Prophylactic or therapeutic agent for neurodegenerative disease or delirium

Abstract

The present invention provides a novel prophylactic or therapeutic agent for neurodegenerative diseases or delirium. The prophylactic or therapeutic agent for neurodegenerative diseases or delirium 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 halogen atom, an amino group, -SH, a C1-6 alkylthio group, a C2-6 alkenyl-thio 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

Preventive or therapeutic agent for neurodegenerative diseases or delirium

[0001] The present invention relates to an agent for preventing or treating neurodegenerative diseases or delirium.

[0002] 1. The Need for a Therapeutic Drug for Neurodegenerative Diseases Neurodegenerative diseases are a group of conditions in which neurons in the central nervous system gradually lose function and eventually die. These conditions include Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS) (Non-Patent Document 1). These diseases cause serious symptoms, such as memory loss, motor dysfunction, and cognitive decline, significantly impairing patients' quality of life. Neurodegenerative diseases have been increasing worldwide in recent years, partly due to the increasing elderly population (Non-Patent Document 2). However, currently, treatment for neurodegenerative diseases is primarily symptomatic, and no fundamental cure has been established. For example, acetylcholinesterase inhibitors and NMDA receptor antagonists are used to treat Alzheimer's disease, but these drugs only slow the progression of symptoms and are not believed to prevent neuronal death (Non-Patent Documents 3 and 4). Furthermore, dopamine replacement therapy such as levodopa is used to treat Parkinson's disease, but this also aims to alleviate symptoms and is thought to be unable to halt the progression of the disease itself (Non-Patent Document 5). Similar symptomatic treatments are also used for other neurodegenerative diseases, but they have not yet led to a fundamental cure.

[0003] 2. Removal of Already Formed Amyloid Has Limited Therapeutic Efficacy. The accumulation of amyloid, an abnormal protein aggregate, in the brain is one of the characteristic pathological findings of these neurodegenerative diseases. The type of amyloid that accumulates varies with each disease: amyloid beta and tau accumulate in Alzheimer's disease, α-synuclein accumulates in Parkinson's disease, and huntingtin-derived amyloid accumulates in Huntington's disease (Non-Patent Document 6). Recent research has made progress in elucidating the mechanisms by which these amyloids accumulate in the brain, making it possible to develop drugs that remove or prevent amyloid accumulation in the brain. One example of such a drug is aducanumab, an antibody against amyloid beta that was approved by the FDA in 2021. The amyloid cascade hypothesis, which posits that the accumulation of amyloid plaques in the brain leads to neuronal destruction, resulting in cognitive decline, has long been accepted in Alzheimer's disease. If this hypothesis is correct, developing a drug that removes amyloid from the brain would be expected to be a fundamental inhibitor of cognitive decline, even if it makes it difficult to regenerate already destroyed neurons. However, clinical trials have not fully met this expectation. Although aducanumab administration significantly reduced amyloid plaques in the brain, its effects on improving cognitive function and slowing cognitive decline were limited. This suggests that cognitive function cannot be improved by simply inhibiting the accumulation of a single type of amyloid, such as amyloid beta (Non-Patent Documents 7, 8, 9). Furthermore, amyloid beta is also present in the brains of healthy people and has been shown to play a role in various normal physiological functions, including neuronal protection, synaptic regulation, and cognitive function. Therefore, removal of amyloid beta may have a negative impact on neuronal protection and brain function. Just as dementia treatment drugs that remove amyloid beta have limited effectiveness, there are concerns that the therapeutic effect of administering drugs aimed at removing amyloid that has already formed will also be limited for amyloid associated with other neurodegenerative diseases.

[0004] 3. Increasing ATP in the brain is expected to improve cognitive function and inhibit amyloid deposition. ATP synthesis in cells, not just neurons and glial cells in the brain, generally depends on mitochondrial function. When mitochondrial function is impaired, the generation of reactive oxygen species increases, causing cellular dysfunction and exacerbated inflammation. This results in further cellular and mitochondrial dysfunction, leading to a decline in ATP production. Mitochondrial abnormalities are often observed in neurodegenerative diseases, and it has been suggested that the decline in ATP associated with mitochondrial abnormalities may be the cause of neurodegenerative diseases (Non-Patent Document 10).

[0005] Maintaining normal cognitive and motor control functions requires maintaining communication in neural networks, which requires a large amount of energy. ATP is the cellular energy source. In the brains of patients with neurodegenerative diseases, inflammation and mitochondrial dysfunction can cause a lack of ATP, making it difficult to maintain normal cognitive and motor control functions.

[0006] ATP is also necessary to prevent amyloid formation. Amyloid-causing proteins and peptides are endogenous biomolecules naturally present in the brain and do not interfere with brain function under normal conditions. However, when these proteins fold abnormally, they promote aggregation, forming fibrillar amyloids and depositing in the brain. Chaperone proteins are important for folding proteins into their correct structure and repairing misfolding, and ATP is required for their function. ATP is also known to function as a biological hydrotrope, more directly dissolving hydrophobic molecules and preventing aggregation (Non-Patent Document 11). In relation to Alzheimer's disease, it has been reported that ATP binds to amyloid beta and prevents misfolding, and that ATP levels in cerebrospinal fluid decrease in patients with advanced Alzheimer's disease (Non-Patent Document 12).

[0007] Based on these findings, drugs that protect and strengthen mitochondrial function in the brain and increase intracellular ATP are expected to maintain normal information processing in neural networks, prevent amyloid accumulation, and prevent neuronal damage caused by reactive oxygen species and inflammation. Several drugs have been reported to increase neuronal ATP (Non-Patent Documents 13, 14). The increase rate is approximately 10%. The development of drugs that more effectively increase ATP in the brain may lead to more desirable therapeutic effects.

[0008] 4. Acetylcholine not only improves cognitive function but also has neuroprotective functions. Acetylcholine in the brain is involved in a wide range of cognitive functions, including memory, learning, attention, and consciousness, as well as the control of sleep and wakefulness. Dementia and delirium cause cognitive decline. It is believed that cognitive abnormalities in these diseases are caused by a decrease in brain acetylcholine (Non-Patent Documents 15, 16). In fact, administration of drugs that increase brain acetylcholine improves cognitive function in patients with dementia or delirium (Non-Patent Documents 17, 18). Until now, drugs that increase acetylcholine can temporarily improve cognitive function in patients with dementia, but because they do not have the effect of preventing the progressive destruction of nerve cells, they have not been considered to be a fundamental treatment for slowing the progression of dementia (Non-Patent Document 19).

[0009] However, the present inventors have discovered a new phenomenon called acetylcholine-decreased neuronal death, in which a hypoxic environment places a strain on neuronal ATP production, causing a decrease in acetylcholine signaling in the brain, which in turn induces fatal calcium influx through voltage-dependent calcium channels via muscarinic acetylcholine receptors. This discovery has revealed for the first time that an increase in acetylcholine in the brain not only improves cognitive function as previously assumed, but also prevents neuronal destruction.

[0010] The development of new therapeutic agents that slow or stop the progression of neurodegenerative diseases is an extremely important and urgent issue. However, there are currently no therapeutic agents that have sufficient efficacy. In this context, the present invention aims to provide novel drugs that are useful for treating neurodegenerative diseases.

[0011] The present invention also relates to pharmaceuticals, particularly to drugs used for the prevention or treatment of abnormalities in cognitive function or emotional state in delirium or dementia.

[0012] Dementia is a disease in which the brain's normal cognitive functions, such as memory, learning, judgment, language, and behavior, fail, and abnormalities also occur in the brain's functions controlling emotional states, such as anger, sadness, and appetite, which form the basis of emotions. There are several types of dementia. Alzheimer's disease, the most common, is characterized by the accumulation of amyloid in the brain and widespread loss of neurons. Other types include vascular dementia, in which specific areas of the brain are damaged by impaired blood flow (Non-Patent Documents 20, 21). Diseases in which widespread neuronal loss progresses, such as Alzheimer's dementia, generally progress gradually over years.

[0013] In addition to dementia, delirium is another disease in which cognitive dysfunction is a problem. Delirium is a disease in which cognitive function and emotional state are abnormal due to various factors that inhibit brain function, including excessive stress from surgery or ICU admission. Unlike Alzheimer's disease, delirium develops within a short period of time (Non-Patent Documents 22, 23). While the two diseases differ in their causes and progression speed, they share the commonality of causing cognitive decline and changes in emotional state. Therefore, dementia and delirium are thought to share a common cause of onset. Potential causes are listed below, along with potential therapeutic agents based on these.

[0014] Hypoxia and inflammation are thought to impair neural function, leading to cognitive decline and the exacerbation of dementia and delirium. Neurons require large amounts of oxygen to synthesize ATP to maintain energy-requiring signaling functions, such as neuronal firing and endocrine secretion. Reduced ATP production, caused by hypoxia or other conditions, impairs normal neural function. Furthermore, severe or persistent hypoxia can accelerate neuronal destruction, increasing the likelihood of cognitive decline. Reflecting this, it has been reported that patients in hypoxic conditions are more likely to develop delirium (Non-Patent Documents 24, 25). Brain inflammation has also been shown to contribute to the exacerbation of dementia and delirium (Non-Patent Documents 26-30). To prevent and treat cognitive decline caused by hypoxia and inflammation, drugs that alleviate brain hypoxia and inflammation are effective.

[0015] Various types of neurotransmitters function in the brain, and maintaining a normal balance between these is essential for maintaining normal cognitive function. A decrease in acetylcholine in the brain is thought to be important for dementia symptoms. Furthermore, in delirium, acetylcholine levels in the brain decrease, while dopamine and noradrenaline levels increase (Non-Patent Document 31). Since acetylcholine is known to be involved in the control of memory and learning, attention and consciousness, and sleep and wakefulness, it makes sense that its decrease would cause cognitive dysfunction. For these reasons, the acetylcholine dysfunction hypothesis has been proposed for both dementia and delirium (Non-Patent Documents 16, 32). Therefore, drugs that increase the availability of acetylcholine in the brain are thought to improve cognitive function in patients with dementia or delirium.

[0016] International Publication No. 2019 / 177142

[0017] Dugger BN et al., Cold Spring Harb Perspect Biol. 2017; 9(7): a028035Heemles MT et al., Nature 2016; 539(7628): 179Grossberg GT et al., Curr Ther Res. 2003; 64(4): 216-235Yiannopoulou KG et al., J Cent Nerv Syst Dis. 2020; 12: 1-12Parkinson Study Group, New Eng J Med. 2004; 351: 2948-2508Wells C et al., Int J Biol Macromol. 2021; 181: 582-604Synnott PG et al., J Manag Care Spec Pharm. 2021; 27(11): 1613-1617Fedele E, Int J Mol Sci. 2023; 24(19): 14499Granzotto A and Sensi SL, Ageing Res Rev. 2024; 93:102161.Pathak D et al., Annals Neurol. 2013; 74: 506-516Patel A et al., Science. 2017; 356(6339):753-756Coskuner O et al., J Alzheimers Dis. 2014; 41(2):561-74Zheng X et al., Elife. 2016; 5:e13378Namao M et al., EBioMedicine. 2017: 225-241Ferreira-Vieira TH et al., Curr Neuropharmacol. 2016; 14(1): 101-115Hshieh TT et al., J Gerontol A Biol Sci Med Sci. 2008; 63(7): 764-772Trinh NH et al., JAMA 2003; 289(2): 210-216Lieberman OJ et al., Alzheimers Dement.2023; 19(5): 1742-1751Sharma K, Mol Med Rep. 2019; 20: 1479-1487Knopman DS et al., Alzheimer disease, Nat Rev Dis Primers. 2021 May 13;7(1):33.Elahi FM and Miller BL, A clinicopathological approach to the diagnosis of dementia, Nat Rev Neurol. 2017 Aug;13(8):457-476.Wilson JE et al., Delirium, Nat Rev Dis Primers. 2020 Nov 12;6(1):90.Nabal Vicuna M, et al., Pathophysiology of Delirium in End-of-Life Patient: A Systematic Review, J Hosp Palliat Med Care 2023, 5:021.Wood MD et al., Low brain tissue oxygenation contributes to the development of delirium in critically ill patients: A prospective observational study. Journal of Critical Care, 15 Jun 2017, 41:289-295.Feng Q et al., Relationship Between Cerebral Hemodynamics, Tissue Oxygen Saturation, and Delirium in Patients With Septic Shock: A Pilot Observational Cohort Study. Front Med (Lausanne). 2021; 8:641104.Cooper J et al., A meta-analysis investigating the relationship between inflammation in autoimmune disease, elevated CRP, and the risk of dementia. Front Immunol. 2023 Jan 27:14:108757Walker et al., The role of peripheral inflammatory insults in Alzheimer’s disease: a review and research roadmap. Mol Neurodegener. 2023 Jun 5;18(1):37.Simone MJ and Tan ZS, The role of inflammation in the pathogenesis of delirium and dementia in older adults: a review. CNS Neurosci Ther. 2011 Oct;17(5):506-13.McNeil JB et al., Plasma biomarkers of inflammation, coagulation, and brain injury as predictors of delirium duration in older hospitalized patients. PLoS One. 2019 Dec 19;14(12):e0226412.Kinney JW et al., Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement (N Y). 2018 Sep 6:4:575-590.Bellelli G et al., Delirium: A Marker of Vulnerability in Older People. Front Aging Neurosci. 2021; 13:626127.P T Francis et al., The cholinergic hypothesis of Alzheimer's disease: a review of progress.J Neurol Neurosurg Psychiatry. 1999 Feb;66(2):137-47.

[0018] In neurodegenerative diseases, ATP depletion in the brain leads to the progressive destruction of neurons and a decline in the function of neural networks supporting cognitive and motor functions. Furthermore, cognitive function declines due to the depletion of neurotransmitters such as acetylcholine in the brain. Therefore, a fundamental treatment for neurodegenerative diseases must have a pharmacological effect that increases ATP in the brain, and it is even more desirable to have a pharmacological effect that simultaneously increases ATP and acetylcholine. However, ATP and acetylcholine are currently thought to be synthesized via different pathways, and the mechanisms controlling their synthesis remain unclear. Furthermore, while drugs that increase brain ATP are known, their effectiveness is limited. Therefore, in order to fundamentally treat neurodegenerative diseases, new technologies must be developed to efficiently increase brain ATP or simultaneously increase ATP and acetylcholine.

[0019] A major cause of cognitive abnormalities in patients with dementia or delirium is a decrease in acetylcholine levels, which can be caused by damage to brain function due to hypoxic and inflammatory disorders. It is believed that the combined occurrence of these brain abnormalities exacerbates symptoms. Therefore, it is desirable for an effective therapeutic agent for dementia or delirium to have pharmacological activity that increases acetylcholine levels in the brain while suppressing hypoxic and inflammatory disorders. Drugs with such activity have not been known until now, but this problem is solved by the present invention.

[0020] The present invention relates to thiazoline odor molecules that stimulate sensory neurons, etc., by increasing ATP in the brain or simultaneously increasing ATP and acetylcholine, making them a fundamental treatment for neurodegenerative diseases. The inventors have previously demonstrated that thiazoline odor molecules, such as 2-methyl-2-thiazoline and thiomorpholine, induce hypoxia resistance and anti-inflammatory effects via TRPA1 and other sensory receptors expressed in sensory neurons (Patent Document 1). These thiazoline odor molecules transmit sensory information to specific neurons in the parabrachial nucleus of the brainstem via TRPA1 and other sensory receptors expressed in sensory neurons, thereby activating the brain's integrated biological response control mechanism. This novel mechanism has been shown to efficiently increase ATP in the brain or simultaneously increase ATP and acetylcholine, a feat previously difficult to achieve with conventional techniques. It was previously thought that increasing acetylcholine would increase ATP. However, the inventors have discovered a new principle that increasing acetylcholine in neurons increases ATP under normal conditions and under stress, such as hypoxia. Therefore, the thiazoline odor molecule of the present invention can be a fundamental therapeutic drug that prevents the decline in cognitive and motor functions and the destruction of nerve cells in neurodegenerative diseases.

[0021] The present invention also relates to thiazoline odor molecules that stimulate sensory neurons and are capable of increasing acetylcholine levels in the brain while suppressing hypoxic damage and inflammation. The inventors have previously demonstrated that thiazoline odor molecules, such as 2-methyl-2-thiazoline and thiomorpholine, induce hypoxia resistance and anti-inflammatory effects via TRPA1 and other sensory receptors expressed in sensory neurons (Patent Document 1). These thiazoline odor molecules have been shown to induce metabolic changes in the brain, increasing acetylcholine and its raw material, choline, while simultaneously inducing hypoxia resistance and anti-inflammatory effects in the brain through a mechanism that transmits sensory information to the brain via TRPA1 and other sensory receptors expressed in sensory neurons. Therefore, the thiazoline odor molecules of the present invention are expected to improve cognitive function abnormalities caused by dementia or delirium.

[0022] That is, the present invention relates to the following: [1] Formula (I)

[0023]

[0024] 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, 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 ２a heterocyclic compound represented by formula (I) or a salt thereof, wherein R, ... [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 agent for preventing or treating neurodegenerative diseases or delirium is for nasal administration. [7] A method for preventing or treating neurodegenerative diseases or delirium 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 neurodegenerative diseases or delirium.

[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] , which is for nasal administration.

[13] The agent according to any one of [1] to [3], which is an agent for the prevention or treatment of neurodegenerative diseases.

[14] The agent according to any one of [1] to [3], which is a prophylactic or therapeutic agent for dementia or delirium.

[15] The use according to any one of [4] to [6], wherein the prophylactic or therapeutic agent for neurodegenerative diseases or delirium is a prophylactic or therapeutic agent for neurodegenerative diseases.

[16] The use according to any one of [4] to [6], wherein the prophylactic or therapeutic agent for neurodegenerative diseases or delirium is a prophylactic or therapeutic agent for dementia or delirium.

[17] The method according to any one of [7] to [9], wherein the prophylactic or therapeutic agent for neurodegenerative diseases or delirium is a prophylactic or therapeutic agent for dementia or delirium.

[18] The method according to any one of [7] to [9], wherein the prophylactic or therapeutic agent for dementia or delirium is a prophylactic or therapeutic agent for neurodegenerative diseases.

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

[10] to

[12] , wherein the prophylaxis or treatment of neurodegenerative diseases or delirium is the prophylaxis or treatment of neurodegenerative diseases.

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

[10] to

[12] , wherein the prevention or treatment of a neurodegenerative disease or delirium is the prevention or treatment of dementia or delirium.

[0025] The preventive or therapeutic agent for neurodegenerative diseases of the present invention has the effect of efficiently increasing ATP in the brain or simultaneously increasing ATP and acetylcholine, and can be used for the prevention or treatment of neurodegenerative diseases.

[0026] The prophylactic or therapeutic agent for dementia or delirium of the present invention increases acetylcholine in the brain and has the effect of suppressing hypoxic damage and inflammatory damage, and can be used for the prevention or treatment of dementia or delirium.

[0027] This shows the results of metabolome analysis of changes in acetylcholine-related metabolites in the brain following administration or exposure to thiazoline odor molecules (2-methyl-2-thiazoline (2MT), thiomorpholine (TMO)). This shows the results of metabolome analysis of changes in the amount of ATP, GTP, and UTP in the brain following intraperitoneal administration of thiomorpholine (TMO). This shows the results of metabolome analysis of changes in the amount of ATP, GTP, UTP, and their metabolites in the brain following intraperitoneal administration of thiomorpholine (TMO) and exposure to a hypoxic environment. This shows the results of in vivo live imaging monitoring of ATP levels in hippocampal neurons following intraperitoneal administration of 2.5 mg / kg or 5.0 mg / kg thiomorpholine (TMO). This shows the results of in vivo live imaging monitoring of ATP levels in hippocampal neurons following intraperitoneal administration of 10 mg / kg or 20 mg / kg thiomorpholine (TMO). This shows the results of metabolomic analysis of changes in ATP levels in the cerebrum following subcutaneous administration of 2-methyl-2-thiazoline (2MT). This shows the results of in vivo live imaging monitoring of ATP levels in hippocampal neurons following intraperitoneal administration of 2-ethylfuran. This shows the results of in vivo live imaging monitoring of ATP levels in hippocampal neurons following intraperitoneal administration of 2,3-diethylpyrazine. This shows the results of in vivo live imaging monitoring of ATP levels in hippocampal neurons following intraperitoneal administration of 2,4,5-trimethylthiazole. This shows the results of in vivo live imaging monitoring of ATP levels in hippocampal neurons following intraperitoneal administration of 2-acetyl-3,5-dimethylpyrazine. This shows the results of in vivo live imaging monitoring of ATP levels in hippocampal neurons following intraperitoneal administration of 2,6-lutidine. This shows the results of in vivo live imaging monitoring of ATP levels in hippocampal neurons following intraperitoneal administration of 2-acetylpyrrole. This shows the results of monitoring the ATP levels in hippocampal neurons by in vivo live imaging after intraperitoneal administration of 2-methylthiomorpholine.

[0033] Figure 1 shows the results of monitoring the ATP level in hippocampal neurons by in vivo live imaging when 2-ethylthiophene was administered intraperitoneally.

[0034] Figure 2 shows the results of monitoring the ATP level in hippocampal neurons by in vivo live imaging when 2,5-dimethylthiophene was administered intraperitoneally.

[0035] Figure 3 shows the results of monitoring the ATP level in hippocampal neurons by in vivo live imaging when 4-methylthiazole was administered intraperitoneally.

[0036] Figure 4 shows the results of monitoring the ATP level in hippocampal neurons by in vivo live imaging when 4-ethyl-2-methyl-2-thiazoline was administered intraperitoneally.

[0037] Figure 5 shows the chemical structures of the compounds used in Examples 1 to 7.

[0028] 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.

[0029] 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, furan, or 2,3-dihydro-4H-1,4-thiazine, even more preferably thiazoline (e.g., 2-thiazoline), thiazole, thiomorpholine, thiophene, pyrrole, pyridine, pyrazine, or furan, and particularly preferably thiazoline (e.g., 2-thiazoline) or thiomorpholine.

[0030] The "halogen atom" used herein is preferably selected from a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] As used herein, the term "oxo" (when used as a group or part of a group) refers to the group =0.

[0043] As used herein, an "optionally oxidized sulfur atom" refers to S, SO, or SO ２ means.

[0044] 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, and the like.１－６ There are 1 to 4 substituents selected from alkyl groups (e.g., methyl) and oxo groups.

[0045] 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), halogen atoms (e.g., chlorine atoms), amino groups, —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).

[0046] 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.

[0047] In formula (I), preferably, ring A is thiazoline (e.g., 2-thiazoline), thiazole, thiomorpholine, thiophene, pyrrole, pyridine, pyrazine, or furan; R １ , R ２ , R ３ , and R ４ are each independently a hydrogen atom, C １－６ Alkyl group (e.g., methyl, ethyl), or C １－６It is an alkyl-carbonyl group (eg, acetyl); n is 0 or 1 (preferably n is 0).

[0048] In formula (I), more preferably, ring A is thiazoline (e.g., 2-thiazoline) or thiomorpholine; R １ , R ２ , R ３ , and R ４ are each independently a hydrogen atom or C １－６ is an alkyl group; and n is 0 or 1 (preferably n is 0).

[0049] In the present invention, examples of heterocyclic compounds 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-ethylfuran 2,3-diethylpyrazine 2,4,5-trimethylthiazole 2-acetyl-3,5-dimethylpyrazine 2,6-lutidine 2-acetylpyrrole 2-methylthiomorpholine 2-ethylthiophene 2,5-dimethylthiophene 4-methylthiazole 4-ethyl-2-methyl-2-thiazoline As the heterocyclic compound of formula (I), 2-methyl-2-thiazoline (2MT) or thiomorpholine (TMO) are particularly preferred.

[0050] In the present invention, the heterocyclic compound of formula (I) used as an active ingredient includes substances generally known as reagents, and commercially available products can be used, or they can be obtained by methods known per se. The use of the heterocyclic compound of formula (I) as an agent for preventing or treating neurodegenerative diseases or delirium has not been disclosed or suggested up to now.

[0051] Preferred examples of the heterocyclic compound represented by formula (I) include compounds represented by the following formulae (A) to (D) or salts thereof.

[0052]

[0053] (In the formula, X １ is S, O, or N(R １６ ) and X ２ is N or CR １２ and X ３is S, SO ２ , O, or -(CH ２ ) ２ - and X ４ is N or CR １５ and

[0054]

[0055] 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, 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;

[0056]

[0057] 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)

[0058] In formulas (A) to (D), preferably, R １１ , R１２ , 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), halogen atoms (e.g., chlorine atoms), amino groups, —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.

[0059] 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.

[0060] 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.

[0061]

[0062] (In the formula, 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 C１－６ is an alkyl group; R １３Ａ and R １４Ａ may be bonded to each other to form a benzene ring;

[0063]

[0064] represents a single bond or a double bond). In a 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 １３Ａ is 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.

[0065] 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;

[0066]

[0067] indicates a single bond.

[0068]

[0069] (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 C １－４ 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; 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.

[0070] The agents provided by the present invention can be used as agents for preventing or treating neurodegenerative diseases or delirium. Agents provided by the present invention include agents for preventing or treating neurodegenerative diseases, dementia, or delirium.

[0071] Neurodegenerative diseases include dementia including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS).

[0072] Examples of dementia include Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, mixed dementia, and dementia due to Parkinson's disease.

[0073] Prevention or treatment of dementia or delirium includes prevention or treatment of abnormalities in cognitive function associated with dementia or delirium (decline in cognitive function, cognitive impairment, impaired consciousness, memory impairment, decreased attention or thinking ability, impaired executive function, disorientation, apraxia, agnosia, aphasia, etc.) or abnormalities in emotional state (anxiety, restlessness, depression, hallucinations, delusions, sleep disorders, hyperactivity, wandering, overeating, etc.).

[0074] 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 or may develop neurodegenerative diseases or delirium, for the purpose of preventing the onset of disorders 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 frequency of administration 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.).

[0075] When the compound of the present invention is used as an agent for preventing or treating neurodegenerative diseases or delirium (hereinafter also referred to as the agent of the present invention), pharmaceutically acceptable additives can be added as necessary.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] Example 1: Enhancement of acetylcholine release in the brain by thiazoline odor molecules. Experimental method: A: Approximately 8-week-old male C57BL / 6 mice were intraperitoneally administered 200 μL of saline or 1% thiomorpholine (TMO) solution (solvent: saline). 30 minutes later, their brains were rapidly removed and frozen in liquid nitrogen. B: Approximately 8-week-old male C57BL / 6 mice were placed in an innocage and each mouse was placed with four filter papers soaked in 25 μL of saline (no odor) or 25 μL of 2-methyl-2-thiazoline (2MT) (2MT odor). After 20 minutes of exposure to each odor, their brains were rapidly removed and frozen in liquid nitrogen. After pretreatment of the brain samples collected in A and B, metabolome analysis was performed using capillary electrophoresis-time-of-flight mass spectrometry (CE-TOFMS). The amounts of acetylcholine-related metabolites were measured, and the results are shown in Figures 1A and 1B. Each metabolite is shown relative to the mean value under saline conditions, which is set at 100%. The numbers in the figures indicate q values ​​adjusted for the false discovery rate. C: A model of the acetylcholine metabolic pathway is shown in Figure 1C. Substances that increased and decreased with administration of TMO or 2MT are also indicated in the figure as "increase" and "decrease," respectively.

[0081] Results (Figure 1) Intraperitoneal administration of TMO or exposure to the odor of 2MT significantly increased brain acetylcholine and choline levels compared to control conditions. Conversely, the levels of their precursors, CDP-choline (CDP-choline) and glycerophosphorylcholine (αGPC), were significantly decreased. This suggests that administration of TMO or 2MT enhances the metabolic pathways that synthesize choline and acetylcholine from CDP-choline and glycerophosphorylcholine in the brain. Cholinesterase inhibitors, currently used to treat Alzheimer's disease, inhibit the breakdown of acetylcholine into choline, increasing acetylcholine levels but decreasing choline production. In contrast, TMO and 2MT appear to increase brain acetylcholine levels by increasing the synthesis of choline and acetylcholine in the brain.

[0082] Example 2: Thiomorpholine-Induced Increases in Brain ATP, GTP, and UTP Experimental Method: Approximately 8-week-old male C57BL / 6 mice were intraperitoneally administered 200 μL of saline or 1% thiomorpholine solution (TMO, solvent: saline). 30 minutes later, the brains were rapidly removed and frozen in liquid nitrogen. After pretreatment, the collected brain samples were subjected to metabolomic analysis using CE-TOFMS. The amounts of ATP, GTP, and UTP were measured. The results are shown in Figure 2. Each metabolite is expressed as a relative value, with the average value in the saline condition set at 100%. The results of a Student's t-test comparing the saline-treated group and the TMO-treated group are shown in the figure. *P<0.05, ***P<0.001.

[0083] Results (Figure 2): ATP, GTP, and UTP were found to increase in the brains of mice administered TMO. ATP, GTP, and UTP are high-energy substances, suggesting that TMO administration increases the energy state in the brain.

[0084] Example 3: Thiomorpholine-Induced Increases in Brain ATP, GTP, and UTP in a Hypoxic Environment Experimental Method: Male C57BL / 6 mice approximately 8 weeks old were intraperitoneally administered 200 μL of saline or 1% thiomorpholine solution (TMO, solvent: saline) and then exposed to a hypoxic environment (4% oxygen concentration) 30 minutes later. After 20 minutes of exposure, the brains were rapidly removed and frozen in liquid nitrogen. As a control, brains were also removed from mice not exposed to a hypoxic environment 30 minutes after intraperitoneal administration of saline and frozen in liquid nitrogen. After pretreatment, the collected brain samples were subjected to metabolomic analysis using CE-TOFMS to measure the amounts of ATP, GTP, and UTP. The results are shown in Figure 3. The values ​​of each metabolite are expressed relative to the control average, which is set to 100%. A Student t-test comparing the saline-treated and TMO-treated groups is shown in the figure. *P<0.05, **P<0.01, ***P<0.001, # P<0.05, ##P<0.01, ###P<0.001. *, **, *** indicate a significant decrease compared to the control, and #, ##, ### indicate a significant increase compared to the control. The metabolic pathways of purine and pyrimidine are also shown at the bottom of the figure.

[0085] Results (Figure 3): Under conditions of hypoxia exposure after saline administration, the high-energy ATP, GTP, and UTP decreased, while their downstream metabolic products, adenosine, inosine, adenine, hypoxanthine, guanosine, uridine, and cytidine, increased. In contrast, under conditions of hypoxia exposure after TMO administration, the high-energy ATP and GTP did not decrease compared to controls, whereas UTP actually increased. Furthermore, the downstream metabolic products of ATP, GTP, and UTP, adenosine, inosine, hypoxanthine, guanosine, uridine, and cytidine, decreased compared to controls. These results suggest that, under the high-stress conditions of hypoxia exposure, which normally results in an energy deficiency, the TMO-treated group was able to maintain a high-energy state.

[0086] Example 4: Thiomorpholine-induced increase in ATP levels in hippocampal neurons (1) Experimental Method: The hippocampi of approximately 12-week-old male C57BL / 6 mice were infected with an adeno-associated virus (AAV) expressing the ATP sensor iATPSnFR under the control of a neuronal promoter. Three weeks later, an optical fiber was inserted into the hippocampus, and ATP levels in hippocampal neurons were monitored by in vivo live imaging. Figure 4 shows the z-score of iATPSnFR signals over 10 minutes after intraperitoneal administration of 200 μL of saline, 2.5 mg / kg thiomorpholine (TMO), or 5.0 mg / kg TMO.

[0087] Results (Figure 4) It was suggested that the amount of ATP in hippocampal neurons increased immediately after intraperitoneal administration of 2.5 mg / kg and 5.0 mg / kg TMO.

[0088] Example 5: Thiomorpholine-Induced Increase in ATP Levels in Hippocampal Neurons (2) Experimental Method: The hippocampi of approximately 12-week-old male C57BL / 6 mice were infected with an adeno-associated virus (AAV) expressing the ATP sensor iATPSnFR under the control of a neuronal promoter. Three weeks later, an optical fiber was inserted into the hippocampus, and ATP levels in hippocampal neurons were monitored by in vivo live imaging. Figure 5 shows the z-score of iATPSnFR signals over 10 minutes after intraperitoneal administration of 200 μL of saline, 10 mg / kg thiomorpholine (TMO), or 20 mg / kg TMO.

[0089] Results (Figure 5) It was suggested that the amount of ATP in hippocampal neurons increased immediately after intraperitoneal administration of 10 mg / kg and 20 mg / kg TMO.

[0090] Example 6: Increase in cerebral ATP by 2-methyl-2-thiazoline Experimental method: Male C57BL / 6 mice approximately 8 weeks old were subcutaneously administered saline or 50 mg / kg 2-methyl-2-thiazoline (2MT) solution (saline solution). 60 minutes later, the cerebrum was rapidly removed and frozen in liquid nitrogen. After pretreatment, the collected cerebral samples were subjected to metabolomic analysis using CE-TOFMS. ATP levels were measured. The results are shown in Figure 6. A Student t-test comparing the saline-treated group and the 2MT-treated group is shown in the figure. * P<0.05.

[0091] Results (Figure 6): Administration of 2MT significantly increased ATP levels in the cerebrum, suggesting that administration of 2MT increases the energy status of the cerebrum.

[0092] Example 7: Increase in ATP Levels in Hippocampal Neurons by 2MT and TMO-Related Compounds Experimental Method: Adeno-associated virus (AAV) expressing the ATP sensor iATPSnFR under the control of a neuron-specific promoter was injected into the hippocampus of approximately 12-week-old male C57BL / 6 mice. One week after virus injection, a cannula was inserted into the hippocampus, and 3 weeks later, ATP levels in hippocampal neurons were monitored by in vivo live imaging. 200 μL of saline or each compound diluted in saline was administered intraperitoneally at a dose of 80 mg / kg, and iATPSnFR signal fluctuations were measured for 30 minutes after administration. The iATPSnFR signal was normalized to a 1-minute baseline before administration and then subjected to a 1-minute moving average. These results are shown in Figures 7A–K. In Figure 7K, "4-Ethyl-2-methylthiazoline" refers to 4-ethyl-2-methyl-2-thiazoline.

[0093] Results (Figure 7A-K): The dotted line in the figure (60 seconds after the start) indicates the timing of administration of each compound. Administration of 2-ethylfuran (A), 2,3-diethylpyrazine (B), 2,4,5-trimethylthiazole (C), 2-acetyl-3,5-dimethylpyrazine (D), 2,6-lutidine (E), 2-acetylpyrrole (F), 2-methylthiomorpholine (G), 2-ethylthiophene (H), 2,5-dimethylthiophene (I), 4-methylthiazole (J), and 4-ethyl-2-methyl-2-thiazoline (K) suggested that ATP levels in the hippocampus increased immediately after administration.

[0094] The chemical structures of the compounds used in Examples 1 to 7 are shown in FIG.

[0095] The prophylactic or therapeutic agent for neurodegenerative diseases or delirium of the present invention can be used for the prevention or treatment of neurodegenerative diseases such as dementia including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, and for the prevention or treatment of abnormalities in cognitive function or emotional state in dementia or delirium.

[0096] This application is based on patent applications Nos. 2024-103558 and 2024-103559 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, 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 agent 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. The agent according to claim 1 or 2 for nasal administration.

4. A compound represented by formula (I) for producing a prophylactic or therapeutic agent for neurodegenerative diseases or delirium. 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, 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 agent for preventing or treating neurodegenerative diseases or delirium 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, 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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