KR102163775B1 - 7-benzyl-4-(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives and Composition for skin whitening and Pharmaceutical composition for use in preventing or treating disorders of Melanin Hyperpigmentation containing the same as an active ingredient - Google Patents

Abstract

7-benzyl-4(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivative and skin whitening composition containing the same as an active ingredient, the derivative being less Since it exhibits the effect of suppressing the production of melanin even when using an amount, it can be usefully used as a pharmaceutical composition for preventing or treating melanin hyperpigmentation disease, a cosmetic composition for skin whitening, and a health functional food for skin whitening.

Description

7-Benzyl-4(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivative and skin whitening composition containing the same as an active ingredient and prevention of melanin hyperpigmentation disease Or therapeutic pharmaceutical composition {7-benzyl-4-(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives and Composition for skin whitening and Pharmaceutical composition for use in preventing or treating disorders of Melanin Hyperpigmentation containing the same as an active ingredient}

7-Benzyl-4(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivative and skin whitening composition containing the same as an active ingredient and prevention of melanin hyperpigmentation disease Or it relates to a pharmaceutical composition for treatment. Specifically, the composition for skin whitening includes a cosmetic composition for skin whitening and a health functional food for skin whitening.

Human skin color is largely determined by melanin, hemoglobin, and carotene, among which melanin plays the most important role. Melanin (melanin) is a black pigment found in animals, plants, microorganisms, etc., and is not essential for growth or development, but is a substance that enhances viability and competitiveness for the environment. Melanin is a pigment with stability among pigments found in living organisms, and is insoluble in almost all solvents, and the melanogenesis process occurs in melanosomes, organelles of melanocytes, which are specially differentiated cells. Turned out to be. In other words, skin color is determined according to the content and distribution of melanin, and is related to the number and distribution of melanosomes that are produced in melanocytes and then released to the outside of the cell, and melanin has a pure function of protecting the skin from ultraviolet light. However, when over-produced, it is known as an important factor in inducing hyperpigmentation and melanomas such as melasma and freckles (J. Drugs Dermatol., 2004, 3, 668-678).

The synthesis process of melanin in vivo is as follows. In the melanocyte, the cell that synthesizes melanin, by an enzyme called tyrosinase, tyrosine is used as a substrate through dopa, dopaquinone, and dopacrom (Dopa quinone). Through an automatic oxidation reaction that generates DOPA chrome), melanin, a copolymer, is produced. The melanin produced in this way is transferred to keratinocytes through a pocket called melanosomes, and comes up to the skin surface through a 28-day keratinization process from keratinocytes. However, in this process, melanin is produced in excess due to the factors that promote melanin production, and the cycle of the keratinization process is physiologically lengthened, so that melanin along with keratin is not lost from the skin, and pigmentation occurs. Therefore, in order to prevent such pigmentation phenomenon, it can be suppressed by controlling some processes in the melanin production process.

Specifically, tyrosinase (EC 1.14.18.1) converts tyrosine into dopaquinone, a key precursor of melanin biosynthesis, as the most important enzyme in melanin biosynthesis occurring in plants, microorganisms, and mammalian cells. This enzyme functions as a monophenolase that converts L-tyrosine to L-dopa (3,4-dihydroxyphenylalanin) and diphenolase (which converts L-dopa to L-dopaquinone). diphenolase) function (J. Appl. Microbiol., 2006, 100, 219-232; Int. J. Biochem. Cell Biol., 2004, 36, 235-246). Dopaquinone made here is automatically converted to melanin without the aid of enzymatic action. Therefore, by inhibiting the activity of tyrosinase, melanin biosynthesis is suppressed.

There are several mechanisms that inhibit melanin synthesis. A typical melanin synthesis inhibition process is to inhibit the activity of tyrosinase, an important enzyme in melanin synthesis, and as a commercially available representative component, Kojic acid, which inhibits the activity of tyrosinase, which has copper ions as an active site (Korean Patent Publication) No. 10-2015-0062272) or a substance having a structure similar to tyrosine, which is a substrate of tyrosinase, such as arbutin, is used to competitively react with tyrosine to tyrosinase, thereby inhibiting melanin production. Substances that cause pigmentation are also widely used as pigmentation inhibitors. However, most of the whitening ingredients have a disadvantage in that the effect does not last long due to low stability, so there are many limitations in application to products.

One object of the present invention is to provide a 7-benzyl-4(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivative.

Another object of the present invention is to prevent melanin hyperpigmentation disease containing 7-benzyl-4(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivative as an active ingredient Or to provide a therapeutic pharmaceutical composition.

Another object of the present invention is to provide a cosmetic composition for skin whitening containing 7-benzyl-4(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivative as an active ingredient Is to do.

Another object of the present invention is to provide a health functional food for skin whitening containing 7-benzyl-4(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivative as an active ingredient. To provide.

To achieve the above object,

According to an aspect of the present invention, there is provided a compound represented by the following Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

(In Formula 1,

R ¹ is hydrogen, halogen or straight or branched C _1-6 alkyl; And

R ² is hydrogen or C _6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C _1-6 alkyl).

According to another aspect of the present invention, a pharmaceutical for the prevention or treatment of melanin hyperpigmentation disease comprising a compound represented by the following Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient The appropriate composition is provided.

[Formula 1]

(In Formula 1,

R ¹ is hydrogen, halogen or straight or branched C _1-6 alkyl; And

R ² is hydrogen or C _6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C _1-6 alkyl).

According to another aspect of the present invention, there is provided a cosmetic composition for skin whitening comprising a compound represented by the following Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

(In Formula 1,

R ¹ is hydrogen, halogen or straight or branched C _1-6 alkyl; And

R ² is hydrogen or C _6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C _1-6 alkyl).

According to another aspect of the present invention, there is provided a skin whitening cosmetic product comprising the cosmetic composition for skin whitening.

According to another aspect of the present invention, there is provided a functional food for skin whitening comprising a compound represented by the following Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

(In Formula 1,

R ¹ is hydrogen, halogen or straight or branched C _1-6 alkyl; And

R ² is hydrogen or C _6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C _1-6 alkyl).

According to another aspect of the present invention, a pharmaceutical composition or health functional food containing the compound represented by Formula 1, its isomer, solvate, hydrate or pharmaceutically acceptable salt thereof as an active ingredient to a subject in need There is provided a method of preventing or treating melanin hyperpigmentation disease comprising administering.

According to another aspect of the present invention, a pharmaceutical containing a compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof in the prevention or treatment of melanin hyperpigmentation disease The use of a suitable composition or dietary supplement is provided.

The 7-benzyl-4(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivative of the present invention exhibits an effect of inhibiting the production of melanin even when used in a small amount. Therefore, it can be usefully used as a composition for treatment of melanin hyperpigmentation diseases, a cosmetic composition for skin whitening, and a health functional food for skin whitening.

1 is an image showing the results of the melanin production inhibitory effect of the compound according to the present invention performed in Experimental Example 1.

Hereinafter, the present invention will be described in detail.

On the other hand, embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, embodiments of the present invention are provided in order to more completely explain the present invention to those having average knowledge in the art. Furthermore, "including" a certain component throughout the specification means that other components may be further included, rather than excluding other components unless specifically stated to the contrary.

As described above, diseases caused by excessive UV exposure due to changes in the global environment and the destruction of the ozone layer have emerged as a homework to be solved, and as modern people's interest in beauty related to white and clean skin has increased, skin pigmentation such as spots and freckles Cosmetics and the like have begun to be developed to help with treatment and prevention. However, most of the whitening ingredients have a disadvantage that the effect does not last a long time due to their low stability, so they have many limitations in applying to products.

One aspect of the present invention provides a compound represented by the following Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

(In Formula 1,

R ¹ is hydrogen, halogen or straight or branched C _1-6 alkyl; And

R ² is hydrogen or C _6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C _1-6 alkyl).

In Formula 1,

R ¹ is hydrogen or halogen; And

R ² is hydrogen or phenyl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH and halogen.

Examples of the compound represented by Formula 1 according to the present invention include the following compound groups:

(1) 7-benzyl-4-(4-(4-fluorophenyl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine;

(2) 4-(7-benzyl-4-(4-(2-fluorophenyl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 ,6-dichlorophenol.

The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids, trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. Get from Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, i. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Rate, sebacate, fumarate, maleate, butine-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, Glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid May be prepared by filtration and drying, or may be prepared by distilling a solvent and an excess of acid under reduced pressure and drying to crystallize under an organic solvent.

In addition, a pharmaceutically acceptable metal salt can be made using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).

Further, the present invention includes not only the compound represented by Formula 1 and its pharmaceutically acceptable salts, but also solvates, optical isomers, hydrates, etc. that may be prepared therefrom.

The term “hydrate” refers to a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecule force. Or its salt. The hydrate of the compound represented by Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecular force. The hydrate may contain 1 equivalent or more, preferably 1 to 5 equivalents of water. These hydrates may be prepared by crystallizing the compound represented by Formula 1, isomers thereof, or pharmaceutically acceptable salts thereof from water or a solvent containing water.

The term "solvate" refers to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefor include volatile, non-toxic, and/or suitable solvents for administration to humans.

The term “isomer” refers to a compound of the present invention or a salt thereof having the same chemical formula or molecular formula, but structurally or sterically different. Such isomers include structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, stereoisomers such as geometric isomers (trans, cis), and optical isomers. All these isomers and mixtures thereof are also included within the scope of the present invention.

In the compound represented by Formula 1, when R ² is hydrogen, as shown in Reaction Formula 1 below,

Preparing a compound represented by Formula 4 by reacting a compound represented by Formula 2 and a compound represented by Formula 3 (Step 1); And

It can be prepared by a manufacturing method including the step of preparing a compound represented by Formula 1a by reacting the compound represented by Formula 4 and the compound represented by Formula 5 obtained in step 1 (step 2).

[Scheme 1]

In Scheme 1 above,

R ¹ and R ² are as defined in Formula 1;

X ¹ and X ² are each independently halogen; And

The compound represented by Formula 1a is a derivative of the compound represented by Formula 1 of the present invention in which R ² is hydrogen.

In the preparation method of Scheme 1,

Step 1 is a step of preparing a compound represented by Formula 4 in which a halogen of a compound represented by Formula 2 and a secondary amine of a compound represented by Formula 3 are reacted to form an amine bond. It is not limited as long as it is a condition for making, and a method widely known to those skilled in the art may be used. In the present invention, the reaction was carried out under the same conditions as in the examples, but this is only an example and is not limited thereto.

Step 2 is a step of preparing a compound represented by Formula 1a in which a secondary amine of a compound represented by Formula 4 and a halogen of a compound represented by Formula 5 are reacted to form an amine bond, and the halogen and amine are reacted to form an amine bond. It is not limited as long as it is a condition for making, and a method widely known to those skilled in the art may be used. In the present invention, the reaction was carried out under the same conditions as in the examples, but this is only an example and is not limited thereto.

In addition, in the compound represented by Formula 1, when R ² is an aryl of C _6-10 , as shown in Scheme 2 below,

Halogenating the compound represented by Formula 1a to prepare a compound represented by Formula 7 (Step 1);

It can be prepared by a manufacturing method including the step of preparing a compound represented by Formula 1b by reacting the compound represented by Formula 7 and the compound represented by Formula 8 obtained in Step 1 (Step 2).

[Scheme 2]

In Scheme 1 above,

R ¹ and R ² are as defined in Formula 1;

X ³ is halogen;

The compound represented by Formula 1a is a derivative of the compound represented by Formula 1 of the present invention in which R ² is hydrogen; And

The compound represented by Formula 1b is a derivative of the compound represented by Formula 1 of the present invention, wherein R ² is a C _6-10 aryl.

In the preparation method of Scheme 2,

The compound represented by Formula 1a can be prepared by the preparation method of Scheme 1.

Step 1 is a step of preparing a compound represented by Formula 7 in which halogen is introduced by halogenating the compound represented by Formula 1a, and is not limited as long as it is a condition capable of performing halogenation, and a method well known to those skilled in the art may be used. In the present invention, the reaction was carried out under the same conditions as in the examples, but this is only an example and is not limited thereto.

Step 2 is a step of preparing a compound represented by Formula 1b by reacting a halogen of the compound represented by Formula 7 with a boron group of the compound represented by Formula 8 to produce arylation, and a method well known to those skilled in the art may be used. In the present invention, the reaction was carried out under the same conditions as in the examples, but this is only an example and is not limited thereto.

Another aspect of the present invention is a pharmaceutical for the prevention or treatment of melanin hyperpigmentation disease comprising a compound represented by the following Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient The composition is provided.

[Formula 1]

(In Formula 1,

R ¹ is hydrogen, halogen or straight or branched C _1-6 alkyl; And

R ² is hydrogen or C _6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C _1-6 alkyl).

The melanin hyperpigmentation disease may be melasma, freckles, senile pigment spots, or solar lentigines, but this is only an example and is not limited thereto.

The compound can inhibit the production of melanin.

In order to confirm the therapeutic effect of the compound of the present invention in the treatment of melanin hyperpigmentation disease, as a result of evaluating the melanin production inhibitory effect, the compound represented by Formula 1 according to the present invention excellently inhibits melanin production, and conventionally inhibits melanin production. It was confirmed that it exhibits remarkably superior melanin production inhibitory effect than kojic acid, which is well known as a compound.

Therefore, the compound represented by Formula 1 of the present invention can be usefully used as a pharmaceutical composition for preventing or treating melanin hyperpigmentation diseases.

In the pharmaceutical composition according to the present invention, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral formulations at the time of clinical administration, more preferably parenteral It can be a formulation. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient in one or more compounds, such as starch, calcium carbonate, sucrose, or lactose ( lactose), gelatin, etc. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups.In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as humectants, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. As the non-aqueous solvent and suspension, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.

The present invention can also be provided as a formulation of a skin external preparation for skin whitening effect comprising the compound of Formula 1 as an active ingredient.

When the compound of Formula 1 is used for external skin, additionally fatty substances, organic solvents, solubilizers, thickening and gelling agents, emollients, antioxidants, suspending agents, stabilizers, foaming agents, fragrances, surfactants , Water, ionic or nonionic emulsifiers, fillers, sequestering agents and chelating agents, preservatives, vitamins, blockers, wetting agents, essential oils, dyes, pigments, hydrophilic or lipophilic actives, lipid vesicles or external preparations for skin It may contain adjuvants commonly used in the field of dermatology, such as any other ingredients used as. In addition, the ingredients may be introduced in an amount generally used in the field of skin science.

When the compound of Formula 1 is provided in a formulation for external application for skin, it is not limited thereto, but may have a formulation such as an ointment, patch, gel, cream, or spray.

The pharmaceutical composition of the present invention may be particularly preferably used as a parenteral preparation. For example, the external preparation for skin may include a suitable pharmaceutically acceptable base such as petrolatum and stearyl alcohol; Suitable pharmaceutically acceptable surfactants such as polysorbate and sorbitan sesquioleate; Pharmaceutically acceptable suitable moisturizers such as glycerin; Suitable pharmaceutically acceptable solvents; And a flavoring agent, a colorant, a stabilizer, a viscous agent, and the like are homogeneously mixed.

In addition, when the compound of Formula 1 of the present invention is used as a medicine, it may further contain one or more active ingredients exhibiting the same or similar function. For example, it may contain known skin whitening ingredients. If additional skin whitening ingredients are included, the skin whitening effect of the composition of the present invention may be further enhanced.

When the above ingredients are added, skin safety, ease of formulation, and stability of active ingredients can be considered in combination with use. In one embodiment of the present invention, the composition is a whitening component known in the art, a substance that inhibits tyrosinase enzyme activity such as Kojic acid, arbutin, and hydroquinone, Vitamin-C (L-Ascorbic acid); And it may further include one or two or more components selected from the group consisting of derivatives thereof and various plant extracts. Additional ingredients may be included in an amount of 0.0001% to 10% by weight based on the total weight of the composition, and the content range may be adjusted according to requirements such as skin safety and ease of formulation of the compound of Formula 1 .

When the pharmaceutical composition of the present invention contains an effective amount of the compound of Formula 1, it can provide a desirable skin whitening effect. In the present invention, the term "effective amount" means the amount of a compound capable of exhibiting a skin whitening effect.

The effective amount of the compound of Formula 1 included in the composition of the present invention will vary depending on the form in which the composition is commercialized, the method in which the compound is applied to the skin, and the time it stays on the skin. For example, when the composition is commercialized as a pharmaceutical, it may contain the compound of Formula 1 at a higher concentration than when it is commercialized as a cosmetic that is routinely applied to the skin. Therefore, the daily dosage is 0.1 to 100 mg/kg, preferably 30 to 80 mg/kg, more preferably 50 to 60 mg/kg, based on the amount of the compound of Formula 1, and 1 to It can be administered 6 times.

Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and troches.These formulations include diluents (e.g., lactose) in addition to the active ingredients. , Dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salt and/or polyethylene glycol). Tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases, boron such as starch, agar, alginic acid or sodium salt thereof. It may contain release or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.

Another aspect of the present invention provides a cosmetic composition for skin whitening comprising a compound represented by the following Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

(In Formula 1,

R ¹ is hydrogen, halogen or straight or branched C _1-6 alkyl; And

R ² is hydrogen or C _6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C _1-6 alkyl).

The compound can inhibit the production of melanin.

In order to confirm the skin whitening effect of the compound of the present invention, as a result of evaluating the melanin production inhibitory effect, the compound represented by Formula 1 according to the present invention excellently inhibits melanogenesis, and kojic acid, which is well known as a conventional melanin production inhibitory compound. It was confirmed that it exhibits a remarkably superior melanin production inhibitory effect.

Therefore, the compound represented by Formula 1 of the present invention can be usefully used as a cosmetic composition for skin whitening.

In preparing a composition for improving skin beauty containing a compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof, the compound represented by Formula 1 of the present invention or A pharmaceutically acceptable salt thereof may be added in an amount of 3 to 30 parts by weight, preferably 5 or 20 parts by weight.

In addition, the cosmetic composition of the present invention includes fatty substances, organic solvents, solubilizers, thickeners and gelling agents, emollients, antioxidants, suspending agents, in addition to the compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof. Stabilizers, foaming agents, fragrances, surfactants, water, ionic or nonionic emulsifiers, fillers, sequestering and chelating agents, preservatives, vitamins, blockers, wetting agents, essential oils, dyes, pigments, It may contain adjuvants commonly used in the field of dermatology such as hydrophilic or lipophilic active agents, lipid vesicles or any other ingredients commonly used in skin cosmetic improvement compositions.

In addition, the ingredients may be introduced in an amount generally used in the field of dermatology.

Further, the cosmetic composition for skin whitening according to the present invention is a solution, external ointment, cream, foam, nutrient lotion, softening lotion, pack, softening water, emulsion, makeup base, essence, soap, liquid detergent, bathing agent, sunscreen cream, Sun oil, suspension, emulsion, paste, gel, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, patch and spray can be prepared in a formulation selected from the group consisting of However, it is not limited thereto.

In addition, the cosmetic composition of the present invention may additionally include one or more cosmetically acceptable carriers blended in general skin cosmetics, and as common ingredients, for example, oil, water, surfactant, moisturizer, lower alcohol, A thickener, a chelating agent, a colorant, a preservative, a fragrance, and the like may be appropriately mixed, but the present invention is not limited thereto.

The cosmetically acceptable carrier included in the cosmetic composition of the present invention varies depending on the formulation. When the formulation of the present invention is an ointment, paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide or Mixtures of these can be used.

The present invention also provides a skin whitening method comprising the step of applying the compound represented by Formula 1 to the skin of an individual. The subject includes, without limitation, mammals including mice, livestock, humans, and the like.

Another aspect of the present invention provides a skin whitening cosmetic product comprising the skin whitening cosmetic composition.

The whitening products are silver solution, external ointment, cream, foam, nutrient lotion, softening lotion, pack, softening water, emulsion, makeup base, essence, soap, liquid detergent, bathing agent, sunscreen cream, sun oil, suspension, emulsion , Paste, gel, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, patch, and spray can be prepared in a formulation selected from the group consisting of, but is not limited thereto. .

When the formulation of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof may be used as a carrier component, and in particular, in the case of a spray, additional chloro Propellants such as fluorohydrocarbon, propane/butane or dimethyl ether.

When the formulation of the present invention is a solution or emulsion, a solvent, a solubilizing agent, or an emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl benzoate, propylene glycol, 1,3 -Butylglycol oil, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitan.

When the formulation of the present invention is a suspension, as a carrier component, a liquid diluent such as water, ethanol or propylene glycol, an ethoxylated isostearyl alcohol, a suspending agent such as polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, micro Crystalline cellulose, aluminum metahydroxide, bentonite, agar or tracant, and the like may be used.

When the formulation of the present invention is a soap, an alkali metal salt of a fatty acid, a fatty acid hemiester salt, a fatty acid protein hydrolyzate, isethionate, a lanolin derivative, an aliphatic alcohol, vegetable oil, glycerol, sugar, etc. may be used as a carrier component. I can.

Another aspect of the present invention provides a functional food for skin whitening comprising a compound represented by the following Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

(In Formula 1,

R ¹ is hydrogen, halogen or straight or branched C _1-6 alkyl; And

R ² is hydrogen or C _6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C _1-6 alkyl).

In the present specification, the term'health functional food' refers to a food prepared by adding the compound of Formula 1 to food materials such as beverages, teas, spices, gums, confectionery, or encapsulating, powdering, suspension, etc. It means bringing a specific effect on health, but unlike general drugs, it has the advantage of not having side effects that may occur when taking the drug for a long time by using food as a raw material. Since the health functional food of the present invention obtained in this way can be consumed on a daily basis, a high skin whitening effect can be expected, and thus it is very useful.

The compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof may be added to food as it is or may be used together with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of use (for prevention or improvement). In general, the amount of the compound in the health functional food may be added in 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for the purpose of health and hygiene or for the purpose of health control, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

In addition, the health functional beverage composition of the present invention is not particularly limited to other ingredients other than containing the compound as an essential ingredient in the indicated ratio, and may contain various flavoring agents or natural carbohydrates, etc. as additional ingredients, as in ordinary beverages. have. Examples of the above-described natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides, for example, common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.)) and manufactured flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.

Further, in addition to the above, the compound represented by Chemical Formula 1 of the present invention or a pharmaceutically acceptable salt thereof may include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as manufactured flavors and natural flavoring agents, coloring agents and heavy weight agents ( Cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like. In addition, the compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof may contain flesh for the production of natural fruit juice and fruit juice beverages and vegetable beverages.

Another aspect of the present invention is to administer a pharmaceutical composition or health functional food containing a compound represented by Formula 1, its isomer, solvate, hydrate or pharmaceutically acceptable salt thereof as an active ingredient to a subject in need It provides a method for preventing or treating melanin hyperpigmentation disease comprising the step of.

Another aspect of the present invention is a pharmaceutical containing a compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof in the prevention or treatment of melanin hyperpigmentation disease. It provides the use of the composition or health functional food.

Hereinafter, the present invention will be described in detail by examples and experimental examples.

However, the following examples and experimental examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following examples and experimental examples.

<Production Example 1> Preparation of 1-(4-fluorophenyl) piperazine

Step 1: Preparation of tert-butyl 4-(4-fluorophenyl)piperazine-1-carboxylate

Tert-butyl piperazine-1-carboxylate (0.5 g, 2.69 mmol) and 1-bromo-4-fluorobenzene (0.47 g, 2.69 mmol) were dissolved in toluene (10 mL), and nitrogen gas was added for 30 minutes. Purified with. BiNAP (0.17 g, 0.22 mmol), palladium acetate (0.03 g, 0.043 mmol), and sodium tert-butoxide (0.90 g, 4.3 mmol) were added to the reaction and nitrogen gas purification was performed for 20 minutes. It was stirred for 8 hours at 100 ^o C under a nitrogen environment. When the reaction was complete, the reaction was concentrated in vacuo. The residue was dissolved in water, and extracted with ethyl acetate (3 x 50 mL). Purified by a silica gel column to obtain tert-butyl 4-(4-fluorophenyl)piperazine-1-carboxylate (0.59 g, 78%).

¹ H NMR (CDCl ₃ , 300MHz) δ 1.47 (s, 9H), 3.04 (t, 4H, J = 4.2 Hz), 3.58 (t, 4H, J = 3.8 Hz), 6.89-6.90 (m, 2H), 6.97 (d, 2H, J = 7.8 Hz).

Step 2: Preparation of 1-(4-fluorophenyl) piperazine

Tert-butyl 4-(4-fluorophenyl)piperazine-1-carboxylate (0.50 g, 1.78 mmol) was dissolved in dichloromethane (10 mL) and an excess of trifluoroacetic acid was added. When the reaction was completed by stirring at room temperature for 2 hours, the solvent was removed under reduced pressure. Water was added, an aqueous sodium hydrogen carbonate solution was added, extracted with dichloromethane, dried over sodium sulfate, and filtered to obtain 1-(2-fluorophenyl) piperazine (0.27 g, 83%).

<Production Example 2> Preparation of 1-(2-fluorophenyl) piperazine

Step 1: Preparation of tert-butyl 4-(2-fluorophenyl)piperazine-1-carboxylate

Tert-butyl piperazine-1-carboxylate (0.5 g, 2.69 mmol) and 1-bromo-2-fluorobenzene (0.47 g, 2.69 mmol) were dissolved in toluene (10 mL), and nitrogen gas was added for 30 minutes. Purified with. BiNAP (0.17 g, 0.22 mmol), palladium acetate (0.03 g, 0.043 mmol), and sodium tert-butoxide (0.90 g, 4.3 mmol) were added to the reaction and nitrogen gas purification was performed for 20 minutes. It was stirred for 8 hours at 100 ^o C under a nitrogen environment. When the reaction was complete, the reaction was concentrated in vacuo. The residue was dissolved in water, and extracted with ethyl acetate (3 x 50 mL). Purified with a silica gel column to obtain tert-butyl 4-(2-fluorophenyl)piperazine-1-carboxylate (0.59 g, 78%).

¹ H NMR (CDCl ₃ , 300MHz) δ 1.48 (s, 9H), 3.02 (t, 4H, J = 3.9 Hz), 3.59 (t, 4H, J = 3.9 Hz), 6.91-7.00 (m, 2H), 7.05 (d, 2H, J = 7.2 Hz).

Step 2: Preparation of 1-(2-fluorophenyl) piperazine

Tert-butyl 4-(2-fluorophenyl)piperazine-1-carboxylate (0.50 g, 1.78 mmol) was dissolved in dichloromethane (10 mL) and an excess of trifluoroacetic acid was added. When the reaction was completed by stirring at room temperature for 2 hours, the solvent was removed under reduced pressure. Water was added, an aqueous sodium hydrogen carbonate solution was added, extracted with dichloromethane, dried over sodium sulfate, and filtered to obtain 1-(2-fluorophenyl) piperazine (0.23 g, 72%).

<Preparation Example 3> Preparation of 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

Step 1: Preparation of 4-bromo-2,6-dichloro-phenol

2,6-dichlorophenol (8.1 g, 50 mmol) was dissolved in acetonitrile (40 mL), then cooled to 0 ^o C, and bromine (9.6 g) dissolved in acetonitrile (10 mL) was slowly added. . The resulting red solution was stirred at 0 ^° C for 2 hours, and saturated sodium sulfite solution was added until the red color disappeared. The layers were separated, and the aqueous solution layer was extracted with ethyl acetate. The organic layer was concentrated and purified by a silica gel column to obtain 4-bromo-2,6-dichloro-phenol (11.3 g, 94%) as a white solid.

¹ H NMR (CDCl ₃ , 300 MHz) δ 5.82 (brs, 1H, OH), 7.24 (t, 2H, J = 7.2 Hz).

Step 2: Preparation of 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

4-bromo-2,6-dichloro-phenol (1 g, 4.13 mmol), bis(pinacollato)diborane (1.15 g, 4.54 mmol), potassium acetate (0.81 g, 8.26 mmol), Pd(dppf) After dissolving Cl ₂ (0.06 g, 0.08 mmol) in 1,4-dioxane, the mixture was stirred at 80 ^o C for 24 hours. After the reaction was complete, the reaction was concentrated in vacuo. The residue was dissolved in water, and extracted with ethyl acetate (3 x 50 mL). Purified by silica gel column to obtain 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.90 g, 75%) Got it.

¹ H NMR (CDCl ₃ , 300 MHz) δ 1.32 (s, 12H), 6.03 (brs, 1H, OH), 7.68 (s, 2H).

<Example 1> Preparation of 7-benzyl-4-(4-(4-fluorophenyl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

Step 1: 4- (4- (4-phenyl) piperazin-1-yl-fluorophenyl) - Preparation of the pyrrolo [2,3- d] pyrimidin-7 H

4-chloro-7 H -pyrrolo[2,3- d ]pyrimidine (1 eq), 1-(4-fluorophenyl) piperazine (1 eq), DIPEA (2 eq) into DMF (5 mL) Dissolved in, and heated at 120 ^o C for 8 hours. After the reaction was complete, the reaction was concentrated in vacuo. The layers were separated, and the aqueous solution layer was extracted with ethyl acetate. 4 a light brown solid was purified by a silica gel column (4- (4-fluorophenyl) piperazin-1-yl) - 7 H - pyrrolo [2,3- d] pyrimidine was obtained (70% yield) .

¹ H NMR (CDCl ₃ , 300MHz) δ 3.22 (t, 4H, J = 4.5 Hz), 4.13 (t, 4H, J = 4.2 Hz), 6.70 (s, 1H), 7.02-7.11 (m, 5H), 7.23 (s, 1H), 8.21 (s, 1H), 10.67 (brs, 1H, NH).

Step 2: Preparation of 7-benzyl-4-(4-(4-fluorophenyl)-piperazin-1-yl)-7 H -pyrrolo[2,3- d ]pyrimidine

4- (4- (4-fluorophenyl) piperazin-1-yl) -7 H - pyrrolo [2,3- d] pyrimidine (1 eq) is dissolved in the DMF, sodium hydride at 0 ^o C ( 1.5 eq) was added and stirred at room temperature for 10 minutes, then benzyl bromide (1.2 eq) was added and stirred at room temperature for 2 hours. After the reaction was complete, the reaction was concentrated in vacuo. The layers were separated, and the aqueous solution layer was extracted with ethyl acetate. 7-benzyl-4 as a white solid and purified by silica gel column (4- (4-fluorophenyl) piperazin-1-yl) -7 H - pyrrolo [2,3- d] pyrimidine (70% yield ).

¹ H NMR (Acetone-d6, 300MHz) δ 3.30 (t, 4H, J = 4.5 Hz), 3.81 (t, 4H, J = 3.9 Hz), 5.47 (s, 2H), 7.00-7.12 (m, 4H) , 7.30-7.34 (d, 5H), 7.54 (s, 2H), 8.38 (s, 1H).

<Example 2> 4-(7-benzyl-4-(4-(2-fluorophenyl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl) Preparation of -2,6-dichlorophenol

Step 1: 4- (4- (2-phenyl) piperazin-1-yl-fluorophenyl) - Preparation of the pyrrolo [2,3- d] pyrimidin-7 H

4-chloro-7 H -pyrrolo[2,3- d ]pyrimidine (1 eq), 1-(2-fluorophenyl) piperazine (1 eq), DIPEA (2 eq) into DMF (5 mL) Dissolved in, and heated at 120 ^o C for 8 hours. After the reaction was complete, the reaction was concentrated in vacuo. The layers were separated, and the aqueous solution layer was extracted with ethyl acetate. 4 a light brown solid was purified by silica gel column (4- (2-fluorophenyl) piperazin-1-yl) - 7 H - pyrrolo [2,3- d] pyrimidine was obtained (72% yield) .

¹ H NMR (CDCl ₃ , 300MHz) δ 3.24 (t, 4H, J = 4.5 Hz), 4.17 (t, 4H, J = 4.8 Hz), 6.56 (s, 1H), 6.98-7.11 (m, 5H), 8.38 (s, 1H), 10.43 (brs, 1H, NH).

Step 2: 7-Benzyl-4- (4- (2-phenyl) piperazin-1-yl-fluorophenyl) -7 H - Preparation of the pyrrolo [2,3- d] pyrimidine

4- (4- (2-fluorophenyl) piperazin-1-yl) -7 H - pyrrolo [2,3- d] pyrimidine (1 eq) is dissolved in the DMF, sodium hydride at 0 ^o C ( 1.5 eq) was added and stirred at room temperature for 10 minutes, then benzyl bromide (1.2 eq) was added and stirred at room temperature for 2 hours. After the reaction was complete, the reaction was concentrated in vacuo. The layers were separated, and the aqueous solution layer was extracted with ethyl acetate. 7-benzyl-4 as a white solid and purified by silica gel column (4- (2-fluorophenyl) piperazin-1-yl) -7 H - pyrrolo [2,3- d] pyrimidine (71% yield ).

¹ H NMR (CDCl ₃ , 300MHz) δ 3.23 (t, 4H, J = 4.5 Hz), 4.15 (t, 4H, J = 4.2 Hz), 5.41 (s, 2H), 6.94-7.08 (m, 6H), 7.25 (d, 2H, J = 6.0 Hz), 7.30 (d, 3H, J = 7.8 Hz), 8.41 (s, 1H).

Preparation of pyrrolo [2,3- d] pyrimidin-7-benzyl-5-bromo-4- (4- (2-phenyl) piperazin-1-yl-fluorophenyl) -7 H: Step 3

After dissolving 7-benzyl-4-(4-(2-fluorophenyl)piperazin-1-yl)-7 H -pyrrolo[2,3- d ]pyrimidine (1 eq) in DMF, N- Bromosuccinimide (1.1 eq) was added and stirred at room temperature for 2 hours. After the reaction was complete, the reaction was concentrated in vacuo. The layers were separated, and the aqueous solution layer was extracted with ethyl acetate. 7-Benzyl-5-bromo-4 as a white solid and purified by silica gel column (4- (2-fluorophenyl) piperazin-1-yl) -7 H - pyrrolo [2,3- d] pyrimidin Obtained mydin (66% yield).

¹ H NMR (CDCl ₃ , 300MHz) δ 3.32 (t, 4H, J = 4.5 Hz), 3.84 (t, 4H, J = 3.9 Hz), 5.47 (s, 2H), 7.00-7.12 (m, 3H), 7.30-7.34 (m, 5H), 7.54 (s, 5H), 8.38 (s, 1H).

Step 4: 4-(7-benzyl-4-(4-(2-fluorophenyl)piperazin-1-yl)-7 H -pyrrolo[2,3- d ]pyrimidin- 5-yl)- Preparation of 2,6-dichlorophenol

7-benzyl-5-bromo-4-(4-(2-fluorophenyl)piperazin-1-yl)-7 H -pyrrolo[2,3- d ]pyrimidine (1 eq), 2, 6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.2 eq), sodium carbonate (3 eq), PdCl ₂ (PPh ₃ ) ₂ (0.02 eq) was dissolved in 1,4-dioxane:water (2:1), and heated at 100 ^° C. in microwave for 20 minutes. After the reaction was complete, the reaction was concentrated in vacuo. The layers were separated, and the aqueous solution layer was extracted with ethyl acetate. 4- (7-benzyl-4- (4- (2-fluorophenyl as a white solid and purified by silica gel column) piperazin-1-yl) -7 H-pyrrolo [2,3- d] pyrimidine - 5-yl)-2,6-dichlorophenol (45% yield) was obtained.

¹ H NMR (CDCl ₃ , 300MHz) δ 3.00 (t, 4H, J = 4.2 Hz), 3.52 9t, 4H, J = 3.9 Hz), 5.43 (s, 2H), 6.91-6.97 (m, 2H), 7.04 (s, 2H), 7.28-7.34 (m, 4H), 7.42 (s, 2H), 7.49 (s, 2H), 8.56 (s, 1H).

<Experimental Example 1> Melanin production inhibition evaluation

In order to evaluate the inhibition of melanin production of the example compounds according to the present invention, the following experiment was performed, and the results are shown in Table 1 and FIG. 1.

The cells used in the experiment are melanoma cell lines derived from C57/BL6 mice, which are generally used for screening whitening substances, and are capable of inhibiting total melanin and new melanin production, and the activity of various enzymes involved in melanin production. B16F10 cells, a mouse-derived skin cancer cell line, which are reported to be capable of measuring inhibitory activity, related genes and cytokine changes, were used.

Specifically, B16F10 cells were seeded with 1*10 ⁶ cells in a 10 cm dish, and 2 hours later, a compound (an example compound and kojic acid as a comparative example) were treated. On the following day, 1 uM of α-MSH (α-melanocyte stimulating hormome) was treated, and 72 hours after the experimental drug was treated, pellets using 10 mM phosphate buffer (pH 6.8) containing 1% Triton X-100. Collected, 1 N NaOH and DW were added at a ratio of 1:2, and the cells were completely dissolved at 60° C. for 1 hour, and then the amount of melanin was measured at an absorbance of 475 nm. In this case, the lower the value, the more melanin production is inhibited. In addition, in order to visually evaluate the darkness, the sample performed in Experimental Example 1 was photographed and shown in FIG. 1.

On the other hand, α-MSH is a hormone derived from pro-opiomelanocortin (POMC), and POMC is a hormone such as adrenocorticotrophin (ACTH), lipotrophins (LPH), and endorphins. It is a precursor. It has been found that α-MSH and ACTH are produced from keratinocytes, and these have an action that contributes to the activity of melanocytes through the melanocortin receptor. In addition, α-MSH activates the adenylate cyclase system to induce the proliferation of melanocytes and a synergistic effect of tyrosinase activity.

number IBMX processing Compound treatment Absorbance at 475 nm One - - 0.0972 2 100 μM - 0.1763 3 100 μM Kojic acid (20 μM) 0.2253 4 100 μM Example 1 (10 μM) 0.0877 5 100 μM Example 2 (10 μM) 0.0407

In Table 1, as the absorbance value at 475 nm is lower, melanin production is significantly suppressed, indicating that the whitening effect is excellent.

As shown in Table 1, when IBMX was treated (No. 2) compared to cells not treated with IBMX (isobutylmethyl xanthine), a factor known to promote melanin production (No. 1), the amount of melanin was about twice It was elevated, confirming that melanogenesis was induced.

As a result of inducing melanin production with IBMX and 20 μM treatment of kojic acid, which is known as a melanin production inhibitor, (No. 3), melanin production was rather increased.

On the other hand, the cells treated with Examples 1 and 2 of the present invention (numbers 4 and 5) were treated with 1/2 of 10 μM than kojic acid, but in Example 1, the amount of melanin was reduced by 50% or more, In the case of Example 2, it was confirmed that the amount of melanin was reduced by 75% or more.

In addition, as shown in Fig. 1, when the kojic acid is treated, the color of the sample is darker than that of the IBMX treatment, whereas when the examples 1 and 2 of the present invention are treated, the color of the sample is transparent. It could be confirmed with the naked eye that the amount of melanin was significantly reduced.

Therefore, since the compound represented by Formula 1 according to the present invention exhibits an effect of inhibiting the production of melanin even when used in a small amount, it is a composition for treating melanin hyperpigmentation diseases, a cosmetic composition for skin whitening, and a health for skin whitening. It can be usefully used as a nutraceutical.

<Formulation Example 1> Preparation of powder

Compound 2g represented by formula 1

1g lactose

The above ingredients were mixed and filled in an airtight cloth to prepare a powder.

<Formulation Example 2> Preparation of tablets

100 mg of the compound represented by Formula 1

Corn starch 100 mg

100 mg lactose

2 mg of magnesium stearate

After mixing the above ingredients, tablets were prepared by tableting according to a conventional tablet preparation method.

<Formulation Example 3> Preparation of capsules

100 mg of the compound represented by Formula 1

Corn starch 100 mg

100 mg lactose

2 mg of magnesium stearate

After mixing the above ingredients, the gelatin capsules were filled according to a conventional capsule preparation method to prepare a capsule formulation.

<Formulation Example 4> Preparation of injection

100 mg of the compound represented by Formula 1

Mannitol 180 mg

Na ₂ HPO ₄ ㆍ2H ₂ O 26 mg

Distilled water 2974 mg

According to a conventional method for preparing injections, injections were prepared by containing the above ingredients in the indicated amount.

<Formulation Example 5> Preparation of ointment

5 g of a compound represented by Formula 1

20 g cetyl palmitate

40 g of cetanol

40 g of stearyl alcohol

80 g of myristan isopropyl

60 g of polysorbate

1 g of paraoxybenzoic acid propyl

1 g of methyl paraoxybenzoate

Proper amount of phosphoric acid and purified water

According to a conventional method for preparing an ointment, an ointment was prepared by containing the above ingredients in the indicated amount.

<Formulation Example 6> Preparation of health functional food

500 ng of a compound represented by Formula 1

Vitamin mixture right amount

70mg vitamin A acetate

1.0mg vitamin E

0.13mg vitamin

0.15mg vitamin B2

0.5mg vitamin B6

0.2mg vitamin B12

10mg vitamin C

10mg biotin

1.7 mg of nicotinic acid amide

50mg folic acid

0.5mg calcium pantothenate

Suitable amount of inorganic mixture

1.75 mg ferrous sulfate

Zinc oxide 0.82mg

25.3mg magnesium carbonate

15 mg of potassium monophosphate

Dicalcium phosphate 55mg

90mg potassium citrate

100mg calcium carbonate

Magnesium chloride 24.8mg

The composition ratio of the vitamin and mineral mixture is relatively suitable for the health functional food, but it is possible to arbitrarily modify the composition, and the above ingredients are mixed according to the general health functional food manufacturing method. Then, granules are prepared, and can be used to prepare a health functional food composition according to a conventional method.

<Formulation Example 7> Preparation of health functional beverage

500 ng of a compound represented by Formula 1

1000mg citric acid

100g oligosaccharide

2g plum concentrate

1 g taurine

Total 900ml with purified water

After mixing the above ingredients according to the general health function beverage manufacturing method, stirring and heating at 85°C for about 1 hour, the resulting solution is filtered and obtained in a sterilized container, sealed and sterilized, and then stored in a refrigerator. It was used to prepare a beverage composition.

The composition ratio is a mixture of ingredients suitable for a relatively preferred beverage in a preferred embodiment, but the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as the demand class, the country of demand, and the purpose of use.

<Formulation Example 8> Preparation of a composition for improving skin beauty

<8-1> Preparation of cream

4.6 parts by weight of the compound represented by Formula 1

2.8 parts by weight of cetostearyl alcohol

2.6 parts by weight of beeswax

1.4 parts by weight of stearic acid

Lipotype monostearate glycerin 2 parts by weight

PEG-100 stearate 1 part by weight

Sorbital sesquioleate 1.4 parts by weight

4 parts by weight of jojoba oil

3.8 parts by weight of squalane

1.1 parts by weight of polysorbate 60

2 parts by weight of macadamia oil

0.2 parts by weight of tocopherol acetate

0.4 parts by weight of methylpolysiloxane

0.1 parts by weight of ethylparaben

0.1 parts by weight of propyl paraben

0.1 parts by weight of Euxyl K-400

1,3-butylene glycol 7 parts by weight

0.05 parts by weight of methylparaben

6 parts by weight of glycerin

0.2 parts by weight of d-pandenol

0.2 parts by weight of triethanolamine

pt 41891 0.2 parts by weight

pH ₂ O 46.05 parts by weight

<8-2> Preparation of lotion

3.5 parts by weight of the compound represented by Formula 1

1.6 parts by weight of cetostearyl alcohol

1.4 parts by weight of stearic acid

1.8 parts by weight of lipophilic glycerin monostearate

PEG-100 stearate 2.6 parts by weight

Sorbital sesquioleate 0.6 parts by weight

4.8 parts by weight of squalene

2 parts by weight of macadamia oil

2 parts by weight of jojoba oil

Tocopherol acetate 0.4 parts by weight

0.2 parts by weight of methylpolysiloxane

0.1 parts by weight of ethylparaben

0.1 parts by weight of propyl paraben

1,3-butylene glycol 4 parts by weight

0.1 parts by weight of methyl paraben

0.1 parts by weight of xanthan gum

4 parts by weight of glycerin

0.15 parts by weight of d-pandenol

0.1 parts by weight of allantoin

Carbonae (2% aq. Sol) 4 parts by weight

0.15 parts by weight of triethanolamine

3 parts by weight of ethanol

pt 41891 0.1 parts by weight

pH ₂ 0 48.3 parts by weight

<8-3> Preparation of flexible lotion

0.2% by weight of the compound represented by Formula 1

Ethanol 10.0% by weight

1.0% by weight of polyoxyethylene sorbitan polylaurate

0.2% by weight of methyl paraoxybenzoate

5.0% by weight of glycerin

6.0% by weight of 1,3-butyl glycol

Proper amount of incense

Appropriate amount of pigment

Purified water appropriate amount

Total 100

<8-4> Preparation of nutritional lotion

0.1% by weight of the compound represented by Formula 1

Vaseline 2.0% by weight

Sorbitan sesquioleate 0.8% by weight

1.2% by weight of polyoxyethylene oleylethyl

Methyl paraoxybenzoate appropriate amount

5.0% by weight of propylene glycol

3.2 wt% ethanol

18.0% by weight of carboxyvinyl polymer

Appropriate amount of pigment

Proper amount of incense

Purified water appropriate amount

Total 100

<8-5> Preparation of essence

5.0% by weight of the compound represented by Formula 1

10.0% by weight of propylene glycol

Glycerin 10.0% by weight

Sodium hyaluronate aqueous solution (1%) 5.0% by weight

3.2 wt% ethanol

1.0% by weight of polyoxyethylene hydrogenated castor oil

0.1% by weight of methyl paraoxybenzoate

Proper amount of incense

Purified water appropriate amount

Total 100

<8-6> Preparation of the pack

0.5% by weight of the compound represented by Formula 1

5.0% by weight of glycerin

Propylene glycol 4.0% by weight

15.0% by weight of polyvinyl alcohol

Ethanol 8.0% by weight

1.0% by weight of polyoxyethylene oleylethyl

0.2% by weight of methyl paraoxybenzoate

Proper amount of incense

Appropriate amount of pigment

Purified water appropriate amount

Total 100

The composition ratio is mixed with suitable ingredients in a preferred embodiment, but the composition or mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as the demand class, the country of demand, and the purpose of use.

Claims (10)

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

(In Formula 1,
R ¹ is hydrogen, halogen or straight or branched C _1-6 alkyl; And
R ² is hydrogen or C _6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C _1-6 alkyl).
The method of claim 1,
R ¹ is hydrogen or halogen; And
R ² is hydrogen or phenyl, and the aryl is a compound characterized in that one or more substituents selected from the group consisting of -OH and halogen may be substituted, isomers thereof, solvates thereof, hydrates thereof, or pharmaceutically acceptable Possible salts.
The method of claim 1,
The compound represented by Formula 1 is a compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is any one selected from the following compound group:
(1) 7-benzyl-4-(4-(4-fluorophenyl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine; And
(2) 4-(7-benzyl-4-(4-(2-fluorophenyl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 ,6-dichlorophenol.
A pharmaceutical composition for preventing or treating melanin hyperpigmentation disease comprising a compound represented by the following Formula 1, its isomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient:
[Formula 1]

(In Formula 1,
R ¹ is hydrogen, halogen or straight or branched C _1-6 alkyl; And
R ² is hydrogen or C _6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C _1-6 alkyl).
The method of claim 4,
The compound represented by Formula 1 is a pharmaceutical composition, characterized in that it inhibits the production of melanin (melanin).
The method of claim 4,
The melanin hyperpigmentation disease is a pharmaceutical composition, characterized in that melasma, freckles, senile pigment spots or solar melanosis (solar lentigines).
A cosmetic composition for skin whitening comprising a compound represented by the following Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

(In Formula 1,
R ¹ is hydrogen, halogen or straight or branched C _1-6 alkyl; And
R ² is hydrogen or C _6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C _1-6 alkyl).
A cosmetic product for skin whitening comprising the cosmetic composition for skin whitening of claim 7.
The method of claim 8,
The above beauty products are solutions, external ointments, creams, foams, nutritional lotion, softening lotion, pack, softening water, emulsion, makeup base, essence, soap, liquid detergent, bathing agent, sunscreen cream, sun oil, suspension, emulsion, A cosmetic product for skin whitening, characterized in that it is prepared in a formulation selected from the group consisting of paste, gel, lotion, powder, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, patch, and spray.
A health functional food for skin whitening comprising a compound represented by the following Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

(In Formula 1,
R ¹ is hydrogen, halogen or straight or branched C _1-6 alkyl; And
R ² is hydrogen or C _6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C _1-6 alkyl).

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