Nitrotyrosine reducing agents and their use, agents for improving yellowing of the skin, and agents for improving decreased skin elasticity.

Abstract

To provide an excellent nitrotyrosine reducing agent that can directly degrade already formed nitrated protein.SOLUTION: Provided is a nitrotyrosine reducing agent that contains at least one compound selected from the group consisting of (1) to (3) below. (1) A compound that has at least three substituents on the benzene ring and satisfies any of the following (A) to (C): (A) all of said at least three substituents are -OH; (B) of the at least three substituents, the first substituent is -C(=O)H, -C(=O)OH or -C(=O)Ra, and the second substituent group is -OH and the third substituent is -OH or -Rb; (C) the first substituent and the second substituent are bonded to neighboring carbon atoms on the benzene ring, and together with the carbon atoms to which they are bonded form a fused heterocycle, and the third substituent is -OH or -Rc, (2) Gibberellin, and (3) Genipin.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to a nitrotyrosine reducing agent comprising specific components, its use, an agent for improving yellowing of the skin, and an agent for improving decreased skin elasticity. [Background technology]

[0002] Protein nitration is a post-translational modification of proteins caused by reactive nitrogen species generated in living organisms. It involves the addition of a nitro group to the benzene ring in the tyrosine and tryptophan residues of aromatic amino acids that make up proteins. The nitration reaction involves the addition of a nitro group to the benzene ring in the amino acid, which is then converted into a nitronium ion (NO2) by the reactive nitrogen species. + It is produced by electrophilic substitution reactions with tyrosine or nitrogen dioxide radicals (Non-Patent Literature 1). The tryptophan content in many proteins present in living organisms is far smaller than that of tyrosine, and it is thought that protein nitration reactions mainly occur at tyrosine residues (Non-Patent Literature 2).

[0003] It has been reported that protein nitration can affect cellular function by causing impaired function of enzymes and tyrosine kinase receptors (Non-Patent Literature 3). Furthermore, nitrotyrosine in proteins has been reported to accumulate in various age-related diseases such as arteriosclerosis and cerebral ischemic disease, and to be involved in these diseases (Non-Patent Literature 4).

[0004] Furthermore, with age, the skin undergoes changes such as wrinkles, sagging, age spots, and dullness. There are various types of dullness, including dullness due to decreased transparency (due to shadows caused by unevenness of the skin surface, decreased light transmittance due to thickened stratum corneum, decreased luster due to diffuse reflection on the skin surface, etc.), dullness due to decreased redness of the skin (due to poor blood circulation), dullness due to uneven skin tone (unevenness of melanin), and dullness due to increased yellowness of the skin with age (Non-patent Literature 5). Among these, the yellowing of skin color with age (b *An increase in glycation, carbonylation, and nitration is known as yellowish dullness, a characteristic change in skin tone associated with aging. Conventionally, the main causes of yellowish dullness were thought to be glycated proteins (Patent Document 1) and carbonyl proteins (Patent Document 2) of proteins such as elastin and collagen present in the dermis. However, the inventors have clarified that not only dermal proteins, but also nitrated proteins, which are produced when amino acids constituting proteins present in the stratum corneum are nitrated, are a major cause of yellowish dullness (Patent Document 3, Non-Patent Document 6). Since these post-translational modifications of proteins, such as glycation, carbonylation, and nitration, all have different mechanisms of generation and degradation, it is necessary to address each factor in order to effectively improve yellowish dullness. Furthermore, in skin exposed to ultraviolet rays for many years, elastic fibers (elastin fibers), which contribute to skin flexibility and elasticity, accumulate abnormally. This abnormality leads to a loss of skin strength, flexibility, and elasticity, resulting in changes in skin characteristics such as decreased firmness, sagging, and wrinkles. Until now, there have been almost no proposed ingredients to improve the abnormal accumulation of elastic fibers, and the development of an effective method to address the loss of skin elasticity has been desired.

[0005] In particular, with regard to nitrated proteins, proposals have been made for active ingredients that eliminate peroxynitrite, which nitrates tyrosine residues of proteins, in order to improve various diseases associated with the formation of nitrated proteins (Patent Document 4), and for active ingredients that supplement peroxynitrite with substances having thiol groups (Patent Document 5). However, all of these only suppress the formation of nitrated proteins and do not improve nitrated proteins that have already been formed, and have not led to a fundamental solution to the various diseases associated with the formation of nitrated proteins. In this situation, the present inventors have found that Goishi Tea (registered trademark) extract and hibiscus extract have a nitrated protein decomposition effect, and have found that applying these to the skin can improve the yellowing of the skin caused by the presence of nitrated proteins (Patent Document 3, Non-Patent Document 6, Patent Document 8). Furthermore, it has also been reported that nitrated proteins may be involved in decreased skin elasticity, neurodegenerative diseases, hypertension, asthma, rheumatoid arthritis, diabetic nephropathy, and inflammatory bowel disease (Patent Document 9 and Non-Patent Documents 7-12). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Chem Res Toxicol., 22(5):894-898, 2009 [Non-Patent Document 2] Front Chem., 3:70, 2016 [Non-Patent Document 3] Diabetes, 57(4):889-98, 2008 [Non-Patent Document 4] Science, 290(5493):985-9, 2000 [Non-Patent Document 5] Japan Cosmetic Industry Association Technical Documents, 101, 148, 1995. [Non-Patent Document 6] FRAGRANCE JOURNAL, vol.45 / No.8, 2017 [Non-Patent Document 7] Int J Neurosci., 130(10):1047-1062, 2020 [Non-Patent Document 8] JAMA., 289(13):1675-80, 2003 [Non-Patent Document 9] Free Radic Res., 38(1):49-57, 2004 [Non-Patent Document 10] Osteoarthritis Cartilage., 21(1):151-6, 2013 [Non-Patent Document 11] Kidney Int., 57(5):1968-72, 2000 [Non-Patent Document 12] J Pathol., 186(4):416-21, 1998 [Patent Documents]

[0007] [Patent Document 1] Japanese Patent Publication No. 2013-133303 [Patent Document 2] Japanese Patent Publication No. 2012-32287 [Patent Document 3] Japanese Patent Publication No. 2017-178899 [Patent Document 4] Japanese Patent Publication No. 2002-326922 [Patent Document 5] Japanese Patent Publication No. 2005-170849 [Patent Document 6] Japanese Patent Application Publication No. 11-106336 [Patent Document 7] Japanese Patent Publication No. 2006-160630 [Patent Document 8] Japanese Patent Publication No. 2021-147335 [Patent Document 9] Japanese Patent Publication No. 2021-124313 [Overview of the project] [Problems that the invention aims to solve]

[0008] The object of this invention is to provide a nitrotyrosine reducing agent that has excellent nitrotyrosine-reducing activity and can directly decompose already generated nitrated proteins. [Means for solving the problem]

[0009] The inventors of this invention conducted diligent research to solve the above problems and, as a result, discovered a component that effectively reduces nitrotyrosine, thus completing the present invention.

[0010] In other words, the present invention includes the following preferred embodiments. [1] (1) Having at least three substituents on the benzene ring, the following (A)~(C): (A) Of the at least three substituents, the first substituent, the second substituent and the third substituent are -OH, (B) Of the at least three substituents, The first substituent is -C(=O)H, -C(=O)OH, or -C(=O)R a And, The second substituent is -OH, The third substituent is -OH or -R b That is, or (C) Of the at least three substituents, The first substituent and the second substituent bond to adjacent carbon atoms on the benzene ring, and together with the carbon atoms to which they bond, form formula (y1) or (y2): [ka] [In the formula, Y is (ya) ~ (yc): [ka] [In formula (ya), X independently represents a hydrogen atom, an -OH group, an optionally substituted aromatic ring, or a group obtained by removing a hydrogen atom from a hydroxyl group of a sugar skeleton, or two Xs together with the carbon atom to which they are bonded to form a spiro ring.] In formulas (yb) and (yc), X is independently of each other either a hydrogen atom, -OH, an aromatic ring which may have a substituent, or a group obtained by removing a hydrogen atom from one hydroxyl group of a saccharide skeleton, or two Xs bonded to adjacent carbon atoms together with the carbon atoms to which they are bonded form a 6-membered saturated or unsaturated hydrocarbon ring, In formulas (ya) to (yc), * represents a bond. represents to form a heterocyclic ring represented by the third substituent is -OH or -R c is where R a , R b and R c are independently of each other C 1-3 an alkoxy group, or a group obtained by removing a hydrogen atom from one hydroxyl group in any one of a flavan-3-ol skeleton, a saccharide skeleton, a gallic acid skeleton, or a skeleton formed by dehydration condensation of a saccharide skeleton and a gallic acid skeleton, a compound (1) satisfying any one of However, the compounds satisfying (B) or (C) are not included in the compounds satisfying (A), and the compounds satisfying (C) are not included in the compounds satisfying (B). (2) Formula (II):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0011] The nitrotyrosine-reducing agent of the present invention, which consists of specific components, can effectively reduce nitrotyrosine levels. Furthermore, the nitrotyrosine-reducing agent of the present invention can improve various symptoms caused by nitrated proteins, such as arteriosclerosis, cerebral ischemic disease, decreased cell function, and jaundice. [Modes for carrying out the invention]

[0012] The present invention will now be described in detail. However, the scope of the present invention is not limited to the embodiments described herein, and various modifications can be made without departing from the spirit of the invention.

[0013] The nitrotyrosine reducing agent of the present invention is (1) Having at least three substituents on the benzene ring, and the following (A)~(C): (A) Of the at least three substituents, the first substituent, the second substituent and the third substituent are -OH, (B) Of the at least three substituents, The first substituent is -C(=O)H, -C(=O)OH, or -C(=O)R a And, The second substituent is -OH, The third substituent is -OH or -R b That is, or (C) Of the at least three substituents, The first substituent and the second substituent bond to adjacent carbon atoms on the benzene ring, and together with the carbon atoms to which they bond, form formula (y1) or (y2): [ka] [In the formula, Y is (ya) ~ (yc): [ka] 〔In formula (ya), X independently represents any one of a hydrogen atom, -OH, an aromatic ring which may have a substituent, or a group obtained by removing a hydrogen atom from one hydroxyl group of a saccharide skeleton, or two X's together with the carbon atom to which they are attached form a spiro ring, in formulas (yb) and (yc), X independently represents any one of a hydrogen atom, -OH, an aromatic ring which may have a substituent, or a group obtained by removing a hydrogen atom from one hydroxyl group of a saccharide skeleton, or two X's attached to adjacent carbon atoms together with the carbon atoms to which they are attached form a 6-membered saturated or unsaturated hydrocarbon ring, in formulas (ya) to (yc), * represents a bond〕 represents] forming a heterocyclic ring represented by where the third substituent is -OH or -R c is here, R a , R b and R c each independently represents a C 1-3 alkoxy group, or a group obtained by removing a hydrogen atom from one hydroxyl group in any one of a flavan-3-ol skeleton, a saccharide skeleton, a gallic acid skeleton, or a skeleton formed by dehydration condensation of a saccharide skeleton and a gallic acid skeleton, compound (1) satisfying any one of provided that the compounds satisfying (B) or (C) are not included in the compounds satisfying (A), and the compounds satisfying (C) are not included in the compounds satisfying (B), (2) Formula (II):

Chemical formula

Chemical formula

[0014] In the present invention, the nitrotyrosine reducing agent is an agent that has the effect of reducing already generated nitrotyrosine. Although the suppression of nitrotyrosine generation has been studied in the past, agents consisting of specific components that have the effect of reducing already generated nitrotyrosine have been hardly studied. Furthermore, although extracts that have the effect of reducing nitrotyrosine have been studied by the present inventors in the past, extracts contain various components, which sometimes affected the storage stability of the product when incorporated into a product. In addition, in the case of extracts, it was necessary to incorporate a relatively large amount of extract in order to obtain the desired effect. In contrast, the present invention provides a nitrotyrosine reducing agent consisting of at least one compound selected from the group consisting of specific compounds (1), (2), and (3), which has the effect of reducing already generated nitrotyrosine. The reason why an agent consisting of at least one compound selected from the group consisting of compounds (1), (2), and (3) above has the effect of reducing nitrotyrosine is not clear, but it is thought that these compounds may have a structure that readily interacts with nitrotyrosine. As a result, it is believed that the nitrotyrosine-reducing agent effectively approaches nitrotyrosine and efficiently decomposes or inactivates it. By using a nitrotyrosine-reducing agent with such an effect, it is possible to efficiently reduce the amount of nitrotyrosine in nitrated proteins that have already been produced. As a result, it is believed that it will be possible to fundamentally resolve various phenomena caused by nitrated proteins, specifically such as yellowing of the skin, decreased skin elasticity due to abnormal accumulation of elastin, arteriosclerosis, cerebral ischemic disease, neurodegenerative disease, hypertension, asthma, chronic rheumatoid arthritis, diabetic nephropathy, and inflammatory bowel disease. However, the present invention is not limited in any way to the mechanism described above.

[0015] <Compound (1)> Compound (1) has at least three substituents on the benzene ring, and the following (A)~(C): (A) Of the at least three substituents, the first substituent, the second substituent and the third substituent are -OH, (B) Among the at least three substituents, the first substituent is -C(=O)H, -C(=O)OH or -C(=O)R a and the second substituent is -OH, the third substituent is -OH or -R b or or (C) Among the at least three substituents, the first substituent and the second substituent are bonded to adjacent carbon atoms on the benzene ring, and together with the carbon atoms to which they are bonded, form a formula (y1) or (y2):

Chemical formula

Chemical formula

[0016] Compound (1) is a compound having a benzene ring and three specific substituents on the benzene ring. Such a compound is thought to readily engage in π-π interactions with the benzene ring portion of tyrosine at the benzene ring portion. Furthermore, surprisingly, by having three specific substituents on the benzene ring, it is thought to readily interact with the nitro group on the benzene ring of nitrotyrosine, and as a result, it is thought to easily increase the rate of nitrotyrosine reduction.

[0017] (Compounds that satisfy (A)) Of the compounds (1), those that satisfy (A) above are compounds having at least three substituents on the benzene ring, wherein the first substituent, second substituent, and third substituent are -OH. Compounds that satisfy (A) may or may not have further substituents, as long as they have the above-mentioned specific first to third substituents (-OH) on the benzene ring. The further substituents may be -OH or other substituents different from -OH. Other substituents are not particularly limited, but C 1-3 Alkyl alkyl group, C 1-3 Examples include alkoxy groups or halogen groups. In this specification, C 1-3 The alkyl group represents an alkyl group having 1 to 3 carbon atoms, and the alkyl group may be linear or branched. 1-3 The term "alkoxy group" refers to an alkoxy group having 1 to 3 carbon atoms, and the alkyl group contained in the alkoxy group may be linear or branched.

[0018] C 1-3Examples of alkyl groups include methyl, ethyl, n-propyl, and isopropyl groups, with methyl and ethyl groups being preferred, and methyl groups being more preferred. 1-3 Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy groups, with methoxy and ethoxy groups being preferred, and methoxy groups being even more preferred. Examples of halogen groups include fluoro, chloro, and bromo groups.

[0019] The number of substituents other than -OH that a compound satisfying (A) may have on the benzene ring is preferably 2 or less, more preferably 1 or less, and it is even more preferable that a compound satisfying (A) does not have substituents other than -OH.

[0020] In a preferred embodiment of the present invention, a compound satisfying (A) is given by formula (IA): [ka] [In formula (IA), R 1A ~R 6A These represent, independently of each other, a hydrogen atom or -OH. However, R 1A ~R 6A At least three of these represent -OH. It is a compound represented by [formula].

[0021] In the above equation (IA), R 1A ~R 6A These represent, independently of each other, a hydrogen atom or -OH, and R 1A ~R 6AIn this compound, preferably 3 to 5, more preferably 3 to 4, and even more preferably 3 of these represent -OH groups. The compound represented by formula (IA) is preferably trihydroxybenzene, more preferably selected from the group consisting of 1,2,3-benzenetriol, 1,2,4-benzenetriol, and 1,3,5-benzenetriol, and even more preferably selected from the group consisting of 1,2,3-benzenetriol represented by formula (a1) and 1,2,4-benzenetriol represented by formula (a2). [ka]

[0022] (Compounds that satisfy (B)) Of the compounds (1), those that satisfy (B) above have at least three substituents on the benzene ring, and of the at least three substituents, the first substituent is -C(=O)H, -C(=O)OH, or -C(=O)R a The second substituent is -OH, and the third substituent is -OH or -R b It is a compound that is R. a and R b These are, independently of each other, C 1-3 This term represents an alkoxy group, or a group obtained by removing a hydrogen atom from a single hydroxyl group in any of the following skeletons: a flavan-3-ol skeleton, a sugar skeleton, a gallic acid skeleton, or a skeleton formed by the dehydration condensation of a sugar skeleton and a gallic acid skeleton.

[0023] Among compound (1), the compounds satisfying (B) above are not particularly limited as long as they have at least three substituents on the benzene ring, and the first, second, and third substituents among the at least three substituents represent a specific group, and may have further substituents in addition to the first to third substituents.

[0024] The first substituent on the benzene ring of a compound satisfying (B) is -C(=O)H, -C(=O)OH, or -C(=O)R a And R a C 1-3It represents a group obtained by removing a hydrogen atom from one hydroxyl group in any of the skeletons of an alkoxy group, a flavan-3-ol skeleton, a saccharide skeleton, a gallic acid skeleton, or a skeleton formed by dehydration condensation of a saccharide skeleton and a gallic acid skeleton.

[0025] R a The C in 1-3 Examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, and an isopropoxy group. Preferably, they are a methoxy group and an ethoxy group, and more preferably a methoxy group.

[0026] R a Regarding a group obtained by removing a hydrogen atom from one hydroxyl group in any of the skeletons of a flavan-3-ol skeleton, a saccharide skeleton, a gallic acid skeleton, or a skeleton formed by dehydration condensation of a saccharide skeleton and a gallic acid skeleton, all of these skeletons have at least one hydroxyl group (-OH). And through -O- obtained by removing the hydrogen atom of the one -OH, it is bonded to the carbonyl carbon bonded to the benzene ring of the compound satisfying (B). These skeletons may have additional substituents in addition to the above one -OH. Examples of the additional substituents include -OH, C 1-3 alkyl group, C 1-3 alkoxy group, or halogen group. Examples of the C 1-3 alkyl group and C 1-3 alkoxy group are the groups described above.

[0027] The group obtained by removing a hydrogen atom from one hydroxyl group in the flavan-3-ol skeleton is preferably of the formula (d1):

Chemical formula

[0028] Regarding the group obtained by removing a hydrogen atom from a single hydroxyl group in the sugar skeleton, the sugar skeleton may be either a monosaccharide or a polysaccharide, but is preferably a monosaccharide or a disaccharide. Examples of sugar skeletons include monosaccharides such as pentoses, hexoses, deoxypentoses, and deoxyhexoses, or polysaccharides thereof. Examples include monosaccharides such as pentose aldoses, hexose aldoses, and their deoxy sugars, or polysaccharides thereof. Examples of pentose aldoses include ribose, arabinose, arabinoflurose, xylose, and lyxose, and examples of hexose aldoses include allose, altrose, glucose, mannose, gros, idose, galactose, and talose. Furthermore, examples of deoxy sugars of pentose aldoses include deoxypentoses in which one of the hydroxyl groups of the above pentose is replaced by a hydrogen atom, specifically deoxyribose, and examples of deoxy sugars of hexose aldoses include deoxyhexoses in which one of the hydroxyl groups of the above hexose is replaced by a hydrogen atom, specifically fucose, fuucrose, rhamnose, etc.

[0029] A preferred group obtained by removing a hydrogen atom from a single hydroxyl group in a sugar skeleton is formula (d2-1): [ka] [In formula (d2-1), R 21 [This represents -CH2-OH or -CH3] The base represented by formula (d2-2): [ka] [In formula (d2-2), R 22 [where represents -CH2-OH or -CH3, and * represents a bond] The base represented by formula (d2-3): [ka] [In formula (d2-3), R 23 and R 24 [These represent -CH2-OH or -CH3 independently of each other, and * represents a bond.] Examples of groups represented by the above are shown. The stereoisomers of the above sugar skeletons are not particularly limited.

[0030] As a group obtained by removing a hydrogen atom from one hydroxyl group in the gallic acid skeleton, formula (d3-1) is: [ka] [In equation (d3-1), * represents a bond.] Examples of groups represented by the following are given.

[0031] Regarding the group obtained by removing a hydrogen atom from one hydroxyl group in a skeleton formed by the dehydration condensation of a sugar skeleton and a gallic acid skeleton, the skeleton is a skeleton formed by the dehydration condensation of one or more sugar skeletons and one or more gallic acid skeletons. Examples of such skeletons include a skeleton formed by the dehydration condensation of an -OH group in a monocyclic sugar skeleton and an -OH group in the carboxyl portion of a gallic acid skeleton, and a skeleton formed by the dehydration condensation of an -OH group in a monocyclic sugar skeleton and an -OH group in the carboxyl portion of a gallic acid skeleton, and further by the dehydration condensation of an -OH group on the benzene ring of a gallic acid skeleton and an -OH group in the carboxyl portion of another gallic acid skeleton. An example of such a group is formula (d4-1): [ka] [In equation (d4-1), * represents a bond.] Examples include the group represented by and its stereoisomers.

[0032] R a Preferably C 1-3The group is an alkoxy group, a group obtained by removing a hydrogen atom from one hydroxyl group in a flavan-3-ol skeleton, or a group obtained by removing a hydrogen atom from one hydroxyl group in a skeleton formed by dehydration condensation of a sugar skeleton and a gallic acid skeleton, more preferably a methoxy group, a group represented by formula (d1), or a group represented by formula (d4-1).

[0033] The third substituent on the benzene ring of a compound satisfying (B) is either -OH or -R b That is. R b C 1-3 This term represents an alkoxy group, or a group obtained by removing a hydrogen atom from a single hydroxyl group in any of the following skeletons: a flavan-3-ol skeleton, a sugar skeleton, a gallic acid skeleton, or a skeleton formed by the dehydration condensation of a sugar skeleton and a gallic acid skeleton.

[0034] R b C in 1-3 As for alkoxy groups, R a C in 1-3 The alkoxy groups mentioned above are examples, and the preferred groups are similarly applicable.

[0035] R b Regarding the group obtained by removing a hydrogen atom from one hydroxyl group in any of the following skeletons: the flavan-3-ol skeleton, the sugar skeleton, the gallic acid skeleton, or the skeleton obtained by dehydration condensation of the sugar skeleton and the gallic acid skeleton, each of the above skeletons has at least one hydroxyl group (-OH). And, via the -O- obtained by removing the hydrogen atom from the one -OH, it is bonded to a carbon atom on the benzene ring of the compound satisfying (B). These skeletons may have further substituents in addition to the above one hydroxyl group. Further substituents include -OH, C 1-3 Alkyl alkyl group, C 1-3 Examples include alkoxy groups or halogen groups. 1-3 Alkyl and C 1-3 Examples of alkoxy groups are as described above.

[0036] R bIn the flavan-3-ol skeleton, sugar skeleton, gallic acid skeleton, or a skeleton formed by the dehydration condensation of a sugar skeleton and a gallic acid skeleton, the group obtained by removing a hydrogen atom from one hydroxyl group is R. a The basis for this can be found in the above-mentioned points.

[0037] R b Preferably C 1-3 It is an alkoxy group, more preferably a methoxy group or an ethoxy group.

[0038] Compounds satisfying (B) above may have further substituents in addition to the first to third substituents described above, and such further substituents may be -OH, halogen groups, C 1-3 Alkyl alkyl group, C 1-3 Examples include alkoxy groups, or groups obtained by removing a hydrogen atom from one hydroxyl group in any of the following skeletons: a flavan-3-ol skeleton, a sugar skeleton, a gallic acid skeleton, or a skeleton formed by dehydration condensation of a sugar skeleton and a gallic acid skeleton. Halogen groups, C 1-3 Alkyl alkyl group, C 1-3 Examples of alkoxy groups and groups obtained by removing a hydrogen atom from a single hydroxyl group in the flavan-3-ol skeleton mentioned above include the groups described above.

[0039] In a preferred embodiment of the present invention, a compound satisfying (B) above is given by formula (IB): [ka] [In formula (IB), R 1B These are -C(=O)H, -C(=O)OH, or -C(=O)R a This represents, R 2B ~R 6B These are, independently of each other, a hydrogen atom, a halogen atom, -OH, and C. 1-3 Alkyl alkyl group, or -R d It represents one of the following: however, R 2B ~R 6BAt least one of them represents -OH and at least one represents -R d Does it represent, or R 2B ~R 6B At least two of these represent -OH, R a and R d They are independent of each other, C 1-3 [This represents an alkoxy group, or a group obtained by removing a hydrogen atom from a single hydroxyl group in any of the following skeletons: a flavan-3-ol skeleton, a sugar skeleton, a gallic acid skeleton, or a skeleton formed by the dehydration condensation of a sugar skeleton and a gallic acid skeleton.] It is a compound represented by [formula].

[0040] In the above formula (IB), R 1B This corresponds to the first substituent on the benzene ring of a compound satisfying (B) above, and is -C(=O)H, -C(=O)OH, or -C(=O)R a Represents R a Regarding the first substituent, R a The same applies to the description regarding this matter.

[0041] R 2B ~R 6B These are, independently of each other, a hydrogen atom, a halogen atom, -OH, and C. 1-3 Alkyl alkyl group, or -R d It represents one of the following: C 1-3 Examples of alkyl groups include methyl, ethyl, n-propyl, and isopropyl groups, with methyl and ethyl groups being preferred, and methyl groups being even more preferred.

[0042] In formula (IB), R 2B ~R 6B At least one of them represents -OH and at least one represents -R d Represents, or R 2B ~R 6B At least two of these represent -OH. In other words, R 2B ~R 6B One of them is -OH, and R 2B ~R 6B One of them is -OH or -Rd And R 2B ~R 6B The remaining three are hydrogen atoms, halogen atoms, -OH, and C. 1-3 Alkyl alkyl group, or -R d It represents one of the following. d Regarding the group obtained by removing a hydrogen atom from one hydroxyl group in any of the following skeletons: the flavan-3-ol skeleton, the sugar skeleton, the gallic acid skeleton, or the skeleton obtained by dehydration condensation of the sugar skeleton and the gallic acid skeleton, each of the above skeletons has at least one hydroxyl group (-OH). This single -OH is bonded to a carbon atom on the benzene ring of the compound satisfying formula (IB) via an -O- group obtained by removing the hydrogen atom from the single -OH. These skeletons may have further substituents other than the single -OH. Further substituents include -OH, C 1-3 Alkyl alkyl group, C 1-3 Examples include alkoxy groups or halogen groups. 1-3 Alkyl alkyl group, C 1-3 Examples of alkoxy and halogen groups are as described above.

[0043] R d Preferably C 1-3 A group obtained by removing a hydrogen atom from a single hydroxyl group in an alkoxy group or sugar skeleton, more preferably C 1-3 It is an alkoxy group.

[0044] From the viewpoint of more easily enhancing the nitrotyrosine reduction effect, the compound represented by formula (IB) is preferably the compound in formula (IB) that contains R 1B However, this represents -C(=O)H, -C(=O)OH, or -C(=O)-O-CH3. R 2B ~R 6B Of these, Three are hydrogen atoms and two are -OH groups. Three are hydrogen atoms, one is -OH, and one is C 1-3 Is it an alkoxy group? Two are hydrogen atoms and three are -OH groups. Two are hydrogen atoms, two are -OH groups, and one is C1-3 Is it an alkoxy group? or Two are hydrogen atoms, one is -OH, and two are C 1-3 It is an alkoxy group. Compounds, and / or, Formula (b13): [ka] It is a compound represented by [formula].

[0045] The compound represented by formula (IB) is more preferably: R 1B This represents -C(=O)H, and R 2B ~R 6B These two represent -OH, and R 2B ~R 6B The remaining four represent hydrogen atoms, dihydroxybenzaldehyde. R 1B This represents -C(=O)H, and R 2B ~R 6B One of them represents -OH, R 2B ~R 6B Another one is -R d Represents R d As described above, R 2B ~R 6B The remaining four represent hydrogen atoms, dihydroxybenzaldehyde derivatives. R 1B represents -C(=O)OH, R 2B ~R 6B These two represent -OH, and R 2B ~R 6B The remaining four represent hydrogen atoms, dihydroxybenzoic acid, R 1B represents -C(=O)OH, R 2B ~R 6B One of them represents -OH, R 2B ~R 6B Another one is -R d Represents R d As described above, R 2B ~R 6B The remaining four represent hydrogen atoms, dihydroxybenzoic acid derivatives. R 1B This represents -C(=O)H, and R 2B ~R 6B These three represent -OH, and R 2B ~R 6B The remaining two represent hydrogen atoms, trihydroxybenzaldehyde. R 1B This represents -C(=O)H, and R 2B ~R 6B One of them represents -OH, R 2B ~R 6B Another one is -R d Represents R 2B ~R 6B Another one is -OH or -R d Represents R d As described above, R 2B ~R 6B The remaining two represent hydrogen atoms, trihydroxybenzaldehyde derivatives. R 1B represents -C(=O)OH, R 2B ~R 6B These three represent -OH, and R 2B ~R 6B The remaining two represent hydrogen atoms, trihydroxybenzoic acid, R 1B represents -C(=O)OH, R 2B ~R 6B One of them represents -OH, R 2B ~R 6B Another one is -R d Represents R 2B ~R 6B Another one is -OH or -R d Represents R d As described above, R 2B ~R 6B The remaining two represent hydrogen atoms in the trihydroxybenzoic acid derivative. These are some examples.

[0046] The compounds represented by formula (IB) are more preferably the following formulas (b1) to (b13): [ka] It is a compound selected from the group consisting of compounds represented by [formula].

[0047] The compound represented by formula (IB) is preferably a benzaldehyde, benzoic acid, or benzoic acid ester (alkyl benzoate ester, ester of benzoic acid and epigallocatechin, ester of benzoic acid and a sugar skeleton, etc.) having at least two hydroxyl groups or at least one hydroxyl group and at least one alkoxy group, for example, 3,4-dihydroxybenzaldehyde of formula (b1), 2,5-dihydroxybenzoic acid of formula (b2), 3,5-dihydroxybenzoic acid of formula (b3), and formula ( (b4) methyl 2,5-dihydroxybenzoate, (b5) 3-methoxy-4-hydroxybenzaldehyde, (b6) 3-methoxy-2-hydroxybenzaldehyde, (b7) 3-ethoxy-4-hydroxybenzaldehyde, (b8) 2,3,4-trihydroxybenzaldehyde, (b9) gallic acid, (b10) 3,5-dimethoxy-4-hydroxybenzaldehyde, (b11) propyl gallate, (b12) epigallocatechin gallate, and (b13) tannic acid.

[0048] (Compounds that satisfy (C)) Of the compounds (1), those satisfying (C) above have at least three substituents on the benzene ring, and of these at least three substituents, the first substituent and the second substituent are bonded to adjacent carbon atoms on the benzene ring, and together with the carbon atoms to which they are bonded, they form formula (y1) or (y2): [ka] [In the formula, Y is (ya) ~ (yc): [ka] [In formula (ya), X independently represents a hydrogen atom, an -OH group, an optionally substituted aromatic ring, or a group obtained by removing a hydrogen atom from a hydroxyl group of a sugar skeleton, or two Xs together with the carbon atom to which they are bonded to form a spiro ring.] In formulas (yb) and (yc), X independently represents a hydrogen atom, an -OH group, an optionally substituted aromatic ring, or a group obtained by removing a hydrogen atom from a hydroxyl group of a sugar skeleton, or two X atoms bonded to adjacent carbon atoms, together with the carbon atoms to which they are bonded, form a six-membered saturated or unsaturated hydrocarbon ring. In the expression (ya)~(yc), * represents a conjunction. [represents] Form a complex ring represented by , The third substituent is -OH or -R c It is a compound that is R. c C 1-3 This term represents an alkoxy group, or a group obtained by removing a hydrogen atom from a single hydroxyl group in any of the following skeletons: a flavan-3-ol skeleton, a sugar skeleton, a gallic acid skeleton, or a skeleton formed by the dehydration condensation of a sugar skeleton and a gallic acid skeleton.

[0049] Among compound (1), the compounds satisfying (C) above are not particularly limited as long as they have at least three substituents on the benzene ring, the first and second substituents of the at least three substituents form a specific structure, and the third substituent represents a specific group, and may have further substituents in addition to the first to third substituents.

[0050] The first and second substituents are bonded to adjacent carbon atoms on the benzene ring, and together with the carbon atoms to which they are bonded, they form formula (y1) or (y2): [ka] [In the formula, Y is (ya) ~ (yc): [ka] [In formula (ya), X independently represents a hydrogen atom, an -OH group, an optionally substituted aromatic ring, or a group obtained by removing a hydrogen atom from a hydroxyl group of a sugar skeleton, or two Xs together with the carbon atom to which they are bonded to form a spiro ring.] In formulas (yb) and (yc), X independently represents a hydrogen atom, an -OH group, an optionally substituted aromatic ring, or a group obtained by removing a hydrogen atom from a hydroxyl group of a sugar skeleton, or two X atoms bonded to adjacent carbon atoms, together with the carbon atoms to which they are bonded, form a six-membered saturated or unsaturated hydrocarbon ring. In the expression (ya)~(yc), * represents a conjunction. [represents] It forms a complex ring represented by .

[0051] In formula (ya), X independently represents one of the following: a hydrogen atom, an -OH group, an optionally substituted aromatic ring, or a group obtained by removing a hydrogen atom from a hydroxyl group of a sugar skeleton, or two Xs together with the carbon atoms to which they are bonded to form a spiro ring. In formulas (yb) and (yc), X independently represents a hydrogen atom, an -OH group, an optionally substituted aromatic ring, or a group obtained by removing a hydrogen atom from a hydroxyl group of a sugar skeleton, or two X atoms bonded to adjacent carbon atoms together with the carbon atoms to which they are bonded to form a six-membered saturated or unsaturated hydrocarbon ring.

[0052] A substituted aromatic ring may have 0 to 5 -OH and / or C groups. 1-3 A benzene ring having an alkoxy group, preferably with 0 to 3 -OH and / or C groups. 1-3 A benzene ring having an alkoxy group, more preferably 0 to 2 -OH and / or C 1-3 Examples include benzene rings having alkoxy groups.

[0053] As a group obtained by removing a hydrogen atom from one hydroxyl group of a sugar skeleton, R a Regarding the above, examples include groups obtained by removing a hydrogen atom from one hydroxyl group in the sugar skeleton, and preferably groups represented by formulas (d2-1) to (d2-3). The stereoisomers of the sugar skeleton are not particularly limited.

[0054] The third substituent on the benzene ring of a compound satisfying (C) is either -OH or -R c And R c C 1-3 This term represents an alkoxy group, or a group obtained by removing a hydrogen atom from a single hydroxyl group in any of the following skeletons: a flavan-3-ol skeleton, a sugar skeleton, a gallic acid skeleton, or a skeleton formed by the dehydration condensation of a sugar skeleton and a gallic acid skeleton.

[0055] R c C in 1-3 As for alkoxy groups, R a C in 1-3 The alkoxy groups mentioned above are examples, and the preferred groups are similarly applicable.

[0056] R c Regarding the group obtained by removing a hydrogen atom from one hydroxyl group in any of the following skeletons: flavan-3-ol skeleton, sugar skeleton, gallic acid skeleton, or skeleton obtained by dehydration condensation of a sugar skeleton and a gallic acid skeleton, each of the above skeletons has at least one hydroxyl group (-OH). And, via the -O- obtained by removing the hydrogen atom from the one -OH, it is bonded to a carbon atom on the benzene ring of the compound satisfying (C). These skeletons may have further substituents in addition to the above one hydroxyl group. Further substituents include -OH, C 1-3 Alkyl alkyl group, C 1-3 Examples include alkoxy groups or halogen groups. 1-3 Alkyl and C 1-3 Examples of alkoxy groups are as described above.

[0057] R c In the flavan-3-ol skeleton, sugar skeleton, gallic acid skeleton, or a skeleton formed by the dehydration condensation of a sugar skeleton and a gallic acid skeleton, the group obtained by removing a hydrogen atom from one hydroxyl group is R. a The basis for this can be found in the above-mentioned points.

[0058] R c Preferably C 1-3A group obtained by removing a hydrogen atom from an alkoxy group or a hydroxyl group in a sugar skeleton, more preferably a group obtained by removing a hydrogen atom from a hydroxyl group in a sugar skeleton, even more preferably a group represented by formulas (d2-1) to (d2-3), and even more preferably a group represented by formula (d2-1) or formula (d2-3).

[0059] Compounds satisfying (C) above may have further substituents in addition to the first to third substituents described above, and such further substituents may be -OH, a halogen group, C 1-3 Alkyl alkyl group, C 1-3 Examples include alkoxy groups, or groups obtained by removing a hydrogen atom from one hydroxyl group in any of the following skeletons: a flavan-3-ol skeleton, a sugar skeleton, a gallic acid skeleton, or a skeleton formed by dehydration condensation of a sugar skeleton and a gallic acid skeleton. Halogen groups, C 1-3 Alkyl alkyl group, C 1-3 Examples of alkoxy groups and groups obtained by removing a hydrogen atom from a single hydroxyl group in the flavan-3-ol skeleton mentioned above include the groups described above.

[0060] In a preferred embodiment of the present invention, a compound satisfying (C) is given by formula (IC): [ka] [In formula (IC), R 1C and R 2C Together with the carbon atoms to which they bond, they form equations (c1)~(c6): [ka] [In formulas (c1) to (c4), R 7C ~R 14C teeth, Each independently represents one of the following: a hydrogen atom, an -OH group, an aromatic ring which may have substituents, or a group obtained by removing a hydrogen atom from a single hydroxyl group of a sugar skeleton. or R 7C and R 8C , R 9Cand R 10C , R 11C and R 12C , or R 13C and R 14C However, together with the carbon atoms to which they bond, they form a 6-membered saturated or unsaturated hydrocarbon ring. In equations (c5) and (c6), R 15C ~R 18C teeth, Each independently represents one of the following: a hydrogen atom, an -OH group, an aromatic ring which may have substituents, or a group obtained by removing a hydrogen atom from a single hydroxyl group of a sugar skeleton. or R 15C and R 16C , or R 17C and R 18C However, together with the carbon atoms to which they bond, they form a spiro ring. Form a complex ring represented by either of the following: R 3C ~R 6C teeth, Independently of each other, hydrogen atom, halogen atom, -OH, C 1-3 Alkyl or -R e Represents one of the following, however, R 3C ~R 6C At least one of them is -OH or -R e Represents R e C 1-3 It represents an alkoxy group, or a group obtained by removing a hydrogen atom from one hydroxyl group in any of the following skeletons: a flavan-3-ol skeleton, a sugar skeleton, a gallic acid skeleton, or a skeleton formed by the dehydration condensation of a sugar skeleton and a gallic acid skeleton. or R 3C ~R 6C Three of them are, independently of each other, a hydrogen atom, a halogen atom, -OH, and C. 1-3 Alkyl or -R e Represents either of the following, R 3C ~R 6C One of them represents a divalent linking group of *-C(=O)-O-* or *-OC(=O)-* (where * is a bond), however in this case, R 1C and R2C These, together with the carbon atoms to which they are bonded, form a heterocycle represented by one of the formulas (c1) to (c4), and R in formulas (c1) to (c4) 7C and R 8C , R 9C and R 10C , R 11C and R 12C , or R 13C and R 14C These groups, together with the carbon atoms to which they are bonded, form a six-membered saturated or unsaturated hydrocarbon ring, and the divalent linking group links the carbon atoms constituting the hydrocarbon ring to the carbon atoms on the benzene ring of formula (IC). It is a compound represented by [formula].

[0061] Substituent R in formula (IC) 1C ~R 6C Of these, R 1C and R 2C R is a group that bonds to an adjacent carbon atom, and together with the carbon atom to which they bond, they form a heterocycle represented by any of the above formulas (c1) to (c6). 1C and R 2C Preferably, They either form a heterocycle of formula (c1) together with the carbon atoms to which they bond, They either form a heterocycle of formula (c2) together with the carbon atoms to which they bond, They either form a heterocycle of formula (c3) together with the carbon atoms to which they bond, or Together with the carbon atoms to which they bond, they form a heterocycle of formula (c5).

[0062] In equations (c1) to (c4), (ai)R 7C ~R 14C Each of these independently represents a hydrogen atom, an -OH group, an aromatic ring which may have substituents, or a group obtained by removing a hydrogen atom from a hydroxyl group of a sugar skeleton, or (a-ii)R 7C and R 8C , R 9C and R10C , R 11C and R 12C , or R 13C and R 14C However, together with the carbon atoms to which they are bonded, they form a 6-membered saturated or unsaturated hydrocarbon ring. However, in the case of (a-ii), two sets of R 11C and R 12C A configuration in which both of the above hydrocarbon rings and two sets of R 13C and R 14C This does not include embodiments in which both elements form the above-mentioned hydrocarbon ring.

[0063] In the case of the above (ai), R 7C ~R 14C A possible aromatic ring that may have substituents is one with 0 to 5 -OH and / or C groups. 1-3 A benzene ring having an alkoxy group, preferably with 0 to 3 -OH and / or C groups. 1-3 A benzene ring having an alkoxy group, more preferably 0 to 2 -OH and / or C 1-3 Examples include benzene rings having alkoxy groups. A group obtained by removing a hydrogen atom from one hydroxyl group of a sugar skeleton is R. a Regarding the above, examples include groups obtained by removing a hydrogen atom from one hydroxyl group in the sugar skeleton, and preferably groups represented by formulas (d2-1) to (d2-3). The stereoisomers of the sugar skeleton are not particularly limited.

[0064] In the case of (a-ii) above, R 7C and R 8C , R 9C and R 10C , R 11C and R 12C , or R 13C and R 14C However, the 6-membered saturated or unsaturated hydrocarbon ring formed by these atoms together with the carbon atoms to which they are bonded may have substituents, preferably an unsaturated 6-membered ring (benzene ring) which may have substituents, and more preferably a benzene ring having an -OH group. Substituents include -OH, halogen groups, and C 1-3 Alkyl alkyl group, C 1-3Examples include alkoxy groups, or groups obtained by removing a hydrogen atom from one hydroxyl group in any of the following skeletons: a flavan-3-ol skeleton, a sugar skeleton, a gallic acid skeleton, or a skeleton formed by dehydration condensation of a sugar skeleton and a gallic acid skeleton. Halogen groups, C 1-3 Alkyl alkyl group, C 1-3 Examples of alkoxy groups and groups obtained by removing a hydrogen atom from a single hydroxyl group in the flavan-3-ol skeleton mentioned above include the groups described above.

[0065] In equations (c5) and (c6), (bi)R 15C ~R 18C Each of these independently represents a hydrogen atom, an -OH group, an aromatic ring which may have substituents, or a group obtained by removing a hydrogen atom from a hydroxyl group of a sugar skeleton, or (b-ii)R 15C and R 16C , or R 17C and R 18C However, together with the carbon atoms to which they bond, they form a spiro ring.

[0066] In the case of the above (bi), R 15C ~R 18C An aromatic ring that may have substituents can be represented by the above (ai) is R 7C ~R 14C The same applies to the description of an aromatic ring which may have substituents, which can be represented by . Also, for a group obtained by removing a hydrogen atom from one hydroxyl group of a sugar skeleton, in the case of (ai) above, R 7C ~R 14C The same applies to any description of the said group that can be represented by it.

[0067] In the case of (b-ii) above, R 15C and R 16C , or R 17C and R 18C However, the spiro ring formed by them together with the carbon atoms to which they are bonded is preferably of formula (s): [ka] [In formula (s), the carbon atoms marked with * are R 15C and R 16C , or R 17C and R 18C [Represents the spirocarbon atom to which it is bonded] This is a spiro ring represented by .

[0068] Substituent R in formula (IC) 1C ~R 6C Of these, R 1C and R 2C In addition to satisfying the characteristics described above, (ci)R 3C ~R 6C These are, independently of each other, a hydrogen atom, a halogen atom, -OH, and C. 1-3 Alkyl or -R e Represents one of the following, however, R 3C ~R 6C At least one of them is -OH or -R e Represents R e C 1-3 It represents an alkoxy group, or a group obtained by removing a hydrogen atom from one hydroxyl group in any of the following skeletons: a flavan-3-ol skeleton, a sugar skeleton, a gallic acid skeleton, or a skeleton formed by the dehydration condensation of a sugar skeleton and a gallic acid skeleton. or (c-ii)R 3C ~R 6C Three of them are, independently of each other, a hydrogen atom, a halogen atom, -OH, and C. 1-3 Alkyl or -R e Represents either of the following, R 3C ~R 6C One of them represents a divalent linking group of *-C(=O)-O-* or *-OC(=O)-* (where * is a bond), however in this case, R 1C and R 2C These, together with the carbon atoms to which they are bonded, form a heterocycle represented by one of the formulas (c1) to (c4), and R in formulas (c1) to (c4) 7C and R 8C , R 9C and R 10C , R 11C and R 12C, or R 13C and R 14C These groups, together with the carbon atoms to which they are bonded, form a six-membered saturated or unsaturated hydrocarbon ring, and the divalent linking groups link the carbon atoms constituting the hydrocarbon ring to the carbon atoms on the benzene ring of formula (IC).

[0069] In the case of (ci) above, R 3C ~R 6C C that can be represented 1-3 Examples of alkyl groups include methyl, ethyl, n-propyl, and isopropyl groups, with methyl and ethyl groups being preferred, and methyl groups being even more preferred.

[0070] In the case of (ci) above, R 3C ~R 6C -R that can be represented e C in 1-3 As for alkoxy groups, R a C in 1-3 The alkoxy groups mentioned above are examples, and the preferred groups are similarly applicable.

[0071] R e In the flavan-3-ol skeleton, sugar skeleton, gallic acid skeleton, or a skeleton formed by the dehydration condensation of a sugar skeleton and a gallic acid skeleton, the group obtained by removing a hydrogen atom from one hydroxyl group is R. a The basis for this can be found in the above-mentioned points.

[0072] R e Preferably C 1-3 It is a group obtained by removing a hydrogen atom from an alkoxy group or a hydroxyl group in a sugar skeleton.

[0073] In the case of (c-ii) above, R 3C ~R 6C -R that can be represented e C in 1-3 For alkoxy groups, R a C in 1-3 The alkoxy groups mentioned above are examples, and the preferred groups are similarly applicable.

[0074] Also, R e In the flavan-3-ol skeleton, sugar skeleton, gallic acid skeleton, or a skeleton formed by the dehydration condensation of a sugar skeleton and a gallic acid skeleton, the group obtained by removing a hydrogen atom from one hydroxyl group is R. a The bases mentioned above are listed above, and R e Preferably C 1-3 It is a group obtained by removing a hydrogen atom from an alkoxy group or a hydroxyl group in a sugar skeleton.

[0075] Also, in the case of (c-ii) above, R 3C ~R 6C One of the groups represents a divalent linking group of *-C(=O)-O-* or *-OC(=O)-* (where * is a bond), in this case R 1C and R 2C These, together with the carbon atoms to which they are bonded, form a heterocycle represented by one of the formulas (c1) to (c4), and R in formulas (c1) to (c4) 7C and R 8C , R 9C and R 10C , R 11C and R 12C , or R 13C and R 14C (Preferably R in formula (c2)) 9C and R 10C or R in equation (c4) 13C and R 14C , more preferably, R in equation (c2) 9C and R 10C These groups, together with the carbon atoms to which they are bonded, form a six-membered saturated or unsaturated hydrocarbon ring (preferably a six-membered unsaturated hydrocarbon ring), and the divalent linking groups link the carbon atoms constituting the hydrocarbon ring to the carbon atoms on the benzene ring of formula (IC).

[0076] R in equation (IC) 1C and R 2CHowever, compounds represented by formula (IC) that, together with the carbon atoms to which they are bonded, form a heterocycle of formula (c1) are compounds having a chromone skeleton, preferably formula (IC-c1): [ka] [In formula (IC-c1), R 7c’ and R 8c’ R in equation (c1) 7c and R 8c The group described above is represented, preferably a hydrogen atom, -OH, an aromatic ring which may have substituents, or a group obtained by removing a hydrogen atom from one hydroxyl group of a sugar skeleton, more preferably R 7c’ R represents either a hydrogen atom, an -OH group, or a group obtained by removing a hydrogen atom from one hydroxyl group of a sugar skeleton. 8c’ This represents an aromatic ring which may have substituents, R 3C’ ~R 6C’ R in equation (IC) 3C ~R 6C [This represents the basis for the description of the subject.] The compound is represented by formula (c7) to (c11), and more preferably by formula (c7) to (c11).

[0077] R in equation (IC) 1C and R 2C However, compounds represented by formula (IC) that, together with the carbon atoms to which they are bonded, form a heterocycle of formula (c2) are compounds having a coumarin skeleton, preferably formula (IC-c21): [ka] [In formula (IC-c21), R 9c’ and R 10c’ (c2) is R 9c and R 10c The group described above is represented, preferably a hydrogen atom, -OH, an aromatic ring which may have substituents, or a group obtained by removing a hydrogen atom from one hydroxyl group of a sugar skeleton, more preferably R 9c’R represents either a hydrogen atom, an -OH group, or a group obtained by removing a hydrogen atom from one hydroxyl group of a sugar skeleton. 10c’ This represents a hydrogen atom or an aromatic ring which may have substituents, R 3C’ ~R 6C’ R in equation (IC) 3C ~R 6C [This represents the basis for the description of the subject.] A compound represented by formula (IC-c22): [ka] [In formula (IC-c22), R 19c’ , R 20c’ and R 21c’ R preferably represents a hydrogen atom or -OH, 3C’ ~R 5C’ R in equation (IC) 3C ~R 5C [This represents the group described, more preferably a hydrogen atom or -OH] The compound is represented by formula (C12) to (C14), and more preferably by formula (C12) to (C14).

[0078] R in equation (IC) 1C and R 2C However, compounds represented by formula (IC), which, together with the carbon atoms to which they are bonded, form a heterocycle of formula (c3), are compounds having a 4-chromaton skeleton, preferably of formula (IC-c3): [ka] [In formula (IC-c3), R 11c’ and R 12c’ This is R in equation (c3). 11c and R 12c The group described above is represented, preferably a hydrogen atom, an -OH group, an aromatic ring which may have substituents, or a group obtained by removing a hydrogen atom from one hydroxyl group of a sugar skeleton, more preferably two R groups. 11c’ Each of these independently represents a hydrogen atom or -OH, and R 12c’One of them represents a hydrogen atom, R 12c’ Another one of them represents an aromatic ring which may have substituents, R 3C’ ~R 6C’ R in equation (IC) 3C ~R 6C [This represents the basis for the description of the subject.] The compound is represented by formula (c15), and more preferably by formula (c15).

[0079] R in equation (IC) 1C and R 2C However, compounds represented by formula (IC), which, together with the carbon atoms to which they are bonded, form a heterocycle of formula (c5), are compounds having a coumaranone skeleton, preferably of formula (IC-c5): [ka] [In formula (IC-c5), R 15c’ and R 16c’ This is R in equation (c5). 15c and R 16c The groups described above are represented, and preferably together with the carbon atoms to which they are bonded, they form a spiro ring represented by the above formula (s). R 3C’ ~R 6C’ R in equation (IC) 3C ~R 6C [This represents the basis for the description of the subject.] The compound is represented by formula (c16), and more preferably by formula (c16).

[0080] The compounds represented by formula (IC) are more preferably the following formulas (c7) to (c16): [ka] It is a compound selected from the group consisting of compounds represented by [formula].

[0081] Preferred compounds represented by formula (IC) are (c7) quercetin, (c8) 3,3',4',7-tetrahydroxyflavone, (c9) baicalein, (c10) quercitrin, (c11) abiculalin, (c12) esculetin, (c13) esculin, (c14) ellagic acid, (c15) neohesperidin, and (c16) griseofulvin.

[0082] Compound (1) can be produced by chemical synthesis methods known to those skilled in the art, or a commercially available compound can be used.

[0083] <Compound (2)> Compound (2) is given by formula (II): [ka] This is a compound represented by [formula]. This compound is thought to readily interact with nitrotyrosine at the condensed ring portion, similar to compound (1). Furthermore, it is thought that the presence of -C(=O)-OH and -OH bonded to the condensed ring portion can decompose nitrotyrosine, but the present invention is not limited in any way to the above mechanism. Compound (2) is also called gibberellin and is a commercially available compound.

[0084] <Compound (3)> Compound (3) is given by formula (III): [ka] This is a compound represented by [formula]. This compound is also thought to readily interact with nitrotyrosine at the fused ring portion, similar to compound (1). Furthermore, it is thought that the presence of -C(=O)-O-CH3 and -OH bonded to the fused ring portion, as well as the presence of a heterocyclic portion, allows it to decompose nitrotyrosine, but the present invention is not limited in any way to the above mechanism. Compound (3) is also called genipine and is a commercially available compound.

[0085] [Use of nitrotyrosine-reducing agents] A nitrotyrosine-reducing agent comprising at least one compound selected from the group consisting of compound (1), compound (2), and compound (3) above can reduce already generated nitrotyrosine, and therefore can prevent or improve diseases or symptoms caused by proteins containing nitrotyrosine. Accordingly, the present invention also provides the use of a nitrotyrosine-reducing agent comprising the above compounds for the prevention or improvement of diseases or symptoms caused by proteins containing nitrotyrosine. Diseases or symptoms caused by proteins containing nitrotyrosine include diseases or symptoms selected from the group consisting of yellowing of the skin, decreased skin elasticity, arteriosclerosis, cerebral ischemic disease, neurodegenerative disease, hypertension, asthma, rheumatoid arthritis, diabetic nephropathy, and inflammatory bowel disease. The above diseases or symptoms are thought to be caused by the denaturation of tyrosine, which constitutes proteins, into nitrotyrosine. In the present invention, nitrotyrosine includes not only nitrotyrosine compounds but also nitrotyrosine residues, which are formed when tyrosine as an amino acid residue of a protein is nitrated.

[0086] [An agent to improve yellowish dullness of the skin] The present invention also provides a skin yellowing-improving agent comprising at least one compound selected from the group consisting of compound (1), compound (2), and compound (3) described above. By adding this skin yellowing-improving agent to cosmetics or pharmaceuticals as needed and allowing it to act on the skin, it is possible to improve the yellowing-improving skin caused by the production of nitrotyrosine.

[0087] [An agent to improve decreased skin elasticity] The present invention also provides a skin elasticity-improving agent comprising at least one compound selected from the group consisting of compound (1), compound (2), and compound (3) described above. By adding this skin elasticity-improving agent to cosmetics or pharmaceuticals as needed and allowing it to act on the skin, it is possible to improve the skin elasticity-improving effects caused by the production of nitrotyrosine.

[0088] [Cosmetics or pharmaceuticals] The method of using the nitrotyrosine reducing agent, skin yellowing and dullness improving agent, or skin elasticity improving agent of the present invention, which comprises at least one compound selected from the group consisting of the specific compounds (1), (2), and (3) described above, is not particularly limited, but it may be added to a composition such as a cosmetic or pharmaceutical product and acted upon the skin. When the nitrotyrosine reducing agent, skin yellowing and dullness improving agent, or skin elasticity improving agent of the present invention is added to the above composition, since the agent does not contain any other components other than the specific components, it may be possible to improve the storage stability of the composition, for example, or to suppress undesirable side reactions with other additives contained in the composition. The amount of the nitrotyrosine reducing agent, skin yellowing and dullness improving agent, or skin elasticity improving agent of the present invention added to a composition such as a cosmetic or pharmaceutical product is not particularly limited and may be set appropriately according to the desired effect. The amount of the additive may be, for example, 0.00001% to 30% by mass, preferably 0.001% to 10% by mass, and more preferably 0.01% to 1% by mass, based on the total weight of the cosmetic or pharmaceutical composition. Furthermore, the form of the composition is not limited in any way and may be a solid composition, aqueous composition, oil-based composition, emulsion, cream, etc. Such a composition may be used, for example, as an ointment, tablet, nutritional drink, lotion, or foundation.

[0089] When a nitrotyrosine reducing agent, a skin yellowing and dullness improving agent, or a skin elasticity reduction improving agent of the present invention, comprising at least one compound selected from the group consisting of the specific compounds (1), (2), and (3) described above, is added to a composition of cosmetics or pharmaceuticals, for example, to manufacture cosmetics or pharmaceuticals, the composition of the cosmetics or pharmaceuticals may contain other arbitrary components used in cosmetics or pharmaceuticals (e.g., topical skin preparations), other than the nitrotyrosine reducing agent of the present invention, to the extent that it does not impair the purpose or effect of the present invention. Such components may include oils and fats, waxes, hydrocarbon oils, higher fatty acids, higher alcohols, synthetic ester oils, silicone oils, oil phase thickeners, surfactants, water-soluble ultraviolet absorbers, chelating agents, lower alcohols, polyhydric alcohols, pH adjusters, antioxidants, preservatives, powder components, fragrances, water, etc., as appropriate and as needed. However, the present invention is not limited to these examples. [Examples]

[0090] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. Unless otherwise specified, the amounts are expressed in mass percent. Unless otherwise specified, reagent-grade ethanol (99.5%) was used.

[0091] <Preparation of the test substance> In Examples 1 to 27, the test substances used were compounds represented by the following formulas (a1) to (a2), (b1) to (b13), (c7) to (c16), (II), and (III). In Comparative Examples 1 to 25, the test substances used were compounds represented by the following formulas (x1) to (x25). Each compound was dissolved in ethanol (Fujifilm Corporation) or distilled water to prepare a 100 mM solution. Distilled water or ethanol was used as the control substance.

[0092] <Nitrotyrosine Degradation Activity Test> Nitrotyrosine (SIGMA) was dissolved in 1 M phosphate buffer (pH 7.4) to a concentration of 400 μM, and the test substance was added to a concentration of 10 mM. After incubation of the solution at 37°C for 3 days, the amount of nitrotyrosine in the solution was measured by HPLC under the following analytical conditions. (Analysis conditions) Analytical column: Chemcobond 5-ODS-W (150 x 6 mm) Detection wavelength: 355nm Mobile phase: 10 mM phosphate buffer (pH 2.8) - methanol (9:1 (v / v)) Column temperature: 40℃ Flow rate: 1.0mL / min

[0093] The nitrotyrosine decomposition rate (%) was calculated from the amount of nitrotyrosine in the obtained solution according to the following formula. The results are shown in Tables 1 and 2. A nitrotyrosine decomposition rate of 5% or higher was considered to indicate a nitrotyrosine reduction effect, while a rate of less than 5% was considered to indicate no nitrotyrosine reduction effect. Furthermore, a higher nitrotyrosine decomposition rate indicates a greater nitrotyrosine reduction effect. (Nitrotyrosine decomposition rate) Nitrotyrosine decomposition rate (%) = {1 - (A / B)} × 100 A: Amount of nitrotyrosine in the reaction solution to which the test substance was added. B: Amount of nitrotyrosine in the reaction solution with the control substance added.

[0094] <Test substance> [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0095] [Table 1]

[0096] [Table 2]

[0097] In Examples 1 to 27, when a nitrotyrosine reducing agent consisting of at least one compound selected from the group consisting of specific compound (1), compound (2), and compound (3) was used, a high nitrotyrosine reduction effect was obtained. In contrast, in the case of the compounds in Comparative Examples 1 to 5 and 10, which do not have a benzene ring moiety, and in the case of Comparative Examples 6 to 9 and 11 to 25, which have a benzene ring moiety but do not have the specific substituent of the present invention, no nitrotyrosine reduction effect was obtained.

[0098] From the results above, it was confirmed that an agent comprising at least one compound selected from the group consisting of specific compounds (1), (2), and (3) has a nitrotyrosine-reducing effect, and that this agent is useful as a nitrotyrosine-reducing agent. By using such an agent, it is possible to prevent or improve diseases or symptoms caused by proteins containing nitrotyrosine, specifically, yellowing of the skin, decreased skin elasticity, arteriosclerosis, cerebral ischemic disease, neurodegenerative disease, hypertension, asthma, rheumatoid arthritis, diabetic nephropathy, and inflammatory bowel disease. Furthermore, it was found that this agent is also effective as an agent for improving yellowing of the skin and decreased skin elasticity caused by nitrated proteins.

Claims

[Claim 1] (1) (A) Equations (a1) and (a2): 【Chemistry 1】 A compound selected from the group consisting of compounds represented by, (B) Formulas (b1) to (b13): 【Chemistry 2】 A compound selected from the group consisting of compounds represented by, or (C) Formulas (c7) to (c16): 【Transformation 3】 A compound selected from the group consisting of compounds represented by, (1) A compound that is one of the following: (2) Formula (II): 【Chemistry 4】 Compound (2) represented by, and (3) Formula (III): 【Transformation 5】 Compound (3) represented by A nitrotyrosine reducing agent comprising at least one compound selected from the group consisting of the following.

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