KR20110097576A - Composition for whitening of the skin comprising benzaldehyde thiosemicarbazone derivatives - Google Patents

Abstract

상기 식에서,
R₁은 사이클로헥실; C₁~C₆ 알킬, C₁~C₆ 알콕시, 할로겐, 또는 C₁~C₆ 알킬아민이 치환된 페닐; 수소, C₁~C₆ 알킬, 또는 할로겐이 치환된 나프탈렌;이고,
R₂는 H; C₁~C₆ 알킬; 페닐; 나프탈렌;을 나타낸다.The present invention relates to a whitening composition containing, as an active ingredient, a benzaldehyde thiosemicarbazone derivative having the following formula, which is superior to arylthiourea.

Where
R ₁ is cyclohexyl; C ₁ ~ C ₆ alkyl, C ₁ ~ C ₆ alkoxy, halogen, or C ₁ ~ C ₆ alkyl amine is a substituted phenyl; Hydrogen, C ₁ -C ₆ alkyl, or halogen substituted naphthalene;
R ₂ is H; C ₁ -C ₆ alkyl; Phenyl; Naphthalene;

Description

Whitening composition containing benzaldehyde thiosemicarbazone derivative {COMPOSITION FOR WHITENING OF THE SKIN COMPRISING BENZALDEHYDE THIOSEMICARBAZONE DERIVATIVES}

The present invention relates to a whitening composition comprising a benzaldehyde thiosemicarbazone derivative as an active ingredient.

Human skin color is determined by the amount of melanin, carotene and hemoglobin, of which melanin is the most decisive factor. Melanin pigment is a phenolic polymer that has a complex form of black pigment and protein, and acts as a sunscreen. A person who lacks melanin pigment is very sensitive to sunlight and is easily burned. On the other hand, short-wave UV and carcinogens form harmful free radicals in the skin, and melanin removes these free radicals and plays a useful role in protecting proteins and genes.

Melanin is produced through a complex process from tyrosine by the action of tyrosinase present in pigment cells. The melanin produced at this time is delivered to the skin cells and exhibits a circulating action in which the melanin is lost due to epidermal detachment. This melanin production process is a naturally occurring phenomenon, and overproduction of melanin does not occur in normal skin. However, when the skin responds to external stimuli such as ultraviolet rays, environmental pollution or stress, it produces too much melanin and cannot be discharged out of the skin, but it is delivered to keratinocytes and accumulates in the epidermal layer of the skin, causing melasma, freckles and senile surpluses. Not only can it cause serious cosmetic problems, it can also promote skin aging and cause skin cancer.

It is everyone's constant desire to have white, fair skin. If you can suppress the production of melanin pigment, you will get white skin by the whitening effect. In addition, it is possible to treat lesions caused by pigmentation such as blemishes, freckles and surpluses by preventing excessive deposition of melanin pigment on the skin or by thinning the color of melanin pigment already deposited. Kojiic acid (Kojic acid), vitamin C, hydroquinone, arbutin and the like are known as such a representative whitening agent. However, kojic acid is not only effective in inhibiting melanin production in vivo compared to the inhibitory ability of tyrosinase in vitro, but also has a problem in the stability of the formulation and has recently been reported to cause liver cancer in long-term use. Vitamin C is very unstable and low phase stability in the formulation has a problem that the activity of the active ingredient is lowered over time. Recently, various methods for stabilizing the formulation of vitamin C in capsules or liposomes have been proposed, but no clear stabilization method has yet been proposed. Hydroquinone has excellent whitening effect but is limited to its use as it is defined as a carcinogenic substance. Arbutin is a compound in which sugar is attached to hydroquinone. When sugar is separated by skin enzymes when applied to cosmetics, hydroquinone, a carcinogen, is formed, causing cytotoxicity. Recently, various researches and developments have been made regarding functional whitening agents using herbal medicines such as licorice and mulberry and natural products as the side effects of whitening agents have been released. However, most plant extracts are known to show whitening efficacy only at high concentrations and have little effect at low concentrations. There is not enough verification of the toxicity. Therefore, there is an urgent need to develop a safe alternative whitening agent that is excellent in small amount and has fewer side effects.

An object of the present invention is to provide a whitening cosmetic composition that can produce a more safe and excellent whitening effect.

Another object of the present invention to provide a composition for the prevention and treatment of skin diseases associated with hyperpigmentation.

In order to achieve the above and other objects, the present invention provides a cosmetic composition for whitening containing a benzaldehyde thiosemicarbazone derivative of the following chemical formula as an active ingredient:

[Chemical Structural Formula]

Where

R ₁ is cyclohexyl; C ₁ ~ C ₆ alkyl, C ₁ ~ C ₆ alkoxy, halogen, or C ₁ ~ C ₆ alkyl amine is a substituted phenyl; Hydrogen, C ₁ -C ₆ alkyl, or halogen substituted naphthalene;

R ₂ is H; C ₁ -C ₆ alkyl; Phenyl; Naphthalene;

N-phenylthiourea has been known as a representative inhibitor for tyrosinase. These enzymes, along with catechol oxidase, belong to the type-3 copper protein group. The crystal structure of phenylthiourea bound catechol oxidase has been reported [Gerdemann, C .; Eicken, C .; Krebs, B. Acc. Chem. Res. 2002, 35, 183. and Klabunde, T .; Eicken, C .; Sacchettini, J. C .; Krebs, B. Nat. Struct. Biol. 1998, 5, 1084. The sulfur atom of such a compound is bound to both copper ions at the active site of the enzyme [Klabunde, T .; Eicken, C .; Sacchettini, J. C .; Krebs, B. Nat. Struct. Biol. 1998, 5, 1084. In addition to the action with double copper centers, van der Waals interactions between residues lining hydrophobic cavities contribute to the high affinity of phenylthiourea for the enzyme [Klabunde, T]. .; Eicken, C .; Sacchettini, J. C .; Krebs, B. Nat. Struct. Biol. 1998, 5, 1084. Although the crystal structure of phenylthiourea bound tyrosinase is unknown, the binding modes of these compounds will be very similar because the active sites of tyrosinase are predominantly conserved and have a hydrophobic cavity similar to Tyr 98.

On the other hand, as known to the present inventors, there is no report on the structure activity relationship (SAR) of benzaldehyde thiosemicarbazone derivatives. Therefore, the inventors evaluated the inhibitory activity of a series of benzaldehyde thiosemicarbazone derivatives and studied SAR for melanonine formation. The general structural formula of the benzaldehyde thiosemicarbazone derivatives is illustrated in Scheme 1 below. Substituted benzaldehyde semithiocarbazones (Compounds 1 to 21) are synthesized by treating the appropriate benzaldehyde with semicarbazide as shown in Scheme 1 below.

Scheme

The benzaldehyde thiosemicarbazone derivative of the present invention is preferably included in 0.0001-5% by weight relative to the total weight of the composition.

The pharmaceutical composition of the present invention is used for the purpose of preventing or treating hypermelanin pigmentation such as blemishes, freckles, and senile plaques, and includes various pharmaceutically acceptable carriers, excipients, and / or additives. It may be formulated in a dosage form.

Representative examples include transdermal preparations such as creams, ointments, gels, lotions, solutions or patches.

The formulation of the cosmetic composition of the present invention can be selected arbitrarily, conventional external cosmetic ointment, essence, whitening cream, lotion, emulsion, pack, general cosmetic water, skin milk, cream, serum, beauty soap, softening cosmetics, medicinal It can be prepared in various forms, such as lotion, hair tonic, systemic cleanser and oil gel.

Cosmetic composition of the present invention further comprises at least one additive selected from the group consisting of oil, water, surfactants, moisturizers, thickeners, chelating agents, pigments, preservatives, and fragrances to produce a cosmetic composition, characterized in that Can be.

The cosmetic composition for whitening according to the present invention is very excellent in the melanin production inhibitory effect as shown in Table 1.

Hereinafter, the present invention is illustrated by the following examples. These Examples are for explaining the present invention, and the present invention is not limited to these Examples.

Example  One : Preparation of Compound 1

To 0.010 mol of a semicarbazide solution in 15 ml of heated water, 0.010 mol of an aldehyde solution in preheated ethanol was added and stirred for 20 minutes. The reaction mixture was then cooled to 0 ° C. The resulting solid was filtered, washed with cold water and purified by column chromatography to give the purest title compound [Ref. E.J. Med. Chem: 43 (2008), 135-141. For the reaction mechanism, reference was made to the following reaction schemes to synthesize compounds 1 to 21.

(E) -2-Benzylidenehydrazinecarbothioamide; Yield 95%; White solid; mp 146-148 ° C .; IR (neat); 3389, 3235, 3153, 1596, 1555, 1532; ¹ H NMR (CDCl ₃ ): δ 7.38-7.44 (m, 3H, Ar-H), 7.52-7.67 (m, 2H, Ar-H), 7.90 (s, 1H, CH = N), 9.83 (bs, 1H, NH).

Example 2: Preparation of Compound 2

(E) -2- (4-Methylbenzylidene) hydrazinecarbothioamide; Yield 98%; White solid; mp 169-171 ° C; IR (neat); 3367, 3259, 3170, 1650, 1644, 1538; ¹ H NMR (CDCl ₃ ): δ 2.47 (s, 3H, CH ₃ ), 7.39 (d, 2H, Ar-H, J = 8.4 Hz), 7.57 (d, 2H, Ar-H, J = 8.4 Hz) , 7.89 (s, 1H, CH = N), 9.81 (bs, 1H, NH).

Example 3: Preparation of Compound 3

(E) -2- (4-Ethylbenzylidene) hydrazinecarbothioamide; Yield 96%; White solid; mp 132-134 ° C .; IR (neat); 3403, 3251, 3157, 1594, 1538; ¹ H NMR (CDCl ₃ ): δ 1.22 (t, 3H, CH ₃ , J = 7.6 Hz), 2.64 (q, 2H, CH ₂ , J = 7.6 Hz), 7.22 (d, 2H, Ar-H, J = 8.0 Hz), 7.55 (d, 2H, Ar-H, J = 8.4 Hz), 7.93 (s, 1H, CH = N), 10.1 (bs, 1H, NH).

Example  4 : Preparation of Compound 4

(E) -2- (4-tert-Butylbenzylidene) hydrazinecarbothioamide; Yield 98%; Yellow solid; mp 149-151 ° C .; IR (neat); 3404, 3257, 3157, 1594, 1548, 1537; ¹ H NMR (CDCl ₃ ): δ 1.35 (s, 9H, (CH ₃ ) ₃ ), 7.38 (d, 2H, Ar-H, J = 8.4 Hz), 7.54 (d, 2H, Ar-H, J = 8.4 Hz), 7.86 (s, 1 H, CH = N), 9.85 (bs, 1 H, NH).

Example  5: Preparation of Compound 5

(E) -2- (3-Methylbenzylidene) hydrazinecarbothioamide; Yield 98%; White solid; mp 187-189 ° C .; IR (neat); 3443, 3150, 2986, 1594, 1462, 1269; ¹ HNMR (CDCl ₃ ); δ 2.48 (s, 3H, CH ₃ ), 7.30 (m, 4H, Ar-H), 7.60 (m, 2H, Ar-H), 7.91 (s, 1H, CH = N), 9.80 (bs, 1H, NH).

Example  6: Preparation of Compound 6

(E) -2- (2-Methylbenzylidene) hydrazinecarbothioamide; Yield 98%; White solid; mp 185-187 ° C; IR (neat); 3427, 3148, 3022, 1591, 1448, 1367 cm ⁻¹ ; ¹ HNMR (CDCl ₃ ); δ 2.46 (s, 3H, CH ₃ ), 6.34 (bs, 1H, NH), 7.20-7.47 (m, 3H, Ar-H), 7.51 (d, J = 7.8 Hz, 1H, Ar-H), 8.17 (s, 1H, CH = N), 9.60 (bs, 1H, NH).

Example  7: Preparation of Compound 7

(E) -2- (2-Chlorobenzylidene) hydrazinecarbothioamide; Yield 96%; White solid; mp 205-207 ° C; IR (neat); 3333, 3150, 2986, 1686, 1591, 1448 cm ⁻¹ ; ¹ HNMR (CDCl ₃ ); δ 7.23-7.52 (m, 3H, Ar-H), 7.89 (d, J = 8.0 Hz, 1H, Ar-H), 8.23 (s, 1H, CH = N), 9.22 (bs, 1H, NH) .

Example  8 : Preparation of Compound 8

(E) -2- (3-Chlorobenzylidene) hydrazinecarbothioamide; Yield 97%; White solid; mp 192-194 ° C; IR (neat); 3323, 3200, 3022, 1690, 1544, 1461 cm ^-1 ; ¹ HNMR (CDCl ₃ ); δ 7.55-7.61 (m, 2H, Ar-H), 7.71 (s, 1H, Ar-H), 7.92 (d, J = 8.0 Hz, 1H, Ar-H), 8.25 (s, 1H, CH = N ), 9.34 (bs, 1 H, NH).

Example  9: Preparation of Compound 9

(E) -2- (4-Chlorobenzylidene) hydrazinecarbothioamide; Yield 96%; White solid; mp 191-193 ° C; IR (neat); 3425, 3151, 2985, 1688, 1594, 1448 cm ⁻¹ ; ¹ HNMR (CDCl ₃ ); δ 7.38-7.40 (m, 2H, Ar-H) 7.68-7.70 (m, 2H, Ar-H), 8.27 (s, 1H, CH = N), 9.31 (bs, 1H, NH).

Example  10: Preparation of the following Compound 10

(E) -2- (2- Methoxybenzylidene ) hydrazinecarbothioamide ; Yield 98%; White solid; mp 142-144 ° C; IR (neat); 3443, 3314, 3255, 1986, 1698, 1591, 1465 cm ⁻¹ ; ¹ HNMR (CDCl ₃ ); δ 3.85 (s, 3H, OCH ₃ ), 7.27-7.38 (m, 2H, Ar-H), 7.75 (t, J = 8.0 Hz, 1H, Ar-H), 7. 92 (d, J = 8.0 Hz , 1H, Ar-H), 8.19 (s, 1H, CH = N), 9.38 (bs, 1H, NH).

Example  11: Preparation of Compound 11

(E) -2- (3-Methoxybenzylidene) hydrazinecarbothioamide; Yield 98%; Yellow solid; mp 193-195 ° C; IR (neat); 3445, 3321, 3150, 1694, 1594, 1502 cm ⁻¹ ; ¹ HNMR (CDCl ₃ ); δ 3.83 (s, 3H, OCH ₃ ), 6.80 (d, J = 8.0 Hz, 1H, Ar-H), 7.20-7.36 (m, 2H, Ar-H), 7.55 (s, 1H, Ar-H) , 7.94 (s, 1H, CH = N), 11.23 (bs, 1H, NH).

Example  12: Preparation of Compound 12

(E) -2- (4- Methoxybenzylidene ) hydrazinecarbothioamide ; Yield 94%; Yellow solid; mp 173-175 ° C; IR (neat); 3443, 3263, 3149, 3045, 1714, 1686, 1541 cm ⁻¹ ; ¹ HNMR (CDCl ₃ ); δ 3.86 (s, 3H, OCH ₃ ), 7.22 (d, J = 8.4 Hz, 2H, Ar-H), 7.91 (d, J = 8.4 Hz, 2H, Ar-H), 8.23 (s, 1H, CH = N). 9.40 (bs, 1 H, NH).

Example  13: Preparation of the following Compound 13

(E) -2- (2-Hydroxybenzylidene) hydrazinecarbothioamide; Yield 94%; White solid; mp 213-215 ° C; IR (neat); 3443, 3150, 2985, 1686, 1594, 1539 cm ⁻¹ ; ¹ HNMR (DMSO); δ 6.95 (d, J = 8.0 Hz, 1H, Ar-H), 7.27 (d, J = 8.0 Hz, 1H, Ar-H), 7.38 (d, J = 8.0 Hz, 1H, Ar-H), 7.89 (d, J = 8.0 Hz, 1H, Ar-H), 8.39 (s, 1H, CH = N), 9.57 (s, 1H, OH), 11.3 (bs, 1H, NH).

Example  14: Preparation of the following Compound 14

(E) -2- (3- Hydroxybenzylidene ) hydrazinecarbothioamide ; Yield 95%; White solid; mp 142-144 ° C; IR (neat); 3439, 3236, 3149, 1687, 1540, 1341 cm ⁻¹ ; ¹ HNMR (DMSO); δ 6.82 (d, J = 8.0 Hz, 1H, Ar-H), 7.21-7.27 (m, 3H, Ar-H), 8.17 (s, 1H, CH = N), 9.59 (s, 1H, OH), 11.23 (bs, 1 H, NH).

Example  15: Preparation of the following Compound 15

(E) -2- (4- Hydroxybenzylidene ) hydrazinecarbothioamide ; Yield 95%; Yellow solid; mp 158-160 ° C; IR (neat); 3441, 3150, 2986, 1689, 1543, 1287 cm ⁻¹ ; ¹ HNMR (DMSO); δ 6.85 (d, J = 8.4 Hz, 2H, Ar-H), 7.52 (d, J = 8.4 Hz, Ar-H), 8.21 (s, 1H, CH = N), 9.597 (s, 1H, OH) , 11.20 (bs, 1 H, NH).

Example  16: Preparation of Compound 16

(E) -2- (Cyclohexylmethylene) hydrazinecarbothioamide; Yield 98%; White solid; mp; 84-86 ° C .; IR (neat); 3442, 3322, 3151, 2985, 1687, 1595, 1448 cm ⁻¹ ; ¹ HNMR (CDCl ₃ ); δ 1.18-1.35 (m, 5H), 1.61-1.83 (m, 5H), 2.21-2.24 (m, 1H), 6.21 (bs, 1H, NH), 7.12 (d, J = 6.4 Hz, 1H, CH = N), 9.14 (bs, 1 H, NH).

Example  17: Preparation of Compound 17

(E) -2- (4-tert-Butylbenzylidene) -N-phenylhydrazinecarbothioamide; Yield 92%; White solid; mp; 178-180 ° C .; IR (neat); 3443, 3266, 2987, 1686, 1597, 1508 cm ⁻¹ ; ¹ HNMR (CDCl ₃ ); δ 1.34 (s, 9H), 7.28-7.46 (m, 5H, Ar-H), 7.57 (d, J = 8.4 Hz, 2H, Ar-H), 7.63 (d, J = 8.4 Hz, 2H, Ar- H), 7.91 (s, 1 H, CH = N), 9.21 (bs, 1 H, NH), 9.65 (bs, 1 H, NH).

Example  18: Preparation of Compound 18

(E) -2- (4-tert-Butylbenzylidene) -N-methylhydrazinecarbothioamide; Yield 92%; White solid; mp; 142-144 ° C; IR (neat); 3441, 3235, 2984, 1689, 1541, 1447, 1397 cm ⁻¹ ; ¹ HNMR (CDCl ₃ ); δ 1.31 (s, 9H), 3.27 (d, J = 5.5 Hz, 3H), 7.37 (d, J = 8.4 Hz, 2H, Ar-H), 7.45 (bs, 1H, NH), 7.56 (d, J = 8.4 Hz, 2H, Ar-H), 7.87 (s, 1H, CH = N), 9.99 (bs, 1H, NH).

Example  19: Preparation of Compound 19

(E) -2- (Naphthalen-1-ylmethylene) hydrazinecarbothioamide; Yield 97%; Yellow solid; mp 124-126 ° C; IR (neat); 3443, 3236, 3045, 2987, 1686, 1594, 1502, 1341 cm ⁻¹ ; ¹ HNMR (CDCl ₃ ); δ 7.45-7.60 (m, 3H, Ar-H), 7.79-7.88 (m, 4H, Ar-H), 7.97 (s, 1H, CH = N), 9.55 (bs, 1H, NH).

Example  20: Preparation of Compound 20

(E) -2- (Pyridin-4-ylmethylene) hydrazinecarbothioamide; Yield 95%; Yellow solid; mp 212-214 ° C; IR (neat); 3443, 3182, 1686, 1595, 1541 cm ⁻¹ ; ¹ HNMR (DMSO); δ 7.97 (s, 1H, CH = N), 8.06 (d, J = 8.4 Hz, 2H), 8.85 (d, J = 8.4 Hz, 2H), 9.60 (bs, 1H, NH).

Example  21: Preparation of Compound 21

(E) -2- (2-Ethylbenzylidene) hydrazinecarbothioamide; Yield 94%; White solid; mp 186-188 ° C; IR (neat); 3441, 3280, 3142, 2960, 1690, 1597, 1538, 1375 cm ⁻¹ ; ¹ HNMR (CDCl ₃ ); δ 1.25 (t, J = 4.6 Hz, 3H, CH ₃ ), 2.57 (q, J = 5.6 Hz, 2H, CH ₂ ), 7.25-7.27 (m, 3H, Ar-H), 7.72 (d, J = 8.0 Hz, 1 H, Ar-H), 8.19 (s, 1 H, CH = N), 9.61 (bs, 1 H, NH).

Experimental Example

Measurement of melanogenesis inhibitory effect through cAMP / protein kinase A

Cell line melanoma B16 to which alpha-melanosite stimulating hormone was added produces melanin through signal transduction of cAMP / protein kinase A (Rasmussen, N., et al. , Neuroendocrinol . Lett ., 20: 265-282 , 1999; Scott, MC, et al ., J. Cell . Sci. 115: 2349-55, 2002). All synthesized derivatives described above were tested for their inhibitory activity on melanin formation in melanoma B16 cell lines as shown in Table 1 below. The reason why the tyrosinase itself is not used in this experimental example is that these inhibitors have the purpose of reducing melanin formation. Melanin production by comparing the amount of melanin produced after simultaneously treating the compounds prepared in the above embodiments with alpha-melanosite stimulating hormone and the amount of melanin produced when the compounds of the examples were not treated Inhibitory effect was calculated.

Where

Mc is the melanin production amount of the control group which added only alpha-melanosite stimulating hormone;

Mo is the amount of melanin produced in cell lines cultured without the addition of alpha-melanosite stimulating hormone,

Mi represents the amount of melanin produced by the test group to which the compounds 1 to 21 and alpha-melanosite stimulating hormone obtained through the examples are added.

More specifically, 2,500 cell lines of melanoma B16 were dispensed per well of a 96-well plate, and then cultured in DMEM medium containing 10% placental serum at 37 ° C. and 5% CO ₂ for 24 hours. After incubation, the alpha-melanosite stimulating hormone (final concentration 1 nM) and the derivative prepared in Example (one of compounds 1 to 21) were simultaneously treated with various sample concentrations (10 μM, 5 μM, 1 μM, 0.5 μM, or 0.05 μM). After further incubation for 3 days, the amount of melanin released into the medium was quantified by measuring absorbance at a wavelength of 405 nm. All the compounds according to the present invention did not inhibit the growth of B16 cells at the measured concentrations of this example was confirmed that there is no cytotoxicity.

Cell line melanoma B16 cultured in DMEM medium containing 10% placental serum without addition of alpha-melanosite stimulating hormone released melanin of 59 W1 μg / mL and alpha-melano in the same medium. When the site-stimulating hormone was added, 156 W 2 μg / mL of melanin was released. On the other hand, in the same experimental model, the results of 50% inhibition concentration of arbutin and kojic acid were 151 μM and 263 μM, respectively. The inhibitory activity of melanin production in melanoma B16 cells of the benzaldehyde thiosemicarbazone derivatives (compounds 1 to 21) of the present invention is shown in Table 1 below.

In addition, as can be seen through Table 1, benzaldehyde thiosemicarbazone (Compound 1 , less than 10% inhibition at 10μM, IC ₅₀ > 10μM, Clog P = 1.865) bioassay performed by the inventors Although no activity was shown by, para-methyl substituted analogs (Compound 2 , 64% inhibition rate at 10 μM, IC ₅₀ = 6.8 μM, Clog P = 2.364) showed high inhibitory activity. Interestingly, when increasing the hydrophobicity at the para- position, the benzaldehyde thiosemicarbazone analog, namely (E) -2- (4-ethylbenzylidene) hydrazinecarbothioamide (Compound 3 , 100% inhibition at 10 μM, IC ₅₀ = 3.4 μM, Clog P = 2.893) and (E) -2- (4-tert-butylbenzylidene) hydrazinecarbothioamide (Compound 4 , 100% inhibition at 10 μM, IC ₅₀ = 2.7 μM, Clog P = 2.893) showed 100% inhibition as described above. In addition, Compound 5 , Compound 6 , Compound 7 , Compound 17 , Compound 19, and Compound 21 showed 100% inhibition at 10 μM, and Compound 8 , Compound 9 , Compound 16 , and Compound 18 showed 80% or more inhibition.

Formulation example  One : Preparation of nourishing cream

A nutrition cream containing one of the compounds 1 to 21 as an active ingredient in the composition shown in Table 2 was prepared according to a conventional method.

Ingredient Name Added amount (% by weight) Compound 5 0.5 Liquid paraffin 5.0 Squalane 10.0 glycerin 10.0 beeswax 5.0 Glyceryl Stearate 2.0 Stearic acid 3.0 Polysorbate 60 1.5 Sorbitan sesquistearate 0.3 Carboxy Polymer 0.3 Preservative, fragrance, pigment, pH adjuster Quantity Purified water up to 100

Formulation example  2 : Preparation of Soft Cosmetics

In the composition as shown in Table 3 below, the flexible longevity containing one of the compounds 1 to 21 as an active ingredient was prepared according to a conventional method.

Ingredient Name Added amount (% by weight) Compound 5 0.2 Tocopherol Acetate 5.0 ethanol 10.0 glycerin 5.0 1,3-butylglycol 5.0 Carboxy Polymer 0.3 Preservative, fragrance, pigment, pH adjuster Quantity Purified water up to 100

Formulation example  3: Pack

A pack containing one of the compounds 1 to 21 as an active ingredient in a composition as shown in Table 4 was prepared according to a conventional method.

Ingredient Name Added amount (% by weight) Compound 5 0.5 Polyvinyl alcohol 15.0 ethanol 10.0 glycerin 5.0 Polyoxyethylene oleylethyl 1.0 Preservative, fragrance, pigment, pH adjuster Quantity Purified water up to 100

Formulation example  4 : Ointment preparation

To the composition as shown in Table 5 was prepared an ointment containing one of the compounds 1 to 21 as an active ingredient in a conventional manner.

Ingredient Name Added amount (% by weight) Compound 5 1.0 Diethyl sebacate 8.0 Prepayment 5.0 Polyoxyethylene oleyl ether phosphate 6.0 Paraoxybenzoic Acid Ester Quantity vaseline up to 100

Skin irritation test

In a closed patch test method, 20 healthy men and women were checked for the skin irritation degree of the nourishing cream of Formulation Example 1 for 24 hours.

Claims (7)

A whitening composition containing benzaldehyde thiosemicarbazone derivative of the following chemical structural formula as an active ingredient:

Where
R ₁ is cyclohexyl; C ₁ ~ C ₆ alkyl, C ₁ ~ C ₆ alkoxy, halogen, or C ₁ ~ C ₆ alkyl amine is a substituted phenyl; Hydrogen, C ₁ -C ₆ alkyl, or halogen substituted naphthalene;
R ₂ is H; C ₁ -C ₆ alkyl; Phenyl; Naphthalene; (E) -2- (4-methylbenzylidene) hydrazinecarbothioamide,
(E) -2- (4-ethylbenzylidene) hydrazinecarbothioamide,
(E) -2- (4-tert-butylbenzylidene) hydrazinecarbothioamide,
(E) -2- (3-methylbenzylidene) hydrazinecarbothioamide,
(E) -2- (2-methylbenzylidene) hydrazinecarbothioamide,
(E) -2- (2-chlorobenzylidene) hydrazinecarbothioamide,
(E) -2- (3-chlorobenzylidene) hydrazinecarbothioamide,
(E) -2- (4-chlorobenzylidene) hydrazinecarbothioamide,
(E) -2- (2-methoxybenzylidene) hydrazinecarbothioamide,
(E) -2- (3-methoxybenzylidene) hydrazinecarbothioamide,
(E) -2- (4-methoxybenzylidene) hydrazinecarbothioamide,
(E) -2- (2-hydroxybenzylidene) hydrazinecarbothioamide,
(E) -2- (3-hydroxybenzylidene) hydrazinecarbothioamide,
(E) -2- (cyclohexylmethylene) hydrazinecarbothioamide,
(E) -2- (4-hydroxybenzylidene) hydrazinecarbothioamide,
(E) -2- (4-tert-butylbenzylidene) -N-phenylhydrazinecarbothioamide,
(E) -2- (4-tert-butylbenzylidene) -N-phenylhydrazinecarbothioamide,
(E) -2- (naphthalen-1-ylmethylene) hydrazinecarbothioamide,
(E) -2- (2-ethylbenzylidene) hydrazinecarbothioamide,
Whitening composition, characterized in that selected from. A pharmaceutical composition for preventing and treating hyperpigmentation disorders, comprising the whitening composition according to claim 1 or 2 as an active ingredient. The method of claim 3, wherein
A pharmaceutical composition for the prevention and treatment of hyperpigmentation diseases, characterized in that the formulation of the composition is a cream, ointment, gel, lotion, liquid, or patch. A whitening cosmetic composition comprising a composition for whitening according to claim 1 or 2 as an active ingredient. 6. The method of claim 5,
The whitening cosmetic composition is an external skin ointment, essence, whitening cream, lotion, emulsion, pack, general cosmetics, skin milk, cream, serum, cosmetic soap, softening cosmetics, medicinal cosmetics, hair tonic, systemic cleaner or oil gel Whitening cosmetic composition. The method of claim 6,
The whitening cosmetic composition further comprises at least one additive selected from the group consisting of oil, water, surfactants, moisturizers, thickeners, chelating agents, pigments, preservatives, and fragrances.