KR20140124987A - Skin Whitening Composition Comprising Caffeic Acid Derivatives as the Active Ingredients - Google Patents

Abstract

The present invention relates to a skin whitening composition containing a new caffeic acid derivative compound as an active ingredient. According to the present invention, the caffeic acid derivative compound can be developed for a skin whitening cosmetic product or for a medicine for the hyperpigmentation of melanin because having skin whitening activity by inhibiting the biosynthesis of melanin in melanocytes.

Description

(Skin Whitening Composition Comprising Caffeic Acid Derivatives as the Active Ingredients)

The present invention relates to a skin whitening composition comprising a caffeic acid derivative as an active ingredient.

The melanin pigment is synthesized in the melanosome of melanocytes through a process called melanogenesis and is dispersed into the keratinocyte of the epithelium to form a skin color and to protect the skin from ultraviolet light of the sun Protect [1]. The biochemical pathway for melanin biosynthesis is the two characteristic reactions catalyzed by tyrosinase: hydroxylation of L-tyrosine and oxidation of 3,4-dihydroxyphenylalanine (DOPA) (2). The resulting dopaquinone readily reacts with thiol materials such as cysteine or glutathione in the melanosome to produce yellow / red pheomelanin [3]. When the thiol material is depleted, the excess dopaquinone is spontaneously converted to dopachrome and ultimately forms a black / brown eumelanin [3]. Skin color is determined by the blending of melanin pigment, but tyrosinase is essential for biosynthesis of both pio melanin and eumelanin. The paracrine factor secreted from keratinocytes and fibroblasts of the skin can affect the production of melanin in melanocytes. Among these factors, α-MSH (α-melanocyte stimulating hormone) specifically binds to MC1R (melanocortin type 1 receptor) on melanocytes and activates adenylate cyclase to increase intracellular concentration of cAMP , Which in turn leads to the induction of tyrosinase expression [4]. Thus, the balance between paracrine factors plays an important role in regulating skin pigmentation through fine-tuning of melanocyte activation. However, when melanin pigment accumulates abnormally, hyperpigmentation disorders such as melasma, freckles and senile lentigen occur. These diseases include arbutin, which inhibits tyrosinase activity ) Or hydroquinone [5].

Caffeic acid is an organic compound classified as hydroxycinnamic acid, which is composed of a phenol group and an acrylic group. Caffeic acid is found in all plants because it is an important intermediate in lignin biosynthesis, a major source of biomass. Caffeic acid has been shown to have potent antioxidant activity in vitro and in vivo [6], and also has immunomodulatory and anti-inflammatory activity. On the other hand, caffeic acid has been reported to inhibit the development of cancer, while other studies have also been reported to promote the development of cancer.

da Cunha FM et al. reported that caffeic acid and caffeic acid derivatives caffeic acid methyl, ethyl, butyl, octyl, and benzyl ester have anti-inflammatory activity as a potent antioxidant. Sugiura M et al. Synthesized various caffeic acid derivatives and measured their effects on 5-lipoxygenase, 12-lipoxygenase and prostaglandin synthetase. As a result, Reported that caffeic acid octylamide and 1- (3,4-dihydroxyphenyl) -1-octen-3-one have potent inhibitory activity against these enzymes [8].

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

Korean Patent Application No. 2003-0005781

[1] Slominskie, Tobin DJ, Shibahara S, Wortsman J. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev 2004; 84; 1155-1228. [2] Hearing VJ, Tsukamoto K. Enzymatic control of pigmentation in mammals. FASEB J 1991; 5: 2902-2909. [3] Le Pape E, Wakamatsu K, Ito S, Wolber R, Hearing VJ. Regulation of eumelanin / pheomelanin synthesis and visible pigmentation in melanocytes by ligands of the melanocortin 1 receptor. Pigment Cell Melanoma Res 2008; 21: 477-486. [4] Busca R, Ballotti R. Cyclic AMP: a key messenger in the regulation of skin pigmentation. Pigment Cell Res 2000; 13: 60-69. [5] Solano F, Briganti S, Picardo M, Ghanem G. Hypopigmenting agents: an updated review on biological, chemical and clinical aspects. Pigment Cell Res 2006; 19: 550-571. [6] Olthof MR, Hollman PC, Katan MB (January 2001). "Chlorogenic acid and caffeic acid are absorbed in humans ". J. Nutr. 131 (1): 66-71. [7] da Cunha FM, Duma D, Assreuy J, Buzzi FC, Niero R, Campos MM, Calixto JB. Caffeic acid derivatives: in vitro and in vivo anti-inflammatory properties. Free Radic Res. 2004 Nov; 38 (11): 1241-53. [8] Sugiura M, Naito Y, Yamaura Y, Fukaya C, Yokoyama K. Inhibitory activities and inhibitory specificities of caffeic acid derivatives and related compounds toward 5-lipoxygenase. Chem Pharm Bull (Tokyo). 1989 Apr; 37 (4): 1039-43.

The present inventors have sought to discover new compounds having skin whitening activity by inhibiting the synthesis of melanin in melanocytes. As a result, the present inventors have synthesized novel caffeic acid derivatives and confirmed that these derivatives can be developed as a skin whitening active compound by significantly inhibiting melanin synthesis in melanoma cells, thereby completing the present invention .

Accordingly, an object of the present invention is to provide a skin whitening composition comprising a caffeic acid derivative compound as an active ingredient.

The objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, there is provided a skin whitening composition comprising, as an active ingredient, a caffeic acid derivative compound represented by the following formula (1) to (3).

[Chemical Formula 1]

이고; Wherein R is C ₃ -C ₈ cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl or

ego;

The substituted phenyl is optionally substituted with one or more substituents selected from the group consisting of straight or branched C ₁ -C ₆ alkyl, nitro (-NO ₂ ), and straight or branched C ₁ -C ₆ alkyl substituted by halogen Substituted phenyl;

Wherein said substituted benzyl is a linear or branched C ₁ -C ₆ alkyl, C ₁ -C ₃ alkoxy, halogen, sulfamoyl (-SO ₂ NH _2), and C ₁ of the straight-chain or branched-chain optionally substituted by halogen - Benzyl substituted by one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl;

The halogen is fluorine (F), bromine (Br), chlorine (Cl), or iodine (I).

(2)

Wherein R ₁ and R ₂ are independently hydroxyl or acetate; R ₃ is C ₃ -C ₈ cycloalkyl.

(3)

In Formula 3, R is piperidinyl.

As used herein, the term "alkyl" means a straight or branched saturated aliphatic hydrocarbon group of the specified number of carbon atoms and includes, for example, methyl, ethyl, propyl, isobutyl, pentyl, hexyl, heptyl, octyl, Tridecyl, and the like. C ₁ -C ₄ alkyl represents an alkyl group having 1 to 4 carbon atoms, and includes not only n-propyl and n-butyl, but also branched isopropyl, isobutyl and t-butyl.

As used herein, the term "cycloalkyl" refers to a non-aromatic saturated monocyclic, fused bicyclic or bridged cyclic, cyclic hydrocarbon group containing the specified number of cyclic carbon atoms. For example, C ₃ -C ₆ cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

As used herein, the term "alkoxy" means a radical formed by the removal of hydrogen from an alcohol of the specified carbon number. For example, C ₁ -C ₃ alkoxy includes methoxy, ethoxy and propoxy.

As used herein, the term " halogen " refers to a halogen group element substituent and includes, for example, fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

As used herein, the term "straight-chain or branched alkyl substituted by halogen" means alkyl as defined above wherein at least one hydrogen atom is replaced by halogen, for example, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ CH ₂ CF ₃ , -CH ₂ CF ₂ CF _3, and the like.

According to a preferred embodiment of the present invention, the caffeic acid derivative compound of the present invention is a compound of any one of the following compounds:

(E) -N -cyclohexyl-3- (3,4-dihydroxyphenyl) acrylamide;

(E) - N -benzyl-3- (3,4-dihydroxyphenyl) acrylamide;

(E) -3- (3,4-dihydroxyphenyl) -N -phenylacrylamide;

(E) -N -cyclopentyl-3- (3,4-dihydroxyphenyl) acrylamide;

(E) -3- (3,4-dihydroxyphenyl) -1- (piperidin-1-yl) prop-2-en-1-one;

(E) -4- {3- (cyclohexyloxy) -3-oxoprop-1-en-1-yl} 1,2-phenylene diacetate;

(E) -cyclohexyl-3- (3,4-dihydroxyphenyl) acrylate;

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) phenyl 4- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) phenyl 3- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - (4- isopropyl-phenyl) acrylamide;

(E) - N - (4- butylphenyl) -3- (3,4-hydroxyphenyl) acrylamide;

(E) -3- (3,4- dihydroxyphenyl) - N - (3- nitrophenyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - (4- nitrophenyl) acrylamide;

(E) - N - (4- (4- bromo-phenyl) -3-methyl -1H- pyrazol-5-yl) -3- (3,4-hydroxyphenyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) benzyl-4- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - (4- methylbenzyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - (4- methoxybenzyl) acrylamide;

(E) - N - (4- chlorobenzyl) -3- (3,4-hydroxyphenyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - (4- sulfamoyl-benzyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) benzyl-3- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - (2- methoxybenzyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - (2- methylbenzyl) acrylamide;

(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) benzyl-2- (trifluoromethyl);

(E) -3- (3,4- dihydroxy-phenyl) - N - (3- methylbenzyl) acrylamide;

(E) - N - (2- chloro-benzyl) -3- (3,4-hydroxyphenyl) acrylamide; And

(E) - N - (3- chloro-benzyl) -3- (3,4-hydroxyphenyl) acrylamide.

The caffeic acid derivative compounds of the present invention exhibit skin whitening activity by inhibiting the synthesis of melanin in melanin-producing cells.

According to a preferred embodiment of the present invention, the caffeic acid derivative compound is contained in the composition of the present invention in an amount of 0.0001 to 30% by weight, more preferably 0.001 to 30% by weight, 0.01 to 30% by weight.

The skin whitening composition of the present invention may be provided in the form of a cosmetic composition.

The cosmetic composition of the present invention may be prepared into any of the formulations conventionally produced in the art, and may be prepared, for example, as a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, But are not limited to, cleansing, oils, powder foundations, emulsion foundations, wax foundations and sprays. More specifically, it can be prepared in the form of a soft lotion, a nutritional lotion, a lotion, a nutritional cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray or a powder.

When the formulation of the present invention is a paste, a cream, a lotion, or a gel, an animal oil, vegetable oil, wax, paraffin, starch, tracer, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide Can be used.

When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In the case of a spray, in particular, / Propane or dimethyl ether.

When the formulation of the present invention is a solution or an emulsion, a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.

In the case where the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.

When the formulation of the present invention is an interfacial active agent-containing cleansing, the carrier component may include 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.

The ingredients included in the cosmetic composition of the present invention include, in addition to the active ingredient and the carrier ingredient, the ingredients conventionally used in cosmetic compositions and include conventional ingredients such as antioxidants, stabilizers, solubilizers, vitamins, May include adjuvants.

The compositions of the present invention may be used in the form of pharmaceutical compositions for the treatment or prophylaxis of melanin pigment hyperproliferative disorders.

As used herein, the term " hyperpigmentation of melanin pigment "means darkening or darkening of melanin compared to other areas due to excessive increase of melanin in specific areas of the skin or nail. The melanin pigment hyperpigmentation disorder includes, but is not limited to, spots, freckles, senile pigment, or solar lentigines.

The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier in addition to the active ingredient. Such a carrier is usually used in the formulation, and may be selected from lactose, dextrose, sucrose, sorbitol, mannitol, starch, , Calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and Mineral oil, and the like, but are not limited thereto. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . On the other hand, the dosage of the pharmaceutical composition of the present invention is preferably 0.0001-100 mg / kg (body weight) per day.

The pharmaceutical composition of the present invention can be administered orally or parenterally. In the case of parenteral administration, the composition can be administered by local application to the skin, intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, .

In view of the fact that the pharmaceutical composition of the present invention is applied for the treatment or prevention of a melanin pigment hyperpigmentation disease, it is preferable that the composition is topically applied to the skin.

The concentration of the active ingredient contained in the composition of the present invention can be determined in consideration of the purpose of treatment, the condition of the patient, the period of time required, and the like, and is not limited to a specific range of concentration.

The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.

According to a preferred embodiment of the present invention, the pharmaceutical composition of the present invention has an external preparation for skin. The external preparation for skin is not particularly limited and is preferably a powder, a gel, an ointment, a cream, a lotion, a liquid or an aerosol formulation.

The present invention relates to a skin whitening composition comprising a novel caffeic acid derivative compound as an active ingredient. The caffeic acid derivative compound of the present invention exhibits skin whitening activity by inhibiting the biosynthesis of melanin in melanocytes, and can be developed as a cosmetic for skin whitening or as a medicament for the treatment of hyperpotension disorders of melanin pigment.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Ⅰ. Synthesis method

1. Synthesis method 1

HOBt (1.0 eq) and EDCI (1.0 eq) in DMF were added to a solution of caffeic acid (1.0 eq), and the mixture was stirred at room temperature for 20 minutes. Amine (1.0 eq) was added to the solution, and the mixture was stirred at room temperature for 20 minutes. The mixture was treated with DIPEA (2.0 eq) at ambient temperature and the reaction mixture was stirred at ambient temperature for 16 hours. After dissolving the mixture into EtOAc, H ₂ O, 1N-HCl, and brine (brine), dried the organic layer with MgSO ₄ filtered and concentrated in vacuo. The product was loaded onto silica gel and purified by column chromatography (EA in HX conditions).

2. Synthesis method 2

Caffeic acid (300 mg, 1.67 mmol) in benzene (3 mL) was stirred at room temperature. The mixture was treated with SOCl ₂ (0.666 mL, 9.13 mmol) and stirred at 50 < 0 > C for 4 hours. The solvent was concentrated and used directly in the next reaction without purification. K ₂ CO ₃ (207 mg, 1.50 mmol) in CH ₃ CN (2 mL) was stirred at room temperature. The mixture was treated with 1-methylimidazole (0.00800 mL, 0.100 mmol), TMEDA (0.0150 mL, 0.100 mmol) and amine at ambient temperature. CH ₃ CN (2 mL) in the (E) -3- (3,4-dihydroxy-phenyl) acryloyl chloride was added to the solution at room temperature, the reaction mixture was stirred at room temperature for 14 hours. The mixture was dissolved in EtOAc (3 X 5 mL), MeOH (3 X 5 mL) and the solvent was concentrated. The product was loaded onto silica gel and purified by column chromatography (EA in HX conditions).

3. Synthesis Method 3

A solution of caffeic acid (300 mg, 1.67 mmol) in pyridine was stirred at room temperature. DMAP (4.89 mg, 0.0400 mmol) was added to the solution and the reaction mixture was stirred at 0 < 0 > C. Ac ₂ O (1.08 mL, 16.7 mmol) was then added to the solution and the reaction mixture was stirred at ambient temperature for 13 hours. The solvent was concentrated.

(E) -3- (3,4-diacetoxyphenyl) acrylic acid in benzene was stirred at room temperature. The mixture was treated with SOCl ₂ (0.205 mL, 3.50 mmol) and stirred at 50 < 0 > C for 3 h. After 3 h, the SOCl ₂ was removed under vacuum and the residue was dissolved in DCM. The reaction mixture was then treated with DMAP (8.55 mg, 0.0699 mmol) and the mixture was stirred at room temperature. Cyclohexanol (0.0740 mL, 0.699 mmol) was added to the solution and the reaction mixture was stirred at ambient temperature for 12 hours. The solvent was concentrated in vacuo. The product was loaded onto silica gel and purified via column chromatography (EA in HX conditions).

4. Synthesis Method 4

(E) -4- (3- (cyclohexyloxy) -3-oxoprop-1-phenyl) -1,2-phenylene diacetate (47.8 mg, 0.138 mmol) in THF was stirred at room temperature. The reaction mixture was treated with a _{2% Na 2 CO 3 (1.00} mL) and MeOH (2.00 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction was adjusted to pH 1 with 1 N HCl, washed with H ₂ O and extracted with diethyl ether. After the organic layer was dried using MgSO _4, filtered and concentrated under vacuum. The product was loaded onto silica gel and purified using column chromatography (EA in HX conditions).

Ⅱ. Synthesis Example of Compound

1. Synthesis Example 1: Synthesis of (E) - N -Cyclohexyl-3- (3,4-dihydroxyphenyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (165 mg, 1.22 mmol) and EDCI (234 mg, 1.22 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, cyclohexylamine (0.12 mL, 1.0 mmol) was added dropwise and the mixture was stirred at room temperature for 20 minutes. After 20 minutes DIPEA (0.38 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCI and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 10.9%; ^{1 H NMR (MeOD, 500 MHz} ) δ 7.38 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.00 (s, 1H, Ar- H) 6.90 (dd, 1H, J = 8.2, 2.0 Hz , Ar- H), 6.77 (d , 1H, J = 8.2 Hz, Ar- H), 6.36 (d, 1H, J = 15.7 Hz, Ar-CHC H), 3.76 (m, 1H, NHC H CH 2) , 1.80 (m, 5H, NHC 6 H 5), 1.38 (m, 5H, NHC 6 H 5); ¹³ C NMR (MeOD, 100 MHz) ? 166.9, 147.3, 145.3, 140.6, 127.0, 120.63, 117.3, 115.0, 113.6, 48.4, 32.5, 25.3, 24.8; MS m / z (M + H ) - calculated for C 15 H 19 NO 3 262.3. found: 262.3; IR (NaTe) 3280, 1649, 1579, 1522, 1445 cm < ^-1 >

2. Synthesis Example 2: Synthesis of (E) - N -Benzyl-3- (3,4-dihydroxyphenyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (165 mg, 1.22 mmol) and EDCI (234 mg, 1.22 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, benzylamine (0.12 mL, 1.0 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 minutes DIPEA (0.38 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCI and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 52.3%; ^{1 H NMR (MeOD, 500 MHz} ) δ 7.46 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.34 (m, 4H, Ar- H), 7.27 (m, 1H, Ar- H), 7.03 (s, 1H, Ar- H ), 6.94 (dd, 1H, J = 8.2, 2.1 Hz, Ar- H), 6.78 (d, 1H, J = 8.2 Hz, Ar- H), 6.43 (d, 1H , J = 15.6 Hz, Ar- CHC H), 4.50 (s, 2H, NHC H 2); ¹³ C NMR (MeOD, 100 MHz) ? 167.8, 147.4, 145.3, 141.2, 138.6, 128.2, 127.2, 126.9, 126.8, 120.7, 116.8, 115.0, 113.7, 42.9; MS m / z (M + Na) ^- calculated for C ₁₆ H ₁₅ NO ₃ 270.3. found: 270.2; IR (neat) 3285, 1650, 1598, 1524, 1448 cm ^-1

3. Synthesis Example 3: (E) -3- (3,4-Dihydroxyphenyl) - N - phenylacrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (165 mg, 1.22 mmol) and EDCI (234 mg, 1.22 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, aniline (0.10 mL, 1.0 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 minutes DIPEA (0.38 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCI and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 7.06%; ^{1 H NMR (MeOD, 500 MHz} ) δ 7.81 (d, 1H, J = 8.5 Hz, Ar-C H CH), 7.67 (d, 1H, J = 8.3 Hz, Ar-CHC H), 7.67 (d, 1H , J = 8.1 Hz, Ar- H ), 7.57 (d, 1H, J = 8.1 Hz, Ar- H), 7.25 (t, 2H, J = 8.0 Hz, Ar- H), 7.03 (t, 1H, J = 7.4 Hz, Ar- H), 6.99 (s, 1H, Ar- H), 6.72 (d, 1H, J = 8.2 Hz, Ar- H), 6.49 (d, 1H, J = 15.6 Hz, Ar- H ); ¹³ C NMR (MeOD, 100.6 MHz) ? 166.0, 147.6, 145.4, 142.0, 128.5, 128.4, 126.9, 123.8, 121.0, 119.9, 117.4, 115.1, 113.8; MS m / z (M + H ) - calculated for C 15 H 13 NO 3 256.3. found: 256.2; IR (neat) 3266, 1596, 1535, 1439, 1250 cm < ^-1 >

4. Synthesis Example 4: Synthesis of (E) - N - cyclopentyl-3- (3,4-dihydroxyphenyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (165 mg, 1.22 mmol) and EDCI (234 mg, 1.22 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, cyclopentylamine (0.10 mL, 1.0 mmol) was added and the mixture was stirred at room temperature for 20 minutes. DIPEA (0.38 mL, 2.22 mmol) was then added and stirred for 16 h before extraction with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 7.29%; ^{1 H NMR (Acetone, 500 MHz} ) δ 7.36 (d, 1H, J = 15.6 Hz, Ar-C H CH), 7.03 (s, 1H, Ar- H), 6.91 (dd, 1H, J = 8.0, 2.1 Hz, Ar- H), 6.82 ( d, 1H, J = 8.2 Hz, Ar- H), 6.39 (d, 1H, J = 15.6 Hz, Ar-CHC H), 4.24 (m, 1H, NHC H CH 2 ), 1.93 (m, 2H, NHCHC ₂ H ₂ ), 1.70 (m, 2H, NHCHC ₂ H ₂ ), 1.61 (m, 2H, NHCHCH ₂ C H ₂ ), 1.50 (m, 2H, NHCHCH ₂ C H ₂ ); ¹³ C NMR (MeOD, 100 MHz) ? 167.4, 147.3, 145.3, 140.1, 127.0, 120.6, 117.2, 115.0, 113.6, 51.1, 32.3, 23.4; MS m / z (M + H ) - calculated for C 14 H 17 NO 3 248.3. found: 248.3; IR (neat) 3258, 2950, 1650, 1278 cm < ^-1 >

Synthesis Example 5 Synthesis of (E) -3- (3,4-dihydroxyphenyl) -1- (piperidin-1-yl) prop-

Caffeic acid (200 mg, 1.11 mmol), HOBt (165 mg, 1.22 mmol) and EDCI (234 mg, 1.22 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes piperidine (0.10 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.38 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1N-HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography (EtOAc: n-Hexane: MeOH = 1: 2: 7%).

Yield 5.47%; ^{1 H NMR (MeOD, 500 MHz} ) δ 6.84 (s, 1H, Ar- H), 6.71 (m, 2H, Ar-C H CH), 6.54 (d, 1H, J = 12.5 Hz, Ar- H), 5.85 (d, 1H, J = 12.5 Hz, Ar- H), 3.61 (t, 2H, J = 5.6 Hz, NC H 2 CH 2), 3.40 (t, 2H, J = 5.6 Hz, NC H 2 CH 2 ), 1.58 (m, 4H, C H ₂ CH ₂ ), 1.28 (m, 2H, CH ₂ C H ₂ ); ¹³ C NMR (MeOD, 100 MHz) ? 166.7, 147.4, 145.3, 143.2, 127.2, 120.7, 115.1, 113.9, 113.5, 46.8, 43.2, 24.2; MS m / z (M + H ) - calculated for C 14 H 17 NO 3 248.3. found: 248.3; IR (neat) 3439, 2932, 1561, 1432, 1262 cm < ^{-1 &}

Synthesis Example 6 Synthesis of (E) -4- {3- (cyclohexyloxy) -3-oxoprop-1-en-1-yl} -1,2-phenylene diacetate

Caffeic acid (300 mg, 1.67 mmol) was dissolved in distilled pyridine and DMAP (4.89 mg, 0.04 mmol) was added. After cooling to 0 ℃ dropwise to _{Ac 2 O (1705 mg, 16.7mmol} ). After stirring at room temperature for 16 hours, the solvent was removed and the product was recrystallized from EtOAc / n-hexane to give the product. The resultant was dissolved in benzene (3 mL), SOCl ₂ (0.25 mL, 3.50 mmol) was added dropwise, and the mixture was stirred at 50 ° C for 3 hours. After removal of the solvent, the residue was dissolved in CH ₂ Cl ₂ , DMAP (8.55 mg, 0.07 mmol) and cyclohexanol (0.074 mL, 0.70 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After 16 hours, the solvent was removed and purified by column chromatography.

Yield 8.23%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.59 (d, 1H, J = 16.0 Hz, Ar-C H CH), 7.40 (dd, 1H, J = 8.4, 2.0 Hz, Ar-H), 7.35 (d, 1H, J = 1.9 Hz, Ar -H), 7.20 (d, 1H, J = 8.4 Hz, Ar-H), 6.37 (d, 1H, J = 16.0 Hz, Ar-C H CH), 4.88 (m, 1H, Ar-OC H), 2.30 (s, 3H, OC H 3), 2.29 (s, 3H, OC H 3), 1.90 (m, 2H, OCHC H 2), 1.76 (m, 2H, OCHC H 2 ), 1.42 (m, 6H, OCHC H ₂ C H ₂ C H ₂ ); ¹³ C NMR (MeOD, 100 MHz) ? 168.0, 168.0, 166.0, 143.4, 142.4, 142.3, 133.5, 126.3, 123.9, 122.7, 120.1, 72.9, 31.7, 25.5, 25.4, 24.1, 23.8, 20.6, 20.6; MS m / z (M + Na ) - calculated for C 19 H 22 O 6 369.4. found: 369.3; IR (neat) 2937, 1774, 1707, 1178 cm < ^-1 >

7. Synthesis Example 7: Synthesis of (E) -cyclohexyl-3- (3,4-dihydroxyphenyl) acrylate

(E) -4- (3- (cyclohexyloxy) -3-oxoprop-1-enyl) -1,2-phenylene diacetate was dissolved in THF, MeOH was added to 2% Na ₂ CO ₃ Solution. After stirring at room temperature for 4 h, it was extracted with water, 6 N HCl and diethyl ether.

Yield 4.12%; ^{1 H NMR (MeOD, 500 MHz} ) δ 7.53 (d, 1H, J = 15.9 Hz, Ar-C H CH), 7.04 (s, 1H, Ar- H), 6.95 (dd, 1H, J = 8.2, 2.0 Hz, Ar- H), 6.79 ( d, 1H, J = 8.1 Hz, Ar- H), 6.25 (d, 1H, J = 15.9 Hz, Ar-CHC H), 4.82 (m, 1H, OC H CH 2 ) 1.92 (m, 2H, OCHC H ₂ ), 1.79 (m, 2H, OCHC H ₂ ), 1.49 (m, 6H, OCHC H ₂ C H ₂ C H ₂ ); ¹³ C NMR (MeOD, 100 MHz) ? 167.4, 148.1, 145.4, 145.1, 126.4, 121.5, 115.1, 114.3, 113.7, 72.5, 60.1, 31.4, 25.1, 23.4, 13.0; ^{MS m / z (MH) -} calculated for C 15 H 18 O 4 261.3. found: 261.0; IR (neat) 3301, 2941, 1683, 1025 cm < ^-1 >

8. Synthesis Example 8: (E) -3- (3,4-Dihydroxyphenyl) - N - (4- (trifluoromethyl) phenyl) acrylamide

To a flask with two necks was added K ₂ CO ₃ (207 mg, 1.5 mmol), 1-methylimidazole (0.008 mL, 0.1 mmol), TMEDA (0.015 mL, 0.1 mmol) and 3- (trifluoromethyl) Aniline (161 mg, 1.0 mmol) was added and dissolved in CH ₃ CN (1 mL), and the reaction was allowed to proceed at 0 ° C in an ice bath. (E) -3- (3,4-dihydroxyphenyl) acryloyl chloride (210 mg, 1.5 mmol) was dissolved in CH ₃ CN (1 mL) and stirred. After 12 h, it was extracted with EtOAc, concentrated and purified by column chromatography.

Yield 6.05%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.84 (d, 2H, J = 8.4 Hz, Ar- H), 7.61 (d, 2H, J = 8.7 Hz, Ar- H), 7.55 (d, 1H, J = 15.6 Hz, Ar-C H CH ), 7.06 (d, 1H, J = 2.0 Hz, Ar- H), 6.96 (dd, 1H, J = 8.2, 2.1 Hz, Ar- H), 6.78 (d, 1H, J = 8.2 Hz, Ar- H ), 6.55 (d, 1H, J = 15.6 Hz, Ar-CHC H ); ¹³ C NMR (MeOD, 100 MHz) ? 166.2, 147.9, 145.4, 142.9, 142.4, 126.7, 125.6, 125.6, 121.2, 119.3, 116.9, 115.1, 113.8, 60.1; MS m / z (M + H ) - calculated for C 16 H 12 FNO 3 324.3. found: 324.2

IR (neat) 3276, 1651, 1590, 1517, 1115 cm < ^{-1 &}

Synthesis Example 9: (E) -3- (3,4-Dihydroxyphenyl) - N - (3- (trifluoromethyl) phenyl) acrylamide

To a flask with two necks was added K ₂ CO ₃ (207 mg, 1.5 mmol), 1-methylimidazole (0.008 mL, 0.1 mmol), TMEDA (0.015 mL, 0.1 mmol) and 3- (trifluoromethyl) Aniline (161.12 mg, 1.0 mmol) was added and dissolved in CH ₃ CN (1 mL), followed by reaction in an ice bath at 0 ° C. (E) -3- (3,4-dihydroxyphenyl) acryloyl chloride (210 mg, 1.5 mmol) was dissolved in CH ₃ CN (1 mL) and stirred. After 12 h, it was extracted with EtOAc, concentrated and purified by column chromatography.

Yield 7.26%; ^{1 H NMR (MeOD, 400 MHz} ) δ 8.11 (s, 1H, Ar- H), 7.80 (d, 1H, J = 8.24 Hz, Ar- H), 7.54 (d, 1H, J = 15.6 Hz, Ar- C H CH), 7.49 (t , 1H, J = 8.1 Hz, Ar- H), 7.35 (d, 1H, J = 7.8 Hz, Ar- H), 7.06 (s, 1H, Ar- H), 6.96 ( (d, 1H, J = 8.2, 2.0 Hz, Ar- H ), 6.78 (d, 1H, J = 8.2 Hz, Ar- H ), 6.53 (d, 1H, J = 15.6 Hz, Ar-CHC H ); ¹³ C NMR (MeOD, 100 MHz) ? 166.2, 147.9, 145.4, 142.7, 139.7, 129.3, 126.7, 122.8, 121.1, 119.8, 119.8, 116.8, 116.0, 115.1, 113.8, 60.1; ^{MS m / z (MH) -} calculated for C 16 H 12 FNO 3 322.2. found: 322.0; IR (neat) 3273, 2839, 1661, 1599, 1550 cm < ^{-1 &}

Synthesis Example 10: (E) -3- (3,4-Dihydroxyphenyl) - N - (4-isopropylphenyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 4-isopropylaniline (0.15 mL, 1.11 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.38 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 13.6%; _{^{1 H NMR (CDCl 3, 500}} MHz) δ 7.56 (d, 2H, J = 8.5 Hz, Ar- H), 7.52 (d, 1H, J = 15.6 Hz, Ar-C H CH), 7.21 (d, 2H , J = 8.5 Hz, Ar- H ), 7.08 (d, 1H, J = 2.0 Hz, Ar- H), 6.97 (dd, 1H, J = 8.1, 2.0 Hz, Ar- H), 6.80 (d, 1H , J = 8.2 Hz, Ar- H ), 6.56 (d, 1H, J = 15.6 Hz, Ar-CHC H), 2.88 (m, 1H, C H (CH 3) 2), 1.26 (s, 3H, CHC H ₃ ), 1.25 (s, 3H, CH ₃ H ₃ ); ¹³ C NMR (MeOD, 100 MHz) ? 164.4, 146.1, 143.8, 143.1, 140.3, 134.9, 125.4, 124.7, 119.4, 118.4, 115.9, 113.6, 112.2, 32.0, 21.5; ^{MS m / z (MH) -} calculated for C 18 H 19 NO 3 296.4. found: 296.0; IR (neat) 3210, 2960, 1650, 1568, 1459 cm < ^{-1 &}

11. Synthesis Example 11: Synthesis of (E) - N - (4-butylphenyl) -3- (3,4-dihydroxyphenyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 4-butyl aniline (0.18 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.38 mL, 2.22 mmol) was added and stirred for 16 h and extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 16.6%; _{^{1 H NMR (CDCl 3, 400}} MHz) δ 7.54 (d, 2H, J = 8.3 Hz, Ar- H), 7.52 (d, 1H, J = 15.5 Hz, Ar-C H CH), 7.14 (d, 2H , J = 8.4 Hz, Ar- H ), 7.08 (d, 1H, J = 1.6 Hz, Ar- H), 6.96 (dd, 1H, J = 8.2, 1.6 Hz, Ar- H), 6.80 (d, 1H , J = 8.1 Hz, Ar- H ), 6.56 (d, 1H, J = 15.6 Hz, Ar-CHC H), 2.58 (t, 2H, J = 7.6 Hz, Ar-C H 2 CH 2), 1.59 ( _{m, 2H, Ar-CH 2} C H 2 CH 2), 1.36 (m, 2H, Ar-CH 2 CH 2 C H 2), 0.95 (t, 3H, J = 7.6 Hz, Ar-CH 2 CH 2 CH ₂ C H ₃ ); ¹³ C NMR (CDCl ₃ , 100 MHz) δ 169.8, 151.5, 149.3, 145.8, 142.6, 140.2, 132.3, 130.9, 124.9, 123.9, 121.3, 119.0, 117.7, 38.6, 37.5, 25.9, 16.9; ^{MS m / z (MH) -} calculated for C 19 H 21 NO 3 310.4. found: 310.2

IR (neat) 3315, 2925, 1652, 1602, 1437 cm < ^-1 >

Synthesis Example 12: Synthesis of (E) -3- (3,4-dihydroxyphenyl) - N - (3-nitrophenyl) acrylamide

To a two necked flask was added K ₂ CO ₃ (207 mg, 1.5 mmol), 1-methylimidazole (0.008 mL, 0.1 mmol), TMEDA (0.015 mL, 0.1 mmol) and 4- nitroaniline (138 mg, 1.0 mmol) was dissolved in CH ₃ CN (1 mL), and the reaction was allowed to proceed at 0 ° C in an ice water bath. (E) -3- (3,4-dihydroxyphenyl) acryloyl chloride (210 mg, 1.5 mmol) was dissolved in CH ₃ CN (1 mL) and stirred. After 12 h, it was extracted with EtOAc, concentrated and purified by column chromatography.

Yield 12.7%; ^{1 H NMR (MeOD, 500 MHz} ) δ 8.76 (s, 1H, Ar- H), 7.94 (d, 2H, J = 8.2 Hz, Ar- H), 7.57 (d, 1H, J = 15.7 Hz, Ar- C H CH), 7.54 (dd , 1H, J = 16.3, 7.9 Hz, Ar- H), 7.07 (s, 1H, Ar- H), 6.97 (d, 1H, J = 8.2 Hz, Ar- H), 6.79 (d, 1H, J = 8.1 Hz, Ar- H), 6.53 (d, 1H, J = 15.5 Hz, Ar-CHC H); ¹³ C NMR; ^{MS m / z (MH) -} calculated for C 15 H 12 N 2 O 5 299.3. found: 299.1; IR (neat) 3348, 2923, 1600, 1527, 1350 cm < ^{-1 &}

13. Synthesis Example 13: (E) -3- (3,4-Dihydroxyphenyl) - N - (4-nitrophenyl) acrylamide

To a two necked flask was added K ₂ CO ₃ (207 mg, 1.5 mmol), 1-methylimidazole (0.008 mL, 0.1 mmol), TMEDA (0.015 mL, 0.1 mmol) and 4- nitroaniline (138 mg, 1.0 mmol) were dissolved in CH ₃ CN (1 mL), and the reaction was allowed to proceed at 0-5 ° C in an ice water bath. (E) -3- (3,4-dihydroxyphenyl) acryloyl chloride (210 mg, 1.5 mmol) was dissolved in CH ₃ CN (1 mL) and stirred. After 12 h, it was extracted with EtOAc, concentrated and purified by column chromatography.

Yield 10.2%; ^{1 H NMR (MeOD, 400 MHz} ) δ 8.22 (d, 2H, J = 9.3 Hz, Ar- H), 7.89 (d, 2H, J = 9.4 Hz, Ar- H), 7.58 (d, 1H, J = 15.5 Hz, Ar-C H CH ), 7.07 (d, 1H, J = 2.0 Hz, Ar- H), 6.97 (dd, 1H, J = 8.3, 2.0 Hz, Ar- H), 6.78 (d, 1H, J = 8.1 Hz, Ar- H) , 6.55 (d, 1H, J = 15.5 Hz, Ar-CHC H); ¹³ C NMR; ^{MS m / z (MH) -} calculated for C 19 H 21 NO 3 299.3. found: 299.0; IR (neat) 3329, 2950, 1673, 1501, 1331 cm < ^{-1 &}

14. Synthesis Example 14: (E) - N - (4- (4-bromophenyl) -3-methyl-1H-pyrazol-5-yl) -3- (3,4-dihydroxyphenyl)

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 5-amino-4- (4-bromophenyl) -3-methylpyrazole (280 mg, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.38 mL, 2.22 mmol) was added and stirred for 16 h before extraction with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ , concentrated under reduced pressure and purified by recrystallization (EtOAc: n- Hexane).

Yield 12.7%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.69 (d, 1H, J = 15.8 Hz, Ar-C H CH), 7.51 (d, 1H, J = 15.8 Hz, Ar-CHC H), 7.49 (dd, 2H , J = 8.4, 1.9 Hz, Ar- H), 7.20 (d, 1H, J = 8.6Hz, Ar- H), 7.19 (dd, 1H, J = 8.4, 1.9 Hz, Ar- H), 7.09 (d , 1H, J = 2.0 Hz, Ar- H), 6.99 (dd, 1H, J = 8.4, 1.9 Hz, Ar- H), 6.74 (d, 1H, J = 8.2 Hz, Ar- H), 2.14 (s , 3H, C H ₃ ); ¹³ C NMR (MeOD, 100 MHz) ? 167.4, 151.4, 148.9, 148.1, 147.0, 145.6, 131.6, 131.2, 130.3, 126.7, 122.3, 119.7, 115.2, 114.2, 113.1, 101.5, 11.9; ^{MS m / z (MH) -} calculated for C 19 H 16 BrN 3 O 3 413.3. found: 413.8; IR (neat) 2923, 1678, 1391, 637 cm < ^-1 >

15. Synthesis Example 15: (E) -3- (3,4-Dihydroxyphenyl) - N - (4- (trifluoromethyl) benzyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 4- (trifluoromethyl) benzylamine (0.16 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 76.0%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.74, 7.61 (d, d 5H, J = 7.2, 7.2 Hz, Ar- H), 7.20 (s, 1H, Ar- H), 7.06 (d, 1H, J = 7.6 Hz, Ar- H), 6.93 (d, 1H, J = 7.6 Hz, Ar- H), 6.61 (d, 1H, J = 14.8 Hz, Ar- H), 4.69 (s, 2H, Ar-C H ₂ NH); ^{13 C NMR (MeOD, 100 MHz} ) δ 168.0, 147.5, 145.3, 143.4, 141.5, 129.1, 128.8, 127.6, 126.8, 125.7, 125.0, 125.0, 125.0, 123.0, 120.8, 116.6, 115.1, 113.7, 60.1, 42.3, 13.1; ^{MS m / z (MH) -} calculated for C 17 H 14 F 3 NO 3 336.3. found: 336.1

IR (neat) 3299, 2926, 1649, 1589, 1442, 1112 cm -1

16. Synthesis Example 16: (E) -3- (3,4-Dihydroxyphenyl) - N - (4-methylbenzyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 4-methylbenzylamine (0.14 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl, and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 87.0%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.62 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.36 (d, 2H, J = 7.6 Hz, Ar- H), 7.29 (d, 2H, J = 7.7 Hz, Ar- H) , 7.21 (s, 1H, Ar- H), 7.09 (d, 1H, J = 8.2 Hz, Ar- H), 6.95 (d, 1H, J = 8.1 Hz, Ar- H ), 6.60 (d, 1H, J = 15.6 Hz, Ar-CHC H ), 4.60 (s, 2H, NHC H ₂ ), 2.47 (s, 3H, Ar-C H ₃ ); ¹³ C NMR (MeOD, 100 MHz) ? 167.7, 147.4, 145.3, 141.0, 136.6, 135.5, 128.8, 127.2, 126.9, 120.7, 116.9, 115.0, 113.7, 42.6, 19.7; MS m / z (M + H ) - calculated for C 17 H 17 NO 3 284.3. found: 284.2; IR (neat) 3314, 2923, 1645, 1577, 1457 cm < ^{-1 &}

17. Synthesis Example 17: (E) -3- (3,4-Dihydroxyphenyl) - N - (4-methoxybenzyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 4-methoxybenzylamine (0.15 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h before extraction with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 87.8%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.62 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.39 (d, 2H, J = 8.0 Hz, Ar- H), 7.21 (s, 1H, Ar- H), 7.08 (d, 1H, J = 8.2 Hz, Ar- H), 7.02 (d, 2H, J = 8.0 Hz, Ar- H), 6.95 (d, 1H, J = 8.1 Hz, Ar- H ), 6.59 (d, 1H, J = 15.6 Hz, Ar-CHC H ), 4.57 (s, 2H, NHC H ₂ ), 3.91 (s, 3H, Ar-OC ₃ H ); ¹³ C NMR (MeOD, 100 MHz) ? 167.7, 159.1, 147.4, 145.3, 141.1, 130.6, 128.6, 126.9, 120.7, 116.9, 115.0, 113.7, 113.5, 54.3, 42.4; MS m / z (M + H ) - calculated for C 17 H 17 NO 4 300.3. found: 300.1; IR (neat) 3488, 3326, 2927, 1646, 1029 cm < ^{-1 &}

18. Synthesis Example 18: (E) - N - (4-chlorobenzyl) -3- (3,4-dihydroxyphenyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 4-chlorobenzylamine (0.14 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 86.6%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.42 (d, 1H, Ar-C H CH), 7.30 (m, 4H, Ar- H), 7.01 (d, 1H, J = 2.0 Hz, Ar- H), 6.90 (dd, 1H, J = 8.2, 2.0 Hz, Ar- H), 6.75 (d, 1H, J = 8.2 Hz, Ar- H), 6.39 (d, 1H, J = 15.6 Hz, Ar-CHC H) , 4.44 (s, 2H, NHC H ₂ ); _{^{13 C NMR (CDCl 3, 100}} MHz) δ 170.2, 149.8, 147.7, 143.7, 139.9, 134.9, 131.2, 130.6, 129.2, 123.2, 119.1, 117.4, 116.1, 44.5; MS m / z (M + H) ^- calculated for C ₁₆ H ₁₄ ClNO ₃ 304.7. found: 304.1; IR (neat) 3467, 2926, 1652, 1591, 1456, 605 cm -1

19. Synthesis Example 19: (E) -3- (3,4-Dihydroxyphenyl) - N - (4-sulfamoylbenzyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 4-aminobenzylbenzenesulfonamide (207 mg, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h before extraction with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 89.5%; 1H NMR (MeOD, 400 MHz) δ 7.84 (s, 2H, J = 8.4 Hz, Ar- H), 7.45 (d, 2H, J = 8.4 Hz, Ar- H), 7.43 (d, 1H, J = 15.9 Hz, Ar-C H CH) , 7.01 (d, 1H, J = 2.0 Hz, Ar- H), 6.91 (dd, 1H, J = 8.2, 2.0 Hz, Ar- H), 6.76 (d, 1H, J = 8.2 Hz, Ar- H), 6.42 (d, 1H, J = 15.7 Hz, Ar-CHC H), 4.53 (s, 2H, NHC H 2); ¹³ C NMR (MeOD, 100 MHz) ? 168.0, 147.5, 145.3, 143.5, 142.4, 141.5, 127.6, 127.5, 126.0, 120.9, 116.6, 115.1, 113.7, 42.3; MS m / z (M + H ) - calculated for C 16 H 16 N 2 O 5 S; 349.4. found: 349.1; IR (neat) 3347, 1648, 1274, 1151 cm < ^-1 >

20. Synthesis Example 20: (E) -3- (3,4-Dihydroxyphenyl) - N - (3- (trifluoromethyl) benzyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 3- (trifluoromethyl) benzylamine (0.16 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 80.2%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.61 (s, 1H, Ar- H), 7.53 (m, 3H, Ar- H), 7.43 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.01 (d, 1H, J = 2.0 Hz, Ar- H), 6.91 (dd, 1H, J = 8.2, 2.0 Hz, Ar- H), 6.75 (d, 1H, J = 15.6 Hz, Ar-CHC H) , 4.54 (s, 2H, NHC H ₂ ); ¹³ C NMR (MeOD, 100 MHz) ? 167.9, 147.5, 145.3, 141.5, 140.3, 131.0, 129.0, 126.8, 123.8, 123.8, 123.6, 123.5, 120.8, 116.5, 115.1, 113.7, 42.3; ^{MS m / z (MH) -} calculated for C 17 H 14 F 3 NO 3 336.3. found: 336.1; IR (neat) 3195, 2924, 1649, 1580, 1440, 1114 cm -1

21. Synthesis Example 21: (E) -3- (3,4-Dihydroxyphenyl) - N - (2-methoxybenzyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 2-methoxybenzylamine (0.15 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 5.74%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.40 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.24 (m, 2H, Ar- H), 6.99 (d, 1H, J = 2.0 Hz, Ar- H), 6.95 (d, 1H, J = 7.9 Hz, Ar- H), 6.89 (m, 2H, Ar- H), 6.74 (d, 1H, J = 8.2 Hz, Ar- H), 6.42 ( d, 1H, J = 15.7 Hz , Ar-CHC H), 4.46 (s, 2H, NHC H 2), 3.85 (s, 3H, OC H 3); ¹³ C NMR (MeOD, 100 MHz) ? 167.8, 157.4, 147.4, 145.3, 141.0, 128.4, 128.3, 127.0, 126.1, 120.7, 120.0, 117.0, 115.0, 113.7, 110.0, 54.4, 38.3; MS m / z (M + H ) - calculated for C 17 H 17 NO 4 300.3. found: 300.2; IR (neat) 3258, 1652, 1524, 1247 cm < ^-1 >

Synthesis Example 22: (E) -3- (3,4-Dihydroxyphenyl) - N - (2-methylbenzyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 2-methylbenzylamine (0.14 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h before extraction with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 7.19%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.42 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.24 (t, 1H, J = 4.3 Hz, Ar- H), 7.15 (m, 3H, Ar- H), 6.99 (d, 1H, J = 1.0 Hz, Ar- H), 6.90 (dd, 1H, J = 8.2, 2.0 Hz, Ar- H), 6.75 (d, 1H, J = 8.2 Hz, Ar- H), 6.41 (d, 1H, J = 15.7 Hz, Ar-CHC H), 4.46 (s, 2H, NHC H 2), 2.33 (s, 3H, ArC H 3); ¹³ C NMR (MeOD, 100 MHz) ? 167.7, 147.4, 145.3, 141.1, 136.0, 136.0, 129.9, 127.7, 127.1, 126.9, 125.7, 120.7, 116.8, 115.0, 113.7, 41.1, 17.7; ^{MS m / z (MH) -} calculated for C 17 H 17 NO 3 282.3. found: 282.1; IR (neat) 3275, 2928, 1652, 1596, 1523 cm < ^-1 >

23. Synthesis Example 23: (E) -3- (3,4-Dihydroxyphenyl) - N - (2- (trifluoromethyl) benzyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 2- (trifluoromethyl) benzylamine (0.16 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 7.13%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.68 (d, 1H, J = 8.0 Hz, Ar- H), 7.58 (m, 2H, Ar- H), 7.45 (d, 1H, J = 15.6 Hz, Ar- C H CH), 7.43 (m , 1H, Ar- H), 7.02 (d, 1H, J = 2.0 Hz, Ar- H), 6.92 (dd, 1H, J = 8.0, 2.0 Hz, Ar- H), 6.76 (d, 1H, J = 8.4 Hz, Ar- H ), 6.45 (d, 1H, J = 15.6 Hz, Ar-CHC H ), 4.68 (s, 2H, NHC H ₂ ); ¹³ C NMR (MeOD, 100 MHz) ? 170.0, 147.5, 145.4, 141.6, 136.9, 132.1, 129.4, 129.0, 127.2, 126.8, 125.6, 125.6, 125.5, 120.1, 116.5, 115.1, 113.7, 39.4; MS m / z (M + Na ) - calculated for C 17 H 17 F 3 NO 3 360.3. found: 360.2; IR (neat) 3279, 2924, 1653, 1598, 1116 cm < ^-1 >

24. Synthesis Example 24: (E) -3- (3,4-Dihydroxyphenyl) - N - (3-methylbenzyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 3-methylbenzylamine (0.14 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 67.1%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.42 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.18 (t, 1H, J = 7.5 Hz, Ar- H), 7.12 (s, 1H, Ar- H), 7.06 (m, 2H, Ar- H), 7.00 (d, 1H, J = 2.0 Hz, Ar- H), 6.90 (dd, 1H, J = 8.3, 2.0 Hz, Ar- H), 6.75 (d, 1H, J = 8.2 Hz, Ar- H), 6.40 (d, 1H, J = 15.7 Hz, Ar-CHC H), 4.42 (s, 2H, NHC H 2), 2.30 (s, 3H, Ar-C H _3); ¹³ C NMR (MeOD, 100 MHz) ? 167.8, 147.4, 145.3, 141.2, 138.5, 137.9, 128.1, 127.9, 127.5, 126.9, 124.3, 120.1, 116.9, 115.1, 113.7, 42.9, 20.1; MS m / z (M + H ) - calculated for C 17 H 17 NO 3 284.3. found: 284.3; IR (neat) 3314, 2924, 1649, 1583, 1441 cm < ^{-1 &}

25. Synthesis Example 25: (E) - N - (2-chlorobenzyl) -3- (3,4-dihydroxyphenyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 2-chlorobenzylamine (0.14 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h, then extracted with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 79.6%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.42 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.38 (m, 2H, Ar- H), 7.28 (m, 2H, Ar- H), 7.01 (d, 1H, J = 2.0 Hz, Ar- H), 6.91 (dd, 1H, J = 8.5, 2.0 Hz, Ar- H), 6.75 (d, 1H, J = 8.2 Hz, Ar- H), 6.43 (d, 1H, J = 15.7 Hz, Ar-CHC H), 4.56 (s, 2H, NHC H 2); ¹³ C NMR (MeOD, 100 MHz) ? 167.9, 147.5, 145.4, 141.4, 135.7, 133.0, 129.1, 129.0, 128.4, 126.8, 126.7, 120.8, 116.5, 115.0, 113.7, 40.8; MS m / z (M + H) ^- calculated for C ₁₆ H ₁₄ ClNO ₃ 304.7. found: 304.2; IR (neat) 3327, 1649, 1585, 1443, 749 cm < ^{-1 &}

26. Synthesis Example 26: (E) - N - (3-chlorobenzyl) -3- (3,4-dihydroxyphenyl) acrylamide

Caffeic acid (200 mg, 1.11 mmol), HOBt (150 mg, 1.11 mmol) and EDCI (212 mg, 1.11 mmol) were dissolved in DMF (3 mL) and the mixture was stirred at room temperature for 20 minutes. After 20 minutes, 3-chlorobenzylamine (0.14 mL, 1.11 mmol) was added and the mixture was stirred at room temperature for 20 minutes. After 20 min DIPEA (0.39 mL, 2.22 mmol) was added and stirred for 16 h before extraction with EtOAc, water, 1 N HCl and brine. The organic layer was dried over anhydrous Mg ₂ SO ₄ and concentration under reduced pressure was purified by column chromatography.

Yield 53.1%; ^{1 H NMR (MeOD, 400 MHz} ) δ 7.43 (d, 1H, J = 15.7 Hz, Ar-C H CH), 7.32 (s, 1H, Ar- H), 7.29 (d, 1H, J = 7.5 Hz, Ar- H), 7.24 (m, 2H, Ar- H), 7.01 (d, 1H, J = 2.0 Hz, Ar- H), 6.91 (dd, 1H, J = 8.2, 2.0 Hz, Ar- H), 6.75 (d, 1H, J = 8.2 Hz, Ar- H), 6.40 (d, 1H, J = 15.7 Hz, Ar-CHC H), 4.46 (s, 2H, NHC H 2); ¹³ C NMR (MeOD, 100 MHz) ? 167.9, 147.5, 145.3, 141.4, 141.2, 134.0, 129.7, 127.2, 126.9, 126.8, 125.5, 120.8, 116.6, 115.1, 113.7, 42.3; MS m / z (M + H) ^- calculated for C ₁₆ H ₁₄ ClNO ₃ 302.7. found: 302.1; IR (neat) 3196, 2925, 1647, 1535, 1440, 1183 cm < ^{-1 &}

Ⅲ. Quantification of melanin

Mouse melanoma (melanoma) 2.5 X the B16 cells in a 96-well culture plates 10 ³ cells / well seeded in a concentration of (well), were cultured for 24 hours at 37 ℃ incubator is 5% CO ₂ is supplied. After 24 hours, the medium of each well was removed and replaced with DMEM (Dulbecco's modified Eagle's medium) containing fresh 10% FBS (Fetal Bovine Serum), followed by serial dilution with 100 nM of α-MSH stimulating hormone). After 72 hours, the amount of melanin released into the medium was measured using a microplate reader at 405 nm. The number of viable cells was measured by MTT assay at 590 nm. Melanin production per unit cell was calculated by absorbance value (405 nm) / absorbance value (590 nm), and the whitening effect was examined at three or more different sample concentrations to determine the ED ₅₀ (sample required to inhibit melanin production by 50% Concentration) values.

IV. Cell viability test (MTT) analysis

Mouse melanoma B16 cells were plated on a 96-well culture plate at 2.5 × 10 ³ cells / well and cultured in a 37 ° C. incubator with 5% CO ₂ for 24 hours. After 24 hours, the medium of each well was removed and replaced with DMEM medium containing fresh 10% FBS (fetal bovine serum), and the serially diluted samples and α-MSH were treated respectively. After 72 hours, the cells were changed to DMEM containing fresh 10% FBS and stabilized for 2 hours. After 2 hours at MTT [3- (4,5-dimethylthiazol- 2-yl) -2,5-diphenyltetrazolium bromide] per well of 100 μg / ml 37 ℃ incubator with 5% CO ₂ which is supplied to a treatment with a concentration of 2 Lt; / RTI > After removing the MTT solution, 200 쨉 l of DMSO (dimethyl sulfoxide) was added to dissolve the cells. The absorbance at 590 nm was measured using a microplate reader.

Ⅴ. Results of whitening activity measurement

Table 1 shows the results of measuring the whitening activity of the compound of the present invention.

number Compound name Whitening activity
(ED ₅₀ ) One (E) -N-cyclohexyl-3- (3,4-dihydroxyphenyl) acrylamide 2.8-2.9 [mu] M 2 (E) -N-benzyl-3- (3,4-dihydroxyphenyl) acrylamide 8 μM 3 (E) -3- (3,4-dihydroxyphenyl) -N-phenylacrylamide 6.8-8.5 μM 4 (E) -N-cyclopentyl-3- (3,4-dihydroxyphenyl) acrylamide 30 μM 5 (E) -3- (3,4-dihydroxyphenyl) -1- (piperidin-1-yl) prop- 24 μM 6 (E) -4- (3- (cyclohexyloxy) -3-oxoprop-1-en-1-yl) -1,2-phenylene diacetate 0.2-0.3 [mu] M 7 (E) -cyclohexyl-3- (3,4-dihydroxyphenyl) acrylate 7 μM 8 (E) -3- (3,4-dihydroxyphenyl) -N- (4- (trifluoromethyl) phenyl) acrylamide 1.4 [mu] M 9 (E) -3- (3,4-dihydroxyphenyl) -N- (3- (trifluoromethyl) phenyl) acrylamide 0.9-1.8 [mu] M 10 (E) -3- (3,4-dihydroxyphenyl) -N- (4-isopropylphenyl) acrylamide 3.4-3.5 [mu] M 11 (E) -N- (4-butylphenyl) -3- (3,4-dihydroxyphenyl) acrylamide 0.7-1.6 [mu] M 12 (E) -3- (3,4-dihydroxyphenyl) -N- (3-nitrophenyl) acrylamide 1.7-2.1 [mu] M 13 (E) -3- (3,4-dihydroxyphenyl) -N- (4-nitrophenyl) acrylamide 1.3-1.6 [mu] M 14 (E) -N- (4- (4-bromophenyl) -3-methyl-1H-pyrazol-5-yl) -3- (3,4-dihydroxyphenyl) 0.9-1.2 [mu] M 15 (E) -3- (3,4-dihydroxyphenyl) -N- (4- (trifluoromethyl) benzyl) acrylamide 1.2-2.0 [mu] M 16 (E) -3- (3,4-dihydroxyphenyl) -N- (4-methylbenzyl) acrylamide 3.7-3.8 [mu] M 17 (E) -3- (3,4-dihydroxyphenyl) -N- (4-methoxybenzyl) acrylamide 4.5-8.0 μM 18 (E) -N- (4-chlorobenzyl) -3- (3,4-dihydroxyphenyl) acrylamide 1.5-2.0 [mu] M 19 (E) -3- (3,4-dihydroxyphenyl) -N- (4-sulfamoylbenzyl) acrylamide > 40 μM 20 (E) -3- (3,4-dihydroxyphenyl) -N- (3- (trifluoromethyl) benzyl) acrylamide 1.1-1.8 [mu] M 21 (E) -3- (3,4-dihydroxyphenyl) -N- (2-methoxybenzyl) acrylamide 4.5-9.6 [mu] M 22 (E) -3- (3,4-dihydroxyphenyl) -N- (2-methylbenzyl) acrylamide 17-24 [mu] M 23 (E) -3- (3,4-dihydroxyphenyl) -N- (2- (trifluoromethyl) benzyl) acrylamide 1.6-2.1 [mu] M 24 (E) -3- (3,4-dihydroxyphenyl) -N- (3-methylbenzyl) acrylamide 2.1-3.9 [mu] M 25 (E) -N- (2-chlorobenzyl) -3- (3,4-dihydroxyphenyl) acrylamide 5.9-7.1 [mu] M 26 (E) -N- (3-chlorobenzyl) -3- (3,4-dihydroxyphenyl) acrylamide 6 μM

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (8)

A skin whitening composition comprising a caffeic acid derivative compound represented by the following formula (1) to (3) as an active ingredient.
[Chemical Formula 1]

Wherein R is C ₃ -C ₈ cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl or

ego;
The substituted phenyl is optionally substituted with one or more substituents selected from the group consisting of straight or branched C ₁ -C ₆ alkyl, nitro (-NO ₂ ), and straight or branched C ₁ -C ₆ alkyl substituted by halogen Substituted phenyl;
Wherein said substituted benzyl is a linear or branched C ₁ -C ₆ alkyl, C ₁ -C ₃ alkoxy, halogen, sulfamoyl (-SO ₂ NH _2), and C ₁ of the straight-chain or branched-chain optionally substituted by halogen - Benzyl substituted by one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl;
The halogen is fluorine (F), bromine (Br), chlorine (Cl), or iodine (I).

(2)

Wherein R ₁ and R ₂ are independently hydroxyl or acetate; R ₃ is C ₃ -C ₈ cycloalkyl.

(3)

In Formula 3, R is piperidinyl.
The composition according to claim 1, wherein the caffeic acid derivative compound is any one of the following compounds:
(E) -N -cyclohexyl-3- (3,4-dihydroxyphenyl) acrylamide;
(E) - N -benzyl-3- (3,4-dihydroxyphenyl) acrylamide;
(E) -3- (3,4-dihydroxyphenyl) -N -phenylacrylamide;
(E) -N -cyclopentyl-3- (3,4-dihydroxyphenyl) acrylamide;
(E) -3- (3,4-dihydroxyphenyl) -1- (piperidin-1-yl) prop-2-en-1-one;
(E) -4- {3- (cyclohexyloxy) -3-oxoprop-1-en-1-yl} 1,2-phenylene diacetate;
(E) -cyclohexyl-3- (3,4-dihydroxyphenyl) acrylate;
(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) phenyl 4- (trifluoromethyl);
(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) phenyl 3- (trifluoromethyl);
(E) -3- (3,4- dihydroxy-phenyl) - N - (4- isopropyl-phenyl) acrylamide;
(E) - N - (4- butylphenyl) -3- (3,4-hydroxyphenyl) acrylamide;
(E) -3- (3,4- dihydroxyphenyl) - N - (3- nitrophenyl) acrylamide;
(E) -3- (3,4- dihydroxy-phenyl) - N - (4- nitrophenyl) acrylamide;
(E) - N - (4- (4- bromo-phenyl) -3-methyl -1H- pyrazol-5-yl) -3- (3,4-hydroxyphenyl) acrylamide;
(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) benzyl-4- (trifluoromethyl);
(E) -3- (3,4- dihydroxy-phenyl) - N - (4- methylbenzyl) acrylamide;
(E) -3- (3,4- dihydroxy-phenyl) - N - (4- methoxybenzyl) acrylamide;
(E) - N - (4- chlorobenzyl) -3- (3,4-hydroxyphenyl) acrylamide;
(E) -3- (3,4- dihydroxy-phenyl) - N - (4- sulfamoyl-benzyl) acrylamide;
(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) benzyl-3- (trifluoromethyl);
(E) -3- (3,4- dihydroxy-phenyl) - N - (2- methoxybenzyl) acrylamide;
(E) -3- (3,4- dihydroxy-phenyl) - N - (2- methylbenzyl) acrylamide;
(E) -3- (3,4- dihydroxy-phenyl) - N - acrylamide (methyl) benzyl-2- (trifluoromethyl);
(E) -3- (3,4- dihydroxy-phenyl) - N - (3- methylbenzyl) acrylamide;
(E) - N - (2- chloro-benzyl) -3- (3,4-hydroxyphenyl) acrylamide; And
(E) - N - (3- chloro-benzyl) -3- (3,4-hydroxyphenyl) acrylamide.
The skin whitening composition according to claim 1, wherein the caffeic acid derivative compound is contained in an amount of 0.0001 to 30% by weight.
2. The composition of claim 1, wherein the composition is a cosmetic composition.
The cosmetic composition according to claim 4, wherein the cosmetic composition is in the form of a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation or spray ≪ / RTI >
2. The composition of claim 1, wherein the composition is a pharmaceutical composition for the treatment or prevention of a melanin pigment hyperpigmentation disorder.
7. The composition of claim 6, wherein the melanin pigment hyperpigmentation disorder is spiny, freckle, senile pigment, or solar lentigines.
7. The composition of claim 6, wherein the composition has a formulated for external use in the form of a powder, gel, ointment, cream, lotion, liquid or aerosol formulation.