KR100506423B1 - Novel benzoic acid derivatives, preparation method thereof and whitening cosmetic composition containing same - Google Patents

Abstract

The present invention relates to a novel benzoic acid derivative represented by the following general formula (I), a preparation method thereof, and a cosmetic composition containing the same, wherein the benzoic acid derivative of the following general formula (I) and a cosmetic composition containing the same inhibit the production of melanin pigment in the skin. This can prevent blackening and blemishes of the skin.

Formula (I)

Description

Novel benzoic acid derivatives, preparation method thereof and whitening cosmetic composition containing same

The present invention relates to a novel benzoic acid derivative represented by the following general formula (I), and more particularly to a benzoic acid derivative in which an unsaturated alkyl group is substituted at the ortho position, a preparation method thereof, and a cosmetic composition containing the same.

In the formula, R represents an unsaturated alkyl group having 6 to 20 carbon atoms including at least one double bond, wherein the double bond is cis type.

It is everyone's constant desire to have white, fair skin. Human skin color is genetically determined by the concentration and distribution of melanin in the skin, but is also influenced by environmental or physiological conditions such as solar ultraviolet rays, fatigue and stress. Recently, in the cosmetics industry, skin whitening agents have been of interest, and such skin whitening agents suppress excessive production of melanin, which occurs according to environmental or physiological conditions such as sun ultraviolet rays, fatigue, stress, etc. It is to suppress the occurrence of and to maintain the white skin.

Recently, Hideya Ando et al. Reported that unsaturated fatty acids inhibit melanin production in B-16 mouse melanoma cells (Fragrance Journal, 1995, pp. 145-150). This suggests the possibility that these unsaturated fatty acids can be used as skin whitening agents.

Accordingly, the present inventors found that melanin in a mouse melanoma cell (B-16 mouse melanoma cell) in which a substance substituted with an unsaturated alkyl group of an unsaturated fatty acid to benzoic acid in the course of examining the structural transformants of the unsaturated fatty acid was cultured than an unsaturated fatty acid. The present invention has been found to have a high production inhibitory effect. Accordingly, an object of the present invention is to provide a novel benzoic acid derivative, a method for preparing the same, and a whitening cosmetic composition containing the same, which can prevent melanin pigmentation of the skin and prevent blackening and blemishes of the skin.

The present invention provides a whitening cosmetic composition comprising the benzoic acid derivative having the unsaturated alkyl group substituted at the ortho position and the benzoic acid derivative as shown in the following general formula (I).

Formula (I)

(Wherein R represents an unsaturated alkyl group having 6 to 20 carbon atoms containing at least one double bond, wherein the double bond is of cis type).

In addition, the present invention is obtained by reacting a compound of the general formula (III) with magnesium to obtain an organic magnesium intermediate, and then adding it to a mixed solution of the compound of the general formula (II) and a catalyst of the general formula (IV) The present invention provides a process for preparing the benzoic acid derivative of formula (I), wherein the compound of formula (IV) is reacted with a metal and then reacted with carbon dioxide.

Formula (II)

General formula (III)

General formula (IV)

In which R is as described above.

Hereinafter, the present invention will be described in detail.

The novel benzoic acid derivatives of the present invention are those in which an unsaturated alkyl group is substituted at the ortho position of benzoic acid and has the same structure as in general formula (I). Wherein R represents an unsaturated alkyl group having 6 to 20 carbon atoms including at least one cis-type double bond, preferably CH ₃ (CH ₂ ) ₇ CH = CH (CH ₂ ) ₇ CH _2- (double bond is oleyl group represented by cis type, and linoleyl represented by CH ₃ (CH ₂ ) ₄ CH = CHCH ₂ CH = CH (CH ₂ ) ₇ CH ₂ − (double bond is cis type) Linoleyl) or CH ₃ (CH ₂ ) ₅ CH = CH (CH ₂ ) ₇ CH _2- (double bond is cis type) is a Palmitoleyl (Palmitoleyl) group.

In order to prepare the benzoic acid derivative, first, the compound of formula (III) is reacted with magnesium for 30 minutes to 2 hours to obtain an organic magnesium intermediate (BrMg-R), and then the compound of formula (II) It is added to the mixed solution of the catalyst and stirred for 1 to 12 hours to obtain a compound of formula (IV). Tetrahydrofuran, 1, 4-dioxane, diethyl ether and the like may be used as the solvent used in the reaction, but tetrahydrofuran is most preferably used, and Li ₂ CuCl ₄ , CuI, Preference is given to using at least one copper compound selected from CuCl. The compound of formula (IV) thus obtained is charged to the next reaction in a purified or unpurified state.

Next, the compound of general formula (IV) is reacted with a metal such as magnesium or lithium (including a metal compound such as alkyl lithium) for 30 minutes to 2 hours to replace the bromine radical with a metal such as magnesium or lithium. After cooling the mixture, carbon dioxide was added and stirred for 2 minutes to 2 hours to prepare a benzoic acid derivative of formula (I). Tetrahydrofuran, 1, 4-dioxane, diethyl ether and the like may be used as the solvent used in the reaction, but tetrahydrofuran is most preferably used. In addition, the reactions can be carried out in a temperature range up to the boiling point of the solvent used at -78 ℃, in particular when the solid carbon dioxide is added to maintain the mixture at -78 ℃, then raising the temperature to the boiling point of the solvent It is preferable to make it react. In addition, the time required for the reaction is set to properly indicate the yield and efficiency of the reaction, and in general, if the reaction time is less than the time, the reaction does not proceed completely, and the reaction yield is no longer improved even after the time. Do not. In the above reaction, as the compound of general formula (II) and general formula (III), not only a bromine substituent, but also a halogen substituent such as chlorine or iodine may be used, but in the case of a chlorine substituent, the reactivity is inferior, and the iodine substituent is a substituent It has its own drawbacks.

The benzoic acid derivatives of general formula (I) thus synthesized are mixed with conventional cosmetic carriers to prepare cosmetics such as cosmetic creams, soft cosmetics, essences, cosmetic packs and nourishing cosmetics, or to prepare external skin ointments. As the cosmetic carrier, diethyl sebacate, stearic acid, glycerin, etc. which are commonly used may be used, but are not limited thereto.

At this time, the content of the benzoic acid derivative in the cosmetic or skin ointment is 0.001 to 10% by weight, the amount of the remaining components such as cosmetic carrier is preferably from 90 to 99.9% by weight, if the content is less than 0.001% by weight of the skin whitening effect Is not sufficiently exhibited, and if it is 10% by weight or more, the skin whitening effect is not increased as much as the excess benzoic acid derivative is used, and the other cosmetic effects of the cosmetic are lowered.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated concretely based on an Example. However, these examples are intended to help the understanding of the present invention, the present invention is not limited thereto.

Example 1

Oleyl bromide (3.0 g) and magnesium (1.0 g) were added to tetrahydrofuran (40 ml) and refluxed for 1 hour. After the mixture was cooled to room temperature, it was added to a mixed solution of 2-bromo benzyl bromide (1.5 g), Li ₂ CuCl ₄ (0.O5 g), and tetrahydrofuran (40 mL), cooled to 0 ° C., at room temperature. Stir for 10 hours. Distilled water (50ml) was added, tetrahydrofuran was removed under reduced pressure, extracted with methylene chloride (50ml), washed with saturated brine, dehydrated with anhydrous forget-me-not and the solvent was removed under reduced pressure. Tetrahydrofuran (40 ml) was added thereto, magnesium (1.0 g) was added thereto, and the mixture was refluxed for 1 hour. After cooling the mixture to -78 ° C, solid carbon dioxide (dry ice, 2.0 g) was added thereto and stirred for 1 hour. Distilled water (40 ml) was added, tetrahydrofuran was removed under reduced pressure, extracted with methylene chloride (40 ml), washed with saturated brine, dehydrated with anhydrous forget-me-not and the solvent was removed under reduced pressure. Separation and purification by column chromatography Crude acid (formula (V) 1.5g (yield: 64%) was obtained and FIG. 1 shows an NMR chart of the compound of formula (V)).

Structural Formula (V)

Example 2

Linoleyl bromide (3.0 g) and magnesium (1.0 g) were added to tetrahydrofuran (40 ml) and refluxed for 1 hour. After the mixture was cooled to room temperature, it was added to a mixed solution of 2-bromo benzyl bromide (1.5 g), Li ₂ CuCl ₄ (0.O5 g), and tetrahydrofuran (40 mL), cooled to 0 ° C., at room temperature. Stir for 10 hours. Distilled water (50 ml) was added, tetrahydrofuran was removed under reduced pressure, extracted with methylene chloride (50 ml), washed with saturated brine, dehydrated with anhydrous forget-me-not and the solvent was removed under reduced pressure. Tetrahydrofuran (40 ml) was added thereto, magnesium (1.0 g) was added thereto, and the mixture was refluxed for 1 hour. After cooling the mixture to -78 ° C, solid carbon dioxide (dry ice, 2.0 g) was added thereto and stirred for 1 hour. Distilled water (40 ml) was added, tetrahydrofuran was removed under reduced pressure, extracted with methylene chloride (40 ml), washed with saturated brine, dehydrated with anhydrous forget-me-not and the solvent was removed under reduced pressure. Separation and purification by column chromatography 1.6 g (yield: 70%) were obtained, and an NMR chart of the compound of formula VI was shown in FIG. 2.

Structural Formula (VI)

Example 3

Palmitoleyl bromide (3.5 g) and magnesium (1.0 g) were added to tetrahydrofuran (40 ml) and refluxed for 1 hour. The mixture was cooled to room temperature, and then added to a mixture of 2-bromo benzyl bromide (1.5 g), Li ₂ CuCl ₄ (O ₅ g) and tetrahydrofuran (4O ml) cooled to 0 ° C., at room temperature for 10 hours. Stir. Distilled water (50ml) was added, tetrahydrofuran was removed under reduced pressure, extracted with methylene chloride (50ml), washed with saturated brine, dehydrated with anhydrous forget-me-not and the solvent was removed under reduced pressure. Tetrahydrofuran (40 ml) was added thereto, magnesium (1.0 g) was added thereto, and the mixture was refluxed for 1 hour. After cooling the mixture to -78 ° C, solid carbon dioxide (dry ice, 2.0 g) was added thereto and stirred for 1 hour. Distilled water (40 ml) was added, tetrahydrofuran was removed under reduced pressure, extracted with methylene chloride (40 ml), washed with saturated brine, dehydrated with anhydrous forget-me-not and the solvent was removed under reduced pressure. Separation and purification by column chromatography 1.6g (yield: 74%) was obtained.

Structural Formula (VII)

Experimental Example 1

The compound obtained in Examples 1 to 3 was added to the culture medium of B16 mouse melanoma cells to test the whitening effect at the cellular level (Lotan R., Lotan D. Cancer Res. 40: 3345-). 3350, 1980). The compounds obtained in Examples 1 to 3, oleic acid, linoleic acid, and hydroquinone were added to the culture medium of the rat melanoma (B16 melanoma cell) cells, and then cultured for 3 days, and the cells were trypsinized to separate them from the culture vessel. Melanin was extracted after centrifugation. To this, 1 ml of sodium hydroxide solution (1N concentration) was added, boiled for 10 minutes to dissolve melanin, and the absorbance was measured at 400 nanometers (nm) using a spectrophotometer to determine the amount of melanin produced per unit cell number (10 ⁶ cells). It was carried out by the method shown as, the relative melanin production relative to the control was calculated as the inhibition rate (%) and the results are shown in Table 1.

TABLE 1 Examples 1 to 3, melanin production inhibitory effect at the cellular level of oleic acid, linoleic acid and hydroquinone (number of experiments repeated = 3)

From the above results, it can be seen that the compounds of Examples 1 to 3 have a significantly greater whitening effect at the cellular level compared to the control, oleic acid and linoleic acid.

[Production Example 1] and [Comparative Example 1]

Examples of prescription external skin ointments containing the compound of Example 1 are as follows.

[Production Example 2] and [Comparative Example 2]

The prescription example of the cream in the cosmetics containing the compound of Example 1 is as follows.

[Production Example 3] and [Comparative Example 3]

The prescription example of the flexible cosmetics in the cosmetics containing the compound of Example 2 is as follows.

[Production Example 4] and [Comparative Example 4]

Prescription examples of essences in the cosmetics containing the compound of Example 2 are as follows.

Production Example 5 and Comparative Example 5

The prescription example of the pack in the cosmetics containing the compound of Example 2 is as follows.

Production Example 6 and Comparative Example 6

The prescription example of the nutrient cosmetics in the cosmetics containing the compound of Example 3 is as follows.

Experimental Example 2

20 healthy males and females were placed in the lower arm of each arm with 6 holes of 7mm diameter in two rows of aluminum foil, and 60mJ / cm ² light was irradiated using ORIEL solar simulator l00OW at a distance of 10cm from the arm. . The irradiation site was washed well with 70% ethanol aqueous solution before irradiation. The bases prepared according to Preparation Example 1-6 and Comparative Example 1-6 were applied twice a day from 3 days before irradiation to 3 weeks after irradiation, in pairs on the same line. (In the case of the pack formulations of Production Example 5 and Comparative Example 5, after the application, 15 minutes after peeling off), the pigmentation degree of the Preparation Example and Comparative Example was visually determined for each, and the Production Example suppressed the pigmentation compared with the Comparative Example. One degree was evaluated in three stages of distinct effects, effects, and no difference, and the results are shown in Table 2.

TABLE 2 Pigmentation inhibitory effect of ointments and cosmetics containing the compound of the present invention

From the results in Table 2 above, ointments and cosmetics containing the compound of the present invention prepared according to Preparation Example 1-6 showed a whitening effect on at least 10 or more of 20 subjects, in particular a large amount of compounds In the comparative experiments of Preparation Example 1 and Comparative Example 1, 35% showed a marked pigmentation inhibitory effect, and no side effects appeared in the skin, so that the compound of the present invention was safe and very effective in improving blemishes or freckles or skin. It can be seen that it is a whitening agent.

therefore. The novel benzoic acid derivatives of the present invention and the whitening cosmetic composition containing the same can prevent the skin blackening, blemishes and the like by inhibiting the production of melanin pigmentation of the skin.

1 is prepared according to the first embodiment of the present invention NMR chart of.

2 is prepared according to a second embodiment of the present invention

Claims (8)

Benzoic acid derivative represented by the following general formula (I). Formula (I) (Wherein R represents an unsaturated alkyl group having 6 to 20 carbon atoms containing at least one double bond, wherein the double bond is of cis type). The compound of claim 1, wherein R is CH ₃ (CH ₂ ) ₇ CH═CH (CH ₂ ) ₇ CH ₂ − (double bond is of cis type) or CH ₃ (CH ₂ ) ₄ CH═CHCH ₂ CH═CH (CH ₂ ) Benzoic acid derivatives with ₇ CH _2- (double bond is cis type) The compound of formula (III) was reacted with magnesium to obtain an organic magnesium intermediate, which was then added to a mixed solution of the compound of formula (II) and a catalyst to obtain a compound of formula (IV). A process for preparing the benzoic acid derivative of the general formula (I), wherein the compound of formula (IV) is reacted with a metal or a metal compound and then reacted with carbon dioxide. Formula (II) General formula (III) Br-R General formula (IV) (Wherein R represents an unsaturated alkyl group having 6 to 20 carbon atoms containing at least one double bond, wherein the double bond is of cis type). The method of claim 3, wherein the reaction is carried out in a solvent selected from the group consisting of tetrahydrofuran, 1, 4-dioxane and diethyl ether. The method of claim 3, wherein the catalyst is selected from the group consisting of Li ₂ CuCl ₄ , CuI, CuCl, and mixtures thereof. The method of claim 3, wherein the metal is magnesium or lithium. The reaction of claim 3, wherein the reaction of obtaining the organic magnesium intermediate is performed for 30 minutes to 2 hours, and the reaction for preparing the compound of Formula (IV) is performed for 1 to 12 hours, and the metal and the general formula The reaction with the compound of (IV) proceeds for 30 minutes to 2 hours, the addition of carbon dioxide proceeds for 2 minutes to 2 hours, and the reactions are carried out at −78 ° C. to the boiling point of the solvent of the reactions. Method for producing a benzoic acid derivative, characterized in that carried out in. A whitening cosmetic composition comprising 0.001 to 10% by weight of the benzoic acid derivative of claim 1 or 2 as an active ingredient and 90 to 99.999% by weight of a cosmetic carrier.