WO2023002979A1 - Novel compound, and prophylactic or ameliorating agent for peripheral neuropathy which comprises same - Google Patents

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

Novel compound and preventive or ameliorating agent for peripheral neuropathy using the same

TECHNICAL FIELD The present invention relates to a preventive or ameliorating agent for peripheral neuropathy, and more particularly to a preventive or ameliorating agent for peripheral neuropathy that can be suitably used for the prevention or amelioration of peripheral neuropathy caused by anticancer agents or diabetes. be.

Various mechanisms of action have been developed for drugs used in chemotherapy for malignant tumors. These agents inhibit tumor cell survival or proliferation based on their defined mechanism of action. However, they generally act not only on tumor cells, but also on normal cells as well. Therefore, administration of drugs used in chemotherapy causes side effects such as peripheral neuropathy, alopecia, vomiting, gastrointestinal disorders, hepatotoxicity, nephrotoxicity, and neurotoxicity, in addition to the effect of suppressing tumors.

Among these, peripheral neuropathy has a sensory hypersensitivity response (allodynia) that causes pain to stimuli that healthy people do not feel. Since the numbness and pain associated with this hyperesthesia response continues continuously for a long period of time, chemotherapy may be forced to be discontinued, which is regarded as a serious problem for chemotherapy.

Conventionally, for peripheral neuropathy that develops as a side effect of chemotherapy, anesthetics such as ketamine, antiepileptic drugs such as gabapentin, lamotrigine and clonazepam, antidepressants such as clomipramine and duloxetine, and Kampo medicines such as goshajinkigan and shakuyakukanzoto have been given vitamin B preparations. However, it cannot be said that the effect is large.

Therefore, drugs have been proposed to improve this peripheral neuropathy. Patent Document 1 proposes a composition containing an amino acid containing serine and a lipid containing an n-3 fatty acid.

In addition, Patent Document 2 discloses that a specific cyclic amine compound can be a therapeutic or preventive agent for peripheral neuropathy.

In addition, it is known that peripheral neuropathy with similar symptoms develops as one of the symptoms of diabetes. This peripheral neuropathy reduces the patient's quality of life. Therefore, there is a strong demand for an improvement in the symptoms of diabetic peripheral neuropathy.

In addition, Patent Document 3 discloses that a lactam compound is effective as a sugar transport enhancing agent, and prevents and treats diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic macroangiopathy, impaired glucose tolerance, or obesity. / Or it is described that it can be used as a therapeutic agent.

JP 2019-182881 A WO2018/181860 Japanese Patent Application Laid-Open No. 2006-213732

Since Patent Document 1 is composed of amino acids and fatty acids, it can be said that it has a relatively proven track record of safety for the human body. However, since it is a peptide, it is thought that further investigation is necessary regarding favorable pharmacokinetic properties. Although Patent Document 2 is a non-peptide, it is therefore necessary to verify the side effects of the drug itself.

Patent document 3 discloses that the lactam compound has the ability to transport sugar, including examples. Stay. The cause of diabetic peripheral neuropathy is still unclear. Diabetic peripheral neuropathy is a complication of diabetes, and it is important to stop the progression of diabetes first.

The present invention has been conceived in view of the above problems, and provides a preventive or ameliorating agent for peripheral neuropathy using ingredients other than peptides that have few side effects. The preventive or ameliorating agent for peripheral neuropathy according to the present invention is effective both for chemotherapy-induced peripheral neuropathy and for diabetic peripheral neuropathy. In addition, the preventive or ameliorating agent for peripheral neuropathy according to the present invention has the action of inhibiting the NK1 receptor.

More specifically, the agent for preventing or improving peripheral neuropathy according to the present invention is a compound represented by the following formulas (1), (2), and (3), which is a derivative of D-(+)-arabinitol. characterized by containing at least one or more selected from

The present invention can provide a preventive or ameliorating agent for peripheral neuropathy. That is, they are three new substances obtained by adding specific functional groups to arabinitol. By administering or ingesting at least one selected from these three substances, numbness in the extremities, pain in the extremities, decreased deep tendon reflexes, decreased muscle strength, allodynia, and allodynia induced by cancer chemotherapy or diabetes. Hyperalgesia, finger dexterity dysfunction, gait disturbance, stumbling, falling, flexion disturbance (difficulty or inability to sit upright, cross-legged, sideways or chair sitting), paralysis of limbs, etc. are improved. In addition, the preventive or ameliorating agent according to the present invention can also be used to prevent the above peripheral neuropathy by taking it at the same time as the start of chemotherapy or after being conscious of taking too much sugar.

Until now, in order to deal with peripheral neuropathy, it was inevitable to reduce the dose of anticancer drugs and discontinue cancer chemotherapy, but with the agent of the present invention, it is possible to continue appropriate cancer treatment. It leads to early recovery from cancer.

In addition, providing a preventive or ameliorating agent for peripheral neuropathy that can be easily taken or taken at home according to the present invention is very useful for patients undergoing cancer treatment at home. Furthermore, the patient's quality of life (QOL) is improved by preventing or improving peripheral neuropathy caused by cancer chemotherapy or diabetes.

Furthermore, as is well known, arabinitol itself is a sugar alcohol and is known to be safe for the human body. Moreover, the added functional group is a fatty acid and does not have a serious effect on the human body. Therefore, it is highly expected that it is highly safe to the human body and has no major side effects.

Peripheral neuropathy is caused not only by cancer chemotherapy and diabetes, but also by administration of other drugs, trauma, infectious diseases, etc., but if the preventive or improving agent according to the present invention is used, these peripheral neuropathies can be prevented. It can also prevent or ameliorate symptoms.

FIG. 2 shows the results of a cold plate test when an arabinitol derivative was administered to mice together with oxaliplatin. FIG. 3 shows the results of the von Frey test when an arabinitol derivative was administered to mice together with oxaliplatin. FIG. 3 shows the results of a cold plate test when an arabinitol derivative was administered to mice together with paclitaxel. FIG. 3 shows the results of the von Frey test when arabinitol derivatives were administered to mice together with paclitaxel. FIG. 3 shows the results of a cold plate test when arabinitol derivatives were administered to mice together with vincristine. FIG. 3 shows the results of the von Frey test when arabinitol derivatives were administered to mice together with vincristine. FIG. 10 shows the results of a cold plate test when arabinitol derivatives were administered to mice together with bortezomib. FIG. 3 shows the results of the von Frey test when arabinitol derivatives were administered to mice together with bortezomib. FIG. 2 shows the results of a cold plate test in which an arabinitol derivative was administered to mice that developed peripheral neuropathy due to oxaliplatin. FIG. 2 shows the results of the von Frey test when arabinitol derivatives were administered to mice that developed peripheral neuropathy due to oxaliplatin. FIG. 3 shows the results of a cold plate test when arabinitol derivatives were administered to mice that developed peripheral neuropathy due to paclitaxel. FIG. 2 shows the results of the von Frey test when an arabinitol derivative was administered to mice that developed peripheral neuropathy due to paclitaxel. FIG. 10 shows the results of a cold plate test when arabinitol derivatives were administered to mice that developed peripheral neuropathy due to vincristine. Fig. 10 shows the results of the von Frey test when arabinitol derivatives were administered to mice that developed peripheral neuropathy due to vincristine. FIG. 2 shows the results of a cold plate test when arabinitol derivatives were administered to mice that developed peripheral neuropathy due to bortezomib. FIG. 3 shows the results of the von Frey test when arabinitol derivatives were administered to mice that developed peripheral neuropathy due to bortezomib. FIG. 10 shows the results of a cold plate test when arabinitol derivatives were administered from the day streptozotocin was administered to mice. FIG. 10 shows the results of the von Frey test when arabinitol derivatives were administered from the day streptozotocin was administered to mice. Fig. 2 shows the results of a cold plate test in which an arabinitol derivative was administered to mice that developed diabetes and peripheral neuropathy due to administration of streptozotocin. Fig. 10 shows the results of the von Frey test when an arabinitol derivative was administered to mice that developed diabetes and peripheral neuropathy due to administration of streptozotocin. This is a panel in which an arabinitol derivative was added to U251 cells, and binding between substance P-FAM and NK1 receptor was measured using flow cytometry. (a) arabinitol-linoleic acid diester, (b) arabinitol-linolenic acid diester, and (c) arabinitol-eicosapentaenoic acid diester.

The preventive or improving agent according to the present invention will be described below with reference to drawings and examples. These agents for preventing or improving peripheral neuropathy are pharmaceutical compositions and NK1 receptor inhibitors. In addition, the following description illustrates one embodiment and one example of the present invention, and the present invention is not limited to the following description. The following description can be modified without departing from the spirit of the invention.

In the prophylactic or ameliorating agent according to the present invention, "prevention" means not only preventing the onset of peripheral neuropathy, but also includes the action of reducing the degree of symptoms at the time of onset, and "improving" means peripheral nerve It does not mean only radical treatment of disorders, but also includes the action of reducing or alleviating the degree of symptoms of peripheral neuropathy. In this specification, "-" indicates a range of "above, below".

The preventive or ameliorating agent according to the present invention is a compound represented by Formula (1), Formula (2), and Formula (3) as an active ingredient.

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

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

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

These compounds can also be expressed as in (4).

However, here, R is either formula (5), formula (6), or formula (7).

From now on, when these are collectively referred to, they will be referred to as "arabinitol derivatives" or "various arabinitol derivatives". The synthesis methods for these will be described in detail later, but raw materials are arabinitol and respective fatty acids (linoleic acid, linolenic acid, eicosapentaenoic acid). Each fatty acid is industrially produced and readily available.

In addition, D-(+)-arabinitol can be obtained by the conventional chemical reduction method of D-arabinol, or by the decomposition of microorganisms using glycerol as a carbon source.

The preventive or ameliorating agent according to the present invention can be provided in the form of pharmaceuticals, foods, and the like. Further, the improving agent according to the present invention can be provided with a label indicating that it is for improving peripheral neuropathy or preventing peripheral neuropathy.

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

When the preventive or ameliorating agent according to the present invention is used as a pharmaceutical, it may be administered orally, transdermally, enterally, intravenously, transpulmonary, subcutaneously, transmucosally, intramuscularly, or the like. It may be appropriately set according to the degree of target peripheral neuropathy.

When the preventive or ameliorating agent according to the present invention is used as a drug, the arabinitol derivative may be prepared as it is or in combination with other additives into a desired dosage form. Specific examples of pharmaceuticals include internal preparations such as capsules, granules, powders, pills, tablets, jellies, and syrups; liquids, ointments, creams, lotions, gelling agents, patches , external preparations such as aerosols; injections and the like.

When the preventive or ameliorating agent according to the present invention is to be made into a pharmaceutical, binders, lubricants, disintegrants, coloring agents, corrigents, preservatives, antioxidants, stabilizers, Additives such as water, lower alcohols, solubilizers, surfactants, emulsion stabilizers, gelling agents, adhesives, fragrances, and pigments may be appropriately selected and formulated. In addition, pharmacological ingredients such as vasodilating agents, adrenal corticosteroids, keratolytic agents, moisturizing agents, bactericidal agents, antioxidants, and cooling agents may also be contained, if necessary.

When the preventive or ameliorating agent according to the present invention is used as a drug, the content of the arabinitol derivative in the drug may be appropriately set according to the dosage form of the drug, etc. so that the daily dosage described later can be satisfied. . For example, in the case of internal preparations, the total amount of arabinitol derivatives is (0.1 to 100)% by mass, preferably (15 to 80)% by mass, more preferably (30 to 70)% by mass, In the case of external preparations, the total amount of arabinitol derivatives is (0.01 to 50)% by mass, preferably (0.1 to 40)% by mass, more preferably (0.5 to 30)% by mass. .

In addition, when the preventive or ameliorating agent according to the present invention is made into a food, the food is provided as a food for preventing or improving peripheral neuropathy.

When the preventive or ameliorating agent according to the present invention is made into a food, the arabinitol derivative may be prepared in a desired form as it is or in combination with other food materials or additives. Foods include general processed foods such as luxury foods and health foods, foods with health claims such as foods with specified health uses, foods with nutrient claims, and foods with function claims, which are defined in the food with health claims system of the Ministry of Health, Labor and Welfare.

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

When the preventive or ameliorating agent according to the present invention is used as a food, the content of the arabinitol derivative in the food may be appropriately set according to the type of food, etc., so as to satisfy the daily intake to be described later. . For example, the total amount of arabinitol derivatives is (0.05 to 100)% by mass, preferably (10 to 80)% by mass, more preferably (20 to 60)% by mass.

The preventive or ameliorating agent according to the present invention is used for preventing or ameliorating peripheral neuropathy. Applicable peripheral neuropathy symptoms include, for example, limb numbness, limb pain, decreased deep tendon reflex, decreased muscle strength, allodynia, hyperalgesia, dysgeusia, finger dexterity dysfunction, gait disorder, and stumbling. , falls, flexion disorders (difficulty or inability to sit upright, cross-legged, sitting sideways or sitting on a chair, etc.), paralysis of the limbs, etc.

In addition, the prophylactic or ameliorating agent according to the present invention is not particularly limited in terms of the inducer of peripheral neuropathy to which it is applied. Although it can be applied to any peripheral neuropathy caused by cancer chemotherapy or diabetes, it is particularly preferably applied to peripheral neuropathy induced by cancer chemotherapy or diabetes.

When the preventive or ameliorating agent according to the present invention is applied to peripheral neuropathy induced by various anticancer agents, the type of anticancer agent is not particularly limited. For example, platinum agents, alkylating agents, antimetabolites, microtubule agonists, 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, immune checkpoint inhibitors and the like. Specific examples of platinum agents include oxaliplatin, cisplatin, carboplatin, nedaplatin and the like. Specific examples of alkylating agents include cyclophosphamide, ifosfamide, thiotepa, carbocone, nimustine hydrochloride and the like. Specific examples of antimetabolites include 5-fluorouracil, methotrexate, doxifluridine, tegafur, cytarabine, gemcitabine and the like. Specific examples of microtubule active agents include docetaxel, paclitaxel, vincristine, vinblastine, vindesine, vinorelbine, cabazitaxel, embulin and the like. Specific examples of anticancer antibiotics include doxorubicin hydrochloride, mitomycin, amrubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, aclarubicin hydrochloride, mitoxantrone hydrochloride, bleomycin hydrochloride, and pepromycin sulfate. Specific examples of topoisomerase inhibitors include irinotecan, nogitecan hydrochloride, and the like. Specific examples of proteasome inhibitors include bortezomib, carfilzomib, ixazomib and the like. Specific examples of histone deacetylase inhibitors include romidepsin and the like. Specific examples of FLT3 tyrosine kinase inhibitors include gilteritinib and the like. Antibody drugs specifically include pertuzumab, trastuzumab emtansine, brentuximab vedotin, polatuzumab vedotin, rituximab, obinutuzumab, blinatumomab, and bevacizumab. Specific examples of ALK inhibitors include alectinib and brigtinib. Specific examples of HER2/EGFR tyrosine kinase inhibitors include lapatinib and the like. 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 and the like. Specific examples of BCR-ABL inhibitors include ponatinib and the like. Specific examples of FGFR inhibitors include pemigatinib and the like. Specific examples of MET inhibitors include tepotinib and the like. Specific examples of BRAF inhibitors include vemurafenib and encorafenib. Specific examples of MEK inhibitors include binimetinib and the like. Specific examples of immunomodulators include thalidomide, lenalidomide, ponalidomide, and the like. Specific examples of immune checkpoint inhibitors include nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab.

When the preventive or ameliorating agent according to the present invention is applied to peripheral neuropathy induced by the administration of an anticancer agent, the preventive or ameliorating agent according to the present invention is administered before or simultaneously with the start of administration of the anticancer agent. Administration or intake may be started, but administration or intake of the preventive or improving agent according to the present invention may be started during the period of administration of the anticancer agent or after the period of administration of the anticancer agent is completed.

When the preventive or ameliorating agent according to the present invention is applied to diabetic peripheral neuropathy, it can be ingested as an ameliorating agent after the onset of peripheral neuropathy. In addition, even before the onset of peripheral neuropathy, if the onset of diabetes can be confirmed, it can be used as a preventive agent by ingesting it.

The administration or intake amount of the preventive or improving agent according to the present invention can be appropriately selected according to symptoms, age, body weight, elapsed time after onset, combined therapeutic measures, and the like. In the examples of the present invention, the total daily intake of arabinitol derivatives in mice effective for improving peripheral neuropathy when 6 mg/kg body weight of an anticancer agent was administered was 25 mg/kg body weight of mouse. 100 mg/mouse kg body weight or more is more preferable.

In the technical field, when an ingredient is effective in mice, the dose at which an equivalent effect is expressed in humans is calculated as Human Equivalent Dose (HED). Assuming a mouse weight of 30 g and a human weight of 60 kg, the dose in mice divided by 12.3 is considered the human equivalent dose.

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

In addition, excessive intake of sugar alcohols is said to cause stomach upset, and although there are individual differences, the limit amount is said to be 20-30g/day. Therefore, it is considered that in many cases, the dose required for the improvement of peripheral neuropathy does not cause almost any side effects. Therefore, when the preventive or ameliorating agent according to the present invention is orally administered or ingested, the total amount of administration or ingestion of the arabinitol derivative is 0.12 g / day / adult to 30 g / day / adult. .49 g/day/adult to 20 g/day/adult or less is preferred.

The preventive or ameliorating agent according to the present invention may be administered or taken in 1 or 2 to 3 divided doses per day so as to satisfy the daily dosage or intake.

In addition, at least one compound of the formulas (1) to (3) according to the present invention can be used to treat peripheral neuropathy caused by anticancer agents or diabetes.

The method for synthesizing the arabinitol derivative according to the present invention is described below. In these synthetic methods, D-(+)-arabinitol and the corresponding fatty acid are added to a dehydration condensing agent, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, in an anhydrous pyridine solvent to form a fatty acid ester. A certain arabinitol derivative is obtained.

(Example 1)
<Synthesis 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) and linoleic acid (3.37 g, 12 mmol) was added followed by 1-(3-dimethylaminopropyl) -3-Ethylcarbodiimide hydrochloride (2.30 g, 24 mmol) was added and 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 ethyl acetate layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration, and the resulting filtrate was evaporated under reduced pressure to obtain a composition. The resulting composition 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%).

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). From the above, compound I-1 was confirmed to have the structure of formula (1).

<Synthesis of method for producing 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) and α-linolenic acid (3.34 g, 12 mmol) was added followed by 1-(3-dimethylamino Propyl)-3-ethylcarbodiimide hydrochloride (2.30 g, 24 mmol) was added and 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 ethyl acetate layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration, and the resulting filtrate was evaporated under reduced pressure to obtain a composition. The resulting composition 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%).

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). From the above, compound I-2 was confirmed to have the structure of formula (2).

<Synthesis of 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) and eicosapentaenoic acid (3.63 g, 12 mmol) was added followed by 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide hydrochloride (2.30 g, 24 mmol) was added and 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 ethyl acetate layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration, and the resulting filtrate was evaporated under reduced pressure to obtain a composition. The resulting composition 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%).

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.
13C-NMR (200 MHz, CDCl3) 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). As described above, compound I-3 was confirmed to have the structure of formula (3).

(Example 2) Preventive Effect of Oxaliplatin on Peripheral Neuropathy Hyperesthesia such as allodynia (severe pain induced by tactile stimulation that does not normally cause pain) due to mechanical stimulation that occurs when the anticancer drug oxaliplatin is administered We investigated the preventive effect of arabinitol derivatives on paresthesia in cold stimulation. Various arabinitol derivatives were orally administered to mice while administering oxaliplatin, and the following tests (Cold plate test and von Frey test) were performed. In addition, oxaliplatin is an anticancer drug that corresponds to a platinum drug. In addition, the dose (mg/kg) in all the examples below indicates the weight of the administered substance per 1 kg of body weight of the mouse.

(2-1) Administration of test substance Balb/c female mice aged 6 to 7 weeks were used. The animals were divided into 5 groups: a control group, an oxaliplatin-administered group, and an arabinitol derivative-administered group (oxaliplatin + 3 types of arabinitol derivatives-administered group). Each group consisted of 9 animals.

6 mg/kg of oxaliplatin was intraperitoneally administered to the mice of the oxaliplatin administration group and the oxaliplatin + arabinitol derivative administration group. This day was designated as day 0 of administration, and thereafter, 6 mg/kg of oxaliplatin was intraperitoneally administered to these mice on days 7 and 14.

For the oxaliplatin + arabinitol derivative administration group, 5 mg/kg of arabinitol derivative was orally administered daily from day 0.

These groups were respectively a control group, a 6 mg/kg oxaliplatin administration group, a 6 mg/kg oxaliplatin + 5 mg/kg arabinitol-linoleic acid diester administration group, a 6 mg/kg oxaliplatin + 5 mg/kg arabinitol-linolenic acid diester administration group, and a 6 mg/kg oxaliplatin administration group. kg oxaliplatin + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group.

(2-2) Cold plate test
A cold plate test was performed to test the effect of arabinitol derivatives on paresthesia in cold stimulation. The 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. It is considered that the shorter the latency, the more avoidance of cold stimulation by the cold plate. The results are shown in FIG.

With reference to FIG. 1, the horizontal axis is the elapsed time after administration (days), and the vertical axis is the average escape reaction time (seconds) of mice in each group. The white circle solid line is the control group, the black circle dashed line is the 6 mg / kg oxaliplatin administration group, the black square dashed line is the 6 mg / kg oxaliplatin + 5 mg / kg arabinitol-linoleic acid diester administration group, and the black triangle dashed line is 6 mg/kg oxaliplatin + 5 mg/kg arabinitol-linolenic acid diester administration group, and the dotted black diamond line is the administration group of 6 mg/kg oxaliplatin + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to Fig. 1, the oxaliplatin-administered group (black circle dashed line) is considered to have developed a peripheral neuropathy (peripheral nerve hypersensitivity symptom) due to a shortened withdrawal response time after administration. On the other hand, in the arabinitol derivative-administered group, the withdrawal reaction time after administration was the same as that of the control, despite the administration of oxaliplatin. From this, the arabinitol derivative-administered group suppressed peripheral neuropathy caused by the administration of oxaliplatin.

(2-3) von Frey test
The five groups of mice shown in (2-1) were placed in cages, and filaments with a strength of 0.16 g were pressed against the soles of their hind limbs to measure the number of avoidance reactions (scores). If the avoidance frequency is large, it is considered that the stimulation by the filament is avoided more. The results are shown in FIG.

With reference to FIG. 2, the horizontal axis is the elapsed time (days) after administration, and the vertical axis is the average avoidance response (score) of mice in each group. The white circle solid line is the control group, the black circle dashed line is the 6 mg / kg oxaliplatin administration group, the black square dashed line is the 6 mg / kg oxaliplatin + 5 mg / kg arabinitol-linoleic acid diester administration group, and the black triangle dashed line is 6 mg/kg oxaliplatin + 5 mg/kg arabinitol-linolenic acid diester administration group, and the dotted black diamond line is the administration group of 6 mg/kg oxaliplatin + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to Fig. 2, the oxaliplatin-administered group (broken black circle) is considered to have developed peripheral neuropathy (peripheral nerve hypersensitivity symptoms) with an increase in the score (number of avoidance reactions) after administration. On the other hand, in the arabinitol derivative-administered group, the score after administration was almost the same as that of the control, although oxaliplatin was administered. From this, it can be said that the arabinitol derivative-administered group suppressed peripheral neuropathy caused by the administration of oxaliplatin.

(Example 3) Preventive Effect of Paclitaxel on Peripheral Neuropathy Hyperesthesia such as allodynia (severe pain induced by tactile stimulation that does not normally cause pain) caused by mechanical stimulation that occurs when paclitaxel, an anticancer agent, is administered, and low temperature The preventive effect of arabinitol derivatives against paresthesia in stimulation was investigated. 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 corresponds to a microtubule active drug.

(3-1) Administration of test substance Balb/c female mice aged 6 to 7 weeks were used. The animals were divided into five groups: a control group, a paclitaxel-administered group, and an arabinitol derivative-administered group (paclitaxel + three types of arabinitol derivatives-administered group). Each group consisted of 9 animals.

Paclitaxel 6 mg/kg was intraperitoneally administered to the paclitaxel-administered group and the paclitaxel + arabinitol derivative-administered group. This day was designated as day 0 of administration, and thereafter 6 mg/kg of paclitaxel was intraperitoneally administered to these mice on days 7 and 14.

For the paclitaxel + arabinitol derivative administration group, 5 mg/kg of arabinitol derivative was orally administered daily from day 0.

These groups were respectively a control group, a 6 mg/kg paclitaxel administration group, a 6 mg/kg paclitaxel + 5 mg/kg arabinitol-linoleic acid diester administration group, a 6 mg/kg paclitaxel + 5 mg/kg arabinitol-linolenic acid diester administration group, and a 6 mg/kg paclitaxel + 5 mg administration group. /kg arabinitol-eicosapentaenoic acid diester administration group.

(3-2) Cold plate test
A cold plate test was performed to test the effect of arabinitol derivatives on paresthesia in cold stimulation. The 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. It is considered that the shorter the latency, the more avoidance of cold stimulation by the cold plate. The results are shown in FIG.

With reference to FIG. 3, the horizontal axis is the elapsed time after administration (days), and the vertical axis is the average escape reaction time (seconds) of mice in each group. The open circle solid line is the control group, the black circle dashed line is the 6 mg / kg paclitaxel administration group, the black square dashed line is the 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linoleic acid diester administration group, the black triangle dashed line is 6 mg / kg paclitaxel + 5 mg/kg arabinitol-linolenic acid diester administration group, and the dotted black diamond line is the administration group of 6 mg/kg paclitaxel + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to Fig. 3, the paclitaxel-administered group (black circle dashed line) is considered to have had a shortened withdrawal reaction time after administration and developed peripheral neuropathy (peripheral nerve hypersensitivity symptom). On the other hand, in the arabinitol derivative-administered group, the withdrawal reaction time after administration was the same as that of the control, despite the administration of paclitaxel. From this, the arabinitol derivative-administered group suppressed peripheral neuropathy caused by administration of paclitaxel.

(3-3) von Frey test
The five groups of mice shown in (3-1) were placed in cages, and filaments with a strength of 0.16 g were pressed against the soles of their hind limbs to measure the number of avoidance reactions (scores). If the avoidance frequency is large, it is considered that the stimulation by the filament is avoided more. The results are shown in FIG.

With reference to FIG. 4, the horizontal axis is the elapsed time (days) after administration, and the vertical axis is the average avoidance response (score) of mice in each group. The open circle solid line is the control group, the black circle dashed line is the 6 mg / kg paclitaxel administration group, the black square dashed line is the 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linoleic acid diester administration group, the black triangle dashed line is 6 mg / kg paclitaxel + 5 mg/kg arabinitol-linolenic acid diester administration group, and the dotted black diamond line is the administration group of 6 mg/kg paclitaxel + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to FIG. 4, the paclitaxel-administered group (black circle dashed line) is considered to have developed peripheral neuropathy (peripheral nerve hypersensitivity symptom) with an increase in score (number of avoidance reactions) after administration. On the other hand, in the arabinitol derivative-administered group, the score after administration was almost the same as that of the control, although paclitaxel was administered. From this, it can be said that the arabinitol derivative-administered group suppressed the peripheral neuropathy caused by the administration of paclitaxel.

(Example 4) Preventive Effect of Vincristine on Peripheral Neuropathy Hyperesthesia such as allodynia (severe pain induced by tactile stimuli that does not normally cause pain) and low temperature due to mechanical stimulation that occurs when the anticancer drug vincristine is administered The preventive effect of arabinitol derivatives against paresthesia in stimulation was investigated. Various arabinitol derivatives were orally administered to mice while administering vincristine, and the following tests (Cold plate test and von Frey test) were performed. Vincristine is an anticancer drug that corresponds to a microtubule active drug.

(4-1) Administration of test substance Balb/c female mice aged 6 to 7 weeks were used. They were divided into 5 groups: a control group, a vincristine-administered group, and an arabinitol derivative-administered group (vincristine + 3 kinds of arabinitol derivatives-administered group). Each group consisted of 9 animals.

0.2 mg/kg of vincristine was intraperitoneally administered to mice in the vincristine administration group and the vincristine + arabinitol derivative administration group. This day was designated as day 0 of administration, and 0.2 mg/kg vincristine was intraperitoneally administered to these mice on days 7 and 14 thereafter.

For the vincristine + arabinitol derivative administration group, 5 mg/kg of arabinitol derivative was orally administered daily from day 0.

These groups were respectively a control group, a 0.2 mg/kg vincristine administration group, a 0.2 mg/kg vincristine + 5 mg/kg arabinitol-linolenic acid diester administration group, and a 0.2 mg/kg vincristine + 5 mg/kg arabinitol-linolenic acid diester administration group. , 0.2 mg/kg vincristine + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group.

(4-2) Cold plate test
A cold plate test was performed to test the effect of arabinitol derivatives on paresthesia in cold stimulation. The 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. It is considered that the shorter the latency, the more avoidance of cold stimulation by the cold plate. The results are shown in FIG.

With reference to FIG. 5, the horizontal axis is the post-administration elapsed time (days), and the vertical axis is the average escape reaction time (seconds) of mice in each group. The white circle solid line is the control group, the black circle dashed line is the 0.2 mg/kg vincristine administration group, the black square dashed line is the 0.2 mg/kg vincristine + 5 mg/kg arabinitol-linoleic acid diester administration group, and the black triangle dashed line. is the 0.2 mg/kg vincristine + 5 mg/kg arabinitol-linolenic diester administration group, and the dotted black diamond line is the 0.2 mg/kg vincristine + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to FIG. 5, the vincristine-administered group (black circle dashed line) is considered to have had a shortened withdrawal response time after administration and developed peripheral neuropathy (peripheral nerve hypersensitivity symptom). On the other hand, in the arabinitol derivative-administered group, the withdrawal reaction time after administration was the same as that of the control, despite the administration of vincristine. From this, the arabinitol derivative-administered group suppressed peripheral neuropathy caused by administration of vincristine.

(4-3) von Frey test
The five groups of mice shown in (4-1) were placed in cages, and filaments with a strength of 0.16 g were pressed against the soles of their hind limbs to measure the number of avoidance reactions (scores). If the avoidance frequency is large, it is considered that the stimulation by the filament is avoided more. The results are shown in FIG.

With reference to FIG. 6, the horizontal axis is the elapsed time (days) after administration, and the vertical axis is the average avoidance response (score) of mice in each group. The white circle solid line is the control group, the black circle dashed line is the 0.2 mg/kg vincristine administration group, the black square dashed line is the 0.2 mg/kg vincristine + 5 mg/kg arabinitol-linoleic acid diester administration group, and the black triangle dashed line. is the 0.2 mg/kg vincristine + 5 mg/kg arabinitol-linolenic diester administration group, and the dotted black diamond line is the 0.2 mg/kg vincristine + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to FIG. 6, the vincristine-administered group (black circle dashed line) is considered to have developed peripheral neuropathy (peripheral nerve hypersensitivity symptoms) with an increase in score (number of avoidance reactions) after administration. On the other hand, in the arabinitol derivative-administered group, the score after administration was almost the same as that of the control, although vincristine was administered. From this, it can be said that the arabinitol derivative administration group suppressed the peripheral neuropathy that develops due to the administration of vincristine.

(Example 5) Preventive effect of bortezomib on peripheral neuropathy Hyperesthesia and low temperature such as allodynia (severe pain induced by tactile stimulation that does not normally cause pain) due to mechanical stimulation that occurs when the anticancer agent bortezomib is administered The preventive effect of arabinitol derivatives against paresthesia in stimulation was investigated. Various arabinitol derivatives were orally administered to mice while administering 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.

(5-1) Administration of test substance Balb/c female mice aged 6 to 7 weeks were used. The animals were divided into 5 groups: a control group, a bortezomib-administered group, and an arabinitol derivative-administered group (bortezomib + 3 kinds of arabinitol derivatives-administered group). Each group consisted of 9 animals.

Bortezomib 1 mg/kg was intraperitoneally administered to the mice in the bortezomib-administered group and the bortezomib + arabinitol derivative-administered group. This day was designated as day 0 of administration, and 1 mg/kg of bortezomib was intraperitoneally administered to these mice on days 7 and 14 thereafter.

For the bortezomib + arabinitol derivative administration group, 5 mg/kg of arabinitol derivative was orally administered daily from day 0.

These groups were respectively a control group, a 1 mg/kg bortezomib administration group, a 1 mg/kg bortezomib + 5 mg/kg arabinitol-linoleic acid diester administration group, a 1 mg/kg bortezomib + 5 mg/kg arabinitol-linolenic acid diester administration group, and a 1 mg/kg bortezomib + 5 mg group. /kg arabinitol-eicosapentaenoic acid diester administration group.

(5-2) Cold plate test
A cold plate test was performed to test the effect of arabinitol derivatives on paresthesia in cold stimulation. The 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. It is considered that the shorter the latency, the more avoidance of cold stimulation by the cold plate. The results are shown in FIG.

With reference to FIG. 7, the horizontal axis is the elapsed time after administration (days), and the vertical axis is the average escape reaction time (seconds) of mice in each group. The open circle solid line is the control group, the black circle dashed line is the 1 mg / kg bortezomib administration group, the black square dashed line is the 1 mg / kg bortezomib + 5 mg / kg arabinitol-linoleic acid diester administration group, the black triangle dashed line is 1 mg / 1 mg/kg bortezomib + 5 mg/kg arabinitol-linolenic acid diester administration group, and the dotted black diamond line is the 1 mg/kg bortezomib + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to FIG. 7, the bortezomib-administered group (black circle dashed line) is considered to have had a shortened withdrawal reaction time after administration and developed peripheral neuropathy (peripheral nerve hypersensitivity symptom). On the other hand, in the arabinitol derivative-administered group, the withdrawal reaction time after administration was the same as that of the control, despite the administration of bortezomib. From this, the arabinitol derivative administration group suppressed the peripheral neuropathy that develops due to the administration of bortezomib.

(5-3) von Frey test
The five groups of mice shown in (5-1) were placed in cages, and filaments with a strength of 0.16 g were pressed against the soles of their hind limbs to measure the number of avoidance reactions (scores). If the avoidance frequency is large, it is considered that the stimulation by the filament is avoided more. The results are shown in FIG.

With reference to FIG. 8, the horizontal axis is the elapsed time (days) after administration, and the vertical axis is the average avoidance response (score) of mice in each group. The open circle solid line is the control group, the black circle dashed line is the 1 mg / kg bortezomib administration group, the black square dashed line is the 1 mg / kg bortezomib + 5 mg / kg arabinitol-linoleic acid diester administration group, the black triangle dashed line is 1 mg / 1 mg/kg bortezomib + 5 mg/kg arabinitol-linolenic acid diester administration group, and the dotted black diamond line is the 1 mg/kg bortezomib + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to FIG. 8, the bortezomib-administered group (black circle dashed line) is considered to have developed peripheral neuropathy (peripheral nerve hypersensitivity symptoms) with an increase in the score (number of avoidance reactions) after administration. On the other hand, in the arabinitol derivative-administered group, the score after administration was almost the same as that of the control, although bortezomib was administered. From this, it can be said that the arabinitol derivative administration group suppressed the peripheral neuropathy that develops due to the administration of bortezomib.

(Example 6) Therapeutic effect of oxaliplatin on peripheral neuropathy It was found that the arabinitol derivative according to the present invention can prevent peripheral neuropathy caused by oxaliplatin. Next, we examined whether arabinitol derivatives have a therapeutic effect to alleviate peripheral neuropathy after the onset of peripheral neuropathy due to administration of an anticancer drug (oxaliplatin).

(6-1) Administration of test substance Balb/c female mice aged 6 to 7 weeks were used. The animals were divided into 5 groups: a control group, an oxaliplatin-administered group, and an arabinitol derivative-administered group (oxaliplatin + 3 types of arabinitol derivatives-administered group). Each group consisted of 9 animals.

Mice other than the control group were intraperitoneally administered 6 mg/kg of oxaliplatin. This day was defined as the first day of administration (day 0), and the same dose of oxaliplatin was intraperitoneally administered to these mice three times on the 7th and 14th days.

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

These groups were respectively a control group, a 6 mg/kg oxaliplatin administration group, a 6 mg/kg oxaliplatin + 10 mg/kg arabinitol-linoleic acid diester administration group, a 6 mg/kg oxaliplatin + 5 mg/kg arabinitol-linolenic acid diester administration group, and a 6 mg/kg oxaliplatin administration group. kg oxaliplatin + 25 mg/kg arabinitol-eicosapentaenoic acid diester administration group.

(6-2) Cold plate test
The five groups of mice shown in (6-1) were tested for the effect of the arabinitol derivative on paresthesia due to cold stimulation. Each group of mice was placed on a cold plate set at 10° C., and the reaction time (latency) until escape was measured. It is considered that the shorter the latency, the more avoidance of cold stimulation by the cold plate. The results are shown in FIG.

With reference to FIG. 9, the horizontal axis is the elapsed time after administration (days), and the vertical axis is the average escape reaction time (seconds) of mice in each group. The white circle solid line is the control group, the black circle dashed line is the 6 mg / kg oxaliplatin administration group, the black square dashed line is the 6 mg / kg oxaliplatin + 10 mg / kg arabinitol-linoleic acid diester administration group, and the black triangle dashed line is 6 mg/kg oxaliplatin + 5 mg/kg arabinitol-linolenic acid diester administration group, and the dotted black diamond line is the administration group of 6 mg/kg oxaliplatin + 25 mg/kg arabinitol-eicosapentaenoic acid diester. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

　With reference to Figure 9, the withdrawal reaction time (latency) decreased uniformly by the 6th day after administration in the 4 groups administered with oxaliplatin other than the control group. It was considered that oxaliplatin caused peripheral neuropathy (peripheral nerve hypersensitivity symptom). However, 6 mg/kg oxaliplatin + 10 mg/kg arabinitol-linoleic acid diester administration group, 6 mg/kg oxaliplatin + 5 mg/kg arabinitol-linolenic acid diester administration group and 6 mg/kg oxaliplatin + 25 mg/kg arabinitol-d The three icosapentaenoic acid diester-administered groups tended to have longer latencies from day 6 onwards, and on the 12th day, these three groups and the control group were significantly higher than the 6 mg/kg oxaliplatin-administered group. Escape reaction time (latency) increased.

(6-3) von Frey test
The five groups of mice shown in (1) of this example (Example 6) were placed in cages, and filaments with a strength of 0.16 g were pressed against the soles of the hind limbs to measure the number of avoidance reactions (scores). The results are shown in FIG.

With reference to FIG. 10, the horizontal axis is the elapsed time (days) after administration, which is the average avoidance response (score) of mice in each group. If the avoidance frequency is large, it is considered that the stimulation by the filament is avoided more. The white circle solid line is the control group, the black circle dashed line is the 6 mg / kg oxaliplatin administration group, the black square dashed line is the 6 mg / kg oxaliplatin + 10 mg / kg arabinitol-linoleic acid diester administration group, and the black triangle dashed line is 6 mg/kg oxaliplatin + 5 mg/kg arabinitol-linolenic acid diester administration group, and the dotted black diamond line is the administration group of 6 mg/kg oxaliplatin + 25 mg/kg arabinitol-eicosapentaenoic acid diester. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to FIG. 10, in the oxaliplatin-administered group (black circle dashed line), the score (number of avoidance reactions) increased after administration, and it is considered that peripheral neuropathy (peripheral nerve hypersensitivity symptom) developed. On the other hand, in the arabinitol derivative-administered group, the score after administration decreased despite the administration of oxaliplatin, and was almost the same as the control after 18 days. From this, it can be said that the arabinitol derivative administration group suppressed the peripheral neuropathy developed by the administration of oxaliplatin.

The above means that peripheral neuropathy (symptoms of peripheral nerve hypersensitivity) that had developed once due to administration of oxaliplatin was improved by taking arabinitol derivatives. Therefore, it was found that the arabinitol derivative also functions as a therapeutic composition (therapeutic agent) for peripheral neuropathy (peripheral nerve hypersensitivity symptom).

(Example 7) Therapeutic effect of paclitaxel on peripheral neuropathy It was found that the arabinitol derivative according to the present invention can prevent peripheral neuropathy caused by paclitaxel. Next, we examined whether arabinitol derivatives have a therapeutic effect to alleviate peripheral neuropathy after the onset of peripheral neuropathy due to administration of an anticancer drug (paclitaxel).

(7-1) Administration of test substance Balb/c female mice aged 6 to 7 weeks were used. The animals were divided into five groups: a control group, a paclitaxel-administered group, and an arabinitol derivative-administered group (paclitaxel + three types of arabinitol derivatives-administered group). Each group consisted of 9 animals.

Mice other than the control group were intraperitoneally administered 6 mg/kg of paclitaxel. This day was defined as the first day of administration (day 0), and the same amount of paclitaxel was intraperitoneally administered to these mice three times on the 7th and 14th days.

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

These groups were respectively a control group, a 6 mg/kg paclitaxel administration group, a 6 mg/kg paclitaxel + 5 mg/kg arabinitol-linoleic acid diester administration group, a 6 mg/kg paclitaxel + 5 mg/kg arabinitol-linolenic acid diester administration group, and a 6 mg/kg paclitaxel + 5 mg administration group. /kg arabinitol-eicosapentaenoic acid diester administration group.

(7-2) Cold plate test
The effect of arabinitol derivatives on hypoesthesia due to cold stimulation was tested on the five groups of mice shown in (1) of this example (Example 7). Each group of mice was placed on a cold plate set at 10° C., and the reaction time (latency) until escape was measured. It is considered that the shorter the latency, the more avoidance of cold stimulation by the cold plate. The results are shown in FIG.

With reference to FIG. 11, the horizontal axis is the post-administration elapsed time (days), and the vertical axis is the average escape reaction time (seconds) of mice in each group. The open circle solid line is the control group, the black circle dashed line is the 6 mg / kg paclitaxel administration group, the black square dashed line is the 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linoleic acid diester administration group, the black triangle dashed line is 6 mg / kg paclitaxel + 5 mg/kg arabinitol-linolenic acid diester administration group, and the dotted black diamond line is the administration group of 6 mg/kg paclitaxel + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

　With reference to Figure 11, the withdrawal reaction time (latency) decreased uniformly by the 6th day after administration in the four groups administered with paclitaxel other than the control group. Peripheral neuropathy (peripheral nerve hypersensitivity symptoms) was thought to have developed due to paclitaxel. However, 6 mg/kg paclitaxel + 5 mg/kg arabinitol-linoleic acid diester administration group, 6 mg/kg paclitaxel + 5 mg/kg arabinitol-linolenic acid diester administration group and 6 mg/kg paclitaxel + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group administered arabinitol derivatives Three of the administration groups tended to have longer latencies after the 6th day, and on the 12th day, these three groups and the control group showed significantly higher withdrawal response times than the 6 mg/kg paclitaxel administration group ( latency) increased.

(7-3) von Frey test
The five groups of mice shown in (1) of this example (Example 7) were placed in cages, and filaments with a strength of 0.16 g were pressed against the soles of their hind limbs to measure the number of avoidance reactions (scores). The results are shown in FIG.

With reference to FIG. 12, the horizontal axis is the elapsed time (days) after administration, which is the average avoidance response (score) of mice in each group. If the avoidance frequency is large, it is considered that the stimulation by the filament is avoided more. The open circle solid line is the control group, the black circle dashed line is the 6 mg / kg paclitaxel administration group, the black square dashed line is the 6 mg / kg paclitaxel + 5 mg / kg arabinitol-linoleic acid diester administration group, the black triangle dashed line is 6 mg / kg paclitaxel + 5 mg/kg arabinitol-linolenic acid diester administration group, and the dotted black diamond line is the administration group of 6 mg/kg paclitaxel + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to FIG. 12, the paclitaxel-administered group (black circle dashed line) is considered to have developed peripheral neuropathy (peripheral nerve hypersensitivity symptom) with an increase in score (number of avoidance reactions) after administration. On the other hand, in the arabinitol derivative-administered group, the score after administration decreased despite the administration of paclitaxel, and became almost the same as the control after 21 days. From this, it can be said that the arabinitol derivative-administered group suppressed the peripheral neuropathy caused by the administration of paclitaxel.

The above means that paclitaxel administration improved peripheral neuropathy (peripheral nerve hypersensitivity symptoms) by taking arabinitol derivatives. Therefore, it was found that the arabinitol derivative also functions as a therapeutic composition (therapeutic agent) for peripheral neuropathy (peripheral nerve hypersensitivity symptom).

(Example 8) Therapeutic effect of vincristine on peripheral neuropathy It was found that the arabinitol derivative according to the present invention can prevent peripheral neuropathy caused by vincristine. Next, we examined whether arabinitol derivatives have a therapeutic effect to alleviate peripheral neuropathy after the onset of peripheral neuropathy due to administration of an anticancer drug (vincristine).

(8-1) Administration of test substance Balb/c female mice aged 6 to 7 weeks were used. They were divided into 5 groups: a control group, a vincristine-administered group, and an arabinitol derivative-administered group (vincristine + 3 kinds of arabinitol derivatives-administered group). Each group consisted of 9 animals.

　Mice other than the control group were intraperitoneally administered 0.2 mg/kg of vincristine. This day was defined as the first day of administration (day 0), and the same amount of vincristine was intraperitoneally administered to these mice three times on the 7th and 14th days.

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

These groups were respectively a control group, a 0.2 mg/kg vincristine administration group, a 0.2 mg/kg vincristine + 5 mg/kg arabinitol-linolenic acid diester administration group, and a 0.2 mg/kg vincristine + 5 mg/kg arabinitol-linolenic acid diester administration group. , 0.2 mg/kg vincristine + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group.

(8-2) Cold plate test
The five groups of mice shown in (8-1) were tested for the effect of arabinitol derivatives on paresthesia due to cold stimulation. Each group of mice was placed on a cold plate set at 10° C., and the reaction time (latency) until escape was measured. It is considered that the shorter the latency, the more avoidance of cold stimulation by the cold plate. The results are shown in FIG.

With reference to FIG. 13, the horizontal axis is the post-administration elapsed time (days), and the vertical axis is the average escape reaction time (seconds) of mice in each group. The white circle solid line is the control group, the black circle dashed line is the 0.2 mg/kg vincristine administration group, the black square dashed line is the 0.2 mg/kg vincristine + 5 mg/kg arabinitol-linoleic acid diester administration group, and the black triangle dashed line. is the 0.2 mg/kg vincristine + 5 mg/kg arabinitol-linolenic diester administration group, and the dotted black diamond line is the 0.2 mg/kg vincristine + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to FIG. 13, the withdrawal reaction time (latency) uniformly decreased by 6 days after administration in the four groups other than the control group that had been administered vincristine. Peripheral neuropathy (peripheral hypersensitivity symptom) was considered to have developed due to vincristine. However, 0.2 mg/kg vincristine + 5 mg/kg arabinitol-linoleic acid diester administration group, 0.2 mg/kg vincristine + 5 mg/kg arabinitol-linolenic acid diester administration group and 0.2 mg/kg vincristine + 5 mg/kg The three arabinitol-eicosapentaenoic acid diester-administered groups tended to have longer latencies from the 6th day onwards, and on the 12th day, these three groups and the control group were significantly different from the 0.2 mg/kg vincristine-administered group. In contrast, the withdrawal reaction time (latency) was significantly longer.

(8-3) von Frey test
The five groups of mice shown in (1) of this example (Example 8) were placed in cages, and filaments with a strength of 0.16 g were pressed against the soles of their hind limbs to measure the number of avoidance reactions (scores). The results are shown in FIG.

With reference to FIG. 14, the horizontal axis is the elapsed time (days) after administration, which is the average avoidance response (score) of mice in each group. If the avoidance frequency is large, it is considered that the stimulation by the filament is avoided more. The white circle solid line is the control group, the black circle dashed line is the 0.2 mg/kg vincristine administration group, the black square dashed line is the 0.2 mg/kg vincristine + 5 mg/kg arabinitol-linoleic acid diester administration group, and the black triangle dashed line. is the 0.2 mg/kg vincristine + 5 mg/kg arabinitol-linolenic diester administration group, and the dotted black diamond line is the 0.2 mg/kg vincristine + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to FIG. 14, the vincristine-administered group (black circle dashed line) is considered to have developed peripheral neuropathy (peripheral nerve hypersensitivity symptoms) with an increase in score (number of avoidance reactions) after administration. On the other hand, in the arabinitol derivative-administered group, the score after administration decreased despite the administration of vincristine, and after 21 days, it became almost the same as the control. From this, it can be said that the arabinitol derivative administration group suppressed the peripheral neuropathy that develops due to the administration of vincristine.

The above means that peripheral neuropathy (symptoms of peripheral nerve hypersensitivity) that had developed once with vincristine administration was improved by taking arabinitol derivatives. Therefore, it was found that the arabinitol derivative also functions as a therapeutic composition (therapeutic agent) for peripheral neuropathy (peripheral nerve hypersensitivity symptom).

(Example 9) Therapeutic effect of bortezomib on peripheral neuropathy It was found that the arabinitol derivative according to the present invention can prevent peripheral neuropathy caused by bortezomib. Next, we investigated whether arabinitol derivatives have a therapeutic effect to alleviate peripheral neuropathy after the onset of peripheral neuropathy due to administration of an anticancer drug (bortezomib).

(9-1) Administration of test substance Balb/c female mice aged 6 to 7 weeks were used. The animals were divided into 5 groups: a control group, a bortezomib-administered group, and an arabinitol derivative-administered group (bortezomib + 3 kinds of arabinitol derivatives-administered group). Each group consisted of 9 animals.

Bortezomib 1 mg/kg was intraperitoneally administered to mice other than the control group. This day was defined as the first day of administration (day 0), and the same dose of bortezomib was intraperitoneally administered to these mice three times on days 7 and 14.

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

These groups were respectively a control group, a 1 mg/kg bortezomib administration group, a 1 mg/kg bortezomib + 5 mg/kg arabinitol-linoleic acid diester administration group, a 1 mg/kg bortezomib + 5 mg/kg arabinitol-linolenic acid diester administration group, and a 1 mg/kg bortezomib + 5 mg group. /kg arabinitol-eicosapentaenoic acid diester administration group.

(9-2) Cold plate test
The effect of arabinitol derivatives on hypoesthesia due to cold stimulation was tested on the five groups of mice shown in (1) of this example (Example 9). Each group of mice was placed on a cold plate set at 10° C., and the reaction time (latency) until escape was measured. It is considered that the shorter the latency, the more avoidance of cold stimulation by the cold plate. The results are shown in FIG.

With reference to FIG. 15, the horizontal axis is the post-administration elapsed time (days), and the vertical axis is the average escape reaction time (seconds) of mice in each group. The open circle solid line is the control group, the black circle dashed line is the 1 mg / kg bortezomib administration group, the black square dashed line is the 1 mg / kg bortezomib + 5 mg / kg arabinitol-linoleic acid diester administration group, the black triangle dashed line is 1 mg / 1 mg/kg bortezomib + 5 mg/kg arabinitol-linolenic acid diester administration group, and the dotted black diamond line is the 1 mg/kg bortezomib + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to FIG. 15, the withdrawal reaction time (latency) uniformly decreased by 6 days after administration in the four groups administered with bortezomib other than the control group. Bortezomib was considered to have caused peripheral neuropathy (peripheral nerve hypersensitivity symptom). However, 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 administered arabinitol derivatives Three of the administration groups tended to have longer latencies from day 6 onwards, and on day 12, these three groups and the control group showed significant withdrawal response times ( latency) increased.

(9-3) von Frey test
The five groups of mice shown in (1) of this example (Example 9) were placed in cages, and filaments with a strength of 0.16 g were pressed against the soles of their hind limbs to measure the number of avoidance reactions (scores). The results are shown in FIG.

With reference to FIG. 16, the horizontal axis is the elapsed time (days) after administration, which is the average avoidance response (score) of mice in each group. If the avoidance frequency is large, it is considered that the stimulation by the filament is avoided more. The open circle solid line is the control group, the black circle dashed line is the 1 mg / kg bortezomib administration group, the black square dashed line is the 1 mg / kg bortezomib + 5 mg / kg arabinitol-linoleic acid diester administration group, the black triangle dashed line is 1 mg / 1 mg/kg bortezomib + 5 mg/kg arabinitol-linolenic acid diester administration group, and the dotted black diamond line is the 1 mg/kg bortezomib + 5 mg/kg arabinitol-eicosapentaenoic acid diester administration group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to FIG. 16, in the bortezomib administration group (broken black circle), the score (number of avoidance reactions) increased after administration, and it is considered that peripheral neuropathy (peripheral nerve hypersensitivity symptom) developed. On the other hand, in the arabinitol derivative-administered group, the score after administration decreased despite the administration of bortezomib, and after 21 days, it became almost the same as the control. From this, it can be said that the arabinitol derivative administration group suppressed the peripheral neuropathy that develops due to the administration of bortezomib.

The above means that the administration of bortezomib improved peripheral neuropathy (peripheral nerve hypersensitivity symptoms) by taking arabinitol derivatives. Therefore, it was found that the arabinitol derivative also functions as a therapeutic composition (therapeutic agent) for peripheral neuropathy (peripheral nerve hypersensitivity symptoms).

(Example 10) Preventive effect on streptozotocin-induced diabetic mouse peripheral neuropathy Allodynia caused by mechanical stimulation (severe pain induced by tactile stimulation that does not normally cause pain) and cold stimulation caused by mechanical stimulation occurring during diabetic peripheral neuropathy We investigated the preventive effect of arabinitol derivatives against paresthesia in Simultaneously with administration of streptozotocin, various arabinitol derivatives were orally administered to mice as test drugs, and the following tests (von Frey test and Cold plate test) were performed.

(10-1) Administration of test substance 6- to 7-week-old C57BL/6J male mice were used. They were divided into 5 groups: a control group, a streptozotocin-administered group, and an arabinitol derivative-administered group (streptozotocin + 3 kinds of arabinitol derivative-administered groups). Each group consisted of 9 animals.

200 mg/kg of streptozotocin was intraperitoneally administered to the mice of the streptozotocin-administered group and the streptozotocin + arabinitol derivative-administered group. A high dose of streptozotocin destroys pancreatic cells in mice. As a result, insulin secretion is lost, and mice can develop diabetes. This day was defined as the first day of administration (day 0). The streptozotocin was administered only on the first day of administration.

For the streptozotocin + arabinitol derivative administration group, 1 mg/kg of arabinitol derivative was orally administered daily from day 0.

These groups are respectively referred to as a control group, a streptozotocin administration group, a streptozotocin + 1 mg/kg arabinitol-linoleic acid diester administration group, a streptozotocin + 1 mg/kg arabinitol-linolenic acid diester administration group, and a streptozotocin + 1 mg/kg arabinitol-eicosapentaenoic acid diester administration group. .

(10-2) Cold plate test
A cold plate test was performed to test the effect of arabinitol derivatives on paresthesia in cold stimulation. The 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. It is considered that the shorter the latency, the more avoidance of cold stimulation by the cold plate. The results are shown in FIG.

With reference to FIG. 17, the horizontal axis is the post-administration elapsed time (days), and the vertical axis is the average escape reaction time (seconds) of mice in each group. The white circle solid line is the control group, the black circle dashed line is the streptozotocin administration group, the black square dashed line is the streptozotocin + 1 mg/kg arabinitol-linoleic acid diester administration group, and the black triangle dashed line is streptozotocin + 1 mg/kg arabinitol-linolenic acid. The diester-administered group, and the dotted black diamond line is the streptozotocin + 1 mg/kg arabinitol-eicosapentaenoic acid diester-administered group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to FIG. 17, the streptozotocin-administered group (broken black circle) is considered to have had a shortened withdrawal response time after the administration and developed peripheral neuropathy (peripheral nerve hypersensitivity symptom). On the other hand, in the arabinitol derivative-administered group, the withdrawal reaction time after administration was the same as that of the control, despite the administration of streptozotocin. From this, the arabinitol derivative administration group suppressed diabetes-induced peripheral neuropathy developed by administration of streptozotocin.

(10-3) von Frey test
The five groups of mice shown in (10-1) were placed in cages, and filaments with a strength of 0.16 g were pressed against the soles of their hind limbs to measure the number of avoidance reactions (scores). If the avoidance frequency is large, it is considered that the stimulation by the filament is avoided more. The results are shown in FIG.

With reference to FIG. 18, the horizontal axis is the elapsed time (days) after administration, and the vertical axis is the average avoidance response (score) of mice in each group. The white circle solid line is the control group, the black circle dashed line is the streptozotocin administration group, the black square dashed line is the streptozotocin + 1 mg/kg arabinitol-linoleic acid diester administration group, and the black triangle dashed line is streptozotocin + 1 mg/kg arabinitol-linolenic acid. The diester-administered group, and the dotted black diamond line is the streptozotocin + 1 mg/kg arabinitol-eicosapentaenoic acid diester-administered group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to FIG. 18, in the streptozotocin-administered group (broken black circle), the score (number of avoidance reactions) increased after administration, and it is thought that peripheral neuropathy (peripheral nerve hypersensitivity symptom) developed. On the other hand, in the arabinitol derivative-administered group, the score after administration was almost the same as that of the control, although streptozotocin was administered. From this, it can be said that diabetes-induced peripheral neuropathy developed by administration of streptozotocin was suppressed in the arabinitol derivative administration group.

(Example 11) Therapeutic effect on streptozotocin-induced diabetic mouse peripheral neuropathy It was found that the arabinitol derivative according to the present invention can prevent diabetes-induced peripheral neuropathy caused by streptozotocin. Next, we investigated whether arabinitol derivatives have a therapeutic effect to alleviate peripheral neuropathy after the onset of diabetes-induced peripheral neuropathy.

(11-1) Administration of test substance 6- to 7-week-old C57BL/6J male mice were used. They were divided into 5 groups: a control group, a streptozotocin-administered group, and an arabinitol derivative-administered group (streptozotocin + 3 kinds of arabinitol derivative-administered groups). Each group consisted of 9 animals.

200 mg/kg of streptozotocin was intraperitoneally administered to the mice of the streptozotocin-administered group and the streptozotocin + arabinitol derivative-administered group. A high dose of streptozotocin destroys pancreatic cells in mice. As a result, insulin secretion is lost, and mice can develop diabetes. This day was defined as the first day of administration (day 0). The streptozotocin was administered only on the first day of administration.

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

These groups are respectively referred to as a control group, a streptozotocin administration group, a streptozotocin + 1 mg/kg arabinitol-linoleic acid diester administration group, a streptozotocin + 1 mg/kg arabinitol-linolenic acid diester administration group, and a streptozotocin + 1 mg/kg arabinitol-eicosapentaenoic acid diester administration group. .

(11-2) Cold plate test
The five groups of mice shown in this example (Example 11-1) were tested for the effect of arabinitol derivatives on hypoesthesia due to cold stimulation. Each group of mice was placed on a cold plate set at 4° C., and reaction time (latency) until escape was measured. It is considered that the shorter the latency, the more avoidance of cold stimulation by the cold plate. The results are shown in FIG.

With reference to FIG. 19, the horizontal axis is the post-administration elapsed time (days), and the vertical axis is the average escape reaction time (seconds) of mice in each group. The white circle solid line is the control group, the black circle dashed line is the streptozotocin administration group, the black square dashed line is the streptozotocin + 1 mg/kg arabinitol-linoleic acid diester administration group, and the black triangle dashed line is streptozotocin + 1 mg/kg arabinitol-linolenic acid. The diester-administered group, and the dotted black diamond line is the streptozotocin + 1 mg/kg arabinitol-eicosapentaenoic acid diester-administered group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to FIG. 19, in the four groups administered with streptozotocin other than the control group, the withdrawal reaction time (latency) uniformly decreased by 21 days after administration. It was considered that streptozotocin caused diabetic peripheral neuropathy (peripheral nerve hypersensitivity symptoms). However, for the three groups of streptozotocin + 1 mg/kg arabinitol-linoleic acid diester administration group, streptozotocin + 1 mg/kg arabinitol-linolenic acid diester administration group, and streptozotocin + 1 mg/kg arabinitol-eicosapentaenoic acid diester administration group in which arabinitol derivatives were administered, 21 Latency tended to increase from day 3 onwards, and on day 30, these three groups and the control group had significantly longer withdrawal response times (latencies) than the streptozotocin-administered group.

(11-3) von Frey test
The five groups of mice shown in this example (Example 11-1) were placed in cages, and filaments with a strength of 0.16 g were pressed against the soles of their hind limbs to measure the number of avoidance reactions (scores). The results are shown in FIG.

With reference to FIG. 20, the horizontal axis is the elapsed time (days) after administration, which is the average avoidance response (score) of mice in each group. If the avoidance frequency is large, it is considered that the stimulation by the filament is avoided more. The white circle solid line is the control group, the black circle dashed line is the streptozotocin administration group, the black square dashed line is the streptozotocin + 1 mg/kg arabinitol-linoleic acid diester administration group, and the black triangle dashed line is streptozotocin + 1 mg/kg arabinitol-linolenic acid. The diester-administered group, and the dotted black diamond line is the streptozotocin + 1 mg/kg arabinitol-eicosapentaenoic acid diester-administered group. Those that can be judged to have significant differences from the control group by a test with a significance level of 1% are marked with "*" (indicated as "*P<0.01 vs control group" in the figure).

With reference to FIG. 20, in the streptozotocin-administered group (dotted line with black circles), the score (number of avoidance reactions) increased after administration, and it is believed that peripheral neuropathy (peripheral nerve hypersensitivity) due to diabetes developed. On the other hand, in the arabinitol derivative-administered group, the score after administration decreased despite the administration of streptozotocin, and became almost the same as the control after 30 days. From this, it can be said that diabetes-induced peripheral neuropathy developed by administration of streptozotocin was suppressed in the arabinitol derivative administration group.

The above means that streptozotocin administration improved diabetes-induced peripheral neuropathy (peripheral nerve hypersensitivity symptoms) by taking arabinitol derivatives. Therefore, it was found that the arabinitol derivative also functions as a therapeutic composition (therapeutic agent) for diabetic peripheral neuropathy (peripheral hypersensitivity symptoms).

(Example 12) NK1 Receptor Binding Inhibitory Effect U251 cells (human glioblastoma cell line) were cultured in RPMI1640 medium for 2 days. Then, 1 μM arabinitol-linoleic acid diester, 1 μM arabinitol-linolenic acid diester, 10 μM arabinitol-eicosapentaenoic acid diester were added, stained with substance P-FAM after 1 hour, and stained with substance P-FAM using BD LSRFortessa. The amount of binding was measured.

The results are shown in FIG. In both figures, the horizontal axis represents the binding amount of substance P-FAM, and the vertical axis represents the number of cells (indicated as "Count"). In addition, the solid line in the panel indicates the control containing neither Substance P-FAM nor the compound, the dashed line indicates the addition of 1 μM Substance P-FAM, and the dotted line indicates the addition of 1 μM Substance P-FAM and each compound. The amount of binding of substance P-FAM was remarkably increased in the substance P-FAM addition group compared to the control group to which the compound and substance P-FAM were not added.

Arabinitol - linoleic acid diester administration group (Fig. 21 (a)), arabinitol - linolenic acid diester administration group (Fig. 21 (b)), arabinitol - eicosapentaenoic acid diester administration group (Fig. 21 (c)) Substance P-FAM Compared with the addition group, the substance P-FAM binding amount was remarkably decreased. That is, it was found that arabinitol-linoleic acid diester, arabinitol-linolenic acid diester, and arabinitol-eicosapentaenoic acid diester inhibit binding between substance P and NK1 receptor. Thus, these compounds can be called NK1 receptor inhibitors.

The preventive or ameliorating agent according to the present invention can be used as a selective NK1 receptor inhibitor to ameliorate or prevent peripheral neuropathy. It can also be used to treat peripheral neuropathy. In particular, it should be suitably used for reducing, mitigating or preventing peripheral neuropathy caused by administration of DNA replication inhibitors (platinum agents (oxaliplatin, etc.) and alkylating agents) and peripheral neuropathy concomitant with diabetes. can be done.

Claims (5)

Compounds represented by formulas (1) to (3).

A preventive or ameliorating agent for peripheral neuropathy containing at least one of the compounds represented by the formulas (1) to (3) described in claim 1 as an active ingredient. The preventive or ameliorating agent for peripheral neuropathy according to claim 2, wherein the peripheral neuropathy is peripheral neuropathy caused by taking an anticancer agent. The preventive or ameliorating agent for peripheral neuropathy according to claim 1, wherein the peripheral neuropathy is diabetic peripheral neuropathy. An NK1 receptor inhibitor comprising at least one compound among the compounds represented by formulas (1) to (3) as an active ingredient.

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