KR20050101448A - Novel selenourea derivatives and the cosmetic composition containing the same - Google Patents

Abstract

 The present invention relates to a novel seleno urea derivative of the general formula (I) and to a whitening cosmetic composition comprising the same.

(Ⅰ)

Where

R is an amine group, pyrrolidine or piperidine group substituted with a lower alkyl group of C ₁ to C ₃ ,

E is a selenium atom or a sulfur atom.

Since the novel selenourea derivative compounds of the general formula (I) of the present invention significantly inhibit tyrosinase involved in melanin biosynthesis and inhibit melanin production, the composition comprising the same is useful as a cosmetic composition for whitening. Can be used.

Description

 Novel Selenourea Derivatives and Cosmetic Compositions Comprising the Same {NOVEL SELENOUREA DERIVATIVES AND THE COSMETIC COMPOSITION CONTAINING THE SAME}

The present invention relates to a novel seleno urea derivative and a whitening cosmetic composition containing the same.

Melanogenesis is a defense mechanism against melanocyte pigmentation cells (melanocytes) in the skin cells, which increases the melanogenesis activity, and the large amount of melanin produced by this transfers to the keratinocytes. It is the result of accumulation in the epidermis. Although melanin protects the skin, hyperpigmentation of the skin causes blemishes, freckles, darkening of the skin after skin inflammation, and senile pigment spots. It may also result. Therefore, recently, various whitening cosmetics and medicines for preventing and improving such problems have been developed and marketed.

The research of whitening agent as cosmetics has recently been increasingly needed as skin blackening is recognized as skin aging caused by ultraviolet rays along with the improvement of living standard in the Asian region which prefers emotionally white skin. Since 1990, arbutin, kojic acid, vitamin C, and derivatives thereof have been developed, and whitening cosmetics containing them are commercially available, but the actual clinical effect is not satisfactory.

On the other hand, in order to develop a whitening cosmetics having relatively low toxicity and nature-friendly, researches are being conducted to search for and use herbal medicines with whitening effects. Through these studies, several herbal medicines have been derived. For example, Korean Patent Publication No. 1991-8660 discloses whitening cosmetics containing extract of Dacchi, and Korean Patent Publication No. 1991-11645 contains Hojang-geun extract. A whitening cosmetic has been disclosed, and Korean Patent Publication No. 1993-28783 discloses a whitening composition containing an extract of lettuce, and more recently, a whitening cosmetic containing melberin isolated from mulberry trees is disclosed in Korean Patent Publication No. 1997. Published in -47260.

 In the development of the whitening agent, the main part of the oxidation inhibitory function of tyrosine by tyrosinase, the first step of the melanin pigmentation process, is considered as a main focus. Therefore, screening tyrosinase activity inhibitors in vitro is an important whitening agent development tool. Arbutin, kojic acid, vitamin C, and the like, which are currently used, are also widely used as derivatives of tyrosinase.

 The present inventors tried to select a new functional whitening agent by measuring the inhibitory effect of tyrosinase activity of the candidate substance, and synthesized cyanamide by a simple method to prepare a selenourea derivative and to inhibit tyrosinase thereof. As a result of searching for activity, the present invention was completed by confirming that the seleno urea derivative of the present invention had a higher tyrosinase inhibitory activity than the well-known kojic acid.

  It is an object of the present invention to provide novel seleno urea derivatives and methods for their preparation. It is another object of the present invention to provide a functional cosmetic composition for whitening comprising a novel selenourea derivative that inhibits tyrosinase activity and has excellent whitening activity.

In order to achieve the above object, the present invention provides a novel seleno urea derivative compound of the general formula (I):

(Ⅰ)

Where

R is an amine group, pyrrolidine or piperidine group substituted with a C ₁ to C ₃ lower alkyl group,

E is a selenium atom or a sulfur atom.

Particularly preferred groups of compounds of the above formula (I) include the following compounds:

N, N-Dimethylselenourea (Compound 1), 1- (N, N-selenourea) pyrrolidine (Compound 2), 1- (N, N-selenourea) piperidine (Compound 3) Phosphorus compounds.

The present invention also provides a functional cosmetic composition for whitening containing the novel selenourea derivative compound of the general formula (I) as an active ingredient.

Hereinafter, the present invention will be described in detail.

The novel compounds of the general formula (I) according to the present invention can be prepared as follows, the following scheme shows the preparation method of the representative compounds of the present invention step by step, the various compounds of the present invention is a synthetic process of the reaction scheme It can be prepared with minor changes such as changing the reagents, solvents and reaction sequences used in the process.

First, a first step of reacting cyanamide (II) with a halogenated reagent such as hydrochloric acid or hydrogen bromide dissolved in a solvent such as diethyl ether to prepare a dihalogenated cyanamide body (III); Selenourea derivatives of the general formula (I) of the present invention can be prepared by a second step of reacting the dihalogenated cyanamide (III) with a sulfur atom or a selenium atom donor such as LiAlHSeH.

Scheme (I) shows a second step of preparing a selenourea derivative compound of the general formula (I) using cyanamide (II) as a starting material, and E of the selenourea derivative is as defined above. .

In detail, the reaction was carried out with 1-normal hydrochloric acid (2 equivalents) dissolved in diethyl ether in cyanamide, and then changed from a colorless solution to a milky white suspension in at least 30 seconds. Preferably, the reaction is carried out at 0 ° C. for 1 hour to 4 hours, preferably 2 hours, followed by LiAlHSeH (1 equivalent) at -10 to 20 ° C., preferably at 0 ° C. for 1 hour to 5 hours, preferably Can be reacted for 3 hours (Ishihara., Et al., Nada, FJ Chem. Soc. ) To prepare selenourea derivative compounds of general formula (I).

The preparation of LiAlHSeH may be prepared by dissolving selenium powder in THF solution and adding lithium aluminum hydride under 0 ° C. argon gas, followed by stirring the product for 30 minutes.

Representative examples of the general formula (I) compound which can be prepared according to the above-described method are shown in Table 1 below.

Compound # One 2 3 R N (CH ₃ ) ₂

The present invention provides selenium urea derivative compounds of the general formula (I) prepared by the above production method.

The present inventors measured the inhibitory activity of tyrosinase, a major enzyme involved in melanin biosynthesis of the compound of general formula (I), and the compounds of the present invention exhibited excellent tyrosinase inhibitory activity. It was confirmed that the compound of inhibits melanin production strongly.

Accordingly, the present invention provides a functional cosmetic composition for whitening containing the seleno urea derivative compound of the general formula (I) having the above effects as an active ingredient.

In addition, the composition of the present invention is a group consisting of skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisturizing lotion, nutrition lotion, massage cream, nutrition cream, moisture cream, hand cream, essence, nutrition essence, pack It includes a cosmetic composition characterized in that it has one or more formulations selected from.

The cosmetic composition comprising the compound of the general formula (I) of the present invention may be applied according to the dosage form and the application method thereof according to the formulation and purpose of use.

 For example, the compound of general formula (I) may be mixed with a base material for preparing cosmetics to prepare a cosmetic composition for whitening.

 In the present invention, the compound of formula (I) alone or in combination with a whitening ingredient is used in an amount of 0.0001% to 30.00% by weight based on the skin cosmetic composition. In addition, the base material for preparing the cosmetic composition is purified water, monohydric or polyhydric alcohol fats and oils, surfactants, and the like on the emulsion, and other additives may include flavoring agents, colorants, preservatives, etc. in the composition. In the solubilized composition, purified water, surfactants, monohydric and polyhydric alcohols, and the like, flavoring agents, colorants, and preservatives are used.

 In skin cosmetics, creams and lotions may be prepared in W / O emulsions or O / W emulsions, respectively, and the type of emulsifier used may be anionic form, cationic form, nonionic form, or the like.

 In addition, the cosmetic composition of the present invention is applied and formulated as necessary components, such as oil, water, surfactants, moisturizers, lower alcohols, thickeners, chelating agents, pigments, preservatives, fragrances, etc., which are formulated in general skin cosmetics. It is possible.

The cosmetic composition containing the mixed plant extract of the present invention as an active ingredient may be used in a variety of moisturizing cosmetics, face wash, body cosmetics and the like.

Examples of products to which the present composition can be added include cosmetics such as astringent cosmetics, soft cosmetics, nourishing cosmetics, various creams, essences, packs, foundations, and cleansing agents, face washes, soaps, treatments, and essences. .

Specific examples of the cosmetic of the present invention include skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisturizing lotion, nutrition lotion, massage cream, nutrition cream, moisture cream, hand cream, essence, nutrition essence, pack, soap, Shampoo, cleansing foam, cleansing lotion, cleansing cream, body lotion, body cleanser, latex, press powder, loose powder, eye shadow and the like.

Hereinafter, the present invention will be described in detail by Examples, Formulation Examples and Experimental Examples.

However, the following Examples, Formulation Examples and Experimental Examples are merely illustrative of the present invention, the contents of the present invention is not limited by the following Examples, formulation examples and experimental examples.

Example 1 N, N-dimethylselenourea (1)

2 ml of N, N-dimethylcyanamide (500 mM) was reacted with 2 equivalents of 1-normal hydrochloric acid dissolved in 10 ml of diethyl ether to prepare a 1-chloro-vinylamine compound. This can be confirmed by changing from a colorless solution to a milky white suspension in about 30 seconds, which was then reacted at 0 ° C. for 2 hours, and then 0.8 g of selenium powder (10 mmol) was dissolved in 100 ml of THF and 0 ° C. argon gas. After 0.38 g of lithium aluminum hydride (10 mmol) was added thereto, 1 equivalent of LiAlHSeH (3 mM) prepared by stirring the product for 30 minutes was added and reacted at 0 ° C. for 3 hours. The product was extracted with dichloromethane and washed with water, water was removed with sodium sulfate, and the residue obtained by evaporation under reduced pressure was purified by silica gel column chromatography (developing solvent: CH ₂ Cl ₂ = 100%) to obtain N, 49 mg (yield 70%) of N-dimethylselenourea (named Compound 1) were obtained.

Melting Point (mp): 172.2-172.8 ℃

IR (KBr): 3366, 3162, 1551cm ^-1

MS (CI): m / z = 153 [M ⁺ +1]

¹ H-NMR (CDCl ₃ ): δ 3.18 (6H, br s, CH ₂ ), 7.60 (2H, br s, NH)

¹³ C-NMR (CDCl ₃ ): δ 37.9, 45.3, 177.7, ⁷⁷ (Se)

NMR (CDCl ₃ ): δ 230.4

HRMS (EI): Calcd C ₃ H ₈ N ₂ Se 151.99, found 151.99

Example 2. 1- (N, N-Selenourea) pyrrolidine (2)

2 ml of 1-cyano-pyrrolidine was reacted with 2 equivalents of 1-normal hydrochloric acid dissolved in 10 ml of diethyl ether to prepare a 1-chloro-1-pyrrolidinyl-vinylamine compound. This can be confirmed by changing from a colorless solution to a milky white suspension in about 30 seconds, which was then reacted at 0 ° C. for 2 hours, and then 0.8 g of selenium powder (10 mmol) was dissolved in 100 ml of THF and 0 ° C. argon gas. After 0.38 g of lithium aluminum hydride (10 mmol) was added thereto, 1 equivalent of LiAlHSeH (3 mM) prepared by stirring the product for 30 minutes was added and reacted at 0 ° C. for 3 hours. The product was extracted with dichloromethane and washed with water, water was removed with sodium sulfate, and the residue obtained by evaporation under reduced pressure was purified by silica gel column chromatography (developing solvent: CH ₂ Cl ₂ = 100%) to obtain 1- 84.59 mg (yield 88%) of (N, N-selenourea) pyrrolidine (named Compound 2) were obtained.

Melting Point (mp): 46.2-46.4 ℃

IR (KBr): 1508 cm ^-1

¹ H-NMR: (DMSO-d ₆ ): δ 1.94 (4H, m), 3.156 (3H, s), 3.162 (3H, s), 3.65 (4H, m)

¹³ C-NMR (DMSO-d ₆ ): δ 25.4, 44.4, 54.8, 188.8, ⁷⁷ (Se)

NMR (DMSO-d ₆ ): δ 310.8, MS (CI)

m / z = 179 [M ⁺ +1],

HRMS (EI): C ₅ H ₁₀ N ₂ Se

Example 3. 1- (N, N-Selenourea) piperidine (3)

2 ml of 1-cyano-piperidine was reacted with 2 equivalents of 1-normal hydrochloric acid dissolved in 10 ml of diethyl ether to prepare a 1-chloro-1-piperidinyl-vinylamine compound. This can be confirmed by changing from a colorless solution to a milky white suspension in about 30 seconds, which was then reacted at 0 ° C. for 2 hours, and then 0.8 g of selenium powder (10 mmol) was dissolved in 100 ml of THF and 0 ° C. argon gas. After 0.38 g of lithium aluminum hydride (10 mmol) was added thereto, 1 equivalent of LiAlHSeH (3 mM) prepared by stirring the product for 30 minutes was added and reacted at 0 ° C. for 3 hours. The product was extracted with dichloromethane, washed with water, water was removed with sodium sulfate, and the residue obtained by evaporation under reduced pressure was purified by silica gel column chromatography (developing solvent: CH ₂ Cl ₂ = 100%) to obtain 1- 100.24 mg (yield 91%) of (N, N-selenourea) piperidine (named compound 3) were obtained.

Melting Point (mp): 145.0-146.2 ° C

IR (KBr): 3303, 3169, 1522 cm ^-1

¹ H-NMR: (DMSO-d ₆ ): δ 1.47 (4H, m, CH ₂ ), 1.59 (2H, m, CH ₂ ), 3.76 (4H, br s, CH ₂ ), 7.75 (2H, br s , NH)

¹³ C-NMR (DMSO-d ₆ ): δ 23.6, 25.3, 176.0, ⁷⁷ (Se)

NMR (DMSO-d ₆ ): δ 218.5, MS (CI)

m / z = 193 [M ⁺ +1],

HRMS (EI): Calcd C ₆ H ₁₂ N ₂ Se 192.02, found 192.01

Reference Example 1. Target Samples and Reagents

Tyrosinase (product no .: T7755) was extracted from mushrooms and purchased from Sigma, L-dopa (product no .: D9682), TPA (phobol 12- Myristate 13- Acetate) (product no. : P3135) and the like were also purchased from Sigma, and all reagents used for kojic acid (product number: K3125) and organic synthesis were purchased from Aldrich.

In addition, penicillin-streptomycin (product number: 15140-122), fetal bovine serum (FBS, product number: 26140-079), RPMI1640 (product number: 31800-014) are manufactured by Gibco Inc. No .: 3R1902) was purchased from Tedia and used for the experiment.

Reference Example 2. Instrument Analysis

Or when the activity test as a tie, Gamelan -A test has spectrophotometer (precision microplate reader, Model E09090, Molecular Devices Corporation) was used identify material structure, JEOL-JNM-α400 model is using ¹ H-NMR and ¹³ C -NMR was obtained and Mass Spectrum used Shimadzu 9020-DF.

In addition, the tyrosinase inhibitory activity involved in melanin biosynthesis is described by Aroca et al. (Aroca. P., et al., J. Biol. Chem., 268 (34) , pp25650-25655, 1993) and Tommy See the activity assay described in Tomita. K., et al., J. Antibiot., 43 (12) , pp1601-1604, 1990, using a melan-A cell. See Bennet et al. (Bennette, et al., Int. J. Cancer., 39 , pp . 414-418, 1987) for a method of verifying melanin production inhibitory effect.

Experimental Example 1. Confirmation of inhibitory effect on melanogenesis-related enzyme tyrosinase

The present invention is to examine the inhibitory effect of the test substance of the target test against tyrosinase, an enzyme associated with melanogenesis, in order to confirm the whitening activity of the compounds of Examples 1 to 3 120 mM (67 mM phosphate buffer) of 8 mM L-dopa pH 6.8) and test samples (10 μM, 100 μM, 500 μM, 1 mM) dissolved in 40 μl of methanol were added to a 96-well microplate and 40 μl of mushroom extract tyrosinase (125 U / mL) was added. After incubation at 37 ° C. for 20 minutes, the amount of dopachrome produced was measured at 492 nm using a spectrophotometer (precision microplate reader, Molecular Devices E09090), and Mazda et al. (Matsuda. H. et al. , Biol. Pharm. Bull., 19 (1) , pp153-153, 1996), based on Equation 1 below to determine the inhibitory effect of tyrosinase on the basis of the control group is not added.

Tyrosinase inhibitory effect (%) =

{(Control OD ₄₉₂ -Sample OD ₄₉₂ ) / Control OD ₄₉₂ } × 100

As a result, the compounds of the present invention was found to exhibit excellent tyrosinase inhibitory activity than the well-known koji acid, the inhibitory activity against the mushroom extract tyrosinase at 200μM concentration of each compound 2 is shown (each figure is the average of three experiments).

sample One 2 3 Kojisan Inhibition Rate (%) 36.73 43.28 55.51 39.14

Experimental Example 2. Melan-A Cell Experiment

2-1. Cell culture

Melan-A cell line in 10% bovine placental serum (Fetal Bovine Serum, Article No. 26140-079) and 200 nm Phorbol 12-Myristate 13-Acetate in RPMI1640 medium (31800-104) Number: P3135). When 100π cell into the culture medium in a Petri dish 10㎖ growth has about 5 × 10 ⁵ cells after the inoculation, at 37 ℃, 5% CO ₂ environment 3 ~ 4 days after confluent in 24-well plate at 10 ⁵ cells / The wells were inoculated and incubated again for 24 hours.

10 µl of the sample was treated for 3 days (solvent: 50% propylene glycol, 30% ethanol, 20% distilled water) while 990 µl of the culture medium was changed daily, and then cultured for 1 day.

2-2. Melanin content measurement

After removing the medium, washed with PBS and immediately added 1 ml of 1N sodium hydroxide to dissolve the melanin and the absorbance was measured at 400 nm.

2-3. Cell viability measurement

The medium was removed and washed with phosphate buffered saline (PBS). 200 μl of a crystal violet (CV 0.1%, 10% ethanol, remaining PBS) reagent was added thereto, followed by incubation at room temperature for 5 minutes, and then washed twice with water. After adding 1 ml of ethanol and shaking for 10 minutes at room temperature, the absorbance was measured at 590 nm.

As a result of the experiment, as shown in Table 3 and FIG. 1, it was confirmed that the compound 3 inhibits melanin production with relatively low toxicity.

 Melanin production  Cell viability  compound  Concentration (μM) Melanin (%) Survival rate (%) 3 100 49.5 60.6 10 95.7 103.3

Preparation Example 1

The manufacturing example of the lotion in the cosmetics containing the novel selenourea derivative compound of General formula (I) of this invention is as follows. The compound used herein was prepared in Example 3.

number Raw material Formulation Example 1 One Compound of Example 3 20.0 2 Butylene glycol 7.0 3 glycerin 5.0 4 Polyoxyethylene (60) hardening oil 0.2 5 ethanol 5.0 6 Betaine 2.0 7 Citric acid 0.02 8 Sodium citrate 0.06 9 antiseptic a very small amount 10 Spices a very small amount 11 Purified water Remaining amount

<Production method>

Formulation Example 1 Raw material 2, 3, 4, 6, 7, 8, 9 was added to the purified water of raw material No. 11, stirred and dissolved (A). And stir. To this was added 1 and stirred sufficiently before aging.

Preparation Example 2 Lotion

The preparation example of the lotion in the cosmetics containing the novel selenourea derivative compound of the general formula (I) of the present invention is as follows. The compound used herein was prepared in Example 3.

number Raw material Formulation Example 2 One Compound of Example 3 20.0 2 Butylene glycol 8.0 3 glycerin 5.0 4 Squalane 10.0 5 Butylene Glycol Dicaprylate / Dicaprate 5.0 6 Sorbitan stearate 1.5 7 Polysorbate 60 1.0 8 Glyceryl Stearate 0.5 9 Steaglycitinate 0.2 10 Carboxy Vinyl Polymer 0.1 11 Arginine 0.1 12 antiseptic a very small amount 13 Spices a very small amount 14 Purified water Remaining amount

<Production method>

Formulation Example 2: Raw materials 1, 2, 3, 10, 11, 12, and 14 are mixed by heating to 70-75 ° C. while stirring (A). Raw materials 4, 5, 6, 7, 8, and 9 were heated to 75 to 80 ° C. while stirring (B), and then added to A to emulsify and then cooled to 45 ° C. while stirring, and 13 times were added thereto. After stirring, the solution is cooled to 30 ° C. and aged.

Preparation Example 3 Essence

The preparation example of the essence in the cosmetics containing the novel selenourea derivative compound of General formula (I) of this invention is as follows. The compound used herein was prepared in Example 3.

number Raw material Formulation Example 3 One Compound of Example 3 10.0 2 Cytostolol 1.7 3 Polyglyceryl 2-oleate 1.5 4 Ceramide 0.7 5 Ceraares-4 1.2 6 cholesterol 1.5 7 Dicetylphosphate 0.4 8 Concentrated glycerin 5.0 9 Carboxy Vinyl Polymer 0.2 10 Xanthan Gum 0.2 11 antiseptic a very small amount 12 Spices a very small amount 13 Purified water Remaining amount

<Production method>

Formulation Example 3: Raw materials 2, 3, 4, 5 and 6 are stirred and mixed (A), and raw materials 1, 7, 8 and 13 are separately stirred and mixed (B). After adding B to emulsification and emulsifying, when it is cooled to about 45 ° C. while stirring, 12 times are added, stirred, cooled to 30 ° C., and aged. The raw materials 9, 10 and 11 are added to disperse, stabilized, and aged.

As described above, the present invention provides a novel seleno urea derivative compound of the general formula (I), and the novel seleno urea derivative compound of the present invention is also important for tyrosinase involved in melanin biosynthesis. Since it has the effect of inhibiting the, as a cosmetic composition containing it as an active ingredient can be usefully used as a functional cosmetic composition for pigmentation and whitening.

 1 is a diagram showing the effect of compound 3 on the melanin production and cell viability of melanocytes according to the concentration.

Claims (4)

Novel Selenourea Derivative Compounds of Formula (I) (Ⅰ) Where R is an amine group, pyrrolidine or piperidine group substituted with a C ₁ to C ₃ lower alkyl group; E is a selenium atom or a sulfur atom. The method of claim 1, characterized in that it is selected from N, N-dimethyl selenourea, 1- (N, N-selenourea) pyrrolidine, 1- (N, N-selenourea) piperidine compound. Whitening functional cosmetic composition containing the novel selenourea derivative compound of the general formula (I) of Claim 1 as an active ingredient. The composition according to claim 3, wherein the composition is a group consisting of skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisturizing lotion, nutrition lotion, massage cream, nutrition cream, moisture cream, hand cream, essence, nutrition essence, pack Cosmetic composition characterized in that it has at least one formulation selected from.