JP2013032299A - External preparation for skin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an external preparation for skin suitable for cosmetics (including quasi drugs).SOLUTION: The external preparation for skin includes compounds represented by formulas (1) and (2). In the formula (1), Rand Reach independently represents a 1-6C linear or branched alkyl group or a hydrogen atom; Rrepresents a hydrogen atom or a 1-4C linear or branched alkyl group. In the formula (2), Rrepresents an aromatic group or a hydrogen atom; and Rand Reach represents an aromatic group; Rand Rare joined together to form a 2-8C heterocyclic ring with nitrogen.

Description

  The present invention relates to a skin external preparation suitable for cosmetics (including quasi-drugs), and more specifically 1) compounds represented by the following general formula (1) and / or their pharmacologically acceptable And / or a pharmacologically acceptable salt thereof represented by the following general formula (2).

（１）
[式中、Ｒ１及びＲ２は、それぞれ独立に、炭素数１〜６の直鎖又は分岐のアルキル基、水素原子を表し、Ｒ３は、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表す。]

(1)
[Wherein, R1 and R2 each independently represent a linear or branched alkyl group having 1 to 6 carbon atoms or a hydrogen atom, and R3 represents a hydrogen atom or a linear or branched alkyl having 1 to 4 carbon atoms. Represents a group. ]

（２）
[式中、Ｒ４は、無置換又は置換基を有する芳香族基、水素原子を表し、Ｒ５及びＲ６は、それぞれ独立に、無置換又は置換基を有する芳香族基を表す。Ｒ７及びＲ８は互いに結合し、窒素原子と共に環形成している炭素数２〜８の複素環を表し、一部の水素原子又は炭素原子が複素原子に置換されていてもよい基を表す。]

(2)
[Wherein, R4 represents an unsubstituted or substituted aromatic group or a hydrogen atom, and R5 and R6 each independently represents an unsubstituted or substituted aromatic group. R7 and R8 are bonded to each other and represent a heterocyclic ring having 2 to 8 carbon atoms which forms a ring with a nitrogen atom, and a part of hydrogen atoms or carbon atoms may be substituted with a heteroatom. ]

  In addition to temporary pigmentation symptoms such as sunburn, there are chronic pigmentation symptoms such as spots, dullness, liver spots, and senile pigmentation. In particular, since chronic pigmentation symptoms have a great influence on the appearance of others, when a skin survey is carried out, it is recognized as a skin problem that is always ranked higher.

  Pigmentation symptoms are regulated by complex intertwining of various information transmitters, cytokines, and the like, and are ultimately caused by enhanced production of melanin in pigment cells (melanocytes). In addition, many whitening agents have been developed and used in cosmetics and the like based on research results on the mechanism of action that causes pigmentation. As the whitening agent, whitening agents such as ascorbic acids, hydrogen peroxide, colloidal sulfur, glutathione, hydroquinone, catechol, ellagic acid, kojic acid and the like are well known (for example, Non-Patent Document 1 and Non-Patent Documents). Reference 2). Furthermore, in recent years, as a whitening agent having a new mechanism of action, a plant extract obtained from a leguminous clara (bitter) of α-MSH (MSH: Melanocyte stimulating hormone) inhibitor (see, for example, Patent Document 1) Whitening of plant extracts (for example, see Patent Document 2) obtained from honeysuckle, a melanocyte dendrite elongation inhibitor, and chayote fruit extract (for example, see Patent Document 3) of endothelin-1 production inhibitor A drug has been found. However, although these whitening agents have a certain whitening effect (pigmentation prevention or improvement effect), it is difficult to say that the whitening effect and sustainability desired by the user are sufficiently obtained. On the other hand, creation of new whitening agents is difficult due to extensive whitening material search research to date. For this reason, many attempts have been made to obtain a high whitening effect by combining a plurality of conventional whitening agents, combining a whitening agent with a component that enhances the effect of the whitening agent, and improving formulation technology. . However, even in such an attempt, it cannot be said that a sufficiently satisfactory whitening effect is obtained.

  Steric bulky aromatic groups (particularly diphenylmethyl or triphenylmethyl groups) or aromatic heterocyclic groups are known as effective protecting groups for hydroxyl groups or amino groups in organic low molecular weight compounds, peptides and nucleic acid synthesis. (For example, see Non-Patent Document 3 and Non-Patent Document 4). In addition, the physiological activity of a compound having a sterically bulky substituent has been actively studied, and the physiological activity of such a sterically bulky compound includes antitumor activity (for example, Non-Patent Document 5). Reference), antifungal action (for example, see Patent Document 4), antihistamine action (for example, see Non-Patent Document 6), dopamine uptake inhibitory action (for example, see Non-Patent Document 7), calcium antagonistic action (for example, And non-patent document 8). In addition, the present applicant has already reported that the compound represented by the general formula (2) has an excellent melanin production inhibitory action (see, for example, Patent Document 5). However, since the compound represented by the general formula (2) has a bulky substituent, it cannot be said that the solubility in a base or the like widely used for the production of a skin external preparation is necessarily high. There were limitations in the manufacture of the drug. Therefore, a technique for improving the compounding amount of the compound represented by the general formula (2) into the external preparation for skin, a technique for maintaining or improving the pigmentation prevention or improvement effect while reducing the content of the compound. It was anxious.

On the other hand, various studies have been conducted on the essential amino acid glycine and its derivatives. Examples of glycine derivatives in the cosmetic field include N-acyl and N-long-chain alkyl glycine derivatives, betaine-type amphoteric surfactant activity, or semipolar surfactant activity (see, for example, Patent Document 6 and Patent Document 7). It has a known surface activating effect and is blended as a surfactant in cosmetics, cleaning agents, hair styling agents, toothpastes and the like. In addition, N- (methyl) glycine has been reported to have a wrinkle improving action (see, for example, Patent Document 8) and a moisturizing action (see, for example, Patent Document 9), but the compound has a whitening effect. Has not been reported to the best of the inventors' knowledge. The present inventor expresses the compound represented by the general formula (1) and the compound represented by the general formula (2) in the general formula (2) by including both in the skin external preparation. It has been found that the compound represented by the general formula (1) effectively enhances the melanin production inhibitory action possessed by the compound, and exhibits excellent pigmentation prevention or improvement action.

JP 2009-0667804 A JP 2003-081747 A JP 2008-094737 A JP 09-255634 A WO2010-074052 JP 2002-322491 A JP 2001-261431 A Table 2007-013662 JP 2000-178118 A

Supervised by Katsuyuki Takeda et al., “Usefulness of cosmetics, evaluation technology and future prospects”, published by Yakuji Nippo (2001) Noriyuki Omori, FRAGRANCE JOURNAL Special Issue, No. 14, 1995, 118-126 Theodora W. Green, Protective Groups in Organic Synthesis, A Wiley-Interscience Publication .: 1981, P173-176 and P273-274 Nobuo Izumiya, Tetsuo Kato, Tohiko Aoyagi, Michinori Waki, Basics and Experiments of Peptide Synthesis .: Maruzen Co., Ltd., 1985, P38 Naohisa Ogo et. Al., Bioorganic & Medicinal Chemistry, 17 (14), 3921-3924 (2007) Sasse A., et. Al., Bioorganic & Medicinal Chemistry, 8 (5), 1139-1149 (2000) Dutta AK. Et. Al., Bioorganic & Medicinal Chemistry, 11 (17), 2337-2340 (2001) Shanklin JR Jr., et al., J. Med. Chem., 34 (10), 3011-3022 (1991)

This invention is made | formed under such a condition, and makes it a subject to provide the skin external preparation suitable for the pigmentation prevention or improvement.

In view of such a situation, as a result of intensive efforts for the skin external preparation suitable for preventing or improving pigmentation, the present inventor has 1) the compound represented by the general formula (1) and / or A skin external preparation containing a pharmacologically acceptable salt thereof, 2) a compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof is an excellent pigment. It has been found that it has an action to prevent or improve deposition, and has completed the present invention. The present invention is as follows.
<1> 1) Compounds represented by the following general formula (1) and / or pharmacologically acceptable salts thereof; 2) Compounds represented by the following general formula (2) and / or their drugs A skin external preparation characterized by containing a salt that is physically acceptable.

（１）
[式中、Ｒ１及びＲ２は、それぞれ独立に、炭素数１〜６の直鎖又は分岐のアルキル基、水素原子を表し、Ｒ３は、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表す。]

(1)
[Wherein, R1 and R2 each independently represent a linear or branched alkyl group having 1 to 6 carbon atoms or a hydrogen atom, and R3 represents a hydrogen atom or a linear or branched alkyl having 1 to 4 carbon atoms. Represents a group. ]

（２）
[式中、Ｒ４は、無置換又は置換基を有する芳香族基、水素原子を表し、Ｒ５及びＲ６は、それぞれ独立に、無置換又は置換基を有する芳香族基を表す。Ｒ７及びＲ８は互いに結合し、窒素原子と共に環形成している炭素数２〜８の複素環を表し、一部の水素原子又は炭素原子が複素原子に置換されていてもよい基を表す。]

(2)
[Wherein, R4 represents an unsubstituted or substituted aromatic group or a hydrogen atom, and R5 and R6 each independently represents an unsubstituted or substituted aromatic group. R7 and R8 are bonded to each other and represent a heterocyclic ring having 2 to 8 carbon atoms which forms a ring with a nitrogen atom, and a part of hydrogen atoms or carbon atoms may be substituted with a heteroatom. ]

<2> The compound represented by the general formula (1) is a compound represented by the following general formula (3) and / or a pharmacologically acceptable salt thereof, <1 > The external preparation for skin described in>.

（３）
[式中、Ｒ９は、炭素数１〜６の直鎖又は分岐のアルキル基を表す。]

(3)
[Wherein, R 9 represents a linear or branched alkyl group having 1 to 6 carbon atoms. ]

<3> The compound represented by the general formula (1) is N- (methyl) glycine (compound 1) and / or a pharmacologically acceptable salt thereof, <1> or The skin external preparation as described in <2>.

N−（メチル）グリシン（化合物１）

N- (methyl) glycine (compound 1)

<4> In the general formula (2), R7 and R8 are bonded to each other and represent a C2-C8 heterocycle that forms a ring with a nitrogen atom, and some of the hydrogen atoms or carbon atoms are heteroatoms. The optionally substituted group is a heteroaliphatic hydrocarbon group having 2 to 8 carbon atoms in which some hydrogen atoms or carbon atoms may be substituted with heteroatoms, < The skin external preparation according to any one of 1> to <3>.
<5> In the general formula (2), R7 and R8 are bonded to each other and represent a heterocyclic ring having 2 to 8 carbon atoms that forms a ring with a nitrogen atom, and some of the hydrogen atoms or carbon atoms are heteroatoms. The optionally substituted group is a heteroaromatic hydrocarbon group having 2 to 8 carbon atoms in which some hydrogen atoms or carbon atoms may be substituted with hetero atoms, <1 The external preparation for skin according to any one of> to <4>.
<6> The compound represented by the general formula (2) is 1-[(triphenyl) methyl] piperidine (compound 2), 1-[(triphenyl) methyl] pyrrolidine (compound 3), 1-[( Triphenyl) methyl] piperazine (compound 4), 1-[(triphenyl) methyl] morpholine (compound 5), 1-[(diphenyl) methyl] pyrrolidine (compound 6), 1-[(diphenyl) methyl] piperidine ( Compound 7), 1-[(triphenyl) methyl] imidazole (compound 8), 1-[(diphenyl) methyl] imidazole (compound 9), and / or pharmacologically acceptable salts thereof The skin external preparation according to any one of <1> to <5>, which is

１−[（トリフェニル）メチル]ピペリジン（化合物２）

1-[(Triphenyl) methyl] piperidine (Compound 2)

１−[（トリフェニル）メチル]ピロリジン（化合物３）

1-[(Triphenyl) methyl] pyrrolidine (Compound 3)

１−[（トリフェニル）メチル]ピペラジン（化合物４）

1-[(Triphenyl) methyl] piperazine (Compound 4)

１−[（トリフェニル）メチル]モルホリン（化合物５）

1-[(Triphenyl) methyl] morpholine (Compound 5)

１−[（ジフェニル）メチル]ピロリジン（化合物６）

1-[(Diphenyl) methyl] pyrrolidine (Compound 6)

１−[（ジフェニル）メチル]ピペリジン（化合物７）

1-[(Diphenyl) methyl] piperidine (Compound 7)

１−[（トリフェニル）メチル]イミダゾ−ル（化合物８）

1-[(Triphenyl) methyl] imidazole (Compound 8)

１−[（ジフェニル）メチル]イミダゾ−ル（化合物９）

1-[(Diphenyl) methyl] imidazole (Compound 9)

<7> 0.0001% by mass to 20% by mass of the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof with respect to the total amount of the external preparation for skin. The skin external preparation according to any one of <1> to <6>.
<8> 0.001% by mass to 10% by mass of the compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof with respect to the total amount of the external preparation for skin. The external preparation for skin according to any one of <1> to <7>.
<9> The external preparation for skin according to any one of <1> to <8>, which is a cosmetic (including quasi-drugs).
<10> The skin external preparation according to any one of <1> to <9>, which is for preventing or improving pigmentation.

ADVANTAGE OF THE INVENTION According to this invention, the skin external preparation suitable for the pigmentation prevention or improvement can be provided.

  The skin external preparation of the present invention comprises 1) a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, 2) a compound represented by the general formula (2), and And / or a pharmacologically acceptable salt thereof. The external preparation for skin of the present invention has an excellent effect of preventing or improving pigmentation. Such an effect is obtained by adding the compound represented by the general formula (1) and the compound represented by the general formula (2) to the skin external preparation, whereby the compound represented by the general formula (1) The compound represented by the general formula (2) effectively enhances the melanin production inhibitory action, and exhibits an excellent pigmentation prevention or improvement action. In addition, the effect of preventing or improving the pigmentation of the external preparation for skin of the present invention includes an action of preventing pigmentation in addition to the action of thinning or returning the pigmentation already formed. The pigmentation prevention or improvement action in the present invention can be applied without particular limitation as long as it is a pigmentation prevention or improvement action. Among these actions, a particularly preferred one is specifically described in Example 2 described later. The “pigmentation prevention or improvement action” in “Evaluation of pigmentation inhibitory effect of topical skin preparation in humans” can be preferably exemplified. In Example 2, “Evaluation of pigmentation inhibitory effect of topical skin preparations in humans”, as a component having a pigmentation inhibitory action, a formulation containing an evaluation substance as compared with a control group (a formulation group containing no evaluation substance) Ingredients that have an effect of preventing or improving pigmentation in the group (components having a smaller ΔL * value in the evaluation substance combination preparation group than in the control group) can be preferably exemplified, and more preferably, prevention or improvement of pigmentation is preferred. A component having a statistically significant difference in the effect can be suitably exemplified.

<Compound represented by the general formula (1) of the present invention and / or a pharmacologically acceptable salt thereof>
The skin external preparation of the present invention comprises 1) a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, 2) a compound represented by the general formula (2), and And / or a pharmacologically acceptable salt thereof. The compound represented by the general formula (1) and / or the pharmacologically acceptable salt thereof of the present invention is the compound represented by the general formula (2) and / or the pharmacologically acceptable salt thereof. When included in an external preparation for skin together with the salt to be produced, it exhibits an excellent effect of preventing or improving pigmentation. The compound represented by the general formula (1) of the present invention effectively enhances the melanin production inhibitory action of the compound represented by the general formula (2). Moreover, it is possible to reduce the compounding quantity in the skin external preparation of the compound represented by the said General formula (2) of this invention, maintaining or improving the pigmentation prevention or improvement effect by this enhancement effect. Furthermore, reducing the compounding amount of the compound represented by the general formula (2) eliminates restrictions on the production of an external preparation for skin, such as solubility of the compound represented by the general formula (2). Preparation of a simple formulation is possible. Among the compounds represented by the general formula (1) and / or pharmacologically acceptable salts thereof of the present invention, preferred are the compounds represented by the general formula (3) and / or Alternatively, pharmacologically acceptable salts thereof can be preferably exemplified, and more specific examples thereof include N- (methyl) glycine and / or pharmacologically acceptable salts thereof. I can do it. The compound represented by the general formula (1) of the present invention and / or a pharmacologically acceptable salt thereof, particularly N- (methyl) glycine and / or a pharmacologically acceptable salt thereof. In addition, it has already been incorporated into external preparations for skin such as cosmetics, and has been reported to have functions such as a surface activating action, a moisturizing action, and a wrinkle improving action. However, the compound represented by the general formula (1) and / or the pharmacologically acceptable salt thereof has an effect of preventing or improving pigmentation, and further, the compound represented by the general formula (2). As far as the inventor knows, it has not been reported that the effect of preventing or improving pigmentation is exerted by adding the compound and / or pharmacologically acceptable salt thereof to an external preparation for skin.

Here, the compound represented by the general formula (1) and / or the pharmacologically acceptable salt thereof will be described. In the formula, R 1 and R 2 are each independently of 1 to 6 carbon atoms. A linear or branched alkyl group represents a hydrogen atom, and R3 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. R1 and R2 each independently represents a linear or branched alkyl group having 1 to 6 carbon atoms, more preferably a straight or branched carbon group, or a hydrogen atom. Atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group can be preferably exemplified, hydrogen atom, methyl group An ethyl group is preferred. One of R1 and R2 is preferably a hydrogen atom, and in this case, the remaining substituents are particularly preferably a methyl group or an ethyl group. R3 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and specific examples of preferable ones include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, An n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group can be suitably exemplified, and a hydrogen atom, a methyl group, and an ethyl group are particularly preferable.
Specifically, among the compounds represented by the general formula (1), the compounds represented by the general formula (3) and / or the compounds not included in the pharmacologically acceptable salts thereof are specifically exemplified. N, N- (dimethyl) glycine, N- (ethyl) -N- (methyl) glycine, N- (methyl) -N- (n-propyl) glycine, N- (methyl) -N- (isopropyl) glycine N- (n-butyl) -N- (methyl) glycine, N- (isobutyl) -N- (methyl) glycine, N- (sec-butyl) -N- (methyl) glycine, N- (tert-butyl) ) -N- (methyl) glycine, N- (methyl) -N- (pentyl) glycine, N- (hexyl) -N- (methyl) glycine, N, N- (diethyl) glycine, N- (ethyl)- N- (n-propyl) glycine, N- (ethyl) -N- (isobutyl) glycine, N- (ethyl -N- (n-butyl) glycine, N- (ethyl) -N- (isobutyl) glycine, N- (ethyl) -N- (sec-butyl) glycine, N- (ethyl) -N- (tert-butyl ) Glycine, N- (ethyl) -N- (pentyl) glycine, N- (ethyl) -N- (hexyl) glycine, N, N- (di-n-propyl) glycine, N, N- (diisopropyl) glycine N, N- (di-n-butyl) glycine, N, N- (di-isobutyl) glycine, N, N- (di-sec-butyl) glycine, N, N- (di-tert-butyl) glycine N, N- (di-pentyl) glycine, N, N- (dihexyl) glycine, and / or a pharmacologically acceptable salt thereof can be preferably exemplified. Among the compounds represented by the general formula (1), particularly preferable compounds include N- (methyl) glycine (compound 1), N- (ethyl) glycine (compound 10), and / or them. The pharmacologically acceptable salt of can be illustrated suitably. The compound represented by the general formula (1), the compound represented by the general formula (3), and / or a pharmacologically acceptable salt thereof is a compound represented by the general formula (2). In addition, by including in a skin external preparation together with a pharmacologically acceptable salt thereof, an excellent effect of preventing or improving pigmentation is exhibited. Further, the pigmentation preventing or improving action of the external preparation for skin of the present invention is not only the enhancement effect of the pigmentation preventing or improving action by including both components in the external preparation for skin, but also the accumulation of both components on the target site. Or it is thought that it is exhibited when storage property increases. In addition, the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof has high safety. In addition, when it is contained in an external preparation for skin, it has high safety in terms of skin sensitization and irritation. In addition, the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof has solubility in a general-purpose polar or nonpolar medium used in the manufacture of a skin external preparation. Since it is high, it is possible to produce various forms of external preparation for skin, and the production is also easy.

  Here, the compound represented by the general formula (3) will be described. In the formula, R9 represents a linear or branched alkyl group having 1 to 6 carbon atoms. R9 represents a linear or branched alkyl group having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, An isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, and a hexyl group can be suitably exemplified, and a methyl group and an ethyl group are particularly preferable. Specifically, among the compounds represented by the general formula (3), N- (methyl) glycine (compound 1), N- (ethyl) glycine (compound 10), N- (n- Propyl) glycine, N- (isopropylglycine), N- (n-butyl) glycine, N- (isobutyl) glycine, N- (sec-butyl) glycine, N- (tert-butyl) glycine, N- (pentyl) Glycine, N- (hexyl) glycine, and / or a pharmacologically acceptable salt thereof can be suitably exemplified. Among such compounds, N- (methyl) glycine (compound 1), N- (ethyl) glycine (Compound 10) and / or their pharmacologically acceptable salts are particularly preferred.

  The compound represented by the general formula (1) of the present invention, the compound represented by the general formula (3), and / or a pharmacologically acceptable salt thereof are commercially available unsubstituted or tert. -Starting with a glycine derivative having a protecting group such as butoxycarbonyl (Boc group), for example, an alkylation reaction using sodium hydride and the corresponding alkyl halide in an anhydrous N, N-dimethylformamide solvent. Followed by removal of the protecting group by a deprotection reaction. Moreover, the compound represented by the said General formula (1) or the compound represented by the said General formula (3) also has a commercially available compound, and about this compound, Tokyo Chemical Industry Co., Ltd., etc. It can also be purchased and used from other reagent manufacturers. Such a compound can be contained in a skin external preparation as it is, but it can also be treated with a pharmacologically acceptable salt, converted into a salt form, and used as a salt. For example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate; maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, para Organic acid salts such as toluene sulfonate and benzene sulfonate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; triethylamine salt, triethanolamine salt, ammonium salt, And organic amine salts such as monoethanolamine salts and piperidine salts; basic amino acid salts such as lysine salts and alginates;

  The compound represented by the general formula (1), the compound represented by the general formula (3), and / or a pharmacologically acceptable salt thereof thus obtained are represented by the general formula (2). ) And / or a pharmacologically acceptable salt thereof, the skin external preparation contains an excellent effect of preventing or improving pigmentation. Moreover, the skin external preparation of this invention is 1 type from the compound represented by the said General formula (1), the compound represented by the said General formula (3), and / or those pharmacologically acceptable salts. Or 2 or more types can be selected and it can be made to contain in a skin external preparation. In order for the skin external preparation of the present invention to exhibit the above pharmacological action, the compound represented by the general formula (1), the compound represented by the general formula (3), and / or their pharmacological properties One or two or more selected from acceptable salts in a total amount of 0.0001% to 20% by weight, more preferably 0.001% to 10% by weight, based on the total amount of the external preparation for skin. Preferably, it is preferable to contain 0.01 mass%-3 mass%. This is because the content of the compound represented by the general formula (1), the general formula (3) and / or a pharmacologically acceptable salt thereof with respect to the total amount of the external preparation for skin is 0.0001% by mass. If the amount is too small, the effect of preventing or improving pigmentation tends to decrease, and even if an amount exceeding 20% by mass is added, the effect tends to reach its peak, which may reduce the degree of freedom of formulation. is there.

N−（メチル）グリシン（化合物１）

N- (methyl) glycine (compound 1)

N−（エチル）グリシン（化合物１０）

N- (Ethyl) glycine (Compound 10)

<Production Example 1: Production method of Compound 1 and Compound 10>
Compound 1 and Compound 10 can be synthesized, for example, according to the method described in “Basics and Experiments of Peptide Synthesis” (Maruzen Co., Ltd.). Boc-Gly (Peptide Institute, Inc.) was used as a starting material, dissolved in anhydrous N, N-dimethylformamide (Wako Pure Chemical Industries, Ltd.), sodium hydride and the corresponding alkyl halide (methyl iodide or iodide) After carrying out an alkylation reaction using ethyl, Wako Pure Chemical Industries, Ltd., deprotection with an acid such as hydrochloric acid, and further using ion exchange to obtain the desired compound 1 or compound 10 Can be obtained. Such a compound can also be purchased as a commercially available reagent from a reagent manufacturer such as Tokyo Chemical Industry Co., Ltd. The compound used in the examples of the present invention was a compound purchased from Tokyo Chemical Industry Co., Ltd.

<Physical constant of compound 1>
¹ H-NMR (d ₆ -DMSO): δ 2.44 (2H, s), 3.09 (3H, s).

<Physical constant of compound 10>
¹ H-NMR (D ₂ O): δ 1.30 (3H, t, J = 7.8 Hz), 3.12 (2H, q, J = 7.8 Hz), 3.61 (2H, s).

<Compound represented by the general formula (2) of the present invention and / or a pharmacologically acceptable salt thereof>
The skin external preparation of the present invention comprises 1) a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, 2) a compound represented by the general formula (2), and And / or a pharmacologically acceptable salt thereof. The external preparation for skin of the present invention is an external preparation for skin suitable for cosmetics (including quasi-drugs), and has an excellent effect of preventing or improving pigmentation. The skin external preparation of the present invention has excellent pigmentation by effectively enhancing the melanin production inhibitory action of the compound represented by the general formula (2) by the compound represented by the general formula (1). Demonstrate the prevention or improvement effect. Moreover, the skin external preparation of this invention maintains or improves the pigmentation prevention or improvement effect by containing together the compound represented by the compound represented by the said General formula (1), and the said General formula (2). Thus, the compounding amount of the compound represented by the general formula (2) can be reduced. Furthermore, reducing the compounding amount of the compound represented by the general formula (2) eliminates restrictions on the production of an external preparation for skin, such as solubility of the compound represented by the general formula (2). Preparation of a simple formulation is possible. Among the compounds represented by the general formula (2) of the present invention and / or pharmacologically acceptable salts thereof, the compounds according to claim 4 or 5 and / or the compounds thereof are preferred. The pharmacologically acceptable salt of can be illustrated suitably. Further, among the compounds represented by the general formula (2) and / or pharmacologically acceptable salts thereof, particularly preferred ones are specifically exemplified by 1-[(triphenyl) methyl] piperidine ( Compound 2), 1-[(Triphenyl) methyl] pyrrolidine (Compound 3), 1-[(Triphenyl) methyl] piperazine (Compound 4), 1-[(Triphenyl) methyl] morpholine (Compound 5), 1 -[(Diphenyl) methyl] pyrrolidine (compound 6), 1-[(diphenyl) methyl] piperidine (compound 7), 1-[(triphenyl) methyl] imidazole (compound 8), 1-[(diphenyl) Methyl] imidazole (Compound 9) and / or a pharmacologically acceptable salt thereof can be suitably exemplified.

  Here, the compound represented by the general formula (2) will be described. In the formula, R4 represents an unsubstituted or substituted aromatic group or a hydrogen atom, and R5 and R6 each independently represent: Represents an unsubstituted or substituted aromatic group, R7 and R8 are bonded to each other and represent a heterocyclic ring having 2 to 8 carbon atoms which forms a ring with a nitrogen atom, and some hydrogen atoms or carbon atoms are complex A group which may be substituted with an atom is represented. R4 represents an unsubstituted or substituted aromatic group or a hydrogen atom, and specific examples of preferred R4 include a hydrogen atom, a phenyl group, a methylphenyl group, an ethylphenyl group, a propylphenyl group, Butylphenyl, methoxyphenyl, ethoxyphenyl, propyloxyphenyl, butyloxyphenyl, hydroxyphenyl, aminophenyl, N-methylaminophenyl, N-ethylaminophenyl, N, N-dimethylamino Phenyl group, N, N-diethylaminophenyl group, chlorophenyl group, bromophenyl group, fluorophenyl group, trifluoromethylphenyl group, acetylphenyl group, carboxyphenyl group, methoxycarbonylphenyl group, pyridyl group, methylpyridyl group, ethylpyridyl group Group, propylpyri Group, butylpyridyl group, methoxypyridyl group, ethoxypyridyl group, propyloxypyridyl group, butyloxypyridyl group, hydroxypyridyl group, aminopyridyl group, N-methylaminopyridyl group, N-ethylaminopyridyl group, N, N -Dimethylaminopyridyl group, N, N-diethylaminopyridyl group, chloropyridyl group, bromopyridyl group, fluoropyridyl group, trifluoromethylpyridyl group, acetylpyridyl group, carboxypyridyl group, methoxycarbonylpyridyl group, naphthyl group, methylnaphthyl Group, ethyl naphthyl group, methoxy naphthyl group, ethoxy naphthyl group, biphenyl group, methyl biphenyl group, ethyl biphenyl group, methoxy biphenyl group, ethoxy biphenyl group and the like can be suitably exemplified, more preferably phenyl group, A phenyl group, a methoxyphenyl group, a chlorophenyl group, a fluorophenyl group, a pyridyl group, a naphthyl group, and a biphenyl group can be preferably exemplified, and more preferably, a phenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, and a 4-chlorophenyl group. A group and 4-fluorophenyl group can be preferably exemplified. When the aromatic group of R4 is a phenyl group, the number of substituents on the phenyl group can be suitably exemplified by 0 to 3, more preferably 0 or 1, and the substituent on the phenyl group is , Each can exist independently. Further, the substitution position of the substituent on the phenyl group of R4 is not particularly limited, but more preferably a para position to the carbon atom of the phenyl group to which the carbon atom to which R5 or R6 is bonded is bonded. . In addition, R5 and R6 each independently represents an unsubstituted or substituted aromatic group, and among R5 and R6, as preferred, the hydrogen atom described in the above R4 is excluded. The same unsubstituted or substituted aromatic group as the aromatic group having a substituent can be suitably exemplified, and among these, a phenyl group, a methylphenyl group, a methoxyphenyl group, a chlorophenyl group, a fluoro group are preferable. A phenyl group, a pyridyl group, a naphthyl group, and a biphenyl group can be preferably exemplified, and a phenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, a 4-chlorophenyl group, and a 4-fluorophenyl group are preferably exemplified. I can do it. When the aromatic group of R5 and R6 is a phenyl group, the number of substituents on the phenyl group can be suitably exemplified by 0 to 3, more preferably 0 or 1, and the substitution on the phenyl group Each group can exist independently. Further, the substitution position of the substituent on the phenyl group of R5 and R6 is not particularly limited, but more preferably, the para-position relative to the carbon atom of the phenyl group to which the carbon atom to which R5 or R6 is bonded is bonded. Is preferred. R7 and R8 are bonded to each other and represent a heterocyclic ring having 2 to 8 carbon atoms that forms a ring with a nitrogen atom, and a part of hydrogen atoms or carbon atoms that may be substituted with a heteroatom. Represent. Among these groups, preferred are some hydrogen atoms or heteroaliphatic groups having 2 to 8 carbon atoms, in which some of the hydrogen atoms or carbon atoms may have a substituent, or some of the hydrogen atoms. A heteroaromatic hydrocarbon group having 2 to 8 carbon atoms in which an atom or a carbon atom may be substituted with a heteroatom can be suitably exemplified. R7 and R8 are bonded to each other and represent a heterocyclic ring having 2 to 8 carbon atoms which forms a ring with a nitrogen atom, and a part of hydrogen atoms or a group in which carbon atoms may be substituted with a heteroatom. Of these, specific examples include ethylimino group, azetidino group, pyrrolidino group, hydroxypyrrolidino group, piperidino group, piperazino group, morpholino group, hexamethyleneimino group, heptamethyleneimino group, pyrrole group, Pyrazol group, imidazole group, pyridyl group, pyrimidyl group, oxazole group, thiazol group and the like can be preferably exemplified, and more preferred are pyrrolidino group, piperidino group and imidazole group. Can be illustrated. Of the compounds represented by the general formula (2), particularly preferred compounds are specifically exemplified by 1-[(triphenyl) methyl] piperidine (compound 2), 1-[(triphenyl) methyl] pyrrolidine. (Compound 3), 1-[(Triphenyl) methyl] piperazine (Compound 4), 1-[(Triphenyl) methyl] morpholine (Compound 5), 1-[(Diphenyl) methyl] pyrrolidine (Compound 6), 1 -[(Diphenyl) methyl] piperidine (compound 7), 1-[(triphenyl) methyl] imidazole (compound 8), 1-[(diphenyl) methyl] imidazole (compound 9), and / or The pharmacologically acceptable salt of can be illustrated suitably. The compound represented by the general formula (2) of the present invention and / or a pharmacologically acceptable salt thereof, and the compound according to claim 4 or 5 and / or a pharmacologically acceptable salt thereof. When the salt is contained in a skin external preparation together with the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, an excellent effect of preventing or improving pigmentation is exhibited. In addition, the compound represented by the general formula (2) of the present invention and / or a pharmacologically acceptable salt thereof has an effect of preventing or improving pigmentation due to a melanin production inhibitory action, and the general formula ( By containing the compound represented by 1) and / or a pharmacologically acceptable salt thereof in an external preparation for skin, an excellent effect of preventing or improving pigmentation is exhibited. In addition, the compound represented by the general formula (2) is used for external application to the skin while maintaining or improving the effect of preventing or improving pigmentation by being contained in a skin external preparation together with the compound represented by the general formula (1). The content in the agent can be effectively reduced. Such an action is represented by the general formula (2) in addition to the potentiating effect of the compound represented by the general formula (1) on the pharmacological effect of the compound represented by the general formula (2). An excellent effect is exhibited by increasing the accumulation property or storage property of the compound at the target site.

Moreover, it describes about the compound of Claim 4, and / or those pharmacologically acceptable salts. The compound according to claim 4, in the general formula (2), R 7 and R 8 are bonded to each other and represent a heterocyclic ring having 2 to 8 carbon atoms that forms a ring with a nitrogen atom, and a part of hydrogen atoms or The group in which the carbon atom may be substituted with a hetero atom is a part of hydrogen atoms or a heterocyclic aliphatic hydrocarbon group having 2 to 8 carbon atoms in which a carbon atom may be substituted with a hetero atom. It is a compound characterized by these. The compound according to claim 4 has the same substituents R4, R5 and R6 as the compound represented by the general formula (2). Moreover, R7 and R8 of the compound represented by the general formula (2) are bonded to each other and represent a heterocyclic ring having 2 to 8 carbon atoms which forms a ring with a nitrogen atom, and some hydrogen atoms or carbon atoms are The group which may be substituted with a hetero atom is a C2-C8 heterocyclic aliphatic hydrocarbon group in which a part of hydrogen atoms or carbon atoms may be substituted with a hetero atom. Examples of the heterocyclic aliphatic hydrocarbon group include an ethylimino group, an azetidino group, a pyrrolidino group, a hydroxypyrrolidino group, a piperidino group, a piperazino group, a morpholino group, a hexamethyleneimino group, a heptamethyleneimino group, and a succinimide group. Preferable examples are pyrrolidino group, piperidino group, piperazino group and morpholino group. Specific examples of preferred compounds among the compounds according to claim 4 are 1- (diphenylmethyl) pyrrolidine, 1-{[(methylphenyl) phenyl] methyl} pyrrolidine, 1- [bis (methylphenyl). Methyl] pyrrolidine, 1-{[(ethylphenyl) phenyl] methyl} pyrrolidine, 1- [bis (ethylphenyl) methyl] pyrrolidine, 1-{[(methoxyphenyl) phenyl] methyl} pyrrolidine, 1- [bis (methoxy) Phenyl) methyl] pyrrolidine, 1-{[(ethoxyphenyl) phenyl] methyl} pyrrolidine, 1- [bis (ethoxyphenyl) methyl] pyrrolidine, 1-{[(fluorophenyl) phenyl] methyl} pyrrolidine, 1- [bis (Fluorophenyl) methyl] pyrrolidine, 1-{[(quorophenyl) phenyl] methyl} pyrrolidine, 1- [bi (Chlorophenyl) methyl] pyrrolidine, 1- (diphenylmethyl) piperidine, 1-{[(methylphenyl) phenyl] methyl} piperidine, 1- [bis (methylphenyl) methyl] piperidine, 1-{[(ethylphenyl) phenyl ] Methyl} piperidine, 1- [bis (ethylphenyl) methyl] piperidine, 1-{[(methoxyphenyl) phenyl] methyl} piperidine, 1- [bis (methoxyphenyl) methyl] piperidine, 1-{[(ethoxyphenyl) ) Phenyl] methyl} piperidine, 1- [bis (ethoxyphenyl) methyl] piperidine, 1-{[(fluorophenyl) phenyl] methyl} piperidine, 1- [bis (fluorophenyl) methyl] piperidine, 1-{[( Quorophenyl) phenyl] methyl} piperidine, 1- [bis (chlorophenyl) methyl] Peridine, 1- (diphenylmethyl) piperazine, 1-{[(methylphenyl) phenyl] methyl} piperazine, 1- [bis (methylphenyl) methyl] piperazine, 1-{[(ethylphenyl) phenyl] methyl} piperazine, 1- [bis (ethylphenyl) methyl] piperazine, 1-{[(methoxyphenyl) phenyl] methyl} piperazine, 1- [bis (methoxyphenyl) methyl] piperazine, 1-{[(ethoxyphenyl) phenyl] methyl} Piperazine, 1- [bis (ethoxyphenyl) methyl] piperazine, 1-{[(fluorophenyl) phenyl] methyl} piperazine, 1- [bis (fluorophenyl) methyl] piperazine, 1-{[(quorophenyl) phenyl] methyl } Piperazine, 1- [bis (chlorophenyl) methyl] piperazine, 1- (diphenyl Methyl) piperidine, 1-{[(methylphenyl) phenyl] methyl} morpholine, 1- [bis (methylphenyl) methyl] morpholine, 1-{[(ethylphenyl) phenyl] methyl} morpholine, 1- [bis (ethyl) Phenyl) methyl] morpholine, 1-{[(methoxyphenyl) phenyl] methyl} morpholine, 1- [bis (methoxyphenyl) methyl] morpholine, 1-{[(ethoxyphenyl) phenyl] methyl} morpholine, 1- [bis (Ethoxyphenyl) methyl] morpholine, 1-{[(fluorophenyl) phenyl] methyl} morpholine, 1- [bis (fluorophenyl) methyl] morpholine, 1-{[(quorophenyl) phenyl] methyl} morpholine, 1- [ Bis (chlorophenyl) methyl] morpholine, N- (diphenylmethyl) succinimide, N- [(Methylphenyl) phenyl] methyl} succinimide, N- [bis (methylphenyl) methyl] succinimide, N-{[(ethylphenyl) phenyl] methyl} succinimide, N- [bis (ethylphenyl) methyl] succinimide, N -{[(Methoxyphenyl) phenyl] methyl} succinimide, N- [bis (methoxyphenyl) methyl] succinimide, N-{[(fluorophenyl) phenyl] methyl} succinimide, N- [bis (fluorophenyl) methyl] succinimide 1-diphenylmethyl-3-pyrrolidinol, 1-{[(methylphenyl) phenyl] methyl} -3-pyrrolidinol, 1-{[bis (methylphenyl)] methyl} -3-pyrrolidinol, 1-{[(ethylphenyl) phenyl] methyl} -3-pyrrolidinol, 1-{[bis (ethyl Phenyl)] methyl} -3-pyrrolidinol, 1-{[(memethoxyphenyl) phenyl] methyl} -3-pyrrolidinol, 1-{[bis (methoxyphenyl)] methyl} -3-pyrrolidinol 1-{[(ethoxyphenyl) phenyl] methyl} -3-pyrrolidinol, 1-{[bis (ethoxyphenyl)] methyl} -3-pyrrolidinol, 1-{[(fluorophenyl) phenyl] methyl } -3-pyrrolidinol, 1-{[bis (fluorophenyl)] methyl} -3-pyrrolidinol, 1- (triphenylmethyl) pyrrolidine, 1-{[diphenyl (methylphenyl) methyl]} pyrrolidine, 1-{[bis (methylphenyl) phenyl] methyl} pyrrolidine, 1-[(tris (methylphenyl) methyl] pyrrolidine, 1-{[diphenyl (ethylphenyl) methyl]} pi Lysine, 1-{[bis (ethylphenyl) phenyl] methyl} pyrrolidine, 1-[(tris (ethylphenyl) methyl] pyrrolidine, 1-{[diphenyl (methoxyphenyl) methyl]} pyrrolidine, 1-{[bis ( Methoxyphenyl) phenyl] methyl} pyrrolidine, 1-[(tris (methoxyphenyl) methyl] pyrrolidine, 1-{[diphenyl (ethoxyphenyl) methyl]} pyrrolidine, 1-{[bis (ethoxyphenyl) phenyl] methyl} pyrrolidine 1-[(tris (ethoxyphenyl) methyl] pyrrolidine, 1-{[diphenyl (fluorophenyl) methyl]} pyrrolidine, 1-{[bis (fluorophenyl) phenyl] methyl} pyrrolidine, 1-[(tris (fluoro Phenyl) methyl] pyrrolidine, 1-{[diphenyl (chlorophenyl) methyl]} pyrrolidine, 1 {[Bis (chlorophenyl) phenyl] methyl} pyrrolidine, 1-[(tris (chlorophenyl) methyl] pyrrolidine, 1- (triphenylmethyl) piperidine, 1-{[diphenyl (methylphenyl) methyl]} piperidine, 1- { [Bis (methylphenyl) phenyl] methyl} piperidine, 1-[(tris (methylphenyl) methyl] piperidine, 1-{[diphenyl (ethylphenyl) methyl]} piperidine, 1-{[bis (ethylphenyl) phenyl] Methyl} piperidine, 1-[(tris (ethylphenyl) methyl] piperidine, 1-{[diphenyl (methoxyphenyl) methyl]} piperidine, 1-{[bis (methoxyphenyl) phenyl] methyl} piperidine, 1-[( Tris (methoxyphenyl) methyl] piperidine, 1-{[diphenyl (ethoxyphenyl) methyl] } Piperidine, 1-{[bis (ethoxyphenyl) phenyl] methyl} piperidine, 1-[(tris (ethoxyphenyl) methyl] piperidine, 1-{[diphenyl (fluorophenyl) methyl]} piperidine, 1-{[bis (Fluorophenyl) phenyl] methyl} piperidine, 1-[(tris (fluorophenyl) methyl] piperidine, 1-{[diphenyl (chlorophenyl) methyl]} piperidine, 1-{[bis (chlorophenyl) phenyl] methyl} piperidine, 1-[(tris (chlorophenyl) methyl] piperidine, 1- (triphenylmethyl) piperazine, 1-{[diphenyl (methylphenyl) methyl]} piperazine, 1-{[bis (methylphenyl) phenyl] methyl} piperazine, 1-[(tris (methylphenyl) methyl] piperazine, 1-{[diphenyl (ethyl Ruphenyl) methyl]} piperazine, 1-{[bis (ethylphenyl) phenyl] methyl} piperazine, 1-[(tris (ethylphenyl) methyl] piperazine, 1-{[diphenyl (methoxyphenyl) methyl]} piperazine, 1 -{[Bis (methoxyphenyl) phenyl] methyl} piperazine, 1-[(tris (methoxyphenyl) methyl] piperazine, 1-{[diphenyl (ethoxyphenyl) methyl]} piperazine, 1-{[bis (ethoxyphenyl) Phenyl] methyl} piperazine, 1-[(tris (ethoxyphenyl) methyl] piperazine, 1-{[diphenyl (fluorophenyl) methyl]} piperazine, 1-{[bis (fluorophenyl) phenyl] methyl} piperazine, 1- [(Tris (fluorophenyl) methyl] piperazine, 1-{[diphenyl (chlorophenyl Methyl]} piperazine, 1-{[bis (chlorophenyl) phenyl] methyl} piperazine, 1-[(tris (chlorophenyl) methyl] piperazine, 1- (triphenylmethyl) morpholine, 1-{[diphenyl (methylphenyl) methyl ]} Morpholine, 1-{[bis (methylphenyl) phenyl] methyl} morpholine, 1-[(tris (methylphenyl) methyl] morpholine, 1-{[diphenyl (ethylphenyl) methyl]} morpholine, 1-{[ Bis (ethylphenyl) phenyl] methyl} morpholine, 1-[(tris (ethylphenyl) methyl] morpholine, 1-{[diphenyl (methoxyphenyl) methyl]} morpholine, 1-{[bis (methoxyphenyl) phenyl] methyl } Morpholine, 1-[(tris (methoxyphenyl) methyl] morpholine, 1-{[diphenyl (Ethoxyphenyl) methyl]} morpholine, 1-{[bis (ethoxyphenyl) phenyl] methyl} morpholine, 1-[(tris (ethoxyphenyl) methyl] morpholine, 1-{[diphenyl (fluorophenyl) methyl]} morpholine 1-{[bis (fluorophenyl) phenyl] methyl} morpholine, 1-[(tris (fluorophenyl) methyl] morpholine, 1-{[diphenyl (chlorophenyl) methyl]} morpholine, 1-{[bis (chlorophenyl) Phenyl] methyl} morpholine, 1-[(tris (chlorophenyl) methyl] morpholine, N- (triphenylmethyl) succinimide, N-{[diphenyl (methylphenyl)] methyl} succinimide, N-{[bis (methylphenyl) Phenyl] methyl} succinimide, N- [tris (methylphenyl) methyl] Succinimide, N-{[diphenyl (ethylphenyl)] methyl} succinimide, N-{[bis (ethylphenyl) phenyl] methyl} succinimide, N- [tris (ethylphenyl) methyl] succinimide, N-{[diphenyl (methoxy) Phenyl)] methyl} succinimide, N-{[bis (methoxyphenyl) phenyl] methyl} succinimide, N- [tris (methoxyphenyl) methyl] succinimide, N-{[diphenyl (ethoxyphenyl)] methyl} succinimide, N- {[Bis (ethoxyphenyl) phenyl] methyl} succinimide, N- [tris (ethoxyphenyl) methyl] succinimide, N-{[diphenyl (fluorophenyl)] methyl} succinimide, N-{[bis (fluorophenyl) phenyl ] Methyl} succinimide, N- [Tris (F Fluorophenyl) methyl] succinimide, 1- (triphenylmethyl) -3-hydroxypyrrolidinol, 1-{[diphenyl (methylphenyl)] methyl} -3-hydroxypyridinol, 1-{[bis (methyl Phenyl) phenyl] methyl} -3-pyrrolidinol, 1- [tris (methylphenyl) methyl] -3-pyrrolidinol, 1-{[diphenyl (ethylphenyl)] methyl} -3-hydroxypyridinol 1-{[bis (ethylphenyl) phenyl] methyl} -3-pyrrolidinol, 1- [tris (ethylphenyl) methyl] -3-pyrrolidinol, 1-{[diphenyl (methoxyphenyl)] methyl} -3-hydroxypyridinol, 1-{[bis (methoxyphenyl) phenyl] methyl} -3-pyrrolidinol, 1- [tris (methoxyphenyl) Methyl] -3-pyrrolidinol, 1-{[diphenyl (ethoxyphenyl)] methyl} -3-hydroxypyridinol, 1-{[bis (ethoxyphenyl) phenyl] methyl} -3-pyrrolidinol, 1- [tris (ethoxyphenyl) methyl] -3-pyrrolidinol, 1-{[diphenyl (fluorophenyl)] methyl} -3-hydroxypyridinol, 1-{[bis (fluorophenyl) phenyl] methyl } -3-Pyrrolidinol, 1- [tris (fluorophenyl) methyl] -3-pyrrolidinol, and / or pharmacologically acceptable salts thereof can be preferably exemplified, and more preferably, 1- (triphenylmethyl) piperidine (compound 2), 1- (triphenylmethyl) pyrrolidine (compound 3), 1- (triphenylmethyl) piperazine (compound) ), 1- (triphenylmethyl) morpholine (compound 5), 1- (diphenylmethyl) pyrrolidine (compound 6), 1- (diphenylmethyl) piperidine (compound 7), 1-{[diphenyl (4-pyridyl)] Methyl} piperidine, 1-{[(4-methoxyphenyl) diphenyl] methyl} piperidine, 1-{[bis (4-methoxyphenyl) phenyl] methyl} piperidine, 1- [tris (4-methoxyphenyl) methyl] piperidine 1-{[diphenyl (4-methylphenyl)] methyl] piperidine, 1-{[bis (4-methylphenyl) phenyl] methyl} piperidine, 1- [tris (4-methylphenyl) methyl] piperidine, N- (Triphenylmethyl) succinimide, 1-triphenylmethyl-3-pyrrolidinol, and / or their pharmacologically acceptable More preferable salts are 1- (triphenylmethyl) piperidine (compound 2), 1- (triphenylmethyl) pyrrolidine (compound 3), 1- (triphenylmethyl) piperazine (compound 4), (Triphenylmethyl) morpholine (compound 5), 1- (diphenylmethyl) pyrrolidine (compound 6), 1- (diphenylmethyl) piperidine (compound 7), and / or pharmacologically acceptable salts thereof are preferred Can be illustrated.

  Furthermore, if it mentions about the compound of Claim 5, and / or those pharmacologically acceptable salts, the compound of Claim 5 is the compound represented by the said General formula (2). , R7 and R8 are bonded to each other and represent a heterocyclic ring having 2 to 8 carbon atoms which forms a ring with a nitrogen atom, and a part of hydrogen atoms or a group in which carbon atoms may be substituted with a heteroatom is It is characterized by being a C2-C8 heteroaromatic hydrocarbon group in which a part of hydrogen atoms or carbon atoms may be substituted with a heteroatom. The compound according to claim 5 has the same substituents R4, R5 and R6 as the compound represented by the general formula (2). In the compound represented by the general formula (2), R7 and R8 are bonded to each other and represent a heterocyclic ring having 2 to 8 carbon atoms which forms a ring with a nitrogen atom, and a part of hydrogen atoms or carbon atoms Is a heteroaromatic hydrocarbon group having 2 to 8 carbon atoms in which some hydrogen atoms or carbon atoms may be substituted with heteroatoms. As such heteroaromatic hydrocarbon group, a pyrrole group, a pyrazole group, an imidazole group, a pyridyl group, a pyrimidyl group, an oxazole group, a thiazol group, and the like can be suitably exemplified, and more preferable. Preferred examples thereof include imidazole groups. Specific examples of preferable compounds among the compounds according to claim 5 are 1- (diphenylmethyl) imidazole, 1-{[(methylphenyl) phenyl] methyl} imidazole, 1- [bis (Methylphenyl) methyl] imidazole, 1-{[(ethylphenyl) phenyl] methyl} imidazole, 1- [bis (ethylphenyl) methyl] imidazole, 1-{[(methoxyphenyl) phenyl] Methyl} imidazole, 1- [bis (methoxyphenyl) methyl] imidazole, 1-{[(ethoxyphenyl) phenyl] methyl} imidazole, 1- [bis (ethoxyphenyl) methyl] imidazole, 1-{[(fluorophenyl) phenyl] methyl} imidazole, 1- [bis (fluorophenyl) methyl] imidazole, 1- (triphenylmethyl) imidazole 1-{[diphenyl (methylphenyl)] methyl} imidazole, 1-{[bis (methylphenyl) phenyl] methyl} imidazole, 1- [tris (methylphenyl) methyl] imidazole, 1- { [Diphenyl (ethylphenyl)] methyl} imidazole, 1-{[bis (ethylphenyl) phenyl] methyl} imidazole, 1- [tris (ethylphenyl) methyl] imidazole, 1-{[diphenyl ( Methoxyphenyl)] methyl} imidazole, 1-{[bis (methoxyphenyl) phenyl] methyl} imidazole, 1- [tris (methoxyphenyl) methyl] imidazole, 1-{[diphenyl (ethylphenyl) ] Methyl} imidazole, 1-{[bis (ethylphenyl) phenyl] methyl} imidazole, 1- [tris (ethylphenyl) methyl] imidazole 1-{[diphenyl (fluorophenyl)] methyl} imidazole, 1-{[bis (fluorophenyl) phenyl] methyl} imidazole, 1- [tris (fluorophenyl) methyl] imidazole, and And / or pharmacologically acceptable salts thereof can be suitably exemplified. Among these, 1- (triphenylmethyl) imidazole (compound 8), 1- (diphenylmethyl) imidazole are preferable. Preferred examples include -l (compound 9), 1- [bis (methylphenyl) methyl] imidazole, and / or pharmacologically acceptable salts thereof.

  The compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof, and further, the compound represented by claim 4 or 5 and / or a pharmacologically acceptable salt thereof. A salt can be synthesized from a commercially available compound as a starting material, and can be synthesized according to the production method described in WO20150074052 filed by the present applicant, and a part of the salt is purchased and used as a reagent. You can also Such a compound can be used as it is by adding it to the external preparation for skin of the present invention, but it can also be treated with a pharmacologically acceptable acid or base, converted into a salt form, and used as a salt. . For example, mineral salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, para Preferable examples include organic acid salts such as toluene sulfonate and benzene sulfonate, alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt and magnesium salt.

  The compound represented by the general formula (2) thus obtained, the compound according to claim 4 or 5 and / or a pharmacologically acceptable salt thereof is the above-described general formula (1). In combination with the compounds represented by the above and / or pharmacologically acceptable salts thereof, an external skin preparation exhibits an excellent effect of preventing or improving pigmentation. The skin external preparation of the present invention is selected from the compound represented by the general formula (2), the compound represented by claim 4 or 5, and / or a pharmacologically acceptable salt thereof. Species or two or more kinds can be contained in the external preparation for skin. In order for the external preparation for skin of the present invention to exert the pharmacological action, the compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof, 1 or 2 or more types selected from the compounds described in 5 and / or pharmacologically acceptable salts thereof in a total amount of 0.001% by mass to 10% by mass with respect to the total amount of the external preparation for skin, More preferably, it is 0.01 to 5% by mass, and still more preferably 0.05 to 3% by mass. This is because when the content of the compound represented by the general formula (2) with respect to the total amount of the external preparation for skin, the compound according to claim 4 or 5, is less than 0.001% by mass, the effect of preventing or improving pigmentation decreases. There is a tendency, and even if an amount exceeding 10% by mass is blended, the effect tends to reach its peak, so the degree of freedom of prescription may be reduced, and the content relative to the total amount of the external preparation for skin is preferable.

（化合物２）

(Compound 2)

<Production Example 2: Production Method of Compound 2>
Piperidine (1.50 g, 17.6 mmol) (Wako Pure Chemical Industries, Ltd.), Triphenylchloromethane (5.40 g, 19.4 mmol) (Wako Pure Chemical Industries, Ltd.) and potassium carbonate (2.68 g, 19. 4 mmol) (Wako Pure Chemical Industries, Ltd.) was added to acetonitrile (30 mL) (Wako Pure Chemical Industries, Ltd.) and refluxed for 5 hours. Saturated sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) aqueous solution was added to the reaction liquid, and extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized using a mixed solvent of chloroform (Wako Pure Chemical Industries, Ltd.) and n-hexane (Wako Pure Chemical Industries, Ltd.), and the title compound (yield 1.80 g, 31% yield). )
m. p. 156-158 ° C
¹ H-NMR (CDCl ₃ ): δ 0.70-3.50 (m, 10H), 7.14-7.80 (m, 15H).
IR (cm < ^-1 >): 2923, 1485, 1448, 708.

（化合物３）

(Compound 3)

<Production Example 3: Production Method of Compound 3>
Pyrrolidine (0.26 g, 3.66 mmol) (Wako Pure Chemical Industries, Ltd.), Triphenylchloromethane (1.02 g, 3.66 mmol) (Wako Pure Chemical Industries, Ltd.) and potassium carbonate (0.51 g, 2. 66 mmol) (Wako Pure Chemical Industries, Ltd.) was added to acetonitrile (30 mL) (Wako Pure Chemical Industries, Ltd.) and refluxed for 5 hours. Saturated sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) aqueous solution was added to the reaction liquid, and extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent n-hexane (Wako Pure Chemical Industries, Ltd.): Ethyl acetate (Wako Pure Chemical Industries, Ltd.) = 9: 1) to give the title compound (yield 0.45 g, yield). 80%).
m. p. 127-129 ° C
¹ H-NMR (CDCl ₃ ): δ 1.53-1.65 (m, 4H), 2.00-2.30 (4H, m), 7.11-7.28 (m, 5H), 7. 48-7.52 (m, 10H).
IR (cm ⁻¹ ): 2961, 2819, 1486, 1448, 711.

（化合物４）

(Compound 4)

<Production Example 4: Production Method of Compound 4>
Piperazine (1.00 g, 11.6 mmol) (Wako Pure Chemical Industries, Ltd.) was dissolved in dimethylformamide (25 mL) (Wako Pure Chemical Industries, Ltd.) and triphenylchloromethane (0.65 g, 2.33 mmol) ( Wako Pure Chemical Industries, Ltd.) was added in small portions and stirred overnight at room temperature. Water was poured into the reaction solution and extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer is dried over anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent, chloroform (Wako Pure Chemical Industries, Ltd.): methanol (Wako Pure Chemical Industries, Ltd.) = 9: 1). The residue was dissolved in an aqueous solution of ethyl acetate and saturated sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.), and after shaking, the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and then the solvent was distilled off under reduced pressure to obtain the title compound (yield 0.76 g, yield 99%).
¹ H-NMR (CDCl ₃ ): δ 1.20-1.92 (m, 4H), 2.68-3.20 (m, 4H), 7.12-7.29 (10H, m), 7. 32-7.60 (m, 5H)

（化合物５）

(Compound 5)

<Production Example 5: Method for producing Compound 5>
Morpholine (0.47 g, 5.39 mmol) (Wako Pure Chemical Industries, Ltd.), Triphenylchloromethane (1.50 g, 5.39 mmol) (Wako Pure Chemical Industries, Ltd.) and potassium carbonate (0.75 g, 5. 39 mmol) (Wako Pure Chemical Industries, Ltd.) was added to N, N-dimethylformamide (5 mL) (Wako Pure Chemical Industries, Ltd.) and stirred overnight at room temperature. Saturated sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) aqueous solution was added to the reaction liquid, and extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent, n-hexane (Wako Pure Chemical Industries, Ltd.): Ethyl acetate (Wako Pure Chemical Industries, Ltd.) = 9: 1) to give the title compound (yield 0.42 g, Yield 71%).
m. p. 168-172 ° C
¹ H-NMR (CDCl ₃ ): δ 1.45-1.65 (m, 4H), 3.82-3.83 (m, 4H), 7.13-7.29 (m, 10H), 7. 47-7.50 (m, 10H).
IR (cm ⁻¹ ): 2846, 1490, 1447, 709.

（化合物６）
＜製造例６ ： 化合物６の製造方法＞
化合物６は、特開昭５３−１６８７９号公報に記載された方法に従い合成した。なお、化合物１９は、和光純薬工業株式会社より試薬として購入することもできる。

(Compound 6)
<Production Example 6: Method for producing Compound 6>
Compound 6 was synthesized according to the method described in JP-A-53-16879. Compound 19 can also be purchased as a reagent from Wako Pure Chemical Industries, Ltd.

（化合物７）

(Compound 7)

<Production Example 7: Method for producing Compound 7>
Piperidine (0.60 g, 7.41 mmol) (Wako Pure Chemical Industries, Ltd.), Chlorodiphenylmethane (0.50 g, 2.47 mmol) (Wako Pure Chemical Industries, Ltd.) and potassium carbonate (0.34 g, 2.47 mmol) (Wako Pure Chemical Industries, Ltd.) was added to acetonitrile (30 mL) (Wako Pure Chemical Industries, Ltd.) and refluxed for 5 hours. Saturated sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) aqueous solution was added to the reaction liquid, and extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent n-hexane (Wako Pure Chemical Industries, Ltd.): Ethyl acetate (Wako Pure Chemical Industries, Ltd.) = 9: 1) to give the title compound (yield 0.43 g, yield). 48%).
¹ H-NMR (CDCl ₃ ): δ 0.70-3.50 (m, 8H), 7.14-7.80 (m, 15H).

１−（トリフェニルメチル）イミダゾ−ル（化合物８）

1- (Triphenylmethyl) imidazole (Compound 8)

<Skin external preparation of the present invention>
The skin external preparation of the present invention comprises 1) a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, 2) a compound represented by the general formula (2), and And / or a pharmacologically acceptable salt thereof. The external preparation for skin of the present invention has an excellent effect of preventing or improving pigmentation. Such an effect is obtained by adding the compound represented by the general formula (1) and the skin external preparation together with the compound represented by the general formula (2) to the compound represented by the general formula (2). It is considered that the melanin production inhibitory action possessed by is enhanced and exhibits excellent pigmentation prevention or improvement action. In addition, the effect of preventing or improving the pigmentation of the external preparation for skin of the present invention includes an action of preventing pigmentation in addition to the action of thinning or returning the pigmentation already formed. The pigmentation prevention or improvement action in the present invention can be applied without particular limitation as long as it is a pigmentation prevention or improvement action. Among these actions, the action of preventing or improving pigmentation in “Evaluation of pigmentation inhibitory effect of topical skin preparation in humans” in Example 2 described later can be preferably exemplified. In Example 2, “Evaluation of pigmentation inhibitory effect of topical skin preparations in humans”, as a component having a pigmentation inhibitory action, a formulation containing an evaluation substance as compared with a control group (a formulation group containing no evaluation substance) Ingredients that have an effect of preventing or improving pigmentation in the group (components having a smaller ΔL * value in the evaluation substance combination preparation group than in the control group) can be preferably exemplified, and more preferably, prevention or improvement of pigmentation is preferred. A component having a statistically significant difference in the effect can be suitably exemplified.

  Moreover, as a skin external preparation of this invention, since a pharmaceutical, a quasi-drug, cosmetics, etc. can be illustrated suitably and can be ingested on a daily basis, it is preferable to apply to cosmetics, a quasi-drug, etc. The administration route is preferably such that these components are administered continuously, or transdermally in consideration of safety. The external skin preparation of the present invention can be used without particular limitation as long as it is applied externally to the skin, for example, cosmetics, skin external medicine, skin external goods and the like can be suitably exemplified, It is particularly preferable to apply to cosmetics. This is because the external preparation for skin of the present invention has an unparalleled feeling of use and is particularly suitable for cosmetics where the feeling of use is important. Further, the dosage form of the external preparation for skin of the present invention is not particularly limited as long as it is known in the cosmetics field, and is a lotion preparation, an oil-in-water emulsion preparation, a water-in-oil emulsion preparation, a composite. Emulsified emulsion formulations and the like can be suitably exemplified, but particularly emulsifier forms such as an oil-in-water emulsifier form, a water-in-oil emulsifier form, and a composite emulsion emulsifier form are preferred. Examples of the external preparation for skin of the present invention preferably include lotions such as cosmetics, emulsions, essences, creams, pack cosmetics, facial cleansing cosmetics, and cleansing cosmetics. Further, the water-in-oil emulsifier type preparations include, for example, basic cosmetics such as essence, milky lotion, cream, etc., under-make-up, foundation, teak color, mascara, eyeliner, etc. Suitable examples include makeup cosmetics and hair cosmetics such as hair creams.

  In the external preparation for skin of the present invention, in addition to the essential components described above, optional components that are usually used in external preparations for skin can be contained. Such optional ingredients include, for example, macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, palm oil, palm oil, liquid Lanolin, hydrogenated coconut oil, hydrogenated oil, molasses, hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax, oils, waxes; liquid paraffin, squalane, pristane, ozokerite, Hydrocarbons such as paraffin, ceresin, petrolatum, microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid; cetyl alcohol, stearyl alcohol -Le, Isosteari Higher alcohols such as alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol, cetostearyl alcohol; cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, sebacic acid Di-2-ethylhexyl, cetyl lactate, diisostearyl malate, ethylene glycol di-2-ethylhexanoate, neopentyl glycol dicaprate, glycerin di-2-heptylundecanoate, glycerin tri-2-ethylhexanoate Synthetic ester oils such as trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate, pentane erythritol tetra-2-ethylhexanoate; dimethylpolysiloxane, methylphenylpoly Chain polysiloxanes such as Loxane and diphenylpolysiloxane; Cyclic polysiloxanes such as octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, and dodecamethylcyclohexanesiloxane; Amino-modified polysiloxane, polyether-modified polysiloxane, and alkyl-modified polysiloxane , Oil agents such as silicone oil such as modified polysiloxane such as fluorine-modified polysiloxane; anionic surface activity such as fatty acid soap (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, triethanolamine alkyl sulfate Agents; cationic surfactants such as stearyltrimethylammonium chloride, benzalkonium chloride, laurylamine oxide; imidazoline-based amphoteric surfactants (2-cocoyl-2-imida) Zolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), betaine surfactants (alkyl betaine, amide betaine, sulfobetaine, etc.), and amphoteric surfactants such as acylmethyltaurine; sorbitan fatty acid esters (sorbitan) Monostearate, sorbitan sesquioleate, etc.), glycerin fatty acids (such as glyceryl monostearate), propylene glycol fatty acid esters (such as propylene glycol monostearate), hardened castor oil derivatives, glycerin alkyl ether POE sorbitan fatty acid esters (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbite fatty acid esters (POE-sorbitol monolaurate, etc.), POE glycerin fatty acid ester Tells (POE-glycerol monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkylphenyl ethers (POE nonylphenyl ether, etc.), Pluronic types, POE / POP alkyl ethers (POE / POP2-decyltetradecyl ether, etc.), Tetronics, POE castor oil, Hardened castor oil derivatives (POE castor oil, POE hardened castor oil, etc.), nonionic surfactants such as sucrose fatty acid ester, alkyl glucoside; moisturizing ingredients such as sodium pyrrolidone carboxylate, lactic acid, sodium lactate; surface treatment May be mica, talc, kaolin, synthetic mica, Powders such as calcium oxide, magnesium carbonate, anhydrous silicic acid (silica), aluminum oxide, barium sulfate; surface may be treated, bengara, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, bitumen Inorganic pigments such as titanium oxide and zinc oxide; surfaces may be treated; pearling agents such as titanium mica, fish phosphorus foil, bismuth oxychloride; red 202 which may be laked , Red 228, Red 226, Yellow 4, Blue 404, Yellow 5, Red 505, Red 230, Red 223, Orange 201, Red 213, Yellow 204, Yellow 203, Blue Organic dyes such as No. 1, Green No. 201, Purple No. 201, Red No. 204; Organic powders such as polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer; Paraaminobenzoic acid UV absorbers; Anthranilic acid UV absorbers; Salicylic acid UV absorbers; Cinnamic acid UV absorbers; Benzophenone UV absorbers; Sugar UV absorbers; 2- (2'-hydroxy-5 ' UV absorbers such as -t-octylphenyl) benzotriazole and 4-methoxy-4'-t-butyldibenzoylmethane, lower alcohols such as ethanol and isopropanol; vitamin A or a derivative thereof, vitamin Vitamin Bs such as B6 hydrochloride, vitamin B6 tripalmitate, vitamin B6 dioctanoate, vitamin B2 or derivatives thereof, vitamin B12, vitamin B15 or derivatives thereof; α-tocopherol, β-tocopherol, γ- Vitamin E such as tocopherol, vitamin E acetate, vitamin D, vitamin H, Preferable examples include vitamins such as pantothenic acid, panthetin and pyrroloquinoline quinone; antibacterial agents such as phenoxyethanol; and organically modified clay minerals such as hectorite and dimethyl distearyl ammonium modified hectorite.

  Among the above optional components, a non-surfactant can be preferably exemplified as a particularly preferable one. The skin external preparation of the present invention can contain a non-surfactant used in skin external preparations such as ordinary cosmetics. Furthermore, it is also preferable to contain an alkyl-modified carboxyvinyl polymer and / or a salt thereof in order to improve the stability of the emulsified state and to effectively exhibit or prevent pigmentation. The preferable content of such components is 0.01 to 0.5 mass%, more preferably 0.05 to 0.3 mass%, based on the total amount of the external preparation for skin. Such alkyl-modified carboxyvinyl polymers include commercially available products, which can be purchased and used. Preferable commercially available products are “PEMUREN (registered trademark) TR-1” and “PEMUREN (registered trademark)” which are commercially available from Nippon Surfactant Kogyo Co., Ltd. and are alkyl-modified with an alkyl group having 10 to 30 carbon atoms. (Trademark) TR-2 "," Carbopol (registered trademark) 1382 "commercially available from BF Goodrich (USA), and the like. “Carbopol (registered trademark) Ultrez 10”, “Carbopol (registered trademark) 940”, and the like, which are commercially available from BF Goodrich (USA). Such hydrophilic polymers may be used alone or in combination of two or more. The oil-in-water emulsified skin external preparation of the present invention preferably contains 0.05 to 1% by mass of such hydrophilic polymer, more preferably 0.08 to 0.5% by mass. When less than this, an emulsification system will become unstable, and when more than this, the viscosity of a system will become high too much and applicability | paintability will worsen.

  Further, among the above optional components, nonionic surfactants are particularly preferable, and among them, lipophilic surfactants that are excellent in structure formation in an emulsified state are preferable. As the ionic surfactant, sorbitan stearate, glycerin monostearate and the like can be particularly preferably exemplified. The preferable content of such components is 0.1 to 5% by mass, and more preferably 0.2 to 3% by mass. By adding such a component, the adhesiveness with the skin becomes excellent.

  1) a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, and 2) a compound represented by the general formula (2) of the present invention and / or Some external preparations for skin containing these pharmacologically acceptable salts exhibit effects other than pigmentation prevention or improvement. Even when the external preparation for skin of the present invention is used for the purpose of expressing such an action, the effect of the present invention is utilized when the above effect is exhibited. It belongs to the technical scope. Examples of the action other than the pigmentation prevention or improvement action of the present invention include actions for preventing or improving rough skin, for anti-aging, for preventing or improving wrinkle formation, anti-inflammatory action, moisturizing action and the like.

  The external preparation for skin of the present invention can be produced by treating the above-mentioned optional components and essential components according to a conventional method.

Hereinafter, the present invention will be described in more detail with reference to examples, but it is needless to say that the present invention is not limited to such examples.

<Manufacture example 8: Manufacturing method 1 of the skin external preparation (milky lotion) of this invention>
According to the formulations shown in Table 1 and Table 2, external preparations for skin of the present invention (emulsion type, cosmetics 1 to 4) were prepared. That is, after the components (a) and (b) were heated to 80 ° C. and dissolved, the component (a) was added to the component (b) while stirring and emulsified, and the particles were homogenized with a homogenizer. An appropriate amount of 10% (mass%) potassium hydroxide aqueous solution was added thereto to adjust the pH to 6.5. Finally, water was added so that the total weight became 1000 g, and the mixture was stirred and cooled to prepare an external preparation for skin (emulsion formulation, cosmetics 1-2). By the same operation, “the compound represented by the general formula (1) of the present invention” is changed to “the compound represented by the general formula (2)” in the components of the cosmetic 1 shown in Table 1 and Table 2. Substituted Comparative Example 1, “Compound represented by the general formula (2) of the present invention” substituted by “Compound represented by the general formula (1)”, Comparative Example 2, “Previously represented by the general formula (1)” Comparative Example 3 was prepared by substituting “water” for both the “compound represented by” and “the compound represented by the general formula (2)”.

<Test Example 1: Evaluation 1 of pigmentation inhibitory effect in human of topical skin preparation of the present invention>
Using the external preparation for skin (emulsion formulation, cosmetics 1-2) prepared according to the method described in Example 1 and the external preparation for skin (emulsion formulation) of Comparative Examples 1-3, the pigmentation inhibitory effect was examined. A test site of 1.5 cm × 1.5 cm was provided on the first day (1st day) on the back of the panel that participated voluntarily, and the skin lightness (L * value) of the test site was measured using a color difference meter (CR-300 , Konica Minolta Co., Ltd.). After the skin brightness was measured on the first day of the test, the test site was irradiated with ultraviolet rays twice the minimum erythema amount (2 MED) once. 50 μL of each specimen (Cosmetic 1-2 or Cosmetics of Comparative Examples 1 to 3) was applied to each test site three times a day for 14 consecutive days immediately after the end of ultraviolet irradiation. 24 hours after application (15th day), the skin brightness (L * value) of each test site was measured with a color difference meter (CR-300, Konica Minolta Co., Ltd.), and 15 days from the L * value on the first day of the test. The ΔL * value was calculated by subtracting the L * value of the eye. A larger L * value indicates higher skin brightness. Therefore, the smaller the ΔL * value, the smaller the difference between the L * value on the first day of the test and the L * value on the 15th day, and it can be determined that pigmentation has been suppressed. The results are shown in Table 3. It can be seen that cosmetics 1 and 2 which are external preparations for skin of the present invention have a small ΔL * value as compared with Comparative Example 3, and have an excellent pigmentation inhibitory effect. Moreover, although the comparative example 1 and the comparative example 2 also had (DELTA) L * value small compared with the comparative example 3, and the pigmentation inhibitory action was recognized, the effect was weak compared with cosmetics 1-2. Thereby, it turns out that the cosmetics 1-2 which are the skin external preparation of this invention show the prevention or improvement effect with respect to the outstanding pigmentation.

<Production Example 9: Method 2 for producing skin external preparation of the present invention>
In the formulation components of the cosmetic 1 shown in Table 1 and Table 2 of Example 1, “the compound represented by the general formula (1) of the present invention” and “the general formula (2) of the present invention” An external preparation for skin (emulsion type, cosmetics 3 to 4) in which the content of “compound” was changed to the content shown in Table 4 was prepared in the same manner as cosmetic 1.

<Test Example 2: Evaluation 2 of pigmentation inhibitory effect in humans of the external preparation for skin of the present invention>
Using the external preparation for skin (Cosmetics 1, Cosmetics 3, Cosmetics 4) described in Example 1 and Example 3 and Comparative Example 3, the effect of inhibiting pigmentation by ultraviolet rays in humans according to the method described in Example 2 Evaluated. The results are shown in Table 5. Similarly to the cosmetic 1, the cosmetics 3 to 4 which are external preparations of the present invention have a smaller ΔL * value compared to the comparative example 3, and it can be seen that they have an excellent preventive or improving effect on pigmentation.

<Manufacture example 10: Manufacturing method 3 of the skin external preparation of this invention>
An attempt was made to produce cosmetic 5 in which “Pemlen TR-2” was replaced with POE (25) stearic acid in the prescription ingredients of the external preparation for skin (cosmetic 1) shown in Tables 1 and 2. Was separated immediately after production, and no emulsion was obtained.

  The present invention can be applied to cosmetics for whitening and the like (including quasi-drugs).

Claims (10)

1) a compound represented by the following general formula (1) and / or a pharmacologically acceptable salt thereof, and 2) a compound represented by the following general formula (2) and / or a pharmacologically thereof. A skin external preparation characterized by containing an acceptable salt.

(1)
[Wherein, R1 and R2 each independently represent a linear or branched alkyl group having 1 to 6 carbon atoms or a hydrogen atom, and R3 represents a hydrogen atom or a linear or branched alkyl having 1 to 4 carbon atoms. Represents a group. ]

(2)
[Wherein, R4 represents an unsubstituted or substituted aromatic group or a hydrogen atom, and R5 and R6 each independently represents an unsubstituted or substituted aromatic group. R7 and R8 are bonded to each other and represent a heterocyclic ring having 2 to 8 carbon atoms which forms a ring with a nitrogen atom, and a part of hydrogen atoms or carbon atoms may be substituted with a heteroatom. ] The compound represented by the general formula (1) is a compound represented by the following general formula (3) and / or a pharmaceutically acceptable salt thereof. Topical skin preparation.

(3)
[Wherein, R 9 represents a linear or branched alkyl group having 1 to 6 carbon atoms. ] 3. The compound represented by the general formula (1) is N- (methyl) glycine (compound 1) and / or a pharmacologically acceptable salt thereof. Topical skin preparation.

N- (methyl) glycine (compound 1) In the general formula (2), R7 and R8 are bonded to each other and represent a heterocyclic ring having 2 to 8 carbon atoms that forms a ring with a nitrogen atom, and some of the hydrogen atoms or carbon atoms are substituted with heteroatoms. The group which may be substituted is a C2-C8 heterocyclic aliphatic hydrocarbon group in which some hydrogen atoms or carbon atoms may be substituted with heteroatoms, 4. The external preparation for skin according to any one of 3 above. In the general formula (2), R7 and R8 are bonded to each other and represent a heterocyclic ring having 2 to 8 carbon atoms that forms a ring with a nitrogen atom, and some of the hydrogen atoms or carbon atoms are substituted with heteroatoms. The group that may be substituted is a heteroaromatic hydrocarbon group having 2 to 8 carbon atoms in which a part of hydrogen atoms or carbon atoms may be substituted with a heteroatom. The external preparation for skin according to any one of the above. The compound represented by the general formula (2) is 1-[(triphenyl) methyl] piperidine (compound 2), 1-[(triphenyl) methyl] pyrrolidine (compound 3), 1-[(triphenyl) Methyl] piperazine (compound 4), 1-[(triphenyl) methyl] morpholine (compound 5), 1-[(diphenyl) methyl] pyrrolidine (compound 6), 1-[(diphenyl) methyl] piperidine (compound 7) 1-[(triphenyl) methyl] imidazole (compound 8), 1-[(diphenyl) methyl] imidazole (compound 9), and / or a pharmacologically acceptable salt thereof. The external preparation for skin according to any one of claims 1 to 5, wherein:

1-[(Triphenyl) methyl] piperidine (Compound 2)

1-[(Triphenyl) methyl] pyrrolidine (Compound 3)

1-[(Triphenyl) methyl] piperazine (Compound 4)

1-[(Triphenyl) methyl] morpholine (Compound 5)

1-[(Diphenyl) methyl] pyrrolidine (Compound 6)

1-[(Diphenyl) methyl] piperidine (Compound 7)

1-[(Triphenyl) methyl] imidazole (Compound 8)

1-[(Diphenyl) methyl] imidazole (Compound 9) 0.0001% by mass to 20% by mass of the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof with respect to the total amount of the external preparation for skin, The skin external preparation of any one of Claims 1-6. 0.001% by mass to 10% by mass of the compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof with respect to the total amount of the external preparation for skin, The skin external preparation of any one of Claims 1-7. The skin external preparation according to any one of claims 1 to 8, which is a cosmetic (however, including quasi-drugs). The external preparation for skin according to any one of claims 1 to 9, wherein the preparation is for preventing or improving pigmentation.