and ponalidomide. Specific examples of immune checkpoint inhibitors include nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab.

[0051] When the preventive or ameliorating agent of the present invention is applied to peripheral neuropathy induced by the administration of an anticancer drug, the administration or intake of the preventive or ameliorating agent of the present invention may be started before or simultaneously with the start of administration of the anticancer drug, but the administration or intake of the preventive or ameliorating agent of the present invention may also be started during or after the end of the administration period of the anticancer drug.

[0052] When the prophylactic or ameliorating agent according to the present invention is applied to diabetic peripheral neuropathy, it can be taken as an ameliorating agent after the onset of peripheral neuropathy, or it can be used as a preventive agent by taking it even before the onset of peripheral neuropathy, if the onset of diabetes can be confirmed.

[0053] The administration or intake amount of the preventive or ameliorative agent according to the present invention can be appropriately selected depending on the symptoms, age, body weight, time elapsed since onset, concomitant therapeutic measures, etc. In the examples of the present invention, the total daily intake of arabinitol derivatives by a mouse effective for ameliorating peripheral neuropathy when administered with 6 mg of an anticancer agent / kg body weight of mouse is 25 mg / kg body weight or more, and more preferably 100 mg / kg body weight or more.

[0054] In the art, when a compound is effective in mice, the dose that produces the same effect in humans is calculated as the human equivalent dose (HED). When the body weight of a mouse is 30 g and the body weight of a human is 60 kg, the human equivalent dose is calculated by dividing the mouse dose by 12.3.

[0055] According to this, the total daily intake of arabinitol derivatives should be at least 2.04 mg / kg of human body weight, preferably at least 8.14 mg / kg of human body weight. Therefore, the total daily intake of arabinitol derivatives for an adult male should be at least 122.4 mg / day / adult, more preferably at least 489.2 mg / day / adult.

[0056] In addition, excessive intake of sugar alcohols is known to cause diarrhea, and the limit is set at 20 to 30 g / day, although this varies from person to person. Therefore, it is believed that the amount required to improve peripheral neuropathy often does not cause any significant side effects. Therefore, when the preventive or improving agent of the present invention is orally administered or ingested, the total amount of arabinitol derivative administered or ingested may be 0.12 g / day / adult to 30 g / day / adult, and preferably 0.49 g / day / adult to 20 g / day / adult or less.

[0057] The prophylactic or ameliorative agent according to the present invention may be administered or ingested once a day or in two or three divided doses a day so as to satisfy the daily dosage or intake amount.

[0058] Furthermore, at least one compound of formula (1) to formula (3) according to the present invention can be used to treat an anticancer agent or peripheral neuropathy caused by diabetes.

Example

[0059] The method for synthesizing the arabinitol derivative according to the present invention will be described below. In these synthesis methods, D-(+)-arabinitol and the corresponding fatty acid are added with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, which is a dehydrating condensing agent, in an anhydrous pyridine solvent to obtain an arabinitol derivative which is a fatty acid ester.

[0060] (Example 1) (Synthesis of the production method of D-(+)-arabinitol linoleic acid diester (arabinitol-linoleic acid diester)) D-(+)-arabinitol (Compound I, 760.7 mg, 5 mmol) was dissolved in anhydrous pyridine (100 mL), linoleic acid (3.37 g, 12 mmol) was added, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.30 g, 24 mmol) was added, and the mixture was stirred at room temperature for 48 hours under an argon atmosphere. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the filtrate obtained was evaporated under reduced pressure to obtain a crude product. The obtained crude product was separated and purified by silica gel column chromatography (mobile phase: n-hexane:ethyl acetate 5:1, v / v) to obtain Compound I-1 (880.0 mg, 26%).

[0061] Compound I-1 was measured by NMR. The spectrum was as follows. High-resolution positive-ion ESIMS: Calcd for C41H72O7Na [M+Na]+: 699.5170. Found: 699.5187. 13C-NMR (200 MHz, CDCl3) δc: 14.1 (q), 22.6 (t), 24.8 (t), 24.9 (t), 25.6 (t), 27.16 (t), 27.18 (t), 29.08 (t), 29.15 (t), 29.3 (t), 29.6 (t), 31.5 (t), 34.13 (t), 34.14 (t), 66.0 (t), 66.1 (t), 68.9 (d), 70.5 (d), 71.0 (d), 127.9 (d), 128.1 (d), 130.0 (d), 130.2 (d), 174.4 (s), 174.8 (s). As described above, it was confirmed that Compound I-1 has the structure of formula (1).

[0062] <Synthesis of the method for producing the α-linolenic acid diester of D-(+)-arabinitol (arabinitol-linolenic acid diester)> D-(+)-Arabinitol (Compound I, 760.7 mg, 5 mmol) was dissolved in anhydrous pyridine (100 mL), α-linolenic acid (3.34 g, 12 mmol) was added, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.30 g, 24 mmol) was added. The mixture was stirred at room temperature for 48 hours under an argon atmosphere. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the filtrate obtained was evaporated under reduced pressure to obtain a crude product. The obtained crude product was separated and purified by silica gel column chromatography (mobile phase: n-hexane:ethyl acetate 5:1, v / v) to obtain Compound I-2 (1080.0 mg, 32%).

[0063] Compound I-2 was measured by NMR. The spectrum was as follows. High-resolution positive-ion ESIMS: Calcd for C41H68O7Na [M+Na]+: 695.4857. Found: 695.4857. 13C-NMR (200 MHz, CDCl3) δc: 14.3 (q), 20.5 (t), 24.85 (t), 24.87 (t), 25.5 (t), 25.6 (t), 27.2 (t), 29.07 (t), 29.14 (t), 29.55 (t), 29.58 (t), 34.1 (t), 66.03 (t), 66.13 (t), 68.9 (d), 70.5 (d), 71.0 (d), 127.1 (d), 127.7 (d), 128.2 (d), 128.3 (d), 130.2 (d), 132.0 (d), 174.4 (s), 171.8 (s). As above, it was confirmed that Compound I-2 has the structure of formula (2).

[0064] <Synthesis of the method for producing D-(+)-arabinitol eicosapentaenoic acid diester (arabinitol-eicosapentaenoic acid diester)> D-(+)-Arabinitol (Compound I, 760.7 mg, 5 mmol) was dissolved in anhydrous pyridine (100 mL), eicosapentaenoic acid (3.63 g, 12 mmol) was added, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.30 g, 24 mmol) was added. The mixture was stirred at room temperature for 48 hours under an argon atmosphere. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the filtrate obtained was distilled off under reduced pressure to obtain a crude product. The obtained crude product was separated and purified by silica gel column chromatography (mobile phase: n-hexane:ethyl acetate 5:1, v / v) to obtain Compound I-3 (865.3 mg, 24%).

[0065] Compound I-3 was measured by NMR. The spectrum was as follows. High-resolution positive-ion ESIMS: Calcd for C45H68O7Na [M+Na]+: 743.4857. Found: 743.4838. C-NMR (200 MHz, CDCl) δc: 14.3 (q), 20.5 (t), 24.68 (t), 24.69 (t), 25.5 (t), 25.6 (t), 26.5 (t), 33.5 (t), 66.1 (t), 66.2 (t), 68.9 (d), 70.5 (d), 71.0 (d), 127.0 (d), 127.8 (d), 128.0 (d), 128.1 (d), 128.2 (d), 128.3 (d), 128.6 (d), 128.72 (d), 128.73 (d), 129.01 (d), 129.03 (d), 132.0 (d), 174.2 (s), 174.5 (s). From these results, it was confirmed that compound I-3 has the structure of formula (3).

[0066] (Example 2) Preventive effect of oxaliplatin on peripheral neuropathy The preventive effects of arabinitol derivatives on hyperesthesia, such as mechanical allodynia (severe pain induced by tactile stimuli that do not normally cause pain), and paresthesia due to cold stimuli, which occur when the anticancer drug oxaliplatin is administered, were investigated. Various arabinitol derivatives were orally administered to mice while they were administered oxaliplatin, and the following tests (cold plate test and von Frey test) were performed. Oxaliplatin is an anticancer drug that falls under the platinum group. In all of the following examples, the dose (mg / kg) refers to the weight of the administered substance per kg of mouse body weight.

[0067] (2-1) Administration of test substance Six- to seven-week-old Balb / c female mice were used. They were divided into five groups: a control group, an oxaliplatin-administered group, and an arabinitol derivative-administered group (oxaliplatin + three types of arabinitol derivatives). Each group consisted of nine mice.

[0068] Mice in the oxaliplatin group and the oxaliplatin + arabinitol derivative group were intraperitoneally administered 6 mg / kg of oxaliplatin. This day was designated as day 0 of administration, and these mice were subsequently intraperitoneally administered 6 mg / kg of oxaliplatin on days 7 and 14.

[0069] The oxaliplatin + arabinitol derivative administration group was orally administered 5 mg / kg of arabinitol derivative every day from day 0.

[0070] These groups are called the control group, 6 mg / kg oxaliplatin group, 6 mg / kg oxaliplatin + 5 mg / kg arabinitol-linoleic acid diester group, 6 mg / kg oxaliplatin + 5 mg / kg arabinitol-linolenic acid diester group, and 6 mg / kg oxaliplatin + 5 mg / kg arabinitol-eicosapentaenoic acid diester group, respectively.

[0071] (2-2) Cold plate test A cold plate test was conducted to examine the effects of arabinitol derivatives on sensory abnormalities caused by cold stimuli. Five groups of mice shown in (2-1) were placed on a cold plate set at 10°C, and the reaction time (latency) until escape was measured. The shorter the latency, the more averse the mice are to cold stimuli caused by the cold plate. The results are shown in Figure 1.

[0072] Referring to Figure 1, the horizontal axis represents the time elapsed since administration (days), and the vertical axis represents the mean escape reaction time (seconds) for each group of mice. The solid white circle represents the control group, the dashed black circle represents the 6 mg / kg oxaliplatin-treated group, the dashed black square represents the 6 mg / kg oxaliplatin + 5 mg / kg arabinitol-linoleic acid diester-treated group, the dashed black triangle represents the 6 mg / kg oxaliplatin + 5 mg / kg arabinitol-linolenic acid diester-treated group, and the dotted black diamond represents the 6 mg / kg oxaliplatin + 5 mg / kg arabinitol-eicosapentaenoic acid diester-treated group. Significant differences from the control group, as determined by a 1% significance level test, are marked with an asterisk (*P<0.01 vs. control group).

[0073] Referring to Figure 1, the oxaliplatin-administered group (black dotted line) showed a shortened escape reaction time after administration, suggesting that peripheral neuropathy (peripheral hypersensitivity symptoms) had developed. On the other hand, the arabinitol derivative-administered group showed the same escape reaction time after administration as the control, despite the administration of oxaliplatin. This suggests that the arabinitol derivative-administered group suppressed peripheral neuropathy caused by oxaliplatin administration.

[0074] (2-3) von Frey test The five groups of mice shown in (2-1) were placed in cages, and a 0.16g filament was pressed against the soles of the hind paws to measure the number of avoidance responses (score). The more avoidance responses, the more averse the mice were to the stimulation by the filament. The results are shown in Figure 2.

[0075] Referring to Figure 2, the horizontal axis represents the time elapsed since administration (days), and the vertical axis represents the mean avoidance response (score) of mice in each group. The solid white circle represents the control group, the dashed black circle represents the 6 mg / kg oxaliplatin-treated group, the dashed black square represents the 6 mg / kg oxaliplatin + 5 mg / kg arabinitol-linoleic acid diester-treated group, the dotted black triangle represents the 6 mg / kg oxaliplatin + 5 mg / kg arabinitol-linolenic acid diester-treated group, and the dotted black diamond represents the 6 mg / kg oxaliplatin + 5 mg / kg arabinitol-eicosapentaenoic acid diester-treated group. Differences from the control group that were determined to be significant at a significance level of 1% are marked with an asterisk (*P<0.01 vs. control group).

[0076] Referring to Figure 2, the oxaliplatin-administered group (black dotted line) showed an increase in score (number of avoidance responses) after administration, suggesting that peripheral neuropathy (peripheral hypersensitivity symptoms) had developed. On the other hand, the arabinitol derivative-administered group, despite having been administered oxaliplatin, had scores after administration that were almost the same as the control group. This suggests that the arabinitol derivative-administered group suppressed peripheral neuropathy caused by oxaliplatin administration.

[0077] (Example 3) Preventive effect of paclitaxel on peripheral neuropathy We investigated the preventive effects of arabinitol derivatives on hyperesthesia, such as mechanical allodynia (severe pain induced by tactile stimuli that do not normally cause pain), and paresthesia caused by cold stimuli, which occur when the anticancer drug paclitaxel is administered. Various arabinitol derivatives were orally administered to mice while administering paclitaxel, and the following tests (cold plate test and von Frey test) were performed. Paclitaxel is an anticancer drug that acts on microtubules.

[0078] (3-1) Administration of test substance Six- to seven-week-old Balb / c female mice were used. They were divided into five groups: a control group, a paclitaxel-administered group, and an arabinitol derivative-administered group (a group administered paclitaxel plus three types of arabinitol derivatives). Each group consisted of nine mice.

[0079] Mice in the paclitaxel group and the paclitaxel + arabinitol derivative group were intraperitoneally administered paclitaxel at 6 mg / kg, which was designated as day 0 of administration. Thereafter, these mice were intraperitoneally administered 6 mg / kg of paclitaxel on days 7 and 14.

[0080] The paclitaxel + arabinitol derivative administration group was orally administered 5 mg / kg of arabinitol derivative every day from day 0 onwards.

[0081] These groups are called the control group, 6 mg / kg paclitaxel group, 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linoleic acid diester group, 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linolenic acid diester group, and 6 mg / kg paclitaxel + 5 mg / kg arabinitol-eicosapentaenoic acid diester group, respectively.

[0082] (3-2) Cold plate test A cold plate test was conducted to examine the effects of arabinitol derivatives on sensory abnormalities caused by cold stimuli. Five groups of mice shown in (3-1) were placed on a cold plate set at 10°C, and the reaction time (latency) until escape was measured. The shorter the latency, the more averse the mice are to cold stimuli caused by the cold plate. The results are shown in Figure 3.

[0083] Referring to Figure 3, the horizontal axis represents the time elapsed since administration (days), and the vertical axis represents the mean escape reaction time (seconds) for each group of mice. The solid white circle represents the control group, the dashed black circle represents the 6 mg / kg paclitaxel-treated group, the dashed black square represents the 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linoleic acid diester-treated group, the dashed black triangle represents the 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linolenic acid diester-treated group, and the dotted black diamond represents the 6 mg / kg paclitaxel + 5 mg / kg arabinitol-eicosapentaenoic acid diester-treated group. Differences from the control group that were determined to be significant at a 1% significance level are marked with an asterisk (*P<0.01 vs. control group).

[0084] Referring to Figure 3, the paclitaxel-administered group (black dotted line) showed a shortened escape reaction time after administration, suggesting that peripheral neuropathy (peripheral hypersensitivity symptoms) had developed. On the other hand, the arabinitol derivative-administered group showed the same escape reaction time after administration as the control, despite the administration of paclitaxel. This suggests that the arabinitol derivative-administered group suppressed peripheral neuropathy caused by paclitaxel administration.

[0085] (3-3) von Frey test The five groups of mice shown in (3-1) were placed in cages, and a 0.16g filament was pressed against the soles of the hind paws to measure the number of avoidance responses (score). A higher number of avoidance responses is considered to indicate a greater aversion to the stimulation by the filament. The results are shown in Figure 4.

[0086] Referring to Figure 4, the horizontal axis represents the time elapsed since administration (days), and the vertical axis represents the mean avoidance response (score) of mice in each group. The solid white circle represents the control group, the dashed black circle represents the 6 mg / kg paclitaxel-treated group, the dashed black square represents the 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linoleic acid diester-treated group, the dotted black triangle represents the 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linolenic acid diester-treated group, and the dotted black diamond represents the 6 mg / kg paclitaxel + 5 mg / kg arabinitol-eicosapentaenoic acid diester-treated group. Differences from the control group that were determined to be significant at a significance level of 1% are marked with an asterisk (*P<0.01 vs. control group).

[0087] Referring to Figure 4, the paclitaxel-administered group (black dotted line) showed an increase in score (number of avoidance responses) after administration, suggesting that peripheral neuropathy (peripheral hypersensitivity symptoms) had developed. On the other hand, the arabinitol derivative-administered group, despite having been administered paclitaxel, had scores after administration that were almost the same as the control. This suggests that the arabinitol derivative-administered group suppressed peripheral neuropathy caused by paclitaxel administration.

[0088] (Example 4) Preventive effect of vincristine on peripheral neuropathy We investigated the preventive effects of arabinitol derivatives on hypersensitivity, such as mechanical allodynia (severe pain induced by tactile stimuli that do not normally cause pain), and paresthesia caused by cold stimuli, which occur when the anticancer drug vincristine is administered. Various arabinitol derivatives were orally administered to mice while they were being administered vincristine, and the following tests (cold plate test and von Frey test) were performed. Vincristine is an anticancer drug that acts on microtubules.

[0089] (4-1) Administration of test substance Six- to seven-week-old Balb / c female mice were used. They were divided into five groups: a control group, a vincristine-administered group, and an arabinitol derivative-administered group (vincristine + three arabinitol derivative-administered groups). Each group consisted of nine mice.

[0090] Mice in the vincristine-treated group and the vincristine + arabinitol derivative-treated group were intraperitoneally administered 0.2 mg / kg of vincristine on day 0 of administration, and subsequently received intraperitoneal administration of 0.2 mg / kg of vincristine on days 7 and 14.

[0091] The vincristine + arabinitol derivative administration group was orally administered 5 mg / kg of the arabinitol derivative every day from day 0 onwards.

[0092] These groups are called the control group, 0.2 mg / kg vincristine group, 0.2 mg / kg vincristine + 5 mg / kg arabinitol-linoleic acid diester group, 0.2 mg / kg vincristine + 5 mg / kg arabinitol-linolenic acid diester group, and 0.2 mg / kg vincristine + 5 mg / kg arabinitol-eicosapentaenoic acid diester group, respectively.

[0093] (4-2) Cold plate test A cold plate test was conducted to examine the effects of arabinitol derivatives on sensory abnormalities caused by cold stimuli. Five groups of mice shown in (4-1) were placed on a cold plate set at 10°C, and the reaction time (latency) until escape was measured. The shorter the latency, the more averse the mice are to cold stimuli caused by the cold plate. The results are shown in Figure 5.

[0094] Referring to Figure 5, the horizontal axis represents the time elapsed since administration (days), and the vertical axis represents the mean escape reaction time (seconds) for each group of mice. The solid white circle represents the control group, the dashed black circle represents the 0.2 mg / kg vincristine-treated group, the dashed black square represents the 0.2 mg / kg vincristine + 5 mg / kg arabinitol-linoleic acid diester-treated group, the dotted black triangle represents the 0.2 mg / kg vincristine + 5 mg / kg arabinitol-linolenic acid diester-treated group, and the dotted black diamond represents the 0.2 mg / kg vincristine + 5 mg / kg arabinitol-eicosapentaenoic acid diester-treated group. Differences from the control group that were determined to be significant at a 1% significance level are marked with an asterisk (*P<0.01 vs. control group).

[0095] Referring to Figure 5, the vincristine-administered group (black dotted line) showed a shortened escape reaction time after administration, suggesting that peripheral neuropathy (peripheral hypersensitivity symptoms) had developed. On the other hand, the arabinitol derivative-administered group showed the same escape reaction time after administration as the control, despite the administration of vincristine. This suggests that the arabinitol derivative-administered group suppressed peripheral neuropathy caused by vincristine administration.

[0096] (4-3) von Frey test The five groups of mice shown in (4-1) were placed in cages, and a 0.16g filament was pressed against the soles of the hind paws to measure the number of avoidance responses (score). A higher number of avoidance responses is considered to indicate a greater aversion to the stimulation by the filament. The results are shown in Figure 6.

[0097] Referring to Figure 6, the horizontal axis represents the time elapsed since administration (days), and the vertical axis represents the mean avoidance response (score) of mice in each group. The solid white circle represents the control group, the dashed black circle represents the 0.2 mg / kg vincristine-treated group, the dashed black square represents the 0.2 mg / kg vincristine + 5 mg / kg arabinitol-linoleic acid diester-treated group, the dotted black triangle represents the 0.2 mg / kg vincristine + 5 mg / kg arabinitol-linolenic acid diester-treated group, and the dotted black diamond represents the 0.2 mg / kg vincristine + 5 mg / kg arabinitol-eicosapentaenoic acid diester-treated group. Differences from the control group that were determined to be significant at a significance level of 1% are marked with an asterisk (*P<0.01 vs. control group).

[0098] Referring to Figure 6, the vincristine-administered group (black dotted line) showed an increase in score (number of avoidance responses) after administration, suggesting that peripheral neuropathy (peripheral hypersensitivity symptoms) had developed. On the other hand, the arabinitol derivative-administered group, despite having been administered vincristine, had scores after administration that were almost the same as the control. This suggests that the arabinitol derivative-administered group suppressed peripheral neuropathy caused by vincristine administration.

[0099] (Example 5) Preventive effect of bortezomib on peripheral neuropathy We investigated the preventive effects of arabinitol derivatives on hypersensitivity, such as mechanical allodynia (severe pain induced by tactile stimuli that do not normally cause pain), and paresthesia caused by cold stimuli, which occur when the anticancer drug bortezomib is administered. Various arabinitol derivatives were orally administered to mice while they were receiving bortezomib, and the following tests (cold plate test and von Frey test) were performed. Bortezomib is an anticancer drug that corresponds to a proteasome inhibitor.

[0100] (5-1) Administration of test substance Six- to seven-week-old Balb / c female mice were used. They were divided into five groups: a control group, a bortezomib-treated group, and an arabinitol derivative-treated group (bortezomib + three arabinitol derivative-treated groups). Each group consisted of nine mice.

[0101] Mice in the bortezomib group and the bortezomib + arabinitol derivative group were intraperitoneally administered 1 mg / kg of bortezomib. This day was designated as day 0 of administration, and these mice were subsequently intraperitoneally administered 1 mg / kg of bortezomib on days 7 and 14.

[0102] The bortezomib + arabinitol derivative administration group was orally administered 5 mg / kg of arabinitol derivative every day from day 0.

[0103] These groups are referred to as the control group, 1 mg / kg bortezomib-administered group, 1 mg / kg bortezomib + 5 mg / kg arabinitol-linoleic acid diester-administered group, 1 mg / kg bortezomib + 5 mg / kg arabinitol-linolenic acid diester-administered group, and 1 mg / kg bortezomib + 5 mg / kg arabinitol-eicosapentaenoic acid diester-administered group, respectively.

[0104] (5-2) Cold plate test A cold plate test was conducted to examine the effects of arabinitol derivatives on sensory abnormalities caused by cold stimuli. Five groups of mice shown in (5-1) were placed on a cold plate set at 10°C, and the reaction time (latency) until escape was measured. The shorter the latency, the more averse the mice are to cold stimuli caused by the cold plate. The results are shown in Figure 7.

[0105] Referring to Figure 7, the horizontal axis represents the time elapsed since administration (days), and the vertical axis represents the average escape reaction time (seconds) for each group of mice. The solid white circle represents the control group, the dashed black circle represents the 1 mg / kg bortezomib-treated group, the dashed black square represents the 1 mg / kg bortezomib + 5 mg / kg arabinitol-linoleic acid diester-treated group, the dotted black triangle represents the 1 mg / kg bortezomib + 5 mg / kg arabinitol-linolenic acid diester-treated group, and the dotted black diamond represents the 1 mg / kg bortezomib + 5 mg / kg arabinitol-eicosapentaenoic acid diester-treated group. Differences from the control group that were determined to be significant at a 1% significance level are marked with an asterisk (indicated as "*P<0.01 vs. control group" in the figure).

[0106] Referring to Figure 7, the bortezomib-administered group (black dotted line) showed a shortened escape reaction time after administration, suggesting that peripheral neuropathy (peripheral hypersensitivity symptoms) had developed. On the other hand, the arabinitol derivative-administered group showed the same escape reaction time after administration as the control, despite the administration of bortezomib. This suggests that the arabinitol derivative-administered group suppressed peripheral neuropathy caused by the administration of bortezomib.

[0107] (5-3) von Frey test Mice from the five groups shown in (5-1) were placed in cages, and a 0.16g filament was pressed against the soles of the hind paws to measure the number of avoidance responses (score). A higher number of avoidance responses is considered to indicate a greater aversion to the stimulation by the filament. The results are shown in Figure 8.

[0108] Referring to Figure 8, the horizontal axis represents the time elapsed since administration (days), and the vertical axis represents the mean avoidance response (score) of mice in each group. The solid white circle represents the control group, the dashed black circle represents the 1 mg / kg bortezomib-treated group, the dashed black square represents the 1 mg / kg bortezomib + 5 mg / kg arabinitol-linoleic acid diester-treated group, the dotted black triangle represents the 1 mg / kg bortezomib + 5 mg / kg arabinitol-linolenic acid diester-treated group, and the dotted black diamond represents the 1 mg / kg bortezomib + 5 mg / kg arabinitol-eicosapentaenoic acid diester-treated group. Differences from the control group that were determined to be significant at a significance level of 1% are marked with an "*" (indicated as "*P<0.01 vs. control group" in the figure).

[0109] Referring to Figure 8, the bortezomib-administered group (black dotted line) showed an increase in score (number of avoidance responses) after administration, suggesting that peripheral neuropathy (peripheral hypersensitivity symptoms) had developed. On the other hand, the arabinitol derivative-administered group, despite having been administered bortezomib, had scores after administration that were almost the same as the control. This suggests that the arabinitol derivative-administered group suppressed peripheral neuropathy caused by administration of bortezomib.

[0110] (Example 6) Therapeutic effect of oxaliplatin on peripheral neuropathy It has been found that the arabinitol derivatives according to the present invention can prevent peripheral neuropathy caused by oxaliplatin. Therefore, we next investigated whether the arabinitol derivatives have a therapeutic effect in alleviating peripheral neuropathy after the onset of peripheral neuropathy due to the administration of an anticancer drug (oxaliplatin).

[0111] (6-1) Administration of test substance Six- to seven-week-old Balb / c female mice were used. They were divided into five groups: a control group, an oxaliplatin-administered group, and an arabinitol derivative-administered group (oxaliplatin + three types of arabinitol derivatives). Each group consisted of nine mice.

[0112] Mice other than those in the control group were intraperitoneally administered 6 mg / kg of oxaliplatin. This day was designated as the first day of administration (day 0), and these mice were then intraperitoneally administered the same amount of oxaliplatin three times on days 7 and 14.

[0113] In the oxaliplatin + arabinitol derivative administration group, arabinitol derivative was orally administered daily from day 6 after oxaliplatin administration at a dose of 10 mg / kg in the arabinitol-linoleic acid diester administration group, 5 mg / kg in the arabinitol-linolenic acid diester administration group, and 25 mg / kg in the arabinitol-eicosapentaenoic acid diester administration group.

[0114] These groups are called the control group, 6 mg / kg oxaliplatin group, 6 mg / kg oxaliplatin + 10 mg / kg arabinitol-linoleic acid diester group, 6 mg / kg oxaliplatin + 5 mg / kg arabinitol-linolenic acid diester group, and 6 mg / kg oxaliplatin + 25 mg / kg arabinitol-eicosapentaenoic acid diester group, respectively.

[0115] (6-2) Cold plate test The effects of arabinitol derivatives on sensory abnormalities caused by cold stimuli were tested on the five groups of mice shown in (6-1). Mice from each group were placed on a cold plate set at 10°C, and the reaction time (latency) until escape was measured. The shorter the latency, the more averse the mice are to the cold stimuli caused by the cold plate. The results are shown in Figure 9.

[0116] Referring to Figure 9, the horizontal axis represents the time elapsed since administration (days), and the vertical axis represents the mean escape reaction time (seconds) for each group of mice. The solid white circle represents the control group, the dashed black circle represents the 6 mg / kg oxaliplatin-treated group, the dashed black square represents the 6 mg / kg oxaliplatin + 10 mg / kg arabinitol-linoleic acid diester-treated group, the dotted black triangle represents the 6 mg / kg oxaliplatin + 5 mg / kg arabinitol-linolenic acid diester-treated group, and the dotted black diamond represents the 6 mg / kg oxaliplatin + 25 mg / kg arabinitol-eicosapentaenoic acid diester-treated group. Differences from the control group determined to be significant at a 1% significance level are marked with an asterisk (*P<0.01 vs. control group).

[0117] Referring to Figure 9, the four oxaliplatin-administered groups, excluding the control group, showed a uniform decrease in escape reaction time (latency) by the sixth day after administration. It was thought that oxaliplatin caused peripheral neuropathy (peripheral hypersensitivity symptoms). However, the three groups administered with arabinitol derivatives (6 mg / kg oxaliplatin + 10 mg / kg arabinitol-linoleic acid diester, 6 mg / kg oxaliplatin + 5 mg / kg arabinitol-linolenic acid diester, and 6 mg / kg oxaliplatin + 25 mg / kg arabinitol-eicosapentaenoic acid diester) showed a tendency for their latencies to increase from the sixth day onwards. By the 12th day, these three groups and the control group had significantly longer escape reaction times (latencies) than the 6 mg / kg oxaliplatin group.

[0118] (6-3) von Frey test The five groups of mice shown in (1) of this Example (Example 6) were placed in cages, and a filament with a strength of 0.16 g was pressed against the soles of the hind paws to measure the number of avoidance responses (score). The results are shown in Figure 10.

[0119] Referring to Figure 10, the horizontal axis represents the time elapsed since administration (days) and the mean avoidance response (score) of mice in each group. A higher number of avoidances indicates a stronger aversion to stimulation by the filament. The solid white circle represents the control group, the dashed black circle represents the 6 mg / kg oxaliplatin-treated group, the dashed black square represents the 6 mg / kg oxaliplatin + 10 mg / kg arabinitol-linoleic acid diester-treated group, the dotted black triangle represents the 6 mg / kg oxaliplatin + 5 mg / kg arabinitol-linolenic acid diester-treated group, and the dotted black diamond represents the 6 mg / kg oxaliplatin + 25 mg / kg arabinitol-eicosapentaenoic acid diester-treated group. Differences from the control group that were determined to be significant at a significance level of 1% are marked with an asterisk (*P<0.01 vs. control group in the figure).

[0120] Referring to Figure 10, the oxaliplatin-administered group (black dotted line) showed an increase in score (number of avoidance responses) after administration, suggesting that peripheral neuropathy (peripheral hypersensitivity symptoms) had developed. On the other hand, the arabinitol derivative-administered group showed a decrease in score after administration despite the administration of oxaliplatin, and after 18 days, the score was almost the same as that of the control. This suggests that the arabinitol derivative-administered group suppressed the peripheral neuropathy that developed due to the administration of oxaliplatin.

[0121] The above results indicate that peripheral neuropathy (peripheral hypersensitivity symptoms) that had developed due to oxaliplatin administration was improved by taking an arabinitol derivative. Therefore, it was found that the arabinitol derivative also functions as a therapeutic composition (therapeutic agent) for peripheral neuropathy (peripheral hypersensitivity symptoms).

[0122] (Example 7) Therapeutic effect of paclitaxel on peripheral neuropathy It has been found that the arabinitol derivatives according to the present invention can prevent peripheral neuropathy caused by paclitaxel. Therefore, we next investigated whether the arabinitol derivatives have a therapeutic effect in alleviating peripheral neuropathy after the onset of peripheral neuropathy due to the administration of an anticancer drug (paclitaxel).

[0123] (7-1) Administration of test substance Six- to seven-week-old Balb / c female mice were used. They were divided into five groups: a control group, a paclitaxel-administered group, and an arabinitol derivative-administered group (a group administered paclitaxel plus three types of arabinitol derivatives). Each group consisted of nine mice.

[0124] Mice other than those in the control group were intraperitoneally administered paclitaxel at 6 mg / kg. This day was designated as the first day of administration (day 0), and these mice were then intraperitoneally administered the same amount of paclitaxel three times on days 7 and 14.

[0125] In the paclitaxel + arabinitol derivative administration group, 5 mg / kg of arabinitol derivative was orally administered daily from day 6 after paclitaxel administration.

[0126] These groups are called the control group, 6 mg / kg paclitaxel group, 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linoleic acid diester group, 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linolenic acid diester group, and 6 mg / kg paclitaxel + 5 mg / kg arabinitol-eicosapentaenoic acid diester group, respectively.

[0127] (7-2) Cold plate test The effects of arabinitol derivatives on sensory abnormalities caused by cold stimuli were tested on the five groups of mice shown in (1) of this Example (Example 7). Mice from each group were placed on a cold plate set at 10°C, and the reaction time (latency) until escape was measured. It is believed that the shorter the latency, the more averse the mice are to the cold stimuli caused by the cold plate. The results are shown in Figure 11.

[0128] Referring to Figure 11, the horizontal axis represents the time elapsed since administration (days), and the vertical axis represents the average escape reaction time (seconds) for each group of mice. The solid white circle represents the control group, the dashed black circle represents the 6 mg / kg paclitaxel-treated group, the dashed black square represents the 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linoleic acid diester-treated group, the dotted black triangle represents the 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linolenic acid diester-treated group, and the dotted black diamond represents the 6 mg / kg paclitaxel + 5 mg / kg arabinitol-eicosapentaenoic acid diester-treated group. Differences from the control group that were determined to be significant at a 1% significance level are marked with an asterisk (*P<0.01 vs. control group).

[0129] Referring to Figure 11, the four groups administered paclitaxel except for the control group showed a uniform decrease in escape reaction time (latency) by the sixth day after administration. It was thought that paclitaxel had caused peripheral neuropathy (peripheral hypersensitivity symptoms). However, the three groups administered with arabinitol derivatives (6 mg / kg paclitaxel + 5 mg / kg arabinitol-linoleic acid diester, 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linolenic acid diester, and 6 mg / kg paclitaxel + 5 mg / kg arabinitol-eicosapentaenoic acid diester) showed a tendency for their latencies to increase from the sixth day onwards. By the 12th day, these three groups and the control group had significantly longer escape reaction times (latencies) than the 6 mg / kg paclitaxel group.

[0130] (7-3) von Frey test The five groups of mice shown in (1) of this Example (Example 7) were placed in cages, and a filament with a strength of 0.16 g was pressed against the soles of the hind paws to measure the number of avoidance responses (score). The results are shown in Figure 12.

[0131] Referring to Figure 12, the horizontal axis represents the time elapsed since administration (days) and the mean avoidance response (score) of mice in each group. A higher number of avoidances indicates a stronger aversion to filament stimulation. The solid white circle represents the control group, the dashed black circle represents the 6 mg / kg paclitaxel-treated group, the dashed black square represents the 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linoleic acid diester-treated group, the dotted black triangle represents the 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linolenic acid diester-treated group, and the dotted black diamond represents the 6 mg / kg paclitaxel + 5 mg / kg arabinitol-eicosapentaenoic acid diester-treated group. Significant differences from the control group, as determined by a 1% significance level test, are marked with an asterisk (*P<0.01 vs. control group).

[0132] Referring to Figure 12, the paclitaxel-administered group (black dotted line) showed an increase in score (number of avoidance responses) after administration, suggesting that peripheral neuropathy (peripheral hypersensitivity symptoms) had developed. On the other hand, the arabinitol derivative-administered group showed a decrease in score after administration despite the administration of paclitaxel, and after 21 days, the score was almost the same as that of the control. This suggests that the arabinitol derivative-administered group suppressed peripheral neuropathy caused by the administration of paclitaxel.

[0133] These results indicate that peripheral neuropathy (peripheral hypersensitivity symptoms) that had developed due to paclitaxel administration was improved by taking the arabinitol derivative. Therefore, it was found that the arabinitol derivative also functions as a therapeutic composition (therapeutic agent) for peripheral neuropathy (peripheral hypersensitivity symptoms).

[0134] (Example 8) Therapeutic effect of vincristine on peripheral neuropathy It has been found that the arabinitol derivatives according to the present invention can prevent peripheral neuropathy caused by vincristine. Therefore, we next investigated whether the arabinitol derivatives have a therapeutic effect in alleviating peripheral neuropathy after the onset of peripheral neuropathy due to the administration of an anticancer drug (vincristine).

[0135] (8-1) Administration of test substance Six- to seven-week-old Balb / c female mice were used. They were divided into five groups: a control group, a vincristine-administered group, and an arabinitol derivative-administered group (vincristine + three arabinitol derivative-administered groups). Each group consisted of nine mice.

[0136] Mice other than those in the control group were intraperitoneally administered 0.2 mg / kg of vincristine. This was designated the first day of administration (day 0), and these mice were then intraperitoneally administered the same amount of vincristine three times on days 7 and 14.

[0137] In the vincristine + arabinitol derivative administration group, 5 mg / kg of the arabinitol derivative was orally administered daily from day 6 after vincristine administration.

[0138] These groups are called the control group, 0.2 mg / kg vincristine group, 0.2 mg / kg vincristine + 5 mg / kg arabinitol-linoleic acid diester group, 0.2 mg / kg vincristine + 5 mg / kg arabinitol-linolenic acid diester group, and 0.2 mg / kg vincristine + 5 mg / kg arabinitol-eicosapentaenoic acid diester group, respectively.

[0139] (8-2) Cold plate test The effects of arabinitol derivatives on sensory abnormalities caused by cold stimuli were tested on the five groups of mice shown in (8-1). Mice from each group were placed on a cold plate set at 10°C, and the reaction time (latency) until escape was measured. The shorter the latency, the more averse the mice are to the cold stimuli caused by the cold plate. The results are shown in Figure 13.

[0140] Referring to Figure 13, the horizontal axis represents the time elapsed since administration (days), and the vertical axis represents the mean escape reaction time (seconds) for each group of mice. The solid white circle represents the control group, the dashed black circle represents the 0.2 mg / kg vincristine-treated group, the dashed black square represents the 0.2 mg / kg vincristine + 5 mg / kg arabinitol-linoleic acid diester-treated group, the dotted black triangle represents the 0.2 mg / kg vincristine + 5 mg / kg arabinitol-linolenic acid diester-treated group, and the dotted black diamond represents the 0.2 mg / kg vincristine + 5 mg / kg arabinitol-eicosapentaenoic acid diester-treated group. Differences from the control group determined to be significant at a 1% significance level are marked with an asterisk (*P<0.01 vs. control group).

[0141] Referring to Figure 13, the four vincristine-administered groups, excluding the control group, showed a uniform decrease in escape reaction time (latency) by the sixth day after administration. It was thought that vincristine had caused peripheral neuropathy (peripheral hypersensitivity symptoms). However, the three groups administered with arabinitol derivatives (0.2 mg / kg vincristine + 5 mg / kg arabinitol-linoleic acid diester, 0.2 mg / kg vincristine + 5 mg / kg arabinitol-linolenic acid diester, and 0.2 mg / kg vincristine + 5 mg / kg arabinitol-eicosapentaenoic acid diester) showed a tendency for their latencies to increase from the sixth day onwards. By the 12th day, these three groups and the control group had significantly longer escape reaction times (latencies) than the 0.2 mg / kg vincristine group.

[0142] (8-3) von Frey test The five groups of mice shown in (1) of this Example (Example 8) were placed in cages, and a filament with a strength of 0.16 g was pressed against the soles of the hind paws to measure the number of avoidance responses (score). The results are shown in Figure 14.

[0143] Referring to Figure 14, the horizontal axis represents the time (days) since administration and the mean avoidance response (score) of mice in each group. A higher number of avoidances indicates a stronger aversion to filament stimulation. The solid white circle represents the control group, the dashed black circle represents the 0.2 mg / kg vincristine-treated group, the dashed black square represents the 0.2 mg / kg vincristine + 5 mg / kg arabinitol-linoleic acid diester-treated group, the dotted black triangle represents the 0.2 mg / kg vincristine + 5 mg / kg arabinitol-linolenic acid diester-treated group, and the dotted black diamond represents the 0.2 mg / kg vincristine + 5 mg / kg arabinitol-eicosapentaenoic acid diester-treated group. Significant differences from the control group, as determined by a 1% significance level test, are marked with an asterisk (*P<0.01 vs. control group).

[0144] Referring to Figure 14, the vincristine-administered group (black dotted line) showed an increase in score (number of avoidance responses) after administration, suggesting that peripheral neuropathy (peripheral hypersensitivity symptoms) had developed. On the other hand, the arabinitol derivative-administered group showed a decrease in score after administration despite the administration of vincristine, and after 21 days, the score was almost the same as that of the control. This suggests that the arabinitol derivative-administered group suppressed peripheral neuropathy caused by the administration of vincristine.

[0145] These findings indicate that peripheral neuropathy (peripheral hypersensitivity symptoms) that had developed due to vincristine administration was improved by taking an arabinitol derivative. Therefore, it was found that the arabinitol derivative also functions as a therapeutic composition (therapeutic agent) for peripheral neuropathy (peripheral hypersensitivity symptoms).

[0146] (Example 9) Therapeutic effect of bortezomib on peripheral neuropathy It has been found that the arabinitol derivatives according to the present invention can prevent peripheral neuropathy caused by bortezomib. Therefore, we next investigated whether the arabinitol derivatives have a therapeutic effect in alleviating peripheral neuropathy after the onset of peripheral neuropathy due to the administration of an anticancer drug (bortezomib).

[0147] (9-1) Administration of test substance Six- to seven-week-old Balb / c female mice were used. They were divided into five groups: a control group, a bortezomib-treated group, and an arabinitol derivative-treated group (bortezomib + three arabinitol derivative-treated groups). Each group consisted of nine mice.

[0148] Mice other than those in the control group were intraperitoneally administered 1 mg / kg of bortezomib. This was designated the first day of administration (day 0), and these mice were then intraperitoneally administered the same amount of bortezomib three times on days 7 and 14.

[0149] In the bortezomib + arabinitol derivative administration group, 5 mg / kg of arabinitol derivative was orally administered daily from day 6 after bortezomib administration.

[0150] These groups are referred to as the control group, 1 mg / kg bortezomib-administered group, 1 mg / kg bortezomib + 5 mg / kg arabinitol-linoleic acid diester-administered group, 1 mg / kg bortezomib + 5 mg / kg arabinitol-linolenic acid diester-administered group, and 1 mg / kg bortezomib + 5 mg / kg arabinitol-eicosapentaenoic acid diester-administered group, respectively.

[0151] (9-2) Cold plate test The effects of arabinitol derivatives on paresthesia caused by cold stimulation were tested on the five groups of mice shown in (1) of this Example (Example 9). Mice from each group were placed on a cold plate set at 10°C, and the reaction time (latency) until escape was measured. The shorter the latency, the more averse the mice are to cold stimulation caused by the cold plate. The results are shown in Figure 15.

[0152] Referring to Figure 15, the horizontal axis represents the time elapsed since administration (days), and the vertical axis represents the average escape reaction time (seconds) of mice in each group. The solid white circle represents the control group, the dashed black circle represents the 1 mg / kg bortezomib-treated group, the dashed black square represents the 1 mg / kg bortezomib + 5 mg / kg arabinitol-linoleic acid diester-treated group, the dotted black triangle represents the 1 mg / kg bortezomib + 5 mg / kg arabinitol-linolenic acid diester-treated group, and the dotted black diamond represents the 1 mg / kg bortezomib + 5 mg / kg arabinitol-eicosapentaenoic acid diester-treated group. Differences from the control group that were determined to be significant at a significance level of 1% are marked with an "*" (indicated as "*P<0.01 vs. control group" in the figure).

[0153] Referring to Figure 15, the four bortezomib-administered groups, excluding the control group, showed a uniform decrease in escape reaction time (latency) by day 6 after administration. It was thought that bortezomib had caused peripheral neuropathy (peripheral hypersensitivity symptoms). However, the three groups administered with arabinitol derivatives, namely the 1 mg / kg bortezomib + 5 mg / kg arabinitol-linoleic acid diester group, the 1 mg / kg bortezomib + 5 mg / kg arabinitol-linolenic acid diester group, and the 1 mg / kg bortezomib + 5 mg / kg arabinitol-eicosapentaenoic acid diester group, showed a tendency for their latencies to increase from day 6 onwards. By day 12, these three groups and the control group had significantly longer escape reaction times (latencies) than the 1 mg / kg bortezomib group.

[0154] (9-3) von Frey test The five groups of mice shown in (1) of this Example (Example 9) were placed in cages, and a filament with a strength of 0.16 g was pressed against the sole of the hind paw to measure the number of avoidance responses (score). The results are shown in Figure 16.

[0155] Referring to Figure 16, the horizontal axis represents the time (days) since administration and the mean avoidance response (score) of mice in each group. A higher number of avoidances indicates a stronger aversion to stimulation by the filament. The solid white circle line represents the control group, the dashed black circle line represents the 1 mg / kg bortezomib-treated group, the dashed black square line represents the 1 mg / kg bortezomib + 5 mg / kg arabinitol-linoleic acid diester-treated group, the dotted black triangle line represents the 1 mg / kg bortezomib + 5 mg / kg arabinitol-linolenic acid diester-treated group, and the dotted black diamond line represents the 1 mg / kg bortezomib + 5 mg / kg arabinitol-eicosapentaenoic acid diester-treated group. Differences from the control group determined to be significant at a significance level of 1% are marked with an asterisk (indicated as "*P<0.01 vs. control group" in the figure).

[0156] Referring to Figure 16, the bortezomib-administered group (black dotted line) showed an increase in score (number of avoidance responses) after administration, suggesting that peripheral neuropathy (peripheral hypersensitivity symptoms) had developed. On the other hand, the arabinitol derivative-administered group showed a decrease in score after administration despite the administration of bortezomib, and after 21 days, the score was almost the same as that of the control. This suggests that the arabinitol derivative-administered group suppressed peripheral neuropathy caused by the administration of bortezomib.

[0157] These results indicate that peripheral neuropathy (peripheral hypersensitivity symptoms) that had developed due to bortezomib administration was improved by taking an arabinitol derivative. Therefore, it was found that the arabinitol derivative also functions as a therapeutic composition (therapeutic agent) for peripheral neuropathy (peripheral hypersensitivity symptoms).

[0158] (Example 10) Preventive effect against peripheral neuropathy in streptozotocin-induced diabetic mice We investigated the preventive effects of arabinitol derivatives on hypersensitivity, such as mechanical allodynia (severe pain induced by tactile stimuli that do not normally cause pain), and paresthesia due to cold stimuli, which occur in diabetic peripheral neuropathy. Various arabinitol derivatives were orally administered to mice as test drugs simultaneously with streptozotocin administration, and the following tests (von Frey test and cold plate test) were performed.

[0159] (10-1) Administration of test substance Six- to seven-week-old C57BL / 6J male mice were used. They were divided into five groups: a control group, a streptozotocin-administered group, and an arabinitol derivative-administered group (a streptozotocin + three arabinitol derivative-administered group). Each group consisted of nine mice.

[0160] Mice in the streptozotocin group and the streptozotocin + arabinitol derivative group were given 200 mg / kg of streptozotocin intraperitoneally. Large doses of streptozotocin destroy the pancreatic cells of mice. As a result, insulin secretion ceases and the mice develop diabetes. This day was designated the first day of administration (day 0). Note that streptozotocin was only administered on the first day of administration.

[0161] The streptozotocin + arabinitol derivative administration group was orally administered 1 mg / kg of arabinitol derivative every day from day 0.

[0162] These groups are called the control group, streptozotocin-administered group, streptozotocin + 1 mg / kg arabinitol-linoleic acid diester-administered group, streptozotocin + 1 mg / kg arabinitol-linolenic acid diester-administered group, and streptozotocin + 1 mg / kg arabinitol-eicosapentaenoic acid diester-administered group, respectively.

[0163] (10-2) Cold plate test A cold plate test was conducted to examine the effects of arabinitol derivatives on sensory abnormalities caused by cold stimuli. Five groups of mice shown in (10-1) were placed on a cold plate set at 4°C, and the reaction time (latency) until escape was measured. The shorter the latency, the more averse the mice are to cold stimuli caused by the cold plate. The results are shown in Figure 17.

[0164] Referring to Figure 17, the horizontal axis represents the time elapsed since administration (days), and the vertical axis represents the average escape reaction time (seconds) of mice in each group. The solid white circle represents the control group, the dashed black circle represents the streptozotocin-administered group, the dashed black square represents the streptozotocin + 1 mg / kg arabinitol-linoleic acid diester-administered group, the dotted black triangle represents the streptozotocin + 1 mg / kg arabinitol-linolenic acid diester-administered group, and the dotted black diamond represents the streptozotocin + 1 mg / kg arabinitol-eicosapentaenoic acid diester-administered group. Differences from the control group that were determined to be significant at a 1% significance level are marked with an "*" (indicated as "*P<0.01 vs. control group" in the figure).

[0165] Referring to Figure 17, the streptozotocin-administered group (black dotted line) showed a shortened escape reaction time after administration, suggesting that peripheral neuropathy (peripheral hypersensitivity symptoms) had developed. On the other hand, the arabinitol derivative-administered group showed the same escape reaction time after administration as the control, despite the administration of streptozotocin. This suggests that the arabinitol derivative-administered group suppressed diabetes-induced peripheral neuropathy caused by streptozotocin administration.

[0166] (10-3) von Frey test Mice from the five groups shown in (10-1) were placed in cages, and a 0.16g filament was pressed against the soles of the hind paws to measure the number of avoidance responses (score). A higher number of avoidance responses is considered to indicate a greater aversion to the stimulation by the filament. The results are shown in Figure 18.

[0167] Referring to Figure 18, the horizontal axis represents the time elapsed since administration (days), and the vertical axis represents the average avoidance response (score) of mice in each group. The solid white circle represents the control group, the dashed black circle represents the streptozotocin-administered group, the dashed black square represents the streptozotocin + 1 mg / kg arabinitol-linoleic acid diester-administered group, the dotted black triangle represents the streptozotocin + 1 mg / kg arabinitol-linolenic acid diester-administered group, and the dotted black diamond represents the streptozotocin + 1 mg / kg arabinitol-eicosapentaenoic acid diester-administered group. Differences from the control group that were determined to be significant at a significance level of 1% are marked with an "*" (indicated as "*P<0.01 vs. control group" in the figure).

[0168] Referring to Figure 18, the streptozotocin-administered group (black dotted line) showed an increase in score (number of avoidance responses) after administration, suggesting that peripheral neuropathy (symptoms of peripheral hypersensitivity) had developed. On the other hand, the arabinitol derivative-administered group, despite having been administered streptozotocin, had scores after administration that were nearly the same as the control. This suggests that the arabinitol derivative-administered group suppressed diabetes-induced peripheral neuropathy that develops with streptozotocin administration.

[0169] (Example 11) Therapeutic effect on peripheral neuropathy in streptozotocin-induced diabetic mice Since the arabinitol derivatives according to the present invention have been found to be able to prevent streptozotocin-induced diabetes-induced peripheral neuropathy, we next investigated whether the arabinitol derivatives have a therapeutic effect in alleviating peripheral neuropathy after the onset of diabetes-induced peripheral neuropathy.

[0170] (11-1) Administration of test substance Six- to seven-week-old C57BL / 6J male mice were used. They were divided into five groups: a control group, a streptozotocin-administered group, and an arabinitol derivative-administered group (a streptozotocin + three arabinitol derivative-administered group). Each group consisted of nine mice.

[0171] Mice in the streptozotocin group and the streptozotocin + arabinitol derivative group were given 200 mg / kg of streptozotocin intraperitoneally. Large doses of streptozotocin destroy the pancreatic cells of mice. As a result, insulin secretion ceases and the mice develop diabetes. This day was designated the first day of administration (day 0). Note that streptozotocin was only administered on the first day of administration.

[0172] In the streptozotocin + arabinitol derivative administration group, 1 mg / kg of arabinitol derivative was orally administered daily from the 21st day after streptozotocin administration.

[0173] These groups are called the control group, streptozotocin-administered group, streptozotocin + 1 mg / kg arabinitol-linoleic acid diester-administered group, streptozotocin + 1 mg / kg arabinitol-linolenic acid diester-administered group, and streptozotocin + 1 mg / kg arabinitol-eicosapentaenoic acid diester-administered group, respectively.

[0174] (11-2) Cold plate test The effects of arabinitol derivatives on sensory abnormalities caused by cold stimuli were tested on the five groups of mice shown in this Example (Example 11-1). Mice from each group were placed on a cold plate set at 4°C, and the reaction time (latency) until escape was measured. It is believed that the shorter the latency, the more averse the mice are to the cold stimuli caused by the cold plate. The results are shown in Figure 19.

[0175] Referring to Figure 19, the horizontal axis represents the time elapsed since administration (days), and the vertical axis represents the average escape reaction time (seconds) of mice in each group. The solid white circle represents the control group, the dashed black circle represents the streptozotocin-administered group, the dashed black square represents the streptozotocin + 1 mg / kg arabinitol-linoleic acid diester-administered group, the dotted black triangle represents the streptozotocin + 1 mg / kg arabinitol-linolenic acid diester-administered group, and the dotted black diamond represents the streptozotocin + 1 mg / kg arabinitol-eicosapentaenoic acid diester-administered group. Differences from the control group that were determined to be significant at a significance level of 1% are marked with an "*" (indicated as "*P<0.01 vs. control group" in the figure).

[0176] Referring to Figure 19, the escape reaction time (latency) was uniformly reduced in all four streptozotocin-administered groups except for the control group by the 21st day after administration. It was thought that streptozotocin had caused diabetic peripheral neuropathy (peripheral hypersensitivity symptoms). However, the three groups administered with arabinitol derivatives, namely the streptozotocin + 1 mg / kg arabinitol-linoleic acid diester group, the streptozotocin + 1 mg / kg arabinitol-linolenic acid diester group, and the streptozotocin + 1 mg / kg arabinitol-eicosapentaenoic acid diester group, showed a tendency for the latency to increase from the 21st day onwards. By the 30th day, these three groups and the control group had significantly longer escape reaction times (latency) than the streptozotocin-administered group.

[0177] (11-3) von Frey test The five groups of mice shown in this example (Example 11-1) were placed in cages, and a filament with a strength of 0.16 g was pressed against the sole of the hind paw to measure the number of avoidance responses (score). The results are shown in Figure 20.

[0178] Referring to Figure 20, the horizontal axis represents the time (days) since administration and the average avoidance response (score) of mice in each group. A higher number of avoidances indicates a stronger aversion to stimulation by the filament. The solid white circle represents the control group, the dashed black circle represents the streptozotocin-administered group, the dashed black square represents the streptozotocin + 1 mg / kg arabinitol-linoleic acid diester-administered group, the dotted black triangle represents the streptozotocin + 1 mg / kg arabinitol-linolenic acid diester-administered group, and the dotted black diamond represents the streptozotocin + 1 mg / kg arabinitol-eicosapentaenoic acid diester-administered group. Significant differences from the control group, as determined by a 1% significance level test, are marked with an asterisk (*P<0.01 vs. control group).

[0179] Referring to Figure 20, the streptozotocin-administered group (black dotted line) showed an increase in score (number of avoidance responses) after administration, suggesting that diabetes-induced peripheral neuropathy (peripheral hypersensitivity symptoms) had developed. On the other hand, the arabinitol derivative-administered group showed a decrease in score after administration despite the administration of streptozotocin, and after 30 days, the score was almost the same as that of the control. This suggests that the arabinitol derivative-administered group suppressed diabetes-induced peripheral neuropathy caused by streptozotocin administration.

[0180] These results indicate that diabetes-induced peripheral neuropathy (peripheral hypersensitivity symptoms) that had developed due to streptozotocin administration was improved by taking arabinitol derivatives. Therefore, it was found that arabinitol derivatives also function as therapeutic compositions (therapeutic agents) for diabetic peripheral neuropathy (peripheral hypersensitivity symptoms).

[0181] (Example 12) NK1 receptor binding inhibitory effect U251 cells (human glioblastoma cell line) were cultured in RPMI 1640 medium for 2 days. 1 μM arabinitol-linoleic acid diester, 1 μM arabinitol-linolenic acid diester, and 10 μM arabinitol-eicosapentaenoic acid diester were then added. After 1 hour, the cells were stained with substance P-FAM and the amount of substance P-FAM binding was measured using a BD LSR Fortessa.

[0182] The results are shown in Figure 21. In both figures, the horizontal axis represents the amount of substance P-FAM binding, and the vertical axis represents the number of cells (labeled "Count"). The solid line in each panel represents the control, which contained neither substance P-FAM nor any compound; the dashed line represents the control, which contained 1 μM substance P-FAM; and the dotted line represents the control, which contained 1 μM substance P-FAM and each compound. Compared to the control, which contained no compound or substance P-FAM, the substance P-FAM-added group exhibited a significantly increased amount of substance P-FAM binding.

[0183] The amount of substance P-FAM binding was significantly reduced in the arabinitol-linoleic acid diester-administered group (Figure 21(a)), the arabinitol-linolenic acid diester-administered group (Figure 21(b)), and the arabinitol-eicosapentaenoic acid diester-administered group (Figure 21(c)) compared to the substance P-FAM-added group. This indicates that arabinitol-linoleic acid diester, arabinitol-linolenic acid diester, and arabinitol-eicosapentaenoic acid diester inhibit the binding of substance P to the NK1 receptor. These compounds can therefore be considered NK1 receptor inhibitors. [Industrial Applicability]

[0184] The preventive or ameliorating agent according to the present invention can be used as a selective NK1 receptor inhibitor to improve or prevent peripheral neuropathy. It can also be used to treat peripheral neuropathy. In particular, it can be suitably used to reduce, alleviate, or prevent peripheral neuropathy caused by the administration of DNA replication inhibitors (platinum preparations (such as oxaliplatin) or alkylating agents) and peripheral neuropathy associated with diabetes.

Claims

1. Compounds represented by formulas (1) to (3). 【Chemistry 100】 【Chemistry 101】 【Chemistry 102】

2. 10. An agent for preventing or improving peripheral nerve disorders, comprising at least one compound represented by formula (1) to (3) according to claim 1 as an active ingredient.

3. 3. The agent for preventing or improving peripheral neuropathy according to claim 2, wherein the peripheral neuropathy is peripheral neuropathy caused by taking an anticancer drug.

4. The agent for preventing or ameliorating peripheral neuropathy according to claim 2, wherein the peripheral neuropathy is diabetic peripheral neuropathy.

5. An NK1 receptor inhibitor comprising at least one compound selected from the compounds represented by formulas (1) to (3) as an active ingredient. 【Chemistry 103】 【Chemistry 104】 【Chemistry 105】

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