Ascorbic acid derivatives or their salts and cosmetics containing them

Abstract

To provide an anti-glycation agent having an excellent anti-glycation effect, and a cosmetic preparation thereof. [Solution] An anti-glycation agent containing an ascorbic acid derivative or its salt in which the hydrogen of the hydroxyl group at the 2nd or 3rd position of ascorbic acid is substituted with RO-CH2-CH(OH)-CH2-, RO-CH2-CH(CH2OH)-, R-CH(CH2OH)-, R-CH(OH)-CH2- (R is H, an alkyl group, an alkenyl group, or a phenyl group), HO-C(CH3)2-CH2-, or HO-CH2-C(CH3)2- (provided that at least one is HO-C(CH3)2-CH2- or HO-CH2-C(CH3)2-), and a cosmetic preparation containing these ascorbic acid derivatives.

Description

[Technical Field]

[0001] The present invention relates to an anti-glycation agent containing an ascorbic acid derivative or a salt thereof, and a cosmetic preparation containing the anti-glycation agent. [Background technology]

[0002] Carbohydrates are extremely important as an energy source for humans and other living organisms. However, they are known to undergo glycation reactions with proteins. Glycation is a series of reactions that begins with a non-enzymatic reaction between the carbonyl group of a carbohydrate and the amino group of a protein, leading to the formation of Schiff bases, Amadori compounds, and finally to the formation of advanced glycation end products (hereinafter sometimes referred to as "AGEs"). Glycation non-enzymatically modifies proteins with sugars, causing denaturation of the protein and cross-linking between proteins, resulting in a decrease in protein function.

[0003] Glycation not only causes direct damage by modifying and structurally altering extracellular matrix proteins such as collagen, but also induces cellular responses by being recognized by receptors that use glycated proteins as ligands.

[0004] Because extracellular matrix components such as collagen account for more than half of the dry weight of skin, for example, when collagen is glycated and abnormally cross-linked, it can cause a decrease in elasticity, dullness due to yellowing, etc. Furthermore, because abnormally cross-linked collagen is less susceptible to degradation by collagenases, etc., the expression of collagenases, etc., can be induced, leading to problems such as the degradation of normal collagen as well.

[0005] Therefore, it is expected that inhibiting glycation reactions in some way, i.e., inhibiting the formation of AGEs or promoting the breakdown of AGEs, will be effective in preventing or improving skin problems such as loss of elasticity and dullness.

[0006] N-phenethylthiazolium bromide has been known as a compound with anti-glycation activity (Non-Patent Document 1). However, this compound has safety issues and is not suitable as a topical skin preparation. In addition, extracts from mugwort, for example, are known as naturally occurring components with anti-glycation activity (Patent Document 1). However, it cannot be said that there are sufficient substances with anti-glycation activity, and there is a strong demand for the development and provision of new substances with anti-glycation activity. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Japanese Patent Application Laid-Open No. 2001-122758 [Non-patent literature]

[0008] [Non-Patent Document 1] Vasan S. et al.,Nature,July 18, 1996,Vol. 82,No. 6588,p.275-278 Summary of the Invention [Problem to be solved by the invention]

[0009] An object of the present invention is to provide an anti-glycation agent having an excellent anti-glycation effect, and a cosmetic preparation containing the anti-glycation agent. [Means for solving the problem]

[0010] The present inventors have conducted extensive research in light of the above-mentioned circumstances and have found that a novel ascorbic acid derivative represented by the following formula (I) or a salt thereof has an excellent anti-glycation effect. The present invention was completed based on these findings.

[0011] The present invention provides an anti-glycation agent containing an ascorbic acid derivative represented by the following general formula (I) or a salt thereof (claim 1).

[0012] [ka]

[0013] [In the formula, R 1 and R 2 is H, an alkyl group having 1 to 22 carbon atoms, an alkenyl group having 2 to 22 carbon atoms, a benzyl group, R 3 -O-CH2-CH(OH)-CH2-, R 3 -O-CH2-CH(CH2OH)-, R 3 -CH(CHOH)-, R 3 -CH(OH)-CH-, HO-C(CH)-CH- or HO-CH-C(CH)-, and R 3 is H, an alkyl group having 1 to 22 carbon atoms, an alkenyl group having 2 to 22 carbon atoms, or a phenyl group. 1 and R 2 At least one of the groups is HO-C(CH3)2-CH2- or HO-CH2-C(CH3)2-.]

[0014] The salt of the ascorbic acid derivative is a salt of the ascorbic acid derivative represented by R 1 or R 2 is H, means a compound in which H in the ascorbic acid derivative is substituted with a cation such as a metal ion or an ammonium ion, and this salt is also included in the present invention.

[0015] An ascorbic acid derivative represented by general formula (I), wherein R 1 or R 2 As described below, ascorbic acid in which one of the groups is H can be obtained by reacting ascorbic acid with isobutylene oxide or halogenated tert-butyl alcohol, and regiospecifically etherifying only the 2nd or 3rd position of the four hydroxyl groups at the 2nd, 3rd, 5th, and 6th positions of ascorbic acid with HO-C(CH3)2-CH2- or HO-CH2-C(CH3)2-.

[0016] In the reaction of ascorbic acid with isobutylene oxide or halogenated tert-butyl alcohol, depending on the reaction conditions for etherification, the hydroxyl group at the 2-position may be etherified primarily, or the hydroxyl group at the 3-position may be etherified primarily. When the hydroxyl group at the 2-position is etherified primarily, R 2 However, a mixture of HO-C(CH3)2-CH2- and HO-CH2-C(CH3)2- may be produced. When the hydroxyl group at the 3-position is mainly etherified, R 1 However, a mixture of HO-C(CH3)2-CH2- and HO-CH2-C(CH3)2- may occur.

[0017] Among the ascorbic acid derivatives represented by general formula (I), R 1 or R 2 one of which is HO-C(CH3)2-CH2- or HO-CH2-C(CH3)2-, and the other is an alkyl group having 1 to 22 carbon atoms, an alkenyl group having 2 to 22 carbon atoms, a benzyl group, or R 3 -O-CH2-CH(OH)-CH2-, R 3 -O-CH2-CH(CH2OH)-, R 3 -CH(CHOH)- or R 3 -CH(OH)-CH2- R obtained by reacting ascorbic acid with isobutylene oxide or halogenated tert-butyl alcohol 1 or R 2 is HO-C(CH3)2-CH2- or HO-CH2-C(CH3)2-, and reacting it with glycidol, alkyl glycidyl ether of a specific structure, alkenyl glycidyl ether, phenyl glycidyl ether, sulfate ester, alkylene oxide, alkenyl oxide, styrene oxide, alkyl halide, hydroxyalkyl halide, benzyl halide, alkenyl halide, hydroxyalkenyl halide, halogenated phenethyl alcohol, or the like, Ascorbic acid, glycidol, alkyl glycidyl ethers of specific structures, alkenyl glycidyl ethers, phenyl glycidyl ethers, sulfate esters, alkylene oxides, alkenyl oxides, styrene oxides, alkyl halides, hydroxyalkyl halides, benzyl halides, alkenyl halides, hydroxyalkenyl halides, and halogenated phenethyl alcohols are R 1 or R 2 The compound obtained by reacting either one of the above with isobutylene oxide or a halogenated tert-butyl alcohol can also be obtained.

[0018] By incorporating the ascorbic acid derivative or salt thereof of the present invention into a cosmetic, it is possible to obtain a cosmetic that has excellent whitening and moisturizing effects, which are inherently possessed by ascorbic acid, and has a high anti-glycation effect. Therefore, the present invention provides a cosmetic characterized by incorporating the ascorbic acid derivative or salt thereof of the present invention (claim 2). [Effects of the Invention]

[0019] The ascorbic acid derivative or salt thereof of the present invention represented by the general formula (I) has the excellent functions inherent to ascorbic acid, such as whitening and moisturizing effects, and also has a high anti-glycation effect. Therefore, by incorporating this compound into cosmetics such as topical skin preparations, it is possible to obtain cosmetics that have excellent whitening and moisturizing effects and high physiological activity. The cosmetics of the present invention are cosmetics that have excellent whitening and moisturizing effects, as well as a high anti-glycation effect. DETAILED DESCRIPTION OF THE INVENTION

[0020] Hereinafter, HO-C(CH)-CH or HO-CH-C(CH)- will be referred to as a "hydroxyisobutyl group." Hydroxyisobutyl ascorbic acid refers to ascorbic acid in which a hydroxyisobutyl group is bonded to one or more oxygen atoms of each hydroxyl group. The ascorbic acid derivative of the present invention is hydroxyisobutyl ascorbic acid in which a hydroxyisobutyl group is bonded to the 2- and / or 3-position.

[0021] Specific examples of the ascorbic acid derivative represented by general formula (I) include the compounds shown below, but the scope of the present invention is not limited to these.

[0022] In the following examples, Glyceryl refers to HO-CH2-CH(OH)-CH2- or HO-CH2-CH(CH2OH)-; The alkylglyceryl group refers to RO-CH-CH(OH)-CH- or RO-CH-CH(CHOH)- (wherein R represents an alkyl group). The hydroxyalkyl group refers to a 2-alkyl-2-hydroxyethyl group represented by R-CH(OH)-CH2- (R represents an alkyl group). The hydroxyalkenyl group refers to a 2-alkenyl-2-hydroxyethyl group represented by R-CH(OH)-CH2- (R represents an alkenyl group). The alkyl group refers to a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, a hexyl group, an ethylhexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an eicosyl group, a behenyl group, or the like. The alkenyl group refers to a vinyl group, an allyl group, a butenyl group, an isobutenyl group, a crotyl group, an octenyl group, a decenyl group, a dodecenyl group, and the like.

[0023] (1) 3-O-hydroxyisobutyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-alkyl ascorbic acids, such as 3-O-hydroxyisobutyl-2-O-ethyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-butyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-hexyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-octyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-decyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-ethylhexyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-dodecyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-tetradecyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-hexadecylascorbic acid; 3-O-hydroxyisobutyl-2-O-alkenyl ascorbic acids, such as 3-O-hydroxyisobutyl-2-O-allyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-octenyl ascorbic acid, 3-O-hydroxyisobutyl-2-O-dodecenyl ascorbic acid; 3-O-hydroxyisobutyl-2-O-glyceryl ascorbate; 3-O-hydroxyisobutyl-2-O-alkylglyceryl ascorbate, for example, 3-O-hydroxyisobutyl-2-O-butylglyceryl ascorbate, 3-O-hydroxyisobutyl-2-O-ethylhexylglyceryl ascorbate, 3-O-hydroxyisobutyl-2-O-dodecylglyceryl ascorbate; 3-O-hydroxyisobutyl-2-O-alkenylglyceryl ascorbate, for example, 3-O-hydroxyisobutyl-2-O-dodecenylglyceryl ascorbate; 3-O-hydroxyisobutyl-2-O-phenylglyceryl ascorbate; 3-O-hydroxyisobutyl-2-O-benzyl ascorbic acid; 3-O-hydroxyisobutyl-2-O-(2-hydroxyalkyl)ascorbic acids, such as 3-O-hydroxyisobutyl-2-O-(2-hydroxypropyl)ascorbic acid, 3-O-hydroxyisobutyl-2-O-(2-hydroxydecyl)ascorbic acid, 3-O-hydroxyisobutyl-2-O-(2-hydroxyhexadecyl)ascorbic acid, 3-O-hydroxyisobutyl-2-O-(2-hydroxyethylbenzene)ascorbic acid; 3-O-hydroxyisobutyl-2-O-(2-alkyl-2-hydroxyethyl)ascorbic acids, such as 3-O-hydroxyisobutyl-2-O-(2-methyl-2-hydroxyethyl)ascorbic acid, 3-O-hydroxyisobutyl-2-O-(2-ethyl-2-hydroxyethyl)ascorbic acid, 3-O-hydroxyisobutyl-2-O-(2-octyl-2-hydroxyethyl)ascorbic acid, 3-O-hydroxyisobutyl-2-O-(2-tetradecyl-2-hydroxyethyl)ascorbic acid, 3-O-hydroxyisobutyl-2-O-(2-phenyl-2-hydroxyethyl)ascorbic acid.

[0024] (2) 2-O-hydroxyisobutyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-alkyl ascorbic acids, such as 2-O-hydroxyisobutyl-3-O-ethyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-butyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-hexyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-octyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-decyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-ethylhexyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-dodecyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-tetradecyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-hexadecylascorbic acid; 2-O-hydroxyisobutyl-3-O-alkenyl ascorbic acids, such as 2-O-hydroxyisobutyl-3-O-allyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-octenyl ascorbic acid, 2-O-hydroxyisobutyl-3-O-dodecenyl ascorbic acid; 2-O-hydroxyisobutyl-3-O-glyceryl ascorbate; 2-O-hydroxyisobutyl-3-O-alkylglyceryl ascorbate, for example, 2-O-hydroxyisobutyl-3-O-butylglyceryl ascorbate, 2-O-hydroxyisobutyl-3-O-ethylhexylglyceryl ascorbate, 2-O-hydroxyisobutyl-3-O-dodecylglyceryl ascorbate; 2-O-hydroxyisobutyl-3-O-alkenylglyceryl ascorbate, for example, 2-O-hydroxyisobutyl-3-O-dodecenylglyceryl ascorbate; 2-O-hydroxyisobutyl-3-O-phenylglyceryl ascorbate; 2-O-hydroxyisobutyl-3-O-benzyl ascorbic acid; 2-O-hydroxyisobutyl-3-O-(2-hydroxyalkyl)ascorbic acids, such as 2-O-hydroxyisobutyl-3-O-(2-hydroxypropyl)ascorbic acid, 2-O-hydroxyisobutyl-3-O-(2-hydroxydecyl)ascorbic acid, 2-O-hydroxyisobutyl-3-O-(2-hydroxyhexadecyl)ascorbic acid, 2-O-hydroxyisobutyl-3-O-(2-hydroxyethylbenzene)ascorbic acid; 2-O-hydroxyisobutyl-3-O-(2-alkyl-2-hydroxyethyl)ascorbic acids, such as 2-O-hydroxyisobutyl-3-O-(2-methyl-2-hydroxyethyl)ascorbic acid, 2-O-hydroxyisobutyl-3-O-(2-ethyl-2-hydroxyethyl)ascorbic acid, 2-O-hydroxyisobutyl-3-O-(2-octyl-2-hydroxyethyl)ascorbic acid, 2-O-hydroxyisobutyl-3-O-(2-tetradecyl-2-hydroxyethyl)ascorbic acid, 2-O-hydroxyisobutyl-3-O-(2-phenyl-2-hydroxyethyl)ascorbic acid.

[0025] (3) 2,3-di-O-hydroxyisobutyl ascorbic acid.

[0026] The ascorbic acid derivatives or salts thereof of the present invention can be produced by various methods. For example, ascorbic acid is reacted with isobutylene oxide or a halogenated tert-butyl alcohol to introduce a hydroxyisobutyl group into the oxygen atom bonded to the 2- or 3-position of ascorbic acid, thereby synthesizing 2-O- or 3-O-hydroxyisobutylascorbic acid. The other oxygen atom bonded to the 2- or 3-position is then alkylated or alkenylated by known means to obtain the ascorbic acid derivatives of the present invention. Alternatively, the oxygen atom bonded to the 2- or 3-position of ascorbic acid may first be alkylated or alkenylated, and then the compound of the present invention may be obtained by reacting the oxygen atom with isobutylene oxide or a halogenated tert-butyl alcohol.

[0027] Examples of the compound for introducing a hydroxyisobutyl group of the present invention include, but are not limited to, isobutylene oxide and halogenated tert-butyl alcohol. Examples of halogenated tert-butyl alcohol include fluorinated tert-butyl alcohol, chlorinated tert-butyl alcohol, and bromized tert-butyl alcohol.

[0028] In the reaction of ascorbic acid with isobutylene oxide or halogenated tert-butyl alcohol, depending on the reaction conditions for etherification, the hydroxyl group at the 2-position may be etherified primarily, or the hydroxyl group at the 3-position may be etherified primarily. When the hydroxyl group at the 2-position is etherified primarily, R 2 However, a mixture of HO-C(CH3)2-CH2- and HO-CH2-C(CH3)2- may be produced. When the hydroxyl group at the 3-position is mainly etherified, R 1 However, a mixture of HO-C(CH3)2-CH2- and HO-CH2-C(CH3)2- may occur.

[0029] The amount of isobutylene oxide or halogenated tert-butyl alcohol used in the present invention is not particularly limited, but is preferably 0.8 to 1.5 mol, more preferably 1.0 to 1.2 mol, per 1 mol of ascorbic acid.

[0030] The reaction for introducing a hydroxyisobutyl group in the production of the present invention can be carried out in various solvents, including, but not limited to, water, lower alcohols such as methanol, ethanol, and isopropanol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dioxane, tetrahydrofuran (THF), N-methylpyrrolidone, and mixtures thereof. The reaction temperature is not particularly limited, but is preferably in the range of 30 to 100°C, more preferably in the range of 50 to 90°C, and particularly preferably in the range of 60 to 90°C.

[0031] The pH of the reaction solvent is not particularly limited, but when a hydroxyisobutyl group is introduced at the 3-position of the ascorbic acid structure in the production of the ascorbic acid derivative or a salt thereof, acidic conditions are preferred, with a pH of 2 to 6 being particularly preferred. When a hydroxyisobutyl group is introduced at the 2-position of the ascorbic acid structure in the production of the ascorbic acid derivative or a salt thereof, alkaline conditions are preferred, with a pH of 8 to 11 being particularly preferred.

[0032] Examples of pH adjusters used during the reaction include hydrochloric acid, sulfuric acid, lactic acid, citric acid, glycolic acid, succinic acid, tartaric acid, malic acid, gluconic acid, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, ammonium hydrogencarbonate, and triethylamine.

[0033] The ascorbic acid derivative or a salt thereof of the present invention produced as described above can be purified by means of column chromatography using silica gel, column chromatography using a resin such as an ion exchange resin, activated carbon treatment, extraction, distillation, crystallization, or the like.

[0034] The ascorbic acid derivative represented by the general formula (I) is 1 or R 2 In compounds where R is H, the hydrogen ion dissociated from H can be replaced with a cation such as a metal ion or an ammonium ion to form a salt, and such salts are also included within the scope of the present invention. Examples of such salts include inorganic salts and organic salts. Examples of inorganic salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and ammonium salts, while examples of organic salts include diethanolamine salts, triethanolamine salts, and basic amino acid salts. The formation of a salt is achieved by the reaction of R 1 or R 2 This can be carried out by a method similar to that for forming a known salt, such as a method of neutralizing an aqueous solution of an ascorbic acid derivative in which is H with a basic substance.

[0035] The ascorbic acid derivative of the present invention can be obtained by alkylating, alkenylating, benzylating, hydroxyalkylating, or the like the hydroxyisobutylascorbic acid synthesized as described above with glycidol, alkyl glycidyl ethers of specific structures, alkenyl glycidyl ethers, phenyl glycidyl ethers, sulfates, alkylene oxides, alkenyl oxides, styrene oxides, alkyl halides, hydroxyalkyl halides, benzyl halides, alkenyl halides, hydroxyalkenyl halides, halogenated phenethyl alcohols, or the like.

[0036] There are no particular restrictions on the amount of glycidol, alkyl glycidyl ether, alkylene oxide, alkenyl oxide, styrene oxide, etc. used in alkylation, alkenylation, benzylation, phenylation, etc., but it is preferably 0.8 to 2.0 moles per mole of hydroxyisobutylascorbic acid.

[0037] The reaction with glycidol, alkyl glycidyl ether, alkylene oxide, alkenyl oxide, styrene oxide, or the like can be carried out in the same solvent, at the same reaction temperature, and at the same pH as in the reaction for introducing a hydroxyisobutyl group. The ascorbic acid derivative of the present invention can be synthesized by purifying the product by means of column chromatography using silica gel, column chromatography using a resin such as an ion exchange resin, activated carbon treatment, extraction, distillation, crystallization, or the like. In addition, even when first reacting the oxygen atom bonded to the 2- or 3-position of ascorbic acid with glycidol, alkyl glycidyl ether, alkylene oxide, alkenyl oxide, styrene oxide, or the like, and then introducing a hydroxyisobutyl group into the other oxygen atom, each reaction can be carried out under the same conditions as above.

[0038] The ascorbic acid derivative or a salt thereof of the present invention can be suitably used as a component of various cosmetics such as external skin preparations and hair cosmetics.

[0039] When the ascorbic acid derivative or salt thereof of the present invention is blended into various cosmetics, the blending amount is preferably 1% to 20% by weight, and particularly preferably 3% to 10% by weight. If the blending amount is less than 1% by weight, the anti-glycation effect of the ascorbic acid derivative or salt thereof of the present invention is often not fully exhibited, while if the blending amount exceeds 20% by weight, the effect commensurate with the blending amount is often not expected, and there is also a risk of damaging the formulation system.

[0040] In addition to these essential ingredients, the cosmetic of the present invention may contain, as appropriate, commonly used ingredients such as oily raw materials, surfactants, moisturizers, polymeric compounds, antioxidants, whitening agents, pharmaceuticals, ultraviolet absorbers, sequestering agents, proteins, protein hydrolysates or derivatives thereof, amino acids or derivatives thereof, pH adjusters, preservatives, etc. The ascorbic acid derivative or salt thereof of the present invention also exhibits an effect as a moisturizer, and other moisturizers may also be incorporated into the cosmetic of the present invention as appropriate.

[0041] Examples of the oily raw materials, surfactants, other moisturizers, polymeric compounds, antioxidants, other whitening agents, other drugs, ultraviolet absorbers, sequestering agents, proteins, protein hydrolysates or derivatives thereof, amino acids or derivatives thereof, pH adjusters, preservatives, and the like can include those similar to those described in WO2022 / 080287.

[0042] The cosmetic composition of the present invention may be formulated in any system, including a solution system, a solubilized system, an emulsion system, a gel system, a powder dispersion system, and a water-oil two-layer system, and can be produced by blending the ascorbic acid derivative represented by the above general formula (I) or a salt thereof with the above optional ingredients according to the desired product. [Example]

[0043] Next, specific embodiments for carrying out the present invention will be described with reference to Examples, but the scope of the present invention is not limited to these Examples. Prior to the Examples, production examples of the ascorbic acid derivatives of the present invention used in the Examples and Comparative Examples will be shown as Synthesis Examples.

[0044] Synthesis Example 1: Synthesis of 2-O-(2-hydroxyisobutyl)ascorbic acid Water (10.5 mL), DMF (5 mL), ascorbic acid (10.0 g), sodium hydroxide (2.50 g), and isobutylene oxide (4.50 g) were added to a recovery flask and stirred at 60°C for 4 hours. After the reaction was completed, 5 mol / L hydrochloric acid was added to adjust the pH to acidic. The mixture was concentrated under reduced pressure, and isopropanol was added. The mixture was then filtered and concentrated under reduced pressure. The resulting residue (10.1 g) was subjected to silica gel chromatography, eluted with a mixture of chloroform and methanol (10 / 0 to 6 / 4), and concentrated under reduced pressure to obtain 2-O-(2-hydroxyisobutyl)ascorbic acid (8.83 g).

[0045] The resulting product was analyzed by mass spectrometry. 1 H-NMR, 13 C-NMR measurement was carried out, and the results confirmed that the product was 2-O-(2-hydroxyisobutyl)ascorbic acid represented by the following structural formula.

[0046] [ka]

[0047] In this structural formula, carbon atoms and hydrogen atoms bonded to the carbon atoms are omitted. For example, in this formula, positions 1, 2, 4, 6, and 7 are carbon atoms, position 5 is a CH group, positions 3 and 9 are CH groups, and position 8 is a CH group. In the following structural formulas, hydrogen atoms and carbon atoms are omitted, just like in this formula.

[0048] In the synthesis examples shown below, the products obtained were analyzed by mass spectrometry, 1 H-NMR, and 13 C-NMR measurements were carried out, and the results confirmed that each product was an ascorbic acid derivative represented by the structural formula or compound name shown in each synthesis example. 1 H-NMR and 13The results of C-NMR measurements are shown in Tables 1 to 3.

[0049] Synthesis Example 2: Synthesis of 3-O-(2-hydroxyisobutyl)ascorbic acid DMF (50 mL), ascorbic acid (10.0 g), triethylamine (1.72 g), and isobutylene oxide (4.5 g) were added to a recovery flask and stirred at 90°C for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and isopropanol was added. The mixture was then filtered and concentrated under reduced pressure. The resulting residue (8.21 g) was subjected to silica gel chromatography, eluted with a mixture of chloroform and methanol (10:0 to 6:4), and concentrated under reduced pressure to obtain 3-O-(2-hydroxyisobutyl)ascorbic acid (7.42 g) represented by the following structural formula:

[0050] [ka]

[0051] Synthesis Example 3: Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-ethylascorbic acid 2-O-(2-hydroxyisobutyl)ascorbic acid (1.50 g) obtained in Synthesis Example 1, DMF (6 mL), triethylamine (1.22 g), and diethyl sulfate (1.86 g) were added to a recovery flask and stirred at 70°C for 4 hours. After the reaction was completed, ion-exchanged water and ethyl acetate were added, and the mixture was separated. The ethyl acetate layer was collected, and the extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue (1.16 g) was subjected to silica gel chromatography, eluting with a mixture of chloroform and methanol (10:0 to 7:3), and concentrated under reduced pressure to obtain 2-O-(2-hydroxyisobutyl)-3-O-ethylascorbic acid (148.5 mg) represented by the following structural formula:

[0052] [ka]

[0053] Synthesis Example 4 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-hexyl ascorbic acid In a recovery flask, 2-O-(2-hydroxyisobutyl)ascorbic acid (1.50 g) obtained in Synthesis Example 1, DMF (6 mL), sodium bicarbonate (1.27 g), and hexyl bromide (1.30 g) were added and stirred at 75°C for 5 hours. After the reaction was completed, ion-exchanged water and ethyl acetate were added, and the mixture was separated. The ethyl acetate layer was collected, and the extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue (1.99 g) was subjected to silica gel chromatography, eluting with a chloroform / methanol mixture (10 / 0 to 7 / 3), and concentrated under reduced pressure to obtain 2-O-(2-hydroxyisobutyl)-3-O-hexyl ascorbic acid (473.7 mg) represented by the following structural formula:

[0054] [ka]

[0055] Synthesis Example 5 Synthesis of 2-O-(2-hydroxyisobutyl)-3-O-glyceryl ascorbic acid 3-O-Glyceryl ascorbic acid (3.00 g), DMF (12 mL), triethylamine (0.24 g), and isobutylene oxide (1.04 mL) were added to a recovery flask and stirred at 85°C for 18 hours. After the reaction was completed, ion-exchanged water and ethyl acetate were added, and the mixture was separated. The ethyl acetate layer was collected, and the extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue (1.12 g) was subjected to silica gel chromatography, eluted with a mixture of chloroform / methanol (9.5 / 0.5 to 7 / 3), and concentrated under reduced pressure to obtain 2-O-(2-hydroxyisobutyl)-3-O-glyceryl ascorbic acid (178.6 mg) represented by the following structural formula:

[0056] [ka]

[0057] Synthesis Example 6 Synthesis of 2-O-octyl-3-O-(2-hydroxyisobutyl)ascorbic acid In a recovery flask, 3-O-(2-hydroxyisobutyl)ascorbic acid (1.50 g) obtained in Synthesis Example 2, DMF (6 mL), sodium bicarbonate (0.56 g), and octyl bromide (1.40 g) were added and stirred at 80°C for 4 hours. After the reaction was completed, ion-exchanged water and ethyl acetate were added, and the mixture was separated. The ethyl acetate layer was collected, and the extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue (2.37 g) was subjected to silica gel chromatography, eluting with a mixture of chloroform / methanol (10 / 0 to 8 / 2), and concentrated under reduced pressure to obtain 2-O-octyl-3-O-(2-hydroxyisobutyl)ascorbic acid (525.0 mg) represented by the following structural formula.

[0058] [ka]

[0059] Synthesis Example 7 Synthesis of 2-O-decyl-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-decyl-3-O-(2-hydroxyisobutyl)ascorbic acid (216.7 mg) was obtained in the same manner as in Synthesis Example 6, except that decyl bromide (1.60 g) was used instead of octyl bromide.

[0060] [ka]

[0061] Synthesis Example 8 Synthesis of 2-O-allyl-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-allyl-3-O-(2-hydroxyisobutyl)ascorbic acid (276.0 mg) was obtained in the same manner as in Synthesis Example 6, except that allyl bromide (0.88 g) was used instead of octyl bromide.

[0062] [ka]

[0063] Synthesis Example 9 Synthesis of 2-O-(2-hydroxy-3-O-ethylhexyl)-3-O-(2-hydroxyisobutyl)ascorbic acid In a recovery flask, 3.00 g of 3-O-(2-hydroxyisobutyl)ascorbic acid obtained in Synthesis Example 2, 12 mL of DMF, 0.20 g of sodium bicarbonate, and 2.70 g of ethylhexyl glycidyl ether were added and stirred at 85°C for 18 hours. After the reaction was completed, ion-exchanged water and ethyl acetate were added, and the mixture was separated. The ethyl acetate layer was collected, and the extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue (2.49 g) was subjected to silica gel chromatography, eluting with a mixture of chloroform and methanol (10:0 to 9:1), followed by concentration under reduced pressure to obtain 358.8 mg of 2-O-(2-hydroxy-3-O-ethylhexyl)-3-O-(2-hydroxyisobutyl)ascorbic acid, which has the following structural formula:

[0064] [ka]

[0065] Synthesis Example 10: Synthesis of 2-O-(2-hydroxy-3-O-dodecyl)-3-O-(2-hydroxyisobutyl)ascorbic acid The title 2-O-(2-hydroxy-3-O-dodecyl)-3-O-(2-hydroxyisobutyl)ascorbic acid (916.0 mg) was obtained in the same manner as in Synthesis Example 9, except that lauryl glycidyl ether (3.52 g) was used instead of ethylhexyl glycidyl ether.

[0066] [ka]

[0067] Mass spectrometry of the products obtained in Synthesis Examples 1 to 10 was carried out using an LCMS-2020 (Shimadzu Corporation). The measurement results are shown in Table 1.

[0068] [Table 1] *Ionization was performed by electrospray ionization (ESI).

[0069] The products obtained in Synthesis Examples 1 to 10 1 H-NMR was performed using a JNM-ECS400 (manufactured by JEOL Ltd.) The measurement results are shown in Table 2.

[0070] [Table 2]

[0071] The products obtained in Synthesis Examples 1 to 10 13 C-NMR was performed using a JNM-ECS400 (manufactured by JEOL Ltd.) The measurement results are shown in Table 3.

[0072] [Table 3]

[0073] Test Example 1 [Anti-glycation effect] The anti-glycation test of the ascorbic acid derivative of the present invention was carried out according to the following procedure. For comparison, a similar evaluation was also carried out on a known ascorbic acid derivative. The results are shown in Table 4.

[0074] Normal human dermal fibroblasts (NHDFs) were cultured at 5.0 × 10 4 Cells were seeded onto 48-well plates using 5% DL (Dulbecco's modified Eagle's medium, low glucose) to a cell density of 100 cells / well. The medium was replaced with sample-containing medium and cultured for 24 hours. After removing the medium, the cells were washed with HBSS(+) and treated with 10 mM glyoxal for 30 minutes. After further washing with HBSS(+), the medium was replaced with 5% DL and cultured for 48 hours. The cells were lysed, and the amount of CML produced in the cells was quantified by ELISA. Protein was then quantified by BCA, and the amount of CML produced per protein was calculated.

[0075] The glycation inhibition rate was calculated using the following formula. Glycation inhibition rate (%)=[1-(AB) / (CB)]×100 [In the formula, A represents the amount of CML produced per unit protein (ng / μg) at the time of sample addition, B represents the amount of CML produced per unit protein (ng / μg) in the normal group, and C represents the amount of CML produced per unit protein (ng / μg) in the control group.]

[0076] The glycation inhibition rate when the sample was measured at a concentration of 10 mM or less is shown below. Note that the measurement was performed in triplicate. 10%> :± 10-20% :+ 20-30% :++ >30% :+++

[0077] [Table 4]

[0078] The results in Table 4 show that the ascorbic acid derivatives of the present invention have a superior anti-glycation effect than known ascorbic acid derivatives.

[0079] Example 9 Cream The oil phase ingredients (1) to (5) and the aqueous phase ingredients (6) to (10) shown in Table 5 were each heated to 70°C and dissolved to prepare an oil phase and an aqueous phase, respectively. The oil phase was then added to the aqueous phase and pre-emulsified, and the mixture was homogeneously emulsified using a homomixer. The mixture was then cooled to room temperature while stirring well to prepare a cream.

[0080] [Table 5] *The amount required to make the total blended amount 100 parts by mass. The same applies to the following tables.

[0081] Example 10 Emulsion The oil phase ingredients (1) to (9) and the aqueous phase ingredients (10) to (13) in the compositions shown in Table 6 were each heated to 70°C and dissolved to prepare an oil phase and an aqueous phase, respectively. The oil phase was then added to the aqueous phase for pre-emulsification, and the mixture was homogeneously emulsified using a homomixer. The mixture was then cooled to room temperature while stirring well to prepare an emulsion.

[0082] [Table 6]

Claims

1. An anti-glycation agent comprising an ascorbic acid derivative represented by the following general formula (I) or a salt thereof: 【Chemistry 1】 [In the formula, R １ and R ２ represents H, an alkyl group having 1 to 22 carbon atoms, an alkenyl group having 2 to 22 carbon atoms, a benzyl group, R ３ -O-CH ２ -CH(OH)-CH ２ -, R ３ -O-CH ２ -CH(CH ２ OH)-, R ３ -CH(CH ２ OH)-, R ３ -CH(OH)-CH ２ -, HO-C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ - and R ３ is H, an alkyl group having 1 to 22 carbon atoms, an alkenyl group having 2 to 22 carbon atoms, or a phenyl group. １ and R ２ At least one of the following is HO—C(CH ３ ) ２ -CH ２ - or HO-CH ２ -C(CH ３ ) ２ - is.]

2. A cosmetic comprising the anti-glycation agent according to claim 1.

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