Cerebral plasmalogen-increasing agent, oral composition for increasing cerebral plasmalogen, and use of compound

Abstract

The present invention provides a brain plasmalogen increasing agent comprising a compound represented by formula (I) (in the formula, X represents a carbon atom or an oxygen atom, R1 represents a saturated aliphatic hydrocarbon group which may contain a cyclic structure, R2 represents a saturated or unsaturated aliphatic hydrocarbon group which may have a substituent and has 10 to 30 carbon atoms), a racemate thereof, or a salt of the compound or the racemate, and a salt of the racemate or the salt of the compound represented by formula (I) (in the formula, X represents a carbon atom or an oxygen atom, R1 represents a saturated aliphatic hydrocarbon group which may have a cyclic structure). The substituent group is an alkyl group with a carbon atom number of 1-4 or an alkoxy group with a carbon atom number of 1-4.

Description

Technical Field

[0001] The present invention relates to a plasmalogen increasing agent, an oral composition for increasing plasmalogen, and uses of a compound. Background Art

[0002] Plasmalogen is a kind of phospholipid with antioxidant effects and is one of the glycerophospholipids. Plasmalogen exists in all tissues of mammals and accounts for about 18% of human phospholipids.

[0003] Since many plasmalogens are bound to polyunsaturated fatty acids such as docosahexaenoic acid and arachidonic acid, they are involved in the storage of polyunsaturated fatty acids and the release of second messengers of intercellular signals such as prostaglandins and leukotrienes produced from these polyunsaturated fatty acids. In addition, plasmalogen is also involved in cell fusion, ion transfer, etc. Since the vinyl ether bond (alkenyl bond) of plasmalogen is particularly sensitive to oxidative stress, plasmalogen also exerts an antioxidant function of cells.

[0004] In addition, it is well known that plasmalogen has a promoting effect on neurogenesis, an inhibitory effect on neuroinflammation caused by lipopolysaccharide (LPS), and an inhibitory effect on the accumulation of amyloid-β (Aβ) protein in the brain.

[0005] It is well known that plasmalogen is reduced in cerebrovascular diseases such as dementia, Parkinson's disease, depression, and schizophrenia. For example, it is reported in Non-Patent Document 1 that ethanolamine plasmalogen is significantly reduced in the frontal lobe and hippocampus of the brain of patients with Alzheimer's disease. Therefore, it is considered that by increasing the reduced plasmalogen, preventive and ameliorating effects on the above diseases can be expected. For example, Patent Document 1 discloses an anti-central nervous system inflammatory agent containing plasmalogen. It is reported in Non-Patent Document 2 that in a randomized double-blind clinical trial with subjects suffering from mild Alzheimer's disease and mild cognitive impairment, plasmalogen extracted from scallops is orally administered, and as a result, it is strongly suggested that the cognitive function of mild Alzheimer's disease is improved. Non-Patent Document 3 shows that the learning ability and memory ability of mice orally administered plasmalogen extracted from scallops are enhanced.

[0006] Prior Art Documents

[0007] Patent Documents

[0008] Patent Document 1: WO 2012 / 039472

[0009] Non-Patent Documents

[0010] Non-Patent Document 1: Z. Guan et al, Decrease and Structural Modifications of Phosphatidylethanolamine Plasmalogen in the Brain with Alzheimer Disease, J Neuropathol Exp Neurol, 58(7), 740 - 747, 1999

[0011] Non-Patent Document 2: T. Fujino et al, Efficacy and Blood Plasmalogen Changes by Oral Administration of Plasmalogen in Patients with Mild Alzheimer's Disease and Mild Cognitive Impairment: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial, EBioMedicine, 17:199 - 205, 2017

[0012] Non-Patent Document 3: M.S. Hossain et al, Plasmalogens, the Vinyl Ether-Linked Glycerophospholipids, Enhance Learning and Memory by Regulating Brain-Derived Neurotrophic Factor, Front. Cell Dev. Biol. 10:828282, 2022 Summary of the Invention

[0013] Technical Problem to be Solved

[0014] The present invention has been completed in view of the above circumstances, and its object is to provide a plasmalogen-increasing agent capable of increasing plasmalogen in the brain, an oral composition for increasing plasmalogen in the brain, and uses of a compound.

[0015] Solution to the Problem

[0016] The plasmalogen-increasing agent according to the first aspect of the present invention contains a compound represented by formula (I), its racemate, or a salt thereof.

[0017]

[0018] (In formula (I), X represents a carbon atom or an oxygen atom, and R 1 represents a saturated aliphatic hydrocarbon group which may contain a ring structure, and R 2 represents a saturated or unsaturated aliphatic hydrocarbon group having 10 to 30 carbon atoms which may have substituents, and the substituents are alkyl groups having 1 to 4 carbon atoms or alkoxy groups having 1 to 4 carbon atoms.)

[0019] The oral composition for increasing plasmalogens in the brain according to the second aspect of the present invention contains a compound represented by formula (I), its racemate or a salt thereof.

[0020]

[0021] (In formula (I), X represents a carbon atom or an oxygen atom, and R 1 represents a saturated aliphatic hydrocarbon group which may contain a ring structure, and R 2 represents a saturated or unsaturated aliphatic hydrocarbon group having 10 to 30 carbon atoms which may have substituents, and the substituents are alkyl groups having 1 to 4 carbon atoms or alkoxy groups having 1 to 4 carbon atoms.)

[0022] X may be an oxygen atom, and R 1 may be an alkyl group having 18 carbon atoms, and R 2 may be an unsaturated aliphatic hydrocarbon group.

[0023] R 2 may be a monovalent group, and when it is R 2 COOH, it represents arachidonic acid.

[0024] Use of the compound according to the third aspect of the present invention is for the use of a compound represented by formula (I), its racemate or a salt thereof for preparing an agent for increasing plasmalogens in the brain or an oral composition for increasing plasmalogens in the brain.

[0025]

[0026] (In formula (I), X represents a carbon atom or an oxygen atom, and R 1 represents a saturated aliphatic hydrocarbon group which may contain a ring structure, and R 2 represents a saturated or unsaturated aliphatic hydrocarbon group having 10 to 30 carbon atoms which may have substituents, and the substituents are alkyl groups having 1 to 4 carbon atoms or alkoxy groups having 1 to 4 carbon atoms.)

[0027] Effects of the Invention

[0028] According to the present invention, plasmalogens in the brain can be increased. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1AIt is a graph showing the concentration of plasmalogens in the cerebral cortex tissue lysate according to Example 2.

[0030] Figure 1B It is a graph showing the concentration of plasmalogens in the cerebral cortex tissue lysate according to Example 2, where the sn-1 position is a saturated aliphatic hydrocarbon group (C18:0) with 18 carbon atoms.

[0031] Figure 2 It is a graph showing the concentration of plasmalogens in the cerebral cortex tissue lysate according to Example 3. Detailed Description of the Invention

[0032] Embodiments of the present invention will be described with reference to the accompanying drawings. In addition, the present invention is not limited to the following embodiments and drawings. Further, in the following embodiments, expressions such as "having", "including", or "containing" also include the meaning of "consisting of" or "composed of".

[0033] The brain plasmalogen increasing agent according to the present embodiment contains a compound represented by formula (I), a racemate thereof, or a salt thereof.

[0034]

[0035] In formula (I), X represents a carbon atom or an oxygen atom. Preferably, X is an oxygen atom. R 1 represents a saturated aliphatic hydrocarbon group that may contain a cyclic structure. The number of carbon atoms in the saturated aliphatic hydrocarbon group is not particularly limited, for example, it is 10 to 30, 10 to 25, or 10 to 20. The number of carbon atoms constituting the cyclic structure is, for example, 3 to 6. The cyclic structure may be included in R as a subcycloalkyl group 1 or may be included in R as a cycloalkyl group 1 . The number of carbon atoms constituting the cyclic structure is preferably 3. The saturated aliphatic hydrocarbon group may have a cyclic structure at the end of R 1 , that is, as a monovalent group. Preferably, R 1 is an alkyl group having 18 carbon atoms.

[0036] R 2 represents a saturated or unsaturated aliphatic hydrocarbon group having 10 to 30 carbon atoms that may have a substituent, and the substituent is an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms. Preferably, R 2 is an unsaturated aliphatic hydrocarbon group. For example, when it is R 2 COOH, R 2 is a monovalent group representing ω-3 fatty acid, ω-6 fatty acid, ω-7 fatty acid, ω-9 fatty acid, or ω-10 fatty acid. Preferably, when it is R 2 COOH, R 2is a monovalent group representing arachidonic acid, a monovalent group representing docosahexaenoic acid, a monovalent group representing oleic acid, a monovalent group representing eicosapentaenoic acid, or a monovalent group representing linoleic acid.

[0037] Salts of the compound represented by the above formula (I) and salts of racemates of the compound, as long as they are pharmaceutically acceptable salts, are not particularly limited and may be acid salts or base salts. Examples of the salts include alkali metal salts such as lithium salt, sodium salt, and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, oxalate, and phosphate; organic acid salts such as acetate, propionate, hexanoate, cyclopentanepropionate, glycolate, pyruvate, lactate, malonate, succinate, malate, fumarate, tartrate, citrate, benzoate, o-(4-hydroxybenzoyl)benzoate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-chlorobenzenesulfonate, 2-naphthalenesulfonate, p-toluenesulfonate, camphorsulfonate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, glutamate, hydroxynaphthoate, salicylate, stearate, trifluoroacetic acid (TFA) salt, maleate, muconate, etc.

[0038] Preferably, the plasmalogen enhancer according to the present embodiment contains a compound represented by the following formula, a racemate thereof, or a salt thereof.

[0039]

[0040] The compound according to the present embodiment can be synthesized by a known method. For example, tert-butyl (2-((tert-butoxy((R)-2-hydroxy-3-(octadecyloxy)propoxy)phosphoryl)oxy)ethyl)carbamate is reacted with arachidonic acid using a condensing agent. The compound according to the present embodiment is obtained by subjecting the resulting product to deprotection by the action of a strong acid such as trifluoroacetic acid. The condensing agent is not particularly limited, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) hydrochloride, dicyclohexylcarbodiimide (DCC), HATU, HBTU, TATU, TBTU, diphenylphosphoryl azide (DPPA), etc. can be used. In order to promote the dehydration condensation reaction caused by the condensing agent, a nucleophilic reagent such as dimethylaminopyridine (DMAP) can also be used.

[0041] The ceramide phospholipid increasing agent according to the present embodiment may further contain other pharmacologically acceptable components in addition to containing the compound represented by the above formula (I), its racemate, or a salt thereof (hereinafter, also referred to as "compound, etc.") as an active ingredient. Other pharmacologically acceptable components are, for example, excipients, lubricants, binders, disintegrants, solvents, solubilizers, suspending agents, tonicity agents, buffers, analgesics, etc. In addition, preservatives, antioxidants, colorants, sweeteners and other additives may be added to the ceramide phospholipid increasing agent as needed.

[0042] Excipients are, for example, lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, etc. Lubricants are, for example, magnesium stearate, calcium stearate, talc, colloidal silica, etc. Binders are, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, etc. Disintegrants are, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, etc.

[0043] Solvents are, for example, water for injection, ethanol, propylene glycol, polyethylene glycol, etc. Solubilizers are, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc. Suspending agents are surfactants and hydrophilic polymers, etc., for example, stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.

[0044] Tonicity agents are, for example, sodium chloride, glycerol, D-mannitol, etc. Buffers are, for example, buffer solutions of phosphates, acetates, carbonates, citrates, etc. Analgesics are, for example, benzyl alcohol, etc. Preservatives are, for example, parabens, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. Antioxidants are, for example, sulfites, ascorbic acid, etc.

[0045] As shown in the following examples, compared with before the administration of plasmalogen increasing agents, the plasmalogen increasing agent according to the present embodiment increases plasmalogens in the brain. Plasmalogens belong to a specific subclass of glycerophospholipids, which are characterized by having a vinyl ether bond at the sn-1 position of the glycerol backbone and an ester bond at the sn-2 position. The plasmalogens in the brain increased by the plasmalogen increasing agent are not particularly limited as long as they are glycerophospholipids generally classified as plasmalogens. Examples of plasmalogens include phosphatidylethanolamine plasmalogen (PlsEtn), phosphatidylcholine plasmalogen (PlsCho), phosphatidylinositol plasmalogen, and phosphatidylserine plasmalogen. In addition, Pls has a structure in which -CH2CH2-NH2 is bonded to the oxygen atom bonded to the phosphorus at the sn-3 position of the glycerol backbone. PlsCho has a structure in which -CH2CH2N(CH3)3 is bonded to the oxygen atom bonded to the phosphorus at the sn-3 position of the glycerol backbone.

[0046] The plasmalogen increasing agent according to the present embodiment increases plasmalogens in the brain, and thus can be used for preventing and treating symptoms or diseases caused by a decrease in plasmalogens in the brain. Examples of diseases caused by a decrease in plasmalogens in the brain include dementia, Alzheimer's disease, Parkinson's disease, depression, and schizophrenia.

[0047] The plasmalogen increasing agent is prepared by a known method and contains the above compounds and the like as active ingredients. The plasmalogen increasing agent contains, for example, 0.1 to 99% by weight, 1 to 50% by weight, preferably 1 to 20% by weight of plasmalogens as active ingredients.

[0048] The administration target of the plasmalogen increasing agent according to the present embodiment is a human or an animal other than a human. As the animal, a mammal is preferred, and more specifically, dogs, cats, cows, pigs, horses, sheep, deer, etc. can be mentioned. The administration route of the plasmalogen increasing agent to humans is not particularly limited. The plasmalogen increasing agent is preferably used as an external preparation, an injection, and an oral administration preparation.

[0049] The plasmalogen increasing agent is provided in the form of, for example, a liquid agent, a tablet, a granule, a fine granule, a powder, a pill, a capsule, etc.

[0050] The dosage of the plasmalogen increasing agent is appropriately determined according to the age, weight, symptoms, etc. of the human or the like as the administration target. The plasmalogen increasing agent administers the above compounds and the like in an effective amount. The effective amount refers to the amount of the compounds and the like required to increase plasmalogens in the brain.

[0051] As described in detail above, the plasmalogen increasing agent according to the present embodiment can increase plasmalogens in the brain.

[0052] In addition, in another embodiment, there is provided an oral composition for increasing brain plasmalogens, which contains the above-mentioned compounds and the like. As the oral composition for increasing brain plasmalogens, specifically, supplements, food compositions, foods and beverages, functional foods, food additives, and the like can be mentioned. In addition, the brain plasmalogen increasing agent can be administered as a supplement or added to foods, beverages, and functional foods.

[0053] The form of the supplement is not particularly limited and can be any form such as tablets, powders, granules, capsules, sugar-coated tablets, films, troches, chewable tablets, solutions, emulsions, suspensions, and the like. The supplement can contain any components commonly used as supplements.

[0054] "Functional foods" refer to foods or beverages ingested for the purpose of maintaining health, including foods for specified health uses as health functional foods, functionally labeled foods, nutritional functional foods, health foods, nutritional supplements, and the like. As functional foods, foods for specified health uses as health functional foods or nutritional functional foods are preferably used. In addition, when commercialized as functional foods, various additives used in foods, specifically, colorants, preservatives, thickening and stabilizing agents, antioxidants, bleaching agents, antibacterial and antifungal agents, acidulants, sweeteners, flavorings, emulsifiers, additives, preparations, fragrances, and the like can be added to the oral composition for increasing brain plasmalogens.

[0055] Functional foods can be foods or beverages and are not particularly limited as long as they can be taken orally. Examples of functional foods include, for example, beverages, snacks, processed cereal products, blended processed foods, dairy products, flavorings, and the like. As beverages, nutritional beverages, soft drinks, black tea, green tea, and the like can be mentioned. As snacks, candies, cookies, tablet candies, chewing gums, jellies, and the like can be mentioned. As processed cereal products, bread, rice, cookies, and the like can be mentioned. As blended processed foods, sausages, hams, fish cakes, and the like can be mentioned. As dairy products, butter, yogurt, and the like can be mentioned.

[0056] The oral composition for increasing brain plasmalogens can be added to foods as a food additive. In this case, the food additive can be a paste, a gel-like agent, a powder, a liquid agent, a suspending agent, an emulsion, a granule, or the like for easy addition to foods.

[0057] The oral composition for increasing brain plasmalogens can contain water, vitamins, minerals, organic acids, organic bases, fruit juices, fragrances, functional components, food additives, and the like within the range of maintaining the effect of increasing brain plasmalogens. The oral composition for increasing brain plasmalogens can be added with other components other than the above-mentioned compounds and the like as needed and prepared by known methods.

[0058] The oral composition for increasing plasmalogens in the brain can be separated and contained in one or more containers so that the daily intake is the above-mentioned intake. In this case, preferably, the oral composition for increasing plasmalogens in the brain for one day's amount is contained in one container.

[0059] In terms of increasing plasmalogens in the brain, the oral composition for increasing plasmalogens in the brain is provided in a manner that can distinguish it as a product from other products. For example, on at least one of the packaging, instructions, and promotional materials of the product related to the oral composition for increasing plasmalogens in the brain, it is indicated that the product has the effect of increasing plasmalogens in the brain.

[0060] When the oral composition for increasing plasmalogens in the brain is provided as a food and beverage composition, it can be provided or sold as a food and beverage labeled with the use of increasing plasmalogens (including health uses). The "labeling" act includes any act aimed at informing the requester of the above uses. As long as it is an expression that can make people associate with or infer the above uses, regardless of the content of the labeling, the object of the labeling, the medium, etc., it is equivalent to the "labeling" act.

[0061] Preferably, the "labeling" is carried out in an expression that the requester can directly recognize the above uses. Specifically, it can include the act of transferring, delivering, displaying for transfer or delivery, or importing a product related to food and beverage or a product with the above uses recorded on the packaging of the product; the act of recording the above uses in an advertisement, price list, or transaction document related to the product and displaying or distributing it, or recording the above uses in the information with these as the content and providing it by electromagnetic means (such as the Internet).

[0062] "Labeling" includes labeling as a health food, functional food, enteral nutrition food, special-purpose food, health care functional food, specific health care food, nutritional functional food, functional labeling food, external medicine for medical use, etc. Among them, in particular, it can include the systems related to specific health care foods, nutritional functional foods, or functional labeling foods, or the labeling recognized by these similar systems. Specifically, it can include the labeling as a specific health care food, the labeling as a conditional specific health care food, the labeling showing an impact on the body structure or function, the disease risk reduction labeling, the functional labeling based on scientific evidence, etc. More specifically, as a typical example, it can include the labeling as a specific health care food (especially the labeling of health uses) and the labeling similar to this.

[0063] In another aspect of the present embodiment, there is provided the use of the above-mentioned compounds and the like for preparing a brain plasmalogen increasing agent or an oral composition for increasing brain plasmalogen. Further, in another aspect of the present embodiment, there is provided a method for increasing brain plasmalogen, which includes the step of administering the above-mentioned compounds and the like to a subject. Further, in another aspect of the present embodiment, there are provided the above-mentioned compounds and the like for use in increasing brain plasmalogen.

[0064] Examples

[0065] [Example 1: Synthesis of Compound KIT-13]

[0066] As follows, KIT-13 was synthesized as a compound according to formula (I).

[0067]

[0068] To a dichloromethane solution (3 mL) of tert-butyl (2-((tert-butoxy((R)-2-hydroxy-3-(octadecyloxy)propoxy)phosphoryl)oxy)ethyl)carbamate (187 mg, 0.30 mmol), EDC hydrochloride (115 mg, 0.60 mmol), DMAP (37 mg, 0.30 mmol) and arachidonic acid (100 mg, 0.33 mmol) were added at room temperature and stirred for 20 hours. The reaction solution was diluted with ethyl acetate and then washed with water. The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography to obtain the target colorless liquid (2R)-1-((tert-butoxy(2-((tert-butoxycarbonyl)amino)ethoxy)phosphoryl)oxy)-3-(octadecyloxy)propan-2-yl (5Z,8Z,11Z,14Z)-eicos-5,8,11,14-tetraenoate (260 mg, 95%).

[0069] 11H NMR (500 MHz, CDCl3) δ 5.43 - 5.31 (m, 8H), 5.16 (quin, J = 4.9 Hz, 1H), 5.16 (br, 1H), 4.21 (m, 1H), 4.14 - 4.09 (m, 1H), 4.07 - 4.02 (m, 2H), 3.55 (d, J = 5.3 Hz, 2H), 3.47 - 3.38 (m, 5.3 Hz), 2.85 - 2.79 (m, 6H), 2.35 (t, J = 7.6 Hz), 2.12 (q, J = 7.0 Hz, 2H), 2.06 (q, J = 7.1 Hz, 2H), 1.74 - 1.67 (m, 2H), 1.56 - 1.54 (m, 2H), 1.502 (s, 9H, one diastereomer), 1.496 (s, 9H, another diastereomer), 1.39 - 1.25 (m, 38H), 0.90 - 0.87 (m, 6H).

[0070]

[0071] To a solution of ethyl (2R)-1-((tert-butoxy(2-((tert-butoxycarbonyl)amino)ethoxy)phosphoryl)oxy)-3-(octadecyloxy)propan-2-yl (5Z,8Z,11Z,14Z)-eicos-5,8,11,14-tetraenoate (260 mg, 0.29 mmol) in dichloromethane (2 mL) was added 2 mL of trifluoroacetic acid at room temperature and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to afford the title colorless liquid 2-(hydroxy((R)-2-(((5Z,8Z,11Z,14Z)-eicos-5,8,11,14-tetraenoyl)oxy)-3-(octadecyloxy)propoxy)phosphoryl)oxy)ethane-1-ammonium 2,2,2-trifluoroacetate (KIT-13) (249 mg, quantitative).

[0072] 1 1H NMR (500 MHz, CDCl3) δ 11.31 (br, 1H), 5.41 - 5.31 (m, 8H), 5.16 - 5.15 (m, 1H), 4.17 (br, 2H), 4.07 - 4.00 (m, 2H), 3.54 (d, J = 4.9 Hz, 2H), 3.45 - 3.39 (m, 2H), 3.27 (br), 2.84 - 2.78 (m, 6H), 2.35 (t, J = 7.4 Hz, 2H), 2.10 (q.J = 7.1 Hz, 2H), 2.05 (q.J = 7.2 Hz, 2H), 1.69 - 1.66 (m, 2H), 1.54 - 1.51 (m, 2H), 1.39 - 1.25 (m, 38H), 0.90 - 0.86 (m, 6H).

[0073] [Example 2: Investigation of the effect of compound KIT-13 on brain plasmalogens]

[0074] Four-week-old male MeCP2-deficient mice lacking the MeCP2 gene located on the X chromosome were used in the experiment. The MeCP2-deficient mice were divided into two groups: a control group (MeCP2-KO) and a KIT-13 administration group (KIT-13).

[0075] For the KIT-13 administration group, KIT-13 suspended in water was administered to the drinking water twice a week by sonication so that it was ingested at 20 ng / g body weight. On the other hand, for the control group, only water was given in the same manner. KIT-13 was administered until the mice were 7 weeks old, and at 3 weeks, the cerebral cortex was collected from the mouse brain.

[0076] The collected cerebral cortex was homogenized with a lysis solution (0.25 M sucrose, 10 mM HEPES-KOH (pH 7.4), 1 mM EDTA, and protease inhibitor cocktail) to prepare a tissue lysate (25 μg protein). 400 μL of methanol and 100 μL of internal standards IS (C12 phosphatidylethanolamine (PE) and C12 phosphatidylcholine (PC)) dissolved in chloroform / methanol (C:M = 1:2) were added to the tissue lysate in the sample tube and mixed, and the sample was transferred to a spitz glass. 200 μL of methanol was added to the above sample tube again, and after the same operation, it was transferred to a spitz glass. 1.2 mL of C / M (1:1) was added to the sample and mixed, sonicated for 5 minutes, and allowed to stand for 60 minutes. 0.625 mL of chloroform was added to the sample and mixed, and then 0.625 mL of MilliQ was added to the sample and mixed. The sample was centrifuged at 3000 rpm for 5 minutes, and the lower layer was transferred to another spitz glass. 1 mL of chloroform was added to the remaining upper layer and mixed, then centrifuged at 3000 rpm for 5 minutes, and combined with the previously separated lower layer. Thereafter, it was dried with nitrogen, dissolved in methanol, and analyzed by liquid chromatography tandem mass spectrometry (LC-MS / MS). The conditions of LC-MS / MS are as follows.

[0077] LC system: Waters ACQUITY UPLC (trademark) H-Class

[0078] MS: Xevo TQ-Smicro

[0079] MS software: MassLynx V4.1

[0080] Data analysis: TargetLynx

[0081] <LC conditions>

[0082] Chromatographic column: ACQUITY UPLC (trademark) BEH C18 1.7μm 1.0x150mm

[0083] Column temperature: 35 °C

[0084] Sample solvent: Methanol

[0085] Mobile phase:

[0086] A) Methanol: Acetonitrile: Water = 2:2:1, 0.1% formic acid, 0.025% ammonia water

[0087] B) 2-Propanol, 0.1% formic acid, 0.025% ammonia water

[0088] Flow rate: 0.07 mL / min

[0089] Time schedule: See Table 1 below.

[0090] [Table 1]

[0091]

[0092]

[0093] Mode: ESI+

[0094] Source voltage

[0095] Capillary: 2.0 kV

[0096] Sampling cone: 20 V

[0097] Source temperature: 150 °C

[0098] Desolvation temperature: 400 °C

[0099] Source gas flow rate:

[0100] Desolvation: 800 L / hour nitrogen

[0101] Sampling cone: 50 L / hour argon

[0102] (Results)

[0103] Figure 1A Shows the PlsEtn concentration in the tissue lysate. Through the action of KIT-13, the PlsEtn in the cerebral cortex increased significantly (p < 0.05). Figure 1B Shows the concentration of PlsEtn with a saturated aliphatic hydrocarbon group with 18 carbon atoms at the sn-1 position in the tissue lysate (PlsEtn-C18:0). Through the action of KIT-13, the PlsEtn-C18:0 in the cerebral cortex increased significantly (p < 0.05).

[0104] [Example 3: Investigation of the effect of compound KIT-13 on PlsEtn in the cerebral cortex]

[0105] Four-week-old wild-type mice (male, C57BL / 6J mice, prepared by Jackson Laboratory Japan) were divided into two groups: a control group and a KIT-13 administration group. For the KIT-13 administration group, KIT-13 was administered in the same manner as in Example 2. For the control group, only water was given in the same manner as in Example 2. After administering KIT-13 for 4 weeks, the cerebral cortex was collected from the mouse brains. PlsEtn in the collected cerebral cortex was quantified in the same manner as in Example 2.

[0106] (Results)

[0107] Figure 2 The relative value of the amount of PlsEtn in the cerebral cortex of the KIT-13 administration group (KIT-13; +) is shown when the amount of PlsEtn in the cerebral cortex of the control group (KIT-13; -) is set to 1. By administering KIT-13, the amount of PlsEtn in the cerebral cortex was significantly increased even in wild-type mice.

[0108] Without departing from the broad spirit and scope of the present invention, the present invention can be implemented in various embodiments and modifications. In addition, the above embodiments are used to illustrate the present invention and do not limit the scope of the present invention. That is, the scope of the present invention is represented by the claims rather than the embodiments. And various modifications implemented within the scope of the claims and their equivalent inventions are considered to be within the scope of the present invention

[0109] This application is based on Japanese Patent Application No. 2022-185424 filed on November 21, 2022. The entire specification, claims, and drawings of Japanese Patent Application No. 2022-185424 are incorporated herein by reference.

[0110] Industrial applicability

[0111] The present invention can be used to prepare drugs or oral compositions.

Claims

1. A plasmalogen-increasing agent, wherein, Comprising a compound represented by formula (I), a racemate thereof, or a salt thereof, In formula (I), X represents a carbon atom or an oxygen atom, and R 1 represents a saturated aliphatic hydrocarbon group which may contain a cyclic structure, and R 2 represents a saturated or unsaturated aliphatic hydrocarbon group having 10 to 30 carbon atoms which may have substituents, and the substituents are alkyl groups having 1 to 4 carbon atoms or alkoxy groups having 1 to 4 carbon atoms.

2. An oral composition for increasing plasmalogen, wherein, Comprising a compound represented by formula (I), a racemate thereof, or a salt thereof, In formula (I), X represents a carbon atom or an oxygen atom, and R 1 represents a saturated aliphatic hydrocarbon group which may contain a cyclic structure, and R 2 represents a saturated or unsaturated aliphatic hydrocarbon group having 10 to 30 carbon atoms which may have substituents, and the substituents are alkyl groups having 1 to 4 carbon atoms or alkoxy groups having 1 to 4 carbon atoms.

3. The plasmalogen-increasing agent according to claim 1 or the oral composition for increasing plasmalogen according to claim 2, wherein, X is an oxygen atom, R 1 is an alkyl group having 18 carbon atoms, R 2 is an unsaturated aliphatic hydrocarbon group.

4. The plasmalogen-increasing agent or the oral composition for increasing plasmalogen according to claim 3, wherein, R 2 is a monovalent group and, when being R 2 COOH, represents arachidonic acid.

5. Use of a compound represented by formula (I), a racemate thereof or a salt thereof for preparing a plasmalogen-increasing agent or an oral composition for increasing plasmalogen, In formula (I), X represents a carbon atom or an oxygen atom, R 1 represents a saturated aliphatic hydrocarbon group which may contain a cyclic structure, R 2 represents a saturated or unsaturated aliphatic hydrocarbon group having 10 to 30 carbon atoms which may have a substituent, and the substituent is an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms.

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