Composition for activating transient receptor potential ankyrin 1 and composition for enhancing amount taken and / or improving anorexia

Abstract

To provide a novel agonist of TRPA1.SOLUTION: The present invention relates to a composition for activating TRPA1 including a compound of the formula (1) below or a glucoside thereof. In the formula (1), R1 is either a hydrogen or a normal chain or a branched chain hydrocarbon group having n carbon atoms combined with m oxygen atoms, the oxygen atoms form hydroxy groups or epoxy groups, n is an integer of 1 to 20, m is a hydrocarbon group being an integer that satisfies the following relational expression: m≥n / 5, R2 to R6 are independently hydrogen, hydroxy group, halogen, alkyl group having 1 to 3 carbon atoms, or alkoxy group having 1 to 3 carbon atoms. The composition enables enhancement of appetite to enhance the amount taken and improvement of anorexia.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a composition for activating transient receptor potential ankyrin 1 (TRPA1), and also to a composition for increasing food intake and / or improving anorexia. [Background technology]

[0002] TRPA1 is a nonselective cation channel that belongs to the transient receptor potential (TRP) ion channel superfamily. TRPA1 is mainly expressed in somatosensory nerves (spinal sensory nerves and trigeminal nerves) and functions as a nociceptor involved in pain and spiciness. In addition to somatosensory nerves, TRPA1 is also expressed in large amounts in the afferent vagus nerve, which is involved in feeding regulation.

[0003] Various compounds or plant extracts are known as agonists that activate TRPA1 (Patent Documents 1 to 9). In particular, the hot components of spices and spicy vegetables contain compounds that act as TRPA1 agonists, and such TRPA1 agonists are known to improve anorexia by increasing food intake (Patent Documents 10 and 11 and Non-Patent Document 1). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Publication No. 2018-177739 [Patent Document 2] Special Publication No. 2017-518963 [Patent Document 3] Japanese Patent Application Publication No. 2017-096785 [Patent Document 4] Japanese Patent Application Laid-Open No. 2014-210725 [Patent Document 5] Japanese Patent Application Laid-Open No. 2014-169240 [Patent Document 6] Japanese Patent Application Laid-Open No. 2014-076979 [Patent Document 7] Japanese Patent Application Laid-Open No. 2014-024810 [Patent Document 8] Special Publication No. 2011-506289 [Patent Document 9] International Publication No. 2009 / 123080 [Patent Document 10] Japanese Patent Publication No. 2020-109065 [Patent Document 11] International Publication No. 2023 / 090313 [Non-patent literature]

[0005] [Non-Patent Document 1] Mishima Kaiun Memorial Foundation Research Report (2014), Vol. 51, pp. 53-56 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a novel agonist of TRPA1. [Means for solving the problem]

[0007] As a result of intensive research aimed at solving the above problems, the present inventors have found that a specific compound having a bergaptol structure exhibits a TRPA1 activating effect (agonist effect), and have completed the present invention. That is, the present invention provides the following compositions for activating TRPA1, and compositions for increasing food intake and / or improving anorexia. [1] Formula (1): [ka] (1) (where R 1is hydrogen or a linear or branched hydrocarbon group having n carbon atoms and m oxygen atoms bonded thereto, the oxygen atoms forming a hydroxy group or an epoxy group, n is an integer of 1 to 20, and m satisfies the following relational formula: m≧n / 5 is a hydrocarbon group, and the integer satisfies R 2 ~R 6 are each independently hydrogen, a hydroxy group, a halogen, an alkyl group having 1 to 3 carbon atoms, or an alkoxy group having 1 to 3 carbon atoms. A composition for activating transient receptor potential ankyrin 1 (TRPA1), comprising the compound of formula (I) or a glycoside thereof. [2] The composition according to [1], wherein the water / octanol partition coefficient (logP) of the compound is 3 or less. [3] The hydrocarbon group is a saturated hydrocarbon group or an unsaturated hydrocarbon group having p double bonds, and p is represented by the following formula: 1≦p<1+n / 5 The composition according to [1] or [2] above, wherein R is an integer satisfying the following formula: [4] The composition according to any one of the above [1] to [3], wherein the hydrocarbon group contains an isoprene unit. [5] R 2 ~R 6 The composition according to any one of the above [1] to [4], wherein is hydrogen. [6] The compound is selected from the group consisting of: [ka] The composition according to any one of [1] to [5] above, wherein the composition is at least one selected from the group consisting of: [7] The composition according to any one of [1] to [6] above, which is a food composition, a pharmaceutical composition, or an agricultural chemical composition. [8] A composition for increasing food intake and / or improving anorexia, comprising a compound defined in any one of [1] to [6] above or a glycoside thereof. [9] The composition described in [8] above, which is a food composition or a pharmaceutical composition. [Effects of the Invention]

[0008] According to the present invention, the compound of formula (1) can activate TRPA1, and this activation effect can increase appetite, enhance food intake, and improve anorexia. [Brief explanation of the drawings]

[0009] [Figure 1] Photograph of a PLC silica plate after development of kaffir lime leaf extract is shown. [Figure 2] The spectra of (A) kaffir lime leaf fraction 2, (B) oxypoisedanine, (C) pangerin, (D) 6,7-dihydroxybergamottin, (E) oxypoisedanine hydrate, and (F) bergaptol analyzed by liquid chromatography-mass spectrometry are shown. [Figure 3] 1 shows a graph of the concentration-dependent TRPA1 activation effect of test compounds. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention will now be described in further detail. The composition of the present invention is used for activating TRPA1, and contains, as an active ingredient, a specific compound having a bergaptol skeleton, i.e., a compound represented by formula (1): [ka] (1) In formula (1), R 1 is hydrogen or a linear or branched hydrocarbon group having n carbon atoms and m oxygen atoms bonded thereto, the oxygen atoms forming a hydroxy group or an epoxy group, n is an integer of 1 to 20, 1 to 15, or 1 to 12, and m is represented by the following relational formula: m≧n / 5 R is a hydrocarbon group whose integer satisfies the following: 1When is the hydrocarbon group, the upper limit of the number of oxygen atoms (m) is not particularly limited, but may be, for example, a group satisfying the following relational formula: m≦2×n+1 and may be at most 20.

[0011] Without being bound by any particular theory, R 1 If the hydrophobicity of the compound is too high, it may affect the TRPA1 activation activity, so if the number of carbon atoms is large, it is thought that it is necessary to appropriately impart polarity by oxygen atoms. In one embodiment, the water / octanol partition coefficient (logP) of the compound may be about 3 or less. This logP may be ClogP calculated by calculation. In other words, the hydrophobicity of the entire compound is estimated by ClogP, and an appropriate R 1 can be designed.

[0012] The hydrocarbon group may be a saturated hydrocarbon group or an unsaturated hydrocarbon group. The number of double bonds (p) of the unsaturated hydrocarbon group is not particularly limited, but may be, for example, a number satisfying the following formula: 1≦p<1+n / 5 The hydrocarbon group may be an integer that satisfies the following formula: Furthermore, the hydrocarbon group may contain at least one isoprene unit, that is, a hydrocarbon unit having 5 carbon atoms and having an isoprene-like branched structure.

[0013] In formula (1), R 2 ~R 6 are each independently hydrogen, a hydroxy group, a halogen, an alkyl group having 1 to 3 carbon atoms, or an alkoxy group having 1 to 3 carbon atoms. 2 ~R 6 may also be hydrogen.

[0014] The term "glycoside" as used herein refers to a compound in which one or more monosaccharides are glycosidicly bonded to the aforementioned compound. The monosaccharides may include, but are not limited to, glucose, maltose, galactose, or the like.

[0015] Specific examples of the compound include, but are not limited to, the following compounds or glycosides thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0016] Specific examples of glycosides of the above compounds are not particularly limited, but include the following glycosides: [ka] [ka]

[0017] The compound was found in an oily extract of kaffir lime leaves, and therefore, in one embodiment, the compound or its glycoside may be contained in the form of an oily extract of kaffir lime leaves.

[0018] In one embodiment, the composition for activating TRPA1 of the present invention is a food composition, a pharmaceutical composition, or an agricultural chemical composition. By activating TRPA1, the composition can be used to impart a spiciness to a food product, increase food intake, stimulate appetite, improve anorexia, respiratory failure, intestinal obstruction, or constipation, enhance energy metabolism, prevent or improve obesity, or repel pests.

[0019] The composition for activating TRPA1 of the present invention may further contain any inactive ingredient commonly used in the art, such as a pharmaceutically or food-acceptable solvent, a buffer, a sweetener, an acidulant, a flavoring, an antifoaming agent, and an antioxidant, as long as the purpose of the present invention is not impaired. Furthermore, the composition may further contain an additional active ingredient commonly used in the art, as long as the purpose of the present invention is not impaired. The additional active ingredient may be a component having a TRPA1 activating activity or a component having another activity.

[0020] In another aspect, the present invention relates to a composition for increasing food intake and / or improving anorexia, which comprises, as an active ingredient, the compound of formula (1) or a glycoside thereof, as described above for the composition for activating TRPA1 of the present invention.

[0021] In one embodiment, the composition for increasing food intake and / or improving anorexia of the present invention is a food composition or a pharmaceutical composition. The composition can be used to increase food intake, increase appetite, or improve anorexia in a subject. For this purpose, the composition may be labeled, for example, as follows: For those who have no appetite For those who want to eat to their heart's content For those who want to build up their body For those who want to maintain their food intake, which tends to be small - For those who want to maintain their motivation to eat

[0022] The subject to which the composition of the present invention for increasing food intake and / or improving anorexia is applied is not particularly limited, and may be, for example, a human (specifically, a human in the recovery period from an illness, a human whose appetite has decreased with age, a slow-growing child, an athlete, a human with low stress tolerance, etc.) or another mammal (a pet such as a dog or cat, or a livestock such as a pig or cow, etc.).

[0023] The composition for increasing food intake and / or improving anorexia of the present invention may further contain any inactive ingredient commonly used in the art, such as additives such as pharmaceutically or food-acceptable solvents, buffers, sweeteners, acidulants, flavorings, antifoaming agents, and antioxidants, as long as the purpose of the present invention is not impaired. Furthermore, the composition may further contain an additional active ingredient commonly used in the art, as long as the purpose of the present invention is not impaired. The additional active ingredient may be an ingredient having an effect of increasing food intake or improving anorexia, or may be an ingredient having another effect.

[0024] In another aspect, the present invention relates to a method for activating TRPA1, increasing food intake, and / or improving anorexia, which comprises administering a composition containing the compound of formula (1) or a glycoside thereof to a subject in need thereof. Specific embodiments of the composition containing the compound of formula (1) or a glycoside thereof used in the methods of the present invention are as described above for the composition for activating TRPA1 of the present invention and the composition for increasing food intake and / or improving anorexia of the present invention.

[0025] In another aspect, the present invention relates to use of the compound of formula (1) or a glycoside thereof for producing a composition for activating TRPA1, a composition for increasing food intake, and / or a composition for improving anorexia. Specific aspects of the various compositions produced by the use of the present invention are as described above for the composition for activating TRPA1 of the present invention and the composition for increasing food intake and / or improving anorexia of the present invention.

[0026] In another aspect, the present invention also relates to a TRPA1 activator, a food intake enhancer, and / or anorexia ameliorator, which comprises the compound of formula (1) or a glycoside thereof. Specific aspects of the TRPA1 activator, food intake enhancer, and anorexia ameliorator of the present invention are as described above for the composition for activating TRPA1 of the present invention and the composition for increasing food intake and / or ameliorating anorexia of the present invention.

[0027] In another aspect, the present invention relates to non-therapeutic use of the compound of formula (1) or its glycoside as a TRPA1 activator, a food intake enhancer, and / or an anorexia ameliorating agent. Specific aspects of the non-therapeutic TRPA1 activator, food intake enhancer, and anorexia ameliorating agent are as described above for the composition for activating TRPA1 of the present invention and the composition for increasing food intake and / or improving anorexia of the present invention.

[0028] The present invention will be specifically explained below with reference to examples, but the scope of the present invention is not limited to these examples. [Example]

[0029] 1. Preparation Example (1) Preparation of Kaffir Lime Leaf Extract Five grams of kaffir lime leaves were ground into powder using a grinder, and then 200 mL of chloroform was added. The mixture was stirred overnight at room temperature using a stirrer. The extract was filtered using filter paper (Advantec 5B) and a suction funnel. The filtrate was evaporated to dryness to obtain the kaffir lime leaf extract.

[0030] (2) Preparation of Kaffir Lime Leaf Fraction The kaffir lime leaf extract was dissolved in chloroform and applied uniformly in a straight line to a PLC silica gel plate (Sigma-Aldrich) using a finely tipped Pasteur pipette, followed by drying. The PLC silica gel plate was then placed in a developing tank filled with the vapor of the developing solvent (hexane:ethyl acetate = 1:3) and developed. When the solvent front rose to the top, the plate was removed and the developing solution was allowed to dry.

[0031] After developing and drying under similar conditions in analytical TLC, spots indicating the presence of components were confirmed using phosphomolybdic acid solution reaction and UV absorption (254 nm). The sample was divided into three regions, including a cluster of yellow spots with an Rf value of approximately 0.5 and the clusters of other spots above and below. Similarly, the PLC silica gel was scraped off from these regions. These fractions are designated Fr. 1, Fr. 2, and Fr. 3 (Figure 1). The collected silica gel was mixed with 20% methanol / 80% chloroform to extract the fractions. The extracts from Fr. 1–3 were collected in a recovery flask and concentrated to dryness using an evaporator to obtain kaffir lime leaf fractions 1–3.

[0032] 2. Test Example (1) Construction of a TRPA1 expression vector and a stable expression cell line (see Patent Document 11) DNA encoding the human TRPA1 (hTRPA1) gene (GenBank accession number: NM_007332.3) was inserted into the pcDNA5 / TO vector (Invitrogen) to prepare an expression vector. This expression vector was transfected into T-REx™-293 cells (Invitrogen) using Lipofectamine LTX (Invitrogen) according to standard procedures. Various transfectants were cultured and cloned according to standard procedures using Dulbecco's modified Eagle's medium (DMEM, Nacalai Tesque) containing 10% fetal bovine serum (FBS, Cytiva), 400 μg / mL hygromycin B, and 5 μg / mL blasticidin S as a drug selection medium. Stable hTRPA1-expressing cell lines were obtained by cloning.

[0033] (2) TRPA1 activation effects of kaffir lime leaf extract and fractions A stable hTRPA1-expressing cell line, previously induced for hTRPA1 expression, was placed on a cover glass (12 mm round cover glass; Matsunami Glass Industry Co., Ltd.). After washing with PBS, 1 mL of assay buffer (Ca- and Mg-free Hank's balanced salt solution containing 1 mM CaCl2 dihydrate, 20 mM HEPES, and 0.1% BSA) containing the calcium fluorescent indicator Calbryte™ 520 AM (AAT Bioquest) at a final concentration of 4 μM was added and incubated at 37°C for 45 min. The cover glass was placed in a platform chamber (RC-26) and the temperature of the chamber was stabilized at 30°C while the assay buffer was pumped with a peristaltic pump.

[0034] 10 μL of DMSO was added to 1 mg of the dried product of the kaffir lime leaf extract obtained in Section 1(1) above or the kaffir lime leaf fraction obtained in Section 1(2) above to dissolve the extract. 1 mL of assay buffer was added to this solution to prepare a test assay solution. Assay buffer alone was used as the negative control assay solution, and a solution of allyl isothiocyanate (AITC; 30 μM) or ionomycin (10 μM) dissolved in assay buffer was used as the positive control assay solution. Each assay solution was flowed into the chamber, and fluorescence (excitation wavelength 490 nm, emission wavelength 525 nm) was measured. The baseline-subtracted fluorescence intensity is shown in Table 1.

[0035] [Table 1]

[0036] TRPA1 activation was confirmed in both the kaffir lime leaf extract before fractionation and in fractions 1 to 3. Fraction 2 had particularly strong TRPA1 activation activity.

[0037] (3) Identification of compounds in kaffir lime leaf fractions Analysis of kaffir lime leaf fraction 2 by liquid chromatography mass spectrometry (LCMS) suggested that the fraction contained a compound with a bergaptol skeleton. Therefore, commercially available compounds with a bergaptol skeleton were prepared and their LCMS spectra were compared.

[0038] As a result, as shown in Figure 2, kaffir lime leaf fraction 2 (spectrum A) was found to contain oxypoisedanine (spectrum B), pangerin (spectrum C), 6,7-dihydroxybergamottin (spectrum D), oxypoisedanine hydrate (spectrum E), and bergaptol (spectrum F). The chemical structures of each compound are shown below. [ka]

[0039] (4) TRPA1 activation activity of individual compounds The TRPA1 activation activity of the compounds contained in kaffir lime leaf fraction 2 was examined by measuring changes in intracellular Ca2+ concentration. Specifically, hTRPA1 stable expressing cell lines in which hTRPA1 expression had been previously induced were prepared in a 96-well clear bottom plate. Each well was washed with PBS and then immersed in calcium fluorescein indicator, Calbryte. TM 50 μL of assay buffer (Ca- and Mg-free Hank's balanced salt solution containing 1 mM CaCl2 dihydrate, 20 mM HEPES, and 0.1% BSA) containing 520 AM (AAT Bioquest) at a final concentration of 4 μM was added, and the plate was incubated for 45 minutes at 30° C. After washing with the assay buffer, 100 μL of the assay buffer was added to each well.

[0040] The plate was placed in a FlexStation 3 (Molecular Devices) and fluorescence intensity (excitation wavelength 490 nm, emission wavelength 525 nm) at 30°C was measured every 2 seconds. 30 seconds after the start of measurement, 100 μL of assay buffer containing dimethyl sulfoxide (DMSO) (final concentration 20 μL / mL) as a negative control, assay buffer containing AITC (AITC dissolved in DMSO and added; final concentration 30 μM) as a positive control, or assay buffer containing the test compounds shown in Table 2 below (dissolved in DMSO and added; final concentration 100 μM) was added. To serve as a reference for fluorescence intensity, wells were also prepared to receive assay buffer containing ionomycin (final concentration 10 μM after addition) instead of these measurement samples. In addition to the above compounds contained in kaffir lime leaf fraction 2, the following compounds with a bergaptol skeleton were also used as test compounds for reference. [ka]

[0041] Measurement was continued until 120 seconds had elapsed since the start of measurement, and the TRPA1 activation rate of the test compound was calculated using the following formula. The results are shown in Table 2. Activation rate (%)=(F max[s] -F0) / (F max[I] -F0) x ​​100 F max[s] : Maximum fluorescence intensity when test sample or positive control is added F0: Average fluorescence intensity for 20 seconds after the start of measurement (baseline) F max[I] : Maximum fluorescence intensity when ionomycin is added

[0042] [Table 2]

[0043] All of the above compounds contained in kaffir lime leaf fraction 2 were able to activate TRPA1, but notopterol or bergamottin, which have similar structures, were unable to activate TRPA1.

[0044] Comparing the chemical structures of each test compound, it appeared that a larger number of oxygen atoms relative to the length (number of carbon atoms) of the substituents extending from the bergaptol skeleton exerted TRPA1 activation. From another perspective, such chemical structural characteristics are thought to be related to the hydrophilicity of the compound, so the water / octanol partition coefficient (LogP) of each test compound was calculated (see the "CLogP" column in Table 2). The results showed that compounds with higher hydrophilicity exhibited TRPA1 activation.

[0045] Furthermore, similar tests were performed on pangerin, oxypoisedanine, oxypoisedanine hydrate, and 6,7-dihydroxybergamottin, which were found to have potent TRPA1 activation. The results, shown in Figure 3, confirmed that the test compounds were able to activate TRPA1 in a concentration-dependent manner.

[0046] (5) Specificity of TRPA1 activation For pangerin, oxypoisedanine, oxypoisedanine hydrate, and 6,7-dihydroxybergamottin, which showed strong TRPA1 activation, the concentrations of each test compound were as shown in Table 3 below. The TRPA1 activation rate was calculated by measuring changes in intracellular Ca2+ concentrations in the same manner as in (4) above, except that a test group was added with the TRPA1-specific antagonist A-967079 at a concentration of 1 μM. The results are shown in Table 3.

[0047] [Table 3]

[0048] The fluorescence induced by the test compounds was inhibited by a TRPA1-specific inhibitor, demonstrating that the fluorescence was due to the activation of TRPA1.

[0049] In addition, for pangerin, oxypoisedanine, oxypoisedanine hydrate, and 6,7-dihydroxybergamottin, the concentrations of each test compound were as shown in Table 4 below. Test groups were established using mock cells without exogenous gene transfection, hTRPV1-stably expressing cell lines, or hTRPM8-stably expressing cell lines (see Patent Document 11, if necessary), in place of the hTRPA1-stably expressing cell line. Intracellular Ca2+ concentration changes were measured and the activation rate of each receptor was calculated as described in (4) above. Capsaicin was used as a positive control for the hTRPV1-stably expressing cell line, and icilin was used as a positive control for the hTRPM8-stably expressing cell line. The results are shown in Table 4.

[0050] [Table 4]

[0051] None of the test compounds activated other receptors in the TRP ion channel superfamily, TRPV1 and TRPM8, suggesting that the test compounds specifically activate TRPA1.

[0052] From the above, it was found that the compound of formula (1) can activate TRPA1, and this activation effect can increase appetite, enhance food intake, and improve anorexia.

[0053] (6) Anorexia improvement test Male ICR mice were housed in individual cages on ALPHA-dri (Shepherd Specialty Papers) bedding and fed powdered food (CE-2, CLEA Japan) using a mouse powder feeder (SN-950, Shinano Seisakusho Co., Ltd.) for at least one week for acclimation. For several days prior to the experiment, the mice underwent daily handling and oral feeding training using a feeding needle (FG4202, Fuchigami Kikai Co., Ltd.). Test samples were prepared using a carrier solution (2% dimethyl sulfoxide and 98% 0.5% methylcellulose solution by volume) or an oxypoisedanine solution (2.86 mg of oxypoisedanine dissolved per mL of carrier solution). Each solution contained either the TRPA1-specific antagonist A-967079 (1.0 μmol of A-967079 per mL of carrier solution) or the TRPA1-specific antagonist A-967079. These solutions were orally administered (10 mL / kg body weight) to 9-11 week-old mice under ad libitum feeding conditions starting at 9:20 AM. The oxypoisedanine dose was converted to a molar concentration of 100 μmol / kg body weight. At 9:30 AM, the cage feeder was replaced with a new feeder filled with a pre-measured amount of powdered diet, marking the start of the feeding experiment. Thirty minutes after the start of the feeding experiment, the mass of food spilled in the feeder and cage was measured, and the amount of food consumed (g) was measured (n = 9-10). The amount of food consumed by each group and the results of a multiple comparison (multiple t-test) using the Dunn-Bonferroni method are shown in Table 5.

[0054] [Table 5]

[0055] The food intake of mice was increased by administration of oxypoisedanine solution (Table 5, "without antagonist" example), but this increase in food intake was not observed when the TRPA1-specific antagonist A-967079 was administered (Table 5, "with antagonist" example). This demonstrated that oxypoisedanine increases appetite and that this increase in appetite is mediated by TRPA1 activation. Therefore, it was found that compounds represented by formula (1), such as oxypoisedanine, can increase appetite by activating TRPA1, thereby increasing food intake and improving anorexia.

Claims

1. Formula (1): 【Chemical 1】 （１） (where R 1 is hydrogen or a linear or branched hydrocarbon group having n carbon atoms and m oxygen atoms bonded thereto, the oxygen atoms forming a hydroxyl group or an epoxy group, n is an integer from 1 to 20, and m satisfies the following relational formula: m≧n / 5 is a hydrocarbon group, and the integer satisfies R 2 ~R 6 are each independently hydrogen, a hydroxy group, a halogen, an alkyl group having 1 to 3 carbon atoms, or an alkoxy group having 1 to 3 carbon atoms. A composition for activating transient receptor potential ankyrin 1 (TRPA1), comprising the compound of formula (I) or a glycoside thereof.

2. 2. The composition of claim 1, wherein the compound has a water / octanol partition coefficient (log P) of 3 or less.

3. The hydrocarbon group is a saturated hydrocarbon group or an unsaturated hydrocarbon group having p double bonds, and p is represented by the following formula: 1≦p<1+n / 5 The composition of claim 1 , wherein R is an integer that satisfies the following formula:

4. The composition of claim 1 , wherein the hydrocarbon group comprises an isoprene unit.

5. R 2 ~R 6 The composition of claim 1 , wherein is hydrogen.

6. The compound is selected from the group consisting of: 【Chemistry 2】 The composition according to claim 1, wherein the composition is at least one selected from the group consisting of:

7. The composition according to any one of claims 1 to 6, which is a food composition, a pharmaceutical composition, or an agricultural chemical composition.

8. A composition for increasing food intake and / or improving anorexia, comprising a compound defined in any one of claims 1 to 6 or a glycoside thereof.

9. The composition of claim 8, which is a food composition or a pharmaceutical composition.

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