CN101177438A - N-acetylglucosamine derivatives and uses thereof - Google Patents

Abstract

The present invention relates to an acetylated N-acetylglucosamine derivative represented by the following general formula (1), a hyaluronic acid production-promoting agent containing the derivative, and an external preparation for skin. In the general formula (1) (wherein, R ¹ is a hydrogen atom or an alkyl group with 2 to 18 carbon atoms; R ² , R ³ and R ⁴ are a hydrogen atom or an acyl group with 2 to 18 carbon atoms, all of which can be are all the same, and different groups may also exist; in addition, the stereostructure of the 1-position may be any of α or β; however, R ¹ , R ² , R ³ , and R ⁴ cannot all be hydrogen atoms). By promoting the production of hyaluronic acid in the skin, the tension and moisture of the skin can be maintained, and as a result, a hyaluronic acid production-promoting agent and an external preparation for skin that are expected to prevent aging of human skin and are easily available can be provided.

Description

N-acetylglucosamine derivatives and uses thereof

This application is a divisional application of the PCT international application with the application number 03824086.6 (PCT/JP2003/009428), the filing date being July 25, 2003, and the invention title being "N-acetylglucosamine derivatives and their uses".

technical field

The present invention relates to N-acetylglucosamine derivatives, and hyaluronic acid production-promoting agents or skin external preparations containing the same. According to the present invention, it is possible to provide an external preparation for skin capable of maintaining the tone and moisture of the skin.

Background technique

Hyaluronic acid is a high-molecular polysaccharide with high water retention capacity, and it has attracted attention as an important extracellular matrix component even in the skin (Shingo Sakai, Shintaro Inoue, "Hyaluronic Acid Metabolism and Wrinkle Formation", "Fragrance Journal", Fragrance Journal, April 15, 1998, Vol. 26, No. 4, pp. 49-58).

Also, it is known that hyaluronic acid has various functions such as maintaining cells, maintaining lubricity and softness of the skin, resisting external forces such as mechanical damage, and preventing bacterial infection ("BIOINDUSTRY", CMC Corporation, May 1991 Issue 1, Vol. 8, No. 5, pp. 66(346)-68(346)).

On the other hand, aging has been reported to cause a decrease in the intensity of hyaluronan staining between epidermal cells (Ludger J.M. Meyer and Robert Stern, "Age-Dependent Changes of Hyaluronan in Human Skin", "The Journal of Investigative Dermatology", The Society for Investigative Dermatology, INC., April 1994, Vol.102, No.4, 385-389 pages), and the hyaluronic acid in the part of solar elastosis (solarelastosis) caused by ultraviolet radiation is almost undetectable ( Takuo Tsuji, "Physiological Aging of the Skin: Differences from Photoaging", "Clinical Dermatology", School of Medicine, Issued April 15, 1997, Supplement Vol. 51, No. 5, pp. 53-57), the results It will cause skin dryness, tension, decrease in elasticity, and then increase in wrinkles. In order to improve this situation, conventional methods have been adopted to maintain the moisturizing properties of the skin surface by applying cosmetics containing hyaluronic acid. However, hyaluronic acid, which is a high molecular weight, is difficult to penetrate the skin, so it cannot be done fundamentally. improve. Therefore, there is a need to develop substances that fundamentally improve skin function by increasing the hyaluronic acid synthesis ability of cells themselves.

Retinoic acid is known as a hyaluronic acid production-promoting substance in the epidermis, which is originally present in the epidermis and is involved in the proliferation or differentiation of epidermal cells. However, retinoic acid is known to be skin irritating, so it is desirable to find hyaluronic acid-boosting substances that avoid this.

On the other hand, it has been reported that N-acetylglucosamine, which is a constituent sugar of hyaluronic acid, can promote the production of hyaluronic acid in cultured epidermal cells by about 1.5 times at a concentration of 5 mmol/L, while This point has nothing to do with cell proliferation. ("Fine chemical", CMC Co., Ltd., issued on December 15, 2001, volume 30, number 22, pages 5-11). However, high concentrations of N-acetylglucosamine are required to exhibit hyaluronic acid production-promoting effects, and it is desired to find materials that can exhibit sufficient effects even at low concentrations in order to be widely used in the fields of cosmetics and pharmaceuticals.

Contents of the invention

Therefore, an object of the present invention is to provide a hyaluronic acid production-promoting agent and an external skin preparation capable of maintaining skin tone or moisture and improving wrinkles by promoting hyaluronic acid production, and having an effect higher than that of N-acetylglucosamine.

Therefore, in view of the above-mentioned circumstances, the present inventors conducted intensive research on methods for solving conventional problems, and found that the production of hyaluronic acid in the epidermis and dermis can be very easily and strongly promoted by using a specific compound described later, thereby The present invention has been accomplished.

That is, the present invention is an N-acetylglucosamine derivative represented by the following general formula (1), an external preparation for skin characterized by containing the N-acetylglucosamine derivative, the N-acetylglucosamine A hyaluronic acid-promoting agent whose derivative is the active ingredient.

Formula (1)

(wherein, R ¹ is a hydrogen atom or an alkyl group with 2 to 18 carbon atoms. ^{R 2} , R ³ and R ⁴ are a hydrogen atom or an acyl group with 2 to 18 carbon atoms, all of which may be the same or may exist Different groups. In addition, the steric structure of the 1-position may be either α or β. However, R ¹ , R ² , R ³ , and R ⁴ cannot all be hydrogen atoms).

In addition, N-acetylglucosamine derivatives represented by the following general formula (2) or (3), skin external preparations characterized by containing the N-acetylglucosamine derivatives, and the N-acetylglucosamine derivatives are preferred. A hyaluronic acid-promoting agent that uses sugar amine derivatives as active ingredients.

Formula (2)

(wherein, R ⁵ is an alkyl group with 2 to 18 carbon atoms. ^{R 6} is a hydrogen atom or an acetyl group. In addition, the stereostructure of the 1-position may be either α or β).

Formula (3)

(Wherein, R ⁷ is a hydrogen atom or an alkyl group with 2 to 18 carbon atoms. ^{R 8} is an acyl group with 2 to 18 carbon atoms. In addition, the three-dimensional structure of the 1-position can be either α or β ).

Specific examples of the N-acetylglucosamine derivatives represented by the above general formula (1), or (2) or (3) include compounds represented by the following general formulas (4) to (15).

Formula (4)

(The steric configuration of the 1-position may be either α or β).

Formula (5)

(The steric configuration of the 1-position may be either α or β).

Formula (6)

(The steric configuration of the 1-position may be either α or β).

Formula (7)

(The steric configuration of the 1-position may be either α or β).

Formula (8)

(The steric configuration of the 1-position may be either α or β).

Formula (9)

(The steric configuration of the 1-position may be either α or β).

Formula (10)

(The steric configuration of the 1-position may be either α or β).

Formula (11)

(The steric configuration of the 1-position may be either α or β).

Formula (12)

(The steric configuration of the 1-position may be either α or β).

Formula (13)

(The steric configuration of the 1-position may be either α or β).

Formula (14)

(The steric configuration of the 1-position may be either α or β).

Formula (15)

(The steric configuration of the 1-position may be either α or β).

Furthermore, the present invention relates to a hyaluronic acid production-promoting agent and an external preparation for skin, wherein an N-acetylglucosamine derivative represented by the following general formula (16) is used as an active ingredient.

Formula (16)

(wherein, R ⁹ is an acyl group having 2 to 16 carbon atoms. In addition, the configuration of the 1-position may be either α or β).

Specific examples of the N-acetylglucosamine derivative represented by the above general formula (16) include compounds represented by the following general formula (17).

Formula (17)

(The steric configuration of the 1-position may be either α or β).

Description of drawings

FIG. 1 is a graph showing the results of a hyaluronic acid production-promoting test (Test Example 1) using epidermal cells of Production Examples 1-3 and 6-8.

Fig. 2 is a graph showing the results of a hyaluronic acid production-stimulating test (Test Example 1) using epidermal cells of Production Examples 4 and 5.

Fig. 3 is to represent and adopt production example 9～12, 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranoside [general formula (17 ) compound] of the results of the hyaluronic acid production-promoting test (Test Example 2) of epidermal cells.

Fig. 4 is a graph showing the results of a hyaluronic acid production-stimulating test (Test Example 3) using dermal cells of Production Examples 1 and 6.

Detailed ways

The N-acetylglucosamine derivative used in the present invention can be represented by the following general formula (1) or general formula (16).

Formula (1)

(wherein, R ¹ is a hydrogen atom or an alkyl group with 2 to 18 carbon atoms. ^{R 2} , R ³ and R ⁴ are a hydrogen atom or an acyl group with 2 to 18 carbon atoms, all of which may be the same or may exist Different groups. In addition, the steric structure of the 1-position may be either α or β. However, R ¹ , R ² , R ³ , and R ⁴ cannot all be hydrogen atoms).

Formula (16)

(wherein, R ⁹ is an acyl group having 2 to 16 carbon atoms. In addition, the configuration of the 1-position may be either α or β).

Here, ^R1 is a hydrogen atom or a linear or branched alkyl group with 2 to 18 carbon atoms, preferably 4 to 16 carbon atoms, most preferably 8 to 12, and may be saturated or unsaturated. R ² , R ³ and R ⁴ are a hydrogen atom or a straight-chain or branched acyl group having 2 to 18 carbon atoms, all of which may be the same or different, but are preferably all hydrogen atoms or acetyl groups. In addition, the steric structure of the 1-position of the pyranose ring may be either α or β. However, R ¹ , R ² , R ³ and R ⁴ cannot all be hydrogen atoms.

As the N-acetylglucosamine derivative represented by the general formula 1, a compound represented by the following general formula (2) or (3) is preferable.

Formula (2)

(wherein, R ⁵ is an alkyl group with 2 to 18 carbon atoms. ^{R 6} is a hydrogen atom or an acetyl group. In addition, the stereostructure of the 1-position may be either α or β).

Formula (3)

(Wherein, R ⁷ is a hydrogen atom or an alkyl group with 2 to 18 carbon atoms. ^{R 8} is an acyl group with 2 to 18 carbon atoms. In addition, the three-dimensional structure of the 1-position can be either α or β ).

Here, R ⁵ is a linear or branched chain alkyl group with 2 to 18 carbon atoms, preferably 4 to 16 carbon atoms, most preferably 8 to 12, and may be saturated or unsaturated. R ⁶ is a hydrogen atom or an acetyl group, preferably all of them are a hydrogen atom or an acetyl group. R ⁷ is a hydrogen atom or a linear or branched alkyl group with 2 to 18 carbon atoms, preferably 4 to 16 carbon atoms, most preferably 8 to 12, and may be saturated or unsaturated. R ⁸ is a straight chain or branched acyl group with 2 to 18 carbon atoms, preferably 6 to 16 carbon atoms, most preferably 8 to 12, and may be saturated or unsaturated. R ⁹ is a straight-chain or branched acyl group with 2-16 carbon atoms, preferably 2-8 carbon atoms, most preferably 2-4 carbon atoms.

In addition, in the general formulas (1) to (17), the stereostructure of the 1-position of the pyranose ring represented by the wavy line may be either α or β. Alternatively, mixtures thereof can also be used without any problems.

Specific examples of the N-acetylglucosamine derivative represented by the general formula (2) or (3) include compounds represented by the following general formulas (4) to (15).

Formula (4)

(The steric configuration of the 1-position may be either α or β).

Formula (5)

(The steric configuration of the 1-position may be either α or β).

Formula (6)

(The steric configuration of the 1-position may be either α or β).

Formula (7)

(The steric configuration of the 1-position may be either α or β).

Formula (8)

(The steric configuration of the 1-position may be either α or β).

Formula (9)

(The steric configuration of the 1-position may be either α or β).

Formula (10)

(The steric configuration of the 1-position may be either α or β).

Formula (11)

(The steric configuration of the 1-position may be either α or β).

These compounds can be synthesized using known glucosylation reactions. For example, if the synthesis method is roughly represented, then in the general formula (2) ^R6 is a compound of a hydrogen atom, under the action of an acid catalyst, through the glucosylation reaction of N-acetylglucosamine and ethanol, Produce mixed glucosides of α and β, and if silica gel column is used, α and β can also be separated. Furthermore, if the oxazoline synthesis method is used, a single compound β-glucoside can be produced. In addition, for the compound represented by the general formula (3), it can be dissolved by heating N-acetylglucosamine or the compound represented by the general formula (2) in a solvent, and then adding various halides of fatty acids thereto, or It is produced by reaction of acid anhydride and appropriate catalyst.

Formula (12)

(The steric configuration of the 1-position may be either α or β).

Formula (13)

(The steric configuration of the 1-position may be either α or β).

Formula (14)

(The steric configuration of the 1-position may be either α or β).

Formula (15)

(The steric configuration of the 1-position may be either α or β).

These compounds can be prepared by commercially available 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranoside [compound of general formula (17)]. Derivatization, or derivatization by a known oxazoline synthesis method using a glucosylation reaction.

Specific examples of the N-acetylglucosamine derivative represented by the general formula (16) include compounds represented by the following general formula (17).

Formula (17)

(The steric configuration of the 1-position may be either α or β).

Based on the total amount of the composition, the amount of the N-acetylglucosamine derivative added to the hyaluronic acid production-promoting agent and the external skin preparation is preferably 0.00001 to 5.0% by mass of the total composition, more preferably 0.001 to 3.0% by mass , most preferably 0.01 to 1.0% by mass. Within this range, the objective effects of the present invention can be sufficiently exhibited.

The hyaluronic acid production-promoting agent and the skin external preparation of the present invention can be made into ointment, lotion, emulsion, milk, paste, wrap (pack) agent, spray (mist), foam (foam) agent, granule, powder, Various dosage forms such as gels. In the present invention, an external preparation for skin refers to a preparation suitable for external use for all skins of the body including the scalp, and includes body washes. There are no particular limitations on the base as long as it is a commonly used external base. In addition, the final form can be made into cosmetics, pharmaceuticals, and non-pharmaceuticals.

In addition, in addition to the above-mentioned substances, the hyaluronic acid production-promoting agent and the external skin preparation of the present invention can also be appropriately formulated with the following compounds within the range that can achieve the purpose of the present invention, that is, tar-based pigments, dimethyl pigments, etc. Silicone oils such as polysiloxane, methylphenyl polysiloxane, and cyclic silicone, carotenoid pigments such as lutein, astaxanthin, and fucoxanthin, and coloring such as iron oxide Pigments, preservatives such as parabens and phenoxyethanol, hydrocarbons such as paraffin and petrolatum, olive triodecane, rice triodecane, rice germ oil, jojoba oil, castor oil, safflower oil , olive oil, macadamia nut oil, sunflower oil and other vegetable oils, beeswax, wood wax, carnauba wax and other waxes, octyldodecyl myristate, cetyl, isostearate Ester oils such as stearyl ester and isopropyl myristate, lower alcohols such as ethanol, higher alcohols such as cetyl alcohol, behenyl alcohol, stearyl alcohol, long-chain branched aliphatic alcohol, cholesterol, phytosterol, branched Cholesterol fatty acid chain esters, macadamia nut fatty acid phytosterol esters and other sterols and derivatives, quenching oil and other processed oils, stearic acid, myristic acid, isostearic acid, oleic acid, iso (iso) long-chain fatty acids , trans-iso (anteiso) type long-chain fatty acid and other higher fatty acids, limonene, hydrobisabolol and other terpenes, trioctyl caprylic acid glyceride, 2-ethylhexanoic acid glyceride, triisomorphic long-chain fatty acid glyceride, Triglycerides such as tripalmitin, anionic surfactants such as sodium cetyl sulfate and N-stearyl-L-glutamate, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene Ethylene oxide polyol fatty acid ester, polyoxyethylene cured castor oil, polyol fatty acid ester, polyethylene oxide modified silicone and other modified silicones, polyglycerol fatty acid ester, sucrose ester and other non-ionic surfactants, Cationic surfactants such as tetraalkylammonium salts, amphoteric surfactants such as betaine type, thiobetaine type, and sulfoamino acids, natural surfactants such as lecithin, lysolecithin, ceramide, and cerebroside , titanium oxide, zinc oxide and other pigments, dibutyl hydroxytoluene and other antioxidants, sodium chloride, magnesium chloride, sodium sulfate, potassium nitrate, sodium sulfate, sodium silicate, calcium chloride and other inorganic salts, sodium citrate, acetic acid Potassium, sodium succinate, sodium aspartate, sodium lactate, dichloroacetic acid, mevalonic acid, glycyrrhetinic acid and other organic acids and their salts, ethanolamine hydrochloride, ammonium nitrate, arginine hydrochloride, diisopropylamine salt , urea, decarboxylated carnosine and other organic amines and their salts, chelating agents such as ethylenediaminetetraacetic acid, xanthane gum, carboxyvinyl polymer, carrageenan, pectin, alkyl modified carboxyvinyl polymer , agar and other thickeners, potassium hydroxide, diisopropanolamine, triethanolamine and other neutralizers, hydroxymethoxybenzophenone sulfonate and other UV absorbers, dipropylene glycol, marvitol, 1,3-butane Glycol, glycerin, propylene glycol, sorbitol, diglycerin, raffinose and other polyvalent alcohols, various amino acids, ascorbic acid, biotin, tocopherol and other vitamins, ascorbyl sulfate, ascorbyl phosphonate, niacin Vitamin derivatives such as tocopherol, etc.

Furthermore, by appropriately blending dermal hyaluronic acid production-promoting agents such as N-methyl-L-serine and yeast extract within the range that can achieve the purpose, along the mushroom extract, black pine mushroom extract, mokkin extract, Hyaluronic acid decomposition inhibitors such as palm catechu extract and clove extract, diisopropylamine dichloroacetic acid, niacin, mevalonic acid, hot spring water, sodium silicate, homogenized fruit, etc. Accelerators, barrier enhancers such as β-hydroxy-γ-aminobutyric acid, mevalonic acid, etc., can obtain the effect of maintaining skin tension or moisture, and high wrinkle improvement effect.

Example

Hereinafter, the present invention will be described in detail through examples. However, the present invention is not limited to the following examples.

(1) Examples of production of N-acetylglucosamine derivatives

Manufacturing example 1

Production of octyl(2-acetamido-2-deoxy)β-D-glucopyranoside [compound of general formula (4)]:

Dissolve 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranoside in 20 mL of anhydrous chloroform, then add trifluoromethanesulfonate Methylsilyl ester 1.0 mL, stirred at room temperature for 5 hours. Chloroform was added to the reaction mixture, washed with a saturated aqueous sodium bicarbonate solution, and the chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 15 mL of dichloroethane, 0.89 mL of 1-octanol and 119 mg of (±)-camphor-10-sulfonic acid were added, and the mixture was stirred at 60° C. for 2 hours. Chloroform was added to the reaction mixture, washed with saturated aqueous sodium bicarbonate, and the chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was isolated by silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=2:3) to obtain a purified product. This was dissolved in a mixed solvent of 10 mL of methane and 5 mL of 1,4-dioxane, a catalytic amount of 28% sodium methoxide in methanol was added, and the mixture was stirred at room temperature for 1 hour. After neutralizing the reaction mixture, the solvent was distilled off. The finally obtained residue was crystallized with water to obtain 840 mg of white crystals of octyl(2-acetamido-2-deoxy)β-D-glucopyranoside.

The 1H-NMR measurement results of octyl(2-acetamido-2-deoxy)β-D-glucopyranoside are shown below.

NMR (DMSO-d ₆ ) δ: 0.85(t, 3H, J=6.6Hz), 1.23(s, 10H), 1.40-1.45(m, 2H), 1.77(s, 3H), 3.00-3.10(m, 2H), 3.20-3.50(m, 4H), 3.65-3.75(m, 2H), 4.25(d, 1H, J=8.3Hz), 4.40(t, 1H), 4.78(d, 1H), 4.87(d , 1H), 7.58 (d, 1H, J=8.7Hz).

Manufacturing example 2

Production of 2-acetamido-2-deoxy-6-O-octanoyl-α-D-glucopyranose [compound of general formula (5)]:

To 0.5 g of N-acetylglucosamine, 5 mL of pyridine and 5 mL of N,N-dimethylformamide were added, heated to 70° C. while stirring, and 0.46 mL of n-octanoyl chloride was added dropwise to react for 4 hours. After the reaction was completed, it was extracted with ethyl acetate, washed with 2 mol/L hydrochloric acid, and then the ethyl acetate layer was dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; chloroform:methanol=15:1) to obtain 2-acetamido-2-deoxy-6-O-octanoyl-α-D-glucopyranose 170mg of white crystals.

The ¹ H-NMR measurement results of 2-acetamido-2-deoxy-6-O-octanoyl-α-D-glucopyranose are shown below.

NMR (DMSO-d ₆ ) δ: 0.92(t, 3H, J=6.8Hz), 1.33(s, 10H), 1.55-1.60(m, 2H), 1.89(s, 3H), 2.34(t, 2H) , 3.15-3.20(m, 1H), 3.55-3.60(m, 1H), 3.65-3.70(m, 1H), 3.85-3.90(m, 1H), 4.08(dd, 1H, J=6.0, 11.6Hz) , 4.35(dd, 1H, J=2.1, 11.8Hz), 4.70(d, 1H, J=5.4Hz), 4.96(t, 1H, J=3.5, 4.3Hz), 5.13(d, 1H, J=5.8 Hz), 6.54(d, 1H, J=4.7H), 7.61(d, 1H, J=8.1Hz).

Manufacturing example 3

Production of octyl(2-acetamido-2-deoxy-6-O-octanoyl)β-D-glucopyranoside [compound of general formula (6)]:

100 mg of the compound [general formula (4)] shown in Production Example 1 was dissolved in 1 mL of pyridine, 61 μL of n-octanoyl chloride was dropped, and the mixture was reacted for 4 hours. After the reaction was completed, it was extracted with chloroform, washed with 2 mol/L hydrochloric acid, and the ethyl acetate layer was dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; chloroform:methanol=20:1) to obtain octyl(2-acetamido-2-deoxy-6-O-octanoyl)β-D- White crystals of glucopyranoside 170mg.

The ¹ H-NMR measurement results of octyl(2-acetamido-2-deoxy-6-O-octanoyl)β-D-glucopyranoside are shown below.

NMR (DMSO-d ₆ ) δ: 0.85(t, 3H, J=6.8Hz), 1.23(s, 18H), 1.40-1.45(m, 2H), 1.50-1.55(m, 2H), 1.78(s, 3H), 2.28(t, 2H), 3.05-3.10(m, 1H), 3.25-3.40(m, 4H), 3.60-3.65(m, 1H), 4.05(dd, 1H, J=7.2, 11.6Hz) , 4.28(d, 1H, J=8.0Hz), 4.30(dd, 1H, J=1.6, 11.6Hz), 4.90(d, 1H, J=4.8Hz), 5.12(d, 1H, J=5.2Hz) , 7.61 (d, 1H, J=8.4Hz).

Manufacturing Example 4

Production of butyl(2-acetamido-2-deoxy)β-D-glucopyranoside [compound of general formula (7)]:

Using 1-butanol instead of 1-octanol in Production Example 1, the same reaction as in Production Example 1 was carried out to obtain 280 mg of white crystal butyl (2-acetamido-2-deoxy) β-D-glucopyranoside .

The 1H-NMR measurement results of butyl(2-acetamido-2-deoxy)β-D-glucopyranoside are shown below.

NMR (DMSO-d ₆ ) δ: 0.83(t, 3H, J=7.1Hz), 1.20-1.30(m, 2H), 1.40-1.50(m, 2H), 1.78(s, 3H), 3.00-3.05( m, 2H), 3.25-3.45(m, 4H), 3.65-3.70(m, 2H), 4.26(d, 1H, J=8.0Hz), 4.39(t, 1H, J=5.8Hz), 4.77(d , 1H, J=5.0Hz), 4.86(d, 1H, J=4.4Hz), 7.57(d, 1H, J=8.7Hz).

Manufacturing Example 5

Production of pentyl(2-acetamido-2-deoxy)β-D-glucopyranoside [compound of general formula (8)]:

Using 1-pentanol instead of 1-octanol in Production Example 1, the same reaction as in Production Example 1 was carried out to obtain 150 mg of white crystal pentyl (2-acetamido-2-deoxy) β-D-glucopyranoside .

The 1H-NMR measurement results of pentyl(2-acetamido-2-deoxy)β-D-glucopyranoside are shown below.

NMR (DMSO-d ₆ ) δ: 0.85(t, 3H, J=6.0Hz), 1.20-1.25(m, 4H), 1.40-1.45(m, 2H), 1.78(s, 3H), 3.05-3.10( m, 2H), 3.20-3.45(m, 4H), 3.65-3.75(m, 2H), 4.26(d, 1H, J=8.0Hz), 4.40(t, 1H, J=6.0Hz), 4.78(d , 1H, J=4.8Hz), 4.87(d, 1H), 7.58(d, 1H, J=8.8Hz).

Manufacturing example 6

Production of lauryl (2-acetamido-2-deoxy) β-D-glucopyranoside [compound of general formula (9)]:

Using 1-dodecanol instead of 1-octanol in Production Example 1, the same reaction as in Production Example 1 was carried out to obtain white crystal lauryl (2-acetamido-2-deoxy) β-D-glucopyranose Glycosides 450mg.

The ¹ H-NMR measurement results of lauryl(2-acetamido-2-deoxy)β-D-glucopyranoside are shown below.

NMR (DMSO-d ₆ ) δ: 0.85(t, 3H, J=6.0Hz), 1.23(s, 18H), 1.40-1.45(m, 2H), 1.84(s, 3H), 3.00-3.10(m, 2H), 3.20-3.50(m, 4H), 3.65-3.75(m, 2H), 4.25(d, 1H, J=8.0Hz), 4.40(t, 1H, J=5.6Hz), 4.79(d, 1H , J=5.2Hz), 4.85(d, 1H, J=4.4Hz)), 7.08(d, 1H, J=8.8Hz).

Manufacturing example 7

Production of 2-acetamido-2-deoxy-6-O-palmitoyl-α-D-glucopyranose [compound of general formula (10)]:

5 mL of pyridine and 15 mL of N,N-dimethylformamide were added to 1 g of N-acetylglucosamine, heated to 70° C. while stirring, 1.37 mL of palmitoyl chloride was dropped, and reacted for 4 hours. After the reaction was completed, it was extracted with ethyl acetate, washed with 2 mol/L hydrochloric acid, and then the ethyl acetate layer was dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; chloroform:methanol=15:1) to obtain 2-acetamido-2-deoxy-6-O-palmitoyl-α-D-glucopyranose 710mg of white crystals.

The ¹ H-NMR measurement results of 2-acetamido-2-deoxy-6-O-palmitoyl-α-D-glucopyranose are shown below.

NMR(DMSO-d ₆ )δ: 0.85(t, 3H, J=6.5Hz), 1.25(s, 24H), 1.45-1.55(m, 2H), 1.82(s, 3H), 2.30(t, 2H) , 3.05-3.15(m, 1H), 3.45-3.65(m, 2H), 3.75-3.85(m, 1H), 4.00(dd, 1H, J=5.7, 11.8 Hz), 4.28(dd, 1H, J= 2.0, 11.8Hz), 4.65(d, 1H, J=5.7Hz), 4.90(t, 1H, J=3.7, 4.1Hz), 5.07(d, 1H, J=5.7Hz), 6.45(d, 1H, J=4.5H), 7.55(d, 1H, J=8.1Hz).

Manufacturing example 8

Production of geranyl (2-acetamido-2-deoxy) β-D-glucopyranoside [compound of general formula (11)]:

Using geraniol instead of 1-octanol in Production Example 1, the same reaction as in Production Example 1 was carried out to obtain white crystals of geranyl (2-acetamido-2-deoxy) β-D-glucopyranose Glycosides 890mg.

The ¹ H-NMR measurement results of geranyl (2-acetamido-2-deoxy) β-D-glucopyranoside are shown below.

NMR(DMSO-d ₆ )δ: 1.57, 1.60, 1.65(3s, 9H), 1.79(s, 3H), 1.95-2.05(m, 4H), 3.05-3.10(m, 2H), 3.30-3.40(m , 2H), 3.47(dt, 1H, J=5.2, 12.0Hz), 3.68(dd, 1H, J=5.6, 11.6Hz), 4.02(dd, 1H, J=7.2, 12.0Hz), 4.17(dd, 1H, J=5.2Hz), 4.87(d, 1H), 5.05-5.10(m, 1H), 5.21(t, 1H, J=6.4Hz), 7.59(d, 1H, J=8.8Hz).

Manufacturing Example 9

Production of ethyl(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy)β-D-glucopyranoside [compound of general formula (12)]:

1 g of 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranoside [compound of general formula (17)] was dissolved in 10 mL of anhydrous chloroform , and then 0.5 mL of trimethylsilyl trifluoromethanesulfonate was added, followed by stirring at room temperature for 5 hours. Chloroform was added to the reaction mixture, and after washing with saturated aqueous sodium bicarbonate solution, the chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 8 mL of dichloroethane, 0.17 mL of ethanol and 60 mg of (±)-camphor-10-sulfonic acid were added, and the mixture was stirred at 60° C. for 2 hours. Chloroform was added to the reaction mixture, washed with a saturated aqueous sodium bicarbonate solution, and the chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was crystallized using ether and n-hexane to obtain ethyl(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy)β-D-glucopyranose Glycoside white solid 0.5g.

The ¹ H-NMR measurement results of ethyl(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy)β-D-glucopyranoside are shown below.

NMR (CDCl ₃ ) δ: 1.18(t, 3H, J=7.3Hz), 1.93, 2.00, 2.05(4s, 12H), 3.56(m, 1H), 3.68(m, 1H), 3.78(dt, 1H, J=8.4, 8.8, 10.4Hz), 3.88(m, 1H), 4.12(dd, 1H, J=2.4, 14Hz), 4.25(dd, 1H, J=4.8, 12.4Hz), 4.69(d, 1H, J=8.4Hz), 5.03(t, 1H, J=9.6Hz), 5.30(t, 1H, J=9.2Hz), 5.43(d, 1H, J=8.8Hz).

Manufacturing example 10

Production of pentyl(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy)β-D-glucopyranoside [compound of general formula (13)]:

Dissolve 1.5 g of 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranoside in 15 mL of anhydrous chloroform, and then add trifluoromethanesulfonic acid 0.75 mL of trimethylsilyl ester was stirred at room temperature for 5 hours. Chloroform was added to the reaction mixture, and after washing with a saturated aqueous sodium bicarbonate solution, the chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 15 mL of dichloroethane, 0.51 mL of n-pentanol and 99 mg of (±)-camphor-10-sulfonic acid were added, and the mixture was stirred at 60° C. for 2 hours. Chloroform was added to the reaction mixture, washed with a saturated aqueous sodium bicarbonate solution, and the chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Using silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=2:3), the residue obtained at last was isolated and purified to obtain pentyl (2-acetamido-3,4,6-tri- O-acetyl-2-deoxy) β-D-glucopyranoside as a white solid 1.1 g.

The ¹ H-NMR measurement results of pentyl(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy)β-D-glucopyranoside are shown below.

NMR (CDCl ₃ ) δ: 0.87(t, 3H, J=6.2Hz), 1.28(s, 4H), 1.50-1.55(m, 2H), 2.00, 2.03, 2.14(4s, 12H), 3.45(dt, 1H, J=7.2, 9.2Hz), 3.65-3.70(m, 1H), 3.75-3.85(m, 2H), 4.13(dd, 1H, J=2.4, 12.4Hz), 4.25(dd, 1H, J= 4.8, 12.4Hz), 4.66(d, 1H, J=8.0Hz), 5.03(t, 1H, J=9.6Hz), 5.29(t, 1H, J=9.2Hz), 5.40(d, 1H, J= 8.8Hz).

Manufacturing Example 11

Production of octyl(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy)β-D-glucopyranoside [compound of general formula (14)]:

Dissolve 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranoside in 20 mL of anhydrous chloroform, then add trifluoromethanesulfonate Methyl silyl ester 1.0 mL, stirred at room temperature for 5 hours. Chloroform was added to the reaction mixture, and after washing with saturated aqueous sodium bicarbonate solution, the chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 15 mL of dichloroethane, 0.89 mL of 1-octanol and 119 mg of (±)-camphor-10-sulfonic acid were added, and the mixture was stirred at 60° C. for 2 hours. Chloroform was added to the reaction mixture, washed with a saturated aqueous sodium bicarbonate solution, and the chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Using silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=2:3), the residue obtained at last was isolated and purified to obtain octyl (2-acetamido-3,4,6-tri- O-acetyl-2-deoxy) β-D-glucopyranoside as a white solid 1.5 g.

The ¹ H-NMR measurement results of octyl(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy)β-D-glucopyranoside are shown below.

NMR (CDCl ₃ ) δ: 0.86(t, 3H, J=6.2Hz), 1.25(s, 10H), 1.50-1.55(m, 2H), 1.92, 1.99, 2.00, 2.05(4s, 12H), 3.40- 3.45(m, 1H), 3.65-3.70(m, 1H), 3.75-3.90(m, 2H), 4.10(d, 1H, J=12.2Hz), 4.23(d, 1H, J=4.8, 12.2Hz) , 4.65(d, 1H, J=8.3Hz), 5.03(t, 1H, J=9.8Hz), 5.28(t, 1H, J=9.8Hz), 5.41(d, 1H, J=8.7Hz).

Manufacturing Example 12

Production of geranyl (2-acetamido-3,4,6-tri-O-acetyl-2-deoxy) β-D-glucopyranoside [compound of general formula (15)]:

Dissolve 5 g of 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranoside in 50 mL of anhydrous chloroform, and then add trifluoromethanesulfonate 2.6 mL of methyl silyl ester was stirred at room temperature for 5 hours. Chloroform was added to the reaction mixture, and after washing with saturated aqueous sodium bicarbonate solution, the chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 20 mL of dichloroethane, 2.5 mL of geraniol and 298 mg of (±)-camphor-10-sulfonic acid were added, and the mixture was stirred at 60° C. for 2 hours. Chloroform was added to the reaction mixture, washed with a saturated aqueous sodium bicarbonate solution, and the chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Using silica gel column chromatography (elution solvent; n-hexane:ethyl acetate=2:3), the residue obtained at last was isolated and purified to obtain geranyl (2-acetamido-3,4,6- Tris-O-acetyl-2-deoxy)β-D-glucopyranoside as a white solid 4.3 g.

The ¹ H-NMR measurement results of geranyl(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy)β-D-glucopyranoside are shown below.

NMR(CDCl ₃ )δ: 1.59, 1.64, 1.67(3s, 9H), 1.91(s, 3H), 1.99, 2.00, 2.05(3s, 9H), 3.60-3.65(m, 1H), 3.78(dt, 1H , J=2.8, 12.4Hz), 4.10-4.30(m, 3H), 4.68(d, 1H, J=8.8Hz), 5.00-5.10(m, 2H), 5.20-5.40(m, 2H).

(2) Test examples using N-acetylglucosamine derivatives

Next, a test example in the evaluation of the present invention using the N-acetylglucosamine derivative obtained in the above-mentioned production example will be described.

Test Example 1 (Hyaluronic Acid Promoting Test for Human Normal Epidermal Cells)

Human normal epidermal cells (manufactured by Kurabo) were seeded on a 24-well plate, cultured in a growth medium until confluent, and N-acetylglucosamine produced in Production Examples 1-3, 6-8 above was added The derivative was added at a final concentration of 50 μmol/L (25 μmol/L only in Production Example 7), and the N-acetylglucosamine derivative produced in Production Examples 4 and 5 was added to a final concentration of 1 mmol/L. Hyaluronic acid released in the culture medium was measured 48 hours after the addition of the culture. For the measurement of hyaluronic acid, a commercially available hyaluronic acid measurement kit (kit) (manufactured by Chugai Pharmaceutical Co., Ltd.) was used.

The amount of hyaluronic acid produced was defined as the amount of hyaluronic acid in epidermal cells cultured in a test substance-containing medium when Comparative Example 1, in which N-acetylglucosamine was added to a final concentration of 1 mmol/L, was defined as 1. The results are shown in Figure 1 and Figure 2.

As shown in Figure 1, the following compounds exhibited 2.5 to 3.5 times the hyaluronic mass at a concentration of about 1/20 (about 1/40 in Production Example 7) compared to N-acetylglucosamine Acid-promoting effect, the compound is octyl (2-acetamido-2-deoxy) β-D-glucopyranoside [compound of general formula (4)] of Production Example 1, 2 of Production Example 2 -Acetamido-2-deoxy-6-O-octanoyl-α-D-glucopyranose [compound of general formula (5)], octyl (2-acetamido-2-deoxy- 6-O-octanoyl) β-D-glucopyranoside [compound of general formula (6)], lauryl (2-acetamido-2-deoxy) β-D-glucopyranoside of Production Example 6 [Compound of general formula (9)] and 2-acetamido-2-deoxy-6-O-palmitoyl-α-D-glucopyranose [compound of general formula (10)] of Production Example 7, Production Example Geranyl (2-acetamido-2-deoxy) β-D-glucopyranoside of 8 [compound of general formula (11)]. In particular, compounds in which R ⁷ is hydrogen in the general formula (3) have higher pro-formation activity.

In addition, as shown in FIG. 2 , the following compound, which is the butylated compound of Production Example 4, exhibited 1.5 to 3 times the hyaluronic acid production-promoting effect at the same concentration as N-acetylglucosamine. Amyl (2-acetamido-2-deoxy) β-D-glucopyranoside [compound of general formula (7)], pentyl (2-acetamido-2-deoxy) β-D of Production Example 5 - glucopyranosides [compounds of general formula (8)].

Test Example 2 (Hyaluronic Acid Promoting Test for Human Normal Epidermal Cells)

Human normal epidermal cells (manufactured by Kurabo) were seeded on a 24-well plate, cultured in a growth medium until confluent, and then added with 2-acetamido-1,3,4,6 expressed by the above general formula (17). -Tetra-O-acetyl-2-deoxy-β-D-glucopyranoside to a final concentration of 100 μmol/L, additionally adding the N-acetylglucosamine derivative produced in Production Example 9 above to a final The concentration was 1 mmol/L, and the N-acetylglucosamine derivative produced in Production Examples 10 to 12 was added so that the final concentration was 100 μmol/L. Hyaluronic acid released in the culture medium was measured 48 hours after the addition of the culture. For the measurement of hyaluronic acid, a commercially available hyaluronic acid measurement kit (manufactured by Chugai Pharmaceutical Co., Ltd.) was used. The result is shown in Figure 3.

As shown in Figure 3, ethyl (2-acetamido-3,4,6-tri-O-acetyl-2-deoxy) β-D-glucopyranoside [general formula (12) compound] at the same concentration as N-acetylglucosamine, showed a 6.5-fold hyaluronic acid-promoting effect. In addition, pentyl(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy)β-D-glucopyranoside [compound of general formula (13)] of Production Example 10, Octyl(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy)β-D-glucopyranoside [compound of general formula (14)] of Production Example 11, Production Example 12 Geranyl (2-acetamido-3,4,6-tri-O-acetyl-2-deoxy) β-D-glucopyranoside [compound of general formula (15)], 2- Acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranoside [compound of general formula (17), respectively showed 3.8, 2.8, 3.7, 3.0 times the hyaluronic acid promoting effect.

Test example 3 (hyaluronic acid promotion test for human normal dermal fibroblasts)

Human normal dermal fibroblasts (manufactured by American Type Culture Collection) were seeded on a 24-well plate, cultured in a growth medium until confluent, and then the N-acetylglucosamine derivative shown in Production Example 1 above was added to its final concentration To 100 μmol/L, 25 μmol/L of the N-acetylglucosamine derivative shown in Production Example 6 was additionally added. Hyaluronic acid released in the culture medium was measured 48 hours after the addition of the culture. For the measurement of hyaluronic acid, a commercially available hyaluronic acid measurement kit (manufactured by Chugai Pharmaceutical Co., Ltd.) was used.

The production amount of hyaluronic acid was defined as the amount of hyaluronic acid relative to the dermal fibroblasts cultured in the test substance-containing medium of Comparative Example 2 to which 1 mmol/L of N-acetylglucosamine was added. The result is shown in Figure 4.

As shown in FIG. 4 , compared with N-acetylglucosamine, octyl(2-acetamido-2-deoxy)β-D-glucopyranoside [compound of general formula (4)] of Production Example 1 , the two compounds of lauryl (2-acetamido-2-deoxy) β-D-glucopyranoside [compound of general formula (9)] of Production Example 6, in about 1/10～1/40 All concentrations showed 1.5 to 2 times the hyaluronic acid production-promoting effect.

Test Examples 4 to 7, Comparative Examples 3 and 4 (evaluated by subjects)

Women aged 40 to 60 were tested and divided into 8 groups, 20 people in each group, and the cream (test example 4, 5 and comparative example 3) of the composition shown in table 1 and the lotion (test example 3) shown in table 2 were divided into 8 groups. Examples 6, 7 and Comparative Example 4) were given to different groups respectively, twice a day, and an appropriate amount was applied to the face for consecutive 3 months. After continuous use, evaluate the tightness of the skin.

The evaluation was carried out in 4 stages: significantly effective (significant improvement in skin tightness), effective (good improvement in skin tightness), slightly effective (improvement in skin tightness), and ineffective (no change). The effect was judged by the ratio (%) of the total number of people who responded significantly and effectively.

Table 1

Test example 4 Test example 5 Comparative example 3 Compound of general formula (4) (production example 1) 0.1 - - Compounds of general formula (17) - 0.1 - stearic acid 2 Glyceryl monostearate 2 cetyl alcohol 3 cholesterol 0.5 vaseline 2 Triacane 10 liquid paraffin 10 Dimethicone 1 Butylparaben 0.1 Methylparaben 0.1 Sodium N-Stearyl Glutamate 1 Glycerin Dipropylene Glycol 5 purified water The remaining amount total 100 evaluate(%) 80 80 45

^* The contents are all % by mass.

Table 2

Test example 4 Test example 5 Comparative example 3 Compound of general formula (4) (production example 1) 0.01 - - Compounds of general formula (17) - 0.01 - ethanol 10 Polyoxyethylene cured castor oil (60E.O.) 1 glycerin 3 1,3-Butanediol 2 Dipropylene glycol 3 Potassium dihydrogen phosphate 0.05 Dipotassium phosphate 0.05 Disodium edetate 0.05 Methylparaben 0.1 purified water The remaining amount total 100 evaluate(%) 55 55 30

^* The contents are all % by mass.

As can be seen from Table 1 and Table 2, the cosmetics using the N-acetylglucosamine derivatives of the present invention have the effect of improving skin tightness.

In addition, when the cosmetics of any of the test examples were used, redness, inflammation, and other side effects did not appear on the skin, and it was confirmed that the cosmetics of the present invention were excellent in safety.

(3) About the embodiment

Embodiment 1 (skin cream)

A skin cream having the following composition was prepared by a usual method.

Raw material composition Compounding amount (mass%)

Beeswax 2.0

Stearic acid 5.0

Stearyl Alcohol 5.0

Reduced Hydrous Lanolin 2.0

Tricosahexaene 20.0

Sorbitan monostearate 3.0

Polyoxyethylene (20) sorbitan monostearate 3.0

Propylene Glycol 5.0

Methylparaben 0.2

Compound of general formula (4) (Manufacture example 1) 0.1

The remaining amount of purified water when the total amount is 100

Embodiment 2 (skin cream)

A skin cream having the following composition was prepared by a usual method.

Raw material composition Compounding amount (mass%)

Beeswax 2.0

Stearic acid 5.0

Stearyl Alcohol 5.0

Reduced Hydrous Lanolin 2.0

Tricosahexaene 20.0

Sorbitan monostearate 3.0

Polyoxyethylene (20) sorbitan monostearate 3.0

Propylene Glycol 5.0

Methylparaben 0.2

Compound of general formula (5) (Manufacture example 2) 0.5

The remaining amount of purified water when the total amount is 100

Embodiment 3 (moisturizing lotion)

A body lotion having the following composition was prepared by the usual method.

Raw material composition Compounding amount (mass%)

Olive oil 10.0

Isopropyl myristate 1.0

Polyoxyethylene(6) nonylphenyl ether 0.5

Propylene Glycol 1.0

Glycerin 2.0

Methylparaben 0.1

Ethanol 7.0

Compound of general formula (6) (Manufacture example 3) 0.5

The remaining amount when the total amount of purified water is 100

Embodiment 4 (moisturizing lotion)

A body lotion having the following composition was prepared by the usual method.

Raw material composition Compounding amount (mass%)

Olive oil 10.0

Isopropyl myristate 1.0

Polyoxyethylene(6) nonylphenyl ether 0.5

Propylene Glycol 1.0

Glycerin 2.0

Methylparaben 0.1

Ethanol 7.0

Compound of general formula (8) (Manufacture example 5) 1.0

The remaining amount when the total amount of purified water is 100

Embodiment 5 (bath liquid)

A body wash having the following composition was prepared by a usual method.

Raw material composition Compounding amount (mass%)

Compound of general formula (5) (Manufacture example 2) 1.0

Sodium Bicarbonate Balanced

Sodium Carbonate 20.0

Sodium Sulfate 15.0

Sodium chloride 7.5

Silicic anhydride 0.5

1,3-Butanediol                                                           

Urea 1.0

Seaweed Extract 1.0

Pigment Appropriate amount

Dextrin Appropriate amount

Spices Appropriate amount

Embodiment 6～8 (skin cream)

Follow the formula below to prepare the skin cream in the usual way.

Raw material composition Compounding amount (mass%)

Example 6 7 8

Compound of general formula (4) (Manufacture example 1) 0.1 - -

Compound of general formula (5) (Manufacture Example 2) - 0.1 -

Compound of general formula (6) (Manufacture Example 3) - - - 0.1

Stearic acid 1 1 -

Isostearic acid - 1

Glyceryl monostearate 2 2 2

Behenyl alcohol 2 2 2

White Beeswax 1 1 1 -

Cetyl myristate 1 1 1

Sorbitan sesquioleate 1 1 1

N-Stearoyl Phytosphingosine 0.1 0.1 0.1

Hydrogenated Lecithin 0.1 0.1 0.1

Phytotriocane 5 5 5

Octyldodecyl myristate 5 5 5

Barkberry Extract 0.1 1 0.1

Pyracantha Extract 0.1 0.3 -

Water-soluble licorice extract - 0.1

1,3-Butanediol 5 10 5

Concentrated Glycerin 5 5 5

Parabens 0.2 0.2 0.2

N-acetylglucosamine oligomer 0.1 0.1 0.1

Ascorbyl Phosphate Mg Salt 0.1 0.1 0.1

Sodium Ascorbyl Phosphate 0.1 0.1 0.1

γ-aminobutyric acid 0.1 0.1 0.1

Sodium N-Stearyl Glutamate 0.2 0.2 0.2

Alkyl modified carboxy vinyl polymer*1 0.05 0.05 0.05

Nicotinamide 0.1 0.1 0.1

Sarcosine 0.1 0.1 0.1

Refined water The remaining amount The remaining amount The remaining amount

*1; PEMULEN TR-1 made by B.F.Goodrich

Embodiment 9～11 (lotion)

Prepare the lotion by the usual method according to the following formula.

Raw material composition Compounding amount (mass%)

Example 9 10 11

Compound of general formula (4) (Manufacture example 1) 0.1 - -

Compound of general formula (5) (Manufacture Example 2) - 0.1 -

Compound of general formula (6) (Manufacture example 3) - - - 0.1

Barkberry Extract 0.1 0.3 0.3

Hibiscus Extract 0.2 0.5 0.5

Lactic acid bacteria culture fluid 0.1 0.1 0.1

1,3-Butanediol 5 5 5

Dipropylene Glycol 5 5 5

Raffinose 1 1 1

Ethanol 1 1 1

Phenoxyethanol 0.2 0.2 0.2

Pectin 0.05 0.05 0.05

Xanthane gum 0.1 0.1 0.1

Sodium citrate 0.05 0.05 0.05

Chinese cabbage extract 0.1 0.1 0.1

Diisopropylamine dichloroacetate 0.2 0.2 0.2 γ-amino-β-hydroxybutyric acid 0.2 0.2 0.2

Sodium Hyaluronate 0.001 0.001 0.01

Dipotassium Glycyrrhetinate 0.2 0.2 0.2

Agaricus extract 0.05 0.05 0.05

Decarboxylated Carnosine Hydrochloride 0.05 0.05 0.05

Spices 0.02 0.02 0.02

Refined water The remaining amount The remaining amount The remaining amount

Embodiment 12～14 (gel)

Prepare the gel by the usual method according to the following formula.

Raw material composition Compounding amount (mass%)

Example 12 13 14

Compound of general formula (4) (Manufacture example 1) 0.1 - -

Compound of general formula (5) (Manufacture example 2) - 0.1 -

Compound of general formula (6) (Manufacture example 3) - - - 0.1

Decamethylcyclopentasiloxane 10 10 10

Isostearyl Isostearate 1   -   -

Olive Oil - 1 -

Macadamia Oil - 1

Eucalyptus Oil 0.1 - 0.1

Hexyldecanol 1 0.1 -

Niacin d1α Tocopherol - 0.1 -

Polyethylene oxide (60) cured castor oil 2 2 2

Spherical silicone powder ^* 2 1 1 5

Barkberry Extract 0.1 1 0.1

Water-soluble chlorophyll 0.02 0.02 0.02

Sage Extract - 0.3 0.1

1,3-Butanediol 5 10 5

Sorbitol Liquid 3 3 3

Macrogol 4000 1 1 1

Carboxyvinyl polymer 0.2 0.2 0.2

Glycoceramide ^* 3 0.1 0.1 0.1

Parabens 0.2 0.2 0.2

Mevalonolactone 0.5 0.5 0.5

EDTA 0.02 0.02 0.02

Potassium Hydroxide 0.05 0.05 0.05

Refined water The remaining amount The remaining amount The remaining amount

^* 2; Tospearl made by GE Toshiba Silicone

^* 3: Biological ceramide produced by Ji Wen Food Chemical Co., Ltd.

Embodiment 15～17 (lipophilic cream)

Prepare the lipophilic cream by the usual method according to the following formula.

Raw material composition Compounding amount (mass%)

Example 15 16 17

Compound of general formula (4) (Manufacture example 1) 0.1 - -

Compound of general formula (5) (Manufacture Example 2) - 0.1 -

Compound of general formula (6) (Manufacture Example 3) - - - 0.1

Co-modified silicone ^* 4 2 2 2

Polyoxyethylene modified silicone dispersion ^* 5 - 2 -

Thiocane - 10

Decamethylcyclopentasiloxane 15 20 10

Methylpolysiloxane 5 2 3

Long-chain branched-chain fatty acid cholesteryl ester ^* 6 - - 3

Silicone Elastomer Dispersion ^* 7 5 2

Barkberry Extract 1 1 1

Licorice Extract 0.1 0.1 0.1

Water-soluble chlorophyll 0.02 0.02 0.02

Sodium chloride 1 1 1

Dipropylene Glycol 5 5 5

Concentrated Glycerin 5 5 5

Raffinose 1 1 1

Parabens 0.3 0.3 0.3

N-methyl-L-serine 0.5 0.5 0.5

Refined water The remaining amount The remaining amount The remaining amount

^* 4; ABIL EM90 made by Goldschmidt

^* 5: Toray Dow Coming silicone BY22-008

^* 6; Japan Seika YOFCO CLE-NH

^* 7; Trefil made by Toray Dow Coming silicone

Embodiment 18～20 (sunscreen)

Follow the recipe below to prepare sunscreen in the usual way.

Raw material composition Compounding amount (mass%)

Example 18 19 20

Compound of general formula (4) (Manufacture example 1) 0.1 - -

Compound of general formula (5) (Manufacture example 2) - 0.1 -

Compound of general formula (6) (Manufacture example 3) - - - 0.1

Dioctyl ether 10 10 10

Co-modified silicone ^* 4 2 2 2

Glyceryl Tris-2-Ethylhexanoate 5 5 5

Cured Oil 0.1 0.1 0.1

Methylphenylpolysiloxane 5 2 3

Macadamia Nut Fatty Acid Phytosterol Esters - 2

2-Ethylhexyl p-methoxycinnamate - 7 7

Titanium oxide 5 5 4

Zinc Oxide 5 5 4

Barkberry Extract 1 1 1

Magnesium chloride 1 1 1

1,3-Butanediol 5 5 5

Phenoxyethanol 0.3 0.3 0.3

Hibiscus Extract 1 1 1

Aloe Vera Extract 0.1 0.1 0.1

Yeast Extract ^* 8 1 1 1

Refined water The remaining amount The remaining amount The remaining amount

^* 4; ABIL EM90 made by Goldschmidt

^* 8: Dismutin made by PentaFarm

Embodiment 21 (lotion)

Ethanol 10

Polyoxyethylene (60) cured castor oil 1

Glycerin 3

1,3-Butanediol 2

Dipropylene Glycol 3

Macrogol 1500 1

Phosphate Appropriate amount

Ethylenediamine tetraacetate in appropriate amount

Methylparaben Appropriate amount

Compound of general formula (10) (Manufacture Example 7) 0.1

Antioxidant Appropriate amount

Refined water remaining

Embodiment 22, 23 (emulsion)

Example 22 Example 23

Stearic acid 1 1

Glyceryl stearate 2 2

Cetyl Alcohol 1 1

Cholesterol 0.5 0.5

Vaseline 2 2

Thiocane 5 5

Liquid paraffin 5 5

Silicone oil 1 1

Acyl glutamate 1 1

Xanthane gum 0.5 0.5

Glycerin 2 2

Dipropylene Glycol 3 3

Compound of general formula (5) (Manufacture example 2) 0.1 -

Compound of general formula (10) (Manufacture Example 7) - 0.1

Butylparaben Appropriate amount Appropriate amount

Antioxidant Appropriate amount Appropriate amount

Refined water The remaining amount The remaining amount

Embodiment 24,25 (cream)

Example 24 Example 25

Stearic acid 2 2

Glyceryl stearate 2 2

Cetyl Alcohol 3 3

Cholesterol 0.5 0.5

Vaseline 2 2

Thiocane 5 5

Liquid paraffin 10 10

Silicone oil 1 1

Acyl glutamate 1 1

Xanthane gum 0.5 0.5

Glycerin 5 5

Dipropylene Glycol 3 3

Compound of general formula (5) (Manufacture example 2) 0.1 -

Compound of general formula (10) (Manufacture Example 7) - 0.1

Butylparaben Appropriate amount Appropriate amount

Antioxidant Appropriate amount Appropriate amount

Refined water The remaining amount The remaining amount

Embodiment 26, 27 (sunscreen)

Example 26 Example 27

Ethanol 10 10

Octyl Methoxycinnamate 7 7

POE/POP modified dimethylpolysiloxane 2 2

Titanium oxide particles 5 5

Zinc Oxide 5 5

Cyclic silicone 10 10

Dimethicone (6cs) 10 10

Compound of general formula (5) (Manufacture example 2) 0.1 -

Compound of general formula (10) (Manufacture Example 7) - 0.1

Antioxidant Appropriate amount Appropriate amount

Refined water The remaining amount The remaining amount

Embodiment 28 (skin cream)

A skin cream having the following composition was prepared by a usual method.

Raw material composition Compounding amount (mass%)

Beeswax 2.0

Stearic acid 5.0

Stearyl Alcohol 5.0

Reduced Hydrous Lanolin 2.0

Tricosahexaene 20.0

Sorbitan monostearate 3.0

Polyoxyethylene (20) sorbitan monostearate 3.0

Propylene Glycol 5.0

Methylparaben 0.2

Compound of general formula (17) 0.1

The remaining amount when the total amount of purified water is 100

Embodiment 29 (skin cream)

A skin cream having the following composition was prepared by a usual method.

Raw material composition Compounding amount (mass%)

Beeswax 2.0

Stearic acid 5.0

Stearyl Alcohol 5.0

Reduced Hydrous Lanolin 2.0

Tricosahexaene 20.0

Sorbitan monostearate 3.0

Polyoxyethylene (20) sorbitan monostearate 3.0

Propylene Glycol 5.0

Methylparaben 0.2

Compound of general formula (12) (Manufacture Example 9) 0.5

The remaining amount when the total amount of purified water is 100

Embodiment 30 (moisturizing lotion)

A body lotion having the following composition was prepared by the usual method.

Raw material composition Compounding amount (mass%)

Olive oil 10.0

Isopropyl myristate 1.0

Polyoxyethylene(6) nonylphenyl ether 0.5

Propylene Glycol 1.0

Glycerin 2.0

Methylparaben 0.1

Ethanol 7.0

Compound of general formula (17) 0.5

The remaining amount when the total amount of purified water is 100

Embodiment 31 (body wash)

A body wash having the following composition was prepared by a usual method.

Raw material composition Compounding amount (mass%)

Compound of general formula (17) 1.0

Sodium Bicarbonate Balanced

Sodium carbonate 20.0

Sodium Sulfate 15.0

Sodium chloride 7.5

Silicic anhydride 0.5

1,3-Butanediol 1.0

Urea 1.0

Seaweed Extract 1.0

Pigment Appropriate amount

Dextrin Appropriate amount

Spices Appropriate amount

Embodiment 32,33 (skin cream)

Follow the formula below to prepare the skin cream in the usual way.

Raw material composition Compounding amount (mass%)

Example 32 33

Compound of general formula (17) 0.1 -

Compound of general formula (14) (Manufacture Example 11) - 0.1

Stearic acid 1 1 -

Isostearic acid - 1

Glyceryl monostearate 2 2

Behenyl alcohol 2 2

Pewter 1 1 1

Cetyl myristate 1 1

Sorbitan sesquioleate 1 1

N-Stearoyl Phytosphingosine 0.1 0.1

Hydrogenated Lecithin 0.1 0.1

Phytotriocane 5 5

Octyldodecyl myristate 5 5

Barkberry Extract 0.1 1

Pyracantha extract 0.1 0.3

Water-soluble licorice extract 0.1 0.1

1,3-Butanediol 5 10

Concentrated Glycerin 5 5

Parabens 0.2 0.2

N-acetylglucosamine oligomer 0.1 0.1

Ascorbyl Phosphate Mg Salt 0.1 0.1

Sodium Ascorbyl Phosphate 0.1 0.1

γ-aminobutyric acid 0.1 0.1

Sodium N-Stearyl Glutamate 0.2 0.2

Alkyl modified carboxy vinyl polymer*1 0.05 0.05

Nicotinamide 0.1 0.1

Sarcosine 0.1 0.1

Refined water The remaining amount The remaining amount

^* 1; PEMULEN TR-1 by BFGoodrich

Embodiment 34, 35 (lotion)

Prepare the lotion by the usual method according to the following formula.

Raw material composition Compounding amount (mass%)

Example 34 35

Compound of general formula (17) 0.1 -

Compound of general formula (12) (Manufacture Example 9) - 0.1

Barkberry Extract 0.1 0.3

Hibiscus Extract 0.2 0.5

Lactic acid bacteria culture fluid 0.1 0.1

1,3-Butanediol 5 5

Dipropylene Glycol 5 5

Raffinose 1 1

Ethanol 1 1

Phenoxyethanol 0.2 0.2

Pectin 0.05 0.05

Xanthane gum 0.1 0.1

Sodium citrate 0.05 0.05

Chinese cabbage extract 0.1 0.1

Diisopropylamine dichloroacetic acid 0.2 0.2

γ-amino-β-hydroxybutyric acid 0.2 0.2

Sodium Hyaluronate 0.001 0.001

Dipotassium Glycyrrhetinate 0.2 0.2

Along the mushroom extract 0.05 0.05

Decarboxylated Carnosine Hydrochloride 0.05 0.05

Spices 0.02 0.02

Refined water The remaining amount The remaining amount

Example 36, 37 (gel)

Prepare the gel by the usual method according to the following formula.

Raw material composition Compounding amount (mass%)

Example 36 37

Compound of general formula (13) (Manufacture Example 10) 0.1 -

Compound of general formula (15) (Manufacture Example 12) - 0.1

Decamethylcyclopentasiloxane 10 10

Isostearyl isostearate 1   -

olive oil - 1

Macadamia Oil 0.1 0.1

Eucalyptus Oil 0.1 -

Hexyldecanol 1 0.1

Niacin d1α Tocopherol - 0.1

Polyoxyethylene (60) cured castor oil 2 2

Spherical silicone powder ^* 2 1 1

Phellodendron bark extract 0.1 1

Water-soluble chlorophyll 0.02 0.02

Sage Extract - 0.3

1,3-Butanediol 5 10

Sorbitol Liquid 3 3

Macrogol 4000 1 1

Carboxyvinyl polymer 0.2 0.2

Glycoceramide ^* 3 0.1 0.1

Parabens 0.2 0.2

Mevalolactone 0.5 0.5

EDTA 0.02 0.02

Potassium Hydroxide 0.05 0.05

Refined water The remaining amount The remaining amount

^* 2; GE Toshiba Silicone Tospearl

^* 3: Biological ceramide produced by Ji Wen Food Chemical Co., Ltd.

Embodiment 38,39 (lipophilic cream)

Prepare the lipophilic cream by the usual method according to the following formula.

Raw material composition Compounding amount (mass%)

Example 38 39

Compound of general formula (17) 0.1 -

Compound of general formula (15) (Manufacture Example 12) - 0.1

Co-modified silicone*4 2 2

Polyoxyethylene modified silicone dispersion ^* 5 - 2

Thiocane 2 2

Decamethylcyclopentasiloxane 15 20

Methylpolysiloxane 5 2

Cholesterol esters of long-chain branched-chain fatty acids ^* 6 1 1

Silicone Elastomer Dispersion ^* 7 5 2

Barkberry Extract 1 1

Licorice Extract 0.1 0.1

Water-soluble chlorophyll 0.02 0.02

Sodium chloride 1 1

Dipropylene Glycol 5 5

Concentrated Glycerin 5 5

Raffinose 1 1

Parabens 0.3 0.3

N-methyl-L-serine 0.5 0.5

Refined water The remaining amount The remaining amount

^* 4; ABIL EM90 made by Goldschmidt

^* 5: Toray Dow Corning silicone BY22-008

^* 6; Japan Seika YOFCO CLE-NH

^* 7; Trefil made of Toray Dow Corning silicone

Embodiment 40, 41 (sunscreen)

Follow the recipe below to prepare sunscreen in the usual way.

Raw material composition Compounding amount (mass%)

Example 40 41

Compounds of general formula (1 7) 0.1 -

Compound of general formula (14) (Manufacture Example 11) - 0.1

Dioctyl ether 10 10

Co-modified silicone ^* 4 2 2

Glyceryl Tris-2-Ethylhexanoate 5 5

Cured Oil 0.1 0.1

Methylphenyl polysiloxane 3 3

Macadamia Nut Fatty Acid Phytosterols 1 1

(phytosteryl) ester

2-Ethylhexyl p-methoxycinnamate - 7

Titanium oxide 5 5

Zinc Oxide 5 5

Barkberry Extract 1 1

Magnesium chloride 1 1

1,3-Butanediol 5 5

Phenoxyethanol 0.3 0.3

Hibiscus Extract 1 1

Aloe Vera Extract 0.1 0.1

Yeast extract*8 1 1

Refined water The remaining amount The remaining amount

^* 4; ABIL EM90 made by Goldschmidt

^* 8: Dismutin made by PentaFarm

Embodiment 42 (lotion)

Ethanol 10

Polyoxyethylene (60) cured castor oil 1

Glycerin 3

1,3-butanediol 2

Dipropylene Glycol 3

Macrogol 1500 1

Phosphate Appropriate amount

Ethylenediaminetetraacetic acid salt in appropriate amount

Methylparaben Appropriate amount

Compound of general formula (15) (Manufacture Example 12) 0.1

Antioxidant Appropriate amount

Refined water remaining amount

Embodiment 43, 44 (emulsion)

Example 43 Example 44

Stearic acid 1 1

Glyceryl Stearate 2 2

Cetyl Alcohol 1 1

Cholesterol 0.5 0.5

Vaseline 2 2

Thiocane 5 5

Liquid paraffin 5 5

Silicone oil 1 1

Acyl glutamate 1 1

Xanthane gum 0.5 0.5

Glycerin 2 2

Dipropylene Glycol 3 3

Compound of general formula (17) 0.1 -

Compound of general formula (15) (Manufacture Example 12) - 0.1

Butylparaben Appropriate amount Appropriate amount

Antioxidant Appropriate amount Appropriate amount

Refined water The remaining amount The remaining amount

Embodiment 45,46 (cream)

Example 45 Example 46

Stearic acid 2 2

Glyceryl stearate 2 2

Cetyl Alcohol 3 3

Cholesterol 0.5 0.5

Vaseline 2 2

Thiocane 5 5

Liquid paraffin 10 10

Silicone oil 1 1

Acyl glutamate 1 1

Xanthane gum 0.5 0.5

Glycerin 5 5

Dipropylene Glycol 3 3

Compound of general formula (13) (Manufacture Example 10) 0.1 -

Compound of general formula (15) (Manufacture Example 12) - 0.1

Butylparaben Appropriate amount Appropriate amount

Antioxidant Appropriate amount Appropriate amount

Refined water The remaining amount The remaining amount

Embodiment 47, 48 (sunscreen)

Example 47 Example 48

Ethanol 10 10

Octyl Methoxycinnamate 7 7

POE/POP modified dimethylpolysiloxane 2 2

Titanium oxide particles 5 5

Zinc Oxide 5 5

Cyclic silicone 10 10

Dimethicone (6cs) 10 10

Compound of general formula (13) (Manufacture Example 10) 0.1 -

Compound of general formula (15) (Manufacture Example 12) - 0.1

Antioxidant Appropriate amount Appropriate amount

Refined water The remaining amount The remaining amount

Industrial availability

As can be seen from the above description, the present invention can provide an epidermal hyaluronic acid production-promoting agent that can be simply and easily synthesized. In addition, anti-aging of the skin (maintenance of tension, elasticity and moisture of the skin) can be realized by the present invention.

Claims (8)

1. a hyaluronic acid is short generates agent, it is characterized in that, with the N-acetyl-glucosamine derivative shown in the following general formula (1) as effective constituent,

General formula (1)

Wherein, R ¹Be that hydrogen atom or carbonatoms are 2～18 alkyl; R ², R ³And R ⁴Be that hydrogen atom or carbonatoms are 2～18 acyl group, can be identical all, also can there be different groups; Perhaps R ¹Be that carbonatoms is 2～16 acyl group; R ², R ³And R ⁴It is ethanoyl; In addition, 1 D structure can be any among α or the β; But, R ¹, R ², R ³, R ⁴Can not all be hydrogen atom.

2. hyaluronic acid according to claim 1 is short to generate agent, it is characterized in that, with the N-acetyl-glucosamine derivative shown in the following general formula (5) as effective constituent,

General formula (5)

Wherein, 1 D structure can be any among α or the β.

3. hyaluronic acid according to claim 1 is short to generate agent, it is characterized in that, with the N-acetyl-glucosamine derivative shown in the following general formula (10) as effective constituent,

General formula (10)

Wherein, 1 D structure can be any among α or the β.

4. hyaluronic acid according to claim 1 is short to generate agent, it is characterized in that, with the N-acetyl-glucosamine derivative shown in the following general formula (12) as effective constituent,

General formula (12)

Wherein, 1 D structure can be any among α or the β.

5. hyaluronic acid according to claim 1 is short to generate agent, it is characterized in that, with the N-acetyl-glucosamine derivative shown in the following general formula (13) as effective constituent,

General formula (13)

Wherein, 1 D structure can be any among α or the β.

6. hyaluronic acid according to claim 1 is short to generate agent, it is characterized in that, with the N-acetyl-glucosamine derivative shown in the following general formula (14) as effective constituent,

General formula (14)

Wherein, 1 D structure can be any among α or the β.

7. hyaluronic acid according to claim 1 is short to generate agent, it is characterized in that, with the N-acetyl-glucosamine derivative shown in the following general formula (16) as effective constituent,

General formula (16)

Wherein, R ⁹Be that carbonatoms is 2～16 acyl group; In addition, 1 D structure can be any among α or the β.

8. hyaluronic acid according to claim 1 is short to generate agent, it is characterized in that, with the N-acetyl-glucosamine derivative shown in the following general formula (17) as effective constituent,

General formula (17)

Wherein, 1 D structure can be any among α or the β.

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