HK1149487B - Skin whitening agent and external preparation for the skin - Google Patents

Description

Skin whitening agent and external preparation for skin

RELATED APPLICATIONS

The present application claims priority from Japanese patent application No. 2008-29106, filed on 8/2008, and Japanese patent application No. 2008-199606, filed on 1/8/2008, incorporated herein by reference.

Technical Field

The present invention relates to a whitening agent and an external preparation for skin, and particularly to an active ingredient thereof.

Background

Pigmentation of the skin, such as spots and freckles, is caused by abnormal hormones or ultraviolet stimulation, and is caused by increased melanin production in the pigment cells of the epidermis and excessive melanin deposition on the epidermis.

For the purpose of preventing and improving such abnormal deposition of melanin, whitening agents have been incorporated into skin external preparations. At present, vitamin C derivatives, kojic acid, arbutin (4-hydroxyphenyl- β -D-glucopyranoside), resveratrol (Rucinol) (4-n-butylresorcinol), ellagic acid, and the like are known as ingredients to be blended in skin external preparations as whitening agents, and these ingredients have a melanin production inhibitory action.

However, a sufficiently satisfactory substance is not yet obtained in terms of its effect, safety, and the like, and development of a new whitening agent has been desired.

On the other hand, patent document 1 describes pyrazolopyrimidine compounds having a potassium channel modulating effect.

In addition, patent documents 2 to 4 describe pyrazolopyrimidine compounds having a controlling activity against rice blast, rice leaf blight, cucumber powdery mildew (Cucurbit powdery mildew) and the like.

In addition, patent document 5 describes pyrazolopyrimidine compounds useful as analgesics.

However, these documents do not describe any melanin production inhibitory action or whitening effect.

[ patent document 1 ] WO2006/100212

[ patent document 2 ] Japanese patent application laid-open No. Sho 54-117029

[ patent document 3 ] Japanese patent application laid-open No. Sho 54-147921

[ patent document 4 ] Japanese patent application laid-open No. 62-404

[ patent document 5 ] Japanese patent publication No. 42-19593

Disclosure of Invention

The present invention has been made in view of the above problems of the prior art, and an object of the present invention is to provide a compound having an excellent melanin production inhibitory action and useful as a whitening agent, and an external preparation for skin containing the compound.

As a result of intensive studies to solve the above problems, the present inventors have found that a specific compound has an excellent melanin production inhibitory action and very low cytotoxicity, and have completed the present invention.

That is, the whitening agent according to the present invention is characterized by having a heterocyclic compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

(in the formula, X₁、X₂And X₃Are each independently of the other, is CR₂Or N;

R₁、R₂and R₃Are each independently H, C_1-6Alkyl radical, C_1-6Alkoxy, SH, OH, or NR_bR_c(R_bAnd R_cAre each independently H, C_1-6Alkyl, or hydroxy C_1-6Alkyl, or NR_bR_cForming a saturated or unsaturated 5-to 6-membered heterocyclic ring);

b is a group represented by the following general formula (B1) or (B2), but X₁＝X₂＝X₃＝CR₂In the case where B is a group represented by the following general formula (B1);

Y₁、Y₂one of which is N and the other is CR₅；

R₄、R₅、R₆Are each independently H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-7Acyloxy, OH,Amino, -NH-A, -NHCO-A, or-NHCOCH₂-A (A is C)_1-6Alkyl, phenyl or a 5-to 6-membered heterocyclic group), or

R₄And R₅Or R₅And R₆Taken together to form a 5-to 6-membered hydrocarbon ring fused to the heterocycle to which they are attached;

the group (B2) is a saturated or unsaturated 6-membered heterocyclic group;

R_ais C_1-6An alkyl group;

p is an integer of 0 to 2, and R is an integer of 2_aMay be the same or different;

however, X₁＝X₂＝Y₁Is N and X₃＝CR₂When R is₁、R₃、R₄And R₆At least 1 of which is C_1-3A group other than an alkyl group. )

In addition, the present invention provides a whitening agent, wherein B is a group (B1).

The present invention also provides a whitening agent, wherein the active ingredient of the whitening agent is a heterocyclic compound represented by the following general formula (1-1) or a pharmaceutically acceptable salt thereof.

(in the formula, X₁、X₂、X₃、R₁、R₃、R₄、R₅And R₆The same as defined in the above general formula (1). )

The present invention also provides a whitening agent, wherein the active ingredient of the whitening agent is a heterocyclic compound represented by the following general formula (1-1a) or a pharmaceutically acceptable salt thereof.

(in the formula, R₁、R₂、R₃、R₄、R₅And R₆The same as defined in the above general formula (1). )

In addition, the invention also provides a whitening agent, in the general formula (1-1), X₁＝X₂＝X₃＝N。

In addition, the invention also provides a whitening agent, in the general formula (1-1), X₁＝X₂＝X₃＝CR₂。

In addition, the present invention provides a whitening agent, wherein B ═ group (B1), X, and a pharmaceutically acceptable carrier₁＝X₂＝N，X₃＝CR₂And Y is₂＝N。

In addition, the present invention provides a whitening agent, wherein B ═ group (B1), R is contained in the whitening agent₁And R₃Each independently is H or C_1-6An alkyl group.

In addition, the present invention provides a whitening agent, wherein B ═ group (B1), R is contained in the whitening agent₁And R₃Any of which is NR_bR_c。

In addition, the present invention provides a whitening agent, wherein B ═ group (B1), X, and a pharmaceutically acceptable carrier₁、X₂And X₃At least 1 of which is CR₂，R₂Is H or C_1-6An alkyl group.

In addition, the present invention provides a whitening agent, wherein B ═ group (B1), R is contained in the whitening agent₅And R₆Each independently is H or C_1-6An alkyl group.

The present invention also provides a whitening agent, wherein the whitening agent contains a group BGroup (B1), R₄Is H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-7Acyloxy, OH, or amino.

In addition, the present invention provides a whitening agent, wherein B ═ group (B1), R is contained in the whitening agent₄is-NH-A, -NHCO-A or-NHCOCH₂-A, or with R₅Taken together to form a 5-to 6-membered hydrocarbon ring fused to the heterocycle to which they are attached.

In addition, the present invention provides a whitening agent, wherein X is₁、X₂And X₃At least 1 of which is N, B being a group (B2).

In addition, the present invention provides a whitening agent, wherein B is a group (B2), and X is₁＝X₂＝N，X₃＝CR₂。

The present invention also provides a whitening agent, wherein the active ingredient of the whitening agent is a heterocyclic compound represented by the following general formula (1-2) or a pharmaceutically acceptable salt thereof.

(in the formula, R₁、R₂、R₃、R_aAnd p is the same as defined in the above general formula (1). )

In addition, the present invention provides a whitening agent, wherein p in the above general formula (1-2) is 0.

In addition, the present invention provides a whitening agent, wherein B is a group (B2), R is₁、R₂、R₃Each independently is H, C_1-6Alkyl radical, C_1-6Alkoxy, or NR_bR_c。

In addition, the present invention provides a whitening agent in which the active ingredient inhibits melanin production.

The present invention also provides an external preparation for skin and a cosmetic, wherein the heterocyclic compound according to any one of the above-mentioned items or a pharmaceutically acceptable salt thereof is blended.

The whitening agent of the present invention has an excellent melanin production-inhibiting effect and very low cytotoxicity, and therefore can be suitably blended as a whitening agent in an external preparation for skin.

Detailed Description

The whitening agent of the present invention contains a compound represented by the following general formula (1).

In the general formula (1), X₁、X₂And X₃Are each independently of the other, is CR₂Or N. Thus, containing X₁、X₂And X₃The unsaturated 6-membered ring of (a) is a benzene ring, a pyridine ring, a pyrimidine ring, or a triazine ring. Among them, preferable examples thereof include benzene ring and X₁＝X₂A more preferred example of the unsaturated 6-membered ring is a pyrimidine ring.

R₁、R₂And R₃Are each independently H, C_1-6Alkyl radical, C_1-6Alkoxy, SH, OH, or NR_bR_cThe group shown. In the presence of a plurality of R₂In the case of (2), these groups may be the same or different.

R_bAnd R_cAre each independently H, C_1-6Alkyl, or hydroxy C_1-6An alkyl group. Or NR_bR_cOr may be R_bAnd R_cTogether with the nitrogen atom to which they are bonded, form a saturated or unsaturated 5-to 6-membered heterocyclic ring.

As NR_bR_cExamples of the saturated or unsaturated 5-to 6-membered heterocyclic ring include heterocyclic rings containing 1 to 4 hetero atoms (N, O or S atom) as ring-forming elements, such as pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, triazole, tetrazole, thiazolidine, piperidine, piperazine, pyridine, and pyridine,Oxazines, morpholines, and the like. Among them, morpholine and pyrazole are preferable examples. In addition, NR_bR_cThe heterocyclic ring may have 1 to 3C's at any possible position_1-6Alkyl as a substituent.

X₁、X₂、X₃When at least one of them is N, B is a group represented by the following general formula (B1) or (B2), X is₁＝X₂＝X₃＝CR₂In the case of (benzene ring), B is a group represented by the following general formula (B1).

In the group (B1), Y₁、Y₂One of which is N and the other is CR₅. Thus, the radical (B1) is pyrazol-1-yl (Y)₁N) or imidazol-1-yl (Y)₂＝N)。

R₄、R₅、R₆Each independently selected from H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-7Acyloxy, OH, amino, -NH-A, -NHCO-A, or-NHCOCH₂-A (A is C)_1-6Alkyl, phenyl or a 5-to 6-membered heterocyclic group), R₅、R₆Preferably H or C_1-6An alkyl group. Or, R₄And R₅Or R₅And R₆Or may be taken together to form a 5-to 6-membered hydrocarbon ring fused with the heterocycle to which they are attached.

However, in the present invention, X₁＝X₂＝Y₁Is N and X₃＝CR₂When R is₁、R₃、R₄And R₆At least 1 of which is C_1-3A group other than an alkyl group.

The 5-to 6-membered heterocyclic group for A may be a saturated or unsaturated heterocyclic group containing 1 to 4 hetero atoms (N, O or S atom) as a ring-forming element. Examples of the heterocyclic ring include furan, tetrahydrofuran, dioxofuran, thiophene, tetrahydrothiophene, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, triazole, tetrazole, and iso-heterocycleAzole,Azole,Oxazoline,Oxadiazole, isothiazole, thiazole, thiazoline, thiazolidine, pyran, tetrahydropyran, dioxaneBritish, thiacyclohexane (チァン), oxathiane, dithiane, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, and mixtures thereof,Oxazines, morpholines, thiazines, and the like. Preferable examples of the heterocycle of A include thiophene and piperazine.

In addition, the phenyl group or heterocyclic group of A may have 1 to 3 substituents at any possible position. As such a substituent, for example, C_1-6Alkyl, halogen (Br, Cl, or I), C_1-6An alkoxycarbonyl group, a carbonyl group,furthermore, methylenedioxy (-OCH) can be mentioned₂O-) or ethylenedioxy (-OCH)₂CH₂O-) and the like C_1-2An alkylenedioxy group.

In addition, R₄And R₅Or R₅And R₆The 5-to 6-membered hydrocarbon ring fused with the heterocyclic ring to which they are bonded, which is connected together, may have 1 to 2 substituents at any possible positions, and as such substituents, a benzylidene group substituted with 1 to 2 halogens may be mentioned.

Among the compounds represented by the general formula (1), as one of preferable examples of the compound having a group (B1), pyrazole compounds represented by the following general formula (1-1) can be exemplified.

(in the formula, X₁、X₂、X₃、R₁、R₃、R₄、R₅And R₆The same as defined in the above general formula (1). )

In addition, R in the general formula (1-1)₄In the case of OH, tautomers are considered, and in the present invention, these tautomers are also included in the compounds of the above general formula (1-1).

As a preferred example of the compound represented by the general formula (1-1), a pyrazole compound represented by the following general formula (1-1a) can be mentioned.

(in the formula, R₁、R₂、R₃、R₄、R₅And R₆The same as defined in the above general formula (1). )

Further, one preferable example of the compound represented by the general formula (1-1) may be X₁＝X₂＝X₃Pyrazole compounds of the formula (I).

Further, one preferable example of the compound represented by the general formula (1-1) may be X₁＝X₂＝X₃＝CR₂The pyrazole compound of (1).

In addition, one of preferable examples of the compound having a B ═ group (B1) may, for example, be X₁＝X₂＝N，X₃＝CR₂And Y is₂An imidazole compound of ═ N.

One of preferable examples of the compound having a B ═ group (B1) is R₁And R₃Both independently of one another are H or C_1-6Alkyl compounds.

One of preferable examples of the compound having a B ═ group (B1) is R₁And R₃At least either of the two being NR_bR_cThe compound of (1).

In addition, one of preferable examples of the compound having a B ═ group (B1) may, for example, be X₁、X₂And X₃At least 1 of which is CR₂，R₂Is H or C_1-6Alkyl compounds.

In the general formula (1), X₁、X₂、X₃In the case where at least 1 of them is N, B may be the above-mentioned group (B2). The group (B2) is a saturated or unsaturated 6-membered heterocyclic group, such heterocyclic ring being piperidine or pyridine.

R_aIs C_1-6An alkyl group.

In addition, p is 0 to 2Is an integer of (1). When p is 2, R_aMay be the same or different.

Among the compounds represented by the general formula (1), one preferable example of the compound having a B ═ group (B2) is X₁＝X₂＝N、X₃＝CR₂The compound of (1). Further, as one preferable example of such a compound, a pyrimidine compound represented by the following general formula (1-2) can be exemplified.

(in the formula, R₁、R₂、R₃、R_aAnd p is the same as defined in the above general formula (1). )

As a preferable example of the compound represented by the general formula (1-2), a compound wherein p is 0 may be mentioned.

One of preferable examples of the compound having a B ═ group (B2) is R₁、R₂、R₃Are each independently H, C_1-6Alkyl radical, C_1-6Alkoxy or NR_bR_cThe compound of (1).

In the present invention, each group is defined as follows.

“C_1-6The alkyl group is a linear, branched or cyclic saturated hydrocarbon group having 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferable examples of the alkyl group include a methyl group and an ethyl group.

“C_1-6Alkoxy "means having C_1-6The oxy group of an alkyl group.

"hydroxy group C_1-6Alkyl "means any possibilityC having 1 to 2 hydroxyl groups at the position of (A)_1-6An alkyl group.

“C_2-7Acyl "denotes a compound having C_1-6Examples of the carbonyl group of an alkyl group or a phenyl group include an acetyl group, a propionyl group, a butyryl group, an acryloyl group, a crotonyl group, and a benzoyl group. A preferred acyl group is an acetyl group.

The compound of the general formula (1) can be synthesized by a known method or can be obtained as a commercially available product. The following describes typical examples of synthesis, but the examples are not intended to limit the scope of the invention. When a functional group exists in a molecule and inhibits or is likely to inhibit a reaction, it is preferable to efficiently perform the reaction by using an appropriate protecting group. The use of protecting Groups can be carried out, for example, according to Protective Groups in organic Synthesis, available from Theodora W.Greene, Peter G.M.Wuts.

When an isomer such as a coordination isomer, a geometric isomer, or an optical isomer exists, a simple isomer or a geometric isomer can be obtained by appropriately selecting a raw material and a reaction condition and performing a separation operation. In the present invention, simple isomers of the compounds of formula (1) or mixtures thereof are also included.

Among the compounds of the general formula (1), for example, the compounds represented by the general formula (1-1) can be obtained by the reaction shown in the following scheme 1.

Scheme 1:

in scheme 1, the reaction of the hydrazine compound (2) with the 1, 3-dicarbonyl compound (3a) or the 1-sulfonyl-3-carbonyl compound (3B) can be carried out in an appropriate solvent such as methanol, in the presence of an acid catalyst such as hydrochloric acid or acetic acid, and if necessary, while heating. This reaction can be carried out, for example, by the method described in Japanese patent application laid-open No. 62-404 (patent document 4), Tetrahedron Lett., 45, 4265(2004), Gazzetta Chemica Italiana, 93, 100(1963), and the like.

In addition, in the compound represented by the general formula (1-1), R₄is-NH₂The compound (1-1b) of (1) can be obtained by a reaction with the compound (4) or the compound (5), as shown in the following scheme 2. R can be produced by reacting the compound (1-1b) with the haloacyl compound (7)₄Compound (1-1c) which is-NHCO-Ar (Ar: aryl). These reactions can be carried out, for example, by the methods described in J.chem.Soc., 285(1941), Japanese patent application laid-open No. 4-275227, Japanese patent application laid-open No. 2006-526015, and the like.

Scheme 2:

the hydrazine compound (2) used as the starting material in the above schemes 1 to 2 can be obtained as a commercially available product or synthesized by a known method.

For example, the desired hydrazine compound (2) can be obtained by the reaction shown in the following scheme 3 using the amine compound (8) as a starting material. The reaction can be carried out, for example, according to the method described in JP-A-8-208620.

Scheme 3:

in addition, the desired hydrazine compound (2) can be obtained from the pyrimidine compound (9) having a leaving group Z (e.g., halogen) by the reaction shown in scheme 4 below. The reaction can be carried out, for example, according to the method described in chem.pharm.bull., 17(7), 1467(1969), chem.pharm.bull., 11(11), 1382(1963), journal of pharmacy, 73, 635(1953), and the like.

Scheme 4:

other compounds used in the above reaction can also be synthesized by appropriately combining known methods.

The compound of the general formula (1) can be converted into an acid addition salt according to a conventional method, if necessary. Examples of the acid addition salt include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as acetic acid, propionic acid, citric acid, lactic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, tartaric acid and methanesulfonic acid.

In addition, there are a number of commercially available products for the compounds of formula (1). For example, they are available from Enamine (Ukraw), Pharmeks (Russian), Labott (Germany), Scientific Exchange (USA), Life Chemicals (Ukraw), Asinex (Russia), Vitas-M Laboratory (Russia), ACB Blocks (Russia), Bionet (USA), Princeton Biomolecular (USA), and various other suppliers.

The compound of the general formula (1) has an excellent melanin production-inhibiting effect and is also very low in cytotoxicity. Therefore, the compound is useful as a whitening agent, and can be suitably blended with various skin external preparations, particularly skin external preparations for the purpose of improving or preventing stains, freckles, dullness, and the like.

When the compound of the general formula (1) is incorporated as a whitening agent into an external preparation for skin, the amount of the external preparation is usually 0.0002 mass% or more, preferably 0.002 mass% or more, based on the total amount of the external preparation. If the amount is too small, the effect cannot be sufficiently exhibited. The upper limit is not particularly limited, and is usually 30% by mass or less, preferably 20% by mass or less, and more preferably 5% by mass or less. Even if the amount is excessively added, a significant effect commensurate with an increase in the amount added may not be obtained, and the design of the preparation and the use thereof may be affected.

The skin preparation for external use of the present invention can be produced by a conventional method, except that the compound of the general formula (1) is blended.

In addition, the external preparation for skin of the present invention may contain, in addition to the compound of the general formula (1), other components used in general external preparations for skin such as cosmetics and medicines, for example, oil components, moisturizers, ultraviolet inhibitors, antioxidants, metal ion blocking agents, surfactants, preservatives, moisturizers, perfumes, water, alcohols, thickeners, powders, colorants, crude drugs, and other various medicinal components, as necessary, within a range that does not impair the effects of the present invention.

In addition, other whitening agents such as vitamin C, magnesium ascorbyl phosphate, ascorbyl glucoside, arbutin, kojic acid, resveratrol, ellagic acid, tranexamic acid, and linoleic acid may be appropriately added.

The skin preparation for external use of the present invention can be widely used in the fields of cosmetics, pharmaceuticals, quasi drugs and the like. The formulation is not particularly limited as long as it can be applied to the skin, and any formulation such as a solution, emulsion, solid, semisolid, powder dispersion, water-oil two-layer separation, water-oil-powder three-layer separation, ointment, gel, aerosol, mousse, and stick can be applied. The form of use is also arbitrary, and examples thereof include facial basic cosmetics such as lotions, milky lotions, creams, pack films (pack), essences, and gels, and makeup cosmetics such as foundation, liquid foundation (under makeup), and concealer.

The present invention will be further described with reference to specific examples, but the present invention is not limited thereto.

Examples

For the compound of the general formula (1), a melanin production inhibition test was performed. The test method is as follows.

Test for inhibition of melanogenesis

(1) Cell inoculation and addition of test substance

Mouse B16 melanoma cells were seeded in 6-well plates at 100,000 cells/well. The next day, the test substance solution (solvent: DMSO) was added.

(2) Cell proliferation assay

After the addition of the test substance solution for 3 days, the medium was removed by suction filtration, and then 1ml of EMEM medium containing 10% Alamar Blue (AlamarBlue) solution was added and allowed to react at 37 ℃. After 30 minutes, 100. mu.l were transferred to a 96-well plate and fluorescence was measured at an excitation wavelength of 544nm and a measurement wavelength of 590 nm. The relative value of the number of cells was used as the value, and the ratio of the number of cells (% number of cells) in the test substance-added group to the test substance-non-added group (only solvent was added) was calculated. Higher% cell number indicates lower cytotoxicity. The cells in% are determined to be non-toxic when the number of cells is 80% or more, and toxic when the number of cells is less than 80%.

(3) Quantification of melanin

After the cell growth test, the cells were washed 3 times with PBS, 200. mu.L of 1M NaOH was added to the cells, and the cells were lysed to measure the absorbance at 475 nm. The ratio (%) of the amount of melanin in the test substance-added group to the amount of melanin in the test substance-non-added group (only solvent was added) was calculated as a relative value of the amount of melanin. The lower the ratio of melanin amount, the higher the melanin production inhibitory effect. The melanin production inhibitory effect was evaluated according to the following criteria, with the minimum test substance final concentration at which the melanin amount ratio (%) reached 80% or less, as the melanin production inhibitory minimum concentration (ppm) in the test substance final concentrations judged to be non-toxic.

Very good: the minimum melanin production inhibition concentration is 1ppm or less.

O: the minimum melanin production inhibition concentration is greater than 1ppm and 10ppm or less.

X: at 10ppm or less, no melanin production-inhibiting effect is exhibited (the melanin content ratio cannot be 80% or less at 10ppm or less).

Tables 1 to 5 show the results of the melanin production inhibition test of the compound of the present invention. The test substances shown in the tables are either commercially available products or synthesized according to the following synthetic examples.

The compounds in tables 1 to 5 were confirmed to have melanin production inhibitory effects, and most of the compounds exhibited effects at an extremely low concentration of 1ppm or less.

In addition, the symbols in the table refer to the following groups.

Me: methyl group, Et: ethyl, iPr: an isopropyl group,

CycHex: cyclohexyl and Ac: acetyl group

[ TABLE 1 ]

[ TABLE 2 ]

[ TABLE 3 ]

[ TABLE 4 ]

[ TABLE 5 ]

The heterocyclic compound of the present invention has a minimum concentration that significantly exhibits a melanogenesis inhibitory effect on melanoma B16 cells, compared to arbutin, which is a whitening agent currently used clinically in compositions in a concentration range of 0.1 to 30% by mass. As a representative example, the results of compounds 7 and 14 are given.

[ TABLE 6 ]

As shown in table 6 above, the compounds of the present invention exhibited melanin production-inhibiting effects on melanoma B16 cells at a concentration of about 1/170 that of arbutin, and it is understood that the effects were exhibited at a very low concentration compared to arbutin.

Hereinafter, representative synthetic examples of the heterocyclic compound relating to the whitening agent of the present invention are given. Various heterocyclic compounds can be obtained by carrying out the reaction according to these synthesis examples using the corresponding starting materials.

Synthesis example 1-11-phenyl-3, 5-dimethylpyrazole (Compound 33)

Phenylhydrazine (1.00g, 9.25mmol), acetylacetone (0.93g, 9.25mmol), ion-exchanged water (3.0mL), and acetic acid (3.0mL) were placed in a 100mL eggplant type flask, and the mixture was refluxed for 1 hour. After the reaction, 10% aqueous sodium hydroxide solution was added to adjust the pH to 10 or more, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine 1 time, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (hexane: ethyl acetate ═ 10: 1) to give 1.56g of 1-phenyl-3, 5-dimethylpyrazole (compound 33) (yield 98%).

Synthesis examples 1-2 Synthesis of (hetero) arylpyrazoles

(hetero) arylpyrazoles shown in tables 7 to 8 were synthesized in the same manner as in Synthesis example 1-1, except that phenylhydrazine was replaced with raw material A and acetylacetone was replaced with raw material B.

[ TABLE 7 ]

[ TABLE 8 ]

Synthesis example 22 Synthesis of (pyrazol-1-yl) -4, 6-dimethylpyrimidine (Compound 12)

In a 100mL eggplant type flask, 1-amidinopyrazole hydrochloride (1.00g, 6.82mmol), acetylacetone (0.72g, 7.16mmol) and methanol (6.82mL) were added, and 2N hydrochloric acid (3.0mL) was added dropwise at room temperature. After completion of the dropwise addition, the reaction solution was refluxed for 5 hours. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to adjust the pH to 10 or more, and the mixture was extracted with ethyl acetate 2 times. The organic phase was washed with saturated brine 1 time, dried over anhydrous magnesium sulfate, and then purified by silica gel column chromatography (chloroform) after removing the solvent by distillation under reduced pressure to obtain 0.08g (yield 7%) of 2- (pyrazol-1-yl) -4, 6-dimethylpyrimidine (compound 12).

¹H-NMR(CDCl₃)：2.55(6H，s)，6.47(1H，dd)，6.93(1H，s)，7.81(1H，d)，8.62(1H，d).

Synthesis example 3-11- (5-ethylpyrimidin-2-yl) -3, 5-dimethylpyrazole (Compound 21)

5-Ethyl-2-hydrazinopyrimidine (400mg, 2.89mmol) was suspended in 3mL of water, and acetylacetone (314. mu.L, 3.04mmol) and 2mol/L hydrochloric acid (330. mu.L) were added to the suspension, followed by stirring at room temperature for 23 hours. To the reaction solution was added 2mL of an aqueous sodium hydroxide solution, the pH was adjusted to 12, and the mixture was extracted 3 times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 90: 10 → 10: 90) and silica gel column chromatography (dichloromethane: methanol ═ 100: 0 → 95: 5), whereby the title compound (203 mg, yield 35%) was obtained.

¹H-NMR(CDCl₃)：1.30(3H，s)，2.34(3H，s).2.64(3H，s)，2.64-2.70(2H，m)，6.03(1H，s)，8.57(2H，s).

Synthesis example 3-21- (4-methylpyrimidin-2-yl) -3, 5-dimethylpyrazole (Compound 22)

In Synthesis example 3-1, the title compound was obtained in the same manner as in Synthesis example 3-1 except that 4-methyl-2-hydrazinopyrimidine was used in place of 5-ethyl-2-hydrazinopyrimidine (yield 37%).

¹H-NMR(CDCl₃)：2.34(3H，s)，2.59(3H，s)，2.66(3H，s)，6.03(1H，s)，7.00(1H，d)，8.57(1H，d).

Synthesis example 41 Synthesis of (4-methylpyridin-2-yl) -3, 5-dimethylpyrazole (Compound 40)

(1) Synthesis of 2-hydrazino-4-methylpyridine hydrochloride

Hydrazine hydrate (5g) was added to a 25mL eggplant type flask, and 2-chloro-4-methylpyridine (1.0g, 7.84mmol) was slowly added thereto with stirring at room temperature, followed by refluxing for 3 hours. After the reaction solution was cooled, it was extracted with chloroform 2 times, and the organic phase was washed with saturated brine 1 time. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 2-hydrazino-4-methylpyridine (crude product, クル - ド).

The obtained crude product was dissolved in methanol (2mL), and 3mL of a 4N dioxane hydrochloride solution was added thereto under cooling and stirring at 0 ℃. After stirring at 0 ℃ for 30 minutes, the precipitated solid was collected by filtration and the resulting solid was crystallized from a mixed solvent of methanol, chloroform and hexane to obtain 0.55g of 2-hydrazino-4-methylpyridine hydrochloride (yield: 44%).

(2) Synthesis of 1- (4-methylpyridin-2-yl) -3, 5-dimethylpyrazole

2-hydrazino-4-methylpyridine hydrochloride (0.5g, 3.13mmol), acetylacetone (0.376g, 3.76mmol), and water (7mL) were put in a 50mL eggplant-type flask, and stirred at room temperature for 16 hours. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to reach pH 14, and extracted 2 times with ethyl acetate. The organic phases were combined, washed with saturated brine 1 time, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to obtain 0.47g of the title compound (yield 80%).

¹H-NMR(CDCl₃)：2.30(3H，s)，2.40(3H，s)，2.61(3H，s)，5.98(1H，s)，6.97(1H，d)，7.66(1H，s)，8.27(1H，d).

Synthesis example 5-11- (pyrimidin-2-yl) -3, 5-dimethylpyrazole (Compound 4) Synthesis

NaH (0.594g, 14.84mmol) was suspended in THF (10mL), and 3, 5-dimethylpyrazole (1.091g, 11.35mmol) was added slowly. After stirring at room temperature for 1 hour, 2-chloropyrimidine (1g, 8.73mmol) was added slowly and refluxed for 3 hours. After confirming the completion of the reaction by TLC, water (5mL) was added, and the solvent was distilled off, followed by extraction with ethyl acetate 2 times. The organic phase was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off, followed by purification by silica gel column chromatography (hexane: ethyl acetate ═ 1: 2 → ethyl acetate) to obtain 1.05g of the title compound (yield 69%).

Synthesis example 5-2 Synthesis of heteroarylpyrimidines

In Synthesis example 5-1, the heteroarylpyrimidines in Table 9 were synthesized in the same manner as in Synthesis example 5-1 except that 2-chloropyrimidine was replaced with raw material A and 3, 5-dimethylpyrazole was replaced with raw material B.

[ TABLE 9 ]

Synthesis example 6 Synthesis of N- (pyrimidin-2-yl) -2, 6-dimethylmorpholine

In a 100mL eggplant type flask, 2-chloropyrimidine (1g, 8.73mmol), 2, 6-dimethylmorpholine ((cis/trans mixture) 1.106g, 9.60mmol), N, N-diisopropyl-N-ethylamine (1.241g, 9.60mmol) and ethanol (17.46mL) were added and the mixture was refluxed for 7 hours. After the reaction was completed, the solvent was distilled off, and saturated sodium bicarbonate was added thereto and extracted with ethyl acetate 2 times. The organic phase was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then purified by silica gel column chromatography (hexane: ethyl acetate ═ 20: 1 → 1: 2) to give the title compound (1.29g, 76% (cis, trans mixture)).

(mixture of cis and trans)

¹H-NMR(CDCl₃)：1.26(6H，d)，2.60(2H，dd)，3.61-3.69(2H，m)，4.52-4.56(2H，m)，6.50(1H，t)，8.32(2H，d).

¹H-NMR(CDCl₃)：1.24(6H，d)，3.52(2H，dd)，3.90(2H，dd)，4.07-4.11(2H，m)，6.48(1H，t)，8.30(2H，d).

Synthesis example 6 Synthesis of 2N- (4, 6-dimethylpyrimidin-2-yl) -3, 5-dimethylpiperidine (Compound 45)

In Synthesis example 6-1, N- (4, 6-dimethylpyrimidin-2-yl) -3, 5-dimethylpiperidine (compound 45) was obtained in the same manner as in Synthesis example 6-1 except that 2-chloropyrimidine was replaced with 2-chloro-4, 6-dimethylpyrimidine and 2, 6-dimethylmorpholine was replaced with 3, 5-dimethylpiperidine (yield 97%).

(mixture of cis and trans)

¹H-NMR(CDCl₃)：0.73-0.82(1H，m)，0.94(6H，d)，1.58-1.64(2H，m)，1.76-1.88(1H，m)，2.27(6H，s)，2.20-2.30(2H，m)，4.75-4.85(2H，m)，6.20(1H，s).

¹H-NMR(CDCl₃)：0.94(6H，d)，1.44-1.46(2H，m)，1.91-1.97(2H，m)，3.42-3.47(2H，m)，3.80-3.86(1H，m)，6.18(1H，s).

The following are formulation examples of the external preparation for skin of the present invention. In each formulation example, 1 or 2 or more compounds can be used as the compound of the present invention. The skin external preparations of the following formulation examples all exhibit whitening effects by blending the compound of the present invention.

Formulation example 1 face cream

(formulation)

Stearic acid 5.0% by mass

Stearyl alcohol 4.0

Isopropyl myristate 18.0

Glycerol monostearate 3.0

Propylene glycol 10.0

Compound 0.1 of the invention

0.2 part of potassium hydroxide

Sodium bisulfite 0.05

Proper amount of preservative

Proper amount of perfume

Ion exchange water balance

(preparation method)

Adding propylene glycol and potassium hydroxide into ion exchange water, dissolving, heating, and maintaining at 70 deg.C (water phase). Mixing the other components, heating to melt, and maintaining at 70 deg.C (oil phase). The oil phase is slowly added to the aqueous phase and, after all the addition, is allowed to react by maintaining it at its temperature for a while. Then, the mixture was uniformly emulsified with a homogenizer and cooled to 30 ℃ while sufficiently stirring.

Formulation example 2 face cream

(formulation)

Stearic acid 5.0% by mass

Sorbitan monostearate 2.5

Polyoxyethylene (20 mol)

Sorbitan monostearate 1.5

Arbutin 7.0

Sodium bisulfite 0.03

Propylene glycol 10.0

Compound 0.05 of the invention

Tricaprylin 10.0

Squalene 5.0

3.0 of octyl p-dimethylaminobenzoate

Ethylenediaminetetraacetic acid disodium salt 0.01

0.3 parts of ethyl p-hydroxybenzoate

Proper amount of perfume

Ion exchange water balance

(preparation method)

Adding propylene glycol and disodium edetate into ion exchange water, dissolving, and maintaining at 70 deg.C (water phase). Mixing other components, heating to dissolve, maintaining at 70 deg.C (oil phase), slowly adding oil phase into water phase, pre-emulsifying at 70 deg.C, homogenizing with homogenizing mixer, and cooling to 30 deg.C while stirring.

Formulation example 3 cream

(formulation)

Solid paraffin 5.0% by mass

Beeswax 10.0

Vaseline 15.0

Liquid paraffin 41.0

Glycerol monostearate 2.0

POE (20) sorbitan monolaurate 2.0

Soap powder 0.1

Borax 0.2

Compound 0.05 of the invention

Sodium bisulfite 0.03

0.3 parts of ethyl p-hydroxybenzoate

Proper amount of perfume

Ion exchange water balance

(preparation method)

Adding soap powder and borax into ion exchange water, heating to dissolve, and maintaining at 70 deg.C (water phase). Mixing the other components, heating to melt, and maintaining at 70 deg.C (oil phase). The oil phase is slowly added into the water phase while stirring, and the reaction is carried out. After the reaction, the mixture was uniformly emulsified in a homogenizer and then cooled to 30 ℃ while being sufficiently stirred.

Formulation example 4 emulsion

(formulation)

Stearic acid 2.5% by mass

Cetyl alcohol 1.5

Vaseline 5.0

Liquid paraffin 10.0

POE (10) monooleate 2.0

Polyethylene glycol 15003.0

Triethanolamine 1.0

Carboxyvinyl Polymer 0.05

Compound 0.01 of the invention

Sodium bisulfite 0.01

0.3 parts of ethyl p-hydroxybenzoate

Proper amount of perfume

Ion exchange water balance

(preparation method)

The carboxyvinyl polymer (phase A) was dissolved in a small amount of ion-exchanged water. Adding polyethylene glycol 1500 and triethanolamine into the rest ion exchange water, heating to dissolve, and maintaining at 70 deg.C (water phase). Mixing the other components, heating to melt, and maintaining at 70 deg.C (oil phase). Adding oil phase into water phase, pre-emulsifying, adding phase A, emulsifying with homogenizing mixer, and cooling to 30 deg.C while stirring.

Formulation example 5 emulsion

(formulation)

Microcrystalline wax 1.0% by mass

Beeswax 2.0

Lanolin 20.0

Liquid paraffin 10.0

Squalane 5.0

Sorbitan sesquioleate 4.0

POE (20) sorbitan monooleate 1.0

Propylene glycol 7.0

Compound 1.0 of the invention

Sodium bisulfite 0.01

0.3 parts of ethyl p-hydroxybenzoate

Proper amount of perfume

Ion exchange water balance

(preparation method)

Propylene glycol was added to the ion-exchanged water, heated, and maintained at 70 deg.C (aqueous phase). Mixing the other components, heating to melt, and maintaining at 70 deg.C (oil phase). The aqueous phase was slowly added thereto while stirring the oil phase, and emulsified uniformly with a homogenizer. After emulsification, the mixture was cooled to 30 ℃ while stirring well.

Formulation example 6 gel

(formulation)

95% ethanol 10.0% by mass

Dipropylene glycol 15.0

POE (50) oleyl ether 2.0

Carboxyvinyl Polymer 1.0

0.15 part of sodium hydroxide

L-arginine 0.1

Compound 5.0 of the invention

Sodium 2-hydroxy-4-methoxybenzophenone sulfonate 0.05

Ethylenediaminetetraacetic acid 3 sodium 2 Water 0.05

0.2 parts of methyl p-hydroxybenzoate

Proper amount of perfume

Ion exchange water balance

(preparation method)

The carboxyvinyl polymer was uniformly dissolved in ion-exchanged water, and the compound of the present invention and POE (50) oleyl ether were dissolved in 95% ethanol and added to the aqueous phase. Then, after adding other components, the mixture was neutralized with sodium hydroxide and L-arginine to increase viscosity.

Formulation example 7 cosmetic liquid

(formulation)

(A phase)

Ethanol (95%) 10.0% by mass

POE (20) octyldodecanol 1.0

Panthenol ethyl ether (Panthenyl Ethyl Ether) 0.1

Compound 2.0 of the invention

0.15 parts of methyl p-hydroxybenzoate

(phase B)

0.1 part of potassium hydroxide

(C phase)

Glycerol 5.0

Dipropylene glycol 10.0

Sodium bisulfite 0.03

Carboxyvinyl Polymer 0.2

Purified water balance

(preparation method)

Dissolving phase A and phase C uniformly, and adding phase A into phase C for dissolving and liquefying. Then, after adding phase B, filling is performed.

Formulation example 8 Soft film

(formulation)

(A phase)

Dipropylene glycol 5.0% by mass

POE (60) hardened Castor oil 5.0

(phase B)

Compound 0.05 of the invention

Olive oil 5.0

Tocopheryl acetate 0.2

0.2 parts of ethyl p-hydroxybenzoate

Fragrance 0.2

(C phase)

Sodium bisulfite 0.03

Polyvinyl alcohol 13.0

(degree of saponification: 90, degree of polymerization: 2,000)

Ethanol 7.0

Purified water balance

(preparation method)

Respectively and uniformly dissolving the phase A, the phase B and the phase C, adding the phase B into the phase A, and dissolving. Then, after adding it to the C phase, filling is performed.

Formulation example 9 solid foundation

(formulation)

Talc 43.1% by mass

Kaolin 15.0

Sericite 10.0

Zinc oxide 7.0

Titanium dioxide 3.8

Iron oxide yellow 2.9

Iron oxide black 0.2

Squalane 8.0

Isostearic acid 4.0

POE sorbitan monooleate 3.0

Isocetyl octanoate 2.0

Compound 0.5 of the invention

Proper amount of preservative

Proper amount of perfume

(preparation method)

The powdery components of talc to black iron oxide were thoroughly mixed by a mixer, and the oily component of squalane to isocetyl octanoate, the compound of the present invention, a preservative and a perfume were added thereto, and after thorough mixing, the mixture was filled in a container and molded.

Formulation example 10 emulsion type Foundation make-up (face cream type)

(formulation)

(powder portion)

Titanium dioxide 10.3% by mass

Sericite 5.4

Kaolin 3.0

Iron oxide yellow 0.8

Iron oxide Red 0.3

Iron oxide black 0.2

(oil phase)

Decamethylcyclopentasiloxane 11.5

Liquid paraffin 4.5

Polyoxyethylene modified dimethyl polysiloxane 4.0

Compound 0.5 of the invention

(aqueous phase)

Purified water 50.0

1, 3-butanediol 4.5

Sorbitan sesquioleate 3.0

Proper amount of preservative

Proper amount of perfume

(preparation method)

The aqueous phase was heated and stirred, and the well-mixed and pulverized powder fraction was added and treated with a homogenizer. Adding the oil phase, treating with homogenizing mixer, adding perfume under stirring, and cooling to room temperature.

Formulation example 11 toner

(1) 0.05% by mass of the Compound of the present invention

(2) Aspartic acid 1.0

(3) Tocopheryl acetate 0.01

(4) Glycerol 4.0

(5)1, 3-butanediol 4.0

(6) Ethanol 8.0

(7) POE (60) hardened Castor oil 0.5

(8) 0.2 parts of methyl p-hydroxybenzoate

(9) Citric acid 0.05

(10) Sodium citrate 0.1

(11) Perfume 0.05

(12) Purified water balance

(preparation method)

Dissolving (2), (4), (5), (9) and (10) in (12) to prepare a purified aqueous solution. Further, (1), (3), (7), (8) and (11) are dissolved in (6), and the resulting solution is added to the purified aqueous solution, solubilized and filtered to obtain a cosmetic lotion.

Formulation example 12 toner

A: alcohol phase

Ethanol 5.0% by mass

POE oleyl ether 2.0

2-ethylhexyl-p-dimethylaminobenzoate 0.18

Compound 0.1 of the invention

Perfume 0.05

B: aqueous phase

1, 3-butanediol 9.5

2-O-Ethyl ascorbic acid 0.5

Pyrrolidone carboxylic acid sodium 0.5

Whey extractive solution 5.0

Nicotinamide 0.3

Glycerol 5.0

Hydroxypropyl-beta-cyclodextrin 1.0

Ethylenediaminehydroxyethyl 3 acetic acid 3Na 1.0

Lysine 0.05

Tranexamic acid 1.0

Purified water balance

(preparation method)

Adding the alcohol phase of A into the water phase of B, and dissolving to obtain cosmetic water.

Formulation example 13 cream (whitening)

Hydrochloric acid trans-4- (trans-aminomethylcyclohexane carbonyl)

1.0% by mass of Aminomethylcyclohexanecarboxylic acid

4-Methoxysalicylic acid potassium salt 1.0

3-O-Ethyl ascorbic acid 1.0

Linoleic acid 0.3

Sodium lipoate 1.0

Compound 3.0 of the invention

Coenzyme Q10(CoQ10) 0.03

Vaseline 2.0

Dimethylpolysiloxane 2.0

Ethanol 5.0

Behenyl alcohol 0.5

Batyl alcohol 0.2

Glycerol 7.0

1, 3-butanediol 5.0

Polyethylene glycol 200000.5

Jojoba oil 3.0

Squalane 2.0

Hydroxystearic acid phytosterol ester 0.5

Pentaerythritol tetra-2-ethylhexanoate 1.0

Polyoxyethylene hardened castor oil 1.0

0.1 part of potassium hydroxide

Sodium metabisulfite 0.01

Sodium hexametaphosphate 0.05

Glycyrrhetinic acid hard alcohol ester 0.1

Panthenol ethyl ether (Panthenyl Ethyl Ether) 0.1

Arbutin 7.0

Tranexamic acid 2.0

Tocopheryl acetate 0.1

Sodium hyaluronate 0.05

Proper amount of p-hydroxybenzoate

Ethylenediaminetetraacetic acid trisodium 0.05

4-tert-butyl-4' -methoxydibenzoylmethane 0.1

Di-p-methoxy cinnamic acid mono-2-ethyl hexanoic acid glyceride 0.1

Proper amount of iron oxide yellow

Xanthan gum 0.1

Carboxyvinyl Polymer 0.2

Purified water balance

Formulation example 14 double-layer cream (sunscreen cream)

Tranexamic acid 2.0% by mass

4-Methoxysalicylic acid potassium salt 1.0

Compound 0.03 of the invention

Dimethylpolysiloxane 5.0

Decamethylcyclopentasiloxane 25.0

Trimethylsiloxysilicates 5.0

Polyoxyethylene-methylpolysiloxane copolymer 2.0

Dipropylene glycol 5.0

Trachyalose palmitate coated particulate zinc oxide (60nm) 15.0

Dipotassium glycyrrhizinate 0.02

Glutathione 1.0

Thiotaurine 0.05

Radix Sophorae Flavescentis extract (Licorice Extract) 1.0

Proper amount of p-hydroxybenzoate

Proper amount of phenoxyethanol

Proper amount of trisodium ethylenediamine tetraacetate

2-ethylhexyl p-methoxycinnamate 7.5

Disteardimonium hectorite 0.5

Spherical polyalkylacrylate powder 5.0

Butyl ethyl propane diol 0.5

Purified water balance

Proper amount of perfume

Formulation example 15 gel (whitening)

4-Methoxysalicylic acid potassium 0.1% by mass

Resveratrol 0.3

Dihydrolipoic acid 1.0

Wild sesame seed 0.1

Dimethylpolysiloxane 5.0

Glycerol 2.0

1, 3-butanediol 5.0

Polyethylene glycol 15003.0

Polyethylene glycol 200003.0

Cetyl octanoate 3.0

Citric acid 0.01

Sodium citrate 0.1

Sodium hexametaphosphate 0.1

Compound 1.0 of the invention

Dipotassium glycyrrhizinate 0.1

Ascorbyl glucoside 2.0

Tocopheryl acetate 0.1

Scutellariae radix extract 0.1

Herba Saxifragae extract 0.1

Ethylenediaminetetraacetic acid trisodium 0.1

Xanthan gum 0.3

Acrylic acid/alkyl methacrylate copolymer (Pemiyuren TR-2) 0.05

Agar powder 1.5

Proper amount of phenoxyethanol

Appropriate amount of dibutylhydroxytoluene

Purified water balance

Formulation example 16 Soft film (moisture)

trans-4-Aminomethylcyclohexanecarboxylic acid formamide hydrochloride 10.0% by mass

Dihydrothiooctanoic acid amide 1.0

Rose fruit 0.1

Ethanol 10.0

1, 3-butanediol 6.0

Polyethylene glycol 40002.0

Olive oil 1.0

Macadamia nut oil 1.0

Hydroxystearic acid phytosterol ester 0.05

Lactic acid 0.05

Sodium lactate 0.1

L-ascorbic acid sulfate 2 sodium 0.1

Compound 0.5 of the invention

Alpha-tocopherol 2-L-ascorbic acid potassium phosphate diester 0.1

Vitamin E acetate 0.1

Fish collagen 0.1

Chondroitin sulfate sodium 0.1

Sodium carboxymethylcellulose 0.2

Polyvinyl alcohol 12.0

Proper amount of p-hydroxybenzoate

Purified water balance

Proper amount of perfume

Formulation example 17 astringent (moisture)

Tranexamic acid 1.0% by mass

4-Methoxysalicylic acid potassium salt 1.0

Lipoic acid 10.0

Witch hazel 0.1

Silica coated Zinc oxide 0.1

Hypotaurine 0.1

0.1 part of Sophora flavescens Aiton extract (Licorice Extract)

Semen Persicae extract 0.1

Beech bud extract 0.1

Retinol 0.1

Compound 0.01 of the invention

Ethanol 5.0

Glycerol 1.0

1, 3-butanediol 5.0

Polyoxyethylene polyoxypropylene decyl tetradecyl ether 0.2

Sodium hexametaphosphate 0.03

Trimethylglycine 1.0

Polyaspartic acid sodium 0.1

Alpha-tocopherol 2-L-ascorbic acid potassium phosphate diester 0.1

Thiotaurine 0.1

Green tea extract 0.1

Peppermint (Peppermint) extract 0.1

Iris root extract 1.0

EDTA3 sodium 0.1

Carboxyvinyl Polymer 0.05

0.02 part of potassium hydroxide

Proper amount of phenoxyethanol

Purified water balance

Proper amount of perfume

Claims (17)

1. A whitening agent characterized by comprising, as an active ingredient, a heterocyclic compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof,

in the formula, X₁And X₂Is N, X₃Is CR₂；

R₁And R₃Are each independently H, C_1-6Alkyl radical, C_1-6Alkoxy, SH, or NR_bR_cWherein R is_bAnd R_cAre each independently H, C_1-6Alkyl, or hydroxy C_1-6Alkyl, or NR_bR_cForming a heterocyclic ring selected from morpholine or pyrazole, NR_bR_cThe heterocyclic ring may have 1 to 3C's at any possible position_1-6Alkyl as a substituent;

R₂is H, C_1-6Alkyl or C_1-6An alkoxy group;

b is a group represented by the following general formula (B1) or (B2);

Y₁、Y₂one of which is N and the other is CR₅；

R₅、R₆Each independently is H or C_1-6An alkyl group;

R₄is H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-7Acyloxy, OH, amino, -NH-A, -NHCO-A or-NHCOCH₂-A, wherein A is C_1-6Alkyl, phenyl or heterocycle selected from thiophene or piperazine, wherein the phenyl or heterocycle of A can also have 1-3 substituents at any possible position, and the substituent is C_1-6Alkyl, halogen, C_1-6Alkoxycarbonyl or C_1-2An alkylenedioxy group, a hydroxyl group,

the group (B2) is a saturated or unsaturated 6-membered heterocyclic group;

R_ais C_1-6An alkyl group;

p is an integer of 0 to 2, and R is an integer of 2_aMay be the same or different;

however, Y₁When not equal to N, R₁、R₃、R₄And R₆At least 1 of which is C_1-3A group other than an alkyl group.

2. The whitening agent according to claim 1, wherein B is the group (B1).

3. The whitening agent according to claim 2, wherein the active ingredient is a heterocyclic compound represented by the following general formula (1-1) or a pharmaceutically acceptable salt thereof,

in the formula, X₁、X₂、X₃、R₁、R₃、R₄、R₅And R₆The same as defined in the above general formula (1).

4. The whitening agent according to claim 3, wherein the active ingredient is a heterocyclic compound represented by the following general formula (1-1a) or a pharmaceutically acceptable salt thereof,

in the formula, R₁、R₂、R₃、R₄、R₅And R₆The same as defined in the above general formula (1).

5. The whitening agent of claim 2, wherein Y is₂＝N。

6. The whitening agent of claim 2, wherein R is R₁And R₃Each independently is H or C_1-6An alkyl group.

7. The whitening agent of claim 2, wherein R is R₁And R₃Each independently is NR_bR_c。

8. The whitening agent of claim 2, wherein R is₂Is H or C_1-6An alkyl group.

9. The whitening agent of claim 2, wherein R is R₄Is H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-7Acyloxy, OH, or amino.

10. The whitening agent according to claim 2, R₄is-NH-A, -NHCO-A or-NHCOCH₂-A。

11. The whitening agent of claim 1, wherein B is a group (B2).

12. The whitening agent according to claim 11, wherein the active ingredient is a heterocyclic compound represented by the following general formula (1-2) or a pharmaceutically acceptable salt thereof,

in the formula, R₁、R₂、R₃、R_aAnd p is the same as defined in the above general formula (1).

13. The whitening agent of claim 12, wherein p is 0.

14. The whitening agent of claim 11, wherein R is R₁、R₃Are each independently H, C_1-6Alkyl radical, C_1-6Alkoxy, or NR_bR_c，R₂Is H or C_1-6An alkoxy group.

15. The whitening agent according to any one of claims 1 to 14, wherein the active ingredient inhibits melanogenesis.

16. A skin external preparation characterized by containing a heterocyclic compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof,

in the formula, X₁And X₂Is N, X₃Is CR₂；

R₁And R₃Are each independently H, C_1-6Alkyl radical, C_1-6Alkoxy, SH, or NR_bR_cWherein R is_bAnd R_cAre each independently H, C_1-6Alkyl, or hydroxy C_1-6Alkyl, or NR_bR_cForming a heterocyclic ring selected from morpholine or pyrazole, NR_bR_cThe heterocyclic ring may have 1 to 3C's at any possible position_1-6Alkyl as a substituent;

R₂is H, C_1-6Alkyl or C_1-6An alkoxy group;

b is a group represented by the following general formula (B1) or (B2);

Y₁、Y₂one of which is N and the other is CR₅；

R₅、R₆Each independently is H or C_1-6An alkyl group;

R₄is H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-7Acyloxy, OH, amino, -NH-A, -NHCO-A or-NHCOCH₂-A, wherein A is C_1-6Alkyl, phenyl or a heterocycle selected from thiophene or piperazine, benzene of AIn the group or the heterocycle, 1 to 3 substituents may be present at any possible position of the group or the heterocycle, and the substituent is C_1-6Alkyl, halogen, C_1-6Alkoxycarbonyl or C_1-2An alkylenedioxy group, a hydroxyl group,

the group (B2) is a saturated or unsaturated 6-membered heterocyclic group;

R_ais C_1-6An alkyl group;

p is an integer of 0 to 2, and R is an integer of 2_aMay be the same or different;

however, Y₁When not equal to N, R₁、R₃、R₄And R₆At least 1 of which is C_1-3A group other than an alkyl group.

17. The external preparation for skin according to claim 16, which is a cosmetic.