Analgesic agent

Abstract

The present invention provides a novel analgesic agent. The analgesic agent contains a heterocyclic compound represented by formula (I) or a salt thereof as an active ingredient (in the formula, ring A is a 5- to 7-membered heterocycle containing one or two heteroatoms selected from among a nitrogen atom, an optionally oxidized sulfur atom, and an oxygen atom; R1, R2, R3, and R4 are each independently a hydrogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a halogen atom, an amino group, -SH, a C1-6 alkylthio group, a C2-6 alkenylthio group, a C1-6 alkyl-carbonyl group, a formyl group, a C6-10 aryl group, a C1-6 alkoxycarbonyl group, a 5- or 6-membered heteroaryl group, or an oxo group; R1 and R2 may be bonded to each other to form an optionally substituted 5- or 6-membered ring; and n is 0, 1, or 2).

Description

painkillers

[0001] The present invention relates to a novel analgesic drug.

[0002] Although many analgesics have been developed to date, many conditions, such as pain after spinal cord injury, trigeminal autonomic headache, chemotherapy-induced peripheral neuropathy, fibromyalgia, treatment-resistant pain associated with terminal cancer, and chronic postoperative pain, are classified as neuropathic or centralized pain, and pathological mechanisms such as sensitization, abnormal neuroplasticity, and neurogenesis are involved. For these pain disorders, existing analgesics, such as NSAIDs, opioids, and gabapentinoids, are insufficiently effective. Furthermore, the lack of effective biomarkers makes diagnosis and objective evaluation of treatment efficacy difficult. Therefore, there is a strong need for the development of new analgesics with different mechanisms of action for these intractable pain conditions.

[0003] Analgesics currently used in medical practice are classified into several categories based on their mechanism of action and target. Representative analgesics with anti-inflammatory properties, such as nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, and cyclooxygenase (COX) inhibitors, are particularly effective against inflammatory pain, such as arthritis, sprains, muscle pain, rheumatoid arthritis, and bacterial infections, by suppressing the production of inflammatory cytokines and prostaglandins. NSAIDs, in particular, inhibit COX-1 and COX-2, thereby suppressing the production of prostaglandin E2 (PGE2) and suppressing the sensitization of pain receptors in peripheral nerves. However, analgesics based on anti-inflammatory properties have limited effectiveness against non-inflammatory conditions, such as neuropathic pain and cancer pain.

[0004] On the other hand, there are many analgesics that exert their analgesic effects not through anti-inflammatory effects, but through intervention in the mechanisms involved in the perception of pain, transmission to the brain, or the perception of pain in the brain. Opioid analgesics exert strong analgesia centrally via μ-opioid receptors, but they have serious side effects such as respiratory depression, constipation, tolerance, dependence, and even the risk of abuse, which have become a social problem in Europe and the United States as the "opioid crisis." Pregabalin and gabapentin are Ca 2+ Although channel-blocking drugs are effective in treating neuropathic pain, they often have side effects such as drowsiness, dizziness, and memory impairment. They are also associated with increased risk of falls in elderly patients, and recent reports of dependency and abuse have been increasing. While cannabinoid drugs (e.g., THC, CBD) are used in some settings, their psychoactive effects, legal restrictions, and unclear mechanisms of action limit their use as general-purpose analgesics. Furthermore, antidepressants such as SNRIs and TCAs activate the descending pain inhibitory system and demonstrate some efficacy in treating chronic pain, but their tolerability is limited by side effects such as dry mouth, constipation, sexual dysfunction, weight gain, and insomnia. The NMDA receptor antagonist ketamine also suppresses central sensitization and is used for intractable pain, but caution is advised due to concerns about dependency and psychiatric symptoms such as hallucinations and dissociation.

[0005] Thus, while existing analgesics each demonstrate a certain degree of effectiveness, they have limitations such as safety, tolerability, dependency, and a narrow range of indications. Therefore, there is a strong need for the development of safer and more effective analgesics with new mechanisms of action that differ from conventional ones.

[0006] Transient Receptor Potential Ankyrin 1 (TRPA1) is known to be stimulated by external and internal invasive substances, inducing pain sensation and inflammation. The molecular mechanism has been elucidated in detail, as outlined below. Invasive substances that bind to TRPA1 include exogenous substances such as allylic isothiocyanate (AITC) and formaldehyde, as well as endogenous substances such as 4-hydroxynonenal (4-HNE), bradykinin, and prostaglandins, which are released from cells damaged by trauma or inflammation. TRPA1 is a nonselective cation channel, and when activated by an agonist, calcium ions enter the cell. This influx results in the activation of calcium-calmodulin-dependent protein kinase (CaMKII) and protein kinase C (PKC). The increase in intracellular calcium ions and activation of calcium-dependent kinases promote the synthesis of calcitonin gene-related peptide (CGRP) and substance P in neurons and their secretion from synapses. This results in pain sensation, enhanced inflammatory responses, and vasodilation. Therefore, antagonists that suppress the activation of TRPA1 in response to noxious stimuli are considered to be candidates for drugs with anti-inflammatory and analgesic effects (Non-patent Document 1).

[0007] International Publication No. 2019 / 177142 International Publication No. 2021 / 193835 International Publication No. 2022 / 030436

[0008] Koivisto, A et al., Basic Clin Pharmacol Toxico. 114(1), 50-55 (2014)Matsuo, T et al., bioRxiv. doi:https: / / doi.org / 10.1101 / 2020.05.17.100933 (2020)Matsuo, T et al., Commun Biol. 4(1), 101 (2021)Nishi, M et al., ESC Heart Fail. 9(1), 428-441 (2022)Onoe, A et al., Shock. 58(4), 341-347 (2022)Matsuo et al., Nat Commun. 12(1), 2074 (2021)

[0009] Contrary to the conventional theory that TRPA1 agonists are stimuli that induce inflammation and pain, and that TRPA1 antagonists are potential therapeutic agents that induce analgesia and anti-inflammatory effects, the inventors have discovered that several types of thiazoline-related fear odors (TFOs), which act as agonists in the sense that they can bind to TRPA1 and generate sensory information, transmit sensory information to the solitary nucleus-parabrachial nucleus pathway in the brainstem, thereby integrating and inducing protective effects such as hypothermia, hypometabolism, hypoxia resistance, resistance to ischemia-reperfusion injury, and improvement of organ ischemia, in addition to anti-inflammatory effects (Patent Documents 1-3, Non-Patent Documents 2-5). The inventors have clarified that this protective effect is not induced by the so-called agonist properties of binding to TRPA1 and generating ionic currents, but is induced by its ability to generate sensory information by increasing the expression of appropriate genes such as c-fos, which is known as a neural activity marker, in neurons of the trigeminal and vagus ganglia that express TRPA1 and in the brainstem pathways to which these neurons project (Non-Patent Document 6).

[0010] For example, AITC and cinnamaldehyde (CNA), which are known as conventional TRPA1 agonists, induce TRPA1-mediated ionic currents but fail to induce c-fos expression in TRPA1-positive neurons in the trigeminal and vagus nerves. In contrast, TFOs such as 2-Methyl-2-thiazoline (2MT), 4-Ethyl-2-methyl-2-thiazoline (4E2MT), and 5-Methyl-2-thiazoline (5MT) not only induce TRPA1-mediated ionic currents but also act as agonists by inducing c-fos expression in TRPA1-positive neurons in the trigeminal and vagus nerves. Although all of these ligands possess TRPA1 agonist properties, AITC and CNA promote inflammation via TRPA1, whereas TFOs such as 2MT, 4E2MT, and 5MT also suppress inflammation via TRPA1, thus inducing the opposite physiological responses.

[0011] The activity of ligands that bind to TRPA1 has generally been measured by their ability to induce ionic currents, using techniques such as patch clamp analysis and calcium imaging. TRPA1 agonists are thought to induce pain, while TRPA1 antagonists are thought to have analgesic effects. However, as shown above, some TRPA1 agonists induce both inflammatory and anti-inflammatory effects, suggesting that this model is not necessarily valid. The physiological effects of ligands that interact with TRPA1 cannot be classified as agonists or antagonists; they are thought to be diverse depending on the nature of the ligand. Although several TRPA1 antagonists have been developed as analgesics, none have proven effective as analgesics to date. The criteria for TRPA1 antagonists may not be sufficient to achieve effective analgesics in humans. To overcome this issue and develop effective analgesics, it is necessary to develop appropriate ligands that induce analgesic effects via TRPA1.

[0012] An object of the present invention is to provide a novel analgesic drug.

[0013] Based on this background, the inventors conducted behavioral pharmacological analyses using mice to verify the analgesic effects of TFO. As a result, it was confirmed that TFO exhibited significant analgesic effects in multiple pain models, including the formalin test, capsaicin test, hot plate test, and neuropathic pain model.

[0014] When AITC is injected into the sole of a mouse's foot, it causes pain and induces paw licking. The activity of candidate analgesic compounds is measured by their ability to reduce paw licking. The specificity of TRPA1 responses to ligands is known to differ between humans and mice. Therefore, animal experiments alone are insufficient to identify desirable candidates for human analgesics. Furthermore, as discussed above, it is difficult to evaluate pharmacological effects solely through in vitro measurements of human TRPA1 agonist or antagonist activity. AITC is the pungent component of wasabi and mustard, and its volatile odor molecules bind to TRPA1 in the trigeminal nerve in the oral cavity and nose, inducing a sharp pain sensation in humans. Odor molecules that suppress this pain sensation could be potential analgesic candidates. Using this and other experimental systems, our technology has successfully developed several molecules that exert potent analgesic effects in humans, utilizing TRPA1 agonists, previously thought to be a potential pain stimulus.

[0015] Using this technology, we have successfully developed several molecules that exert potent analgesic effects by utilizing TRPA1 agonist TFOs, which have previously been thought to be a potential pain stimulus, in human and mouse experimental systems. These molecules selectively regulate the transmission of sensory information via TRPA1, and exhibit effective analgesic effects against a variety of pains while avoiding the side effects and dependency seen in existing analgesics. As analgesics based on a new mechanism, they have extremely high clinical and practical value. The molecules developed here can be used as analgesics by inhaling them as vaporized gases, by injection into the skin or intravenously, or by oral or transdermal administration.

[0016] That is, the present invention relates to the following: [1] Formula (I)

[0017]

[0018] wherein ring A is a 5- to 7-membered heterocycle containing 1 or 2 heteroatoms selected from a nitrogen atom, an optionally oxidized sulfur atom, and an oxygen atom; R １ , R ２ , R ３ , and R ４ are each independently a hydrogen atom, C １－６ Alkyl group, C １－６ Alkoxy group, halogen atom, amino group, —SH, C １－６ Alkylthio group, C ２－６ Alkenylthio group, C １－６ Alkyl-carbonyl group, formyl group, C ６－１０ Aryl group, C １－６ an alkoxycarbonyl group, a 5- or 6-membered heteroaryl group, or an oxo group; R １ and R ２may be bonded to each other to form an optionally substituted 5- or 6-membered ring; and n is 0, 1, or 2), or a salt thereof, as an active ingredient. [2] The analgesic according to [1], wherein ring A is thiazoline, thiazole, thiazolidine, thiomorpholine, thiophene, pyrrole, morpholine, azepane, pyridine, pyrazine, furan, 2,3-dihydro-4H-1,4-thiazine, or imidazole. [3] The analgesic according to [1] or [2], which is for nasal administration. [4] Use of the heterocyclic compound represented by formula (I) or a salt thereof for producing an analgesic. [5] The use according to [4], wherein ring A is thiazoline, thiazole, thiazolidine, thiomorpholine, thiophene, pyrrole, morpholine, azepane, pyridine, pyrazine, furan, 2,3-dihydro-4H-1,4-thiazine, or imidazole. [6] The use according to [4] or [5], wherein the analgesic is for nasal administration. [7] A method for preventing or treating pain in a mammal, comprising administering to the mammal an effective amount of a heterocyclic compound represented by formula (I) or a salt thereof. [8] The method according to [7], wherein ring A is thiazoline, thiazole, thiazolidine, thiomorpholine, thiophene, pyrrole, morpholine, azepane, pyridine, pyrazine, furan, 2,3-dihydro-4H-1,4-thiazine, or imidazole. [9] The method according to [7] or [8], wherein the heterocyclic compound or a salt thereof is nasally administered.

[10] A heterocyclic compound represented by formula (I) or a salt thereof for use in the prevention or treatment of pain.

[11] A heterocyclic compound represented by formula (I) or a salt thereof for use according to

[10] , wherein ring A is thiazoline, thiazole, thiazolidine, thiomorpholine, thiophene, pyrrole, morpholine, azepane, pyridine, pyrazine, furan, 2,3-dihydro-4H-1,4-thiazine, or imidazole.

[12] A heterocyclic compound represented by formula (I) or a salt thereof for use according to

[10] or

[11] , wherein the heterocyclic compound is for nasal administration.

[13] The analgesic according to any one of [1] to [3], for use in the prevention or treatment of neuropathic pain.

[14] The use according to any one of [4] to [6], wherein the analgesic is for use in the prevention or treatment of neuropathic pain.

[15] The method according to any one of [7] to [9], wherein the pain is neuropathic pain.

[16] The heterocyclic compound represented by formula (I) or a salt thereof for use according to any one of

[10] to

[12] , wherein the pain is neuropathic pain.

[0019] According to the present invention, there is provided a compound that acts directly on TRPA1 or other receptors that detect noxious stimuli to suppress the generation of pain sensation, or that suppresses the recognition of pain sensation by transmitting sensory information to the brain. The analgesic of the present invention can be used as an agent for the prevention or treatment of pain.

[0020] 1 shows the results of an experiment evaluating the analgesic effect of TFO on a formalin-induced pain model. 2 shows the results of an experiment evaluating the analgesic effect of TFO on a capsaicin-induced pain model. 3 shows the results of an experiment evaluating the ability of TFO to induce an analgesic effect independent of opioid receptors. 4 shows the results of an experiment evaluating the ability of TFO to induce an analgesic effect independent of CB1 receptors. 5 shows the results of an experiment evaluating the inhibitory effect of TFO on sensory transmission at the spinal cord level using c-fos mapping. 6 shows the results of an experiment evaluating the allodynia-suppressing effect of TFO on a neuropathic pain model. 7 shows the results of an experiment evaluating the centrally mediated analgesic effect of TFO. 8 shows the results of an experiment evaluating the analgesic effect of TFO on acute pain induced by thermal stimulation. 9 shows the chemical structures of the test substances used in Example 8. 10 shows the results of a human sensory test evaluating the intensity of pain induced by AITC in the presence of TFO (2-methyl-2-thiazoline (2MT), thiomorpholine (TMO)).

[0021] Ring A in formula (I) represents a 5- to 7-membered heterocycle containing one or two heteroatoms selected from a nitrogen atom, an optionally oxidized sulfur atom, and an oxygen atom. Ring A is preferably a 5- to 7-membered heterocycle containing one or two heteroatoms selected from a nitrogen atom and an optionally oxidized sulfur atom. Ring A is more preferably a 5- to 7-membered heterocycle containing a nitrogen atom and an optionally oxidized sulfur atom. The number of members in ring A is more preferably 5 or 6.

[0022] Examples of the heterocycle include, but are not limited to, pyrrole, pyridine, pyridazine, pyrimidine, pyrazine, piperazine, pyrrolidine, hexahydropyridazine, imidazole, imidazolidine, piperidine, thiophene, thiolane, tetrahydro-2H-thiopyran, thiazoline (e.g., 2-thiazoline, 3-thiazoline, 4-thiazoline), thiazole, thiazolidine, isothiazole, isothiazoline, thiomorpholine, thiadiazoline, thiadiazole, thiadiazolidine, 1,3-thiazinane, 5,6-dihydro-4H-1,3-thiazine, 2,3-dihydro-4H-1,4-thiazine, furan, 2H-pyran, 4H-pyran, oxazole, isoxazole, morpholine, oxazoline, and azepane. Preferably, it is thiazoline (e.g., 2-thiazoline, 3-thiazoline, 4-thiazoline), thiazole, thiazolidine, thiomorpholine, thiophene, pyrrole, morpholine, azepane, pyridine, pyrazine, furan, 2,3-dihydro-4H-1,4-thiazine, or imidazole, more preferably thiazoline (e.g., 2-thiazoline), thiazole, thiazolidine, thiomorpholine, thiophene, pyrrole, pyridine, pyrazine, or 2,3-dihydro-4H-1,4-thiazine, even more preferably thiazoline (e.g., 2-thiazoline), thiazole, thiazolidine, thiomorpholine, thiophene, pyrrole, pyridine, or pyrazine, and particularly preferably thiazoline (e.g., 2-thiazoline) or thiomorpholine.

[0023] The "halogen atom" used herein is preferably selected from a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0024] As used here, "C １－６ "Alkyl group" (when used as a group or part of a group) means a straight or branched chain alkyl group having from 1 to 6 carbon atoms. １－６Examples of the alkyl group include, but are not limited to, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a 1-methylpropyl group (sec-butyl group), a 2-methylpropyl group (isobutyl group), a tert-butyl group, a pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a 1-ethylpropyl group, a hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, and a 1-ethyl-2-methylpropyl group. １－６ Examples of the alkyl group include C １－４ Examples include alkyl groups (straight-chain or branched-chain alkyl groups having 1 to 4 carbon atoms), with methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and sec-butyl groups being more preferred, and methyl groups being particularly preferred.

[0025] As used here, "C １－６ "Haloalkyl group" means a C alkyl group substituted with 1 to 5 halogen groups. １－６ It means an alkyl group, and when there are two or more halogeno groups, the types of the halogeno groups may be the same or different. Examples of the halogeno group include a fluoro group, a chloro group, and a bromo group. １－６Examples of haloalkyl groups include, but are not limited to, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chlorodifluoromethyl group, a 1-fluoroethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 1,1-difluoroethyl group, a 1,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a 1,1,2,2-tetrafluoroethyl group, a 1,1,2,2,2-pentafluoroethyl group, a 1-fluoropropyl group, a 1,1-difluoropropyl group, a 2,2-difluoropropyl group, a 3-fluoropropyl group, a 3,3,3-trifluoropropyl group, a 4-fluorobutyl group, a 4,4,4-trifluorobutyl group, a 5-fluoropentyl group, a 5,5,5-trifluoropentyl group, a 6-fluorohexyl group, and a 6,6,6-trifluorohexyl group.

[0026] As used here, "C ２－６ "Alkenyl group" (when used as a group or part of a group) means a straight or branched chain alkenyl group having from 2 to 6 carbon atoms. ２－６ Alkenyl groups include, but are not limited to, vinyl, allyl, prop-1-enyl, but-1-en-1-yl, but-2-en-1-yl, pent-4-en-1-yl, 2-methylallyl and the like.

[0027] As used here, "C １－６ "Alkoxy group" (when used as a group or part of a group) means a straight or branched chain alkoxy group having 1 to 6 carbon atoms. １－６ Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 2,2-dimethylpropoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, and hexyloxy groups.

[0028] As used here, "C １－６ The alkylthio group is C１－６ It means an —SH group substituted with an alkyl group. １－６ Examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio, and butylthio groups.

[0029] As used here, "C ２－６ The "alkenylthio group" is C ２－６ It means an alkenyl-substituted —SH group. ２－６ Examples of alkenylthio groups include, but are not limited to, vinylthio, allylthio, prop-1-enylthio, but-1-en-1-ylthio, but-2-en-1-ylthio, pent-4-en-1-ylthio, and 2-methylallylthio groups.

[0030] As used here, "C １－６ The "alkyl-carbonyl group" is C １－６ It means a carbonyl group to which an alkyl group is bonded. １－６ Examples of alkyl-carbonyl groups include, but are not limited to, acetyl, propionyl, butyryl, isobutyryl, valeryl, and hexanoyl groups.

[0031] As used here, "C １－６ The "alkoxycarbonyl group" is C １－６ It means a carbonyl group to which an alkoxy group is bonded. １－６ Examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, and butoxycarbonyl groups.

[0032] As used here, "C ６－１０ "Aryl group" means an aromatic hydrocarbon group having 6 to 10 carbon atoms. ６－１０ Examples of aryl groups include, but are not limited to, phenyl groups, naphthyl groups (1-naphthyl groups, 2-naphthyl groups), and the like.

[0033] The term "5- or 6-membered heteroaryl group" as used herein refers to a 5- or 6-membered heteroaryl group containing at least one (preferably 1 to 3, more preferably 1 or 2) heteroatom selected from a nitrogen atom, an optionally oxidized sulfur atom, and an oxygen atom. As the 5- or 6-membered heteroaryl group, a 5- or 6-membered heteroaryl group containing 1 or 2 heteroatoms selected from a nitrogen atom and an optionally oxidized sulfur atom is preferred.

[0034] Examples of 5- or 6-membered heteroaryl groups include, but are not limited to, pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, furyl, oxazolyl, and isoxazolyl groups. Preferred are pyridyl and thienyl groups.

[0035] As used herein, the term "oxo" (when used as a group or part of a group) refers to the group =0.

[0036] As used herein, an "optionally oxidized sulfur atom" refers to S, SO, or SO ２ means.

[0037] R １ and R ２ are bonded to each other to form an "optionally substituted 5- or 6-membered ring", the "5- or 6-membered ring" means a 5- or 6-membered ring which may contain at least one heteroatom (preferably 1 to 3, more preferably 1 or 2) selected from a nitrogen atom, an optionally oxidized sulfur atom, and an oxygen atom. Examples of the 5- or 6-membered ring include a benzene ring and a tetrahydropyrimidine ring. The 5- or 6-membered ring may be substituted, and examples of the substituent include, for example, C １－６ Alkyl group, halogen atom, amino group, -SH, C １－６ Alkylthio group, C ２－６ Alkenylthio group, C １－６ Alkyl-carbonyl group, formyl group, C １－６ The substituents include 1 to 4 (preferably 1 or 2) selected from an alkoxycarbonyl group, an oxo group, etc.１－６ There are 1 to 4 substituents selected from alkyl groups (e.g., methyl) and oxo groups.

[0038] In formula (I), preferably, R １ , R ２ , R ３ , and R ４ are each independently a hydrogen atom, C １－６ Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl), C １－６ Alkoxy group (e.g., methoxy, ethoxy), halogen atom (e.g., chlorine atom), amino group, —SH, C １－６ Alkylthio group (e.g., methylthio), C ２－６ Alkenylthio group (e.g., allylthio), C １－６ Alkyl-carbonyl group (e.g., acetyl), formyl group, C ６－１０ an aryl group (e.g., phenyl), a 5- or 6-membered heteroaryl group (e.g., thienyl), or an oxo group; R １ and R ２ may be bonded to each other to form an optionally substituted 5- or 6-membered ring (e.g., a benzene ring, a tetrahydropyrimidine ring).

[0039] In formula (I), when n=1 or 2, R １ , R ２ , R ３ , and R ４ In formula (I), when n=0, at least one of R １ , R ２ , and R ３ It is preferred that at least one of these is not a hydrogen atom.

[0040] In the present invention, examples of the heterocyclic compound of formula (I) suitable for use as an active ingredient include, but are not limited to, the following compounds: 2-Methyl-2-thiazoline (2MT) Thiomorpholine (TMO) 2-Acetylthiophene 2,5-Dimethylpyrrole 2-Ethylpyrrole 2-Chlorothiazole 4-Methylthiazole 2,3-Diethylpyrazine 2-Ethoxythiazole 2-(Methylthio)-2-thiazoline Thiomorpholine 1,1-dioxide 2,4,5-Trimethylthiazole 2-Acetyl-3,5-dimethylpyrazine 2-Methylthiazole Thiomorpholine 2-Methylthiomorpholine 2,6-Dimethylpyrazine 2-Amino-2-thiazoline 2,6-Dimethylpyridine 2-Aminothiazole 5-Acetyl-2,4-dimethylthiazole 2-Isobutylthiazole 2-Ethyl-3-(methylthio)pyrazine 2-Acetylpyrrole 4-Ethyl-2-methyl-2-thiazoline 2,4-Dimethylpyrrol 2-Ethyl-3,5-dimethylpyrazine 2-Ethyl-3,6-dimethylpyrazine 2-Ethyl-3,5(6)-dimethylpyrazine (mixture of 2-ethyl-3,5-dimethylpyrazine and 2-ethyl-3,6-dimethylpyrazine) 2,2-Dimethylthiazolidine 2-Acetyl-3-ethylpyrazine

[0041] The heterocyclic compound of formula (I) used as an active ingredient in the present invention includes substances generally known as reagents, and commercially available products are available, or they can be obtained by methods known per se. The use of the heterocyclic compound of formula (I) as an analgesic (a drug for preventing or treating pain) has not been disclosed or suggested up to now.

[0042] Preferred examples of the heterocyclic compound represented by formula (I) include compounds represented by the following formulae (A) to (D) or salts thereof.

[0043]

[0044] (In the formula, X １ is S, O, or N(R １６ ) and X ２ is N or CR １２ and X ３ is S, SO２ , O, or -(CH ２ ) ２ - and X ４ is N or CR １５ and

[0045]

[0046] represents a single bond or a double bond; R １１ , R １２ , R １３ , R １４ , R １５ , and R １６ are each independently a hydrogen atom, C １－６ Alkyl group, C １－６ Alkoxy group, halogen atom, amino group, —SH, C １－６ Alkylthio group, C ２－６ Alkenylthio group, C １－６ Alkyl-carbonyl group, formyl group, C ６－１０ Aryl group, C １－６ an alkoxycarbonyl group, a 5- or 6-membered heteroaryl group, or an oxo group; R １３ and R １４ are bonded to each other to form a benzene ring, or C １－６ may form a tetrahydropyrimidine ring optionally substituted with 1 to 4 substituents selected from an alkyl group and an oxo group; provided that in formula (A), R １１ and R １２ is not an oxo group;

[0047]

[0048] represents a double bond, R １３ and R １４ is not an oxo group; １１ , R １２ , R １３ , R １４ , and R １５ is not an oxo group, and in formula (B), R １１ and R １２ may combine to form an oxo group)

[0049] In formulas (A) to (D), preferably, R１１ , R １２ , R １３ , R １４ , R １５ , and R １６ are each independently a hydrogen atom, C １－６ Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl), C １－６ Alkoxy group (e.g., methoxy, ethoxy), halogen atom (e.g., chlorine atom), amino group, —SH, C １－６ Alkylthio group (e.g., methylthio), C ２－６ Alkenylthio group (e.g., allylthio), C １－６ Alkyl-carbonyl group (e.g., acetyl), formyl group, C ６－１０ an aryl group (e.g., phenyl), a 5- or 6-membered heteroaryl group (e.g., thienyl), or an oxo group; R １３ and R １４ are bonded to each other to form a benzene ring, or C １－６ A tetrahydropyrimidine ring may be formed which may be substituted with 1 to 4 substituents selected from alkyl groups and oxo groups.

[0050] The salt of the compound according to the present invention may be any pharmaceutically acceptable salt, and examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; ammonium salts such as dimethylammonium salts and triethylammonium salts; inorganic acid salts such as hydrochlorides, perchlorates, sulfates and nitrates; and organic acid salts such as acetates and methanesulfonates.

[0051] Preferred examples of the heterocyclic compound represented by formula (I) include compounds represented by the following formula (A-1) or (C-1) or salts thereof.

[0052]

[0053] (In the formula, R １１Ａ is a hydrogen atom, C １－６ Alkyl group, C １－６ Alkoxy group, halogen atom, amino group, —SH, C １－６ an alkylthio group, or C １－６is an alkenylthio group; R １３Ａ is a hydrogen atom or C １－６ is an alkyl group; R １４Ａ is a hydrogen atom, C １－６ Alkyl group, or C １－６ is an alkyl-carbonyl group; R １３Ａ and R １４Ａ may be bonded to each other to form a benzene ring;

[0054]

[0055] indicates a single or double bond)

[0056] In a preferred embodiment of formula (A-1), R １１Ａ is a hydrogen atom, C １－６ Alkyl group, C １－６ Alkoxy group, amino group, —SH, or C １－６ is an alkenylthio group; R １３Ａ is a hydrogen atom or C １－６ is an alkyl group; R １４Ａ is a hydrogen atom or C １－６ is an alkyl group; R １３Ａ and R １４Ａ may be bonded to each other to form a benzene ring;

[0057]

[0058] represents a single or double bond.

[0059] In another preferred embodiment of formula (A-1), R １１Ａ is C １－６ Alkyl group, C １－６ Alkoxy group, amino group, —SH, or C １－６ is an alkenylthio group; R １３Ａ is a hydrogen atom or C １－６ is an alkyl group; R １４Ａ is a hydrogen atom or C １－６ is an alkyl group; R １３Ａ and R １４Ａ may be bonded to each other to form a benzene ring. In another preferred embodiment of formula (A-1), R １１Ａ is a hydrogen atom or C １－６ is an alkyl group; R １３Ａis a hydrogen atom or C １－６ is an alkyl group; R １４Ａ is a hydrogen atom or C １－６ It is an alkyl group.

[0060] In formula (A-1), preferably, R １１Ａ is a hydrogen atom or C １－４ is an alkyl group; R １３Ａ is a hydrogen atom or C １－４ is an alkyl group; R １４Ａ is a hydrogen atom or C １－４ In formula (A-1), R １１Ａ , R １３Ａ , and R １４Ａ In formula (A-1), it is more preferable that at least one of R １１Ａ is C １－４ is an alkyl group; R １３Ａ is a hydrogen atom or C １－４ is an alkyl group; R １４Ａ is a hydrogen atom;

[0061]

[0062] indicates a single bond.

[0063]

[0064] (In the formula, X ３ is S or SO ２ and R １１Ａ is a hydrogen atom or C １－６ is an alkyl group; R １２Ａ is a hydrogen atom or C １－６ is an alkyl group; R １３Ａ is a hydrogen atom or C １－６ is an alkyl group; R １４Ａ is a hydrogen atom or C １－６ is an alkyl group; R １６Ａ is a hydrogen atom or C １－６ In formula (C-1), preferably, R １１Ａ is a hydrogen atom or C １－４ is an alkyl group; R １２Ａ is a hydrogen atom or C １－４ is an alkyl group; R １３Ａ is a hydrogen atom or C１－４ is an alkyl group; R １４Ａ is a hydrogen atom or C １－４ is an alkyl group; R １６Ａ is a hydrogen atom or C １－４ In formula (C-1), X is more preferably an alkyl group. ３ is S or SO ２ and R １１Ａ is a hydrogen atom or C １－４ is an alkyl group; R １２Ａ , R １３Ａ , R １４Ａ , and R １６Ａ are hydrogen atoms.

[0065] The analgesic provided by the present invention can be used as a preventive or therapeutic agent for pain. An analgesic means a medicine used to prevent or treat (including alleviate) pain.

[0066] Pain includes nociceptive pain and neuropathic pain. Exemplary types of pain include acute pain, chronic pain, mild pain, moderate pain, severe pain, musculoskeletal pain, complex regional pain syndrome, neuropathic pain, post-operative pain, inflammatory pain, rheumatoid arthritis pain, osteoarthritis pain, pain associated with temporomandibular joint disorders, back pain (e.g., acute low back pain), trigeminal neuralgia, post-herpetic neuralgia, sciatica, visceral pain, cancer pain, burn pain, oral pain, neuralgia, migraine, neuropathy, pain associated with acute trauma, chemotherapy-induced mononeuropathy pain states, polyneuropathy pain states (e.g., diabetic peripheral neuropathy and chemotherapy-induced neuropathy), autonomic neuropathic pain states, pain states associated with peripheral nervous system (PNS) lesions or central nervous system (CNS) lesions or diseases, polyneuropathy of the neck, lower back, or sciatica type. These include, but are not limited to, pain conditions associated with radiculopathy, cauda equina syndrome, piriformis syndrome, paraplegia, quadriplegia, various infections, chemical injury, radiation exposure, underlying disease or deficiency states (e.g., beriberi, vitamin deficiency, hypothyroidism, porphyria, cancer, HIV, autoimmune diseases such as multiple sclerosis, and spinal cord injury), fibromyalgia, pain conditions associated with various diseases (e.g., nerve injury, ischemia, neurodegeneration, stroke, post-stroke pain, inflammatory disorders, esophagitis, gastroesophageal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, urinary incontinence, cystitis, gastric and duodenal ulcers), crush and injury-induced pain, incisional pain, bone pain, pain associated with sickle cell disease, muscle pain, pain due to colic, pain from hyperalgesia or allodynia, and referred pain.

[0067] A heterocyclic compound represented by formula (I) or a salt thereof (hereinafter also referred to as the compound of the present invention) can be administered to animals, including humans, that have developed or may develop pain, for the purpose of preventing pain onset or alleviating symptoms. Gas generated from the compound of the present invention at a concentration of 0.1 to 100,000 ppm can be inhaled through the nasal cavity or lungs using a gas mask or a device with similar functionality. Alternatively, the compound of the present invention can be administered orally at a dose of 1 μg / kg to 5,000 mg / kg. Alternatively, the compound of the present invention can be injected into the body at a dose of 1 μg / kg to 5,000 mg / kg via intradermal, subcutaneous, intramuscular, intravenous, intraarterial, intrathecal, or intraperitoneal injection. Alternatively, the compounds of the present invention can be administered at a dose of 1 μg / kg to 5,000 mg / kg by transdermal, transmucosal, buccal, sublingual, ocular, otic, nasal, rectal, or vaginal administration. The administration frequency can be a single dose, or continuous administration at regular intervals or at different time intervals. Animals to which the compounds of the present invention can be administered include mammals (humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, pigs, horses, monkeys, etc.).

[0068] When the compound of the present invention is used as an analgesic (hereinafter also referred to as the agent of the present invention), pharmaceutically acceptable additives can be added as needed.

[0069] Specific examples of pharmaceutically acceptable additives include, but are not limited to, antioxidants, preservatives, colorants, flavorants, and diluents, emulsifiers, suspending agents, solvents, fillers, bulking agents, buffers, delivery vehicles, diluents, carriers, excipients and / or pharmaceutical adjuvants.

[0070] The formulation of the agent of the present invention is not particularly limited, and examples thereof include solutions, injections, sustained-release preparations, lotions, creams, gels, sprays, patches (e.g., tapes, poultices), ointments, suspensions, emulsions, syrups, capsules, granules, powders, tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, pills, sublingual tablets, troches, drops, buccal tablets, inhalants, eye drops, ear drops, nasal drops, suppositories, enemas, vaginal suppositories, and vaginal tablets. The above formulations can be prepared by methods known in the art. The solvent used to formulate the agent of the present invention into the above formulations may be either aqueous or non-aqueous.

[0071] Injections can be prepared by methods known in the art. For example, the compound is dissolved in a suitable solvent (such as physiological saline, a buffer solution such as PBS, or sterile water), then sterilized by filtration using a filter or the like, and then filled into a sterile container (such as an ampoule) to prepare an injection. If necessary, the injection may contain a conventional pharmaceutical carrier. A non-invasive catheter-based administration method may also be used. Carriers that can be used in the present invention include neutral buffered saline or saline containing serum albumin.

[0072] The present invention will be explained in more detail and specifically below by showing examples, but the present invention is not limited to these examples.

[0073] Example 1: Analgesic effect of TFO on formalin-induced pain model Experimental method: C57BL / 6 mice (male, 10-12 weeks old) were intraperitoneally (ip) administered saline or 40 mg / kg 2MT. 30 minutes later, 20 μl of 5% formalin was administered to the sole of the mouse's foot and the mouse was placed in an observation chamber. The mouse's behavior was videotaped for 60 minutes after administration. Spontaneous pain behavior was assessed by licking or biting the sole of the foot from the videotaped images.

[0074] Results The results are shown in Figure 1. The time (seconds) spent exhibiting pain behavior (licking and biting time) every 5 minutes after formalin injection is shown for the saline and 2MT groups (A). The periods 0-5 minutes and 10-60 minutes after formalin injection were defined as the first and second phases, respectively. The mean ± standard error of the time spent exhibiting pain behavior during each period is shown for the saline and 2MT groups (B). Statistical calculations were performed using Student's t-test to examine the change in the time spent exhibiting pain behavior between the saline and 2MT groups for each period during the first and second phases. **** indicates p<0.0001, indicating a statistically significant difference.

[0075] Generally, the first phase is also called the acute phase and is thought to represent acute peripheral pain, while the second phase is also called the inflammatory phase and is thought to represent inflammatory and central pain induced by the production of inflammatory mediators. 2MT suppressed pain behavior in both the first and second phases, demonstrating its analgesic effects on acute peripheral pain, as well as inflammatory and central pain.

[0076] Example 2: Analgesic Effect of TFO on Capsaicin-Induced Pain Model Experimental Method: C57BL / 6 mice (male, 10-11 weeks old) were administered saline or 10 mg / kg 2MT i.p. 30 minutes later, 20 μl of capsaicin solution (1.6 μg of capsaicin dissolved in 20 μl of saline containing 0.4% DMSO) was administered to the paw pad and the mice were placed in an observation chamber. The mice's behavior was videotaped for 5 minutes after administration. Spontaneous pain behavior was assessed by licking or biting the paw pad from the videotaped images.

[0077] Results The results are shown in Figure 2. The mean ± standard error of pain behavior is shown for the saline and 2MT groups. Statistical calculations were also performed using Student's t-test to examine the change in the time it took for pain behavior to be exhibited between the saline and 2MT groups. ** indicates p<0.01, indicating a statistically significant difference.

[0078] Formalin induces acute peripheral pain via TRPA1, whereas capsaicin induces acute peripheral pain via TRPV1. Although 2MT has been shown to bind to TRPA1 but not TRPV1, it was shown to have an analgesic effect not only on formalin-induced acute peripheral pain via TRPA1 but also on capsaicin-induced acute peripheral pain via TRPV1. These results suggest that 2MT may be useful as a novel analgesic agent acting on the nervous system above primary nerves.

[0079] Example 3: TFO induces analgesia independently of opioid receptors. Experimental method: C57BL / 6 mice (male, 9-14 weeks old) were given an i.p. injection of vehicle (saline) or 7 mg / kg naltrexone hydrochloride (Naltx), followed 30 minutes later by an i.p. injection of saline or 10 mg / kg 2MT. 30 minutes later, 20 μl of 5% formalin was administered to the paw pad of the mice, who were then placed in an observation chamber and subjected to behavioral analysis similar to that in Example 1.

[0080] Results The results are shown in Figure 3. Bar graphs show the mean ± standard error of pain behavior for the four groups: vehicle-saline, naltrexone-saline, vehicle-2MT, and naltrexone-2MT. A two-way ANOVA was performed on the changes in the time during which pain behavior was observed in these four groups to confirm the significance of main effects and interactions. Post-hoc comparisons between groups were then performed using Fisher's least significant difference test without correction for multiple comparisons. * indicates p<0.05, ** indicates p<0.01, and **** indicates p<0.0001, indicating a statistically significant difference.

[0081] The inhibitory effect of 2MT on Formalin-induced pain behavior was not inhibited by administration of the opioid receptor antagonist naltrexone in either phase 1 or phase 2, and tended to be enhanced instead. This suggests that the analgesic effect of 2MT is induced by an opioid-independent mechanism, and indicates the potential for 2MT as a novel non-opioid analgesic.

[0082] Example 4: TFO induces analgesia independent of CB1 receptors. Experimental method: C57BL / 6 mice (male, 11-14 weeks old) were given an i.p. injection of vehicle (10% DMSO in saline) or 2 mg / kg AM251, followed 30 minutes later by i.p. injection of saline or 10 mg / kg 2MT. 30 minutes later, 20 μl of 5% formalin was administered to the footpad of the mice, which were then placed in an observation chamber. Behavioral analysis was performed as in Example 1. AM251 (CAS Registry Number 183232-66-8) is a cannabinoid (CB1) receptor antagonist.

[0083] Results The results are shown in Figure 4. Bar graphs show the mean ± standard error of pain behavior for the four groups: vehicle-saline, AM251-saline, vehicle-2MT, and AM251-2MT, for each time period during Phase 1 (A) and Phase 2 (B). Two-way ANOVA was performed on the changes in the time period during which pain behavior was exhibited for these four groups to confirm the significance of main effects and interactions. Post-hoc comparisons between groups were then performed using Fisher's least significant difference test without correction for multiple comparisons. *** indicates p<0.001, and **** indicates p<0.0001, indicating a statistically significant difference.

[0084] The inhibitory effect of 2MT on Formalin-induced pain behavior was not affected by the administration of AM251, a cannabinoid (CB1) receptor antagonist, in either phase 1 or phase 2. This result suggests that the analgesic effect of 2MT is induced by a mechanism that is not mediated by cannabinoid receptors, and indicates that 2MT may be useful as a novel non-cannabinoid analgesic agent.

[0085] Example 5: Evaluation of the Inhibitory Effect of TFO on Sensory Transmission at the Spinal Cord Using c-fos Mapping Experimental Method: C57BL / 6 mice (male, 9-12 weeks old) were transferred to a new cage and allowed to acclimate for 2 hours before receiving an intraperitoneal injection of saline or 2MT (40 mg / kg). 30 minutes after administration, 5% formalin (20 μl) was injected into the plantar hind paw. 30 minutes after formalin administration, the mice were anesthetized with isoflurane, and the spinal cords were removed and fixed overnight in 4% PFA solution at 4°C. After fixation, the spinal cord tissue was dehydrated with ethanol and xylene and embedded in paraffin. 5 μm-thick sections were prepared from the spinal cords, and c-fos mRNA was detected by in situ hybridization using a DIG-labeled RNA probe. The sections were incubated with anti-DIG antibody at 37°C, stained for 6 hours, and then nuclear stained for an additional 4 minutes. After staining, the specimens were mounted and images were captured using a virtual slide scanner.

[0086] Results The results are shown in Figure 5. Representative staining images of the saline- and 2MT-treated groups are shown in Figures 5A and 5B, respectively. The number of c-fos-positive cells (c-fos+ cells / section) in the spinal dorsal horn of each group was counted and the results are shown in Figure 5C. The graph in Figure 5C shows the mean ± standard error, and statistical calculations were performed using the Mann-Whitney test for the changes in c-fos-positive cell foci between the saline and 2MT groups. **** indicates p<0.0001, indicating a statistically significant difference.

[0087] c-fos gene expression is widely used as an index of neural activity. Formalin-induced nociceptive stimulation is known to transmit nociceptive information to the dorsal horn of the spinal cord via C and Aδ fibers. In this study, we confirmed that c-fos expression was induced in dorsal horn neurons activated by these fiber inputs. In contrast, c-fos expression in dorsal horn neurons was significantly reduced in the group treated with formalin and 2MT. These results suggest that 2MT exerts an analgesic effect by inhibiting the activation of nociceptive neurons in the dorsal horn of the spinal cord. Therefore, this compound may be useful as a novel analgesic agent that can suppress pain processing through the inhibition of sensory transmission at the spinal cord level.

[0088] Example 6: Anti-allodynic effect of TFO in a neuropathic pain model Experimental method: C57BL / 6 mice (male, 9-12 weeks old) were immobilized in the dorsal recumbent position under triple anesthesia (a mixture of medetomidine, midazolam, and butorphanol), and the skin was incised along the midline slightly to the left of the dorsal midline (the injured side). After incising the fascia, the surgical field was opened using a retractor, and the muscle above the L5 transverse process of the lumbar vertebra was dissected to expose the transverse process. Next, the base of the L5 transverse process was removed using a drill, allowing the L3 and L4 spinal nerves running downward to be visualized. Of the exposed nerves, the L4 spinal nerve was completely transected with scissors, while the L3 spinal nerve was preserved. After checking for bleeding, the muscle layer and skin were sutured with 4-0 silk thread, and the surgery was completed. After surgery, atipamezole was administered intraperitoneally to reverse the anesthesia, and the mice were kept warm on a heating pad until they woke up.

[0089] Mechanical sensitivity was assessed using Von Frey filaments in the neuropathic pain model created using the above method on days 0 and 7 after surgery. Mice were individually placed on an aluminum mesh plate and covered with an opaque mouse cage. A 30- to 1-hour habituation period was allowed before the test. Von Frey filaments weighing 0.02 to 2.0 g were applied perpendicularly to the mid-plantar area of ​​the hind paws on the nerve-transected and uninjured sides, and pain-related behaviors, such as rapid withdrawal of the hind paw or paw licking, were observed. The threshold for the stimulus intensity was calculated as the 50% response threshold using Dixon's up-and-down method. For the test on day 7 after surgery, baseline values ​​were measured after habituation, followed by intraperitoneal administration of saline or 40 mg / kg 2MT. Further measurements were taken 30, 60, and 120 minutes after administration.

[0090] Results are shown in Figure 6. Mechanical sensitivity was assessed for the hind paws of the nerve-transected side (A) and the uninjured side (B) in the saline- and 2MT-treated groups. The results are shown in a line graph as the mean ± standard error of the scores at baseline, before drug administration on day 7 after surgery (Pre), and 30, 60, and 120 minutes after drug administration (Time after ip injection). Statistical calculations were performed using a two-way ANOVA for the saline and 2MT groups to assess the significance of main effects and interactions. Post-hoc evaluation between groups was then performed using Sidak's multiple comparison test. ** indicates p<0.01, and **** indicates p<0.0001, indicating a statistically significant difference between the saline and 2MT groups.

[0091] In mice administered 2MT, the response threshold to mechanical stimulation in the hind paw on the nerve-transected side was significantly elevated compared to the control group, suppressing hypersensitivity to mechanical stimulation (A). On the other hand, no significant change was observed in the response threshold in the uninjured (contralateral) hind paw, indicating that 2MT does not affect normal sensory function (B). These results indicate that 2MT selectively suppresses abnormal pain sensitivity (allodynia) caused by nerve injury without affecting physiological sensory thresholds.

[0092] Example 7: Evaluation of the centrally mediated analgesic effect of TFO Experimental method C57BL / 6 mice (male, 13-14 weeks old) were placed in an analysis chamber and allowed to acclimate for 10-15 minutes, after which administration was performed to the sole of the foot under the following three conditions: 1) 20 μl of saline was administered to the sole of the right hind paw and 20 μl of 5% formalin was administered to the sole of the left hind paw (saline group); 2) 20 μl of 0.12% 2MT solution was administered to the sole of the right hind paw and 20 μl of 5% formalin was administered to the sole of the left hind paw (2MT_R group); and 3) 20 μl of saline was administered to the sole of the right hind paw and 20 μl of 5% formalin / 0.12% 2MT solution was administered to the sole of the left hind paw (2MT_L group). The behavior of the mice in each group was videotaped for 5 minutes after administration. Licking or biting of the sole of the foot was measured from the photographed images as spontaneous pain behavior.

[0093] The results are shown in Figure 7. The bar graph shows the mean ± standard error of the time that pain behavior was exhibited for each group. Statistical calculations were performed using one-way ANOVA and Tukey's multiple comparison test for the three groups. *** indicates p<0.001, **** indicates p<0.0001, indicating a statistically significant difference, and ns indicates p>0.05, indicating no statistically significant difference.

[0094] Formalin-induced acute pain was suppressed not only when Formalin was administered to the ipsilateral leg (2MT_L) but also when it was administered to the contralateral leg (2MT_R), and no statistically significant difference was observed between ipsilateral and contralateral administration. Therefore, the analgesic effect of 2MT cannot be explained solely by its direct antagonistic action on the TRPA1 receptor, formalin's agonist, suggesting that 2MT may be useful as a novel analgesic agent that transmits analgesic signals more centrally.

[0095] Example 8: Analgesic effect of TFO on acute pain induced by thermal stimulation Experimental method: C57BL / 6 mice (male, 8-12 weeks old) were allowed to acclimate to the laboratory for at least 30 minutes, after which saline or each test substance was subcutaneously injected into the dorsal skin at a dose of 40 mg / kg. 30 minutes after administration, the mice were placed on a hot plate at 52°C, and their behavior was recorded by video recording. From the video images, the time from when the mice were placed on the hot plate until they exhibited pain-related behavior (e.g., licking their hind paws, jumping, or shaking their hind paws) was measured. The maximum cutoff time was 60 seconds, and if the mice did not exhibit pain-related behavior, they were removed from the hot plate at that point.

[0096] Results The results are shown in Figure 8A. The chemical structures of the test substances are shown in Figure 8B. The graph shows the mean ± standard error of the latency (seconds) (Latency (s)) until mice exhibited pain-related behavior after administration of each compound. Statistical analysis was performed using Student's t-test against saline conditions, with * indicating p<0.05, ** indicating p<0.01, *** indicating p<0.001, and **** indicating p<0.0001, indicating a statistically significant difference. Administration of each of the following compounds prolonged the latency until mice exhibited pain-related behavior in response to thermal stimulation, indicating that these compounds have an analgesic effect on acute pain induced by thermal stimulation. 2-Acetylthiophene 2,5-Dimethylpyrrole 2-Ethylpyrrole 2-Chlorothiazole 4-Methylthiazole 2,3-Diethylpyrazine 2-Ethoxythiazole 2-(Methylthio)-2-thiazoline Thiomorpholine 1,1-dioxide 2,4,5-Trimethylthiazole 2-Acetyl-3,5-dimethylpyrazine 2-Methylthiazole Thiomorpholine 2-Methylthiomorpholine 2,6-Dimethylpyrazine 2-Amino-2-thiazoline 2,6-Dimethylpyridine 2-Aminothiazoline 5-Acetyl-2,4-dimethylthiazole4-dimethylthiazole, 2-Isobutylthiazole, 2-Methyl-2-thiazoline, 2-Ethyl-3-(methylthio)pyrazine, 2-Acetylpyrrole, 4-Ethyl-2-methyl-2-thiazoline, 2,4-Dimethylpyrrole, 2-Ethyl-3,5(6)-dimethylpyrazine (mixture of 2-ethyl-3,5-dimethylpyrazine and 2-ethyl-3,6-dimethylpyrazine), 2,2-Dimethylthiazolidine 2-Acetyl-3-ethylpyrazine,

[0097] Example 9: Analgesic Effect of TFO in Humans Experimental Method: 5 μL of allyl isothiocyanate (AITC) was applied to the tip of a cotton swab. Next, 0 μL, 5 μL, or 10 μL of 2-methyl-2-thiazoline (2MT), thiomorpholine (TMO), or trans-cinnamaldehyde (CNA) was applied to the tip of the AITC-applied cotton swab. The pain felt when sniffing the cotton swab containing only AITC was scored as 10 points, and the pain felt when sniffing the cotton swab containing no other ingredients was scored as 0 points. The pain felt from 0 to 30 seconds after sniffing the cotton swabs containing AITC, 2MT, TMO, or CNA was measured by a human sensory test (three subjects).

[0098] Results The results are shown in Figure 9. When 2MT and TMO were added to AITC, the pain score induced by AITC was reduced in a dose-dependent manner (A, B). On the other hand, when CNA, a known TRPA1 agonist, was added to AITC, no reduction in the pain score induced by AITC was observed (C). Comparison of pain scores between the control condition (AITC only) and the condition (AITC plus each compound) was evaluated using the Kruskal-Wallis test. *, p<0.05; ***, p<0.001; ns, p>0.05.

[0099] AITC is known to induce pain in humans and mice via TRPA1. Sensory testing suggested that 2MT and TMO have the ability to suppress AITC-induced pain. This effect was not observed with the existing TRPA1 agonist, CNA. In rodent studies, the monophasic pain-like behavior that occurs immediately after AITC administration is evaluated as an acute pain response. Furthermore, AITC itself is known to induce local inflammation, leading to the development of hyperalgesia a certain time after administration. Therefore, while it can be used as an acute pain model, it is also often used as a model to evaluate the development of post-inflammatory hyperalgesia. In this example, the pain felt between 0 and 30 seconds after sniffing AITC was scored, which is considered to be a measure of the effect on acute pain. TFO was shown to suppress TRPA1-induced acute pain in both mice and humans.

[0100] The analgesic of the present invention can suppress the occurrence of pain sensation by directly acting on TRPA1 and other receptors that detect noxious stimuli, or can suppress the recognition of pain sensation by transmitting sensory information to the brain, and can be used for the prevention or treatment of pain.

[0101] This application is based on patent application No. 2024-084662 filed in Japan, the contents of which are incorporated in their entirety herein.

Claims

1. Formula (I) wherein ring A is a 5- to 7-membered heterocycle containing 1 or 2 heteroatoms selected from a nitrogen atom, an optionally oxidized sulfur atom, and an oxygen atom; R １ , R ２ , R ３ , and R ４ are each independently a hydrogen atom, C １－６ Alkyl group, C １－６ Alkoxy group, halogen atom, amino group, —SH, C １－６ Alkylthio group, C ２－６ Alkenylthio group, C １－６ Alkyl-carbonyl group, formyl group, C ６－１０ Aryl group, C １－６ an alkoxycarbonyl group, a 5- or 6-membered heteroaryl group, or an oxo group; R １ and R ２ may be bonded to each other to form an optionally substituted 5- or 6-membered ring; and n is 0, 1, or 2), or a salt thereof.

2. The analgesic of claim 1, wherein ring A is thiazoline, thiazole, thiazolidine, thiomorpholine, thiophene, pyrrole, morpholine, azepane, pyridine, pyrazine, furan, 2,3-dihydro-4H-1,4-thiazine, or imidazole.

3. An analgesic according to claim 1 or 2 for nasal administration.

4. A compound of formula (I) for producing an analgesic drug wherein ring A is a 5- to 7-membered heterocycle containing 1 or 2 heteroatoms selected from a nitrogen atom, an optionally oxidized sulfur atom, and an oxygen atom; R １ , R ２ , R ３ , and R ４ are each independently a hydrogen atom, C １－６ Alkyl group, C １－６ Alkoxy group, halogen atom, amino group, —SH, C １－６ Alkylthio group, C ２－６ Alkenylthio group, C １－６ Alkyl-carbonyl group, formyl group, C ６－１０ Aryl group, C １－６ an alkoxycarbonyl group, a 5- or 6-membered heteroaryl group, or an oxo group; R １ and R ２ may be bonded to each other to form an optionally substituted 5- or 6-membered ring; and n is 0, 1, or 2), or a salt thereof.

5. The use according to claim 4, wherein ring A is thiazoline, thiazole, thiazolidine, thiomorpholine, thiophene, pyrrole, morpholine, azepane, pyridine, pyrazine, furan, 2,3-dihydro-4H-1,4-thiazine, or imidazole.

6. The use according to claim 4 or 5, wherein the analgesic is for nasal administration.

7. An effective amount of a compound of formula (I) wherein ring A is a 5- to 7-membered heterocycle containing 1 or 2 heteroatoms selected from a nitrogen atom, an optionally oxidized sulfur atom, and an oxygen atom; R １ , R ２ , R ３ , and R ４ are each independently a hydrogen atom, C １－６ Alkyl group, C １－６ Alkoxy group, halogen atom, amino group, —SH, C １－６ Alkylthio group, C ２－６ Alkenylthio group, C １－６ Alkyl-carbonyl group, formyl group, C ６－１０ Aryl group, C １－６ an alkoxycarbonyl group, a 5- or 6-membered heteroaryl group, or an oxo group; R １ and R ２ may be bonded to each other to form an optionally substituted 5- or 6-membered ring; and n is 0, 1, or 2), or a salt thereof, to the mammal.

8. The method of claim 7, wherein ring A is thiazoline, thiazole, thiazolidine, thiomorpholine, thiophene, pyrrole, morpholine, azepane, pyridine, pyrazine, furan, 2,3-dihydro-4H-1,4-thiazine, or imidazole.

9. The method according to claim 7 or 8, wherein the heterocyclic compound or salt thereof is administered intranasally.

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