Remedies for myalgic encephalomyelitis / chronic fatigue syndrome

Abstract

To provide a therapeutic agent for myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) and fibromyalgia.SOLUTION: A therapeutic agent for a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia, comprising 2-amino-2 - [2 - (4-heptyloxy-3-trifluoromethylphenyl) ethyl] propane-1, 3-diol or pharmaceutically acceptable salts thereof.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a therapeutic agent for myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) and fibromyalgia. [Background technology]

[0002] Myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), also known as chronic fatigue immune deficiency syndrome or SEID (Systemic exertion intolerance disease), is characterized by severe generalized malaise and fatigue, slight fever, swollen lymph nodes, headache, muscle weakness, sleep disorders, and impaired thinking and concentration, all of which significantly impair daily life. The condition persists for long periods of time, even with rest. Despite some form of treatment, a certain number of patients require constant assistance in their daily lives due to symptoms such as debilitating fatigue, weakness, pain in the joints and muscle-tendon tissues throughout the body, and cognitive impairment.

[0003] However, there are currently no drugs approved by authorities in the United States, Europe, or Japan as therapeutic agents, and although there have been academic reports that some selective serotonin reuptake inhibitors (SSRIs), some monoamine oxidase (MAO) inhibitors, and some herbal medicines can alleviate depression and pain symptoms, these have only been shown to be effective in a small number of cases or in a small percentage of patients. Globally, the only drug approved for use in this setting is rintatolimod (Ampligen®), a double-stranded RNA, in Argentina. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] WO2007 / 069712 Summary of the Invention [Problem to be solved by the invention]

[0005] For myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) and fibromyalgia, no satisfactory treatment method has yet been established, and there has been a need for compounds useful for the treatment or therapeutic agents containing the same. The present invention aims to provide a therapeutic agent for myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) and fibromyalgia. [Means for solving the problem]

[0006] As a result of extensive research, the inventors have surprisingly found that 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol (amiselimod) or a pharmaceutically acceptable salt thereof is useful for myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) and fibromyalgia, particularly myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), and have completed the present invention through further research.

[0007] The present invention is as follows. [1] A therapeutic agent for a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) and fibromyalgia, comprising 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol (amiselimod) or a pharmaceutically acceptable salt thereof (e.g., amiselimod hydrochloride). [2] The therapeutic agent according to the above [1], wherein the selected disease is myalgic encephalomyelitis / chronic fatigue syndrome. [3] The therapeutic agent according to the above [1] or [2], wherein the myalgic encephalomyelitis / chronic fatigue syndrome is myalgic encephalomyelitis / chronic fatigue syndrome accompanied by fatigue symptoms. [4] A method for treating a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia, by administering an effective amount of the therapeutic agent according to any one of [1] to [3] above. [5] The method of treatment described in [4] above, wherein the selected disease is myalgic encephalomyelitis / chronic fatigue syndrome. [6] The method for treating myalgic encephalomyelitis / chronic fatigue syndrome described in [4] or [5] above, wherein the myalgic encephalomyelitis / chronic fatigue syndrome is myalgic encephalomyelitis / chronic fatigue syndrome accompanied by fatigue symptoms. [7] Use of the therapeutic agent according to any one of [1] to [3] above for the treatment of a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia. [8] The use according to [7] above, wherein the selected disease is myalgic encephalomyelitis / chronic fatigue syndrome. [9] The use according to [7] or [8] above, wherein the myalgic encephalomyelitis / chronic fatigue syndrome is myalgic encephalomyelitis / chronic fatigue syndrome accompanied by fatigue symptoms.

[10] Use of the therapeutic agent according to any one of the above [1] to [3] for the manufacture of a therapeutic agent for a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia.

[11] The use according to

[10] above, wherein the selected disease is myalgic encephalomyelitis / chronic fatigue syndrome.

[12] The use according to

[10] or

[11] above, wherein the myalgic encephalomyelitis / chronic fatigue syndrome is myalgic encephalomyelitis / chronic fatigue syndrome accompanied by fatigue symptoms.

[0008]

[13] A therapeutic agent for a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia, comprising 1-[[6-[(2-methoxy-4-propylphenyl)methoxy]-1-methyl-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid (ceralifimod), or a pharmaceutically acceptable salt thereof.

[14] A therapeutic agent for a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia, comprising (2S)-3-[4-[5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl]-2-ethyl-6-methylphenoxy]propane-1,2-diol (cenerimod), or a pharmaceutically acceptable salt thereof.

[15] A therapeutic agent for a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia, comprising 2-[(3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl]methoxy]-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]acetic acid (etrasimod), or a pharmaceutically acceptable salt thereof (e.g., etrasimod arginine salt).

[16] A therapeutic agent for a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia, comprising 5-(3-{(1S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-inden-4-yl}-2-isopropoxybenzonitrile (ozanimod), or a pharmaceutically acceptable salt thereof (e.g., ozanimod hydrochloride).

[17] A therapeutic agent for a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia, comprising (2Z,5Z)-5-{3-chloro-4-[(2R)-2,3-dihydroxypropoxy]benzylidene}-3-(2-methylphenyl)-2-(propylimino)-1,3-thiazolidin-4-one (ponesimod) or a pharmaceutically acceptable salt thereof.

[18] A therapeutic agent for a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia, comprising 1-{4-[(1E)-N-{[4-cyclohexyl-3-(trifluoromethyl)benzyl]oxy}ethanimidoyl]-2-ethylbenzyl}-3-azetidinecarboxylic acid (siponimod), or a pharmaceutically acceptable salt thereof (e.g., siponimod fumarate).

[19] The therapeutic agent according to any one of the above

[13] to

[18] , wherein the selected disease is a therapeutic agent for myalgic encephalomyelitis / chronic fatigue syndrome.

[20] The therapeutic agent according to any one of the above

[13] to

[19] , wherein the myalgic encephalomyelitis / chronic fatigue syndrome is chronic fatigue syndrome accompanied by fatigue symptoms.

[21] A method for treating a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia, which comprises administering an effective amount of the therapeutic agent according to any one of

[13] to

[20] above.

[22] The method of treatment described in

[21] above, wherein the selected disease is myalgic encephalomyelitis / chronic fatigue syndrome.

[23] The method for treatment according to

[21] or

[22] above, wherein the chronic fatigue syndrome is myalgic encephalomyelitis / chronic fatigue syndrome accompanied by fatigue symptoms.

[24] Use of the therapeutic agent according to any one of

[13] to

[20] above for the treatment of a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia.

[25] The use according to

[24] above, wherein the selected disease is myalgic encephalomyelitis / chronic fatigue syndrome.

[26] The use according to

[24] or

[25] above, wherein the chronic fatigue syndrome is myalgic encephalomyelitis / chronic fatigue syndrome with fatigue symptoms.

[27] Use of the therapeutic agent according to any one of

[13] to

[20] above for the manufacture of a therapeutic agent for a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) and fibromyalgia.

[28] The use according to

[27] above, wherein the selected disease is myalgic encephalomyelitis / chronic fatigue syndrome.

[29] The use according to

[27] or

[28] above, wherein the chronic fatigue syndrome is myalgic encephalomyelitis / chronic fatigue syndrome with fatigue symptoms. [Effects of the Invention]

[0009] According to the present invention, a novel therapeutic agent for myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) and a novel therapeutic agent for fibromyalgia can be provided. [Brief explanation of the drawings]

[0010] [Figure 1]Figure 1 shows the efficacy of amiselimod hydrochloride on swimming time in a weight-loaded forced swimming test in an animal model (fatigued rats) of myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS). Significant differences were observed between the fatigued control group and the normal control group (in Figure 1, **: p<0.01, Student's t-test). Significant differences were also observed between the 0.1 mg / kg amiselimod hydrochloride group, the 0.3 mg / kg amiselimod hydrochloride group, and the 1 mg / kg amiselimod hydrochloride group and the fatigued control group (in Figure 1, #: p<0.05, ##: p<0.01, Williams' multiple comparison test). DETAILED DESCRIPTION OF THE INVENTION

[0011] Preferred embodiments of the present invention will be described below. Specific examples of the therapeutic agent of the present invention include 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol (amiselimod), 1-[[6-[(2-methoxy-4-propylphenyl)methoxy]-1-methyl-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid (seralifim), (2S)-3-[4-[5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxopentyl]-2-methyl-1-propanol (seroconverter), 1-[[6-[(2-methoxy-4-propylphenyl)methoxy]-1-methyl-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid (seralifim ... [sadiazol-3-yl]-2-ethyl-6-methylphenoxy]propane-1,2-diol (cenerimod), 2-[(3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl]methoxy]-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]acetic acid (etrasimod), 5-(3-{(1S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-inden-4-yl}-2-isopropoxybenzonitrile (ozani a compound selected from (2Z,5Z)-5-{3-chloro-4-[(2R)-2,3-dihydroxypropoxy]benzylidene}-3-(2-methylphenyl)-2-(propylimino)-1,3-thiazolidin-4-one (ponesimod), and 1-{4-[(1E)-N-{[4-cyclohexyl-3-(trifluoromethyl)benzyl]oxy}ethanimidoyl]-2-ethylbenzyl}-3-azetidinecarboxylic acid (siponimod), or a pharmaceutically acceptable salt thereof; (In this specification, they may be collectively referred to as the active ingredient), preferably a therapeutic agent containing 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol (amiselimod) or a pharmaceutically acceptable salt thereof, and particularly preferably a therapeutic agent containing 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol hydrochloride (amiselimod hydrochloride). In one embodiment, the therapeutic agent is preferably a therapeutic agent containing a compound selected from amiselimod hydrochloride, ceralifim, cenelimod, etrasimod arginine salt, ozanimod hydrochloride, ponesimod, and siponimod fumarate, and more preferably a therapeutic agent containing amiselimod hydrochloride.

[0012] In the present invention, the compound or a pharmaceutically acceptable salt thereof used as an active ingredient can be produced, for example, by the production method described below, but may also be produced by any known method. Amiselimod or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in Patent Document 1. Seralifimdo or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in WO2005 / 020882. Senerimod or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in WO2011 / 007324. Etrasimod or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in WO2010 / 011316. Ozanimod or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in WO2011 / 060389. Ponesimod or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in WO2005 / 054215. Siponimod or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in WO2004 / 103306.

[0013] In the present invention, pharmaceutically acceptable salts include inorganic acid salts, organic acid salts, alkali metal salts, alkaline earth metal salts, and the like.

[0014] The therapeutic agent for a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia in the present invention is preferably a therapeutic agent for myalgic encephalomyelitis / chronic fatigue syndrome, and more preferably a therapeutic agent for myalgic encephalomyelitis / chronic fatigue syndrome accompanied by fatigue symptoms.

[0015] In one embodiment, the therapeutic agent for a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia of the present invention can also be used as a preventive agent for a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia. The preventive agent for a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia is preferably a preventive agent for myalgic encephalomyelitis / chronic fatigue syndrome, and more preferably a preventive agent for myalgic encephalomyelitis / chronic fatigue syndrome accompanied by fatigue symptoms.

[0016] In this specification, fatigue symptoms refer to symptoms that have, for example, severe fatigue that significantly impairs daily life as the main symptom, and that persist or recur for at least six months or more (that are observed for 50% or more of the evaluation period used for diagnosis), and preferably refer to symptoms that include the above symptoms, in particular general malaise that lasts for 24 hours or more after light exertion, that is not alleviated by rest or sleep, and that persist or recur for six months or more.

[0017] In the present invention, examples of the "fatigue symptoms" of "myalgic encephalomyelitis / chronic fatigue syndrome accompanied by fatigue symptoms" include fatigue symptoms that satisfy the following (a); preferably fatigue symptoms that satisfy the following (a) and (b); more preferably fatigue symptoms that satisfy the following (a), (b), and (c); and particularly preferably fatigue symptoms that satisfy the following (a), (b), and (c), as well as (d) and / or (e). (a) Significant decline or impairment in function compared with pre-onset occupational, academic, social, or personal activity levels, which has persisted for at least six months and is accompanied by fatigue, is often severe, is clearly symptomatic, is not due to recent excessive exertion, and does not subside with rest (b) Post-exertional fatigue (c) Sleep doesn't restore (d) cognitive impairment (e) Unable to get up or stand

[0018] The therapeutic agent of the present invention may be administered to a patient as an active ingredient itself, but is preferably administered as a preparation in the form of a pharmaceutical composition containing the active ingredient and pharmaceutically acceptable additives.

[0019] Examples of pharmaceutically acceptable additives that can be used include excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, dyes, diluents, bases, solubilizers or solubilization aids, isotonicity agents, pH adjusters, stabilizers, propellants, and adhesives. Examples of formulations suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups, and examples of formulations suitable for parenteral administration include injections, infusions, and suppositories.

[0020] Formulations suitable for oral administration may contain additives such as excipients such as glucose, lactose, D-mannitol, starch, or crystalline cellulose; disintegrants or disintegration aids such as carboxymethylcellulose, starch, or carboxymethylcellulose calcium; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, or gelatin; lubricants such as magnesium stearate or talc; coating agents such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol, or titanium oxide; and bases such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or hard fat. Formulations suitable for injection or infusion may contain formulation additives such as solubilizers or solubilizers that can be used to form aqueous or ready-to-use injections, such as distilled water for injection, physiological saline, or propylene glycol; isotonicity agents such as glucose, sodium chloride, D-mannitol, or glycerin; and pH adjusters such as inorganic acids, organic acids, inorganic bases, or organic bases.

[0021] The route of administration of the therapeutic agent of the present invention is not particularly limited, and it can be administered orally or parenterally (for example, by intravenous, intramuscular, subcutaneous or intradermal injection, infusion, or inhalation), but is preferably administered orally.

[0022] The dosage of the therapeutic agent of the present invention can be appropriately selected depending on various conditions such as the type of disease to be treated, the progress of the disease or the severity of the symptoms, and the age and body weight of the patient. The daily dose of amiselimod for an adult is, for example, 0.05 mg to 1.0 mg, preferably 0.08 mg to 0.7 mg, and more preferably 0.1 mg to 0.4 mg in terms of amiselimod hydrochloride. The daily dose of selalifimod for an adult is, for example, 0.05 to 0.3 mg, preferably 0.05 to 0.15 mg, and more preferably 0.05 mg, 0.10 mg, or 0.15 mg. The daily dose of cenerimod for an adult is, for example, 0.5 to 25 mg, preferably 0.5 to 4 mg, and more preferably 0.5, 1, 2, or 4 mg. The daily dose of etrasimod for an adult is, for example, 1 to 2 mg, preferably 1 mg or 2 mg, as etrasimod arginine salt. The daily dose of ozanimod for an adult is, for example, 0.25 to 2 mg, preferably 0.5 mg or 1 mg, in terms of ozanimod hydrochloride. The daily dose of ponesimod for an adult is, for example, 1 to 75 mg, preferably 10 to 40 mg, and more preferably 10 mg, 20 mg, or 40 mg. The daily dose of siponimod for an adult is, for example, 0.25 mg to 10 mg, preferably 0.25 mg, 0.5 mg, 1.25 mg, 2 mg, or 10 mg, as siponimod fumarate.

[0023] The number of times the therapeutic agent of the present invention is administered per day can be selected to be increased or decreased as appropriate based on the daily dose, depending on various conditions such as the type of disease to be treated, the progress of the disease or the severity of symptoms, and the age and weight of the patient. Generally, for adults, the administration is, for example, once a day, twice a day, or three times a day, and preferably once a day.

[0024] The therapeutic agent for myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) of the present invention contains an active ingredient, and can be further combined with a known therapeutic agent for myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) to be used in combination or as a combination drug. Known therapeutic agents for myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) include, for example, pregabalin, mirogabalin, tramadol, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, loxoprofen, ibuprofen, celecoxib, etc.), monoamine oxidase (MAO) inhibitors (e.g., selegiline, rasagiline, safinamide, isoniazid, etc.), serotonin selective reuptake inhibitors (SSRIs) (e.g., fluvoxamine, paroxetine, sertraline, estacillopram, etc.), serotonin- Examples include norepinephrine selective reuptake inhibitors (SNRIs) (e.g., milnacipran, duloxetine, etc.), noradrenergic / specific serotonergic antidepressants (NaSSAs) (e.g., mirtazapine, etc.), benzodiazepine hypnotics (e.g., etizolam, etc.), non-benzodiazepine hypnotics (e.g., zolpidem, zopiclone, etc.), clomipramine, extract of inflamed skin of vaccinia virus-inoculated rabbits (e.g., Neurotropin, etc.), Chinese herbal medicines (e.g., Hochuekkito, Juzentaihoto, etc.), and Ampligen (registered trademark). [Example]

[0025] The present invention will be explained in more detail with reference to the following examples, but the present invention is not limited to these examples.

[0026] Example 1: Efficacy in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS) Animal Model

[0027] The ameliorative effect of the administration of the compound of the present invention (amiselimod hydrochloride) on myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) was investigated using a water-immersion stressed rat (fatigue rat) model according to the method of Tanaka et al. (Establishment and assessment of a rat model of fatigue. Neuroscience Letters 2003, 352: 159-162) as follows. Nine-week-old Slc:SD rats were used. They were housed in plastic cages (W: 445 × D: 276 × H: 204 mm) filled with tap water (water temperature: 23 ± 1°C) to a height of 1.5 cm for 6 days (water immersion). On the final day, a weight-loaded forced swimming test was performed. For the weight-loaded forced swimming test, rats with a weight equivalent to 8% of their body weight attached to their tails were placed in a circular tank (diameter: 18 cm, height: 70 cm, water depth: 40 cm, water temperature: 23 ± 1°C). The time from the start of swimming until the rat's nose was submerged below the water surface was measured for 20 seconds. The weight-loaded forced swimming test was performed blind. Amiselimod hydrochloride was orally administered at doses of 0.1, 0.3, and 1 mg / kg once daily for 6 days, starting from the day water immersion rearing began. A normal control group, reared under normal conditions, and a fatigue control group, reared under water immersion, were set up as control groups, and both groups were administered the vehicle (0.5% HPMC). There were 10 animals in each group. As a result, the fatigue control group showed a significantly shorter swimming time than the normal control group. Administration of 0.1, 0.3, and 1 mg / kg of amiselimod hydrochloride significantly prolonged the swimming time compared to the fatigue control group (Figure 1).

[0028] Example 2: Method for creating and evaluating a fibromyalgia (FM (Fibromyalgia)) model FM is a chronic, intractable disease whose main symptom is systemic pain. It has been reported to occur very frequently together with ME / CFS, and the two share many commonalities, such as similar symptoms and the activation of microglia in the spinal cord and brain (Fibromyalgia Treatment Guidelines 2017, Japan Fibromyalgia Society). Several non-clinical FM models have been reported, including (1) stress-induced, (2) drug-induced, and (3) nerve injury-induced models. Examples of (1) include forced swimming stress (Suarez-Roca, H., Quintero, L., Arcaya, JL, Maixner, W., Rao, S.G., Stress-induced muscle and cutaneous hyperalgesia: differential effect of milnacipran, Physiol. Behav., 88 (2006) 82-87), chronic restraint stress (Bardin, L., Malfetes, N., Newman-Tancredi, A., Depoortere, R., Chronic restraint stress induces mechanical and cold allodynia and enhances inflammatory pain in rats: Relevance to human stress-associated painful pathologies, Behav. Brain Res., 205 (2009) 360-366), and repeated cold stress (Nasu, T., Taguchi, T., Mizumura, K., Persistent deep mechanical hyperalgesia induced by repeated cold stress in rats, Eur. J. Pain, 14 (2010) 236-244; and Nishiyori, M., Ueda, H., Prolonged gabapentin analgesia in an experimental mouse model of fibromyalgia, Mol. Pain, 4 (2008) 52), combined sustained stress (Yasui, M., Yoshimura, T., Takeuchi, S., Tokizane, K., Tsuda, M., Inoue, K., Kiyama, H.A chronic fatigue syndrome model demonstrates mechanical allodynia and muscular hyperalgesia via spinal microglial activation, Glia, 62 (2014) 1407-1417), sound stress (Khasar, SG, Dina, OA, Green, PG, Levine, JD, Sound stress-induced long-term enhancement of mechanical hyperalgesia in rats is maintained by sympathoadrenal catecholamines, J. Pain, 10 (2009) 1073-1077), and maternal separation stress (Green, PG, Chen, X., Alvarez, P., Ferrari, LF, Levine, JD, Early-life stress produces muscle hyperalgesia and nociceptor sensitization in the adult rat, Pain, 152 (2011) 2549-2556). As an example of (2), the biogenic amine depletor reserpine can be administered subcutaneously (Green, PG, Chen, X., Alvarez, P., Ferrari, LF, Levine, JD, Early-life stress produces muscle hyperalgesia and nociceptor sensitization in the adult rat, Pain, 152 (2011) 2549-2556), or acidic saline (pH 4) can be administered to the gastrocnemius muscle. As an example of (3), the vagus nerve can be cut below the diaphragm. Both of these methods have been reported to result in phenotypes including a decrease in pain threshold. This paper describes the method for creating and evaluating the FM model using reserpine, a commonly used method. Reserpine was prepared to a final concentration of 0.5% acetic acid and administered subcutaneously to the dorsum of SD rats at a dose of 1 mg / kg once daily for three days. To evaluate the pain threshold for mechanical stimuli, a von Frey test was performed in which a von Frey filament was pressed perpendicularly against the plantar surface of the foot to measure the mechanical threshold for foot lift. To evaluate the pain threshold for pressure stimuli, a Randall-Selitto test was performed in which pressure was applied to the rat's hind paw at a constant rate and the withdrawal threshold was measured. Amiselimod hydrochloride was prepared in a vehicle such as 0.5% HPMC and orally administered simultaneously with reserpine administration or starting 5 days after the final reserpine administration. The preventive and therapeutic effects on pain threshold reduction were confirmed using the above evaluations. [Industrial Applicability]

[0029] A therapeutic agent comprising 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof according to the present invention is useful as a therapeutic agent for myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) and the like.

[0030] This application is based on patent application No. 2020-019153 filed in Japan, the contents of which are incorporated in full herein.

Claims

1. A therapeutic agent for a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia, comprising 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propane-1,3-diol or a pharmaceutically acceptable salt thereof.

2. The therapeutic agent according to claim 1, wherein the selected disease is myalgic encephalomyelitis / chronic fatigue syndrome.

3. The therapeutic agent according to claim 1 or 2, wherein the myalgic encephalomyelitis / chronic fatigue syndrome is myalgic encephalomyelitis / chronic fatigue syndrome accompanied by fatigue symptoms.

4. A method for treating a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia, by administering an effective amount of the therapeutic agent according to any one of claims 1 to 3.

5. 5. The method of claim 4, wherein the selected disease is myalgic encephalomyelitis / chronic fatigue syndrome.

6. The method for treatment according to claim 4 or 5, wherein the myalgic encephalomyelitis / chronic fatigue syndrome is myalgic encephalomyelitis / chronic fatigue syndrome accompanied by fatigue symptoms.

7. Use of the therapeutic agent according to any one of claims 1 to 3 for the treatment of a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia.

8. 8. The use according to claim 7, wherein the selected disease is myalgic encephalomyelitis / chronic fatigue syndrome.

9. The use according to claim 7 or 8, wherein the myalgic encephalomyelitis / chronic fatigue syndrome is myalgic encephalomyelitis / chronic fatigue syndrome accompanied by fatigue symptoms.

10. Use of the therapeutic agent according to any one of claims 1 to 3 for the manufacture of a therapeutic agent for a disease selected from myalgic encephalomyelitis / chronic fatigue syndrome and fibromyalgia.

11. The use according to claim 10, wherein the selected disease is myalgic encephalomyelitis / chronic fatigue syndrome.

12. The use according to claim 10 or 11, wherein the myalgic encephalomyelitis / chronic fatigue syndrome is myalgic encephalomyelitis / chronic fatigue syndrome accompanied by fatigue symptoms.

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