KR101123609B1 - Tetrahydroxycinnamate and tetrahydroxyamide derivatives, preparation method thereof and external application composition for skin whitening comprising same - Google Patents

Abstract

The present invention relates to a tetrahydroxy cinnamate and tetrahydroxy amide derivative represented by the following formula (1), a method for preparing the same, and a whitening skin external composition comprising the same, wherein the tetrahydroxy cinnamate and tetrahydroxy amide derivative according to the present invention. It is useful as a whitening skin external preparation or a health functional food for skin whitening because it shows an excellent inhibitory effect on tyrosinase producing a precursor necessary for melanin production and inhibits melanin biosynthesis and as a result shows excellent skin whitening effect. Can be used to:

<Formula 1>

Wherein A is as defined in the specification.

Tetrahydroxy cinnamate derivatives, tetrahydroxy amide derivatives, tyrosinase, melanin, skin whitening, external skin preparations, health functional foods

Description

TETRAHYDROXYCINNAMATE AND TETRAHYDROXYAMIDE DERIVATIVES, PREPARATION METHOD THEREOF AND EXTERNAL APPLICATION COMPOSITION FOR SKIN WHITENING COMPRISING SAME}

The present invention relates to a tetrahydroxy cinnamic acid derivative and a tetrahydroxy amide derivative exhibiting excellent skin whitening effect with excellent tyrosinase inhibitory effect and melanin biosynthesis inhibitory effect, a preparation method thereof, and a whitening skin external composition comprising the same.

It is everyone's constant desire to have white, fair skin. Human skin color is determined by the concentration and distribution of melanin in the skin. In addition to genetic factors, it is also influenced by environmental or physiological conditions such as ultraviolet rays, fatigue and stress.

Melanin is converted from tyrosine to dopa and dopaquinone by the action of tyrosinase present in pigment cells, and is produced via dopachrome and the like. This melanin is present in the skin and plays an important role in protecting the body from ultraviolet rays. However, it is known that the excessive production of melanin forms spots, freckles, etc., promotes skin aging, and causes skin cancer. Accordingly, in recent years, the development of drugs for preventing melanin overproduction is actively progressing.

Conventional whitening agent para-methoxyphenol (p -methoxyphenol), hydroquinone (hydroquinone), kojic acid (kojic acid), Arbutin (arbutin), but like they are used, and these are the melanin biosynthesis inhibiting activity of about, or denaturation of the dye cell, or There is a risk of causing lethality, and there are also disadvantages such as impairing the original function of the cell. On the other hand, vitamin C and derivatives thereof are used for the purpose of inhibiting melanin production, but they also have the disadvantage of low melanin biosynthesis inhibitory activity.

In addition, the Republic of Korea Patent No. 266740 contains three or more natural products or extracts selected from protetras, blueberries, creation, earth and sand, ripe, raw paper, turmeric, beverages in various formulations, such as granules, tablets, capsules A food composition for whitening which can be used as tea, tea, instant tea and the like is disclosed. In addition, the Republic of Korea Patent No. 406124 discloses one or more components selected from kojic acid or derivatives thereof, albutin (albutin), mulberry extract and ascorbyl 3-aminopropyl phosphate that inhibits tyrosinase in melanocytes (melanocyte) of the skin Cosmetics containing, leaf or fruit extract of Rubus coreanum, leaf or fruit extract of Rubus idaeus, grapes, which reduces the amount of prostaglandin, an inflammation mediator that is increased in skin cells by ultraviolet rays. A whitening cosmetic composition is disclosed which improves whitening function without skin irritation by adding at least one natural product extract selected from stem extract of Vitisvinifera) and leaf extract of Cola nitida.

However, the natural whitening agent described in the Patent Nos. 266740 and 406124 is a mixture of various natural products, and it is difficult to identify which extract has a whitening effect, and also has to be used in large amounts to obtain a sufficient whitening effect. There is this.

Therefore, it is urgently needed to develop a substance with excellent melanin biosynthesis inhibitory activity and low side effects.

Accordingly, the present inventors solve the problems of the existing whitening material, excellent product stability, can be used safely without side effects on the skin, inhibits melanin production, excellent pigmentation inhibitory effect, and using the organic synthesis method As a result of intensive research for a long time to develop a material for easy skin whitening, it was confirmed that tetrahydroxy cinnamate and tetrahydroxy amide derivatives have excellent melanin biosynthesis inhibitory effect, thereby completing the present invention.

Accordingly, it is an object of the present invention to provide tetrahydroxy cinnamate and tetrahydroxy amide derivatives which exhibit excellent skin whitening effect with excellent tyrosinase inhibitory effect and melanin biosynthesis inhibitory effect.

The present invention also provides a method for preparing the tetrahydroxy cinnamate and tetrahydroxy amide derivative.

The present invention also provides a whitening skin external composition comprising the tetrahydroxy cinnamate and tetrahydroxy amide derivative as an active ingredient.

In order to achieve the above object, the present invention provides a compound of formula (1) or a pharmaceutically acceptable salt thereof:

,

,

및

로 이루어진 군에서 선택된다.Where A is

,

,

And

It is selected from the group consisting of.

 The present invention also provides a method for preparing the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention also provides a whitening skin external composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Tetrahydroxy cinnamates and tetrahydroxy amide derivatives according to the present invention exhibit an excellent inhibitory effect on tyrosinase, which produces precursors required for melanin production, thereby inhibiting the biosynthesis of melanin, resulting in an excellent skin whitening effect. Since it is a bet, it can be usefully used as a skin external preparation for skin or a health functional food for skin whitening.

Hereinafter, the present invention will be described in more detail.

As used herein, the term "alkyl" refers to a linear or branched saturated C ₁ to C ₆ hydrocarbon radical chain. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl and hexyl.

As used herein, the term "pharmaceutically acceptable salt of the compound of Formula 1" includes an alkali metal salt by reaction with an alkali metal such as lithium, sodium, potassium, or the like; Alkaline earth metal salts such as calcium or magnesium salts; Or ammonium salts consisting of suitable organic ligands, such as tetravalent ammonium salts, and the like.

As used herein, the term "health functional food" means a food prepared and processed using raw materials or ingredients having functional properties useful for the human body according to the Health Functional Food Act No. 6767, and "functional" means It means ingestion for the purpose of obtaining useful effects on health use such as nutrient control or physiological action on the structure and function of the human body.

The present invention provides a compound or pharmaceutically acceptable salt selected from the group consisting of Formulas 1a, 1b, 1c and 1d:

Specific examples of preferred compounds as compounds according to the invention are as follows:

(1a) (E) -1- (3,4-dihydroxyphenyl) ethyl-3- (3,4-dihydroxyphenyl) acrylate,

(1b) (E) -1- (3,4-dihydroxyphenyl) -2-methoxy-2-oxoethyl-3- (3,4-dihydroxyphenyl) acrylate,

(1c) (E) -methyl 3- (3,4-dihydroxyphenyl) -3- (3- (3,4-dihydroxyphenyl) acrylamido) propanoate, and

(1d) (E) -3- (3,4-dihydroxyphenyl) -3- (3- (3,4-dihydroxyphenyl) acrylamido) propionic acid.

The present invention also provides a method for preparing the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

Specifically, the preparation method comprises the steps of condensation reaction of the compound of formula 2 with a compound of formula 3a or 3b, and the step of deprotecting the compound obtained in the condensation reaction step in the presence of a palladium catalyst and a base Contains:

Wherein R is methyl or -COOCH ₃ , R ₁ is C _1-5 alkylsilyl or allyl, preferably R ₁ is trimethylsilyl, tertiarybutyldimethylsilyl or allyl.

As a specific example, (E) -1- (3,4-dihydroxyphenyl) ethyl-3- (3,4-dihydroxyphenyl) acrylate of formula 1a and (E)-of formula 1b according to the present invention 1- (3,4-dihydroxyphenyl) -2-methoxy-2-oxoethyl-3- (3,4-dihydroxyphenyl) acrylate may be prepared by the same reaction as in Scheme 1 below. Can be.

Wherein R is methyl or CO ₂ Me and R ₁ is as defined above.

First, in step 1, the compound of formula 4 is prepared by condensation reaction of the cinnamic acid compound (2) and the secondary alcohol (3a).

The cinnamic acid compound (2) can be synthesized by a known method (Journal of wood science, 2005, 51, 48-59), preferably used in about 1 to 2 equivalents to the secondary alcohol (3). .

In addition, the condensation reaction includes 1,1'-carbonyldiimidazole (CDI), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1,3-dicyclohexylcarbodiimide Various condensing agents such as (DCC) can be used, and the amount thereof is preferably about 1 to 2 equivalents based on the secondary alcohol 3a. An amine such as 4-dimethylaminopyridine may be used together with the condensing agent, and the amine is preferably used in an amount of about 2 to 5 equivalents based on the secondary alcohol (3a).

In addition, as the solvent usable for the condensation reaction, an aliphatic hydrocarbon solvent such as dichloromethane or chloroform may be used. 20-70 degreeC is preferable and, as for the reaction temperature at the time of a condensation reaction, 2 to 24 hours are preferable.

Subsequently, in step 2, a compound according to Formula 1a or 1b is prepared by dissolving the compound of Formula 4 prepared in Step 1 in a solvent and then deprotecting the alkyl silyl or allyl protecting group in the presence of a palladium catalyst and a base.

As said palladium catalyst, tetrakis triphenylphosphine palladium is preferable and the usage-amount is 1-10 mol%. In addition, morpholine may be used as the base, and the amount thereof is preferably 1 to 20 equivalents. As the reaction solvent, polar solvents such as tetrahydrofuran, acetonitrile and dioxane can be used, and preferably tetrahydrofuran can be used.

Moreover, it is preferable that the temperature at the time of the said deprotection reaction is 20-60 degreeC, More preferably, it is normal temperature. In addition, the reaction time is preferably carried out for 3 to 10 hours.

In another embodiment, (E) -methyl 3- (3,4-dihydroxyphenyl) -3- (3- (3,4-dihydroxyphenyl) acrylamido) of formula 1c according to the present invention Propanoate and (E) -methyl 3- (3,4-dihydroxyphenyl) -3- (3- (3,4-dihydroxyphenyl) acrylamido) propanoic acid of formula (1d) It may be prepared by the same reaction as in Scheme 2.

Wherein R ₁ is as defined above.

First, the compound of Chemical Formula 5 is prepared by condensation reaction of cinnamic acid compound (2) and beta amino acid ester (3b) in step 1. The cinnamic acid compound (2) is preferably used in about 1 to 2 equivalents based on the beta amino acid ester (3b). In addition, the condensation reaction includes 1,1'-carbonyldiimidazole (CDI), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1,3-dicyclohexylcarbodiimide Various condensing agents such as (DCC) can be used, and the amount thereof is preferably about 1 to 2 equivalents based on the beta amino acid ester (3b). An amine such as 4-dimethylaminopyridine may be used together with the condensing agent, and the amine is preferably used in an amount of about 2 to 5 equivalents based on the beta amino acid ester (3b).

In addition, as the solvent usable for the condensation reaction, an aliphatic hydrocarbon solvent such as dichloromethane or chloroform may be used. 20-70 degreeC is preferable and, as for the reaction temperature at the time of a condensation reaction, 2 to 24 hours are preferable.

Subsequently, in step 2, the compound of formula 1c is prepared by dissolving the compound of formula 5 prepared in step 1 in a solvent and then deprotecting the alkyl silyl or allyl protecting group in the presence of a palladium catalyst and a base.

As said palladium catalyst, tetrakis triphenylphosphine palladium is preferable and the usage-amount is 1-5 mol%. In addition, morpholine may be used as the base, and the amount thereof is preferably 1 to 20 equivalents. As the reaction solvent, polar solvents such as tetrahydrofuran, acetonitrile and dioxane can be used, and preferably tetrahydrofuran can be used.

Moreover, it is preferable that the temperature at the time of the said deprotection reaction is 20-60 degreeC, More preferably, it is normal temperature. In addition, the reaction time is preferably carried out for 3 to 10 hours.

In addition, in step 3, the compound of Formula 1d may be prepared by hydrolyzing the compound of Formula 1c prepared in Step 2 in an aqueous solution using a base.

In this case, as the inorganic base, hydroxides of alkali metals such as NaOH, KOH, LiOH, etc. may be used as the inorganic base, and the reaction temperature is preferably from room temperature to 60 ° C., C _1-3 alcohols, tetrahydrofuran, Can be mixed with organic solvents such as dioxane.

The present invention also provides a process for preparing a compound of formula 3a or 3b as an intermediate used in the preparation of the compound of formula 1 or a pharmaceutically acceptable salt thereof.

The compound of formula 3a, which is used as an intermediate in the preparation of the compound of formula 1a or 1b according to the present invention, may be prepared by a reaction as shown in Scheme 3 below.

Wherein R and R ₁ are as defined above.

Specifically, in step 1, the compound of formula 7 is prepared by alkylation reaction with alkylsilyl halide or allyl halide to the compound of formula 6. Subsequently, in step 2, a secondary alcohol 3a is prepared by hydrogenating the compound prepared in step 1 in the presence of a reducing agent such as sodium borohydride (NaBH ₄ ). At this time, the compound of Formula 6 is commercially available.

The reaction solvent may be a solvent such as alcohol (eg, methanol, ethanol, etc.), dioxane, tetrahydrofuran, ethyl acetate, and the like, and preferably ethanol. In addition, the reaction temperature is preferably from -30 ℃ to room temperature, the reaction time is preferably 1 to 5 hours.

The compound of formula 3b, which is used as an intermediate in the preparation of the compound of formula 1c according to the present invention, may be prepared by a reaction as shown in Scheme 4 below.

Wherein R ₁ is as defined above.

Specifically, 3,4-dihydroxybenzaldehyde (8), which is commercially available in Step 1, is alkylated with an alkylsilyl halide or allyl halide in a general known manner to prepare a compound of Formula 9, and then in Step 2 The beta-amino acid (3c) was prepared by heating the compound of Formula 9 prepared in step 1 in ethanol solvent using malonic acid and ammonium acetate (NH ₄ OAc) [Tetrahydron; Asymmetry, 2006, 17, 860-866, and Tetrahydron; Asymmetry, 2008, 19, 2072-2077]. In step 3, beta-amino acid methyl ester (3b) may be prepared by esterifying the beta-amino acid (3c) prepared in step 2 with hydrochloric acid in a methanol solvent.

The compound of Formula 1 and a pharmaceutically acceptable salt thereof according to the present invention, as a result of experiments to determine the tyrosinase inhibitory activity, in the case of kojic acid known as a conventional tyrosinase inhibitory active material tyrosinase Inhibition requires a high concentration of 9 μg / ml, whereas the compounds according to the invention exhibited excellent tyrosinase inhibitory activity even at significantly low concentrations of 0.2 μg / ml. In addition, as a result of measuring the melanin biosynthesis inhibition rate of the compound of the present invention and kojic acid using the method of circumference (Dooley TP et al., Skin Pharmacol. 1994, 7, 188), koji acid has a high concentration in order to inhibit melanin biosynthesis. While (150 μg / ml) treatment was required, the compounds according to the invention showed good melanin biosynthesis inhibition rates even with treatments of at least 2.5 μg / ml and up to 10 μg / ml. That is, the compound according to the present invention showed 15-70 times melanin biosynthesis inhibition efficiency compared to kojic acid. From these results, it can be seen that the compound of formula 1 and the pharmaceutically acceptable salt thereof according to the present invention have excellent tyrosinase inhibitory activity and melanin biosynthesis inhibitory activity.

Accordingly, the present invention provides a tyrosinase inhibitor or a melanogenesis inhibitor comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

In another aspect, the present invention provides a whitening skin external composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The external preparation composition may be a pharmaceutical composition or a cosmetic composition.

When the composition is used as a pharmaceutical composition, oral dosage forms, for example, oral dosage forms such as tablets, capsules, troches, solutions and suspensions; Injectable preparations in the form of injectable solutions or suspensions, or ready-to-use injectable dry powders which can be prepared and used as injectable distilled water at the time of injection; Or it can be formulated into various preparations such as ointment. Pharmaceutical formulations prepared using conventional carriers can be administered orally or parenterally, for example, intravenously, subcutaneously, intraperitoneally or topically.

In particular, solid preparations for oral administration include the compound according to the invention or a pharmaceutically acceptable salt thereof, at least one excipient such as starch, calcium carbonate, sucrose, lactose or It can be prepared by mixing gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate or talc may also be used.

Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients can be used, such as wetting agents, sweeteners, fragrances or preservatives. have.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations or suppositories. The non-aqueous solvent or suspension may be a vegetable oil such as propylene glycol, polyethylene glycol, or olive oil, or an injectable ester such as ethyl oleate. The base of the suppository may be utopsol, macrogol, tween 61, Cacao butter, laurin butter, glycerol or gelatin and the like can be used.

In addition, the human dosage of the pharmaceutical composition according to the present invention may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, but generally in adults 10 to 500 mg per day, preferably The amount of 50 to 300 mg is to be administered, and may be divided several times a day, preferably once to six times at regular intervals according to the judgment of a doctor or pharmacist.

When the composition is used as a cosmetic composition, it may include components such as a substrate, a carrier, and the like commonly used in the manufacture of cosmetics with the active ingredient, and the basic product cosmetics (cosmetics, creams, essences, cleansing foam, cleansing water, Pack), body cosmetics (body lotion, body oil, body gel), color cosmetics (foundation, lipstick, mascara, makeup base), hair cosmetics (shampoo, rinse, hair conditioner, hair gel) Can be formulated. In this case, the compound according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may be included in an amount of 0.05 to 10% by weight based on the dry weight of the cosmetic.

The present invention also provides a whitening health functional food comprising the compound of Formula 1 and a pharmaceutically acceptable salt thereof as an active ingredient.

Accordingly, for the purpose of skin whitening, it is possible to manufacture and process as a health functional food in the form of a pharmaceutical dosage form such as powders, granules, tablets, capsules, pills, suspensions, emulsions, syrups or health drinks. In this case, the compound according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may be included in an amount of 0.05 to 10% by weight based on the dry weight of various health functional foods.

For example, when preparing a health functional beverage, there are no special limitations to the other ingredients except for containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof as essential ingredients in the indicated ratios, and various flavoring agents such as conventional drinks. Or natural carbohydrate or the like as an additional component. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (tauumatin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. .

In addition to the above, the composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid and its Salts, organic acids, protective colloids, thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages and the like. Others may contain pulp for the production of natural fruit juices and fruit juice beverages and vegetable beverages, which components may be used independently or in combination.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

Example  1: (E) -1- (3,4- Dihydroxyphenyl ) Ethyl-3- (3,4- Dihydroxyphenyl ) Acrylate  Produce

Step 1: 1- (3,4- Bis (allyloxy) phenyl ) Ethanone

2.5 g (16.43 mmol) of 1- (3,4-dihydroxyphenyl) ethanone are dissolved in 50 ml of acetone, and 9.94 g (82.16 mmol) of allyl bromide and 11.63 g (82.16 mmol) of potassium carbonate are added thereto for 15 hours. Heated reflux was stirred. After the completion of the reaction, the solvent was concentrated under reduced pressure, crystallized with ether and n-hexane, and then filtered to obtain 2.8 g (yield; 73%) of 1- (3,4-bis (allyloxy) phenyl) ethanone.

¹ H NMR (CDCl ₃ ) ppm: 7.53 (m, 2H), 6.91-6.88 (m, 1H), 6.15-6.01 (m, 2H), 5.48-5.40 (m, 2H), 5.34-5.28 (m, 2H ), 4.69-4.65 (m, 4H), 2.48 (s, 3H)

Step 2: 1- (3,4-bis (allyloxy) phenyl) ethanol

Dissolve 400 mg (1.73 mmol) of 1- (3,4-bis (allyloxy) phenyl) ethanone obtained in step 1 in 20 ml of MeOH, and then add 327 mg (8.65 mmol) of NaBH ₄ to room temperature for 4 hours. Stirred at. After completion of the reaction, the organic layer was extracted with ethyl acetate / brine, dried over MgSO ₄ , concentrated, and then purified by column chromatography (EtOAc: Hex = 1: 4) to give 1- (3,4-bis (allyloxy) phenyl) ethanol. 300 mg (1.28 mmol, 74%, white solid) of (1- (3,4-bis (allyloxy) phenyl) ethanol) were obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 6.95 (s, 1H), 6.86 (s, 2H), 6.13-6.01 (m, 2H), 5.46-5.37 (m, 2H), 5.30-5.24 (m, 2H), 4.84-4.80 (m, 1H), 4.63-4.58 (m, 4H), 1.83 (d, J = 3 Hz, OH), 1.46 (d, J = 6.3 Hz, 3H)

Step 3: (E) -1- (3,4- Bis (allyloxy) phenyl ) Ethyl-3 -(3,4- Bisallyloxy ) Phenyl ) Acrylate

(E) -3- (3,4-bis (allyloxy) phenyl) acrylic acid 300 mg (1.1 mmol) and 1- (3,4-bis (allyloxy) phenyl) ethanol 386 mg (1.65 mmol) in methylene chloride Dissolve in 10 mL, add 421.8 mg (2.2 mmol) of 3- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 268.8 mg (2.2 mmol) of 4-dimethylaminopyridine, and stir at reflux for 2 hours. It was. After completion of the reaction, methylene chloride and sodium chloride solution were added to extract an organic layer, which was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This was separated by column chromatography (ethyl acetate: n -hexane = 1: 4) to give (E) -1- (3,4-bis (allyloxy) phenyl) ethyl-3- (3,4-bisallyloxy) 420 mg (Yield; 80%) of phenyl) acrylate were synthesized.

¹ H NMR (CDCl ₃ ) ppm: 7.60 (d, J = 15.6 Hz, 1H), 7.08-7.05 (m, 2H), 6.96-6.93 (m, 2H), 6.88-6.85 (m, 2H), 6.29 ( d, J = 15.6 Hz, 1H), 6.14-6.00 (m, 4H), 5.98-5.91 (m, 1H), 5.46-5.31 (m, 4H), 5.29-5.24 (m, 4H), 4.65-4, 58 (m, 8H), 1.56 (s, 3H)

Step 4: (E) -1- (3,4- Dihydroxyphenyl ) Ethyl-3- (3,4- Dihydroxyphenyl ) Acrylate

400 mg (0.84 mmol) of (E) -1- (3,4-bis (allyloxy) phenyl) ethyl-3- (3,4-bisallyloxy) phenyl) acrylate obtained in step 3 was added to tetrahydro. It was dissolved in 25 ml of furan, and 48.5 mg (0.042 mmol) of 0-valent tetrakis triphenylphosphine palladium and 2.93 g (33.6 mmol) of morpholine were added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the organic layer was extracted with ethyl acetate and 2N aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This was separated by column chromatography (ethyl acetate: n-hexane = 1: 1) to prepare 100 mg (yield; 40%) of the title compound.

¹ H NMR (DMSO-d6) ppm: 9.57 (s, 1H), 9.11 (s, 1H), 8.90 (s, 1H), 8.88 (s, 1H), 7.43 (d, J = 15.6 Hz, 1H), 7.01-6.96 (m, 2H), 6.75-6.63 (m, 4H), 6.24 (d, J = 15.6 Hz, 1H), 5.74-5.72 (m, 1H), 1.43 (d, J = 6.6 Hz, 3H)

Example  2: (E) -1- (3,4- Dihydroxyphenyl )-2- Methoxy -2- Oxoethyl-3 -(3,4- Dihydroxyphenyl ) Acrylate  Produce

Step 1: methyl  2- (3,4- Bis (allyloxy) phenyl )-2- Oxoacetate

3 g (15.3 mmol) of methyl 2- (3,4-dihydroxyphenyl) -2-oxoacetate are dissolved in 10 ml of N, N-dimethylformamide, and 5.55 g (45.9 mmol) of allyl bromide and 1.38 NaH are added. g (45.9 mmol) was added and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, the organic layer was extracted with ethyl acetate and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. This was separated by column chromatography (ethyl acetate: n-hexane = 1: 3) to obtain 1.11 g (yield; 27%) of methyl 2- (3,4-bis (allyloxy) phenyl) -2-oxoacetate.

¹ H NMR (CDCl ₃ ) ppm: 7.63-7.58 (m, 2H), 6.93-6.91 (m, 1H), 6.15-6.01 (m, 2H), 5.48-5.46 (m, 1H), 5.42-5.41 (m , 1H), 5.35-5.29 (m, 2H), 4.71-4.65 (m, 4H), 3.96 (s, 3H)

Step 2: Methyl 2- (3,4-bis (allyloxy) phenyl) -2-hydroxyacetate

1.3 g (4.71 mmol) of methyl 2- (3,4-bis (allyloxy) phenyl) -2-oxoacetate were dissolved in 20 ml of ethanol at -30 ° C, and 89 mg (2.35 mmol) of NaBH4 was added thereto, followed by room temperature. Stirred for 2 h. After completion of the reaction, the mixture was neutralized with 2N-HCl, extracted with ethyl acetate and brain, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. This was separated by column chromatography (ethyl acetate: n-hexane = 1: 3) to obtain 1.1 g (yield; 84%) of methyl 2- (3,4-bis (allyloxy) phenyl) -2-hydroxyacetate. .

¹ H NMR (CDCl ₃ ) ppm: 6.95-6.85 (m, 3H), 6.14-6.00 (m, 2H), 5.44-5.43 (m, 1H), 5.38-5.37 (m, 1H), 5.29-5.28 (m) , 1H), 5.26-5.25 (m, 1H), 5.09 (d, J = 5.6 Hz, 1H), 4.61-4.60 (m, 4H), 3.76 (d, J = 0.6 Hz, 1H), 3.35 (dd, J = 5.6Hz, 0.6Hz, 1H)

Step 3: (E) -1- (3,4- Bis (allyloxy) phenyl )-2- Methoxy -2- Oxoethyl-3 -(3,4-bis (al Ryloxy ) Phenyl ) Acrylate

1.1 g (4.0 mmol) of (E) -3- (3,4-bis (allyloxy) phenyl) acrylic acid and 1.1 g of methyl 2- (3,4-bis (allyloxy) phenyl) -2-hydroxyacetate 3.95 mmol) was dissolved in 50 ml of methylene chloride, and 138 mg (0.72 mmol) of 3- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 88 mg (0.72 mmol) of 4-dimethylaminopyridine were added thereto. The mixture was stirred under reflux for 2 hours. After completion of the reaction, methylene chloride and sodium chloride solution were added to extract an organic layer, which was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This was separated by column chromatography (ethyl acetate: n-hexane = 1: 4) to give (E) -1- (3,4-bis (allyloxy) phenyl) -2-methoxy-2-oxoethyl-3- 1.7 g (yield; 83%) of (3,4-bis (allyloxy) phenyl) acrylate were synthesized.

¹ H NMR (CDCl ₃ ) ppm: 7.68 (d, J = 15.9 Hz, 1H), 7.10-7.03 (m, 4H), 6.91-6.85 (m, 2H), 6.39 (d, J = 15.9 Hz, 1H) , 6.15-6.00 (m, 4H), 5.97 (s, 1H), 5.47-5.44 (m, 2H), 5.41-5.38 (m, 2H), 5.31-5.29 (m, 2H), 5.28-5.26 (m, 2H), 4.65-4.60 (m, 8H), 3.74 (s, 3H)

Step 4: (E) -1- (3,4- Dihydroxyphenyl )-2- Methoxy -2- Oxoethyl-3 -(3,4- Dihydroxyphenyl ) Acrylate

(E) -1- (3,4-bis (allyloxy) phenyl) -2-methoxy-2-oxoethyl 3- (3,4-bis (allyloxy) phenyl) acrylate 400 mg (0.769 mmol) Was dissolved in 25 ml of tetrahydrofuran, and 45 mg (0.038 mmol) of the 0-valent tetrakis triphenylphosphinepalladium and 2.7 g (30.76 mmol) of morpholine were added thereto, followed by stirring at room temperature for 8 hours. After completion of the reaction, the organic layer was extracted with ethyl acetate and 2N aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This was separated by column chromatography (ethyl acetate: n-hexane = 2: 1) to prepare 200 mg (yield; 72%) of the title compound.

¹ H NMR (DMSO-d6) ppm: 9.64 (s, 1H), 9.14 (s, 3H), 7.51 (d, J = 15.8Hz, 1H), 7.06-7.01 (m, 2H), 6.85 (m, 1H ), 6.77-6.71 (m, 3H), 6.33 (d, J = 15.8 Hz, 1H), 5.78 (s, 1H), 3.63 (s, 3H)

Example 3: Preparation of (E) -methyl 3- (3,4-dihydroxyphenyl) -3- (3- (3,4-dihydroxyphenyl) acrylamido) propanoate

Step 1: 3,4- Bis (allyloxy) benzaldehyde

1.26 g (9.12 mmol) of 3,4-dihydroxybenzaldehyde was dissolved in 150 mL of acetone, and 11.04 g (91.23 mmol) of allyl bromide and 12.6 g (91.23 mmol) of potassium carbonate were added thereto, followed by heating under reflux for 15 hours. . After the reaction was completed, the solvent was concentrated under reduced pressure, crystallized with ether and n-hexane, and then filtered to obtain 1.3 g (yield; 65%) of 3,4-bis (allyloxy) benzaldehyde.

¹ H NMR (CDCl ₃ ) ppm: 9.86 (s, 1H), 7.46-7.44 (m, 2H), 7.00 (d, J = 4.9Hz, 1H), 6.15-6.06 (m, 2H), 6.50-5.45 ( m, 2H), 5.37-5.32 (m, 2H), 4.73-4.68 (m, 4H)

Step 2: 3-Amino-3- (3,4-bis (allyloxy) phenyl) propionic acid

4.78 g (21.9 mmol) of 3,4-bis (allyloxy) benzaldehyde was dissolved in 50 ml of ethanol, and 4.56 g (43.82 mmol) of malonic acid and 3.37 g (0.044 mmol) of NH ₄ OAc were added thereto, followed by heating under reflux for 2 hours. Stirred. After the reaction was completed, the solvent was filtered and then the filtrate was washed with ethanol. The washed filtrate was dried to give 2.5 g (yield; 41%) of 3-amino-3- (3,4-bis (allyloxy) phenyl) propionic acid.

Step 3: methyl  3-amino-3- (3,4- Bis (allyloxy) phenyl ) Propanoate

2.5 g (90.15 mmol) of 3-amino-3- (3,4-bis (allyloxy) phenyl) propionic acid was dissolved in 250 ml of methanol at 0 ° C., and 50 ml of hydrochloric acid was added thereto, followed by stirring under reflux for 1 hour. After the reaction, the organic layer was extracted with ethyl acetate and Na ₂ CO ₃ , dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. This was separated by column chromatography (ethyl acetate: n-hexane = 1: 1) to give 2.6 g (yield; 99%) of methyl 3-amino-3- (3,4-bis (allyloxy) phenyl) propanoate. Synthesized.

¹ H NMR (DMSO-d6) ppm: 8.65 (br, 2H), 7.29 (s, 1H), 7.01-6.94 (s, 2H), 6.12-5.95 (m, 2H), 5.45-5.44 (m, 0.5H ), 5.41-5.39 (m, 1H), 5.35-5.34 (m, 0.5H), 5,27-5,21 (m, 2H), 4.57-4,54 (m, 4H), 4.48 (br, 1H ), 3.54 (s, 3H), 3.19-3.12 (m, 1H), 3.00-2.92 (m, 1H)

Step 4: (E) -Methyl 3- (3,4-bis (allyloxy) phenyl) -3- (3- (3,4-bis (allyloxy) phenyl) acrylamido) propanoate

282.6 mg (1.03 mmol) of (E) -3- (3,4-bis (allyloxy) phenyl) acrylic acid and 300 mg of methyl 3-amino-3- (3,4-bis (allyloxy) phenyl) propanoate (1.03 mmol) was dissolved in 20 ml of methylene chloride, and 39.5 mg (2.06 mmol) of 3- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 6 mg of 4-dimethylaminopyridine were added thereto for 2 hours. Heated reflux was stirred. After completion of the reaction, methylene chloride and sodium chloride solution were added to extract an organic layer, which was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This was separated by column chromatography (ethyl acetate: n-hexane = 1: 1) to give (E) -methyl 3- (3,4-bis (allyloxy) phenyl) -3- (3- (3,4-bis 400 mg (yield; 73%) of (allyloxy) phenyl) acrylamido) propanoate was synthesized.

¹ H NMR (CDCl ₃ ) ppm: 7.54 (d, J = 15.5 Hz, 1H), 7.06-7.04 (m, 2H), 6.88-6.83 (m, 3H), 6.70-6.67 (m, 1H), 6.28 ( d, J = 15.5 Hz, 1H), 6.14-5.99 (m, 4H), 5.52-5.35 (m, 4H), 5.30-5.24 (m, 4H), 4.63-4.56 (m, 8H), 3.63 (S, 3H), 3.01-2.82 (m, 2H)

Step 5: ( E) -Methyl 3- (3,4-dihydroxyphenyl) -3- (3- (3,4-dihydroxyphenyl) acrylamido) propanoate

(E) -Methyl 3- (3,4-bis (allyloxy) phenyl) -3- (3- (3,4-bis (allyloxy) phenyl) acrylamido) propanoate 400 mg (0.750 mmol) Was dissolved in 25 ml of tetrahydrofuran, and 43 mg (0.037 mmol) of the zero-valent tetrakistriphenylphosphinepalladium and 2.6 g (30.0 mmol) of morpholine were added thereto, followed by stirring at room temperature for 8 hours. After completion of the reaction, the organic layer was extracted with ethyl acetate and 2N aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This was separated by column chromatography (ethyl acetate: n-hexane = 5: 1) to prepare 203 mg (yield; 73%) of the title compound.

¹ H NMR (DMSO-d6) ppm: 9.35 (s, 1H), 9.11 (s, 1H), 8.85 (s, 1H), 8.80 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 15.6Hz, 1H), 6.92 (m, 1H), 6.82 (m, 1H), 6.75-6.65 (m, 3H), 6.58 (m, 1H), 6.34 (d, J = 15.6Hz , 1H), 5.17 (m, 1H), 3.54 (s, 3H), 2.82-2.67 (m, 2H)

Example 4: Preparation of (E) -3- (3,4-dihydroxyphenyl) -3- (3- (3,4-dihydroxyphenyl) acrylamido) propionic acid

17 mg (0.402 mmol) of lithium hydroxide was dissolved in 5 ml of water, and then, (E) -methyl 3- (3,4-dihydroxyphenyl) -3- obtained in Example 3 in tetrahydrofuran and methanol was added thereto. A solution of 50 mg (0.134 mmol) of (3- (3,4-dihydroxyphenyl) acrylamido) propanoate was added at room temperature, followed by stirring for 4 hours. After the reaction was completed, the mixture was adjusted to pH 2 with 2 mol aqueous hydrochloric acid. The organic layer was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. It was crystallized from ether and n-hexane and filtered to give 12 mg (yield; 25%) of the title compound.

¹ H NMR (DMSO-d6) ppm: 8.37 (brd, 1H), 7.26 (d, J = 15.6 Hz, 1H), 6.98-6.62 (m, 6H), 6.40 (d, J = 15.6 Hz, 1H), 5.21-5.19 (m, 1H), 2.78-2.65 (m, 2H)

The structural formulas of the compounds prepared according to Examples 1 to 4 are shown in Table 1 below.

rescue Example 1

Example 2

Example 3

Example 4

Experimental Example 1: Tyrosinase Activity Effect

In order to determine the tyrosinase inhibitory activity of the compound prepared in Examples 1-4, the experiment was carried out as follows.

1.0 mL of 1.5 mM L-tyrosine (potassium phosphate buffer, pH 6.8) was prepared, and 0.01 mL of this was placed in a 0.5 mL volumetric spectrophotometer cuvette and 0.06 mM dopa (potassium phosphate) as a cofactor. Buffer, pH 6.8) 0.01 ml was added. To each, 0.05 ml of the compound of Examples 1-4 in appropriate concentration were added, and potassium phosphate buffer was added to 0.31 ml. Tyrosinase (Sigma-aldrich) extracted from the mushrooms was prepared by adding 60 U / ml to potassium phosphate buffer, and the reaction proceeded by adding 0.1 ml. At this time, koji acid was added as a control. After reacting the reaction for 10 minutes at 37 ℃, the test tube was immersed in ice water to stop the reaction, the absorbance at 475 nm using a spectrophotometer (Beckman DU-7500) for the product was measured, The tyrosinase inhibition rate (%) was calculated.

* A: absorbance of the sample to which the inhibitor is added

* B: absorbance (Blank) added with buffer instead of sample

From the measured inhibition rate, the concentration of the compound reaching an enzyme activity inhibition rate of 50% was determined as an IC ₅₀ value, and the determined IC ₅₀ value is shown in Table 2 below.

compound Tyrosinase inhibitory activity; IC ₅₀ (μg / ml) Kojisan 9 Example 1 0.2 Example 2 0.2 Example 3 1.2 Example 4 3.5

As shown in Table 2, while koji acid was treated at a high concentration of 9 μg / ml in order to inhibit tyrosinase, the compounds of Example 1-4 had a large inhibitory activity of tyrosinase even at low concentrations. appear. From these results, it was found that the compound of Examples 1-4 had high inhibitory activity against tyrosinase even at low concentrations.

Experimental Example 2: Determination of melanin production inhibitory effect

In order to determine the melanin biosynthesis inhibition rate of the compound prepared in Examples 1-4, an experiment was conducted using the method of circumference (see Dooley T. P. et al., Skin Pharmacol. 1994, 7, 188). The results are shown in Table 3 below.

Comparison of Melanin Biosynthesis Inhibition Rate of Melan-A Cells

compound Melanin biosynthesis inhibition rate; IC ₅₀ (μg / ml) Kojisan 150 Example 1 5 Example 2 5 Example 3 5 Example 4 10

As shown in Table 3, it was confirmed that Example 1-4 shows excellent melanin biosynthesis inhibition rate while high concentration of kojic acid is required to inhibit melanin biosynthesis.

Examples of formulations for the composition of the present invention are illustrated below.

Preparation Example 1 Preparation of Pharmaceutical Formulation

1-1: Preparation of Powder

2 g of compound of Example 1

1g lactose

The above components were mixed and packed in airtight bags to prepare powders.

1-2: Preparation of Tablets

100 mg of the compound of Example 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

1-3: Preparation of Capsule

100 mg of the compound of Example 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

Preparation Example 2 Preparation of Cosmetic Formulation

2-1: Preparation of Cream

Creams containing a compound of the present invention were prepared according to the formulation of Table 4 below.

ingredient weight% Compound of Example 1 0.5 Stearic acid 15.0 Cetanol 1.0 Potassium hydroxide 0.7 glycerin 5.0 Lofienricole 3.0 antiseptic Quantity incense Quantity Purified water Remainder gun 100

2-2: Preparation of Flexible Lotion

A flexible lotion containing a compound of the present invention was prepared in accordance with the formulation of Table 5 below.

ingredient weight% Compound of Example 1 0.2 ethanol 10.0 Polylauric acid polyoxyethylene sorbitan 1.0 Methyl paraoxybenzoate 0.2 glycerin 5.0 1,3-butylglycol 6.0 incense Quantity Pigment Quantity Purified water Remainder gun 100

2-3: Preparation of Nutritional Lotion

A nourishing lotion containing a compound of the present invention was prepared according to the prescription of Table 6 below.

ingredient weight% Compound of Example 1 0.1 Waselin 2.0 Sesquioleate sorbitan 0.8 Polyoxyethylene oleylethyl 1.2 Methyl paraoxybenzoate Quantity Propylene glycol 5.0 ethanol 3.2 Carboxy Vinyl Polymer 18.0 Potassium hydroxide 0.1 Pigment Quantity incense Quantity Purified water Remainder gun 100

2-4: Preparation of Essence

Essences containing the compounds of the present invention were prepared according to the formulation of Table 7 below.

ingredient weight% Compound of Example 1 5 Propylene glycol 10.0 glycerin 10.0 Sodium hyaluronate aqueous solution (1%) 5.0 ethanol 5.0 Polyoxyethylene Cured Castor Oil 1.0 Methyl paraoxybenzoate 0.1 incense Quantity Purified water Remainder gun 100

2-5: Manufacture of Pack

Packs containing the compounds of the present invention were prepared according to the prescription in Table 8.

ingredient weight% Compound of Example 1 0.5 glycerin 5.0 Propylene glycol 4.0 Polyvinyl alcohol 15.0 ethanol 8.0 Polyoxyethylene oleylethyl 1.0 Methyl paraoxybenzoate 0.2 incense Quantity Pigment Quantity Purified water Remainder gun 100

2-5: Preparation of Ointment

Ointments containing the compounds of the present invention were prepared according to the formulation of Table 9 below.

ingredient weight% Compound of Example 1 5.0 White Vaseline 25.0 Stearyl alcohol 20.0 Propylene glycol 12.0 Propylene Missic Acid 0.1 Sodium Glycerin Monolaurel 0.2 Polyoxyethylene Cured Castor Oil 4.0 Betaine-containing cationic emulsifiers 0.2 Glycerine monostearate 0.1 Paraoxybenzoic acid propyl 0.1 Purified water Remainder gun 100

Preparation Example 3 Preparation of Health Functional Food

3-1: Manufacturing Flour Food

0.1 to 10.0 parts by weight of the compound of Example 1 according to the present invention was added to flour, and bread, cake, cookies, crackers and noodles were prepared in a conventional manner using the mixture to prepare foods for health promotion.

3-2: Preparation of Soups and Gravys

0.1 to 1.0 parts by weight of the compound of Example 1 according to the present invention was added to soup and gravy to prepare a health promoting meat product, soup of noodles and gravy in a conventional manner.

3-3: Preparation of Ground Beef

10 parts by weight of the compound of Example 1 according to the present invention was added to the ground beef to prepare a ground beef for health promotion in a conventional manner.

3-4: Manufacture of Dairy Products

0.1-1.0 parts by weight of the compound of Example 1 according to the present invention was added to milk, and various dairy products such as butter and ice cream were prepared in a conventional manner using the milk.

3-5: Manufacture of Wire

Brown rice, barley, glutinous rice, and yulmu were dried by a known method and dried, and the mixture was granulated to a powder having a particle size of 60 mesh. The black beans, black sesame seeds, and perilla were also steamed and dried in a known manner to prepare a powder having a particle size of 60 mesh by a pulverizer. The compound of formula 1 according to the present invention was reduced in a vacuum condenser, concentrated, sprayed, and hot air dryer. The dried product obtained by drying with a pulverizer was ground to a particle size of 60 mesh to obtain a dry powder. Cereals, seeds and the dry powder of the compound of Example 1 were prepared in the following ratio to prepare a conventional method.

Cereals (30 parts by weight brown rice, 15 parts by weight brittle, 20 parts by weight of barley),

Seeds (7 parts by weight of perilla, 8 parts by weight of black beans, 7 parts by weight of black sesame seeds)

Dry powder (1 part by weight) of the compound of Example 1 according to the present invention,

(0.5 part by weight),

Foxglove (0.5 part by weight)

Preparation Example 4 Preparation of Drinks

4-1: Preparation of Health Beverage

Instant sterilization by homogeneously combining the compound of Example 1 according to the present invention with subsidiary materials such as liquid fructose (0.5%), oligosaccharide (2%), sugar (2%), salt (0.5%) and water (75%) After this, it was packaged in a small packaging container such as glass bottles, plastic bottles to prepare a healthy beverage.

4-2: Preparation of Vegetable Juice

0.5 g of the compound of Example 1 according to the present invention was added to 1,000 ml of a vegetable juice such as tomato or carrot to prepare a vegetable juice for health promotion in a conventional manner.

4-3: Preparation of Fruit Juice

0.1 g of the compound of Example 1 according to the present invention was added to 1,000 ml of fruit juice, such as apple or grape, to prepare fruit juice for health promotion in a conventional manner.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, It is to be understood that the invention may be practiced within the scope of the appended claims.

Claims (7)

A compound of Formula 1 or a pharmaceutically acceptable salt thereof: <Formula 1>

Where A is

or

to be. delete The method of claim 1, The pharmaceutically acceptable salt may be an alkali metal salt; Alkaline earth metal salts; Or ammonium salt, or a pharmaceutically acceptable salt thereof. Condensing the compound of Formula 2 with a compound of Formula 3a, and Deprotecting the compound obtained in the condensation step in the presence of a palladium catalyst and a base. A process for preparing a compound of formula 1 according to claim 1 or a pharmaceutically acceptable salt thereof, comprising: <Formula 2>

<Formula 3a>

Where R is methyl or -COOCH ₃ and R ₁ is C _1-5 alkylsilyl or allyl. Whitening skin external composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The composition of claim 5, wherein the composition is a cosmetic composition or a pharmaceutical composition. A health functional food for skin whitening comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.