KR102202236B1 - Kojic acid sulfide derivative having activity in the promotion of adipocyte differentiation and cosmetic composition containing it - Google Patents

Abstract

R은 사이클로 헥실 또는 아다만틸이다.The present invention relates to a cosmetic composition for promoting adipocyte differentiation comprising a kojic acid sulfide derivative compound represented by the following formula (1) as an active ingredient.
[Formula 1]

R is cyclohexyl or adamantyl.

Description

Kojic acid sulfide derivative having activity in the promotion of adipocyte differentiation and cosmetic composition containing it}

The present invention relates to a kojic acid sulfide derivative compound having an adipocyte differentiation promoting effect and a cosmetic composition containing the same.

The skin is composed of the epidermis, the dermis, and the subcutaneous fat, and the basic structure of the skin is maintained by the subcutaneous fat tissue. This subcutaneous fat tissue plays an important role in determining the volume and strength of the skin. Therefore, as mentioned above, increasing the volume of adipose tissue can be a good solution to maintain the volume and elasticity of the skin than the method of imparting elasticity to the dermis or epidermis in the outer layer of the skin that has been used previously. Research using adipocytes is being actively conducted in various fields. Adipocytes commonly used are cells that are widely used because they have the property of differentiating into adipocytes by differentiation-inducing substances such as insulin. Mesenchymal stem cells have recently attracted attention in research using adipocytes. Adipose-derived mesenchymal stem cells can be differentiated using a method similar to that used to differentiate adipocytes into adipocytes (Exp. Cell Res. 2006, 312, 1856), so they are widely used in adipocyte differentiation studies. (Science 1999, 284, 143). It is known that these adipose-derived mesenchymal stem cells can differentiate into not only adipocytes but also other types of cells such as chondrocytes and bone cells (J. Cell Sci. 2006 119, 2204), and are distributed in most tissues of the body. have.

As aging progresses, wrinkles are formed in the skin and elasticity decreases at the same time. Skin aging, such as wrinkle formation and elasticity reduction, decomposes and decreases skin fibers such as collagen and elastin, which are components of the skin, and decreases the activity of adipocytes, and thereby decreases lipid droplets. It is a complex phenomenon caused by. Therefore, if it is possible to produce and accumulate fat cells by promoting the differentiation of human fat cells, it is possible to improve the wrinkles and elasticity of the skin.

According to the results of previous studies, it was reported that derivatives of cinnamic acid linked to kojic acid through ester bonds have a significantly increased adipocyte differentiation promoting effect than cinnamic acid (Bioorg. Med. Chem. Lett. 2014, 24, 2141, Bioorg. Med. Chem. 2018, 26, 5654, Patent No. 10-2016-0086681). In the adipocyte differentiation promoting effect, it can be seen that the hydroxypyranone hair nucleus of kojic acid plays a role of Pharmacopore. The compounds disclosed in the above document exhibit excellent adipocyte differentiation effect, but as compounds in which cinnamic acid and kojic acid are linked by an ester bond, they are easily hydrolyzed under basic conditions. Accordingly, the inventors of the present invention have shown the effect of promoting adipocyte differentiation and promoting adipocyte differentiation in the case of sulfide kojic acid derivatives containing cyclic hexane and adamantane mother nuclei while conducting research on structurally stable kojic acid derivatives. It was confirmed that the present invention was completed. The sulfide structure is a structure that is stable even under basic conditions. The efficacy of the kojic acid sulfide derivative compound on the whitening effect is known in the prior patent literature (Patent No. 10-1216949). However, the effect of promoting adipocyte differentiation is unknown.

[Document 1] Korean Patent Publication No. 10-1216949 (registered on December 24, 2012)

An object of the present invention is to provide a kojic acid sulfide derivative compound represented by the following formula (1) and a cosmetic composition containing the same.

[Formula 1]

R is cyclohexyl or adamantyl.

The problem to be solved of the present invention is not limited to the mentioned problem. Other technical problems that are not mentioned will be clearly understood by those of ordinary skill in the art from the following description.

In order to solve the above problems, the kojic acid sulfide derivative compound having an adipocyte differentiation promoting effect according to an embodiment of the present invention is a kojic acid sulfide derivative compound represented by the following formula (1).

[Formula 1]

R is cyclohexyl or adamantyl.

The present invention relates to a sulfide derivative compound of kojic acid that exhibits an adipocyte differentiation promoting effect. As a result of the experiment, the amount of adiponectin expression in human adipose-derived mesenchymal stem cells was increased, and as a result of using it as a composition of nutrient cosmetic water and nutrition cream, skin The effect of improving wrinkles and improving elasticity was obtained.

Hereinafter, the present invention will be described in more detail.

The manufacturing method according to the above method will be described by taking the following reaction formula (1) as an example. Preparing a sulfide compound by reacting a chlorinated kojic acid with a cyclohexane thiol metal salt or an adamantane thiol metal salt:

It characterized in that it comprises a.

[Scheme 1]

The method for preparing the kojic acid sulfide derivative compound according to the present invention is described in detail as follows, as can be seen in the above-described Scheme 1. In this step, sodium, potassium, cesium, etc. may be used as the metal, and dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, and the like may be used as the organic solvent. In addition, the reaction temperature can be 10-80 ^o C, but 30 ^o C is preferred.

Specific examples of the kojic acid sulfide derivative compound of Formula 1 obtained by the above production method,

2-(cyclohexylthiomethyl)-5-hydroxy-4H-pyran-4-one,

2-(adamantylthiomethyl)-5-hydroxy-4H-pyran-4-one,

Can be mentioned.

The kojic acid sulfide derivative compound represented by Formula 1 prepared by the above manufacturing method promotes the differentiation of adipocytes to generate and accumulate adipocytes, thereby improving wrinkles and elasticity of the skin.

Hereinafter, the method for preparing the kojic acid sulfide derivative compound according to the present invention and the effect of adipocyte differentiation will be described in more detail through Examples and Test Examples.

[Example 1] Preparation of 2-(cyclohexylthiomethyl)-5-hydroxy-4H-pyran-4-one

To 100 mL of dimethylformamide, chlorokojic acid (5.0 g) and cyclohexane thiol sodium salt (4.3 g) were added, and the reaction temperature was stirred at 30° C. for 3 hours. The completion of the reaction was confirmed by TLC, and dimethylformamide was concentrated to obtain a solid compound. This was again dissolved in 200 mL of ethyl acetate, washed twice with 5% HCl aqueous solution (100 mL), dried over magnesium sulfate, concentrated in half, and the precipitated crystals were filtered to obtain 5.6 g (yield 75%) of the pure target product.

¹ H NMR (300MHz, DMSO-d ₆ ): 9.12 (s, 1H), 8.04 (s, 1H), 6.39 (s, 1H), 3.67 (s, 2H), 2.69 (m, 1H), 1.90 (m , 2H), 1.65 (m, 2H), 1.51-0.90 (m, 6H).

[Example 2] Preparation of 2-(adamantylthiomethyl)-5-hydroxy-4H-pyran-4-one

The target compound (7.3g, 77%) was obtained in the same manner as in Example 1, except that adamantane thiol sodium salt was used instead of hexane thiol sodium salt.

¹ H NMR (300MHz, DMSO-d ₆ ): 9.09 (s, 1H), 8.03 (s, 1H), 6.44 (s, 1H), 3.67 (s, 2H), 1.99 (s, 3H), 1.80 (s , 6H), 1.63 (s, 6H).

[Test Example 1] Measurement of adiponectin expression level in human adipose-derived mesenchymal stem cells

Adiponectin is a representative protein hormone secreted by adipocytes. It has been reported that the expression of adiponectin increases as adipocytes differentiate. Therefore, the amount of adiponectin, an indicator of adipocyte differentiation promotion, secreted into the cell culture medium was measured. To measure the secretion of adiponectin, the cell culture medium was collected on the 14th day of adipogenic differentiation, and then the amount of adiponectin was quantified using the adiponectin ELISA Kit (R&D systems, cat. No. DY1065) (each data value was used as a control group). Corrected.). The specific measurement method using the adiponectin ELISA Kit is as follows. The capture antibody was reacted to a 96-well plate, washed with a washing buffer, added to the sample, and reacted at room temperature for 2 hours. After that, each time each step is passed, the detection antibody, HRP enzyme, substrate solution, and stop solution are sequentially added while washing three times and reacted for the time indicated in the protocol. After the final reaction, the absorbance is measured at a wavelength of 450 nm using a spectrophotometer. The results are shown in Table 1.

[Result of adiponectin expression level] matter Adiponectin (pg/ml, Avg ± S.D.) Untreated group 45 ± 10 IDX treatment group 401 ± 30 IDX + glibenclamide 1850 ± 90 IDX + kojic acid (500μM) 403 ± 95 IDX + Example 1 (100 μM) 1704 ± 100 IDX + Example 2 (100 μM) 1620 ± 110

In the experiment to increase the adiponectin expression level, kojic acid did not show any effect. However, Examples 1 and 2 of the kojic acid sulfide derivative compounds increased the expression level of adiponectim.

[Formulation Example 1] Preparation of nutrient cosmetic water (milk lotion)

A nutrient lotion containing the kojic acid sulfide derivative compound prepared in Example 1-2 was prepared.

ingredient Content (% by weight) 1. Purified water Balance 2. Glycerin 8.0 3. Butylene glycol 4.0 4. Hyaluronic acid extract 5.0 5. Beta Glucan 7.0 6. Carbomer 0.1 7. Example 1-2 Appropriate amount 8. Caprylic/Capric Triglyceride 8.0 9. Squalene 5.0 10. Cetearyl Glucoside 1.5 11.Sorbitan stearate 0.4 12. Cetearyl Alcohol 1.0 13. Preservative Appropriate amount 14. Incense Appropriate amount 15. Pigment Appropriate amount 16. Triethanolamine 0.1

[Formulation Example 2] Preparation of nourishing cream

A nutritional cream containing the kojic acid sulfide derivative compound prepared in Example 1-3 was prepared.

ingredient Content (% by weight) 1. Purified water Balance 2. Glycerin 3.0 3. Butylene glycol 3.0 4. Liquid paraffin 7.0 5. Beta Glucan 7.0 6. Carbomer 0.1 7. Example 1-2 Appropriate amount 8. Caprylic/Capric Triglyceride 3.0 9. Squalene 5.0 10. Cetearyl Glucoside 1.5 11.Sorbitan stearate 0.4 12. Polysorbate 1.2 13. Preservative Appropriate amount 14. Incense Appropriate amount 15. Pigment Appropriate amount 16. Triethanolamine 0.1

Claims (2)

Adipocyte differentiation promoting cosmetic composition using a kojic acid sulfide derivative compound represented by the following formula (1) having an adipocyte differentiation promoting effect.

[Formula 1]

R is cyclohexyl or adamantyl.
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