KR101216949B1 - Kojic acid derivative having depigmenting activity, preparation method thereof and cosmetic composition containing the same - Google Patents

Abstract

(상기 화학식 1 에서
R₁은 S, SO 또는 SO₂, R₂ 는 C1~C8 알킬, 사이클로 펜틸, 사이클로 헥실 또는 아다만틸이다)
상기 화합물은 우수한 티로시나제 저해활성을 가지므로 피부미백용 화장료 조성물로 유용하게 사용될 수 있다.The present invention relates to a novel kojic acid derivative having a whitening activity and represented by the following Chemical Formula 1, a preparation method thereof, and a cosmetic composition for skin whitening comprising the same.
[Formula 1]

(In the above formula 1
R ₁ is S, SO or SO ₂ , R ₂ is C1-C8 alkyl, cyclopentyl, cyclohexyl or adamantyl)
Since the compound has excellent tyrosinase inhibitory activity, it may be usefully used as a cosmetic composition for skin whitening.

Description

Koji acid derivative having whitening activity, preparation method thereof, and whitening cosmetic composition comprising same {Kojic acid derivative having depigmenting activity, preparation method according to cosmetic and cosmetic composition containing the same}

The present invention relates to a kojic acid derivative compound of Formula 1 having an anti-aging activity, a preparation method thereof and an anti-aging cosmetic composition comprising the same.

[Formula 1]

In Chemical Formula 1

R ₁ is S, SO or SO ₂ , R ₂ is C 1 -C 8 alkyl, cyclopentyl, cyclohexyl or adamantyl.

Melanin, which determines human skin color, is made from skin cells called melanocytes and migrates to epidermal cells called keratinocytes. Here, melanin plays an important role in forming a cap-like structure around the nucleus to protect genes from ultraviolet rays and to remove free radicals to protect intracellular proteins. There are no enzymes that break down melanin in vivo, but they are removed by falling off the skin as keratinocytes break off the epidermis. However, when more melanin is produced than necessary, it causes hyperpigmentation such as blemishes, freckles, and moles, which is not good for cosmetics. Also, as the leisure population increases, more people enjoy working outside, There is an increasing demand to prevent melanin pigmentation. Therefore, it was necessary to develop a whitening agent that prevents excessive melanin production and many efforts have been made. However, existing cosmetic raw materials have various problems such as insufficient efficacy or skin side effects. Therefore, studies on raw materials having a whitening effect without causing skin side effects are being actively conducted. As a result of this study, the present invention has found an excellent whitening effect by using the novel kojic acid derivatives as a skin external preparation composition.

Kojic acid is a substance obtained by culturing strains such as Aspergillus, and has an effect of strongly inhibiting the activity of tyrosinase enzymes involved in forming melanin, which is an important factor for determining the tone of human skin. The active mechanism of kojic acid is known to be formed by inhibiting the melanin forming action of tyrosinase by forming chelates with copper ions contained in tyrosinase in 5-position hydroxyl group and 4-position carbonyl group. For this reason, many kojic acid derivatives have been synthesized and studied for the purpose of enhancing tyrosinase activity. There is a research result that the tyrosinase activity is increased when substituted with a thiophenol compound at the 2-position of kojic acid (Korean Patent Registration No. 0157025, Bull. Korean Chem. Soc. 2010, 31, 2375). According to the results of the study, sulfide bonds play an important role in enhancing tyrosinase activity. The compounds disclosed in the patent document have superior tyrosinase inhibitory activity compared to kojic acid, but the solubility in organic solvents such as ethanol is reduced compared to kojic acid due to the substitution of the aromatic compound, which causes problems in cosmetic formulations. Have There is a need for a compound having excellent activity while solving this problem.

Therefore, the present inventors studied the synthesis of such novel kojic acid derivative compounds, and as a result, it was confirmed that the sulfide compound in which 2-position of kojic acid has an alkyl thiol or a cycloalkylthiol substitution has a strong tyrosinase inhibitory activity. To complete.

Therefore, an object of the present invention is to provide a novel kojic acid derivative having more excellent tyrosinase inhibitory activity.

Another object of the present invention is to provide a method for preparing the kojic acid derivative compound.

It is another object of the present invention to provide a cosmetic composition for whitening comprising the novel kojic acid derivative.

According to the present invention to achieve the above object, there is provided a novel kojic acid derivative compound represented by the following formula (1) having a whitening activity.

[Formula 1]

(In the above formula 1

R ₁ is S, SO or SO ₂ , R ₂ is C 1 -C 8 alkyl, cyclopentyl, cyclohexyl or adamantyl.)

In order to achieve the above another object, according to the present invention, the preparation of the compound of formula 1 by reacting chlorinated kojic acid and alkyl thiol metal salt or cyclo alkyl thiol metal salt in the presence of a base, and then oxidizing using an oxidizing agent under certain conditions A method is provided.

According to the present invention in order to achieve the above another object, there is provided a cosmetic composition for whitening comprising 0.1 to 10% by weight of the kojic acid derivative compound of Formula 1 relative to the total weight of the cosmetic composition.

Kojic acid derivatives prepared according to the present invention strongly inhibit the activity of tyrosinase, a melanogenesis enzyme, and can be usefully used as a cosmetic composition for skin whitening due to its high solubility in solvents.

Hereinafter, the present invention will be described in detail.

According to the present invention there is provided a kojic acid derivative compound of Formula 1 having a whitening activity.

[Formula 1]

In Formula 1,

R ₁ is S, SO or SO ₂ , R ₂ is C 1 -C 8 alkyl, cyclopentyl, cyclohexyl or adamantyl.

The kojic acid derivative compound may be prepared as in the following scheme.

[Reaction Scheme 1]

Scheme 2

Scheme 3

R ₂ in the scheme is C 1 -C 8 alkyl, cyclopentyl, cyclohexyl or adamantyl.

Hereinafter, the reaction schemes will be described in detail.

Scheme 1 shows the preparation of the sulfur compound of Formula II from chloric acid. Sulfur compound of formula (II) is prepared by reacting chlorinated kojic acid with an alkylthiol metal salt of C1-C8 or a cycloalkylthiol metal salt such as cyclopentyl, cyclohexyl or adamantyl. Potassium salts, cesium salts, and the like may be used as the metal salts, and dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, and the like may be used as the organic solvent. The reaction is carried out at 10 ~ 80 ℃, preferably about 30 ℃.

Scheme 2 shows that the sulfoxide compound of Formula III is prepared by oxidizing the sulfur compound prepared in Scheme 1. The sulfide group of Compound II prepared in the above step is oxidized using metachloroperbenzoic acid (MCPBA), which is an oxidizing agent, to convert to a sulfoxide compound. As the oxidizing agent, metachloroperbenzoic acid (MCPBA) should be used exactly equivalent to Compound II, and dichloromethane, chloroform, tetrahydrofuran, etc. may be used as the organic solvent. It is preferable that the said reaction is made in about 25-28 degreeC. If the temperature is higher than this, a sulfone compound may be formed, and if it is lower than this, an unreactant may be produced.

Scheme 3 shows that the sulfone compound of Formula IV is prepared by oxidizing the sulfur compound prepared in Scheme 1. The sulfide group of compound II prepared in the above step is oxidized using an oxidizing agent Oxone to convert to a sulfone compound. As the oxidizing agent, metaoxone should be used in an amount of 2.0-2.5 times, preferably 2.2 times, equivalent to Compound II. As a solvent, tetrahydrofuran, acetone, dioxane, and the like can be used by mixing an organic solvent and water. The mixing ratio of water and organic solvent is most preferably 1: 1. In addition, the reaction temperature is 25 ~ 50 ℃. If the temperature is lower than this, sulfoxide compounds may be formed together.

Kojic acid compound represented by the formula (1) prepared according to the present invention can be usefully applied to the cosmetic composition for whitening because it shows an excellent effect on the skin whitening. The sulfoxide and sulfone compounds prepared in Schemes 2 and 3 are more stable compounds than the compounds of Scheme 1, and thus are more stable in formulations such as cosmetics.

Kojic acid derivative compounds according to the invention can be used in the skin cosmetic composition, there is no particular limitation in the formulation. For example, supple cosmetics, astringent cosmetics, nourishing cosmetics, nourishing cream, massage cream, essence, eye cream, eye essence, cleansing cream, cleansing foam, cleansing water, pack, powder, body lotion, body cream, body oil, body It may be formulated into cosmetic compositions such as essences, makeup bases, foundations, hair dyes, shampoos, rinses, body cleansers, ointments, patches or sprays. Each of these formulations may contain various bases and additives necessary and appropriate for the formulation of the formulation.

Hereinafter, preferred examples are provided to help understanding of the present invention, but the following examples are merely to illustrate the present invention, and the scope of the present invention is not limited to the following examples.

[Example]

Example 1: Synthesis of 2- (ethylthiomethyl) -5-hydroxy-4H-pyran-4-one

Chlorocolic acid (10.0 g) and ethanethiol sodium salt (5.2 g) were added to 200 mL of dimethylformamide, and the reaction temperature was stirred at 30 ° C for 3 hours. It was confirmed by TLC that the reaction was completed, and dimethylformamide was concentrated to give a solid compound. This was again dissolved in 500 mL of ethyl acetate, washed twice with 5% aqueous HCl solution (100 mL), dried over magnesium sulfate, concentrated in half, and the precipitated crystals were filtered to give 8.2 g (yield 71%) of the desired compound.

¹ H NMR (300MHz, DMSO-d ₆ ): 9.10 (s, 1H), 8.03 (s, 1H), 6.36 (s, 1H), 3.63 (s, 2H), 2.52 (m, 2H), 1.18 (t , 3H, J = 7.5 Hz).

Example 2: Synthesis of 2- (propylthiomethyl) -5-hydroxy-4H-pyran-4-one

The target compound (8.7 g, 70%) was obtained using the same method as Example 1 except for using propanethiol sodium salt instead of ethanethiol sodium salt.

¹ H NMR (300MHz, DMSO-d ₆ ): 9.12 (s, 1H), 8.05 (s, 1H), 6.37 (s, 1H), 3.63 (s, 2H), 2.52 (m, 2H), 1.53 (m , 2H), 0.93 (t, 3H, J = 7.5 Hz).

Example 3: Synthesis of 2- (butylthiomethyl) -5-hydroxy-4H-pyran-4-one

The target compound (9.9 g, 75%) was obtained using the same method as Example 1 except for using butanethiol sodium salt instead of ethanethiol sodium salt.

¹ H NMR (300MHz, DMSO-d ₆ ): 9.09 (s, 1H), 8.05 (s, 1H), 6.37 (s, 1H), 3.64 (s, 2H), 2.51 (m, 2H), 1.50 (m , 2H), 1.42 (m, 2H), 0.85 (t, 3H, J = 7.5 Hz).

Example 4: Synthesis of 2- (pentylthiomethyl) -5-hydroxy-4H-pyran-4-one

A target compound (10.2 g, 72%) was obtained using the same method as Example 1 except for using pentanethiol sodium salt instead of ethanethiol sodium salt.

¹ H NMR (300MHz, DMSO-d ₆ ): 9.13 (s, 1H), 8.05 (s, 1H), 6.37 (s, 1H), 3.63 (s, 2H), 2.53 (m, 2H), 1.51 (m , 2H), 1.27 (m, 4H), 0.85 (t, 3H, J = 7.5 Hz).

Example 5: Synthesis of 2- (hexylthiomethyl) -5-hydroxy-4H-pyran-4-one

The target compound (10.5 g, 70%) was obtained using the same method as Example 1 except for using hexanethiol sodium salt instead of ethanethiol sodium salt.

¹ H NMR (300MHz, DMSO-d ₆ ): 9.13 (s, 1H), 8.05 (s, 1H), 6.37 (s, 1H), 3.63 (s, 2H), 2.53 (m, 2H), 1.51 (m , 2H), 1.27 (m, 6H), 0.85 (t, 3H, J = 7.5 Hz).

Example 6: Synthesis of 2- (heptylthiomethyl) -5-hydroxy-4H-pyran-4-one

The target compound (12.7 g, 80%) was obtained in the same manner as in Example 1 except that heptane thiol sodium salt was used instead of ethanethiol sodium salt.

¹ H NMR (300MHz, DMSO-d ₆ ): 9.13 (s, 1H), 8.05 (s, 1H), 6.37 (s, 1H), 3.63 (s, 2H), 2.53 (m, 2H), 1.51 (m , 2H), 1.27 (m, 8H), 0.85 (t, 3H, J = 7.5 Hz).

Example 7: Synthesis of 2- (octylthiomethyl) -5-hydroxy-4H-pyran-4-one

The target compound (12.6 g, 75%) was obtained in the same manner as in Example 1 except for using octathiol sodium salt instead of ethanethiol sodium salt.

¹ H NMR (300MHz, DMSO-d ₆ ): 9.13 (s, 1H), 8.05 (s, 1H), 6.37 (s, 1H), 3.63 (s, 2H), 2.53 (m, 2H), 1.51 (m , 2H), 1.27 (m, 10H), 0.85 (t, 3H, J = 7.5 Hz).

Example 8: Synthesis of 2- (cyclohexylthiomethyl) -5-hydroxy-4H-pyran-4-one

The target compound (10.4 g, 70%) was obtained using the same method as Example 1 except for using cyclohexanethiol sodium salt instead of ethanethiol sodium salt.

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 9: Synthesis of 2- (adamantylthiomethyl) -5-hydroxy-4H-pyran-4-one

The target compound (14.2 g, 75%) was obtained in the same manner as in Example 1, except that the adamantanethiol sodium salt was used instead of the ethanethiol 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).

Example 10 Synthesis of 2- (ethylsulfinylmethyl) -5-hydroxy-4H-pyran-4-one

After dissolving 100 mL of 2- (ethylthiomethyl) -5-hydroxy-4H-pyran-4-one (5 g) methylene chloride obtained in Example 1, 4.6 g of metachloroperbenzoic acid (MCPBA) was added thereto, and the mixture was stirred at room temperature for 5 hours. Was stirred. After completion of the reaction, TLC confirmed and concentrated to give a solid compound. This was again dissolved in 200 mL of ethyl acetate, washed twice with 5% aqueous HCl solution (100 mL), dried over magnesium sulfate, concentrated to half, and the precipitated crystals were filtered to give 3.9 g (64% yield) of the pure target compound.

¹ H NMR (300MHz, DMSO-d ₆ ): 9.19 (s, 1H), 8.04 (s, 1H), 6.33 (s, 1H), 4.11 (d, 1H, J = 13.5 Hz), 3.90 (d, 1H , J = 13.5 Hz), 2.80 (m, 2H), 0.87 (t, 3H, J = 7.5 Hz).

Example 11: Synthesis of 2- (propylsulfinylmethyl) -5-hydroxy-4H-pyran-4-one

Except for using 2- (propylthiomethyl) -5-hydroxy-4H-pyran-4-one (5 g) obtained in Example 2, the target compound (3.2 g, 60%).

¹ H NMR (300MHz, DMSO-d ₆ ): 9.19 (s, 1H), 8.05 (s, 1H), 6.33 (s, 1H), 4.11 (d, 1H, J = 13.5 Hz), 3.90 (d, 1H , J = 13.5 Hz), 2.79 (m, 2H), 1.61 (m, 2H), 0.87 (t, 3H, J = 7.5 Hz).

Example 12 Synthesis of 2- (butylsulfinylmethyl) -5-hydroxy-4H-pyran-4-one

Except for using 2- (butylthiomethyl) -5-hydroxy-4H-pyran-4-one (5 g) obtained in Example 3, using the same method as in Example 10, the target compound (3.5 g, 65%).

¹ H NMR (300MHz, DMSO-d ₆ ): 9.18 (s, 1H), 8.04 (s, 1H), 6.34 (s, 1H), 4.12 (d, 1H, J = 13.5 Hz), 3.90 (d, 1H , J = 13.5 Hz), 2.78 (m, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.87 (t, 3H, J = 7.5 Hz).

Example 13: Synthesis of 2- (pentylsulfinylmethyl) -5-hydroxy-4H-pyran-4-one

Except for using 2- (pentylthiomethyl) -5-hydroxy-4H-pyran-4-one (5 g) obtained in Example 4, the target compound (3.7 g, 70%).

¹ H NMR (300MHz, DMSO-d ₆ ): 9.23 (s, 1H), 8.08 (s, 1H), 6.39 (s, 1H), 4.17 (d, 1H, J = 13.5 Hz), 3.95 (d, 1H , J = 13.5 Hz), 2.83 (m, 2H), 1.65 (m, 2H), 1.34 (m, 4H), 0.89 (t, 3H, J = 7.5 Hz).

Example 14 Synthesis of 2- (hexylsulfinylmethyl) -5-hydroxy-4H-pyran-4-one

Except for using 2- (hexylthiomethyl) -5-hydroxy-4H-pyran-4-one (5 g) obtained in Example 5, the target compound (3.6 g, 67%).

¹ H NMR (300MHz, DMSO-d ₆ ): 9.23 (s, 1H), 8.08 (s, 1H), 6.39 (s, 1H), 4.17 (d, 1H, J = 13.5 Hz), 3.95 (d, 1H , J = 13.5 Hz), 2.83 (m, 2H), 1.65 (m, 2H), 1.32-1.27 (m, 6H), 0.86 (t, 3H, J = 7.5 Hz).

Example 15 Synthesis of 2- (heptylsulfinylmethyl) -5-hydroxy-4H-pyran-4-one

Except for using 2- (heptylthiomethyl) -5-hydroxy-4H-pyran-4-one (5 g) obtained in Example 6, the target compound (3.4 g, 70%).

¹ H NMR (300MHz, DMSO-d ₆ ): 9.21 (s, 1H), 8.08 (s, 1H), 6.39 (s, 1H), 4.17 (d, 1H, J = 13.5 Hz), 3.95 (d, 1H , J = 13.5 Hz), 2.83 (m, 2H), 1.65 (m, 2H), 1.32-1.27 (m, 8H), 0.87 (t, 3H, J = 7.5 Hz).

Example 16: Synthesis of 2- (octylsulfinylmethyl) -5-hydroxy-4H-pyran-4-one

Except for using 2- (octylthiomethyl) -5-hydroxy-4H-pyran-4-one (5 g) obtained in Example 7, using the same method as in Example 10, the target compound (3.9 g, 75%).

¹ H NMR (300MHz, DMSO-d ₆ ): 9.21 (s, 1H), 8.08 (s, 1H), 6.39 (s, 1H), 4.17 (d, 1H, J = 13.5 Hz), 3.95 (d, 1H , J = 13.5 Hz), 2.83 (m, 2H), 1.65 (m, 2H), 1.32-1.27 (m, 10H), 0.87 (t, 3H, J = 7.5 Hz).

Example 17 Synthesis of 2- (cyclohexylsulfinylmethyl) -5-hydroxy-4H-pyran-4-one

The target compound (3.6 g) was obtained in the same manner as in Example 10, except that 2- (cyclohexylthiomethyl) -5-hydroxy-4H-pyran-4-one (5 g) obtained in Example 8 was used. , 67%).

¹ H NMR (300MHz, DMSO-d ₆ ): 9.21 (s, 1H), 8.09 (s, 1H), 6.41 (s, 1H), 4.13 (d, 1H, J = 13.5 Hz), 3.96 (d, 1H , J = 13.5 Hz), 2.72 (m, 2H), 1.98-0.72 (m, 10H).

Example 18 Synthesis of 2- (adamantylsulfinylmethyl) -5-hydroxy-4H-pyran-4-one

Using the same method as in Example 10, except that 2- (adamantylthiomethyl) -5-hydroxy-4H-pyran-4-one (5 g) obtained in Example 9 was used, the target compound (3.5 g, 68%).

¹ H NMR (300MHz, DMSO-d ₆ ): 9.20 (s, 1H), 8.09 (s, 1H), 6.45 (s, 1H), 4.09 (d, 1H, J = 13.5 Hz), 3.87 (d, 1H , J = 13.5 Hz), 1.99 (s, 3H), 1.80 (s, 6H), 1.63 (s, 6H).

Example 19: Synthesis of 2- (ethylsulfonylmethyl) -5-hydroxy-4H-pyran-4-one

After dissolving in 200 mL of 2- (ethylthiomethyl) -5-hydroxy-4H-pyran-4-one (5 g) tetrahydrofuran and an aqueous solution of 1: 1 solution obtained in Example 1, 20 g of oxone was added thereto. Stir at room temperature for 5 hours. After completion of the reaction, TLC confirmed and concentrated to give a solid compound. This was dissolved in 200 mL of ethyl acetate again, washed twice with 5% aqueous HCl solution (100 mL), dried over magnesium sulfate, concentrated in half, and the precipitated crystals were filtered to give 4.1 g (yield 70%) of the pure target compound.

¹ H NMR (300MHz, DMSO-d ₆ ): δ 9.29 (s, 1H), 8.06 (s, 1H), 6.44 (s, 1H), 4.54 (s, 2H), 3.20 (m, 2H), 1.21 ( t, 3H, J = 7.5 Hz).

Example 20 Synthesis of 2- (propylsulfonylmethyl) -5-hydroxy-4H-pyran-4-one

Except for using 2- (propylthiomethyl) -5-hydroxy-4H-pyran-4-one (5 g) obtained in Example 2, the target compound (4.1 g, 71%) was obtained in the same manner as in Example 19 )

¹ H NMR (300MHz, DMSO-d ₆ ): δ 9.28 (s, 1H), 8.11 (s, 1H), 6.49 (s, 1H), 4.58 (s, 2H), 3.21 (m, 2H), 1.78 ( m, 2H), 1.21 (t, 3H, J = 7.5 Hz).

Example 21 Synthesis of 2- (butylsulfonylmethyl) -5-hydroxy-4H-pyran-4-one

A target compound (4.6 g, 80%) in the same manner as in Example 19, except that 2- (butylthiomethyl) -5-hydroxy-4H-pyran-4-one (5 g) obtained in Example 3 was used. )

¹ H NMR (300MHz, DMSO-d ₆ ): δ 9.33 (s, 1H), 8.12 (s, 1H), 6.49 (s, 1H), 4.58 (s, 2H), 3.21 (m, 2H), 1.68 ( m, 2H), 1.41 (m, 2H), 0.91 (t, 3H, J = 7.5 Hz).

Example 22 Synthesis of 2- (pentylsulfonylmethyl) -5-hydroxy-4H-pyran-4-one

A target compound (3.8 g, 68%) in the same manner as in Example 19, except that 2- (pentylthiomethyl) -5-hydroxy-4H-pyran-4-one (5 g) obtained in Example 4 was used. )

¹ H NMR (300MHz, DMSO-d ₆ ): δ 9.23 (s, 1H), 8.11 (s, 1H), 6.49 (s, 1H), 4.58 (s, 2H), 3.21 (m, 2H), 1.68 ( m, 2H), 1.33 (m, 4H), 0.89 (t, 3H, J = 7.5 Hz).

Example 23 Synthesis of 2- (hexylsulfonylmethyl) -5-hydroxy-4H-pyran-4-one

Except for using 2- (hexylthiomethyl) -5-hydroxy-4H-pyran-4-one (5g) obtained in Example 5, the target compound (4.4g, 79% )

¹ H NMR (300MHz, DMSO-d ₆ ): δ 9.32 (s, 1H), 8.11 (s, 1H), 6.49 (s, 1H), 4.58 (s, 2H), 3.20 (m, 2H), 1.69 ( m, 2H), 1.50-1.22 (m, 6H), 0.86 (t, 3H, J = 7.5 Hz).

Example 24: Synthesis of 2- (heptylsulfonylmethyl) -5-hydroxy-4H-pyran-4-one

Except for using 2- (heptylthiomethyl) -5-hydroxy-4H-pyran-4-one (5g) obtained in Example 6, the target compound (3.9g, 70% in the same manner as in Example 19). )

¹ H NMR (300MHz, DMSO-d ₆ ): δ 9.33 (s, 1H), 8.11 (s, 1H), 6.49 (s, 1H), 4.59 (s, 2H), 3.20 (m, 2H), 1.69 ( m, 2H), 1.50-1.22 (m, 8H), 0.84 (t, 3H, J = 7.5 Hz).

Example 25 Synthesis of 2- (octylsulfonylmethyl) -5-hydroxy-4H-pyran-4-one

Except for using 2- (octylthiomethyl) -5-hydroxy-4H-pyran-4-one (5 g) obtained in Example 7, the target compound (3.3 g, 60%) in the same manner as in Example 19 )

¹ H NMR (300MHz, DMSO-d ₆ ): δ 9.33 (s, 1H), 8.11 (s, 1H), 6.49 (s, 1H), 4.59 (s, 2H), 3.20 (m, 2H), 1.69 ( m, 2H), 1.50-1.22 (m, 10H), 0.86 (t, 3H, J = 7.5 Hz).

Example 26 Synthesis of 2- (cyclohexanesulfonylmethyl) -5-hydroxy-4H-pyran-4-one

Except for using 2- (cyclohexylthiomethyl) -5-hydroxy-4H-pyran-4-one (5 g) obtained in Example 8, the target compound (3.8 g, 68 was obtained in the same manner as in Example 19. %) Was obtained.

¹ H NMR (300MHz, DMSO-d ₆ ): δ 9.23 (s, 1H), 8.07 (s, 1H), 6.43 (s, 1H), 4.51 (s, 2H), 3.09 (m, 1H), 2.02 ( m, 2H), 1.80 (m, 2H), 1.60-0.95 (m, 6H).

Example 27 Synthesis of 2- (adamantylsulfonylmethyl) -5-hydroxy-4H-pyran-4-one

Except for using 2- (adamantylthiomethyl) -5-hydroxy-4H-pyran-4-one (5 g) obtained in Example 9, the target compound (3.9 g, 70%).

¹ H NMR (300MHz, DMSO-d ₆ ): δ 9.34 (s, 1H), 8.12 (s, 1H), 6.48 (s, 1H), 4.47 (s, 2H), 2.20 (s, 3H), 1.95 ( s, 6H), 1.67 (s, 6H).

Test Example 1 Inhibitory Effect of Tyrosinase Activity

The tyrosinase inhibitory activity of the reaction products of Examples 1 to 27 was measured by the following method, and the koji acid and 2- (4-methoxyphenylthio) methyl-5-hydroxy-4H- Pyran-4-one and 2- (4-hydroxyphenylthio) methyl-5-hydroxy-4H-pyran-4-one were compared with the tyrosinase inhibitory activity. Mushroom-derived tyrosinase and tyrosine were purchased from Sigma Chemical. Tyrosinase activity was correlated with 150 microliters of 0.1 M phosphate buffer (pH 6.5) and 8 microliters of mushroom tyrosinase (2,100 unit / ml, 0.05 M phosphate buffer, pH 6.5) and 36 microliters of 1.5 mM L-tyrosine. Fatty acid derivatives were treated by concentration. Tyrosinase activity was measured at 490 nm using a microplate reader (Bio-Rad 3550, Richmond, CA, U.S.A.) after enzymatic reaction at 37 ° C. for 20 minutes.

The tyrosinase inhibition effect by the reaction product of Examples 1-27 was calculated | required based on the following formula.

Tyrosinase Inhibition Rate (%) = 100-[(Reaction Absorbance of Each Sample / Reaction Absorbance of Control) × 100]

By the above formula, the dose (IC ₅₀ ) of each sample for reducing the tyrosinase activity by 50% from the tyrosinase inhibition rate of the diluting solution of each sample was determined. The results obtained are shown in Table 1 below.

matter IC ₅₀ ([mu] M) matter IC ₅₀ ([mu] M) Kojic acid 87.38 Example 13 79.87 2- (4-methoxyphenylthio) methyl-5-hydroxy-4H-pyran-4-one 2.68 Example 14 73.75 2- (4-hydroxyphenylthio) methyl-5-hydroxy-4H-pyran-4-one 2.97 Example 15 69.9 Example 1 2.62 Example 16 68.0 Example 2 1.93 Example 17 79.03 Example 3 1.48 Example 18 70.01 Example 4 0.097 Example 19 71.20 Example 5 0.19 Example 20 75.02 Example 6 2.65 Example 21 72.32 Example 7 46.18 Example 22 76.60 Example 8 0.087 Example 23 49.15 Example 9 0.086 Example 24 69.83 Example 10 70.90 Example 25 70.00 Example 11 76.60 Example 26 69.01 Example 12 70.80 Example 27 60.00

As can be seen in Table 1, the sulfuric acid derivative compound in the form of a sulfur compound in which a 2-hydroxy group of kojic acid, which is a compound of the present invention, is substituted with alkylthiol, showed a significantly increased tyrosinase inhibitory activity compared to kojic acid. When compared with the kojic acid derivative compound in the sulfide form in which the 2-position hydroxy group of kojic acid was substituted with methoxybenzenethiol or hydroxybenzenethiol, it showed an equivalent or superior tyrosinase inhibitory activity. In particular, compounds substituted with pentanethiol, hexanethiol, cyclohexanethiol, and adamantanethiol showed high activity. In Examples 4, 5, 8 and 9, the compound showed about 1000 times the activity of tyrosinase inhibitory activity of kojic acid. In the case of sulfoxide and sulfone compounds obtained by oxidation of sulfur bonds, the tyrosinase inhibitory activity was decreased compared to the anticompounds.

Formulation Example 1: Preparation of Nutrients (Milk Lotion)

Nutritional longevity containing the kojic acid derivative compound prepared in Example 4 was prepared according to the composition of Table 2.

ingredient Content (% by weight) glycerin 8.0 Butylene glycol 4.0 Hyaluronic acid extract 5.0 Beta Glucan 7.0 Carbomer 0.1 Kojic acid derivative compound (Example 4) 2.0 Caprylic Capric Triglycerides 8.0 Squalane 5.0 Cetearyl Glucoside 1.5 Sorbitan stearate 0.4 Cetearyl Alcohol 1.0 antiseptic Suitable amount incense Suitable amount Pigment Suitable amount Triethanolamine 0.1 Purified water Balance

Formulation Example 2: Preparation of Nutritional Cream

A nourishing cream containing kojic acid derivative compound prepared in Example 4 was prepared according to the composition of Table 3 below.

ingredient Content (% by weight) glycerin 3.0 Butylene glycol 3.0 Liquid paraffin 7.0 Beta Glucan 7.0 Carbomer 0.1 Kojic acid derivative compound (Example 4) 1.0 Caprylic Capric Triglycerides 3.0 Squalane 5.0 Cetearyl Glucoside 1.5 Sorbitan stearate 0.4 Polysorbate 60 1.2 antiseptic Suitable amount incense Suitable amount Pigment Suitable amount Triethanolamine 0.1 Purified water Balance

Formulation Example 3: Preparation of Massage Cream

A nourishing cream containing kojic acid derivative compound prepared in Example 8 was prepared according to the composition of Table 4 below.

ingredient Content (% by weight) glycerin 8.0 Butylene glycol 4.0 Liquid paraffin 45.0 Beta Glucan 7.0 Carbomer 0.1 Kojic acid derivative compound (Example 8) 2.0 Caprylic Capric Triglycerides 3.0 Wax 4.0 Cetearyl Glucoside 1.5 Sesqui oleic acid sorbitan 0.9 Vaseline 3.0 antiseptic Suitable amount incense Suitable amount Pigment Suitable amount paraffin 1.5 Purified water Balance

Formulation Example 4 Preparation of Ointment

An ointment containing the kojic acid derivative compound prepared in Example 9 was prepared according to the composition of Table 5 below.

ingredient Content (% by weight) glycerin 8.0 Butylene glycol 4.0 Liquid paraffin 15.0 Beta Glucan 7.0 Carbomer 0.1 Kojic acid derivative compound (Example 9) 1.0 Caprylic Capric Triglycerides 3.0 Squalane 1.0 Cetearyl Glucoside 1.5 Sorbitan stearate 0.4 Cetearyl Alcohol 1.0 antiseptic Suitable amount incense Suitable amount Pigment Suitable amount Wax 4.0 Purified water Balance

Claims (5)

Kojic acid derivative compound of Formula 1 having a whitening activity.
[Formula 1]

(In Formula 1, R ₁ is S, R ₂ is adamantyl.) In the presence of an organic base, the method for producing a kojic acid derivative of the general formula (1) comprising the step of reacting chloric acid and adamantane thiol sodium salt at a reaction temperature of 30 ℃.
[Formula 1]

(In Formula 1, R ₁ is S, R ₂ is adamantyl.) delete delete A whitening cosmetic composition comprising the following formula 1 compound 0.1 to 10% by weight based on the total weight of the cosmetic composition.
[Formula 1]

(In Formula 1, R ₁ is S, R ₂ is adamantyl.)