KR102182651B1 - Uses for whitening material of 4-(4-methylpiperazin-1-yl)-N-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide derivatives, or pharmaceutical acceptable salt thereof - Google Patents

Abstract

4-(4-methylpiperazin-1-yl)-N-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide derivative, or a derivative thereof It relates to the use of a pharmaceutically acceptable salt for whitening material,
Since the composition for whitening provided in one aspect of the present invention has an excellent effect of inhibiting the promotion of cell melanogenesis even when a small amount is used, a cosmetic product for skin whitening, for preventing, improving, and treating diseases of excessive melanin pigmentation It can be usefully used as a product.

Description

4-(4-methylpiperazin-1-yl)-N-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide derivative, or a derivative thereof Uses for whitening material of 4-(4-methylpiperazin-1-yl)-N-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b] ]pyridin-3-yl)benzamide derivatives, or pharmaceutical acceptable salt thereof}

4-(4-methylpiperazin-1-yl)-N-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide derivative, or a derivative thereof It relates to the use of a pharmaceutically acceptable salt as a whitening material.

Diseases caused by excessive UV exposure due to changes in the global environment and the destruction of the ozone layer are emerging as issues to be resolved. UV rays can directly damage the skin and are a major cause of skin pigmentation. This is combined with whitening, the standard of modern beauty that pursues clearer and clearer skin with transparent makeup, and various solutions are being studied in terms of beauty as well as health.

Human skin color is affected by the environment, race, and sex, but is generally determined by the amount of brown melanin. Melanin is the primary factor in determining the color of the skin, and it also plays a role in determining the color of the hair. Human skin color is usually genetically determined, but it is affected by environmental factors such as UV exposure due to the destruction of the ozone layer, and psychological factors such as social stress. Melanin is classified into eumelanin, which is black or brown, and pheomelanin, which is red. Among eumelanins, black eumelanin appears mostly in non-white people or can be found in older whites. Brown eumelanin, on the other hand, can be found in young whites. Pheomelanin is present in all races and is more common in women than in men.

Melanin is a black pigment produced in the epidermis that absorbs the sun's UV (ultraviolet) light energy and protects cells deeper from UV-induced damage. Melanin has the pure function of protecting the skin from ultraviolet light, but when over-produced, it is known as an important factor in inducing hyperpigmentation and melanomas such as spots, freckles, black spots, age spots, and birthmarks. . In addition, typical skin pigmentation disorders include pigmentation caused by drugs, post-inflammatory pigmentation found in the healed wound site, or hyperpigmentation as a symptom of dermatitis.

Currently, kojic acid is a well-known whitening compound and is used in various whitening products (Korean Patent Laid-Open No. 10-2015-0062272). This substance, also known as malt acid, is a by-product of fermentation of malt, which is traditionally used to make brewed foods such as alcohol, miso, and soy sauce. Through many studies to use kojic acid as a whitening ingredient in cosmetics, it was confirmed that kojic acid prevents spots and freckles by inhibiting the activity of melanin pigment-forming enzymes that cause spots and freckles. Based on the results of these studies, cosmetics have begun to be developed to help treat and prevent skin pigmentation such as spots and freckles.

An object in one aspect of the present invention is 4-(4-methylpiperazin-1-yl)-N-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine- It is to provide a cosmetic composition for skin whitening containing a derivative of 3-yl) benzamide as an active ingredient.

An object in another aspect of the present invention is to provide a skin whitening cosmetic product comprising the skin whitening cosmetic composition.

An object in another aspect of the present invention is 4-(4-methylpiperazin-1-yl)-N-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine It is to provide a pharmaceutical composition for the prevention or treatment of melanin hyperpigmentation disease containing a derivative of -3-yl) benzamide as an active ingredient.

An object in another aspect of the present invention is 4-(4-methylpiperazin-1-yl)-N-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine It is to provide a health functional food composition for preventing or improving melanin hyperpigmentation disease containing a derivative of -3-yl) benzamide as an active ingredient.

To achieve the above object,

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

[Formula 1]

(In Formula 1,

Y is carbon, Z is nitrogen, A is carbon;

는 페닐, 피라졸릴 또는 피리디닐이고;

Is phenyl, pyrazolyl or pyridinyl;

이고, 상기 R^3a 및 R^3b는 각각 독립적으로 수소, 또는 직쇄 또는 분지쇄의 C_{1- 5}알킬이고; 및R ¹ is hydrogen; halogen; Piperidinyl; or

And wherein R ^3a and R ^3b are each independently hydrogen, or linear or branched C _{1- 5} alkyl; And

R ² is C _{1- 5} alkyl, a hydrogen, or straight or branched chain).

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

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating melanin hyperpigmentation disorders containing a compound represented by the following Formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient.

[Formula 1]

(In Formula 1,

Y is carbon, Z is nitrogen, A is carbon;

는 페닐, 피라졸릴 또는 피리디닐이고;

Is phenyl, pyrazolyl or pyridinyl;

이고, 상기 R^3a 및 R^3b는 각각 독립적으로 수소, 또는 직쇄 또는 분지쇄의 C_{1- 5}알킬이고; 및R ¹ is hydrogen; halogen; Piperidinyl; or

And wherein R ^3a and R ^3b are each independently hydrogen, or linear or branched C _{1- 5} alkyl; And

R ² is C _{1- 5} alkyl, a hydrogen, or straight or branched chain).

Another aspect of the present invention provides a health functional food composition for preventing or improving melanin hyperpigmentation diseases containing a compound represented by the following Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

(In Formula 1,

Y is carbon, Z is nitrogen, A is carbon;

는 페닐, 피라졸릴 또는 피리디닐이고;

Is phenyl, pyrazolyl or pyridinyl;

이고, 상기 R^3a 및 R^3b는 각각 독립적으로 수소, 또는 직쇄 또는 분지쇄의 C_{1- 5}알킬이고; 및R ¹ is hydrogen; halogen; Piperidinyl; or

And wherein R ^3a and R ^3b are each independently hydrogen, or linear or branched C _{1- 5} alkyl; And

R ² is C _{1- 5} alkyl, a hydrogen, or straight or branched chain).

Since the composition for whitening provided in one aspect of the present invention has an excellent effect of inhibiting the promotion of cell melanogenesis even when a small amount is used, a cosmetic product for skin whitening, for preventing, improving, and treating diseases of excessive melanin pigmentation It can be usefully used as a product.

1 is a diagram showing the results of an experiment on the inhibitory effect of melanin production of a compound according to the present invention performed in an experimental example.

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" certain elements throughout the specification means that other elements may be further included rather than excluding other elements 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.

In one aspect of the present invention, in order to solve the problems of the existing whitening raw materials, 4-(4-methylpiperazin-1-yl)-N-(5-(pyridin-3-yl)-1H-pyrazolo[ A novel whitening compound containing a derivative of 3,4-b]pyridin-3-yl)benzamide was proposed. The whitening compound according to the present invention exhibits excellent melanin production inhibitory effect even in a small amount, and can greatly contribute to the increase in the efficacy of whitening products.

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

[Formula 1]

(In Formula 1,

Y is carbon, Z is nitrogen, A is carbon;

는 페닐, 피라졸릴 또는 피리디닐이고;

Is phenyl, pyrazolyl or pyridinyl;

이고, 상기 R^3a 및 R^3b는 각각 독립적으로 수소, 또는 직쇄 또는 분지쇄의 C_1-5알킬이고; 및R ¹ is hydrogen; halogen; Piperidinyl; or

And, R ^3a and R ^3b are each independently hydrogen or a straight or branched C _1-5 alkyl; And

R ² is hydrogen or straight or branched C _1-5 alkyl).

On the other side,

는

,

,

,

,

,

,

,

,

,

,

,

,

,

또는

일 수 있고; R¹은 수소, 플루오로, 클로로, 브로모, 피페리디닐 또는

일 수 있고, 여기서, 상기 R^3a 및 R^3b는 각각 독립적으로 수소, 메틸, 에틸 또는 프로필일 수 있고; 및 R²는 수소, 메틸, 에틸 또는 프로필일 수 있다.remind

Is

,

,

,

,

,

,

,

,

,

,

,

,

,

or

Can be; R ¹ is hydrogen, fluoro, chloro, bromo, piperidinyl or

May be, wherein R ^3a and R ^3b may each independently be hydrogen, methyl, ethyl or propyl; And R ² may be hydrogen, methyl, ethyl or propyl.

On the other side,

는

,

,

,

,

또는

일 수 있고; R¹은 수소, 플루오로, 브로모,

또는

일 수 있고; 및 R²는 메틸일 수 있다.remind

Is

,

,

,

,

or

Can be; R ¹ is hydrogen, fluoro, bromo,

or

Can be; And R ² may be methyl.

On the other side,

는

일 수 있고; R¹은 수소, 플루오로, 브로모,

또는

일 수 있고; 및 R²는 메틸일 수 있다.remind

Is

Can be; R ¹ is hydrogen, fluoro, bromo,

or

Can be; And R ² may be methyl.

On the other side,

The compound represented by Formula 1 is 4-(4-methylpiperazin-1-yl)-N-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3 -It may be a benzamide.

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

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

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

On the other side,

The above beauty products are solutions, external ointments, creams, foams, nutritional lotion, softening lotion, pads, packs, softening water, emulsions, makeup bases, essences, soaps, skin cleaners, liquid cleaners, bath agents, sunscreens, sun oils, and suspensions. , Emulsion, paste, gel, lotion, skin, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, patches and sprays, but may be a product selected from the group consisting of, It is not limited thereto.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating melanin hyperpigmentation disorders containing a compound represented by the following Formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient.

[Formula 1]

(In Formula 1,

Y is carbon, Z is nitrogen, A is carbon;

는 페닐, 피라졸릴 또는 피리디닐이고;

Is phenyl, pyrazolyl or pyridinyl;

이고, 상기 R^3a 및 R^3b는 각각 독립적으로 수소, 또는 직쇄 또는 분지쇄의 C_1-5알킬이고; 및R ¹ is hydrogen; halogen; Piperidinyl; or

And, R ^3a and R ^3b are each independently hydrogen or a straight or branched C _1-5 alkyl; And

R ² is hydrogen or straight or branched C _1-5 alkyl).

On the other side,

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.

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 a 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.

Another aspect of the present invention provides a health functional food composition for preventing or improving melanin hyperpigmentation diseases containing a compound represented by the following Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

(In Formula 1,

Y is carbon, Z is nitrogen, A is carbon;

는 페닐, 피라졸릴 또는 피리디닐이고;

Is phenyl, pyrazolyl or pyridinyl;

이고, 상기 R^3a 및 R^3b는 각각 독립적으로 수소, 또는 직쇄 또는 분지쇄의 C_1-5알킬이고; 및R ¹ is hydrogen; halogen; Piperidinyl; or

And, R ^3a and R ^3b are each independently hydrogen or a straight or branched C _1-5 alkyl; And

R ² is hydrogen or straight or branched C _1-5 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.

Since the whitening composition provided in one aspect of the present invention exhibits an effective melanin production inhibitory effect more effectively than the conventional whitening composition even in a small amount, it can be usefully used as a whitening product, which will be described later in Preparation Examples and Experimental Examples. Can be directly supported by

Hereinafter, the present invention will be described in detail through Preparation Examples and Experimental Examples to be described later. However, the preparation examples and experimental examples to be described later are merely illustrative of the present invention and the present invention is not limited thereto.

< Manufacturing example 1> 4-(4- Methylpiperazine -1-yl)-N-(5-(pyridin-3-yl)-1H- Pyrazolo[3,4- b] pyridin-3-yl) benzamide preparation

The title compound was prepared with reference to Korean Patent Registration No. 10-1753654.

In another aspect, the title compound may be synthesized through the following synthesis procedure.

step 1: 2 - Methoxy - Nicotinonitrile Produce

Sodium (2.50 g, 109 mmol) was added to methanol (40 mL) and stirred at room temperature for 30 minutes. 2-chlorocyanopyridine (5.0 g, 36.1 mmol) was added and stirred for 5 hours. After the reaction was terminated by adding water, the solid was separated, washed with water, and dried to obtain 2-methoxy-nicotinonitrile (4.35 g, 90%).

¹ H NMR (CDCl ₃ , 300HMz): δ 4.06 (s, 3H), 6.98 (dd, 1H), 7.88 (dd, 1H), 8.36 (dd, 1H).

step 2: 5 - Bromo -2- Methoxy - Nicotinonitrile Produce

Sodium acetate (4.92 g, 60.0 mmol) and bromine (3.08 mL, 60.0 mmol) were added to 2-methoxy-nicotinonitrile (4.0 g, 30.0 mmol) dissolved in acetic acid (100 mL), and 12 at 70°C. Heated for hours and cooled to room temperature. The solid was separated, washed with water, and dried to obtain 5-bromo-2-methoxy-nicotinonitrile (4.1 g, 65% yield). ¹ H NMR (CDCl ₃ , 300HMz): δ 4.05 (s, 3H), 7.96 (d, 1H), 8.39 (d, 1H).

step 3: 5 - Bromo -1H- Pyrazole[3,4-b]pyridine -3- Amine Produce

5-bromo-2-methoxy-nicotinonitrile (4 g, 18.8 mmol) in hydrazine (40 mL) was heated to reflux for 6 hours. After cooling to room temperature, the solid precipitate was separated, washed with water and dried to obtain 5-bromo-1H-pyrazole[3,4-b]pyridin-3-amine (3.2 g, 80%). ¹ H NMR (CDCl ₃ , 300HMz): δ 5.66 (s, 2H), 8.37 (d, 1H), 8.39 (d, 1H).

step 4: 5 - Bromo -1-[(4- Methoxyphenyl ) methyl ]- Pyrazolo[3,4-b]pyridine -3- Amine Produce

NaH (0.43 g, 10.8 mmol) was added to a DMF (40 mL) solution of 5-bromo-1H-pyrazole[3,4-b]pyridin-3-amine (3.0 g, 9.0 mmol) at 0°C and 30 Stir for a minute. 4-methoxybenzyl bromide (0.5 mL, 10.1 mmol) was added and stirred at room temperature for 7 hours. The reaction was poured into ice, stirred for 10 minutes, and the resulting solid was filtered and dried to 5-bromo-1-[(4-methoxyphenyl)methyl]-pyrazolo[3,4-b]pyridin-3-amine (3.28 g, 70%) was obtained.

¹ H NMR (CDCl ₃ , 300HMz): δ3.79 (s, 3H), 4.05 (s, 2H), 5.40 (s, 2H), 6.82 (dd, 2H), 7.23 (dd, 2H), 7.99 (dd , 1H), 8.49 (dd, 1H).

Step 5: N-[5- Bromo -1-[(4- Methoxyphenyl )- methyl ]- Pyrazolo[3,4-b]pyridine Preparation of -3-yl]-4-(4-methyl-1-piperazinyl)-benzamide

To dichloromethane (10 mL) of 4-methyl-1-piperazinyl-benzoic acid (300 mg, 1.36 mmol) was added oxalyl chloride (0.24 mL, 2.72 mmol). 2 drops of DMF were added and stirred at room temperature for 12 hours. The solution was removed under reduced pressure, and the residue was dried by azeotropic distil with 30 mL of toluene. The crude acid chloride compound was dissolved in DIPEA (0.96 mL, 5.44 mmol) and 1,4-dioxane (20 mL) in 5-bromo-1-[(4-methoxyphenyl)methyl]-pyrazolo[3 ,4-b]pyridin-3-amine (140 mg, 0.42 mmol) was added and stirred at room temperature for 3 hours. It was diluted with ethyl acetate (200 mL), washed with brine solution, and the organic layer was dried over MgSO ₄ . The organic layer was concentrated and chromatographed (5% methanol: DCM) to perform N-[5-bromo-1-[(4-methoxyphenyl)-methyl]-pyrazolo[3,4-b]pyridin-3 -Yl]-4-(4-methyl-1-piperazinyl)-benzamide (235 mg, 81%) was obtained.

¹ H NMR (DMSO-d6, 300 HMz): δ 11.03 (s, 1H), 8.68 (d, 1H), 8.61 (d, 1H), 8.03 (d, 2H), 7.23 (d, 2H), 7.10 ( d, 2H), 6.88 (d, 2H), 5.55 (s, 2H), 3.71 (s, 3H), 3.48 (t, 4H), 3.05 (t, 4H), 2.87 (s, 3H).

step 6: 4 -(4- Methylpiperazine -1-yl)-N-(5-(pyridin-3-yl)-1H- Pyrazolo[3,4-b]pyridine Preparation of -3-yl)benzamide

N-[5-bromo-1-[(4-methoxyphenyl)-methyl]-pyrazolo[3,4-b]pyridin-3-yl]-4-(4-methyl-1-piperazinyl )-Benzamide (80 mg, 0.15 mmol), 3-pyridineboronic acid (0.30 mmol), K ₂ CO ₃ (2 M, 0.7 mL, 3.0 mmol) and DMA (1 mL) are added to a microwave vial. . The solvent was degassed for 15 minutes, and Pd(dppf)Cl ₂ (10 mol %) was added, followed by microwave irradiation at 150° C. for 30 minutes. The solution was filtered through a celite layer, the filtrate was washed with brine (10 mL x 5), and the organic layer was concentrated, followed by chromatography (10% methanol:dichloromethane) to obtain 4-(4-methylpiperazin-1-yl). )-N-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide (40%) was obtained.

¹ H NMR (DMSO-d6, 300 HMz): δ 13.35 (s, 1H), 10.87 (s, 1H), 8.94 (d, 1H), 8.87 (d, 1H), 8.61 (dd, 1H), 8.58 ( d, 1H), 8.15 (td, 1H), 8.04 (d, 2H), 7.52 (dd, 1H), 7.08 (d, 2H) 3.48 (t, 4H), 2.48 (t, 4H), 2.45 (s, 3H).

< Comparative example 1> 3- Isobutyl -One- Of methylxanthine (IBMX) Ready

For comparative experiments, 3-isobutyl-1-methylxanthine (IBMX) was purchased and prepared from Sigma-Aldrich. 3-Isobutyl-1-methylxanthine is known to promote melanogenesis.

< Comparative example 2> Kojic acid ( kojic acid)

For comparative experiments, kojic acid was purchased and prepared from Sigma-Aldrich. Kojic acid is known to have excellent whitening effect.

< Experimental example 1> Melanogenesis inhibition evaluation

In order to evaluate the melanin production inhibitory activity of Preparation Example 1 compound, the following experiment was performed, and the results are shown in Table 1 and FIG. 1.

B16F10 cells, which are melanoma cell lines derived from C57/BL6 mice, and are generally used for screening whitening substances, were prepared. B16F10 cells are known to be capable of measuring total melanin, the ability to inhibit new melanogenesis, the ability to inhibit the activity of various enzymes involved in melanogenesis, and the amount of changes in related genes and cytokines.

Specifically, B16F10 cells were seeded into 1×10 ⁶ cells in a 10 cm dish, and 2 hours later, the test compounds (Preparation Example 1, Comparative Example 1 and/or Comparative Example 2) were treated. The next day, 1 uM of α-MSH (α-melanocyte stimulating hormome) was treated, and 72 hours after treatment with the test compound, pellets using 10 mM phosphate buffer (pH 6.8) containing 1% Triton X-100 1N NaOH and DW were added at a ratio of 1:2, and the cells were completely dissolved at 60° C. for 1 hour, and the absorbance was measured at 475 nm.

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.

The absorbance measurement results are shown in Table 1 below.

In Table 1 below, as the absorbance value at 471 nm is lower, melanin production is significantly suppressed, indicating that the whitening effect is excellent.

No. 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 Preparation Example 1 (10 μM) 0.0638

As shown in Table 1 above,

No. 1, an experimental group that was not treated with any of the test compounds (Preparation Example 1, Comparative Example 1 and/or Comparative Example 2), was found to have an absorbance of 0.0972 nm at 475 nm.

In comparison, No.2, an experimental group treated with IBMX (3-isobutyl-1-methylxanthine), which is known to promote melanogenesis alone, has an absorbance of 0.1763 nm at 475 nm, compared with No. 1 As the intensity increased, it can be seen that melanin production was promoted as expected.

On the other hand, the experimental group No.3 treated with kojic acid with IBMX had an absorbance of 0.2253 nm at 475 nm, which was unexpectedly increased, but rather increased in intensity, indicating that melanin production was not effectively suppressed.

On the other hand, No.4, an experimental group treated with the compound of Preparation Example 1 with IBMX, had an absorbance of 0.0638 nm at 475 nm, and no test compounds (Preparation Example 1, Comparative Example 1 and/or Comparative Example 2) were treated. It can be seen that the inhibition of melanin production was relatively remarkably superior to that of the experimental group No.1.

The results of evaluating the whitening effect with the naked eye are also shown in FIG. 1, and it can be seen that the whitening effect occurs remarkably in the experimental group No. 4, which was treated with the compound of Preparation Example 1 together with IBMX.

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.

As described above, the present invention has been described in detail through preferred preparation examples and experimental examples, but the scope of the present invention is not limited to the characteristic experimental examples, and should be interpreted by the appended claims. In addition, those who have acquired ordinary knowledge in this technical field should understand that many modifications and variations can be made without departing from the scope of the present invention.

<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, a gelatin capsule was filled according to a conventional capsule preparation method to prepare a capsule.

<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, the granules are prepared and can be used for preparing 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)

delete delete delete delete Skin whitening cosmetic composition containing the following compound or a pharmaceutically acceptable salt thereof as an active ingredient:
4-(4-methylpiperazin-1-yl)-N-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide.
A cosmetic product for skin whitening comprising the cosmetic composition for skin whitening of claim 5.
The method of claim 6,
The beauty product is a skin whitening cosmetic product comprising a cream, oil, sunscreen, skin cleanser, pad, pack, lotion, lotion or skin.
As a pharmaceutical composition for the prevention or treatment of melanin hyperpigmentation disease, containing the following compound, or a pharmaceutically acceptable salt thereof, as an active ingredient, the melanin hyperpigmentation disease is spots, freckles, senile pigment spots or sun black Pharmaceutical composition, which is solar lentigines:
4-(4-methylpiperazin-1-yl)-N-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide.
delete As a health functional food composition for preventing or improving melanin hyperpigmentation disease, containing the following compound, or a pharmaceutically acceptable salt thereof, as an active ingredient, the melanin hyperpigmentation disease is spots, freckles, senile pigment spots or sunlight Health functional food composition, which is melanosis (solar lentigines):
4-(4-methylpiperazin-1-yl)-N-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide.

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