KR102635194B1 - Diaryl derivative compounds and compositions for skin whitening comprising the same - Google Patents

Abstract

It relates to a diaryl derivative compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a composition for skin whitening containing the same as an active ingredient. Specifically, the compound according to the present specification is a compound with a novel structure in which a polyphenol group and adamantyl phenyl are linked, and has a whitening effect by suppressing melanin production, so it is widely used in pharmaceutical compositions, cosmetic compositions, or external skin agents. It can be. In addition, since it is manufactured using starting materials that are easier to supply compared to conventional whitening materials, mass production is possible.

Description

Diaryl derivative compounds and compositions containing the same for skin whitening {DIARYL DERIVATIVE COMPOUNDS AND COMPOSITIONS FOR SKIN WHITENING COMPRISING THE SAME}

Disclosed herein are diaryl derivative compounds, isomers thereof, pharmaceutically acceptable salts thereof, hydrates or solvates thereof, and compositions for skin whitening containing the same.

The skin is equipped with physical and chemical UV protection factors and has the effect of preventing skin disorders caused by various photochemical reactions to a minimum. The stratum corneum attenuates the energy of ultraviolet rays by reflecting and diffusing them. In addition, melanin pigment, SOD (superoxide dismutase), and other antioxidant components absorb ultraviolet rays that penetrate into the skin and protect against skin disorders by attenuating the energy or eliminating reactive oxygen species secondaryly generated by ultraviolet rays. do.

However, when the living body receives a large amount of ultraviolet rays that exceed the ability of the above-mentioned defense factors, or when the ability deteriorates with age, various skin disorders occur.

There are various cells in the skin that are responsible for immunity in the living system, such as macrophages and Langerhans cells. When irradiated with ultraviolet rays, these cells are not only reduced in number but also functionally impaired. The biggest factor in determining skin color is the distribution and amount of melanin in the skin. Melanin is produced in melanocytes. Enzymes such as tyrosinase exist in these melanocytes, and they work together to polymerize and oxidize the amino acid tyrosine, which is always present in the body, as a substrate. As a result of the reaction, melanin, a dark brown pigment, is formed. The melanin formed in this way moves to epidermal cells called keratinocytes through the dendrites of melanocytes. Here, melanin plays an important role by forming a hat-like structure around the nucleus, protecting genes from ultraviolet rays and protecting intracellular proteins by removing free radicals.

There is no enzyme in the body to decompose melanin, but it is removed by falling off from the skin when keratinocytes fall off from the epidermis. However, if more melanin is produced than necessary, it causes hyperpigmentation such as spots, freckles, and moles, resulting in poor cosmetic results.

There are many known factors that affect melanin production, and the increase in melanin production caused by ultraviolet rays and the resulting pigmentation are very important in the cosmetics field. The basic mechanisms of drugs mixed in whitening cosmetics for the purpose of preventing pigmentation are inhibition of tyrosinase action, inhibition of tyrosinase production, inhibition of melanin production mediator, inhibition of reduction and photo-oxidation of existing melanin, promotion of melanin excretion, and ultraviolet ray cuts.

As women desire to have white skin even in an environment exposed to ultraviolet rays, the need for prevention and improvement of abnormal skin pigmentation symptoms and hyperpigmentation is increasing. Accordingly, the development of whitening products that prevent excessive melanin production has become necessary. A lot of effort has been made over the years. Specific examples include inhibitors that inhibit tyrosinase activity such as kojic acid and arbutin, hydroquinone, vitamin A, vitamin C and their derivatives. However, their use is limited due to safety issues on the skin, stability issues within the formulation, and insufficient whitening effect.

In addition, in the case of Nivitol (=4-[3-(2,4-dimethoxy-3-methyl-phenyl)-propyl]-benzene-1,3-diol), known as a novel whitening substance, it requires an expensive starting point for synthesis. Because it requires materials, it is not suitable for commercial mass production.

In response to this, research is being actively conducted on new compounds that have excellent skin whitening efficacy by suppressing melanin production and can be mass-produced due to the easy supply of starting materials and simple manufacturing process.

Korean Patent Publication No. 10-2016-0026678 (2016.03.09)

In one aspect, the purpose of the present invention is to provide a novel diaryl derivative compound that inhibits melanin production and has an excellent skin whitening effect and a composition for skin whitening containing the same.

In one aspect, the present invention provides novel diaryl derivative compounds, isomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof.

In one aspect, the present invention provides a method for producing a novel diaryl derivative compound, its isomer, its pharmaceutically acceptable salt, its hydrate, or its solvate.

In one aspect, the present invention provides a composition for skin whitening comprising a novel diaryl derivative compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient.

In one aspect, the novel diaryl derivative compound of the present invention has a whitening effect by inhibiting melanin production, so it can be used in a variety of ways, such as pharmaceutical compositions, cosmetic compositions, or external skin agents.

In another aspect, the novel diaryl derivative compound of the present invention is manufactured using starting materials that are easier to supply compared to conventional whitening materials, so mass production is possible.

Figure 1 shows the manufacturing process of a diaryl derivative compound according to an embodiment of the present invention.
Figure 2 shows the manufacturing process of Nivitol, conventionally known as a whitening substance.

Term Definition

In this specification, when a part “includes” a certain component, this means that it may further include other components rather than excluding other components unless specifically stated to the contrary.

exemplary Examples of implementations explanation

Hereinafter, the present invention will be described in detail.

In exemplary embodiments of the present invention, the present invention relates to a diaryl derivative compound represented by the following formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[Formula 1]

In Formula 1,

R1 and R2 are the same or different and are each independently an alkyl group having 1 to 10 carbon atoms,

X is -CO- or -CH ₂ -.

In this specification means a site connected to another substituent. Additionally, in this specification, -Me means a methyl group (-CH ₃ ), and -MOM means a methoxymethyl group (-CH ₂ OCH ₃ ).

In the present specification, the alkyl group may be straight chain or branched, and the number of carbon atoms is not particularly limited, but is preferably 1 to 10, more preferably 1 to 5, and specifically includes methyl, ethyl, propyl, etc. , but is not limited to these.

As used herein, “isomer” specifically refers to optical isomers (e.g., essentially pure enantiomers, essentially pure diastereomers, or mixtures thereof), as well as conformational isomers ( Includes conformation isomers (i.e. isomers that differ only in the angle of one or more chemical bonds), position isomers (especially tautomers), or geometric isomers (e.g. cis-trans isomers). do.

As used herein, “essentially pure” means, for example, when used in relation to enantiomers or partial isomers, the specific compound, including enantiomers or partial isomers, is about 90% or more, preferably about 95% or more. , more preferably about 97% or more or about 98% or more, even more preferably about 99% or more, and even more preferably about 99.5% or more (w/w).

As used herein, “pharmaceutically acceptable” means approval by the government or equivalent regulatory body that it can be used in animals, more specifically in humans, by avoiding significant toxic effects when used in normal medicinal dosages. means available, approved, listed in a pharmacopoeia, or otherwise recognized by a general pharmacopoeia.

As used herein, “pharmaceutically acceptable salt” refers to a salt according to one aspect of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. The salts are (1) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-Toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2,2,2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert -acid addition salts formed with organic acids such as butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid; or (2) a salt formed when an acidic proton present in the parent compound is replaced.

In this specification, “hydrate” refers to a compound to which water is bound, and is a broad concept that includes embedded compounds in which there is no chemical bond between water and the compound.

In this specification, “solvate” refers to a higher-order compound formed between a solute molecule or ion and a solvent molecule or ion.

In one embodiment, Formula 1 may be represented by Formula 1-1 or 1-2 below.

[Formula 1-1]

[Formula 1-2]

The IUPAC name of the diaryl derivative compound of Formula 1-1 is 4-[3-(5-adamantane-1-yl-2,4-dimethoxy-phenyl)-propyl]-benzene-1,3-diol ( 4-[3-(5-Adamantan-1-yl-2,4-dimethoxy-phenyl)-propyl]-benzene-1,3-diol).

The IUPAC name of the diaryl derivative compound of Formula 1-2 is 1-(5-adamantane-1-yl-2,4-dimethoxy-phenyl)-3-(2,4-dihydroxy-phenyl)- It is propan-1-one (1-(5-Adamantan-1-yl-2,4-dimethoxy-phenyl)-3-(2,4-dihydroxy-phenyl)-propan-1-one).

The compound of Formula 1-1 is a pale yellow solid compound at room temperature, and the compound of Formula 1-2 is a pink solid compound at room temperature.

In exemplary embodiments of the present invention, the present invention is a method for producing the above-described diaryl derivative compound, and a compound of the following formula (2) can be used as a starting material.

[Formula 2]

In Formula 2, R1 and R2 are as defined in Formula 1.

The starting material can be prepared as follows, and specifically, the adamantyl group can be substituted through a Friedel Craft alkylation reaction under acid conditions.

In the above formula, R1 and R2 are as defined in Formula 1.

In one embodiment, the method for producing the above-described diaryl derivative compound may include a reaction step represented by Scheme 1 below. Specifically, a chalcone derivative can be synthesized through Aldol condensation reaction of starting material and protected benzaldehyde using potassium hydroxide (methanol solution), a strong base.

[Scheme 1]

In Scheme 1, R1 and R2 are as defined in Formula 1, and Protect is or am.

In one embodiment, the method for producing the above-described diaryl derivative compound may further include a reaction step represented by Scheme 2 below. Specifically, the chalcone derivative can be reduced through a hydrogenation reaction using a palladium/activated carbon catalyst under 1 atm pressure hydrogen gas conditions to produce a linking group into a propane or propanone chain.

[Scheme 2]

In Scheme 2, R1, R2 and X are as defined in Formula 1, and Protect is as defined in Scheme 2.

Thereafter, the protecting group (Protect) is removed from the final compound of Scheme 2, and finally, the diaryl derivative compound represented by Chemical Formula 1 can be obtained.

In exemplary embodiments of the present invention, the present invention provides a skin whitening product comprising a diaryl derivative compound represented by Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient. It is a composition.

In one embodiment, the concentration of the active ingredient may be 0.01-20% by weight based on the total weight of the composition.

In one embodiment, the concentration of the active ingredient may be 0.01-20% by weight based on the total weight of the composition, for example, 0.01% by weight or more, 0.1% by weight or more, 0.2% by weight or more, 0.3% by weight or more, 0.4% by weight. It may be % or more, 0.5% or more, 0.7% or more, 0.8% or more, 0.9% or more, or 1% by weight or more, and may be 15% or less, 10% or less, 9% or less, 8% by weight or less. , may be 7% by weight or less, 6% by weight or less, 5% by weight or less, 4% by weight or less, 3% by weight, 2% by weight or less, or 1% by weight or less. In one embodiment of the present specification, preferably, the concentration of the active ingredient may be 0.01 to 5% by weight.

If the concentration is less than 0.01% by weight, the anti-inflammatory or skin anti-aging effect may be minimal, and if the concentration is more than 20% by weight, cytotoxicity may occur.

In one embodiment, the composition for skin whitening can be applied in various fields, for example, as a pharmaceutical composition, cosmetic composition, or external skin agent, and preferably can be used as an active ingredient in a cosmetic composition. Specifically, when the diaryl derivative compound is included as an active ingredient, melanin production can be suppressed to exhibit a skin whitening effect.

The composition for skin whitening according to an embodiment of the present invention may be a pharmaceutical composition, and may contain pharmaceutical auxiliaries such as preservatives, stabilizers, hydrators or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and other therapeutically useful substances. It may contain additional substances and can be formulated into various oral or parenteral dosage forms according to conventional methods.

The oral administration agents include, for example, tablets, pills, hard and soft capsules, solutions, suspensions, emulsifiers, syrups, powders, powders, fine granules, granules, pellets, etc., and these dosage forms contain surfactants in addition to the active ingredients. , may contain diluents (e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salts and polyethylene glycol). . Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidine, and in some cases starch, agar, alginic acid or its sodium salt. It may contain pharmaceutical additives such as disintegrants, absorbents, colorants, flavoring agents, and sweeteners. The tablets can be prepared by conventional mixing, granulating or coating methods. In addition, the parenteral dosage form may be a transdermal dosage form, for example, injections, drops, ointments, lotions, gels, creams, sprays, suspensions, emulsions, suppositories, patches, etc. However, it is not limited to this.

The pharmaceutical composition according to an embodiment of the present invention may be administered parenterally, rectally, topically, transdermally, subcutaneously, etc.

The determination of the dosage of the active ingredient is within the level of those skilled in the art, and the daily dosage of the drug varies depending on various factors such as the degree of progression of the subject to be administered, time of onset, age, health condition, complications, etc., but is recommended for adults. As a standard, the composition may generally be 1 μg/kg to 100 mg/kg, for example, 0.1 mg/Kg to 20 mg/Kg, 0.5 mg/Kg to 20 mg/Kg, or 1 mg/kg to 20 mg/kg, preferably 5 mg/kg to 10 mg/kg can be administered in divided doses 1 to 3 times a day, and the above dosage does not limit the scope of the present invention in any way.

The composition for skin whitening according to an embodiment of the present invention may be a cosmetic composition, and the external appearance of the cosmetic composition contains a cosmetically or dermatologically acceptable medium or base. These are all dosage forms suitable for topical application, such as solutions, gels, solids, pasty anhydrous products, emulsions obtained by dispersing the oil phase in the water phase, suspensions, microemulsions, microcapsules, microgranules or ionic forms (liposomes). and non-ionic vesicular dispersants, or in the form of creams, skins, lotions, powders, ointments, sprays or conceal sticks. These compositions can be prepared according to conventional methods in the art. The composition according to the invention can also be used in the form of a foam or in the form of an aerosol composition further containing a compressed propellant.

The cosmetic composition according to an embodiment of the present invention is not particularly limited in its formulation, and includes, for example, softening lotion, astringent lotion, nourishing lotion, nourishing cream, massage cream, essence, eye cream, eye essence, and cleansing lotion. It can be formulated into cosmetics such as cream, cleansing foam, cleansing water, pack, powder, body lotion, body cream, body oil, and body essence.

When the formulation of the present invention is a paste, cream or gel, animal fiber, plant fiber, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier ingredient. You can.

When the formulation of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder can be used as the carrier component. In particular, when the formulation is a spray, chlorofluorohydrocarbon and propane may be used as carrier ingredients. /May contain propellants such as butane or dimethyl ether.

When the formulation of the present invention is a solution or emulsion, a solvent, solvating agent or emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 , 3-butyl glycol oil, glycerol aliphatic esters, polyethylene glycol or fatty acid esters of sorbitan.

When the formulation of the present invention is a suspension, the carrier ingredients include 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, and microcrystalline Cellulose, aluminum metahydroxide, bentonite, agar, or tracant may be used.

When the formulation of the present invention is a surfactant-containing cleansing agent, the carrier ingredients include aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, and fatty acid amide. Ether sulfate, alkylamidobetaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, linoline derivative, or ethoxylated glycerol fatty acid ester can be used.

The cosmetic composition according to an embodiment of the present invention may further include functional additives and components included in general cosmetic compositions in addition to the above active ingredients. The functional additive may include ingredients selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, polymer peptides, polymer polysaccharides, sphingolipids, and seaweed extract.

In addition to the above-mentioned functional additives, the cosmetic composition of the present invention may also contain components included in general cosmetic compositions, if necessary. Other ingredients included include oils and fats, moisturizers, emollients, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, disinfectants, antioxidants, plant extracts, pH adjusters, alcohol, pigments, fragrances, and blood circulation agents. Examples include accelerators, cooling agents, restrictors, and purified water.

In addition, the composition for skin whitening according to an embodiment of the present invention may be a skin external preparation, and the skin external preparation is a general term that can include anything applied outside the skin, and various formulations of cosmetics and pharmaceuticals may be included here. .

Hereinafter, the present invention will be described in more detail through the following examples. However, the following examples are provided only for illustrative purposes to aid understanding of the present invention, and the scope and scope of the present invention are not limited thereto.

Example

Example : new diaryl compound manufacturing

[Example 1] Preparation of 4-[3-(5-adamantane-1-yl-2,4-dimethoxyphenyl)-propyl]-benzene-1,3-diol

(1) Preparation of 1-(5-adamantane-1-yl-2,4-dimethoxyphenyl)-ethanone

Dissolve 1-(2,4-dimethoxyphenyl)-ethanone (26.1g) and 1-adamantanol (23.2g) in chloroform (400mL) and stir. Concentrated sulfuric acid (8 mL) was added dropwise and refluxed for 5 hours. Water (200 mL) was added to the stirred mixed solution and neutralized with sodium bicarbonate. The organic layer was dried, concentrated under reduced pressure, and recrystallized using dichloromethane and hexane to obtain 1-(5-adamantane-1-yl-2,4-dimethoxyphenyl)-ethanone (28.3 g).

^1H NMR (300MHz, DMSO-d ₆ ) 7.54(s, 1H), 6.66 (s, 1H), 3.92(s, 3H), 3.91(s, 3H), 2.46(s, 3H), 1.98(s, 9H), 1.71(s, 6H).

(2) Preparation of 1-(5-adamantane-1-yl-2,4-dimethoxyphenyl)-3-(2,4-diisopropoxyphenyl)-propenone

1-(5-adamantane-1-yl-2,4-dimethoxyphenyl)-ethanone (6.29 g) obtained in (1) above was dissolved in methanol (100 mL) and potassium hydroxide (5.6 g) was dissolved in methanol. It was dissolved in (20mL) and added dropwise for 10 minutes. To this solution, 2,4-diisopropoxybenzaldehyde (5.33 g) dissolved in methanol (20 mL) was added dropwise and refluxed for 6 hours. The temperature was lowered to room temperature, the pH was adjusted to 2 with a 2N hydrochloric acid solution, and the resulting solid was filtered. This solid was then recrystallized using dichloromethane and hexane to obtain 1-(5-adamantane-1-yl-2. ,4-dimethoxyphenyl)-3-(2,4-diisopropoxyphenyl)-propenone (11.3 g) was obtained.

¹ H NMR (300MHz, DMSO-d ₆ ) 7.74~7.42(m, 4H), 6.69~6.54(m, 3H), 4.75~4.69(m, 2H), 3.92(s, 3H), 3.91(s, 3H) ), 2.01(s, 9H), 1.72(s, 6H), 1.31~1.21(m, 12H)

(3) Preparation of 1-{5-[3-(2,4-diisopropoxyphenyl)-propyl]-2,4-dimethoxyphenyl}-adamantane

1-(5-adamantane-1-yl-2,4-dimethoxyphenyl)-3-(2,4-diisopropoxyphenyl)-propenone (2.07 g) obtained in (2) above It was dissolved in trifluoroacetic acid (5 mL), triethylsilane (3.67 g) was added dropwise, and stirred at room temperature for 24 hours. The reaction solution was diluted with water (100mL), extracted with dichloromethane (100mLx3), dried, concentrated, and separated by column chromatography to obtain a colorless and transparent liquid product (0.55g).

^1H NMR (300MHz, DMSO-d ₆ ) 6.97~6.94(m, 1H), 6.81(s, 1H), 6.55(s, 1H), 6.43~6.36(m, 2H), 4.57~4.51(m, 2H) ), 3.78(s, 3H), 3.76(s, 3H), 2.45~2.40(m, 4H), 1.98(s, 9H), 1.70~1.65(m, 8H), 1.21(t, J= 6.6Hz, 12H)

(4) Preparation of 4-[3-(5-adamantane-1-yl-2,4-dimethoxyphenyl)-propyl]-benzene-1,3-diol

1-{5-[3-(2,4-diisopropoxyphenyl)-propyl]-2,4-dimethoxyphenyl}-adamantane (1.5 g) obtained in the same manner as (3) above was dissolved in dichloro. It was dissolved in methane (100 mL), the temperature of the solution was lowered to 0 ^o C, trichloroboron (18 ml) was added dropwise, and the temperature was raised to room temperature and stirred for 10 minutes. The reaction was stopped with cold water, extracted with dichloromethane, dried, concentrated, and separated by column chromatography to obtain a solid product (0.43 g). The molecular weight was 422.5565 g/mol.

^1H NMR (300MHz, DMSO-d ₆ ) 8.97(s, 1H), 8.89(s, 1H), 6.81~6.74(m, 2H), 6.53(s, 1H), 6.21(s, 1H), 6.09~ 6.08(m, 1H), 3.76(s, 3H), 3.74(s, 3H), 2.44~2.36(m, 4H), 1.96(s, 9H), 1.68(s, 6H), 1.64~1.63(m, 2H)

[Example 2] Preparation of 1-(5-adamantane-1-yl-2,4-dimethoxyphenyl)-3-(2,4-dihydroxyphenyl)-propan-1-one

(1) Preparation of 1-(5-adamantane-1-yl-2,4-dimethoxyphenyl)-3-(2,4-bismethoxymethoxyphenyl)-propenone

1-(5-adamantane-1-yl-2,4-dimethoxyphenyl)-ethanone (6.29 g) obtained in (1) of Example 1 was dissolved in methanol (100 mL) and dissolved in potassium hydroxide methanol solution ( 5.6g KOH/20mL MeOH) was added dropwise for 10 minutes. 2,4-bis-methoxymethoxy-benzaldehyde (5.43 g) dissolved in methanol (50 mL) was added dropwise to this solution and refluxed for 18 hours. After the reaction solution was brought to room temperature, the reaction was stopped with 2N aqueous hydrochloric acid solution. The resulting solid was filtered, dissolved in dichloromethane, extracted with water, and the organic layer was dried, concentrated under reduced pressure, and separated by column chromatography to obtain a yellow foamy product (7.9 g).

^1H NMR (300MHz, DMSO-d ₆ ) 7.79~7.46(m, 4H), 6.81~6.69(m, 3H), 5.31(s, 2H), 5.23(s, 2H), 3.92(s, 6H), 3.43(s, 3H), 3.38(s, 3H), 2.00(s, 9H), 1.71(s, 6H).

(2) Preparation of 1-(5-adamantane-1-yl-2,4-dimethoxyphenyl)-3-(2,4-bismethoxymethoxyphenyl)-propan-1-one

1-(5-adamantane-1-yl-2,4-dimethoxyphenyl)-3-(2,4-bismethoxymethoxyphenyl)-propenone obtained in (1) of Example 2 above (3g) was dissolved in ethanol (80mL), 5% palladium/activated carbon catalyst (20mg) was added, and hydrogenation reaction was performed for 2 and a half hours under hydrogen (1 atm). After completion of the reaction, it was filtered and concentrated under reduced pressure to obtain a liquid product (3g).

^1H NMR (300MHz, DMSO-d ₆ ) 7.51(s, 1H), 7.05(d, J=5.1Hz, 1H), 6.70(d, J=1.2Hz, 1H), 6.64(s, 1H), 6.59 ~6.56 (m, 1H), 5.19(s, 2H), 5.12(s, 2H), 3.90(s, 3H), 3.88(s, 3H), 3.37(s, 3H), 3.36(s, 3H), 3.11(t, J=4.5Hz, 2H), 2.78(t, J=4.5Hz, 2H), 2.01~1.97(m, 9H), 1.71(s, 6H).

(3) Preparation of 1-(5-adamantane-1-yl-2,4-dimethoxyphenyl)-3-(2,4-dihydroxyphenyl)-propan-1-one

1-(5-adamantane-1-yl-2,4-dimethoxyphenyl)-3-(2,4-bismethoxymethoxyphenyl)-propane- obtained in (2) of Example 2 above. 1-one (1.5 g) was dissolved in methanol (40 mL), 3N aqueous hydrochloric acid solution (2.5 mL) was added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and extracted with water. The organic layer was dried, concentrated under reduced pressure, and separated by column chromatography to obtain a brown solid product (0.5 g). The molecular weight was 436.5400 g/mol.

^1H NMR (300MHz, DMSO-d ₆ ) 9.09(s, 1H), 8.94(s, 1H), 7.49(s, 1H), 6.78(d, J=5.1Hz, 1H), 6.64(s, 1H) , 6.25~6.24 (m, 1H), 6.11~6.09 (m, 1H), 3.90(s, 3H), 3.89(s, 3H), 3.04(t, J=4.5Hz, 2H), 2.65(t, J =4.5Hz, 2H), 2.02~1.98(m, 9H), 1.71(s, 6H).

In addition, Nivitol (Nivitol, purchased from Jinan Rouse Industry Co. Ltd.) and Arbutin (Arbutin, purchased from Sigma Aldrich) were prepared as Comparative Examples 1 and 2.

Test example : Confirmation of melanin production inhibition effect

The inhibitory effect of the compounds prepared in the above examples on melanin production in melanin pigment-producing cells was measured by Dooley's method.

The cell line used was mouse-derived B16F10 (melanoma cells) purchased from the Korea Cell Line Bank. DMEM (Cat No. 11995), FBS (Cat No. 16000-044), and antibiotic-antifungal reagent (Cat No. 15240-062) required for cell culture were purchased from Invitrogen (GIBCO). The cell line was cultured under conditions of 37°C and 5% CO ₂ . The cultured B16F10 cells were removed with 0.05% Trypsin-EDTA, inoculated again into a ⁴⁸ -well plate at the same number (1 Examples 1 and 2 and Comparative Examples 1 and 2 were replaced with medium containing 10 ppm each. Arbutin was used as a positive control in Comparative Example 2.

After the 5th day, the cells were treated with 1N NaOH and reacted at 60°C for 2 hours to dissolve the melanin contained in the cells, and the amount of melanin was measured by measuring absorbance at 405 nm. From there, the concentrations (IC ₅₀ ) of Examples 1 and 2 and Comparative Examples 1 and 2 required to reduce melanin production in melanocytes by half were calculated in μM units and are shown in Table 1 below.

structure IC50
(%inhibition@μM) Example 1 2.8 μM
[67%@5μM]
[44%@2.5μM]
[20%@1.25μM] Example 2 >5 μM
[45%@5μM]
[26%@2.5μM]
[0%@1.25μM] Comparative Example 1 >5 μM
[37%@5μM]
[19%@2.5μM]
[6%@1.25μM] Comparative Example 2 [51%@200μM]

Referring to the above results, the compound of Example 1 showed the best effect by inhibiting melanin production by about 50% at a concentration of only 2.8 μM, and in the case of the compound of Example 2, to inhibit melanin production by about 50%, Concentrations of 5 μM or higher were found to be necessary.

However, when Nibitol (Comparative Example 1) and the compound of Example 2 were applied at the same concentration (5 μM), Nibitol (Comparative Example 1) inhibited melanin production by about 37%, compared to that of Example 2. It was found that the compound was inhibited by about 45%, so the skin whitening effect was much better. This is presumed to be because the compound according to the embodiment of the present invention, unlike nibitol, structurally contains an adamantyl group and has excellent lipophilicity, making it advantageous for cellular absorption.

Therefore, the composition containing the compounds of Examples 1 and 2 has a very excellent melanin inhibition effect compared to nibitol (Comparative Example 1) and arbutin (Comparative Example 2), which are known to be excellent whitening agents, and thus has a skin whitening effect. I could guess that it was excellent.

Hereinafter, a formulation example of a composition having a skin whitening effect according to one aspect of the present invention as described above will be described below, but various other formulations can also be applied, and this is not intended to limit the present invention, but is only specifically described. It is intended to be done.

[Formulation Example 1] Toner

A lotion is prepared according to a conventional method with the composition shown in Table 2 below.

ingredient Content (% by weight) 4-[3-(5-adamantane-1-yl-2,4-dimethoxy-phenyl)-propyl]-benzene-1,3-diol 0.1 glycerin 3.0 Butylene glycol 2.0 propylene glycol 2.0 Carboxy vinyl polymer 0.1 PEG 12 nonylphenyl ether 0.2 Polysorbate 80 0.4 ethanol 10.0 Triethanolamine 0.1 Preservatives, coloring, flavoring Appropriate amount Purified water remaining amount

[Formulation example 2] Nutrition cream

A nutritious cream is prepared according to a conventional method with the composition shown in Table 3 below.

ingredient Content (% by weight) 4-[3-(5-adamantane-1-yl-2,4-dimethoxy-phenyl)-propyl]-benzene-1,3-diol 2.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.5 PEG 60 hydrogenated castor oil 2.0 liquid paraffin 10.0 squalane 5.0 Caprylic/Caprotriglyceride 5.0 glycerin 5.0 Butylene glycol 3.0 propylene glycol 3.0 Triethanolamine 0.2 Preservatives, coloring, flavoring Appropriate amount Purified water remaining amount

[Formulation Example 3] Massage Cream

Massage cream is prepared according to a conventional method with the composition shown in Table 4 below.

ingredient Content (% by weight) 4-[3-(5-adamantane-1-yl-2,4-dimethoxy-phenyl)-propyl]-benzene-1,3-diol 1.0 beeswax 10.0 Polysorbate 60 1.5 PEG 60 hydrogenated castor oil 2.0 Sorbitan sesquioleate 0.8 liquid paraffin 40.0 squalane 5.0 Caprylic/Capric Triglyceride 4.0 glycerin 5.0 Butylene glycol 3.0 propylene glycol 3.0 Triethanolamine 0.2 Preservatives, coloring, flavoring Appropriate amount Purified water remaining amount

[Formulation Example 4] Pack

A pack is prepared according to a conventional method with the composition shown in Table 5 below.

ingredient Content (% by weight) 4-[3-(5-adamantane-1-yl-2,4-dimethoxy-phenyl)-propyl]-benzene-1,3-diol 0.2 polyvinyl alcohol 13.0 Sodium Carboxymethylcellulose 0.2 glycerin 5.0 allantoin 0.1 ethanol 6.0 PEG 12 nonylphenyl ether 0.3 Polysorbate 60 0.3 Preservatives, coloring, flavoring Appropriate amount Purified water remaining amount

[Formulation Example 5] Gel

A gel is prepared according to a conventional method with the composition shown in Table 6 below.

ingredient Content (% by weight) 4-[3-(5-adamantane-1-yl-2,4-dimethoxy-phenyl)-propyl]-benzene-1,3-diol 0.5 Sodium ethylenediamine acetate 0.05 glycerin 5.0 Carboxy vinyl polymer 0.3 ethanol 5.0 PEG 60 hydrogenated castor oil 0.5 Triethanolamine 0.3 Preservatives, coloring, flavoring Appropriate amount Purified water remaining amount

[Formulation Example 6] Ointment

An ointment was prepared by a conventional method with the composition shown in Table 7 below.

ingredient Content (% by weight) 4-[3-(5-adamantane-1-yl-2,4-dimethoxy-phenyl)-propyl]-benzene-1,3-diol 1.5 glycerin 8.0 Butylene glycol 4.0 liquid paraffin 15.0 beta glucan 7.0 carbomer 0.1 Caprylic/Capric Triglyceride 3.0 squalane 1.0 Cetearyl Glucoside 1.5 Sorbitan Stearate 0.4 cetearyl alcohol 1.0 beeswax 4.0 Preservatives, coloring, flavoring Appropriate amount Purified water remaining amount

Claims (13)

A diaryl derivative compound represented by the following formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof:
[Formula 1]

In Formula 1,
R1 and R2 are the same or different and are each independently an alkyl group having 1 to 10 carbon atoms,
X is -CO- or -CH ₂ -. According to paragraph 1,
The above Chemical Formula 1 is a diaryl derivative compound represented by the following Chemical Formula 1-1 or 1-2, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.
[Formula 1-1]

[Formula 1-2]
A method for producing a diaryl derivative compound according to claim 1 or 2,
Method for producing a diaryl derivative compound, comprising the reaction steps represented by Scheme 1:
[Scheme 1]

In Scheme 1,
R1 and R2 are as defined in Formula 1,
Protect is or am. According to paragraph 3,
A method for producing a diaryl derivative compound, further comprising the reaction step represented by Scheme 2:
[Scheme 2]

In Scheme 2,
R1, R2 and X are as defined in Formula 1,
Protect is as defined in Scheme 1. A composition for skin whitening,
Containing the diaryl derivative compound according to claim 1 or 2, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient,
The composition for skin whitening is a cosmetic composition. According to clause 5,
A composition for skin whitening, wherein the concentration of the active ingredient is 0.01-20% by weight based on the total weight of the composition. According to clause 5,
The composition for skin whitening is characterized in that it inhibits melanin production. A composition for skin whitening,
Containing the diaryl derivative compound according to claim 1 or 2, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient,
The composition for skin whitening is a pharmaceutical composition for treating hyperpigmentation. According to clause 8,
A composition for skin whitening, wherein the concentration of the active ingredient is 0.01-20% by weight based on the total weight of the composition. According to clause 8,
The composition for skin whitening is characterized in that it inhibits melanin production. A composition for skin whitening,
Containing the diaryl derivative compound according to claim 1 or 2, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient,
The composition for skin whitening is a skin whitening composition for external use. According to clause 11,
A composition for skin whitening, wherein the concentration of the active ingredient is 0.01-20% by weight based on the total weight of the composition. According to clause 11,
The composition for skin whitening is characterized in that it inhibits melanin production.