JP5469013B2 - Skin whitening composition, plant-extracted skin whitening composition, and composition having skin whitening effect - Google Patents

Description

  The present invention relates to a skin whitening composition, and more particularly to a skin whitening composition, a plant-extracted skin whitening composition, and a composition having a skin whitening effect, which contains a spermidine derivative having tyrosinase inhibitory activity. is there.

  By the catalytic action of tyrosinase, tyrosine originally present in melanocytes is converted to L-dopa, and then L-dopa is converted to L-dopaquinone. Thereafter, L-dopaquinone forms melanin by a series of oxidation actions. Melanin is the cause of skin darkening. Tyrosinase is the only important enzyme in the synthesis reaction of melanin. Therefore, if tyrosinase is suppressed, these two oxidation processes of converting tyrosine into L-dopa and converting L-dopa into L-dopaquinone can be delayed. Therefore, by inhibiting tyrosinase in melanocytes, melanin synthesis can be reduced and a whitening effect can be achieved.

  Examples of compounds known to be used for inhibiting melanin synthesis include hydroquinone, ellagic acid, kojic acid, arbutin, glycopeptide, and azelaic acid.

  The lotus is the whole plant of the flower lotus (Nelumbo Nucifera Gaertn) belonging to the family Nymphaeaceae. According to the literature, the chemical constituents of flower lotus are anonaine, asimilobine, dehydronucleiline, dehydroelineine, and dehydroanineine. liensine), isoriensinine and the like. The present inventors have discovered a spermidine derivative, a keyanidine compound, as a skin whitening component by using a bioactivity-inducing fractionation method.

Biological and Pharmaceutical Bulletin (Biol. Pharm. Bull.), 2002, 25, 8, p. 1045-1048 Biological and Pharmaceutical Bulletin (Biol. Pharm. Bull.), 2004, 27, 12, p. 1976-1978

  An object of this invention is to provide the composition for skin whitening, the plant extraction skin whitening composition, and the composition which has a skin whitening effect.

  The present invention relates to the following formula (I):

Wherein the R1 to R5, independently of one another, H, OH or OCH _3, at least one of R1 to R5 is OH]
And a spermidine derivative having a tyrosinase inhibitory activity, and a cosmetically or pharmaceutically acceptable excipient, the composition for skin whitening is provided.

  The present invention also provides the following formula (I):

Wherein the R1 to R5, independently of one another, H, OH or OCH _3, at least one of R1 to R5 is OH]
A plant-extracted skin whitening comprising an effective amount of a spermidine derivative extracted from a plant material and a cosmetically or pharmaceutically acceptable excipient, and having a tyrosinase inhibitory activity A composition is provided.

  Furthermore, the present invention provides the following formula (I):

Wherein the R1 to R5, independently of one another, H, OH or OCH _3, at least one of R1 to R5 is OH]
In shown, and the skin whitening characterized by containing an effective amount of Hasushin (a bud of a Nelumbo nucifera Gaertn ) extract having a tyrosinase inhibiting activity, and a acceptable excipient cosmetically or pharmaceutically A composition having an effect is provided.

  ADVANTAGE OF THE INVENTION According to this invention, the composition for skin whitening containing the effective amount of spermidine derivative which has tyrosinase inhibitory activity as a skin whitening component, a plant extraction skin whitening composition, and the composition which has skin whitening effect are provided.

  In the present invention, a composition containing a spermidine derivative is used as a skin whitening composition to suppress tyrosinase and whiten the skin.

  The composition of the present invention contains an effective amount of a spermidine derivative and a cosmetically or pharmaceutically acceptable excipient. Spermidine derivatives have tyrosinase inhibitory activity. The spermidine derivative has the following formula (I):

Indicated by

In the above formula (I), R1 to R5 independently of one another, H, OH or OCH _3, at least one of R1 to R5 is OH. In certain embodiments, R3 is OH. In certain embodiments, R1, R2, R4, and R5 are H and R3 is OH. In another embodiment, R1, R2 and R5 are H, R3 is OH, R4 is OCH _3. In yet another embodiment, R2, R3, R4 and R5 are H and R1 is OH. In yet another embodiment, R1, R2 and R5 are H and R3 and R4 are OH.

The spermidine derivative may be a plant extract. Examples of the plant, for example, Hasushin (a bud of a Nelumbo nucifera Gaertn ), groundnut (Arachis hypogaea), blue蒿(success) (Artemisia caruifolia), Kashiwa (Quercus dentate), rose family (Rosaceae), acanthaceae (Acanthaceae) And pandaaceae (Pandaceae). These plants may be used alone or in combination of two or more. In one embodiment, the plant is a lotus heart .

  A method for extracting a spermidine derivative from a plant performs the extraction process on the plant using a suitable solvent. In one embodiment, acetone is used to perform the extraction process on the plant. In another embodiment, the plant is extracted with acetone and then further extracted with another solvent. Examples of other solvents include n-hexane, ethyl ether, dichloromethane, ethyl acetate and the like. These solvents may be used alone or in combination of two or more.

The spermidine derivative has a 50% tyrosinase inhibitory concentration (IC ₅₀ ) of less than about 450 μg / mL. In certain embodiments, the spermidine derivative has a 50% tyrosinase inhibitory concentration (IC ₅₀ ) of less than about 37 μg / mL. In another embodiment, the 50% tyrosinase inhibitory concentration (IC ₅₀ ) of the spermidine derivative is less than about 19 μg / mL.

  The spermidine derivative has a tyrosinase inhibition rate of greater than about 10% at a concentration of 100 μg / mL. In certain embodiments, the spermidine derivative has a tyrosinase inhibition rate of about 10% to about 65% at a concentration of 100 μg / mL.

  In certain embodiments, the spermidine derivative has the formula (II):

Indicated by

The spermidine derivative represented by the above formula (II) may be a plant extract. Examples of the plant, for example, Hasushin (a bud of a Nelumbo nucifera Gaertn ), groundnut (Arachis hypogaea), blue蒿(success) (Artemisia caruifolia), Kashiwa (Quercus dentate), rose family (Rosaceae), acanthaceae (Acanthaceae) And pandaaceae (Pandaceae). These plants may be used alone or in combination of two or more. In one embodiment, the plant is a lotus heart .

The spermidine derivative has a 50% tyrosinase inhibitory concentration (IC ₅₀ ) of less than about 37 μg / mL. The spermidine derivative has a tyrosinase inhibition rate of 60% or more, preferably about 62% at a concentration of 100 μg / mL.

  In another embodiment, the spermidine derivative has the following formula (III):

Indicated by

The spermidine derivative has a 50% tyrosinase inhibitory concentration (IC ₅₀ ) of less than about 19 μg / mL. The spermidine derivative has a tyrosinase inhibition rate of 60% or more, preferably about 63% at a concentration of 100 μg / mL.

  In another aspect, the present invention provides a plant extract whitening composition. The plant extract whitening composition contains an effective amount of a spermidine derivative extracted from a plant and a cosmetically or pharmaceutically acceptable excipient. The spermidine derivative has the following formula (I):

Indicated by

In the above formula (I), R1 to R5 independently of one another, H, OH or OCH _3, at least one of R1 to R5 is OH. In certain embodiments, R3 is OH. In certain embodiments, R1, R2, R4, and R5 are H and R3 is OH. In another embodiment, R1, R2 and R5 are H, R3 is OH, R4 is OCH _3. In yet another embodiment, R2, R3, R4 and R5 are H and R1 is OH. In yet another embodiment, R1, R2 and R5 are H and R3 and R4 are OH.

The spermidine derivative may be a plant extract. Examples of the plant, for example, Hasushin (a bud of a Nelumbo nucifera Gaertn ), groundnut (Arachis hypogaea), blue蒿(success) (Artemisia caruifolia), Kashiwa (Quercus dentate), rose family (Rosaceae), acanthaceae (Acanthaceae) And pandaaceae (Pandaceae). These plants may be used alone or in combination of two or more. In one embodiment, the plant is a lotus heart .

  A method for extracting a spermidine derivative from a plant performs the extraction process on the plant using a suitable solvent. In one embodiment, acetone is used to perform the extraction process on the plant. In another embodiment, the plant is extracted with acetone and then further extracted with another solvent. Examples of other solvents include n-hexane, ethyl ether, dichloromethane, ethyl acetate and the like. These solvents may be used alone or in combination of two or more.

The spermidine derivative has a 50% tyrosinase inhibitory concentration (IC ₅₀ ) of less than about 450 μg / mL. In certain embodiments, the 50% tyrosinase inhibitory concentration (IC ₅₀ ) of the spermidine derivative is less than about 19 μg / mL. Furthermore, the spermidine derivative has a tyrosinase inhibition rate of greater than about 10% at a concentration of 100 μg / mL. In certain embodiments, the spermidine derivative has a tyrosinase inhibition rate of about 10% to about 65% at a concentration of 100 μg / mL.

  In one specific example, the spermidine derivative has the following formula (II):

Indicated by

The spermidine derivative represented by the above formula (II) may be a plant extract. Examples of the plant, for example, Hasushin (a bud of a Nelumbo nucifera Gaertn ), groundnut (Arachis hypogaea), blue蒿(success) (Artemisia caruifolia), Kashiwa (Quercus dentate), rose family (Rosaceae), acanthaceae (Acanthaceae) And pandaaceae (Pandaceae). These plants may be used alone or in combination of two or more. In one embodiment, the plant is a lotus heart .

The spermidine derivative has a 50% tyrosinase inhibitory concentration (IC ₅₀ ) of less than about 37 μg / mL. The spermidine derivative has a tyrosinase inhibition rate of 60% or more, preferably about 62% at a concentration of 100 μg / mL.

In yet another aspect, the present invention provides a composition having a skin whitening effect comprising an effective amount of lotus extract and a cosmetically or pharmaceutically acceptable excipient.

Lotus root extract has tyrosinase inhibitory activity. The method for preparing lotus root extract performs an extraction process on plants using a suitable solvent. In one embodiment, acetone is used to perform the extraction process on the plant. In another embodiment, the plant is extracted with acetone and then further extracted with another solvent. Examples of other solvents include n-hexane, ethyl ether, dichloromethane, ethyl acetate and the like. These solvents may be used alone or in combination of two or more.

Lotus root extract contains a spermidine derivative as an active ingredient. The spermidine derivative has the following formula (I):

Indicated by

In the above formula (I), R1 to R5 independently of one another, H, OH or OCH _3, at least one of R1 to R5 is OH. In one specific example, R3OH. In certain embodiments, R1, R2, R4, and R5 are H and R3 is OH. In another embodiment, R1, R2 and R5 are H, R3 is OH, R4 is OCH _3. In yet another embodiment, R2, R3, R4 and R5 are H and R1 is OH. In yet another embodiment, R1, R2 and R5 are H and R3 and R4 are OH.

The spermidine derivative has a 50% tyrosinase inhibitory concentration (IC ₅₀ ) of less than about 450 μg / mL. In certain embodiments, the 50% tyrosinase inhibitory concentration (IC ₅₀ ) of the spermidine derivative is less than about 19 μg / mL. Furthermore, the spermidine derivative has a tyrosinase inhibition rate of greater than about 10% at a concentration of 100 μg / mL. In certain embodiments, the spermidine derivative has a tyrosinase inhibition rate of about 10% to about 65% at a concentration of 100 μg / mL.

  In certain embodiments, the spermidine derivative has the formula (II):

Indicated by

The spermidine derivative has a 50% tyrosinase inhibitory concentration (IC ₅₀ ) of less than about 37 μg / mL. The spermidine derivative has a tyrosinase inhibition rate of 60% or more, preferably about 62% at a concentration of 100 μg / mL.

  Furthermore, the cosmetically or pharmaceutically acceptable excipients of all the above-mentioned compositions serve as diluents, dispersants or carriers for the active ingredient. Cosmetically or pharmaceutically acceptable excipients include materials commonly used in skin care products, such as water, liquid or solid emollients, silicone oils, emulsifiers, solvents, humectants, thickeners, Examples thereof include powders and propellants.

  The excipient is contained in a proportion of preferably 5% by mass to 99.9% by mass, more preferably 25% by mass to 80% by mass with respect to 100% by mass of all the above-described compositions, In the absence of additives, the remaining portion of all the compositions described above, excluding the active ingredient, is formed.

  Moreover, all the above-mentioned compositions may contain, for example, sunscreens, skin lightening agents, sunscreens, etc. as other specific components useful for the skin. Further, the excipient may contain an antioxidant, a flavoring agent, an opacifier, a preservative, a coloring agent, a buffering agent and the like.

  Further, in certain embodiments, all of the compositions described above are manufactured as skin coatings such as, but not limited to, creams, ointments, gels, sprays, lotions, tonics, shampoos, mousses and the like. Skin spray is generally composed of an aerosolized copolymer such as polyvinyl pyrrolidone or vinyl acetate, and also functions as a set lotion. Skin gel preparations are similar in composition to sprays, but are gel-like and can be coated on the skin without the addition of alcohol. Skin mousse is a foam released by pressure from an aerosol can. Skin creams may be hydrophobic or hydrophilic creams, ointments, gels, emollients, sprays, lotions, skin tonics, shampoos or mousses, suitable for use in skin creams of types known in the art. Other components are appropriately contained. Examples of such other ingredients include petrolatum, wax, lanolin, silicone, liposome, vegetable oil, mineral oil, plasticizer, fragrance, preservative, penetration enhancer, pH adjuster, and other suitable skin cream ingredients. Is mentioned. Such ingredients can moisturize the skin, stabilize the active compound, increase contact between the composition and the skin, increase the local concentration of the composition, and control the release of the composition.

  Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to the following examples, and appropriate modifications are made within a range that can meet the purpose described above and below. Any of these can be carried out and are included in the technical scope of the present invention.

  Compounds 1 to 4 having a common structure represented by the following formula (I) were extracted from plants or prepared by synthesis. Table 1 shows the structures of Compounds 1 to 4.

  In the Examples, skin whitening effects were analyzed using a tyrosinase inhibition test and a melanin content test as described below.

<Tyrosinase inhibition test>
See Non-Patent Documents 1 and 2 for this test.

  1. Tyrosinase (Sigma T3824) was diluted with 0.1 M phosphate buffer to obtain a 0.1 U / μL tyrosinase solution.

  2. L-dopa (Sigma D9628) was diluted with 0.1 M phosphate buffer to obtain a 1 mM L-dopa solution. The L-dopa solution was stored in the dark.

  3. The sample solution was diluted with 100% DMSO to prepare a 10 mg / mL test sample solution. The test sample solution was then diluted to the desired concentration with 0.1 M phosphate buffer buffer.

4). 50 μL / well of the test sample solution prepared as above was added to the wells of the 96-well plate (Note: DMSO at the same dilution concentration used to dilute the test sample solution was added to the wells of the 96-well plate, Used as blank group). Then, 90 μL / well of 0.1 U / μL tyrosinase solution was added (in the dC control group, only 0.1 phosphate buffer was added and 0.1 U / μL tyrosinase solution was not added). The 96-well plate was placed at a temperature of 37 ° C., mixed at 450 rpm for 5 minutes, and then placed in an ELISA reader (Molecular Devices M2). The wavelength of the ELISA reader was set at 492 nm, and the absorbance value of the solution added to the 96-well plate was measured. Absorbance values were measured twice and the average value was used as the background value. Next, 60 μL / well of 1 mM L-dopa solution prepared as described above was added to the 96-well plate (in the dD control group, only 0.1 M phosphate buffer was added and 1 mM L-dopa solution was not added. ) The 96 well plate was then placed in the dark at a temperature of 37 ° C., mixed for 15 minutes at 450 rpm, and then placed in an ELISA reader (Molecular Devices M2). The wavelength of the ELISA reader was set at 492 nm, and the absorbance value of the solution added to the 96-well plate was measured. The absorbance value was measured twice, and the average value was used as the measured value. After subtracting the background value from the measured value, the tyrosinase inhibition rate of the sample was calculated. The formula for calculating the tyrosinase inhibition rate of the sample is as follows:
[(A-A ₀ )-(B-B ₀ ) -dC-dD] / (A-A ₀ ) × 100%
A: Absorbance value of blank group B: Absorbance value of sample A ₀ : Background value of blank group B ₀ : Background value of sample dC: Absorbance change of sample reacting only with L-dopa dD: Reacting with tyrosinase Sample absorbance change

<Melanin suppression test>
1. Cell line culture Mouse melanoma B16-F0 (ATCC CRL-6322, Food Industry Development Institute (FIRDI) (331 Shih-Pin Road, Hsinchu, 300 Taiwan ROC) .)) Was cultured in a medium containing 10% fetal calf serum and 1% penicillin-streptomycin (Dulbecco's MEM, DMEM) at a temperature of 37 ° C. in a 5% CO ₂ incubator. did.

2. Melanin content analysis Inhibition of B16 cell melanin by extract B16 cells in the medium were added to the test sample and after 48 hours the medium was removed. After washing B16 cells twice with PBS buffer, 300 μL of 1N NaOH preheated to a temperature of 70 ° C. was added to the B16 cells, and the B16 cells were allowed to stand for 60 minutes in a 60 ° C. incubator. Next, 200 μL of 1N NaOH was added to the 96-well plate and the absorbance value was measured at a wavelength of 405 nm. The formula for calculating melanin content is as follows:
Melanin content = (M / M ₀ ) × 100%
M: Absorbance value of B16 cells treated with sample M ₀ : Absorbance value of B16 cells not treated with sample

Example 1
<Extraction and Purification of Compound 1 from Plant>
Lotus root was extracted with acetone to obtain an extract. Next, 4.5 g of the extract was dissolved and mixed in 22.5 mL of methanol and water to obtain a mixed solution. The mixed solution was extracted 3 times with 22.5 mL of n-hexane, ethyl ether, dichloromethane and ethyl acetate, respectively, and the n-hexane layer extraction solution, ethyl ether layer extraction solution, dichloromethane layer extraction solution and An ethyl acetate extraction solution was obtained. After each layer extraction solution was concentrated and dried, each layer extract was obtained and a tyrosinase inhibition test was performed.

  The result showed that the ethyl acetate layer extract had tyrosinase inhibitory activity.

  After the ethyl acetate layer extract solution was concentrated and dried, 1.7883 g of ethyl acetate layer extract was obtained. The tyrosinase inhibition rate of the ethyl acetate layer extract was 86.98 ± 2.6%.

  The 1.5 g ethyl acetate layer extract was then separated by reverse phase open chromatography column (packed with 37.5 g RP-18 silica gel, 2 × 33 cm). The column mobile phase was changed in the order of methanol: water = 1: 10 → 1: 8 → 1: 4 → 1: 2 → 1: 1 → methanol. The ethyl acetate layer extract was separated by column chromatography to obtain 0.0875 g of the compound. This compound was subjected to spectral analysis and mass spectrometry. The results are shown below.

Spectrum analysis:
¹ H-NMR (500 MHz, CD ₃ OD): 7.56-7.34 (m, 9H); 6.88-6.72 (m, 7H), 6.44-6.35 (m, 2H) 3.57-3.47 (m, 4H); 3.36-3.31 (m, 4H); 1.94-1.84 (m, 2H); 1.74-1.58 (m, 4H)
Mass spectrometry:
ESI ⁺ -MS: 606 [M + Na] ⁺ ; 438; 204
According to the results of spectral analysis and mass spectrometry, this compound is compound 1.

<Tyrosinase inhibition test>
Next, for compound 1, a tyrosinase inhibition test and a 50% tyrosinase inhibition concentration (IC ₅₀ ) were calculated. The results are shown in Table 2. According to the results, Compound 1 has a tyrosinase inhibition rate of about 61.2 ± 2.5% at a concentration of 100 μg / mL. The 50% tyrosinase inhibitory concentration (IC ₅₀ ) of Compound 1 is 36.2 ± 2.5 μg / mL. Furthermore, when the melanin content test was done about the compound 1, the effect was shown with respect to the intracellular melanin content. According to the test results, Compound 1 has a melanin content inhibition rate of about 19.9 ± 4.2% at a concentration of 100 μg / mL.

<< Example 2 >>
<Synthesis of Compound 2>
0.44 g of ferulic acid, 0.1 g of spermidine, 0.33 g of 1-hydroxybenzotriazole and 0.476 g of N, N′-dicyclohexylcarbodiimide were added to 15 mL of tetrahydrofuran and reacted at room temperature for 16 hours. Subsequently, tetrahydrofuran was removed from the reaction solution using a rotary evaporator to obtain a reaction product. Then, methanol was added to the reaction product, stirred and filtered to remove solid insoluble matter. The filtered methanol solution was evaporated to give 1.2509 g of residue. 0.12 g of the residue was dissolved in 1 mL of methanol, and solid insoluble matter was removed by filtration. The filtered methanol solution was separated by semi-preparative reverse phase chromatography column (mobile phase consisting of water and acetonitrile) and collected to give 3.4 mg of compound. This compound was spectrally analyzed. The results are shown below.

Spectrum analysis:
¹ H-NMR (500 MHz, CD ₃ OD): 7.79-7.69 (m, 2H); 7.55-7.34 (m, 4H); 7.21-6.72 (m, 7H) 6.47-6.37 (m, 2H); 3.92-3.86 (m, 9H); 3.62-3.45 (m, 4H); 3.38-3.34 (m, 4H); 1.95-1.85 (m, 2H); 1.74-1.60 (m, 4H)
According to the results of spectral analysis, this compound is compound 2.

<Tyrosinase inhibition test>
Next, for compound 2, a tyrosinase inhibition test and a 50% tyrosinase inhibition concentration (IC ₅₀ ) were calculated. The results are shown in Table 2. According to the results, Compound 2 has a tyrosinase inhibition rate of 15.0 ± 1.7% at a concentration of 100 μg / mL, and a tyrosinase inhibition rate of 29.2 ± 2.0% at a concentration of 125 μg / mL. Have Further, the 50% tyrosinase inhibitory concentration (IC ₅₀ ) of Compound 2 is 225.4 ± 15.6 μg / mL.

Example 3
<Synthesis of Compound 3>
0.37 g 2-hydroxycinnamic acid, 0.1 g spermidine, 0.33 g 1-hydroxybenzotriazole and 0.5 g N, N′-dicyclohexylcarbodiimide are added to 10 mL tetrahydrofuran and allowed to react at room temperature for 16 hours. It was. Subsequently, tetrahydrofuran was removed from the reaction solution using a rotary evaporator to obtain a reaction product. Then, methanol was added to the reaction product, stirred and filtered to remove solid insoluble matter. The filtered methanol solution was evaporated to give 0.2546 g of residue. 0.06 g of the residue was dissolved in 1 mL of methanol, and solid insoluble matter was removed by filtration. The filtered methanol solution was separated by semi-preparative reverse phase chromatography column (mobile phase consisting of water and acetonitrile) and collected to give 2.2 mg of compound. This compound was spectrally analyzed. The results are shown below.

Spectrum analysis:
¹ H-NMR (500 MHz, CD ₃ OD): 7.84-7.80 (m, 2H); 7.49 (t, 1H); 7.48-7.43 (m, 3H); 7.28 -7.09 (m, 4H); 6.83-6.69 (m, 8H); 3.57-3.49 (m, 4H); 3.45-3.31 (m, 4H); 1 96-1.88 (m, 2H); 1.67-1.61 (m, 4H)
According to the results of spectral analysis, this compound is compound 3.

<Tyrosinase inhibition test>
Next, for compound 3, a tyrosinase inhibition test and a 50% tyrosinase inhibition concentration (IC ₅₀ ) were calculated. The results are shown in Table 2. According to the results, compound 3 has a tyrosinase inhibition rate of 10.4 ± 0.1% at a concentration of 100 μg / mL, and a tyrosinase inhibition rate of 13.2 ± 1.1% at a concentration of 125 μg / mL. Have Further, the 50% tyrosinase inhibitory concentration (IC ₅₀ ) of Compound 3 is 438.7 ± 77.4 μg / mL.

Example 4
<Synthesis of Compound 4>
10 g of caffeic acid was dissolved in 120 mL of tetrahydrofuran to obtain a solution. The solution was then placed in an ice bath and 24 mL of triethylamine and 12 mL of acetyl chloride were added to the solution. After the solution was stirred for 22 hours, the solvent of the solution was removed using a rotary evaporator. The reaction product was dissolved in 200 mL of dichloromethane, washed with 100 mL of water three times, dried over magnesium sulfate, and then the remaining solvent was removed using a rotary evaporator to obtain 13.481 g of product. Got.

  5.251 g of product was added to 47 mL of methanol, heated and dissolved to give a solution. After cooling this solution, it was left in a refrigerator for 3 days. The solid separated from the solution was then filtered, washed with a small amount of methanol and dried to give 0.87 g of purified product.

0.25 g of purified product and 2 mL of SOCl ₂ were dissolved in dry tetrahydrofuran and reacted at room temperature for 23 hours to form a mixture. A rotary evaporator was used to remove solvent and excess SOCl ₂ from the mixture. The reaction product was dissolved in 10 mL tetrahydrofuran and slowly added dropwise to a reaction bottle consisting of 0.042 g spermidine, 0.133 mL triethylamine and 10 mL tetrahydrofuran in an ice bath. The reaction solution was then refluxed for 4 hours. After completion of the reaction, tetrahydrofuran in the reaction solution was removed using a rotary evaporator. The reaction product is dissolved in 20 mL of dichloromethane and washed three times with 10 mL of water, then the dichloromethane layer is dried over magnesium sulfate and concentrated using a rotary evaporator to give 0.2826 g of acetylated O-protected. The product was obtained.

  0.1 g of acetylated O-protected product, 1 mL of tetrahydrofuran, 1 mL of methanol and 0.6 mL of concentrated hydrochloric acid were reacted at 60 ° C. for 30 minutes to obtain a reaction solution. Next, 10 mL of water and 10 mL of dichloromethane were added to the reaction solution, and insoluble matters were separated.

  The insoluble material was dissolved in 1 mL of methanol and separated by RP-18 thin layer chromatography (the mobile phase consisted of water and acetonitrile) and purified to obtain 6.4 mg of the compound. This compound was subjected to spectral analysis and mass spectrometry. The results are shown below.

Spectrum analysis:
¹ H-NMR (500 MHz, CD ₃ OD): 7.49-7.36 (m, 3H); 7.08-6.71 (m, 10H); 6.39-6.32 (m, 2H) 3.60-3.46 (m, 4H); 3.36-3.31 (m, 4H); 1.94-1.82 (m, 2H); 1.73-1.57 (m, 4H)
Mass spectrometry:
ESI ⁺ -MS: 632 [M + 1] ⁺ ; 470
According to the results of spectral analysis and mass spectrometry, this compound is compound 4.

<Tyrosinase inhibition test>
Next, for compound 4, a tyrosinase inhibition test and a 50% tyrosinase inhibition concentration (IC ₅₀ ) were calculated. The results are shown in Table 2. Compound 4 has a tyrosinase inhibition rate of 62.2 ± 27.2% at a concentration of 100 μg / mL and has a tyrosinase inhibition rate of 74.5 ± 16.1% at a concentration of 125 μg / mL. Further, the 50% tyrosinase inhibitory concentration (IC ₅₀ ) of Compound 4 is 18.6 ± 2.9 μg / mL.

  While the preferred embodiments have been disclosed herein, they are not intended to limit the invention in any way, and various modifications and variations will occur to those skilled in the art without departing from the spirit and scope of the invention. Therefore, the protection scope of the present invention is based on what is specified in the claims.

Claims (12)

The following formula (I):
Wherein the R1 to R5, independently of one another, H, OH or OCH _3, at least one of R1 to R5 is OH]
And a skin whitening composition comprising an effective amount of a spermidine derivative having a tyrosinase inhibitory activity and a cosmetically or pharmaceutically acceptable excipient.   The composition for skin whitening according to claim 1, wherein R3 of the spermidine derivative is OH. R1, R2, R4 and R5 of the spermidine derivative are H and R3 is OH, or R1, R2 and R5 of the spermidine derivative are H, R3 is OH and R4 is OCH ₃ Or R2, R3, R4 and R5 of the spermidine derivative are H and R1 is OH; alternatively, R1, R2 and R5 of the spermidine derivative are H and R3 and R4 are OH. The skin whitening composition according to claim 1. The composition for skin whitening according to any one of claims 1 to 3 , wherein the spermidine derivative has a tyrosinase inhibition rate of greater than 10% at a concentration of 100 µg / mL. The composition for skin whitening according to any one of claims 1 to 4 , wherein a 50% tyrosinase inhibitory concentration (IC ₅₀ ) of the spermidine derivative is smaller than 450 µg / mL. The spermidine derivative has the following formula (II):
The composition for skin whitening of Claim 1 shown by these. The spermidine derivative, Hasushin (a bud of a Nelumbo nucifera Gaertn ) from The composition according to claim 6 which is an extract obtained by extracting with at least ethyl acetate. The composition for skin whitening according to claim 6 or 7 , wherein the spermidine derivative has a tyrosinase inhibition rate of 60% or more at a concentration of 100 µg / mL. The composition for skin whitening according to any one of claims 6 to 8 , wherein a 50% tyrosinase inhibitory concentration (IC ₅₀ ) of the spermidine derivative is smaller than 37 µg / mL. The spermidine derivative is represented by the following formula (III):
The composition for skin whitening of Claim 1 shown by these. The composition for skin whitening according to claim 10 , wherein the spermidine derivative has a tyrosinase inhibition rate of 60% or more at a concentration of 100 µg / mL. The skin whitening composition according to claim 10 or 11 , wherein the spermidine derivative has a 50% tyrosinase inhibitory concentration (IC ₅₀ ) of less than 19 µg / mL.