KR20190043800A - NOVEL α-TOCOPHEROL DERIVATIVES, AND COSMETIC USES OF THE SAME - Google Patents

Abstract

여기서, n은 3이고, R₁은, 각각 독립적으로, 수소, 메틸기, 또는 아세틸기이다.The present invention relates to a novel? -Tocopherol derivative compound and its cosmetic use, and more particularly to a compound represented by the following formula (1). The present invention has an antioxidative activity as a novel compound and inhibits the activity of elastase, which is a degradation enzyme of elastin protein, which is related to wrinkle formation of skin, and has an effect of improving skin wrinkles.
[Chemical Formula 1]

Here, n is 3, and R ₁ is each independently hydrogen, a methyl group, or an acetyl group.

Description

TECHNICAL FIELD The present invention relates to a novel? -Tocopherol derivative compound and a cosmetic use thereof,

The present invention relates to novel? -Tocopherol derivative compounds, and cosmetic uses thereof.

Since the skin is always exposed to the external environment, a lot of skin changes due to aging can be attributed to the influence of external factors. Among these, active oxygen leads to damage of skin cells and tissues. Active oxygen can be used to destroy lipid peroxidation, protein oxidation, activation of proteolytic enzymes that break down cellular interstitial components, disruption of elastic fibers such as collagen and elastin, and destruction of abnormal antioxidant defenses, which are composed of antioxidant enzymes and non-enzymatic antioxidants. Cross-linking, cleavage of the hyaluronic acid chain, promotion of melanin production, and damage of biological components such as DNA oxidation. It also causes skin inflammation and inhibits skin immune function, leading to an increase in bacterial infection or carcinogenicity. The result is accelerated skin aging characterized by reduced elasticity, wrinkles and stains, and freckles. Therefore, in order to protect skin cells and inhibit the damage of connective tissues, it is necessary to construct an antioxidant defense system that can inhibit the excessive production of active oxygen and efficiently remove the generated active oxygen in order to delay or prevent skin aging. Is a reality that is constantly being done.

Antioxidant defense systems have been studied using vitamin C, E, and β-carotene, which are classified as antioxidant vitamins, as antioxidant natural substances. These antioxidants suppress the cascade of reactive oxygen species Blocking, active oxygen removal, restoration of damage caused by active oxygen, etc., thereby protecting the skin cells and delaying or preventing aging of the skin. In detail, they explain that they react first with free radicals such as reactive and harmful free radicals, which themselves become stable metabolites and prevent other important compounds from becoming free radicals. In particular, antioxidant vitamins are safe enough to be ingested in the diet, so they are easy to access in terms of skin cosmetics.

Among them, tocopherol compounds called vitamin E are classified into α, β, γ and δ isomers depending on the number and position of methyl groups in the aromatic ring structure. They exist in nature and have inherent physiological activity and inhibit oxidation It is effective and plays an important role in prevention of lipid peroxidation. It has been reported that? -Tocopherol compounds can be applied as a cosmetic raw material due to action of stimulating skin cell growth and collagen synthesis of dermis by anti-oxidative action of tocopherol, antiallergic and anti-inflammatory effect. However, when the? -Tocopherol compound is used in a cosmetic composition, it is easily oxidized or deformed by light, heat, and air to be discolored and transformed, and its activity decreases with time, It is a substance.

Therefore, studies on tocopherol derivatives that are more stable and easy to handle for use as a cosmetic composition, while having the same or higher efficacy as natural tocopherol, have been actively studied.

Examples of conventional techniques for such tocopherol derivatives include those disclosed in Patent Document 1 below. Thus, the entire contents of Patent Document 1 are incorporated into the background art of the specification of the present invention.

Patent Document 1 discloses that introduction of diethanolamine, trihydroxyamine, N-methylglucamine or the like increases the solubility, increases the skin permeation of tocopherol, and increases permeation into the cell membrane, thereby increasing the physiological activity of tocopherol And a tocopherol derivative having a hydrophilic group and a hydrophilic group at the same time in the molecule and having an advantageous shape as a cosmetic. However, diethanolamine, trihydroxyamine, and the like are acute toxic, petroleum-derived synthetic compounds that are highly irritating to skin and eyes, and there is a great possibility that the stability of tocopherol derivatives using such substances is problematic.

KR 10-0787879 B1 (27 Dec 2007)

In order to solve the problems of α-tocopherol mentioned above and to develop an α-tocopherol derivative having skin improving effect, the design of the derivative compound was carried out by using gallic acid, syringic acid) was expected to have synergistic effect besides the simple effect of raw materials. The reason for designing and synthesizing well-known and existing substances as synthesis materials is that the pharmacokinetics and toxic mechanism of the degradation metabolites produced when the synthesized α-tocopherol derivatives are separated by metabolism or decomposition Is well known, it is easy to secure safety in using synthetic derivative compounds. Thus, the present invention provides a novel? -Tocopherol derivative compound which is safe and has excellent antioxidative activity and skin wrinkle improving effect.

SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned problems of the prior art,

There is provided a compound represented by the following formula (1).

[Chemical Formula 1]

Here, n is 3, and R ₁ is each independently hydrogen, a methyl group, or an acetyl group.

Further, a compound represented by the following formula (2) is provided.

(2)

Further, a compound represented by the following general formula (3) is provided.

(3)

Further, a compound represented by the following general formula (4) is provided.

[Chemical Formula 4]

In addition, there is provided a compound represented by the following general formula (5).

[Chemical Formula 5]

Substituting the hydroxy group of the at least one phenolic acid compound selected from gallic acid or sialic acid with an acetyl protecting group;

Reacting the carboxylic acid moiety of the phenolic acid compound with a hydroxy group of? -Tocopherol; And

Optionally degassing the acetyl protecting group, in the presence of a base.

Also provided is an antioxidant cosmetic composition comprising a compound of the present invention.

The present invention also provides a cosmetic composition for improving skin wrinkles, which comprises the compound of the present invention.

The present invention has an antioxidative activity as a novel compound and inhibits the activity of elastase, which is a degradation enzyme of elastin protein, which is related to wrinkle formation of skin, and has an effect of improving skin wrinkles.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a graph showing the antioxidative effect of the tocopherol derivative of the present invention measured.
Fig. 2 is a graph showing the results of measuring the elastase inhibitory effect of the tocopherol derivatives of the present invention.

Hereinafter, the present invention will be described in detail.

First, the terms used in this specification are defined.

'Me' is an abbreviation of 'methyl group' and 'Ac' is an abbreviation of 'acetyl group'. The use of such an abbreviation is a widely used term in the organic synthesis field and is not specifically defined in the present specification .

One aspect of the present invention is a compound represented by the following formula (1).

[Chemical Formula 1]

Here, n is 3, and R ₁ is each independently hydrogen, a methyl group, or an acetyl group.

Examples of the compound represented by the formula (1) include compounds represented by the following formulas (2) to (5), and the compound of the formula (2) is most excellent in the antioxidative and elastase inhibitory effects, . A detailed understanding of this may be made through the following embodiments.

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

The compound of formula (1)

Replacing the hydroxy group of the at least one phenolic acid compound selected from gallic acid or sialic acid with an acetyl protecting group;

Reacting the carboxylic acid moiety of the phenolic acid compound with a hydroxy group of? -Tocopherol; And

And optionally, degassing the acetyl protecting group.

Accordingly, R ₁ in the structure of the above formula (1) is determined according to the type of phenolic acid used in the synthesis (gallic acid or sialic acid).

That is, the present invention relates to a process for the preparation of 5 - (((2,5,7,8-tetramethyl-2- ( 4,8,12-trimethyltridecyl) chroman-6-yl) oxy) carbonyl) benzene-1,2,3-trityl triacetate; 2,5,7,8-tetramethyl-2- (4,8,12-trimethyltridecyl) chroman-6-yl-3,4,5-trihydroxybenzoate; 2, 5, 7, 8-tetramethyl-2- (4,8,12-trimethyltridecyl) chroman-6-yl 4-acetonyl-3,5-dimethoxybenzoate; To obtain a compound named 2,5,7,8-tetramethyl-2- (4,8,12-trimethyltridecyl) chroman-6-yl 4-hydroxy-3,5-dimethoxybenzoate And the overall scheme of the reaction will be understood from the scheme illustrated in Scheme 1 below.

[Reaction Scheme 1]

1) is a step of replacing a hydroxy group with a protecting group for the next reaction, 2) activating a carboxylic acid moiety of benzoic acid to react with? -Tocopherol to synthesize a binding compound, and 3) Followed by deprotecting with a hydroxy group to synthesize an? -Tocopherol derivative compound. The method of substituting a protecting group for a highly reactive hydroxyl group before the reaction and then degassing is obvious to those skilled in the art of organic synthesis, and therefore, a detailed description thereof will be omitted.

Since the method of the present invention uses gallic acid or syringic acid, which is a well-known natural product, the synthesized? -Tocopherol derivative compound is isolated by metabolism or decomposition However, there is an advantage that, even when unreacted materials remain, it is possible to provide a material having a safe and excellent antioxidative and anti-wrinkle activity.

Another aspect of the present invention is a cosmetic composition for improving antioxidant or skin wrinkles comprising the compound of the above-mentioned formulas (1) to (5d).

Here, 'antioxidant' refers to 'inhibiting or reducing oxidative stress', 'skin wrinkle improvement' refers to 'inhibiting or reducing wrinkling of skin, or alleviating already formed wrinkles' It says.

In particular, the present invention is not limited to the synthesis of the above-described tocopherol derivative compounds and the production method thereof, but also confirms the efficacy and effects of antioxidation and skin wrinkle improvement as cosmetic applications and completes them. Therefore, apart from the fact that the substance itself disclosed in the claims is a novel substance, great technical significance should be given to discovering its use as a cosmetic product such as antioxidation, skin wrinkle improvement and the like. A more detailed understanding of this may be made through the following examples and test examples.

The cosmetic composition of the present invention may be blended with other ingredients commonly used in cosmetics which are well known to those skilled in the art. Examples of such a blending component include a preservative component, a moisturizing agent, an emollient agent, a surfactant, an organic and inorganic pigment, an organic powder, an ultraviolet absorbent, a preservative, a bactericide, an antioxidant, a plant extract, a pH adjuster, , Blood circulation accelerators, cold agents, antiperspirants, purified water, vitamins (especially vitamin C, tocopherol, etc.).

The cosmetic composition of the present invention may take the form of a solution, an emulsion, a viscous mixture or the like, and may be prepared into any formulation conventionally produced in the art. For example, Emulsions, creams, lotions, packs, foundation, lotions, essences, and hair cosmetics.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples. It should be understood, however, that the following Examples and Test Examples are provided for the purpose of illustration only and are not intended to limit the scope of the present invention.

Example

Example  One

5 - (((2,5,7,8-tetramethyl-2- (4,8,12-trimethyltridecyl) chroman-6-yl) oxy) carbonyl) benzene- Method for producing til triacetate

Add 3, 4, 5-triacetylbenzoic acid (1.48 g) to a 100 ml flask, add dichloromethane (10 ml) and DME (0.1 ml) and stir at low temperature (5 degrees). Add oxalic chloride (0.7 ml) dropwise thereto. The mixture was stirred at room temperature for 6 hours, and the solution was concentrated under reduced pressure to obtain 3,4,5-triacetoxybenzoyl chloride.

Alpha-tocopherol (1.87 g), dichloromethane (10 ml) and triethylamine (0.8 ml) are placed in a 100 ml flask and stirred at low temperature (5 degrees). To this is added dropwise a solution of 3,4,5-triacetoxybenzoyl chloride obtained in the previous reaction in dichloromethane (10 ml). The mixture was stirred at room temperature for 5 hours and the reaction solution was concentrated under reduced pressure. The concentrated solution was dissolved in ethyl acetate (50 ml), and washed with water, a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and then separated by column chromatography to obtain 2.63 g (85%) of a yellow liquid.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.99 (s, 2H), 2.60-2.52 (m, 2H), 2.10 (s, 3H), 2.01 (s, 3H), 1.86 (s, 3H), 1.80-1.73 (m, 2H), 1.57-1.05 (m, 27H), 0.87-0.84 (m, 12H). _{^{13 C NMR (100MHz, CDCl 3}} ) δ 167.66, 166.46, 162.97, 149.61, 143.57, 140.38, 139.08, 127.84, 126.74, 125.02, 123.17, 122.78, 117.51, 75.12, 39.35, 37.52, 37.43, 37.38, 37.28, 32.76, 37.97, 24.82, 24.80, 24.44, 22.73, 22.63, 21.03, 20.59, 20.23, 19.75, 19.69, 19.66, 19.63, 19.60, 13.10, 12.26, 11.85. FT-IR (Neat) 2926 cm ^-1 , 1783 cm ^-1 , 1737 cm ^-1 , 1325 cm ^-1 , 1181 cm ^-1 , 1157 cm ^-1 , 1053 cm ^-1 ; MS (ESI): m / z = 731.41 [M + Na] < ⁺ >.

Example  2

Preparation of 2,5,7,8-tetramethyl-2- (4,8,12-trimethyltridecyl) chroman-6-yl-3,4,5-trihydroxybenzonate

((2,5,7,8-tetramethyl-2- (4,8,8-trimethyltridecyl) chroman-6-yl) oxy) carbonyl) benzene obtained in [Example 1] 1,2,3-Trityl triacetate (2.6 g) was dissolved in ethanol (7 ml) and hydrazine hydrate (0.8 ml) was added. The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate (50 ml) and washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine. The organic solution layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure and then purified by column chromatography to obtain 1.8 g (80%) of the target compound.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.41 (s, 2H), 6.08 (br, 3H), 2.62-2.59 (m, 2H), 2.04 (s, 3H), 1.99 (s, 3H), 1.87 (s , 3H), 1.85-1.74 (m, 2H), 1.63-1.08 (m, 27H), 1.01-0.84 (m, 12H). _{^{13 C NMR (100MHz, CDCl 3}} ) δ 166.25, 149.37, 143.65, 140.52, 137.06, 126.91, 125.15, 123.20, 120.61, 117.69, 117.69, 110.45, 110.00, 75.25, 39.54, 39.45, 39.35, 37.56, 37.38, 37.28, 32.77, 32.78, 27.97, 24.80, 24.45, 22.72, 22.63, 21.04, 20.58, 19.74, 29.68, 19.64, 19.61, 19.57, 12.97, 12.11, 11.82. FT-IR (Neat) 3345 cm ^-1 , 2926 cm ^-1 , 1461 cm ^-1 , 1376 cm ^-1 , 1345 cm ^-1 , 1313 cm ^-1 , 1216 cm ^-1 , 1094 cm ^-1 , 1033 cm ^-1 .; MS (ESI): m / z = 605.38 [M + Na] < ⁺ >.

Example  3

Preparation of 2, 5, 7, 8-tetramethyl-2- (4,8,12-trimethyltridecyl) chroman-6-yl 4-acetonyl-3,5-dimethoxybenzoate

4-Acetoxy 3, 5-dimethoxybenzoic acid (1.22 g) was added to a 100 ml flask, and dichloromethane (10 ml) and DMEF (0.1 ml) were added thereto, followed by stirring at low temperature (5 degrees). Add oxalic chloride (0.7 ml) dropwise thereto. The mixture was stirred at room temperature for 6 hours, and the solution was concentrated under reduced pressure to obtain 4-acetoxy-3,5-dimethoxybenzoyl chloride.

Alpha-tocopherol (1.87 g), dichloromethane (10 ml) and triethylamine (0.8 ml) are placed in a 100 ml flask and stirred at low temperature (5 degrees). A solution of 4-acetoxy-3, 5-dimethoxybenzoyl chloride obtained in the previous reaction in dichloromethane (10 ml) is added dropwise thereto. The mixture was stirred at room temperature for 5 hours and the reaction solution was concentrated under reduced pressure. The concentrated solution was dissolved in ethyl acetate (50 ml), and washed with water, a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and then separated by column chromatography to obtain 2.84 g (87%) of a yellow solid.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.53 (s, 2H), 3.91 (s, 6H), 2.68-2.58 (m, 2H), 2.38 (s, 3H), 2.13 (s, 3H), 2.06 (s , 3H), 2.02 (s, 3H), 1.90-1.73 (m, 2H), 1.53-1.08 (m, 24H), 0.88-0.84 (m, 12H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.32, 164.45, 152.20, 149.55, 140.52, 132.91, 127.56, 126.84, 125.08, 123.23, 117.59, 106.90, 106.69, 75.12, 56.46, 56.28, 39.37, 37.38, 37.41, 32.79, 32.71, 27.98, 24.82, 24.46, 22.79, 22.68, 22.58, 21.04, 20.65, 20.56, 19.71, 19.65, 13.17, 12.33, 11.95; FT-IR (Neat) 2924 cm ^-1 , 1770 cm ^-1 , 1730 cm ^-1 , 1503 cm ^-1 , 1344 cm ^-1 , 1172 cm ^-1 , 1130 cm ^-1 , 1099 cm ^-1 ; MS (ESI): m / z = 653.2 [M + H] < ⁺ >.

Example  4

Preparation of 2,5,7,8-tetramethyl-2- (4,8,12-trimethyltridecyl) chroman-6-yl 4-hydroxy-3,5-dimethoxybenzoate

2, 5,7,8-Tetramethyl-2- (4,8,12-trimethyltridecyl) chroman-6-yl 4-acetonyl-3,5-dimethoxybenzonate g) is dissolved in ethanol (7 ml) and hydrazine hydrate (0.8 ml) is added. The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate (50 ml) and washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure and then purified by column chromatography to obtain 2.0 g (80%) of the target product.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.53 (s, 2H), 6.03 (br, 1H), 3.98 (s, 6H), 2.64-2.60 (m, 2H), 2.12 (s, 3H), 2.07 (s , 3H), 2.02 (s, 3H), 1.86-1.77 (m, 2H), 1.63-1.08 (m, 24H), 0.88-0.84 (m, 12H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 164.92, 149.44, 146.76, 140.59, 139.65, 126.95, 125.17, 123.45, 117.51, 107.27, 107.05, 75.08, 60.40, 56.56, 56.39, 39.44, 39.37, 37.38, 32.78, 32.72, 27.98, 24.82, 34.45, 22.79, 22.68, 22.58, 21.04, 20.64, 19.71, 19.64, 13.16, 13.02, 12.31, 12.19, 22.94, 11.79. FT-IR (Neat) 3422 cm ^-1 , 2924 cm ^-1 , 1729 cm ^-1 , 1460 cm ^-1 , 1340 cm ^-1 , 1209 cm ^-1 , 1097 cm ^-1 , 1066 cm ^-1 ; MS (ESI): m / z = 611.2 [M + H] < ⁺ >.

[ Test Example  1]? - Tocopherol  Antioxidant effect of derivative compounds

Antioxidant activity of the? -Tocophenol derivative compounds described in the above examples was measured by DPPH radical scavenging activity, and ascorbic acid was used as a positive control.

The 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical required for the test was purchased from Sigma Chemical Co. L-ascorbic acid was used as a control in Sigma (USA).

100 μL of 0.2 mM DPPH solution dissolved in methanol and 100 μL of synthetic compound at various concentrations were dispensed into 96-well culture dishes, respectively, and incubated at room temperature for 10 min. The absorbance was measured at 517 nm.

The results are shown in Fig. 1 and the following Table 1. (Fig. 1 shows the relationship between the absorbance and the concentration of the compound in the measurement, and FSC ₅₀ (쨉 g / ml) to be).

Sample FSC ₅₀ ([mu] g / ml) Example 1 > 1000 Example 2 25.6 Example 3 > 1000 Example 4 > 1000 Ascorbic acid 10.0

As can be seen from FIG. 1, the activity of the compound of Example 2 was similar to that of ascorbic acid, which is a control group, although most of the compounds of the Examples showed less activity than that of ascorbic acid.

Therefore, the? -Tocopherol derivative compound according to the present invention has a strong antioxidant ability and has been shown to be useful for the treatment of diseases associated with active oxygen, that is, skin aging, wrinkle reduction, skin pigmentation inhibition, and the like.

[ Test Example  2] - Tocopherol  Wrinkle-improving effect of derivative compounds

Experiments were conducted on the effect of improving the wrinkles by measuring the elastase inhibitory activity of the elastin protease against the tocopherol derivative compounds described in the above Examples.

N- Succinyl-Ala-Ala-Ala- p -nitroanilide required for the test was obtained from Sigma Chemical Co. (USA).

100 μl of various concentrations of the synthetic compound, 60 μl of 0.2 M Tris buffer (pH 8.0), and 20 μl of 5 mM N- Succinyl-Ala-Ala-Ala- p- nitroanilide are dispensed into a 96-well culture vessel. Subsequently, 20 μl of the enzyme, 10 μg / ml Elastase, was added and reacted at room temperature for 15 min. The amount of p- nitroaniline produced was measured at 410 nm.

The results were as shown in Fig. 2 and Table 2 (Table 2 shows IC ₅₀ (占 퐂 / ml) calculated based on the result of Fig. 2).

Sample IC ₅₀ ([mu] g / ml) Example 1 > 1000 Example 2 68.6 Example 3 > 1000 Example 4 > 2000

As can be seen from FIG. 2, the compounds of Examples 1, 2 and 3 showed an increase in activity in a concentration-dependent manner, and the compound of Example 2 showed the highest inhibition of elastase activity. Therefore, the alpha -tocopherol derivative compound obtained through the present invention can be expected to have an effect of improving wrinkles.

Claims (8)

A compound represented by the following formula (1).
[Chemical Formula 1]

Here, n is 3, and R ₁ is each independently hydrogen, a methyl group, or an acetyl group. A compound represented by the following formula (2).
(2)

A compound represented by the following formula (3).
(3)

A compound represented by the following formula (4).
[Chemical Formula 4]

A compound represented by the following formula (5).
[Chemical Formula 5]

Replacing the hydroxy group of the at least one phenolic acid compound selected from gallic acid or sialic acid with an acetyl protecting group;
Reacting the carboxylic acid moiety of the phenolic acid compound with a hydroxy group of? -Tocopherol; And
Optionally degassing the acetyl protecting group. ≪ RTI ID = 0.0 > 11. < / RTI > An antioxidant cosmetic composition characterized by comprising a compound according to any one of claims 1 to 5. A cosmetic composition for improving skin wrinkles comprising the compound of any one of claims 1 to 3.

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