KR102048982B1 - Idebenone derivative compound and cosmetic composition comprising the same - Google Patents

Abstract

The present invention relates to an idebenone derivative compound having a whitening effect, an antioxidant effect and an anti-inflammatory effect, and a composition for whitening skin and a cosmetic composition comprising the compound or a pharmaceutically acceptable salt thereof.

Description

Idebenone derivative compound and cosmetic composition comprising the same

The present invention relates to an ester derivative compound of idebenone and to a cosmetic composition comprising the same.

The cosmetics industry is a high value-added industry, reflecting the cultural trends of the times. In the past, cosmetics were focused on simply pursuing beauty, but in recent years there has been a growing interest in lifestyles of health and sustainabililty (LOHAS), which is more comprehensive and broader than the concept of well being. The desire to pursue beauty with a sense of beauty has expanded throughout society, and its purpose has changed with the aim of actively improving the condition of the skin, not simply to provide beauty or to protect the skin. Accordingly, recent cosmetic research is focused on the development of functional cosmetics with a concept of healing, and the cosmetic market called cosmeceutical has emerged by further developing such functional cosmetics. This means medicinal cosmetics, and the domestic cosmetics market is estimated at W500bn, which is still estimated at 2.9% of the total cosmetics market. The most necessary thing for the domestic cosmetics industry to leap further is the development of new cosmetic materials, among other things, the development of functional cosmetic materials.

Tyrosinase is a multifunctional oxidase family of copper-containing enzymes widely distributed in animals, plants and microorganisms. This promotes two reactions of melanin synthesis, hydroxylation of L-tyrosine by monophenolation reaction and oxidation of L-DOPA (3,4-dihydroxyphenylalanine) to o-dopaquinone. Tyrosinase promotes melanin biosynthesis, which plays an important role in protecting skin from sun radiation. Melanin can act as a photoprotector and determines the pigmentation and color shape of mammalian skin. Efficient tyrosinase inhibitors have been reported to improve skin pigmentation, neurodegenerative diseases and potentially improve cancer therapies.

Reactive oxygen species (ROS) are produced either naturally in vivo or by exposure to various chemicals, including UV radiation, smoking, and environmental pollution. These free radicals cause aging and chronic diseases such as cerebrovascular disease, cardiovascular disease, and cancer, and cause skin aging. In particular, free radicals cause oxidative stress on skin cells, cause cleavage and damage of collagen and elastin molecules, induce wrinkle formation, and affect DNA damage and activity, thereby increasing melanocyte proliferation and melanin synthesis. In addition, the sebaceous membrane of the skin contains a large amount of unsaturated lipids, which are oxidized by highly reactive free radicals to change into lipid peroxide, which damages the cells and makes the skin rough and dry. Antioxidant enzymes and antioxidants exist as a biological defense mechanism to prevent oxidative damage from free radicals.However, since skin is in direct contact with environmental factors, it is always exposed to oxidative stress, resulting in an imbalance of antioxidant defenses in the body. Lipids and oxidation products accumulate and promote skin aging. Therefore, using antioxidants that can remove free radicals can restore the skin's own antioxidant network, protecting skin tissue and slowing skin aging such as pigmentation.

Excessively produced melanin causes skin disease and free radicals promote skin aging, and there is a need for a new functional cosmetic material that inhibits melanin production and has an antioxidant effect.

Accordingly, an object of the present invention is to provide a compound having a skin whitening effect, an antioxidant effect and an anti-inflammatory effect, and a composition for skin whitening and a cosmetic composition comprising the same.

In order to solve the above problems, the inventors of the present invention synthesized an idebenone derivative compound having a skin whitening effect, an antioxidant effect and an anti-inflammatory effect, the means for solving the problem of the present invention are as follows.

1. A compound represented by the following formula (1):

[Formula 1]

In formula, R is a C _{1- 6} alkyl, -COO or OH.

2. A composition for skin whitening comprising the compound of 1 or a pharmaceutically acceptable salt thereof.

3. A cosmetic composition comprising the compound of 1 or a pharmaceutically acceptable salt thereof.

The compound of the present invention inhibits the production of tyrosinase and melanin, and has an antioxidant effect and an anti-inflammatory effect, and thus is suitable for use as a skin whitening composition and a cosmetic composition.

1 is a diagram showing the cytotoxicity of the compound prepared in Example 1 of the present invention to CCD-986-sk cells.
Figure 2 is a diagram showing the cytotoxicity of B16-F10 cells of the compound prepared in Example 1 of the present invention.
Figure 3 is a diagram showing the cytotoxicity to the CCD-986-sk cells of the compound prepared in Example 2 of the present invention.
Figure 4 is a diagram showing the cytotoxicity of B16-F10 cells of the compound prepared in Example 2 of the present invention.

The present invention provides a compound represented by Formula 1:

[Formula 1]

In formula, R is a C _{1- 6} alkyl, -COO or OH.

In Formula 1, the R group may be bonded to all positions of ortho, meta, and para of the benzene ring.

In the present specification, 'alkyl' means a monovalent substituent having a general formula of C _n H _{2n +1} , and includes both a straight chain and a crushed group. C _x in the context of the present invention _{- y} alkyl refers to a carbon number of x to y of the alkyl. For example, C _{1- 6} alkyl refers to a C 1 to 6 alkyl, and, more specifically, includes both straight-chain or methyl-milling type, ethyl, propyl, butyl, pentyl, hexyl and the like.

In a preferred embodiment of the present invention, the compound represented by Formula 1 is a compound of Formula 2 or 3:

[Formula 2]

[Formula 3]

.

.

Compounds of Chemical Formulas 1 to 3 are derivatives of idebenone synthesized by esterification to idebenone, wherein idebenone is a compound represented by Formula 4 below:

[Formula 4]

.

.

Compounds represented by Formulas 1 to 3 have a tyrosinase inhibitory effect, melanin production inhibitory effect, antioxidant effect and anti-inflammatory effect, these properties are the active ingredient of the composition or cosmetic composition for skin whitening and the salt thereof It is suitable to be used as.

The "whitening" not only makes the skin white, but also removes the pigmentation formed in a part of the skin.

The cosmetic composition may additionally include components commonly added thereto, such as conventional auxiliaries and carriers such as antioxidants, stabilizers, solubilizers, vitamins, pigments and flavorings.

The cosmetic composition may be prepared in any formulation commonly prepared in the art, for example, solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, surfactant-containing cleansing, oils It may be formulated as powder foundation, emulsion foundation, wax foundation, spray, and the like, but is not limited thereto. More specifically, creams such as lotion such as flexible lotion or nourishing lotion, emulsion such as facial lotion, body lotion, nourishing cream, moisture cream, eye cream, etc., essence, cosmetic ointment, spray, gel, pack, sunscreen, makeup Foundation, liquid type, solid type or spray type and the like, powders, cleansing creams, cleansing lotions, makeup removers such as cleansing oils, cleansing foams, soaps, body washes and the like formulations and the like formulation. In this case, the cosmetic composition may include a surfactant, an emulsifier, a soap acid, a solvent, a colorant, a preservative, an antioxidant, an antifoaming agent, an antibacterial agent, an antideposition agent, an enzyme, a plant or mineral oil, a fat, a fluorescent substance, a fungicide, a hydrophobic agent, Excipients, including moisturizers, fragrances, fragrance carriers, preservatives, proteins, silicones, solubilizers, sugar derivatives, sunscreens, vitamins, plant extracts, waxes and the like.

In the case where the formulation of the cosmetic composition is a paste, cream or gel, carrier oils include animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide. Can be used.

Toss, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component when the formulation of the cosmetic composition is a powder or a spray, and in particular, in the case of a spray, additionally chlorofluorohydrocarbon, Propellant such as propane / butane or dimethyl ether.

When the formulation of the cosmetic composition is a solution or emulsion, a solvent, a solubilizer or an emulsifier is used as a carrier component, for example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, Fatty acid esters of 1,3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan.

When the formulation of the cosmetic composition is a suspension, a liquid diluent such as water, ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester as a carrier component Crystalline cellulose, aluminum metahydroxy, bentonite, agar or tragacanth and the like can be used.

When the formulation of the cosmetic composition is a surfactant-containing cleansing agent, the carrier component is aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid. Amide ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters and the like can be used.

EXAMPLE

Hereinafter, preferred examples will be presented to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited thereto.

Instrument and reagents

In the examples of the present invention all reagents were purchased from commercial suppliers (Aldrich, TCI. And Alfa aesar) and used without further purification, and solvents were purified or dried by known methods as needed. Thin membrane chromatography used for separation used a silica gel plate (0.25 mm, 60F-254, manufactured by E. Merck). An IR spectrum Perkin Elmer FT-IR Spectrophotometer spectrophotometer was used to confirm the structure of the synthesized material. ¹ H-NMR and ¹³ C-NMR spectra were JEOL FT / NMR (600Mz) spectrophotometer and CDCl ₃ was used as a solvent. SYNAPT G2-Si HDMS was used as a mass spectrometer to confirm molecular weight.

Example 1.Synthesis of 10- (4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dioen-1-yl) decyl 2-acetoxybenzoate

10- (4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl) decyl 2-acetoxybenzoate was synthesized as in Scheme 1 below. 2, compound):

Scheme 1

.

.

To 100 mL of the dried round flask was added acetylsalicylic acid (2) (0.5 g, 1 equiv), Idebenone (1) (1.17 g, 1.25 equiv), DMAP (0.034 g, 0.1 equiv) and a magnetic spoon. The solvent was dissolved by adding 15 mL of MC using a syringe. The mixture was stirred at 0 ° C. using an ice bath, and after 30 minutes, N, N′-diisopropylcarbodiimide (DIC) (0.473 mL, 1.1 equivalents) was slowly added thereto using a syringe. After 24 hours the reaction was filtered through celite and evaporated to dryness. The reaction mixture was purified by chromatography to an n-hexane: EA = 10: 1 solution in an open column, to obtain an orange liquid product (3) (A.S-Ide) (0.63 g, 45% yield).

The resulting compound was analyzed by ¹ H-NMR and ¹³ C-NMR, the results are as follows.

¹ H-NMR (600 MHz, CDCl ₃ )

 δ 8.01 (dd, J = 7.8Hz, 1.8Hz 1H), 7.55 (td, J = 7.8Hz, 2.4Hz, 1H), 7.31 (td, J = 7.8Hz, 1.8Hz, 1H), 7.1 (d, J = 7.8 Hz, 1H), 4.26 (t, J = 7.2 Hz, 2H), 3.98 (d, 2.4 Hz, 6H), 2.44 (t, J = 8.4 Hz, 2H), 2.35 (s, 3H), 2.01 ( s, 3H), 1.71-1.76 (m, 2H), 1.29-1.43 (m, 14H)

¹³ C-NMR (600 MHz, CDCl ₃ )

 δ 184.716, 184.152, 169.674, 164.542, 150.649, 144.292, 143.066, 138.671, 131.731, 131.730, 125.994, 123.792, 123.495, 65.300, 61.154, 29.816, 29.464, 29.441, 29.337, 29.232, 28.727.

Example 2. Synthesis of 10- (4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dioen-1-yl) decyl 2-hydroxybenzoate

10- (4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl) decyl 2-hydroxybenzoate was synthesized as in Scheme 2 below. Compound of 3):

Scheme 2

.

.

In 100 mL of the dried round flask, salicylic acid (6) (0.5 g, 1 equiv), idebenone (1) (1.23 g, 1.25 equiv), DMAP (0.04 g, 0.1 equiv) and a magnetic spoon were placed. The solvent was dissolved by adding 15 mL of THF using a syringe. The mixture was stirred at 0 ° C. using an ice bath, and after 30 minutes, N, N′-diisopropylcarbodiimide (DIC) (0.62 mL, 1.1 equivalents) was slowly added by stirring using a syringe. After 24 hours the reaction was filtered through celite and evaporated to dryness. Chromatography was performed to separate and purify n-hexane: EA = 20: 1 to 10: 1 using an open column to obtain an orange liquid product (7) (Sal-Ide) (0.68 g, 40% yield).

The resulting compound was analyzed by ¹ H-NMR and ¹³ C-NMR, the results are as follows.

¹ H-NMR (600 MHz, CDCl ₃ )

δ 10.850 (s, 1H), 7.84 (dd, J = 7.8 Hz, 2.4 Hz, 1H), 7.45 (td, J = 8.4 Hz, 2.4 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.88 (t, J = 7.8Hz, 1H), 4.34 (t, J = 7.2Hz, 2H), 3.98 (d, J = 1.2Hz, 6H), 2.44 (t, J = 7.8Hz, 2H), 2.009 (s, 3H), 1.753-7.801 (m, 2H), 1.295-1.450 (m, 14H)

¹³ C-NMR (600 MHz, CDCl ₃ )

δ 184.716, 170.239, 161.641, 144.292, 144.273, 143.057, 138.671, 135.579, 129.863, 119.091, 117.549, 112.638, 65.501, 61.154, 29.816, 29.452, 29.404, 29.328, 29.203, 28.552, 26.338, 25.938

Experimental Example 1 Evaluation of Cytotoxicity of Idebenone Derivative Compounds

The compound samples synthesized in Examples 1 and 2 were diluted and treated in cell culture medium for each concentration. The cells used in the experiment were incubated in DMEM medium supplemented with 10% fetal bovine serum 1% penicillin / streptomycin for about 24 hours. Samples prepared by diluting the stock by diluting 1/2 of each stock by dissolving in DMSO were prepared by diluting to a final concentration in DMEM medium, and then incubated for another 48 hours by replacing them. The cultured B16-F10 cells were replaced with DMEM (FBS 10%, P / S 1%) medium containing 10% EZ-CYTOX, and CCD-986-sk cells were IMDM (10% FBS, 1% P / S). Incubation and sample treatment were performed to determine cell viability by measuring absorbance at 450 nm using a plate reader. The results are shown in Figures 1 to 4, it was confirmed that the compounds of Examples 1 and 2 do not have cytotoxicity is suitable for use in the human body.

Experimental Example 2 Measurement of Tyrosinase Inhibition Effect of Idebenone Derivative Compound

Example In order to evaluate the whitening effect of compound and idebenone, mushroom tyrosinase inhibition assay was performed. To each diluted sample, 220 μl of 0.1 M sodium phosphate buffer (pH 6.5), 40 μl of 1.5 mM tyrosine (soluble in 0.1 M HCl) and 20 μl of 1500 U / ml mushroom tyrosinase (pH 6.5, dissolved in 50 mM potassium phosphate buffer) were mixed. After that, the reaction was carried out at 37 ° C. for 10 minutes. After dispensing 100 μl into a 96-well plate, absorbance was measured at 490 nm. Tyrosinase inhibition was measured therefrom through Equation 1 below.

[Equation 1]

In the formula, a: absorbance after reaction of blank sample b: absorbance after reaction of sample solution a ', b': sample color correction (measurement of buffer instead of tyrosinase) absorbance.

The results are summarized in Table 1 below, and the compounds of Examples 1 and 2 were found to be more excellent in tyrosinase inhibitory effect than idebenone at the same concentration.

density 0 µg / ml 12.5 μg / ml 25 µg / ml 50 µg / ml 100 µg / ml 200 µg / ml Example 1 0 34.21% 38.12% 38.78% 39.12% 42.69% Example 2 0 31.16% 33.29% 35.60% 36.64% 37.49% Idebenon 0 28.31% 30.59% 31.51% 31.51% 34.70%

Experimental Example 3 Determination of Melanin Inhibitory Effect of Idebenone Derivative Compounds

To assess the melanin production of the samples, B16-F10 cells were aliquoted into 1.2 × 10 ⁵ cells / well in 6 well plates and incubated for 24 hours. Samples were prepared by diluting the stock by diluting 1/2 by concentration in DMSO and diluting to a final concentration in DMEM (FBS 10%, P / S 1%) medium. To induce melanin secretion, after treatment with a sample of α-MSH 100 mM, a melanosite stimulating factor was incubated for at least 50 hours. After incubation, the medium was collected and melanin was measured by measuring the absorbance at 490 nm.

The results are shown in Table 2 below, and it was confirmed that the compounds of Examples 1 and 2 inhibit melanin production to a degree similar to that of idebenone.

MSH (-) MSH (+) 0 0 25 μg / ml 50 μg / ml 100 μg / ml 200 μg / ml Example 1 0 0 85.39% 89.99% 94.76% 96.11% Example 2 0 0 86.38% 90.12% 90.73% 92% Idebenon 0 0 90.56% 91.22% 93.69% 94.01%

Experimental Example 4. Determination of anti-inflammatory effect of Idebenone derivative compound

The level of NO produced in RAW 264.7 cells and present in the culture was measured using a NO detection kit (intron) based on griess reaction. 100μl of the culture solution was estimated to be present in a 96 well plate, and 50μl of N1 buffer (sulfanylamide) was added and reacted at room temperature for 10 minutes, followed by adding 50μl of N2 (naphthylethylenediamine) at room temperature for 10 minutes. After absorbance was measured at 540nm. Positive control group was used L-NMMA (N ^G -monomethyl-L-arginine).

The results are shown in the following Table 3, it was confirmed that the compounds of Examples 1 and 2 have an antioxidant effect.

density 12. 25 μg / ml 25 μg / ml Standard (50 μM) Example 1 49.23 57.14 　
　
　
　
　 Example 2 14.18 17.25 Idebenon 29.76 37.24 L-NMMA (Standard Material) 56.89

Experimental Example 5. Determination of Antioxidant Effect of Idebenone Derivative Compound

The antioxidant effect of the idebenone derivative compound was measured by ORAC test. The experiment was performed according to the protocol in the ORAC assay kit, using Trolox as the standard reagent. The results are shown in Table 4 below, and it was confirmed that the compounds of Examples 1 and 2 had antioxidant effects.

compound ORAC Units Example 1 1.55 ± 0.18 Example 2 1.88 ± 0.21 Idebenon 1.38 ± 0.15 trolox 1.00 ± 0.02

Claims (4)

Compound represented by the following formula (2) or (3):
[Formula 2]

[Formula 3]

. delete A composition for skin whitening comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof. Cosmetic composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.

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