KR100643514B1 - Hydroxybenzoic acid amide compound and the method for preparing thereof and the whitening cosmetic composition containing the same - Google Patents

Abstract

Provided are a hydroxybenzoic acid amide compound which suppresses the generation of melanin, its preparation method, and a whitening cosmetic composition containing the compound. The hydroxybenzoic acid amide compound is represented by the formula 1, wherein R1 and R2 are H or OH. The method comprises the steps of dissolving hydroxybenzoic acid in a solvent, adding a catalyst and a base drop by drop, and reacting it with acetic anhydride to prepare an acetylated compound represented by the formula II; dissolving the acetylated compound of the formula II in a solvent and adding a base, ethyl chloroformate and adamantamine to prepare an amide compound represented by the formula III; and reacting the amine compound of the formula III with a base to hydrolyze it (See the reaction scheme 1), wherein R3 and R4 is H or an acetoxy group.

Description

Hydroxybenzoic acid amide compound and preparation method thereof, and whitening cosmetic composition containing the same {Hydroxybenzoic acid amide compound and the method for preparing honey and the whitening cosmetic composition containing the same}

The present invention relates to a hydroxybenzoic acid adamantamine amide compound represented by the following Chemical Formula 1, a preparation method thereof, and a whitening cosmetic composition comprising the same as an active ingredient, and more specifically, has an effect of inhibiting melanin production by an antioxidant action. The present invention relates to a hydroxybenzoic acid adamantamine amide compound represented by the following Chemical Formula 1, and a preparation method thereof, and a whitening cosmetic composition prepared by improving the pigmentation of the skin by containing the same as an active ingredient so as to have excellent whitening efficacy.

Where

R ₁ and R ₂ are hydrogen or hydroxy.

Human skin color is determined by red blood cells, carotene, and melanin in the blood, but differences in race color, hyperpigmentation such as blemishes and freckles are caused by melanin. Melanin in the outer skin layer, which is the outer skin of the skin, protects the skin organs under the dermis by blocking UV rays, and also holds free radicals generated in the skin, and protects proteins and genes in the skin. Do it. However, melanin, produced by internal and external stress stimuli, is a stable substance that does not disappear until it is released to the outside through skin keratinization even when the stress disappears.

In addition, the production of free radicals in the skin is increased or inflammation due to a polymerization oxidation process using an enzyme such as Tyrosinase as a substrate using Tyrosine or DOPA in vivo. When there is a reaction or under ultraviolet light, melanin production is increased. In particular, ultraviolet rays may increase the production of melanin, causing melanin, which is partially increased, to develop blemishes, resulting in undesired results, or even worse, inducing skin cancer.

For these reasons, many melanogenesis inhibitors such as ointments, creams, and lotions containing kojic acid, arbutin, glutathione, vitamin A and vitamin C, etc. are currently being developed, but there is no whitening product with a satisfactory whitening effect. to be.

In addition, the whitening agent containing hydroquinone has a certain whitening effect, but its use is very limited due to severe skin irritation.

Accordingly, the present inventors intensively studied the hydroxybenzoic acid amide compound in order to solve the problem of the whitening agent, and as a result, various amide compounds were synthesized based on hydroxybenzoic acid in the form of polyphenols known as antioxidants. The amide compound containing the tamamine group was found to have a very good melanin production inhibitory effect and to complete the present invention.

It is therefore an object of the present invention to provide a hydroxybenzoic acid adamantamine amide compound having an inhibitory effect on melanin production by an antioxidant action and a method of producing the same.

Furthermore, another object of the present invention is to provide a cosmetic composition for whitening containing a hydroxybenzoic acid amide compound represented by Chemical Formula 1 as an active ingredient.

The present invention provides a hydroxybenzoic acid adamantamine amide compound represented by the following Chemical Formula 1 and a preparation method thereof:

[Formula 1]

Where

R ₁ and R ₂ are hydrogen or hydroxy.

The hydroxybenzoic acid adamantamine amide compound according to the present invention has an excellent melanin inhibitory effect due to the lipophilic properties of adamantamine.

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

Method for producing a hydroxybenzoic acid amide compound according to the present invention,

(A) dissolving hydroxybenzoic acid in a solvent, followed by dropwise addition of a catalyst and a base, followed by reaction with acetic anhydride to produce an acetylated compound;

(B) dissolving the acetylated compound produced in the step (A) in a solvent and then adding a base, ethylchloroformate and adamantamine to prepare an amide; And

(C) hydrolyzing the acetyl group of the amide compound prepared in step (B);

Scheme 1, characterized in that it comprises a:

Where

R ₁ and R ₂ are hydrogen or hydroxy,

R ₃ and R ₄ are hydrogen or acetoxy.

The preparation method of the hydroxybenzoic acid amide compound according to the present invention shown in Scheme 1 will be described in more detail as follows:

(A) dissolving hydroxybenzoic acid in a solvent, followed by dropwise addition of a catalyst and a base, followed by reaction with acetic anhydride to prepare an acetylated compound represented by formula (II):

Examples of the solvent used in the above step include dichloromethane, chloroform and tetrahydrofuran, and the base may include pyridine and triethylamine.

In addition, the compound must be prepared using dimethylaminopyridine as a catalyst in the reaction, otherwise the progress of the reaction is difficult and the yield is low. The reaction temperature may be performed at about 10-80 ° C., but 40 ° C. is most preferred.

(B) dissolving the acetylated compound produced in the step (A) in a solvent and then adding a base, ethylchloroformate and adamantamine to prepare an amide represented by the formula (III):

As the method for preparing the amide compound of formula (III) in this step, all of the acid halide, the active ester method and the acid anhydride method can be used, but the method of substituting an anhydride using ethylchloroformate Most preferred, wherein the amide compound of formula III is prepared by substitution with 1-adamantamine. As for the equivalence ratio of 1-adamantamine which reacts with compound (II), 1.1-1.3 is preferable. If the equivalent ratio is less than 1: 1, the amount of the desired product is small.

Examples of the base used in the above step include pyridine and triethylamine, but triethylamine is preferably used. In addition, the reaction solvent used in the step may include dichloromethane, acetone, N, N- dimethylformamide, acetonitrile and tetrahydrofuran, but using N, N-dimethylformamide and tetrahydrofuran desirable. Meanwhile, the reaction temperature may be performed at about 10-60 ° C., but 30 ° C. is most preferred.

(C) hydrolyzing the compound of the formula (III) obtained in the step (B) with a base:

Examples of the base used in the above step include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. In addition, the reaction solvent used in the above step may include water, methanol, ethanol, propanol, tetrahydrofuran and dichloromethane, but using a mixture of tetrahydrofuran and methanol may complete the reaction in the fastest time. . The ratio of methanol and tetrahydrofuran is suitably in a weight ratio of about 1: 1 to 1: 5, and most preferably used in a 1: 1 weight ratio.

Specific examples of the hydroxybenzoic acid amide compound of the general formula (I) obtained by the above production method are as follows:

N-adamantyl-1-yl-3-hydroxy-benzamide

N-adamantyl-1-yl-4-hydroxy-benzamide

N-adamantyl-1-yl-3,4-dihydroxy-benzamide

The hydroxybenzoic acid amide compound (I) of the present invention prepared by the above process may be contained as an active ingredient of the whitening cosmetic composition, the content of which is effective to achieve a whitening action, for example, the total weight of the composition. It may be contained in an amount of 0.01-20.0% by weight, and may have various non-limiting formulations such as creams, lotions, lotions, massage creams or essences.

The compositions of the present invention may also include other conventional ingredients depending on their formulations, and the types and amounts of these conventional ingredients are well known to those skilled in the art. The composition of the present invention may further contain other existing whitening components in addition to the hydroxybenzoic acid amide compound (I) described above for its whitening action, and the type and content of these existing whitening components can be easily selected by those skilled in the art. Can be used.

Hereinafter, the preparation method of the hydroxybenzoic acid adamantamine amide compound according to the present invention will be described in more detail. However, these examples are intended to illustrate the invention, it is apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

Example 1 N-adamantyl-1-yl-4-hydroxy-benzamide

4-hydroxybenzoic acid (100 g, 0.65 mol) was dissolved in 1000 ml of dichloromethane, dimethylaminopyridine (4 g, 0.03 mol) was added thereto, refluxed for 5 minutes, and triethylamine (199 ml, 1.43 mol) was added dropwise. Acetic anhydride (135 ml, 1.43 mol) was slowly added dropwise thereto and refluxed at a reaction temperature of 40 ° C. for 2 hours. After the reaction was completed, dichloromethane (1000ml) was added dropwise to the reaction solution, diluted with 1000ml of water, washed with 500ml of 1M HCl solution, dried over anhydrous manganese (100g), filtered and concentrated to hexane. It was crystallized with and filtered to give 129 g (yield = 83%) of a compound.

The compound (100 g, 0.42 mol) was dissolved in tetrahydrofuran (1500 ml), triethylamine (76.1 ml, 0.55 mol) was added dropwise, and 1.3 equivalent of ethylchloroformate (52.2 ml, 0.55 mol) was slowly added thereto. After adding dropwise, the mixture was stirred for 30 minutes, and 1-adamantamine (94.6g, 0.50mol) and triethylamine (84.3ml, 0.60ml) were dissolved in 1500ml of N, N-dimethylformamide, and slowly added dropwise. After further stirring for 3 hours. After completion of the reaction, the mixture was filtered, the reaction solution was concentrated, dissolved in 1500 ml of dichloromethane, washed again with distilled water (500 ml), washed with 500 ml of saturated sodium hydrogen carbonate, dried over anhydrous manganese (100 g), filtered and concentrated. Crystallized with hexane and filtered to give 107 g (yield = 88%) of a compound.

The compound (100 g, 0.27 mol) was dissolved in 1500 ml of tetrahydrofuran and methanol (1: 1), 15% potassium hydroxide was added, 100 ml of the mixture was stirred for 30 minutes. After completion of the reaction, neutralize by adding acid, concentrate the reaction solution, add 1500 ml of ethyl acetate, dissolve, wash with 1000 ml of water, filter, concentrate, crystallize with hexane, and then filter and 70 g (yield = 91%) of the target product. Obtained as a pale yellow solid.

TLC (ethyl acetate: hexane = 1: 1) R _f = 0.70

¹ H NMR (DMSO-d ₆ , δ): 9.13 (s, OH, 1H), 7.78 (d, Ar, 2H), 7.19 (s, NH, 1H), 7.02 (d, Ar, 2H) 1.97 (m , 9H), 1.50 (m, 6H).

Example 2 N-adamantyl-1-yl-3-hydroxy-benzamide

Using the same method as in Example 1, except that 3-hydroxybenzoic acid was used instead of 4-hydroxybenzoic acid, 70 g (84% yield) of the target material was obtained as a pale yellow solid.

TLC (ethyl acetate: hexane = 1: 1) R _f = 0.69

¹ H NMR (DMSO-d ₆ , δ): 9.10 (s, OH, 1H), 7.51 (d, Ar, 1H), 7.42 (s, Ar, 1H), 7.21 (m, Ar, 1H), 7.06 ( s, NH, 1H), 6.98 (d, Ar, 1H), 1.96 (m, 9H), 1.52 (m, 6H).

Example 3 N-adamantyl-1-yl-3,4-dihydroxy-benzamide

Using the same method as in Example 1, except that 3,4-dihydroxybenzoic acid was used instead of 4-hydroxybenzoic acid, 70 g (84% yield) of the target material was obtained as a pale yellow solid.

TLC (ethyl acetate: hexane = 1: 1) R _f = 0.57

m. p. 211-212 ℃

¹ H NMR (DMSO-d ₆ , δ): 9.27 (s, OH, 1H), 8.98 (s, OH, 1H), 7.14 (s, NH, 1H), 7.12 (s, Ar, 1H), 7.05 ( d, 1H), 6.62 (d, 1H), 1.96 (m, 9H), 1.57 (m, 6H).

[Test Example 1] melanin production inhibitory effect on melanin pigment producing cells

The effect of inhibiting melanogenesis in cells by the compound prepared in Examples 1-3 was measured by Dooley's method. The cell line was a Mel-Ab cell line derived from C57BL / 6 skin pigment cells. The cell line was 37 ° C., 5% in DMEM medium containing 10% fetal placental serum, 100 nM 12-O-tetradecanoyl Phorbol-13-acetate, 1 nM Cholera Toxin. Incubated under the conditions of CO ₂ . Cultured Mel-Ab cells were detached with 0.25% Trypsin-EDTA, plated on a 24-well plate again with the same number (1 × 10 ⁵ cells / well), and continued for three days from the second day. 10 ppm of the compounds prepared in Examples 1-3, hydroquinone, kojic acid, 4-hydroxybenzoic acid, 3-hydroxybenzoic acid and 3,4-dihydroxybenzoic acid, respectively, were replaced with a medium. After 5 days was treated with 1N NaOH to melt the melanin contained in the cell was measured by measuring the absorbance at 400nm, the results are shown in Table 1 below.

Inhibitory Effect of Hydroxybenzoic Acid Adamantamine Amide Derivatives Test substance Melanin production rate (% control) Hydroquinone 11.46 Kojisan 88.0 4-hydroxybenzoic acid 85.1 3-hydroxybenzoic acid 89.20 3,4-dihydroxybenzoic acid 90.10 Example 1 50.00 Example 2 48.71 Example 3 17.67

Hydroquinone and kojic acid were used as a positive control group, and melanin production inhibitory power was measured by comparing the parent compound hydroxybenzoic acid with Examples 1-3. In the case of the compounds of Examples 1 to 3, the melanin production inhibitory effect was similar to that of hydroquinone. However, the parental hydroxybenzoic acid showed little effect on inhibiting melanogenesis. This result shows that the adamantamine used in the intermediate step in the preparation of the compound of Example 1-3 plays an important role in showing melanin production inhibitory effect.

Test Example 2 Whitening Effect Test on Human Skin

Twelve healthy men were attached with an opaque tape with a 1.5cm diameter hole on the subject's upper arm and irradiated with UVB (1.5-2 times the minimum erythema of each subject) to induce skin blackening. It was. Solution containing 2% of the compound of Example 1-3 after UV irradiation (solvent is 1,3 butylene glycol: ethanol = 7: 3), as a control, hydroquinone, lipoic acid 2%, and solvent for 10 weeks After applying it (leave one without any), the color of the skin was measured with a colorimeter (Colorimeter CR-300, Minolta, Japan) on a weekly basis, and the degree of increase of the "L" value ("ΔL") was applied. ), And the results are shown in Table 2 below. The evaluation method judged that the higher the numerical value of the improvement of pigmentation after use, the higher the relative whitening effect was.

Whitening Effect of Hydroxybenzoic Acid Adamantamine Amide Derivatives on Human Skin Test substance Skin color brightness degree (ΔL) Solvent -6.0 Hydroquinone -1.9 Kojisan -3.0 Example 1 -1.1 Example 2 -2.5 Example 3 -2.0

From the results in Table 2, it was confirmed that the compounds of Examples 1 to 3 exhibit a whitening effect on human skin at a level similar to hydroquinone.

[Prescription Example 1]

A nutritious cream containing the compound of Example 1 was prepared according to the following composition.

ingredient Content (% by weight) Stearic acid palmitic acid myristic acid laurate potassium hydroxide glycerin Compound of Example 1 10 5 15 6 6 15 0.5

Preservatives, nonionic surfactants, pigments and flavors were added thereto, and the remaining amount was filled with purified water.

[Prescription 2]

A nutritious cream containing the compound of Example 2 was prepared according to the following composition.

ingredient Content (% by weight) Stearic Acid Glyceryl Mono Stearate Cetostearyl Alcohol Squalane Macadamia Nut Silicone Oil Polysorbate-60 Glycerin Compound of Example 2 2 3 3 20 10 3 2.5 10 0.5

Preservatives, nonionic surfactants, pigments and flavors were added thereto, and the remaining amount was filled with purified water.

As described above, the hydroxybenzoic acid adamantamine amide compound according to the present invention was excellent in inhibiting melanin production, and the cosmetic composition containing the same may be realized as an effective whitening product by improving pigmentation of the skin. have.

Claims (7)

Hydroxybenzoic acid amide compound represented by the following formula (1): [Formula 1]

Where R ₁ and R ₂ are hydrogen or hydroxy. As a method for producing a hydroxybenzoic acid amide compound shown in Scheme 1 below, (A) dissolving hydroxybenzoic acid in a solvent, followed by dropwise addition of a catalyst and a base, followed by reaction with acetic anhydride to prepare an acetylated compound represented by formula (II): (B) dissolving the acetylated compound produced in step (A) in a solvent, and then adding a base, ethylchloroformate and adamantamine to prepare an amide represented by the formula (III): And (C) hydrolyzing the compound of formula (III) obtained in the step (B) with a base; Method for producing a hydroxybenzoic acid amide compound comprising: Scheme 1

Where R ₁ and R ₂ are hydrogen or hydroxy, R ₃ and R ₄ are hydrogen or acetoxy. The method of claim 2, wherein the reaction solvent used in step (A) is at least one selected from the group consisting of dichloromethane, chloroform and tetrahydrofuran, The catalyst is dimethylaminopyridine, Wherein said base is pyridine or triethylamine. The method of claim 2, wherein the solvent used in the step (B) is at least one selected from the group consisting of dichloromethane, acetone, N, N-dimethylformamide, acetonitrile and tetrahydrofuran, Wherein said base is pyridine or triethylamine. The method according to claim 2, wherein the equivalent ratio of 1-adamantamine reacted with compound (II) in the step (B) is 1.1-1.3. The method of claim 2, wherein the solvent used in step (C) is at least one selected from the group consisting of water, methanol, ethanol, propanol, tetrahydrofuran and dichloromethane, The base is characterized in that the sodium hydroxide or potassium hydroxide. Whitening cosmetic composition containing the hydroxybenzoic acid amide compound of Claim 1 as an active ingredient.