JP6246993B2 - Topical skin preparation - Google Patents

Description

  The present invention relates to a skin external preparation suitable for cosmetics (including quasi-drugs) and the like. Specifically, 1) a compound represented by the following general formula (1) and / or their pharmacological properties And a skin external preparation characterized by containing an anti-inflammatory component.

(1)
[Wherein, A represents a di- or tri-aromatic methyl group independently selected from the group consisting of an unsubstituted or substituted aromatic group and / or an unsubstituted or substituted heteroaromatic group, B represents a hydrogen atom or a cyclic or acyclic aliphatic or aromatic hydrocarbon group in which the bonding site to A is a hetero atom, a hydrogen atom or a carbon atom optionally substituted with a hetero atom, and a hydrogen atom. Also included are rings in which the cycloaliphatic or aromatic ring is formed containing a heteroatom at the binding site of A and B. ]

  Long-term irritation to the skin due to UV exposure, etc., causes skin symptoms due to abnormal pigmentation such as spots, dullness, dark skin, wrinkles and sagging, pores spreading, dryness, rough skin Promotes aging symptoms. In particular, the deterioration of skin symptoms associated with pigmentation abnormalities such as spots and dullness can easily be recognized by others, and thus greatly affects the visual impression. For this reason, for those who are interested in maintaining the beauty of the skin, the deterioration of these skin symptoms can be a major concern.

  It has been clarified that normal pigmentation due to sunburn or the like is caused by a temporary and reversible melanin production enhancing action in pigment cells (melanocytes). On the other hand, skin symptoms such as blotches and dullness are said to be caused by excessive melanin production or chronically elevated conditions. Whitening agents are components that have been developed for the purpose of preventing or improving such pigmentation. So far, components having a whitening effect such as ascorbic acid, hydrogen peroxide, colloidal sulfur, glutathione, hydroquinone, catechols, etc. have been found, and cosmetics containing such components have been widely used (for example, Non-Patent Document 1 and Non-Patent Document 2). Furthermore, elucidation of the mechanism of pigmentation such as sunburn, blotting and dullness has been advanced, and a whitening agent having a new mechanism of action has been created based on such knowledge. Examples of such whitening agents include melanin production inhibitors (see, for example, Patent Document 1), tyrosinase enzyme inhibitors (see, for example, Patent Document 2), tyrosinase enzyme gene expression inhibitors, α-MSH. Inhibitors (for example, see Patent Document 3), antioxidants (for example, see Patent Document 4), and the like have been reported. However, all existing whitening agents have been shown to have a certain effect on sunburn due to UV exposure, but the effect is not always satisfactory. Further, some of these whitening agents have problems in stability and safety in the preparation.

  In addition to searching for a new whitening material (for example, see Patent Document 5), a conventional whitening component is used in combination (for example, see Patent Document 6), a combination of a whitening component and another biologically active component, Furthermore, attempts have been made to improve the whitening effect by improving the skin permeability or retention (see, for example, Patent Document 7) by improving the preparation. However, even in such an attempt, although a certain whitening effect is recognized for normal pigmentation, the whitening effect is not always satisfactory. In particular, abnormal pigmentation resulting from decreased cellular function of keratinocytes due to excessive and chronic melanin production, specifically symptoms such as incurable pigmentation or dullness, abnormal pigmentation with rough skin such as delamination It is difficult to say that the preventive or ameliorating effect on the disease is sufficient. The above-mentioned abnormal pigmentation that gives a dull appearance to the skin is a major concern for people with such skin symptoms, and it is hoped that a means for preventing or improving such pigmentation symptoms will be developed. It was rare. In addition, a wide range of whitening ingredients have been researched and researched, and natural resources or synthetic compounds have been researched and researched. In the situation where the creation of new active ingredients is more difficult than ever, conventional whitening agents are used. The importance of the technology for improving the whitening effect of the material has increased, and the development of the technology is further desired.

  Currently, ingredients having an anti-inflammatory action are blended in cosmetics, quasi-drugs, etc., and are used for applications such as whitening and rough skin. In particular, the glycyrrhetinic acid derivative is a major component of licorice (licorice), which is a perennial plant of the leguminous family native to Eurasia such as southern Siberia, western China, South Korea, Japan and Eastern Europe. It is used for the treatment of allergic rhinitis, rhinitis, and gastric ulcer as a flame analgesic. The biological activity possessed by the glycyrrhetinic acid derivative includes an anti-inflammatory action, an antiviral action (see, for example, Patent Document 8), a melanin production inhibitory action (see, for example, Patent Document 9), and a rough skin improving action (for example, a patent). Reference 10) is known, and is applied to cosmetics and the like. However, the whitening effect by a cosmetic containing an anti-inflammatory component such as a glycyrrhetinic acid derivative is not sufficiently satisfactory and has problems in stability and safety. For this reason, technical developments that ensure high effects and safety, such as combinations with whitening ingredients for efficient use of the biological activity of components having anti-inflammatory effects such as glycyrrhetinic acid derivatives, improvement of formulation technology, etc. Although progress is being made, the results are not always satisfactory.

  On the other hand, sterically bulky aromatic groups or heteroaromatic groups (particularly diphenylmethyl groups or triphenylmethyl groups) are widely used as effective protecting groups for hydroxyl groups or amino groups in organic low molecular weight compounds, peptides and nucleic acid synthesis. It is known (see, for example, Non-Patent Document 3 and Non-Patent Document 4). Reactions using these protecting groups and intermediate compounds (see, for example, Non-Patent Document 5 and Non-Patent Document 6) have been applied to organic synthesis in a wide range of scales from laboratory to industrial production. Moreover, regarding the compound having such a sterically bulky substituent in its chemical structure, antitumor activity (see, for example, Non-patent Document 5), antifungal action (see, for example, Patent Document 11) Exhibit biological activities such as antihistaminic action (for example, see Non-Patent Document 6), dopamine uptake inhibitory action (for example, see Non-Patent Document 7), calcium antagonism (for example, see Non-Patent Document 8), etc. Has been reported. However, by including both the compound represented by the general formula (1) and the anti-inflammatory component in the external preparation for skin, excellent whitening effect, especially, prevention or improvement effect on pigmentation, and further enhancement of melanin production As far as the inventor is aware, it is known that it has a preventive or ameliorating effect on pigmentation accompanied by symptoms such as excessive transport, accumulation and delayed discharge of melanin to keratinocytes due to incurable skin, dullness, and rough skin. It wasn't.

JP 2008-208073 A JP 2009-196895 A JP 2001-220347 A JP 2010-037299 A JP 2009-263258 A JP 2004-352630 A JP 2007-332115 A Japanese Patent Laid-Open No. 06-345748 JP 2004-300048 A JP-A-06-305932 JP 09-255634 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, Toshihiko Aoyagi, Michinori Waki, Basics and Experiments of Peptide Synthesis: Maruzen Co., Ltd., 1985, P38 Naohisa Ogo et. Al., Bioorganic & Medicinal Chemistry, 17 (4), 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)

  The present invention has been made under such circumstances, and is a skin external preparation suitable for cosmetics (however, including quasi-drugs), in particular, for whitening, especially for pigmentation by exposure to ultraviolet rays. It is an object to provide a skin external preparation suitable for prevention or improvement.

In view of such a situation, the present inventors have proposed a skin whitening action suitable for cosmetics (however, including quasi-drugs) and the like, and has an effect of preventing or improving pigmentation caused by ultraviolet exposure. As a result of earnest efforts to find an agent, 1) a topical skin preparation containing the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, and 2) an anti-inflammatory component The inventors have found that such characteristics are provided, and have completed the present invention. That is, the present invention is as follows.
<1> 1) A skin external preparation characterized by containing a compound represented by the following general formula (1) and / or a pharmacologically acceptable salt thereof, and 2) an anti-inflammatory component.

(1)
[Wherein, A represents a di- or tri-aromatic methyl group independently selected from the group consisting of an unsubstituted or substituted aromatic group and / or an unsubstituted or substituted heteroaromatic group, B represents a hydrogen atom or a cyclic or acyclic aliphatic or aromatic hydrocarbon group in which the bonding site to A is a hetero atom, a hydrogen atom or a carbon atom optionally substituted with a hetero atom, and a hydrogen atom. Also included are rings in which the cycloaliphatic or aromatic ring is formed containing a heteroatom at the binding site of A and B. ]

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

(2)
[Wherein, A represents a di- or triaromatic methyl group independently selected from the group consisting of unsubstituted or substituted aromatic groups, and B is a hetero atom at the bonding site with A. A hydrogen atom or a carbon atom represents a cyclic or acyclic aliphatic or aromatic hydrocarbon group, a hydrogen atom, which may be substituted with a hetero atom. Also included are rings in which the cycloaliphatic or aromatic ring is formed containing a heteroatom at the binding site of A and B. ]

<3> The compound represented by the general formula (2) is a compound represented by the following general formula (3) and / or a pharmacologically acceptable salt thereof, <1 > Or <2>.

(3)
[Wherein, A represents a di- or triaromatic methyl group independently selected from the group consisting of unsubstituted or substituted aryl groups, X represents a nitrogen atom or NH group, and R1 represents , A hydrogen atom or a C3-C8 cyclic aliphatic hydrocarbon group which may be substituted with a hetero atom, or a hydrogen atom. In addition, the ring of the cycloaliphatic hydrocarbon group includes a ring in which R1 includes X. ]

<4> The compound represented by the general formula (2) is a compound represented by the following general formula (4) and / or a pharmacologically acceptable salt thereof, <1 > Or <2>.

(4)
[Wherein, A represents a di- or tri-aromatic methyl group independently selected from the group consisting of unsubstituted or substituted aromatic groups, X represents an oxygen atom, and R2 represents a hydrogen atom or It represents a C1-C8 aliphatic hydrocarbon or hydrogen atom in which a carbon atom may be substituted with a hetero atom. ]

<5> The compound represented by the general formula (2) is a compound represented by the following general formula (5) and / or a pharmacologically acceptable salt thereof, <1 > Or <2>.

(5)
[Wherein, A represents a di- or triaromatic methyl group independently selected from the group consisting of unsubstituted or substituted aromatic groups, X represents a nitrogen atom, and R3 and R4 each represent Independently, a hydrogen atom or a C1-C8 aliphatic hydrocarbon or hydrogen atom in which a carbon atom may be substituted with a hetero atom is represented. ]

<6> The compound represented by the general formula (2) is a compound represented by the following general formula (6) and / or a pharmacologically acceptable salt thereof, <1 > Or <2>.

(6)
[In the formula, A represents a di- or triaromatic methyl group independently selected from the group consisting of unsubstituted or substituted aromatic groups, X represents a nitrogen atom or NH group, and R5 represents A hydrogen atom or a carbon atom, a C5-C8 aromatic group which may be substituted with a hetero atom, or a hydrogen atom is represented. In addition, the ring of the aromatic group also includes a ring in which R5 includes X. ]

<7> The compounds represented by the general formulas (1) to (6) are 1-[(diphenyl) methyl] imidazole (compound 1), 1-[(triphenyl) methyl] imidazole (compound 2), 2-{[(diphenyl) methyl] oxy} ethanol (compound 3), 2-{[(triphenyl) methyl] oxy} ethanol (compound 4), 2-{[(diphenyl) methyl Amino} ethanol (compound 5), 2-{[(triphenyl) methyl] amino} ethanol (compound 6), 2-{[(diphenyl) methyl] oxy} ethylamine (compound 7), 2- {[(Triphenyl) methyl] oxy} ethylamine (compound 8), 1-[(diphenyl) methyl] pyrrolidine (compound 9), 1-[(triphenyl) methyl] pyrrolidine (compound 10), 1-[(diphenyl ) Methyl] piperidine (compound 1), 1-[(triphenyl) methyl] piperidine (compound 12) and / or one or more selected from pharmacologically acceptable salts thereof, <1> The external preparation for skin according to any one of to <6>.

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

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

2-{[(Diphenyl) methyl] oxy} ethanol (compound 3)

2-{[(Triphenyl) methyl] oxy} ethanol (compound 4)

2-{[(Diphenyl) methyl] amino} ethanol (Compound 5)

2-{[(Triphenyl) methyl] amino} ethanol (Compound 6)

2-{[(Diphenyl) methyl] oxy} ethylamine (Compound 7)

2-{[(Triphenyl) methyl] oxy} ethylamine (Compound 8)

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

1-[(Triphenyl) methyl] pyrrolidine (Compound 10)

1-[(Diphenyl) methyl] piperidine (Compound 11)

1-[(Triphenyl) methyl] piperidine (Compound 12)

<8> The compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof is 0.001% by mass to 10% by mass 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 above-mentioned anti-inflammatory component is a plant extract obtained from a plant belonging to the asteraceae chamomile, a plant extract obtained from a plant belonging to the genus Asteraceae, a plant extract obtained from a plant belonging to the leguminous clara genus, birch A plant extract obtained from a plant belonging to the genus Birch, a plant extract obtained from a plant belonging to the walnut family, a glycyrrhetinic acid derivative and a salt thereof, and a grabridine derivative and a salt thereof, The external preparation for skin according to any one of <1> to <8>.
<10> The plant belonging to the asteraceae chamomile, the plant belonging to the genus Asteraceae, the plant belonging to the leguminous clara genus, the plant belonging to the birch family birch genus, the plant belonging to the walnut family, or the plant belonging to the leguminous genus genus <1> to <1> characterized by being a chamomile family chamomile (camomiles), asteraceae burdock burdock, leguminous clara kujin, birch family birch birch, walnut family koki, legume licorice The skin external preparation according to any one of 9>.
<11> The skin external preparation according to <1> to <10>, wherein the glycyrrhetinic acid derivative is glycyrrhetinic acid and a salt thereof, alkyl glycyrrhetinate and a salt thereof, and glycyrrhizic acid and a salt thereof. .
<12> The skin external preparation according to any one of <1> to <11>, wherein the anti-inflammatory component is contained in an amount of 0.00001 mass% to 15 mass% with respect to the total amount of the external preparation for skin.
<13> The external preparation for skin according to any one of <1> to <12>, which is a cosmetic (including quasi-drugs).
<14> The external preparation for skin according to any one of <1> to <13>, which is for whitening.
<15> The skin external preparation according to any one of <1> to <14>, wherein the whitening effect is for prevention or improvement of pigmentation due to ultraviolet exposure.
<16> For preventing or improving pigmentation abnormality caused by cell inactivation caused by delayed transport of melanin to keratinocytes, accumulation and / or delayed discharge, the effect of preventing or improving pigmentation by exposure to ultraviolet rays. The skin external preparation according to any one of <1> to <15>, which is characterized in that it exists.

  According to the present invention, a skin external preparation suitable for cosmetics (including quasi-drugs) and the like, more specifically, a skin external preparation suitable for whitening, particularly, prevention or improvement of pigmentation due to exposure to ultraviolet rays. Can be provided. In addition to the above-mentioned pigmentation prevention or improvement action, such an external preparation for skin has a phenomenon such as excessive transport in melanocytes, excessive transport of melanin to keratinocytes, accumulation and discharge delay, etc. induced by melanocytes. It has a preventive or ameliorating action against abnormal pigmentation accompanied by rough skin symptoms such as incurable spots, dullness, and delamination resulting from a decrease in cellular function of keratinocytes.

  The external preparation for skin of the present invention is characterized by comprising 1) a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, and 2) an anti-inflammatory component. The external preparation for skin of the present invention is caused by a whitening effect, particularly, a preventive or ameliorating effect on pigmentation due to ultraviolet exposure, and an excess and / or chronic increase in melanin production in melanocytes due to stimulation such as excessive ultraviolet exposure. It is excellent in preventing or improving hyperpigmentation of pigmentation accompanied by rough skin symptoms such as irritable blemishes, dullness, and delamination resulting from a decrease in cellular functions of keratinocytes due to excessive melanin transport to keratinocytes, accumulation and delayed discharge. Pigmentation due to normal sunburn or the like is caused by transient and reversible enhancement of melanin production in melanocytes. On the other hand, if the stimulus such as UV exposure is excessive or chronic, the melanin production of melanocytes becomes excessive and / or chronically enhanced, and excessive transport, accumulation and accumulation of melanin to keratinocytes. Phenomenon such as discharge delay is caused. These phenomena accumulate as damage such as inactivation of keratinocyte cell function and delayed turnover, and finally, pigments with rough skin symptoms such as incurable healing, dullness, and delamination. It will be recognized as exacerbation of skin symptoms such as abnormal deposition. In those who have exacerbated skin symptoms due to pigmentation, which is associated with decreased cell function of keratinocytes, when horny layer preparations are made, the appearance rate of nucleated cells is higher than the average, and skin such as delamination of the skin Symptoms are observed. The topical skin preparation of the present invention is intended for a person who exhibits skin symptoms accompanied by hyperpigmentation caused by excessive and / or chronic increased melanin production, in addition to the prevention or improvement of pigmentation such as normal sunburn. It is preferable to use for. In order to target such a person, it is preferable to set the target to be administered using as an index the symptoms of observation of skin symptoms such as the appearance rate of nucleated cells by preparation of a stratum corneum specimen and skin delamination.

  The following are attached to 1) the compounds represented by the general formula (1) and / or their pharmacologically acceptable salts, and 2) anti-inflammatory components, which are essential components of the external preparation for skin of the present invention. I will explain.

<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, and 2) an anti-inflammatory component. . The compound represented by the general formula (1) of the present invention and / or a pharmacologically acceptable salt thereof, together with the anti-inflammatory component described below, is contained in an external preparation for skin, and thus has an excellent whitening effect, in particular. It exhibits a preventive or ameliorating effect on pigmentation due to exposure to ultraviolet rays, and further a preventive or ameliorating effect on pigmentation accompanied by rough skin such as incurable spots or dullness and delamination. The skin external preparation of the present invention contains the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof together with an anti-inflammatory component, thereby achieving the above whitening action. In addition, melanin overproduction in melanocytes and / or melanin overtransport to keratinocytes due to chronic enhancement of melanin production, pigmentation abnormality caused by accumulation and discharge delay, specifically, stratification Excellent preventive or ameliorating effect on pigmentation abnormality accompanied by rough skin such as peeling. Moreover, the compound represented by the said General formula (1) and / or those pharmacologically acceptable salts can select 1 type (s) or 2 or more types, and can make it contain in the skin external preparation of this invention. .

  Of the compounds represented by the general formula (1) and / or their pharmacologically acceptable salts, preferred are the compounds represented by the general formula (2) and / or their Pharmacologically acceptable salts can be preferably exemplified, and more preferable examples include compounds represented by the general formulas (3) to (6) and / or pharmacologically acceptable salts thereof. Can be illustrated. Furthermore, regarding the compounds represented by the general formulas (1) to (6), specific examples of preferred compounds include 1-[(diphenyl) methyl] imidazole (compound 1), 1-[(tri Phenyl) methyl] imidazole (compound 2), 2-{[(diphenyl) methyl] oxy} ethanol (compound 3), 2-{[(triphenyl) methyl] oxy} ethanol (compound 4) 2-{[(diphenyl) methyl] amino} ethanol (compound 5), 2-{[(triphenyl) methyl] amino} ethanol (compound 6), 2-{[(diphenyl) methyl] oxy } Ethylamine (compound 7), 2-{[(triphenyl) methyl] oxy} ethylamine (compound 8), 1-[(diphenyl) methyl] pyrrolidine (compound 9), 1-[(triphenyl) methyl] pyrrolidine ( Compound 10), 1- [(Diphenyl) methyl] piperidine (Compound 11), 1-[(Triphenyl) methyl] piperidine (Compound 12) and / or pharmacologically acceptable salts thereof can be preferably exemplified.

  The compounds represented by the general formulas (1) to (6) of the present invention and / or pharmacologically acceptable salts thereof are excellent by containing them in a skin external preparation together with an anti-inflammatory component described later. Whitening, especially, prevention or improvement of pigmentation abnormalities, and pigmentation involving melanin overproduction in melanocytes and / or phenomena such as melanin over-transport to keratinocytes due to chronic increased melanin production, accumulation and discharge delay Demonstrate the prevention or improvement of abnormalities. Such an action is a pharmacological additive or synergistic enhancing action of the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof and an anti-inflammatory component described below, Furthermore, the pigmentation prevention or improvement action is achieved by the action of enhancing the accumulation or storage at the target site by containing both the compounds represented by the general formulas (1) to (6) and / or the anti-inflammatory component. Will improve. The compounds represented by the general formulas (1) to (6) have high safety in skin sensitization and irritation.

Here, the compound represented by the general formula (1) will be described. In the formula, A is an aromatic group having an unsubstituted or substituted group and / or a heteroaromatic group having an unsubstituted or substituted group. Represents a di- or triaromatic methyl group each independently selected from the group consisting of B and B represents a cyclic or non-cyclic group in which a bonding site to A is a hetero atom, a hydrogen atom or a carbon atom optionally substituted with a hetero atom A cyclic aliphatic or aromatic hydrocarbon group and a hydrogen atom are represented. Also included are rings in which the cycloaliphatic or aromatic ring is formed containing a heteroatom at the binding site of A and B. A is a di- or tri-aromatic methyl group which may contain a heteroatom independently selected from the group consisting of an unsubstituted or substituted aromatic group and / or an unsubstituted or substituted heteroaromatic group. Specific examples of the aromatic group having an unsubstituted or substituted group and / or the heteroaromatic group having an unsubstituted or substituted group in A are as follows: phenyl group, naphthyl group, biphenyl group, pyridyl group, furyl group, a thienyl group, a thiazolyl group, main butylphenyl group, ethylphenyl group, propylphenyl group, methoxyphenyl group, ethoxyphenyl group, propyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N- methylamino phenyl group, N- Ethylaminophenyl group, N-propylaminophenyl group, N, N-dimethylaminophenyl group, N, N-diethyl Minophenyl group, N, N-dipropylaminophenyl group, fluorophenyl group, difluorophenyl group, trifluoromethylphenyl group, chlorophenyl group, bromophenyl group, methylpyridyl group, ethylpyridyl group, propylpyridyl group, methoxypyridyl group, Ethoxypyridyl group, propyloxypyridyl group, hydroxypyridyl group, aminopyridyl group, N-methylaminopyridyl group, N-ethylaminopyridyl group, N-propylaminopyridyl group, N, N-dimethylaminopyridyl group, N, N -Diethylaminopyridyl group, N, N-dipropylaminopyridyl group, fluoropyridyl group, difluoropyridyl group, trifluoromethylpyridyl group, chloropyridyl group, bromopyridyl group, methylnaphthyl group, ethylnaphthyl group, propylnaphthyl group, meth Xylnaphthyl group, ethoxynaphthyl group, propyloxynaphthyl group, hydroxynaphthyl group, aminonaphthyl group, N-methylaminonaphthyl group, N-ethylaminonaphthyl group, N-propylaminonaphthyl group, N, N-dimethylaminonaphthyl group, N, N-diethylamino-naphthyl group, N, N-dipropylamino naphthyl group, fluoro naphthyl group, difluoromethyl naphthyl group, a trifluoromethyl naphthyl group, chloronaphthyl group, bromonaphthyl group, imidazolinium group, methyl imidazolinium Le group , ethyl imidazolinium group, propyl imidazolium group, methoxy imidazolidone group, ethoxy imidazolinium group, propyloxy imidazolinium group, hydroxy imidazolinium group, amino imidazolinium Le group, N- methylamino imidazolinium Le group, N- ethylamino imidazolinium Le group, N- Pro Le amino imidazolinium group, N, N-dimethylamino imidazolinium group, N, N-diethylamino imidazolinium group, N, N-dipropylamino imidazolinium group, fluoro imidazolinium group, difluoromethyl imidazolinium Le group, trifluoromethyl imidazolinium group, chloro imidazolinium group, bromo imidazolinium Le group and the like can be preferably exemplified, more preferably a phenyl group, methylphenyl group (tolyl group), a methoxyphenyl group, a naphthyl group, A biphenyl group can be suitably exemplified. B represents a hydrogen atom or a cyclic or acyclic aliphatic or aromatic hydrocarbon group in which the bonding site to A is a hetero atom, a hydrogen atom or a carbon atom optionally substituted with a hetero atom, and a hydrogen atom. Also included are rings in which the cycloaliphatic or aromatic ring is formed containing a heteroatom at the binding site of A and B. Specific examples of B include a mono- or dialkylamino group having a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms in which a hydroxyl group, an amino group, a hydrogen atom or a carbon atom may be substituted with a hetero atom (provided that The hetero atom of the bonding part of A and B includes a cyclic amino group present in the cyclic structure of the cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms), the hydrogen atom or the carbon atom is substituted with a hetero atom An alkyloxy group having a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms, a hydrogen atom or a carbon atom which may be substituted with a hetero atom, more preferably 1 to 4 carbon atoms. A mono- or di-substituted amino group having a straight-chain or branched alkyl group, a hydrogen atom or a carbon atom in which a carbon atom may be substituted by a hetero atom, more preferably an alkyl chain having 1 to 4 carbon atoms Have An alkyloxy group, a mono- or di-substituted amino group having an aromatic hydrocarbon group having 3 to 8 carbon atoms in which a hydrogen atom or a carbon atom may be substituted by a heteroatom (provided that the heteroatom at the binding part of A and B) Includes a cyclic amino group present in the cyclic structure of an aromatic hydrocarbon group having 3 to 8 carbon atoms). Of the compounds represented by the general formula (1),
More preferable examples include compounds represented by the general formula (2) and / or pharmacologically acceptable salts thereof, and more preferable examples include the general formulas (3) to (3). Preferred examples include the compounds represented by 6) and / or their pharmacologically acceptable salts. Specific examples of the compounds represented by the general formula (1) that are not included in the compounds represented by the general formulas (2) to (6) include 1- [phenyl (pyridyl) methyl. ] imidazole, 1- [di (pyridyl) methyl] imidazole, 1 - {[diphenyl (pyridyl)] methyl} imidazole, 1 - {[(dipyridyl) phenyl] methyl} imidazole, 1- (tri-pyridylmethyl) imidazole, 2 - {[phenyl (pyridyl) methyl] oxy} ethanol, 2- [di (pyridylmethyl) oxy] ethanol, 2 - {[diphenyl (pyridyl) methyl] oxy } ethanol, 2 - {[dipyridyl (phenyl) methyl] oxy} ethanol, 2- [tri (pyridylmethyl) oxy] ethanol, 2 - {[phenyl (pyridyl) methyl] amino} ethanol , 2- [di (pyridylmethyl) Mino] ethanol, 2 - {[diphenyl (pyridyl) methyl] amino} ethanol, 2 - {[di (pyridyl) phenylmethyl] amino} ethanol, 2 - {[tri (pyridyl) methyl] amino } ethanol, 2 - {[phenyl (pyridyl) methyl] oxy} ethylamine, 2 - {[di (pyridyl) methyl] oxy} ethylamine, 2 - {[diphenyl (pyridyl) methyl] oxy} ethylamine, 2- { [Di (pyridyl) phenylmethyl] oxy} ethylamine, 2-{[tri (pyridyl) methyl] oxy} ethylamine, 1- [phenyl (pyridyl) methyl] pyrrolidine, 1- [di (pyridyl) methyl] pyrrolidine, 1- {[Diphenyl (pyridyl)] methyl} pyrrolidine, 1-{[(dipyridyl) phenyl] methyl} pyrrolidine, 1- [tri (pyridyl) methyl] pyrrolidine, 1-{[pheny (Pyridyl)] methyl} piperidine, 1- [di (pyridyl) methyl] piperidine, 1- [diphenyl (pyridyl) methyl] piperidine, 1-{[(dipyridyl) phenyl] methyl} piperidine, 1- [tri (pyridyl) Methyl] piperidine and / or pharmacologically acceptable salts thereof can be suitably exemplified. Further, among the compounds represented by the general formula (1), if specifically exemplified preferred, 1 - [(diphenyl) methyl] imidazole (Compound 1), 1 - [(triphenylmethyl) methyl ] imidazole (compound 2), 2 - {[(diphenyl) methyl] oxy} ethanol (compound 3), 2 - {[(triphenylmethyl) methyl] oxy} ethanol (compound 4), 2- {[(diphenyl) methyl] amino} ethanol (compound 5), 2 - {[(triphenylmethyl) methyl] amino} ethanol (compound 6), 2 - {[(diphenyl) methyl] oxy} ethylamine ( Compound 7), 2-{[(triphenyl) methyl] oxy} ethylamine (compound 8), 1-[(diphenyl) methyl] pyrrolidine (compound 9), 1-[(triphenyl) methyl] pyrrolidine (compound 10) , 1-[(Diphenyl Methyl] piperidine (Compound 11), 1 - [(triphenylmethyl) methyl] piperidine (Compound 12) and / or their pharmacologically acceptable salts are suitably be exemplified.

Here, the compound represented by the general formula (2) will be described. In the formula, A is a di- or triaromatic methyl group independently selected from the group consisting of an unsubstituted or substituted aromatic group. B represents a hydrogen atom or a cyclic or non-cyclic aliphatic or aromatic hydrocarbon group in which the bonding site to A is a heteroatom, a hydrogen atom or a carbon atom optionally substituted by a heteroatom, a hydrogen atom Represent. Also included are rings in which the cycloaliphatic or aromatic ring is formed containing a heteroatom at the binding site of A and B. Specific examples of the aromatic group of the di- or triaromatic methyl group independently selected from the group consisting of an unsubstituted or substituted aromatic group in A include a phenyl group, a naphthyl group, Biphenyl group, methylphenyl group, ethylphenyl group, propylphenyl group, methoxyphenyl group, ethoxyphenyl group, propyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylaminophenyl group, N-ethylaminophenyl group, N-propylaminophenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, N, N-dipropylaminophenyl group, fluorophenyl group, difluorophenyl group, trifluoromethylphenyl group, chlorophenyl group , Bromophenyl group, methyl naphthyl group, ethyl na Phthyl group, propylnaphthyl group, methoxynaphthyl group, ethoxynaphthyl group, propyloxynaphthyl group, hydroxynaphthyl group, aminonaphthyl group, N-methylaminonaphthyl group, N-ethylaminonaphthyl group, N-propylaminonaphthyl group, N , N-dimethylaminonaphthyl group, N, N-diethylaminonaphthyl group, N, N-dipropylaminonaphthyl group, fluoronaphthyl group, difluoronaphthyl group, trifluoromethylnaphthyl group, chloronaphthyl group, bromonaphthyl group, etc. are preferable More preferably, a phenyl group, a methylphenyl group (toluyl group), a methoxyphenyl group, a naphthyl group, and a biphenyl group can be suitably exemplified.
B represents a hydrogen atom or a cyclic or acyclic aliphatic or aromatic hydrocarbon group in which the bonding site to A is a hetero atom, a hydrogen atom or a carbon atom optionally substituted with a hetero atom, and a hydrogen atom. Also included are rings in which the cycloaliphatic or aromatic ring is formed containing a heteroatom at the binding site of A and B. Specific examples of B include a mono- or dialkylamino group having a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms in which a hydroxyl group, an amino group, a hydrogen atom or a carbon atom may be substituted with a hetero atom (provided that The hetero atom of the bonding part of A and B includes a cyclic amino group present in the cyclic structure of the cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms), the hydrogen atom or the carbon atom is substituted with a hetero atom An alkyloxy group having a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms, a hydrogen atom or a carbon atom which may be substituted with a hetero atom, more preferably 1 to 4 carbon atoms. A mono- or di-substituted amino group having a straight-chain or branched alkyl group, a hydrogen atom or a carbon atom in which a carbon atom may be substituted by a hetero atom, more preferably an alkyl chain having 1 to 4 carbon atoms Have An alkyloxy group, a mono- or di-substituted amino group having an aromatic hydrocarbon group having 3 to 8 carbon atoms in which a hydrogen atom or a carbon atom may be substituted by a heteroatom (provided that the heteroatom at the binding part of A and B) Includes a cyclic amino group present in the cyclic structure of an aromatic hydrocarbon group having 3 to 8 carbon atoms). Of the compounds represented by the general formula (2), more preferred are the compounds represented by the general formulas (3) to (6) and / or pharmacologically acceptable salts thereof. Specific examples of more preferable compounds are 1-[(diphenyl) methyl] imidazole (compound 1), 1-[(triphenyl) methyl] imidazole (compound 2), 2- {[(Diphenyl) methyl] oxy} ethanol (compound 3), 2-{[(triphenyl) methyl] oxy} ethanol (compound 4), 2-{[(diphenyl) methyl] amino} ethanol- (Compound 5), 2-{[(triphenyl) methyl] amino} ethanol (compound 6), 2-{[(diphenyl) methyl] oxy} ethylamine (compound 7), 2-{[(triphenyl) ) Methyl] oxy} ethylamine (compound ), 1-[(diphenyl) methyl] pyrrolidine (compound 9), 1-[(triphenyl) methyl] pyrrolidine (compound 10), 1-[(diphenyl) methyl] piperidine (compound 11), 1-[(tri Phenyl) methyl] piperidine (compound 12) and / or pharmacologically acceptable salts thereof can be suitably exemplified. The compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof together with an anti-inflammatory component described later in an external preparation for skin has excellent whitening action, particularly, pigmentation. Prophylactic or ameliorating action against abnormalities, and further preventing or ameliorating pigmentation abnormalities involving phenomena such as melanin overproduction in melanocytes and / or chronic melanin production due to excessive transport of melanin to keratinocytes, accumulation and discharge delay Demonstrate. Such an action is a pharmacological additive or synergistic enhancing action of the compound represented by the general formula (2) and / or a pharmacologically acceptable salt thereof and an anti-inflammatory component described below, Furthermore, the preventive or ameliorating action against pigmentation is enhanced by the action of enhancing the accumulation or storage at the target site by containing both the compound represented by the general formula (2) and / or the anti-inflammatory component. The Moreover, the compound represented by the general formula (2) has high safety in skin sensitization and irritation.

Here, the compound represented by the general formula (3) will be described. In the formula, A is a di- or tri-aromatic methyl group independently selected from the group consisting of an unsubstituted or substituted aromatic group. Represents a group, X represents a nitrogen atom or an NH group, and R1 represents a C3-8 cyclic aliphatic hydrocarbon group in which a hydrogen atom, a hydrogen atom, or a carbon atom may be substituted with a hetero atom. . In addition, the ring of the cycloaliphatic hydrocarbon group includes a ring in which R1 includes X. The aromatic group of the di- or triaromatic methyl group independently selected from the group consisting of an unsubstituted or substituted aromatic group in A is described in A in the compound represented by the general formula (2). The substituent is the same as the above-mentioned substituent, and preferred examples thereof include a phenyl group, a methylphenyl group (toluyl group), a methoxyphenyl group, a naphthyl group, and a biphenyl group. X represents a nitrogen atom or an NH group.
R1 is a hydrogen atom, a hydrogen atom or a C3-C8 cyclic aliphatic hydrocarbon group in which a carbon atom may be substituted with a hetero atom (provided that the ring of the cyclic aliphatic hydrocarbon group is R1 Including a ring formed including X). Specific examples of preferred R1 include N-cyclopropyl group, N-cyclobutyl group, N-cyclopentyl group, N-cyclohexyl group, N-cycloheptyl group, N-cyclooctyl group and the like. It can be illustrated. Examples of the substituent having a ring structure in which the ring of the cyclic aliphatic hydrocarbon group is formed by rebonding the other end of R1 to X (including the X moiety) include a pyrrolidino group, a methylpyrrolidino group , Ethylpyrrolidino group, propylpyrrolidino group, methoxypyrrolidino group, ethoxypyrrolidino group, propyloxypyrrolidino group, hydroxypyrrolidino group, aminopyrrolidino group, N-methylpyrrolidino group, N-ethylpyrrolidino group N-propylpyrrolidino group, N, N-dimethylpyrrolidino group, N, N-diethylpyrrolidino group, N, N-dipropylpyrrolidino group, fluoropyrrolidino group, difluoropyrrolidino group, trifluoromethylpyrrole Dino group, chloropyrrolidino group, piperidino group, methylpiperidino group, ethylpiperidino group, propylpiperidino group, methoxypiperidino group Group, ethoxypiperidino group, propyloxypiperidino group, hydroxypiperidino group, aminopiperidino group, N-methylpiperidino group, N-ethylpiperidino group, N-propylpiperidino group, N, N-dimethylpiperidino group Group, N, N-diethylpiperidino group, N, N-dipropylpiperidino group, fluoropiperidino group, difluoropiperidino group, trifluoromethylpiperidino group, chloropiperidino group, piperazino group, methylpiperazino group Group, ethyl piperazino group, propyl piperazino group, methoxy piperazino group, ethoxy piperazino group, propyloxy piperazino group, hydroxy piperazino group, amino piperazino group, N-methyl piperazino group, N-ethyl piperazino group, N -Propylpiperazino group, N, N-dimethylpiperazino group, N, N-diethylpiperazino group N, N-dipropylpiperazino group, fluoropiperazino group, difluoropiperazino group, trifluoromethylpiperazino group, chloropiperazino group, morpholino group, methylmorpholino group, ethylmorpholino group, propylmorpholino group, methoxy Morpholino group, ethoxymorpholino group, propyloxymorpholino group, hydroxymorpholino group, aminomorpholino group, N-methylmorpholino group, N-ethylmorpholino group, N-propylmorpholino group, N, N-dimethylmorpholino group, N, N- Suitable examples include diethylmorpholino group, N, N-dipropylmorpholino group, fluoromorpholino group, difluoromorpholino group, trifluoromethylmorpholino group, chloromorpholino group, succinimide group and the like, more preferably pyrrolidino group, hydroxypyrrolidino group Group, pipette Lizino group, piperazino group and morpholino group can be preferably exemplified, and pyrrolidino group, piperidino group, piperazino group and morpholino group can be suitably exemplified. Specific examples of preferable compounds among the compounds represented by the general formula (3) include N- (diphenylmethyl) succinimide, N-[(methylphenyl) phenylmethyl] succinimide, and N- [bis (methyl Phenyl) methyl] succinimide, N-[(ethylphenyl) phenylmethyl] succinimide, N- [bis (ethylphenyl) methyl] succinimide, N-[(methoxyphenyl) phenylmethyl] succinimide, N- [bis (methoxyphenyl) Methyl] succinimide, N-[(ethoxyphenyl) phenylmethyl] succinimide, N- [bis (ethoxyphenyl) methyl] succinimide, N-[(fluorophenyl) phenylmethyl] succinimide, N- [bis (fluorophenyl) methyl] Succinimide, N- (triphenylmethyl) succinimide, N- [ Diphenyl (methylphenyl) methyl] succinimide, N- [bis (methylphenyl) phenylmethyl] succinimide, N- [tris (methylphenyl) methyl] succinimide, N- [diphenyl (ethylphenyl) methyl] succinimide, N- [bis (Ethylphenyl) phenylmethyl] succinimide, N- [tris (ethylphenyl) methyl] succinimide, N- [diphenyl (methoxyphenyl) methyl] succinimide, N- [bis (methoxyphenyl) phenylmethyl] succinimide, N- [tris (Methoxyphenyl) methyl] succinimide, N- [diphenyl (ethoxyphenyl) methyl] succinimide, N- [bis (ethoxyphenyl) phenylmethyl] succinimide, N- [tris (ethoxyphenyl) methyl] succinimide, N- [diphenyl ( F Olophenyl) methyl] succinimide, N- [bis (fluorophenyl) phenylmethyl] succinimide, N- [tris (fluorophenyl) methyl] succinimide, 1- (diphenylmethyl) pyrrolidine (compound 9), 1-[(methylphenyl) Phenylmethyl] pyrrolidine, 1- [bis (methylphenyl) methyl] pyrrolidine, 1-[(ethylphenyl) phenylmethyl] pyrrolidine, 1- [bis (ethylphenyl) methyl] pyrrolidine, 1-[(methoxyphenyl) phenylmethyl ] Pyrrolidine, 1- [bis (methoxyphenyl) methyl] pyrrolidine, 1-[(ethylphenyl) phenylmethyl] pyrrolidine, 1- [bis (ethylphenyl) methyl] pyrrolidine, 1-[(hydroxyphenyl) phenylmethyl] pyrrolidine , 1- [bis (hydroxyphenyl) methyl Ru] pyrrolidine, 1-[(aminophenyl) phenylmethyl] pyrrolidine, 1- [bis (aminophenyl) methyl] pyrrolidine, 1-[(fluorophenyl) phenylmethyl] pyrrolidine, 1- [bis (fluorophenyl) methyl] Pyrrolidine, 1-[(chlorophenyl) phenylmethyl] pyrrolidine, 1- [bis (chlorophenyl) methyl] pyrrolidine, 1- (triphenylmethyl) pyrrolidine (compound 10), 1- [diphenyl (methylphenyl) methyl] pyrrolidine, 1 -[Bis (methylphenyl) phenylmethyl] pyrrolidine, 1- [tris (methylphenyl) methyl] pyrrolidine, 1- [diphenyl (ethylphenyl) methyl] pyrrolidine, 1- [bis (ethylphenyl) phenylmethyl] pyrrolidine, 1 -[Tris (ethylphenyl) methyl] pyrrolidine, 1- [di Phenyl (methoxyphenyl) methyl] pyrrolidine, 1- [bis (methoxyphenyl) phenylmethyl] pyrrolidine, 1- [tris (methoxyphenyl) methyl] pyrrolidine, 1- [diphenyl (ethoxyphenyl) methyl] pyrrolidine, 1- [bis (Ethoxyphenyl) phenylmethyl] pyrrolidine, 1- [tris (ethoxyphenyl) methyl] pyrrolidine, 1- [diphenyl (hydroxyphenyl) methyl] pyrrolidine, 1- [bis (hydroxyphenyl) phenylmethyl] pyrrolidine, 1- [tris (Hydroxyphenyl) methyl] pyrrolidine, 1-[(aminophenyl) diphenylmethyl] pyrrolidine, 1- [bis (aminophenyl) phenylmethyl] pyrrolidine, 1- [tris (aminophenyl) methyl] pyrrolidine, 1- [diphenyl ( Fluorophenyl) methyl] Loridine, 1- [bis (fluorophenyl) phenylmethyl] pyrrolidine, 1- [tris (fluorophenyl) methyl] pyrrolidine, 1- (diphenylmethyl) piperidine (compound 11), 1-[(methylphenyl) phenylmethyl] pi Peridine, 1- [bis (methylphenyl) methyl] piperidine, 1-[(ethylphenyl) phenylmethyl] piperidine, 1- [bis (ethylphenyl) methyl] piperidine, 1-[(methoxy Phenyl) phenylmethyl] piperidine, 1- [bis (methoxyphenyl) methyl] piperidine, 1-[(ethylphenyl) phenylmethyl] piperidine, 1- [bis (ethylphenyl) methyl] piperidine 1-[(hydroxyphenyl) phenylmethyl] piperidine, 1- [bis (hydroxyphenyl) methyl] piperidine, 1-[(aminophenyl) Nyl) phenylmethyl] piperidine, 1- [bis (aminophenyl) methyl] piperidine, 1-[(fluorophenyl) phenylmethyl] piperidine, 1- [bis (fluorophenyl) methyl] piperidine, 1-[(chlorophenyl) phenyl Methyl] piperidine, 1- [bis (chlorophenyl) methyl] piperidine, 1- (triphenylmethyl) piperidine (compound 12), 1- [diphenyl (methylphenyl) methyl] piperidine, 1- [bis (methylphenyl) phenylmethyl ] Piperidine, 1- [tris (methylphenyl) methyl] piperidine, 1- [diphenyl (ethylphenyl) methyl] piperidine, 1- [bis (ethylphenyl) phenylmethyl] piperidine, 1- [tris (ethylphenyl) methyl] Piperidine, 1- [diphenyl (methoxyphenyl) methyl L] piperidine, 1- [bis (methoxyphenyl) phenylmethyl] piperidine, 1- [tris (methoxyphenyl) methyl] piperidine, 1- [diphenyl (ethoxyphenyl) methyl] piperidine, 1- [bis (ethoxyphenyl) phenyl Methyl] piperidine, 1- [tris (ethoxyphenyl) methyl] piperidine, 1- [diphenyl (hydroxyphenyl) methyl] piperidine, 1- [bis (hydroxyphenyl) phenylmethyl] piperidine, 1- [tris (hydroxyphenyl) methyl ] Piperidine, 1-[(aminophenyl) diphenylmethyl] piperidine, 1- [bis (aminophenyl) phenylmethyl] piperidine, 1- [tris (aminophenyl) methyl] piperidine, 1- [diphenyl (fluorophenyl) methyl] Piperidine, 1- [bis (fluoro Enyl) phenylmethyl] piperidine, 1- [tris (fluorophenyl) methyl] piperidine, 1- (diphenylmethyl) morpholine, 1-[(methylphenyl) phenylmethyl] morpholine, 1- [bis (methylphenyl) methyl] morpholine 1-[(ethylphenyl) phenylmethyl] morpholine, 1- [bis (ethylphenyl) methyl] morpholine, 1-[(methoxyphenyl) phenylmethyl] morpholine, 1- [bis (methoxyphenyl) methyl] morpholine, -[(Ethylphenyl) phenylmethyl] morpholine, 1- [bis (ethylphenyl) methyl] morpholine, 1-[(hydroxyphenyl) phenylmethyl] morpholine, 1- [bis (hydroxyphenyl) methyl] morpholine, 1- [ (Aminophenyl) phenylmethyl] morpholine, 1- [bis ( Minophenyl) methyl] morpholine, 1-[(fluorophenyl) phenylmethyl] morpholine, 1- [bis (fluorophenyl) methyl] morpholine, 1-[(chlorophenyl) phenylmethyl] morpholine, 1- [bis (chlorophenyl) methyl] Morpholine, 1- (triphenylmethyl) morpholine, 1- [diphenyl (methylphenyl) methyl] morpholine, 1- [bis (methylphenyl) phenylmethyl] morpholine, 1- [tris (methylphenyl) methyl] morpholine, [Diphenyl (ethylphenyl) methyl] morpholine, 1- [bis (ethylphenyl) phenylmethyl] morpholine, 1- [tris (ethylphenyl) methyl] morpholine, 1- [diphenyl (methoxyphenyl) methyl] morpholine, 1- [ Bis (methoxyphenyl) phenylmethyl] Ruphorin, 1- [tris (methoxyphenyl) methyl] morpholine, 1- [diphenyl (ethoxyphenyl) methyl] morpholine, 1- [bis (ethoxyphenyl) phenylmethyl] morpholine, 1- [tris (ethoxyphenyl) methyl] morpholine 1- [diphenyl (hydroxyphenyl) methyl] morpholine, 1- [bis (hydroxyphenyl) phenylmethyl] morpholine, 1- [tris (hydroxyphenyl) methyl] morpholine, 1-[(aminophenyl) diphenylmethyl] morpholine, 1- [bis (aminophenyl) phenylmethyl] morpholine, 1- [tris (aminophenyl) methyl] morpholine, 1- [diphenyl (fluorophenyl) methyl] morpholine, 1- [bis (fluorophenyl) phenylmethyl] morpholine, 1- [Tris (fluoroph Nyl) methyl] morpholine and / or a pharmacologically acceptable salt thereof can be suitably exemplified, and more preferable examples include 1-[(diphenyl) methyl] pyrrolidine (Compound 9), 1-[(triphenyl) ) Methyl] pyrrolidine (Compound 10), 1-[(Diphenyl) methyl] piperidine (Compound 11), 1
Preferred examples include-[(triphenyl) methyl] piperidine (Compound 12) and / or their pharmacologically acceptable salts. The compound represented by the general formula (3) and / or a pharmacologically acceptable salt thereof is incorporated into an external preparation for skin together with an anti-inflammatory component to be described later, whereby excellent whitening action, particularly, pigmentation. Prophylactic or ameliorating action against abnormalities, and further preventing or ameliorating pigmentation abnormalities involving phenomena such as melanin overproduction in melanocytes and / or chronic melanin production due to excessive transport of melanin to keratinocytes, accumulation and discharge delay Demonstrate. Such an action is a pharmacological additive or synergistic enhancing action of the compound represented by the general formula (3) and / or a pharmacologically acceptable salt thereof and an anti-inflammatory component described below, Furthermore, the preventive or ameliorating action against pigmentation is enhanced by the action of enhancing the accumulation or storage at the target site by containing both the compound represented by the general formula (3) and / or the anti-inflammatory component. The Moreover, the compound represented by the general formula (3) has high safety in skin sensitization and irritation.

  Here, the compound represented by the general formula (4) will be described. In the formula, A is a di- or triaromatic methyl group independently selected from the group consisting of an unsubstituted or substituted aromatic group. Represents a group, X represents an oxygen atom, and R2 represents a C1-C8 aliphatic hydrocarbon in which a hydrogen atom, a hydrogen atom or a carbon atom may be substituted with a hetero atom. The aromatic group in the di- or tri-aromatic group independently selected from the group consisting of an unsubstituted or substituted aromatic group in A is described in A in the compound represented by the general formula (2). The substituent is the same as the substituent, and preferred examples include a phenyl group, a methylphenyl group (toluyl group), a methoxyphenyl group, a naphthyl group, and a biphenyl group. X represents an oxygen atom. R2 represents a hydrogen atom or an aliphatic hydrocarbon having 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms in which a carbon atom may be substituted with a hetero atom. Group, hydroxyethyl group, hydroxypropyl group, hydroxybutyl group, hydroxypentyl group, hydroxyhexyl group, hydroxyheptyl group, hydroxyoctyl group, methoxymethyl group, methoxyethyl group, methoxypropyl group, methoxybutyl group, methoxypentyl group, Methoxyhexyl, methoxyheptyl, dihydroxymethyl, dihydroxyethyl, dihydroxypropyl, dihydroxybutyl, dihydroxypentyl, dihydroxyhexyl, dihydroxyheptyl, dihydroxyoctyl, aminomethyl, aminoethyl Group, aminopropyl group, aminobutyl group, aminopentyl group, aminohexyl group, aminoheptyl group, aminooctyl group and the like can be preferably exemplified, and hydroxyethyl group, aminoethyl group and methoxyethyl group are more preferable. Can be illustrated. Specific examples of preferred compounds among the compounds represented by the general formula (4) include diphenyl methanol, 1-[(diphenylmethyl) oxy] methanol, 2-[(diphenylmethyl) oxy. Ethanol (Compound 3), 3-[(diphenylmethyl) oxy] propanol, 4-[(diphenylmethyl) oxy] butanol, 5-[(diphenylmethyl) oxy] pentanol, 6- [(Diphenylmethyl) oxy] hexanol, 7-[(diphenylmethyl) oxy] heptanol, 8-[(diphenylmethyl) oxy] octanol, triphenylmethanol, 1-[(triphenylmethyl) ) Oxy] methanol, 2-[(triphenylmethyl) oxy] ethanol (compound 4), 3-[(triphenylmethyl) oxy] propanol, 4-[(triphenylmethyl) Xyl] butanol, 5-[(triphenylmethyl) oxy] pentanol, 6-[(triphenylmethyl) oxy] hexanol, 7-[(triphenylmethyl) oxy] heptanol, 8- [(Triphenylmethyl) oxy] octanol, 1-[(diphenylmethyl) oxy] methylamine, 2-[(diphenylmethyl) oxy] ethylamine (compound 7), 3-[(diphenylmethyl) oxy] propylamine Amine, 4-[(diphenylmethyl) oxy] butylamine, 5-[(diphenylmethyl) oxy] pentylamine, 6-[(diphenylmethyl) oxy] hexylamine, 7-[(diphenylmethyl) oxy] heptylamine, 8 -[(Diphenylmethyl) oxy] octylamine, 1-[(triphenylmethyl) oxy] methylamine, 2-[(triphenylmethyl) L) oxy] ethylamine (compound 8), 3-[(triphenylmethyl) oxy] propylamine, 4-[(triphenylmethyl) oxy] butylamine, 5-[(triphenylmethyl) oxy] pentylamine, 6- [(Triphenylmethyl) oxy] hexylamine, 7-[(triphenylmethyl) oxy] heptylamine, 8-[(triphenylmethyl) oxy] octylamine, 2-{[(methylphenyl) phenyl] methyloxy} Ethanol, 2- [bis (methylphenyl) methyloxy] ethanol, 2-{[(ethylphenyl) phenyl] methyloxy} ethanol, 2-[(bis (ethylphenyl) methyloxy] ethanol , 2-{[(methoxyphenyl) phenyl] methyloxy} ethanol, 2-[(bis (methoxyphenyl) methyloxy] ethanol 2-{[(ethoxyphenyl) phenyl] methyloxy} ethanol, 2-[(bis (ethoxyphenyl) methyloxy] ethanol, 2-{[(hydroxyphenyl) phenyl] methyloxy} ethanol 2-[(bis (hydroxyphenyl) methyloxy] ethanol, 2-{[(aminophenyl) phenyl] methyloxy} ethanol, 2-[(bis (aminophenyl) methyloxy] ethanol 2-{[(fluorophenyl) phenyl] methyloxy} ethanol, 2-[(bis (fluorophenyl) methyloxy] ethanol, 2-{[diphenyl (methylphenyl)] methyloxy} ethanol 2-{[bis (methylphenyl) phenyl] methyloxy} ethanol, 2- [tris (methylphenyl) methyloxy] ethanol, 2-{[diphenyl Ethylphenyl)] methyloxy} ethanol, 2-{[bis (ethylphenyl) phenyl] methyloxy} ethanol, 2- [tris (ethylphenyl) methyloxy] ethanol, 2-{[diphenyl ( Methoxyphenyl)] methyloxy} ethanol, 2-{[bis (methoxyphenyl) phenyl] methyloxy} ethanol, 2- [tris (methoxyphenyl) methyloxy] ethanol, 2-{[diphenyl ( Ethoxyphenyl)] methyloxy} ethanol, 2-{[bis (ethoxyphenyl) phenyl] methyloxy} ethanol, 2- [tris (ethoxyphenyl) methyloxy] ethanol, 2-{[diphenyl ( Hydroxyphenyl)] methyloxy} ethanol, 2-{[bis (hydroxyphenyl) phenyl] methyloxy} ethanol, 2- [ Lis (hydroxyphenyl) methyloxy] ethanol, 2-{[(aminophenyl) diphenyl] methyloxy} ethanol, 2-{[bis (aminophenyl) phenyl] methyloxy} ethanol, 2- [ Tris (aminophenyl) methyloxy] ethanol, 2-{[diphenyl (fluorophenyl)] methyloxy} ethanol, 2-{[bis (fluorophenyl) phenyl] methyloxy} ethanol, 2- [ Tris (fluorophenyl) methyloxy] ethanol, 2-{[(methylphenyl) phenyl] methyloxy} ethylamine, 2- [bis (methylphenyl) methyloxy] ethylamine, 2-{[(ethylphenyl) phenyl] Methyloxy} ethylamine, 2-[(bis (ethylphenyl) methyloxy] ethylamine, 2-{[(methoxyphen L) phenyl] methyloxy} ethylamine, 2-[(bis (methoxyphenyl) methyloxy] ethylamine, 2-{[(ethoxyphenyl) phenyl] methyloxy} ethylamine, 2-[(bis (ethoxyphenyl) methyloxy] Ethylamine, 2-{[(hydroxyphenyl) phenyl] methyloxy} ethylamine, 2-[(bis (hydroxyphenyl) methyloxy] ethylamine, 2-{[(aminophenyl) phenyl] methyloxy} ethylamine, 2-[( Bis (aminophenyl) methyloxy] ethylamine, 2-{[(fluorophenyl) phenyl] methyloxy} ethylamine, 2-[(bis (fluorophenyl) methyloxy] ethylamine, 2-{[diphenyl (methylphenyl)] methyl Oxy} ethylamine, 2-{[bis (methylphenol Nyl) phenyl] methyloxy} ethylamine, 2- [tris (methylphenyl) methyloxy] ethylamine, 2-{[diphenyl (ethylphenyl)] methyloxy} ethylamine, 2-{[bis (ethylphenyl) phenyl] methyloxy } Ethylamine, 2- [tris (ethylphenyl) methyloxy] ethylamine, 2-{[diphenyl (methoxyphenyl)] methyloxy} ethylamine, 2-{[bis (methoxyphenyl) phenyl] methyloxy} ethylamine, 2- [ Tris (methoxyphenyl) methyloxy] ethylamine, 2-{[diphenyl (ethoxyphenyl)] methyloxy} ethylamine, 2-{[bis (ethoxyphenyl) phenyl] methyloxy} ethylamine, 2- [tris (ethoxyphenyl) methyl Oxy] ethylamine, 2 {[Diphenyl (hydroxyphenyl)] methyloxy} ethylamine, 2-{[bis (hydroxyphenyl) phenyl] methyloxy} ethylamine, 2- [tris (hydroxyphenyl) methyloxy] ethylamine, 2-{[(aminophenyl) Diphenyl] methyloxy} ethylamine, 2-{[bis (aminophenyl) phenyl] methyloxy} ethylamine, 2- [tris (aminophenyl) methyloxy] ethylamine, 2-{[diphenyl (fluorophenyl)] methyloxy} ethylamine , 2-{[bis (fluorophenyl) phenyl] methyloxy} ethylamine, 2- [tris (fluorophenyl) methyloxy] ethylamine and / or pharmacologically acceptable salts thereof can be preferably exemplified. Is 2-{[(diphenyl) methyl] o Xyl} ethanol (compound 3), 2-{[(triphenyl) methyl] oxy} ethanol (compound 4), 2-{[(diphenyl) methyl] oxy} ethylamine (compound 7), 2- { [(Triphenyl) methyl] oxy} ethylamine (Compound 8) and / or pharmacologically acceptable salts thereof can be suitably exemplified. When such a compound is contained in an external preparation for skin together with an anti-inflammatory component described later, it has an excellent whitening effect, especially, a preventive or ameliorating effect on pigmentation, and further, melanin overproduction and / or chronic melanin production in melanocytes. It exerts a preventive or ameliorating effect on abnormal pigmentation involving phenomena such as melanin excess transport to keratinocytes due to enhancement, accumulation and delayed discharge. Such an effect is obtained by adding a compound represented by the general formula (4) and / or a pharmacologically acceptable salt thereof and an anti-inflammatory component described later in a skin external preparation, It is considered that the preventive or ameliorating action against pigmentation is enhanced by the synergistic enhancing effect, and further, the action of increasing the accumulation or retention of such compounds and anti-inflammatory components at the target site. Moreover, such a compound has high safety in skin sensitization and irritation.

  Here, the compound represented by the general formula (5) will be described. In the formula, A is a di- or triaromatic methyl group independently selected from the group consisting of an unsubstituted or substituted aromatic group. Represents a group, X represents a nitrogen atom, and R3 and R4 each independently represent a C1-C8 aliphatic hydrocarbon in which a hydrogen atom, a hydrogen atom, or a carbon atom may be substituted with a heteroatom. Represent. The aromatic group in the di- or tri-aromatic group independently selected from the group consisting of an unsubstituted or substituted aromatic group in A is described in A in the compound represented by the general formula (2). The substituent is the same as the substituent, and preferred examples include a phenyl group, a methylphenyl group (toluyl group), a methoxyphenyl group, a naphthyl group, and a biphenyl group. X represents a nitrogen atom. R3 and R4 each independently represent a hydrogen atom, a hydrogen atom or a carbon atom having 1 to 8 carbon atoms, and more preferably an aliphatic hydrocarbon group having 1 to 4 carbon atoms. Specific examples of preferable R3 and R4 include a hydrogen atom, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, a hydroxypentyl group, a hydroxyhexyl group, a hydroxyheptyl group, a hydroxyoctyl group, Methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, methoxyheptyl, dihydroxymethyl, dihydroxyethyl, dihydroxypropyl, dihydroxybutyl, dihydroxypentyl, dihydroxyhexyl Group, A hydroxyheptyl group, a dihydroxyoctyl group, an aminomethyl group, an aminoethyl group, an aminopropyl group, an aminobutyl group, an aminopentyl group, an aminohexyl group, an aminoheptyl group, an aminooctyl group and the like can be suitably exemplified, and more preferably , Hydroxyethyl group, aminoethyl group, and methoxyethyl group can be suitably exemplified. Specific examples of preferred compounds among the compounds represented by the general formula (5) are 2-[(diphenylmethyl) amino] ethanol (compound 5), 3-[(diphenylmethyl) amino]. Propanol, 4-[(diphenylmethyl) amino] butanol, 5-[(diphenylmethyl) amino] pentanol, 6-[(diphenylmethyl) amino] hexanol, 7-[(diphenylmethyl) Amino] heptanol, 8-[(diphenylmethyl) amino] octanol, 2-[(methylphenyl) phenylmethylamino] ethanol, 2- [bis (methylphenyl) methylamino] ethanol, 2 -[(Ethylphenyl) phenylmethylamino] ethanol, 2-[(bis (ethylphenyl) methylamino] ethanol, 2-[(methoxyphenyl) phenylmethylamino] ethanol 2-[(bis (methoxyphenyl) methylamino] ethanol, 2-[(ethoxyphenyl) phenylmethylamino] ethanol, 2-[(bis (ethoxyphenyl) methylamino] ethanol, 2 -[(Hydroxyphenyl) phenylmethylamino] ethanol, 2-[(bis (hydroxyphenyl) methylamino] ethanol, 2-[(aminophenyl) phenylmethylamino] ethanol, 2-[(bis (Aminophenyl) methylamino] ethanol, 2-[(fluorophenyl) phenylmethylamino] ethanol, 2-[(bis (fluorophenyl) methylamino] ethanol, 2-[(triphenylmethyl) Amino] ethanol (compound 6), 3-[(triphenylmethyl) amino] propanol, 4-[(triphenylmethyl) amino] butanol, 5- [ Triphenylmethyl) amino] hexanol, 6-[(triphenylmethyl) amino] heptanol, 8-[(triphenylmethyl) amino] octanol, 2- [diphenyl (methylphenyl) methylamino] ethanol 2- [bis (methylphenyl) phenylmethylamino] ethanol, 2- [tris (methylphenyl) methylamino] ethanol, 2- [diphenyl (ethylphenyl) methylamino] ethanol, -[Bis (ethylphenyl) phenylmethylamino] ethanol, 2- [tris (ethylphenyl) methylamino] ethanol, 2- [diphenyl (methoxyphenyl) methylamino] ethanol, 2- [bis ( Methoxyphenyl) phenylmethylamino] ethanol, 2- [tris (methoxyphenyl) methylamino] ethanol, 2- [diphenyl] (Ethoxyphenyl) methylamino] ethanol, 2- [bis (ethoxyphenyl) phenylmethylamino] ethanol, 2- [tris (ethoxyphenyl) methylamino] ethanol, 2- [diphenyl (hydroxyphenyl) Methylamino] ethanol, 2- [bis (hydroxyphenyl) phenylmethylamino] ethanol, 2- [tris (hydroxyphenyl) methylamino] ethanol, 2-[(aminophenyl) diphenylmethylamino] ethanol 2- [bis (aminophenyl) phenylmethylamino] ethanol, 2- [tris (aminophenyl) methylamino] ethanol, 2- [diphenyl (fluorophenyl) methylamino] ethanol, -[Bis (fluorophenyl) phenylmethylamino] ethanol, 2- [Tris (fluorophenyl) Tilamino] ethanol and / or a pharmacologically acceptable salt thereof can be suitably exemplified, more preferably 2-{[(diphenyl) methyl] amino} ethanol (compound 5), 2- { [(Triphenyl) methyl] amino} ethanol (Compound 6) and / or a pharmacologically acceptable salt thereof can be preferably exemplified. When such a compound is contained in an external preparation for skin together with an anti-inflammatory component described later, it has an excellent whitening effect, particularly, a preventive or ameliorating effect on pigmentation, and further melanin overproduction and / or chronic melanin production in melanocytes. It exerts a preventive or ameliorating effect on abnormal pigmentation involving phenomena such as melanin excess transport to keratinocytes due to enhancement, accumulation and delayed discharge. Such an effect is obtained by adding a compound represented by the general formula (5) and / or a pharmacologically acceptable salt thereof and an anti-inflammatory component described later in a skin external preparation, It is considered that the preventive or ameliorating action against pigmentation is enhanced by the synergistic enhancing effect, and further, the action of increasing the accumulation or retention of such compounds and anti-inflammatory components at the target site. Moreover, such a compound has high safety in skin sensitization and irritation.

Here, the compound represented by the general formula (6) will be described. In the formula, A is a di- or triaromatic methyl group independently selected from the group consisting of an unsubstituted or substituted aromatic group. Represents a group, X represents a nitrogen atom or an NH group, and R5 represents a C5-8 aromatic group in which a hydrogen atom, a hydrogen atom or a carbon atom may be substituted with a hetero atom. In addition, the ring of the aromatic group also includes a ring in which R5 includes X. A represents a di- or triaromatic methyl group independently selected from the group consisting of an unsubstituted or substituted aromatic group, and is the same as the substituent A in the compound represented by the general formula (2). And a phenyl group, a naphthyl group, a methylphenyl group (toluyl group), a methoxyphenyl, a biphenyl group and the like can be preferably exemplified. X represents a nitrogen atom or an NH group. R5 represents a hydrogen atom, a hydrogen atom or an aromatic group having 5 to 8 carbon atoms in which a carbon atom may be substituted with a heteroatom, and the ring of the aromatic group is formed so that R5 contains X. Including the ring. As a specific example relates to the aromatic hydrocarbon group, a phenyl group, imidazolinium group, a furyl group, a thienyl group and the like can be preferably exemplified, and further, the group X is present in the ring, a pyridyl group, imidazo Li Le group and the like can be preferably exemplified, and more preferably, imidazolinium Le group suitably be exemplified. As a specific example relates to a compound represented by the general formula (6), 1- (diphenylmethyl) imidazole (Compound 1), 1 - [(methylphenyl) methyl] imidazole, 1- [bis ( methylphenyl) methyl] imidazole, 1 - [(ethylphenyl) methyl] imidazole, 1- [bis (ethylphenyl) methyl] imidazole, 1 - [(methoxyphenyl) methyl] imidazole, 1 - [bis (methoxyphenyl) methyl] imidazole, 1 - [(ethoxy) methyl] imidazole, 1- [bis (ethoxyphenyl) methyl] imidazole, 1 - [(hydroxyphenyl) methyl] imidazo Lumpur, 1- [bis (hydroxyphenyl) methyl] imidazole, 1 - [(amino) methyl] imidazole, 1- [bis (aminophenyl) methyl] imidazole, - [(fluorophenyl) methyl] imidazole, 1- [bis (fluorophenyl) methyl] imidazole, 1- (triphenylmethyl) imidazole (Compound 2), 1- [diphenyl (methyl phenyl) methyl ] imidazole, 1- [bis (methylphenyl) phenylmethyl] imidazole, 1- [tris (methylphenyl) methyl] imidazole, 1- [diphenyl (ethylphenyl) methyl] imidazole, 1- [bis (ethylphenyl) phenylmethyl] imidazole, 1- [tris (ethylphenyl) methyl] imidazole, 1- [diphenyl (methoxyphenyl) methyl] imidazole, 1- [bis (methoxyphenyl) phenyl methyl] imidazole, 1- [tris (methoxyphenyl) methyl] imidazole, 1- [diphenyl (ethoxy) methyl ] Imidazole, 1- [bis (methoxyphenyl) phenylmethyl] imidazole, 1- [tris (ethoxy) methyl] imidazole, 1- [diphenyl (hydroxyphenyl) methyl] imidazole, 1- [bis (hydroxyphenyl) phenylmethyl] imidazole, 1- [tris (hydroxymethyl) methyl] imidazole, 1 - [(aminophenyl) diphenylmethyl] imidazole, 1- [bis (aminophenyl) phenyl methyl] imidazole, 1- [tris (aminophenyl) methyl] imidazole, 1- [diphenyl (fluorophenyl) methyl] imidazole, 1- [bis (fluorophenyl) phenylmethyl] imidazole, 1 - [tris (fluorophenyl) methyl] imidazole and / or a pharmaceutically acceptable salt thereof pharmacologically be suitably exemplified Years, more preferably, 1 - [(diphenyl) methyl] imidazole (Compound 1), 1 - [(triphenylmethyl) methyl] imidazole (Compound 2), and / or are their pharmacologically acceptable A suitable salt can be exemplified. When such a compound is contained in an external preparation for skin together with an anti-inflammatory component described later, it has an excellent whitening effect, particularly, a preventive or ameliorating effect on pigmentation, and further melanin overproduction and / or chronic melanin production in melanocytes. It exerts a preventive or ameliorating effect on abnormal pigmentation involving phenomena such as melanin excess transport to keratinocytes due to enhancement, accumulation and delayed discharge. Such an effect is obtained by adding a compound represented by the general formula (6) and / or a pharmacologically acceptable salt thereof and an anti-inflammatory component described later in a skin external preparation, It is considered that the preventive or ameliorating action against pigmentation is enhanced by the synergistic enhancing effect, and further, the action of increasing the accumulation or retention of such compounds and anti-inflammatory components at the target site. Moreover, such a compound has high safety in skin sensitization and irritation.

  The compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof can be synthesized according to the method shown below or with reference, using commercially available corresponding reagents as starting materials. Furthermore, regarding a method for synthesizing a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof which is not described below, WO2010 filed by the present applicant. It can be produced according to the synthesis method described in / 074052. The compound represented by the general formula (1) of the present invention and / or a pharmacologically acceptable salt thereof is contained in a skin external preparation as it is, thereby providing excellent whitening action, particularly, exposure to ultraviolet rays, etc. It can also be used to exert a preventive or ameliorating effect on pigmentation, and further, a preventive or ameliorating effect on pigmentation accompanied by keratinocyte cell function decline, incurable healing, dullness, and rough skin. It is also possible to treat it with an acid or base acceptable to convert it into a salt form and use it as a salt. For example, mineral 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 metals such as sodium salt and potassium salt, alkaline earth metals such as calcium salt and magnesium salt, triethylamine salt, triethanolamine salt, ammonium salt, monoethanol Preferred examples include organic amine salts such as ruamine salt and piperidine salt, and basic amino acid salts such as lysine salt and alginate.

  The compound represented by the general formula (1) of the present invention and / or a pharmacologically acceptable salt thereof is contained in a skin external preparation together with an anti-inflammatory component described later, and whitening action, particularly, by UV exposure. Preventive or ameliorating effect on pigmentation or improving pigmentation, as well as abnormal pigmentation associated with decreased keratinocyte cell function caused by melanin overaccumulation and delayed excretion, specifically incurable, dull, rough skin In order to exert a preventive or ameliorating effect on pigmentation accompanied by symptoms, the total amount of the external preparation for skin is 0.001% by mass to 10% by mass, more preferably 0.01% by mass to 5% by mass, Preferably, the content is 0.1 to 3% by mass. This is because if the amount is too small, the above-mentioned effect tends to decrease. If the amount is too large, the effect tends to reach its peak, and the degree of freedom of the system may be impaired.

<Production Example 1: Method for producing Compound 1 and Compound 2>
Compound 1 and Compound 2 were synthesized according to the method described in JP-A-53-16879. Compound 2 can also be purchased as a reagent from Wako Pure Chemical Industries, Ltd.

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

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

<Production Example 2: Production Method of Compound 3 and Compound 4>
Ethylene glycol (3.10 g, 49.9 mmol) (Wako Pure Chemical Industries, Ltd.) and triphenylchloromethane (1.39 g, 49.9 mmol) (Wako Pure Chemical Industries, Ltd.) were mixed with pyridine (6 mL) (Wako Pure Chemical Industries, Ltd.). The solution was dissolved in Kojunkaku Kogyo Co., Ltd., heated to 45 ° C., and stirred for 2 hours. Water (50 mL) was poured into the reaction solution and extracted with toluene (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 purified by silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.): methanol (Wako Pure Chemical Industries, Ltd.) = 9: 1), and compound 4 (yield 0.37 g, Yield 24%). Moreover, the compound 3 can be obtained by performing the same operation using diphenyl chloromethane instead of triphenyl chloromethane.

<Physical constant of compound 4>
mp. 103-106 ° C
¹ H-HMR (CDCl ₃ ): δ 3.26 (t, J = 4.5 Hz, 2H), 3.75 (t, J = 4.5 Hz, 2H), 7.23-7.54 (m, 15H ).
IR (cm ⁻¹ ): 3337, 1448, 1093, 1061.

2-{[(diphenyl) methyl] oxy} ethanol (compound 3)

2-{[(Triphenyl) methyl] oxy} ethanol (compound 4)

<Production Example 3: Production Method of Compound 5 and Compound 6>
Triphenylchloromethane (1.00 g, 3.58 mmol) (Wako Pure Chemical Industries, Ltd.) and aminoethanol (2.00 g, 32.7 mmol) were dissolved in acetonitrile (5 mL) (Wako Pure Chemical Industries, Ltd.). And stirred at room temperature overnight. Water (100 mL) was poured into the reaction solution, and the precipitate was suction filtered and dried. The solid was recrystallized with ethanol (Wako Pure Chemical Industries, Ltd.) and water mixed solvent system to obtain Compound 6 (yield 0.43 g, yield 39%). Moreover, the compound 5 can be obtained by performing the same operation using diphenylchloromethane instead of triphenylchloromethane.

<Physical constant of compound 6>
mp. 94-97 ° C
¹ H-NMR (d ₆ -DMSO): δ 2.07 (t, J = 6.0 Hz, 2H), 3.51 (t, J = 6.0 Hz, 2H), 7.15-7.42 (m , 15H).
IR (cm ^-1 ): 3244, 1488, 1442, 1025.

2-{[(Diphenyl) methyl] amino} ethanol (Compound 5)

2-{[(Triphenyl) methyl] amino} ethanol (Compound 6)

<Production Example 4: Production Method of Compound 7 and Compound 8>
Triphenylchloromethane (1.00 g, 3.58 mmol) (Wako Pure Chemical Industries, Ltd.) and ethanolamine hydrochloride (1.00 g, 10.3 mmol) (Wako Pure Chemical Industries, Ltd.) were added to pyridine (4 mL) (Wako Pure Chemical Industries, Ltd.). The solution was dissolved in Kojun Pharmaceutical Co., Ltd. and stirred at room temperature for 3 days. Water (200 mL) was poured into the reaction solution, and the precipitate was filtered with suction. The solid was suspended in diethyl ether (Wako Pure Chemical Industries, Ltd.), 3 (N) hydrochloric acid (Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred at room temperature for 15 minutes. The insoluble material was dissolved in a mixed solution of an aqueous solution of ethyl acetate (Wako Pure Chemical Industries, Ltd.) 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.), then suction filtered and concentrated under reduced pressure to obtain Compound 8 (yield 0.31 g, yield 28%). Moreover, the compound 7 can be obtained by performing the same operation using diphenyl chloromethane instead of triphenyl chloromethane.

<Physical constant of compound 8>
mp. 87-89 ° C.
¹ H-NMR (CDCl ₃ ): δ 2.88 (t, J = 5.1 Hz, 2H), 3.14 (t, J = 5.1 Hz, 2H), 7.24-7.51 (m, 15H ).
IR (cm ⁻¹ ): 3378, 1594, 1448, 1054.

2-{[(Diphenyl) methyl] oxy} ethylamine (Compound 7)

2-{[(Triphenyl) methyl] oxy} ethylamine (Compound 8)

<Production Example 5: Method for producing Compound 9>
Chlorodiphenylmethane (0.50 g, 2.47 mmol) (Wako Pure Chemical Industries, Ltd.), Pyrrolidine (0.53 g, 7.45 mmol) (Tokyo Chemical Industry Co., Ltd.) and potassium iodide (0.10 g, 0.60 mmol) (Wako Pure Chemical Industries, Ltd.) was added to acetonitrile (20 mL) (Wako Pure Chemical Industries, Ltd.) and refluxed for 2 hours. After leaving to room temperature, an aqueous solution of saturated sodium bicarbonate (Wako Pure Chemical Industries, Ltd.) was added to the reaction solution, and the mixture was 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, chloroform (Wako Pure Chemical Industries, Ltd.): methanol (Wako Pure Chemical Industries, Ltd.) = 99: 1), and compound 9 (yield 0.36 g, yield). 61%).

<Physical constant of compound 9>
mp. 69-72 ° C
¹ H-NMR (CDCl ₃ ): δ 1.73-1.79 (m, 4H), 2.40-2.44 (m, 4H), 4.15 (s, 1H), 7.12-7. 47 (m, 10H).
IR (cm ⁻¹ ): 2793, 1452, 703.

1- (Diphenylmethyl) pyrrolidine (Compound 9)

<Production Example 6: Method for producing Compound 10>
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 compound 10 (yield 0.45 g, yield). 80%).

<Physical constant of compound 10>
mp. 127-129 ° C
¹ H-NMR (CDCl ₃ ): δ 1.53-1.65 (m, 4H), 2.00-2.30 (m, 4H), 7.11-7.28 (m, 5H), 7. 48-7.52 (m, 10H).
IR (cm ^-1 ): 2961, 2819, 1486, 1448, 711.

1-[(Triphenyl) methyl] pyrrolidine (Compound 10)

<Production Example 7: Production Method of Compound 11 and Compound 12>
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 compound 12 (yield 1.80 g, yield 31%). ) Moreover, the compound 11 can be obtained by performing the same operation using diphenyl chloromethane instead of triphenyl chloromethane.

<Physical constant of compound 12>
mp. 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.

1- (Diphenylmethyl) piperidine (Compound 11)

1- (Triphenylmethyl) piperidine (Compound 12)

<Anti-inflammatory component of the present invention>
The skin external preparation of the present invention comprises 1) the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, and 2) an anti-inflammatory component. . The anti-inflammatory component of the present invention can be applied without particular limitation as long as it is a substance having an anti-inflammatory action, and preferred examples include plant extracts obtained from plants belonging to the genus Camellia, Compositae burdock A plant extract obtained from a plant belonging to the plant, a plant extract obtained from a plant belonging to the genus Clara, a plant extract obtained from a plant belonging to the genus Birchaceae, a plant extract obtained from a plant belonging to the walnut family, Anti-inflammatory such as plant extracts having anti-inflammatory activity, such as plant extracts obtained from plants belonging to the genus Lizoaceae, clarinone, grabridine, glycyrrhizic acid and salts thereof, glycyrrhetinic acid and salts thereof, glycyrrhetinic acid derivatives and salts thereof The component etc. which are contained in the plant which has an effect | action can be illustrated preferably. Among the components having such an anti-inflammatory action, more preferable examples include a plant extract obtained from the aceae chamomile chamomile (chamomile), a plant extract obtained from the asteraceae burdock burdock, and a leguminous clara kujin. Plant extract obtained from birch, birch, birch, plant extract obtained from walnut, licorice, plant extract obtained from leguminous licorice, glycyrrhizic acid and its salts, alkyl glycyrrhetinate And a salt thereof, glycyrrhetinic acid and a salt thereof can be preferably exemplified. The plant extract having an anti-inflammatory action of the present invention is added with 1 to 20 times the amount of a plant or a processed product thereof using a lower alcohol such as water or ethanol as a solvent, and if necessary, stirring is appropriately added. After immersion for several days at room temperature or several hours at a temperature near the boiling point, the insoluble matter is removed by filtration or the like, and then the solvent is removed by distillation under reduced pressure or the like. Etc. can be purified and fractionated by column chromatography or the like using them as a carrier. Preferred sites for preparing the plant extract having anti-inflammatory activity of the present invention include flower buds of Camellia genus Chamomile (camomile), roots of Compositae burdock burdock, and Clariaceae In the case of the genus Kujin, the rhizome part, the birch of the birch family Birch genus, the bark, the leaf part of the walnut family Koki, and the rhizome of the licorice licorice can be preferably exemplified. Such plant extracts are also commercially available, and can be purchased and used from companies that handle plant extracts such as Maruzen Pharmaceutical Co., Ltd., for example. Glycyrrhetinic acid derivatives such as glycyrrhizic acid and salts thereof, glycyrrhetinic acid and salts thereof, alkyl glycyrrhetinates and salts thereof can be purchased from Wako Pure Chemical Industries, Ltd. Further, the glycyrrhetinic acid derivative has an anti-inflammatory action, a melanin production inhibitory action, a moisturizing action, and the like. 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, and 2) a whitening effect, In particular, the effect of preventing or improving pigmentation caused by exposure to ultraviolet rays, as well as abnormal pigmentation caused by decreased cellular function of keratinocytes, specifically pigments with skin symptoms such as incurable, dull, irritated or rough skin Excellent anti-pigmentation or improvement effect on abnormal deposition. In general, when using a topical skin preparation for preventing or ameliorating pigmentation, there is a high possibility of causing inflammation due to exposure to ultraviolet rays, and the inflammatory reaction and the various skin reactions associated therewith increase melanin production. It has been known. Therefore, by containing a component having such an anti-inflammatory action, in addition to suppressing the increase in melanin production, the inflammation subsides or further inflammation is suppressed, and the increase in the amount of transdermal water transpiration is suppressed. I can do it. That is, the appearance of rough skin after inflammation can be suppressed, and further, the serious pigmentation can be prevented. Moreover, the anti-inflammatory component of this invention can select the 1 type (s) or 2 or more types of the said anti-inflammatory component, and can make it contain in the skin external preparation of this invention.

  Among the anti-inflammatory components of the present invention, in order for the plant extract having an anti-inflammatory action to exhibit the above pharmacological action, the total amount is preferably 0.00001% by mass to 15% by mass with respect to the total amount of the external preparation for skin. Is preferably 0.0001 mass% to 10 mass%, more preferably 0.01 mass% to 5 mass%. This is because if the amount is too small, the pharmacological action tends to decrease, and if the amount is too large, the effect tends to reach its peak, which may impair the degree of freedom of the system.

  The glycyrrhetinic acid derivatives and salts thereof are components used as active ingredients of quasi drugs, and preferable examples thereof include alkyl glycyrrhetinic acid and salts thereof, and more preferable examples include stearyl glycyrrhetinic acid. Suitable examples include lauryl glycyrrhetinate. Moreover, as said glycyrrhizic acid and its salt, glycyrrhizic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, etc. can be illustrated suitably. Of these glycyrrhetinic acid derivatives and salts thereof, stearyl glycyrrhetinate and dipotassium glycyrrhizinate are particularly preferable. This is because it has already been confirmed that the use record for quasi-drugs is rich and the safety is high. Such glycyrrhetinic acid derivatives and salts thereof can also be purchased and used from reagent manufacturers such as Wako Pure Chemical Industries. The preferable content of such components is 0.01% by mass to 3% by mass, more preferably 0.03% by mass to 1% by mass, and still more preferably 0.05 to 0% with respect to the total amount of the external preparation for skin. 0.5% by mass. This is because if the amount is too small, the pharmacological action tends to decrease, and if the amount is too large, the effect tends to reach its peak, and the degree of freedom of this system may be impaired. Such an ingredient exhibits an anti-inflammatory action, a melanin production inhibitory action, a skin roughness improving action, etc. on the skin. In the skin external preparation of the present invention, the compound represented by the general formula (1) and / or Works with their pharmacologically acceptable salts, whitening effect, especially, pigmentation prevention or improvement effect caused by UV exposure, and further prevention or improvement effect on pigmentation abnormality with irritable blemishes, dullness, and rough skin symptoms Demonstrate.

  The component having an anti-inflammatory action of the present invention contains a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof in an external preparation for skin, thereby whitening effect, in particular, It exhibits an effect of preventing or improving pigmentation caused by exposure to ultraviolet rays, and an additive or synergistic effect on the effect of preventing or improving pigmentation abnormality caused by a decrease in cell function of keratinocytes and a delay in turnover. The anti-inflammatory component of the present invention contains a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof in an external preparation for skin, thereby preventing skin inflammation immediately after sunburn. On the other hand, when the external preparation for skin of the present invention is administered, inflammation is suppressed more quickly, the effect of restoring the skin barrier function is shown, and the preventive effect on the deterioration of the skin condition is increased. As a result, the melanin of the external preparation for skin of the present invention The production suppression effect is also improved. That is, the external preparation for skin of such a form is preferable as an external preparation for preventing pigmentation caused by exposure to ultraviolet rays even when the skin is inflamed.

  The plant extract having an anti-inflammatory action of the present invention can be produced according to the method for producing a plant extract shown below, or purchased from a company that handles plant extracts such as Maruzen Pharmaceutical Co., Ltd. Can also be used.

<Production Example 8: Method 1 for producing plant extract having anti-inflammatory action of the present invention>
Rhizome 1 (kg) of leguminous clara genus rhizome was chopped, 10 (L) ethanol was added thereto, heated under reflux for 3 hours with stirring, cooled to room temperature, and concentrated under reduced pressure. . 2 (L) water and 2 (L) ethyl acetate were added to this product, solubilized, and liquid-liquid extraction was performed. The ethyl acetate phase was taken and concentrated to obtain 105 (g) of amorphous. Furthermore, the amorphous 1.2 (g) was dissolved in 8 (L) of 60% 1,3-butanediol aqueous solution to obtain an extract obtained from the leguminous cucumber of the present invention. Moreover, the plant extract which has the anti-inflammatory action of this invention can be manufactured according to the same method. In addition, such a plant extract (solid matter) can be dissolved in anhydrous or hydrous ethanol, anhydrous or hydrous 1,3-butanediol, etc., and used as the plant extract of the present invention.

<Production Example 9: Method for producing plant extract having anti-inflammatory action of the present invention>
Add 5 (L) of 50% ethanol to 500 (g) of the above-ground legume licorice, heat and reflux for 3 hours, filter, concentrate under reduced pressure, freeze-dry, and then freeze-dried Obtained plant extract 124 (g) was obtained.

<Production Example 10: Method 3 for producing plant extract having anti-inflammatory action of the present invention>
Birch bark dry matter 1 (Kg) was chopped, water 10 (L) was added thereto, and the mixture was heated at 90 ° C. for 4 hours. Insoluble matter was removed by filtration and freeze-dried to obtain 1.1 (g) of amorphous plant extract obtained from birch birch genus birch.

<Production Example 11: Method 4 for producing plant extract having anti-inflammatory action of the present invention>
Shredded dried chamomile chamomile chamomile (500 g), added 5 (L) 50% ethanol aqueous solution, heated to reflux for 3 hours, allowed to cool, then filtered to insoluble matter Were removed, concentrated under reduced pressure, and lyophilized to obtain a plant extract obtained from the chamomile chamomile chamomile.

<Skin external preparation of the present invention>
The external preparation for skin of the present invention is characterized by comprising 1) a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, and 2) an anti-inflammatory component. The skin external preparation of the present invention has a whitening effect, in particular, a preventive or ameliorating effect on pigmentation by exposure to ultraviolet rays, and further melanin excess transport to keratinocytes due to excessive melanin in melanocytes and / or chronic increased melanin production. It is excellent in the effect of preventing or improving keratinocyte inactivation resulting from delayed accumulation and / or elimination, and abnormal pigmentation due to delayed turnover. For this reason, the skin external preparation of this invention is suitable for the prevention or improvement with respect to the pigmentation accompanying rough skin, such as an unhealthy spot or dullness, and delamination. The topical skin preparation of the present invention is an additive or synergistic potentiating effect in preventing or improving pigmentation due to UV exposure, a decrease in cellular function of keratinocytes, or prevention of pigmentation abnormalities caused by turnover delay or It exhibits an additive or synergistic enhancement effect in the improving action. The external preparation for skin of the present invention has an effect of enhancing the prevention or improvement of pigmentation abnormalities that occur particularly in a person with a large amount of melanin in the collected stratum corneum cells. Such an additive or synergistic enhancing effect in preventing or improving pigmentation is obtained by combining the compound represented by the general formula (1) and / or a pharmacologically acceptable salt with an anti-inflammatory component. Addition or synergistic effect in pharmacological action due to inclusion thereof, and further, the compound represented by the general formula (1) and / or the target site due to the action such as improvement of skin permeability or retention This is considered to be due to the effect of improving the delivery efficiency of these pharmacologically acceptable salts and anti-inflammatory components.

  In addition, in the melanocytes in an excessive and / or chronic melanin production-promoting state due to the cause of excessive ultraviolet exposure, etc., among the prevention or improvement effects on pigmentation due to ultraviolet exposure targeted by the external preparation for skin of the present invention, Observed that melanin excess transport to keratinocytes, accumulation and discharge delay are caused, and that skin symptoms are worsened by damage such as cell inactivation of keratinocytes and turnover delay Is done. The external preparation for skin of the present invention is preferably used for a person who exhibits rough skin symptoms caused by excessive production and transport of melanin in addition to preventing or improving pigmentation. When a person with such skin symptoms is observed, phenomena such as an increase in nucleated cells and delamination are observed. Therefore, it is also effective to narrow down the target to be used using these as an index.

  In the preparation of an external preparation for skin containing 1) the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof and 2) an anti-inflammatory component of the present invention. In addition, it can contain optional components used in the preparation of ordinary pharmaceuticals, quasi drugs, cosmetics and the like. As the skin external preparation of the present invention, pharmaceuticals, quasi-drugs, cosmetics and the like can be suitably exemplified, and since they can be taken on a daily basis, it is preferable to apply to cosmetics, quasi-drugs and the like. 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. 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. Furthermore, the dosage form is not particularly limited as long as it is known in the cosmetics field, and is preferably exemplified for lotion preparations, oil-in-water emulsion preparations, water-in-oil emulsion preparations, composite emulsion emulsion preparations and the like. it can.

  The external preparation for skin of the present invention can contain, in addition to such components, optional components that are usually used in external preparations for skin. 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 palm oil, hydrogenated oil, molasses, hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba oil, 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 organic modified clay minerals such as hectorite and dimethyl distearyl ammonium modified hectorite.

  The external preparation for skin of the present invention is not particularly limited as long as it is a dosage form known in the cosmetics field, and includes lotion preparations, oil-in-water emulsion preparations, water-in-oil emulsion preparations, composite emulsion emulsion preparations and the like. It can illustrate suitably. The form of the emulsifier type may be either a water-in-oil emulsifier form or an oil-in-water emulsifier form, but the water-in-oil emulsifier form is particularly preferred. Here, the water-in-oil emulsifier form is a term collectively referred to as an emulsifier form having an oil phase in the outer phase, and may contain an aqueous phase in the inner phase or may have an emulsion such as an oil-in-water emulsion. You may do it.

  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 the sense of keeping the emulsified state stable. 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 a component is preferably contained also in that sense because it forms a composite film with the essential ingredient amodimethicone after administration to the skin and enhances the effect of amodimethicone. Such alkyl-modified carboxyvinyl polymers include commercially available products, which can be purchased and used. Preferable commercial 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. There are “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-forming properties in an emulsified state are preferable. As the nonionic 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.

  The topical skin preparation of the present invention contains 1) a compound represented by the above general formula (1) and / or a pharmacologically acceptable salt thereof, and 2) an anti-inflammatory component. It is effective for preventing or improving pigmentation such as “for preventing or improving pigmentation by exposure”. In addition, in the case of expecting other effects on the skin and including the above-mentioned components in the external preparation for skin, the effect of the present invention is used when the above-mentioned prevention or improvement effect against pigmentation is exhibited. Therefore, it belongs to the technical scope of the present invention. Examples of actions other than the effect of preventing or improving pigmentation include a moisturizing action, a rough skin preventing or improving action, and an anti-aging improving action.

  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.

<Manufacture example 12: Manufacturing method 1 of the skin external preparation of this invention>
According to the formulations shown in Table 1 and Table 2, the external preparation for skin of the present invention was prepared. That is, the components of A, B, and C are heated to 80 ° C., and after neutralizing and adding C to B, the emulsion particles are homogenized and homogenized with a homomixer. Cosmetics 1-12) were obtained. By the same operation, Comparative Example 1 in which “the compound represented by the general formula (1) of the present invention” was replaced with “water” in the formulation component of the cosmetic 1, and “the anti-inflammatory component of the present invention” was “ Comparative Example 2 in which “water” was substituted, and Comparative Example 3 in which “the compound represented by the general formula (1) of the present invention” and “anti-inflammatory component of the present invention” were both replaced with “water” were produced.

<Test Example 1: Evaluation 1 of pigmentation inhibitory action of external preparation for skin of the present invention>
Using the oil-in-water emulsifier type skin external preparation (milky lotion, cosmetics 1 to 12) and the cosmetics of Comparative Examples 1 to 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 (cosmetics 1-12 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 the application (15th day), the skin lightness (L * value) of each test site was measured with a color difference meter (CR-300, Konica Minolta Co., Ltd.). ΔL * value for was calculated. The results are shown in Table 3. Since the L * value decreases as the degree of pigmentation increases, it can be determined that the pigmentation is suppressed as the ΔL * value decreases. Thereby, it turns out that the skin external preparation (milky lotion, cosmetics 1-12) of this invention has the outstanding pigmentation inhibitory effect. Moreover, although the pigmentation inhibitory effect was recognized also in the comparative example 1 and the comparative example 2, the effect was weak compared with cosmetics 1-12. Thereby, it turns out that the cosmetics 1-12 which are the skin external preparations of this invention show the outstanding pigmentation inhibitory effect.

<Test Example 2: Evaluation 2 for inhibiting pigmentation of the external preparation for skin of the present invention>
The skin external preparation of the present invention (milky lotion, cosmetics 1 to 12) and Comparative Examples 1 to 3 produced according to the method described in Example 1 and Comparative Examples 1 to 3 were evaluated for pigmentation inhibitory action according to the following procedure. When selecting a panel with a higher melanin content than the average, a sample of stratum corneum cells collected from the skin by adhesive tape stripping is visualized by melanin staining using an aqueous silver nitrate solution and observed under a microscope. It was judged by. In the determination, the determination was made by scoring around the average existence situation. Further, among the panelists, a person who has a higher nucleated cell appearance rate than the average using a stratum corneum specimen or has a higher degree of delamination than the average was selected by observation and designated as a paneler. Panels that participated freely with the above-mentioned characteristics were divided into two upper and lower sections of 1.5 cm × 1.5 cm on the upper arms of the panel, and four measurement sites were provided, and UV irradiation with a minimum amount of erythema (1 MED) was performed. Irradiation was performed once a day for 3 consecutive days. From the end of irradiation on the third day, 50 μL of sample was applied once a day for 28 consecutive days. One site was an untreated site. After 24 hours from the end of application, the skin lightness (L * value) of each test site was measured with a color difference meter (CR-300, Konica Minolta Co., Ltd.). Calculated. The L * value decreases as the degree of pigmentation increases. Therefore, it can be determined that the greater the ΔL * value, the more pigmentation is suppressed. The results are shown in Table 4. Thereby, it turns out that the cosmetics 1-12 which are the skin external preparations of this invention show the outstanding pigmentation inhibitory effect.

<Production Example 13: Production Example 2 of the skin external preparation of the present invention>
Regarding the cosmetic 4 and the cosmetic 12 described in Example 1, the “compound represented by the general formula (1) of the present invention” and the “anti-inflammatory component of the present invention” in the formulation components described in Table 1 The external preparation for skin (milky lotion, cosmetics 13 to 19) with the concentration of "" changed to the concentration shown in Table 5 was prepared according to the method described in Example 1. In addition, the whole density | concentration (weight%) by change of the density | concentration (mass%) of both components was adjusted with the density | concentration (weight%) of the water in a prescription component.

<Test Example 3: Evaluation 3 of pigmentation inhibitory action of the external preparation for skin of the present invention>
Using the cosmetics 13 to 19, the cosmetic 4 and the cosmetic 12 produced according to the method described in Example 4, the pigmentation inhibitory action was evaluated according to the method described in Example 2. The results are shown in Table 6. Cosmetics 13 to 19, cosmetic 4 and cosmetic 12 showed an excellent pigmentation-inhibiting action.

<Production Example 14: Method 3 for producing skin external preparation of the present invention>
An attempt was made to produce a skin external preparation (milky lotion, cosmetic 20) of the present invention in which “Pemlen TR-2” was replaced with POE (25) stearic acid in the formulation components of the cosmetic 1 described in Example 1. The cosmetic 20 was separated immediately after production, and an emulsion was not obtained.

  The present invention can be applied to cosmetics (however, including quasi drugs).

Claims (16)

1) A compound represented by the following general formula (1) and / or a pharmacologically acceptable salt thereof, and 2) an anti-inflammatory component ,
The anti-inflammatory component is a plant extract obtained from a plant belonging to the genus Camellia belonging to the family Asteraceae, a plant extract obtained from a plant belonging to the genus Asteraceae, a plant extract obtained from a plant belonging to the genus Clariaceae, birch family A plant extract obtained from a plant belonging to the genus Birch, a plant extract obtained from a plant belonging to the walnut family, a plant extract obtained from a plant belonging to the leguminous licorice genus, a glycyrrhetinic acid derivative and a salt thereof, and a grabridine derivative and Ru der those selected from a salt thereof, a skin external preparation.
[In the formula, A represents a di- or triaromatic methyl group, and the aromatic group is an unsubstituted or substituted aromatic group and / or an unsubstituted or substituted heteroaromatic group, respectively. Chosen independently. B is a cyclic or non-cyclic aliphatic or aromatic group having 3 to 8 carbon atoms in which the bonding site to A is an oxygen atom or a nitrogen atom, and a hydrogen atom or carbon atom may be substituted by an oxygen atom or a nitrogen atom. Represents a hydrocarbon group or a hydrogen atom. In addition, the cycloaliphatic or aromatic ring includes a ring formed by containing an oxygen atom or a nitrogen atom at the binding site of A and B. ] The compound represented by the general formula (1) is a compound represented by the following general formula (2) and / or a pharmaceutically acceptable salt thereof. Topical skin preparation.
[In the formula, A represents a di- or triaromatic methyl group, and the aromatic group is independently selected from the group consisting of an unsubstituted or substituted aromatic group. B is a cyclic or non-cyclic aliphatic or aromatic group having 3 to 8 carbon atoms in which the bonding site to A is an oxygen atom or a nitrogen atom, and a hydrogen atom or carbon atom may be substituted by an oxygen atom or a nitrogen atom. Represents a hydrocarbon group or a hydrogen atom. In addition, the cycloaliphatic or aromatic ring includes a ring formed by containing an oxygen atom or a nitrogen atom at the binding site of A and B. ] The skin external preparation according to claim 2, wherein the compound represented by the general formula (2) is a compound represented by the following general formula (3).
[Wherein, A represents a di- or triaromatic methyl group, and the aromatic group is independently selected from the group consisting of unsubstituted or substituted aryl groups. X represents a nitrogen atom or an NH group, and R ₁ represents a pyrrolidino group, piperidino group, piperazino group, morpholino group, or a hydrogen atom. Further, the ring of the cycloaliphatic hydrocarbon group also includes a ring in which R ₁ includes X. ] The compound represented by the general formula (3) is 1-[(diphenyl) methyl] pyrrolidine (compound 9), 1-[(triphenyl) methyl] pyrrolidine (compound 10), 1-[(diphenyl) methyl]. The skin external preparation according to claim 3, wherein the external preparation is one or more selected from piperidine (compound 11) and 1-[(triphenyl) methyl] piperidine (compound 12).
The skin external preparation according to claim 2, wherein the compound represented by the general formula (2) is a compound represented by the following general formula (4).
[Wherein, A represents a di- or triaromatic methyl group, and the aromatic group is independently selected from the group consisting of an unsubstituted or substituted aromatic group. X represents an oxygen atom, and R ₂ represents a C 1-8 aliphatic hydrocarbon or a hydrogen atom in which a hydrogen atom or a carbon atom may be substituted with an oxygen atom or a nitrogen atom. ] The compound represented by the general formula (4) is 2-[[(diphenyl) methyl] oxy] ethanol (compound 3), 2-{[(triphenyl) methyl] oxy} ethanol (compound 4), 2- One or more selected from {[(diphenyl) methyl] oxy} ethylamine (compound 7) and 2-{[(triphenyl) methyl] oxy} ethylamine (compound 8), The skin external preparation of Claim 5.
The skin external preparation according to claim 2, wherein the compound represented by the general formula (2) is a compound represented by the following general formula (5).
[Wherein, A represents a di- or triaromatic methyl group, and the aromatic group is independently selected from the group consisting of an unsubstituted or substituted aromatic group. X represents a nitrogen atom, and R ₃ and R ₄ each independently represent a C 1-8 aliphatic hydrocarbon in which a hydrogen atom or a carbon atom may be substituted with an oxygen atom or a nitrogen atom, or hydrogen Represents an atom. ] The compound represented by the general formula (5) is selected from 2-{[(diphenyl) methyl] amino} ethanol (compound 5) and 2-{[(triphenyl) methyl] amino} ethanol (compound 6). The skin external preparation according to claim 7, wherein the skin external preparation is one or two types.
The skin external preparation according to claim 2, wherein the compound represented by the general formula (2) is a compound represented by the following general formula (6).
[Wherein, A represents a di- or triaromatic methyl group, and the aromatic group is independently selected from the group consisting of an unsubstituted or substituted aromatic group. X represents a nitrogen atom or an NH group, and R ₅ represents a phenyl group, a pyridyl group, an imidazolyl group, a furyl group, or a hydrogen atom. In addition, the ring of the aromatic group also includes a ring in which R ₅ includes X. ] The compound represented by the general formula (6) is one or two selected from 1-[(diphenyl) methyl] imidazole (compound 1) and 1-[(triphenyl) methyl] imidazole (compound 2). The external preparation for skin according to claim 9, wherein the preparation is external.
  0.001% by mass to 10% 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 1-10. The plant belonging to the genus Camellia belonging to the genus Compositae, the plant belonging to the genus Burdaceae, the plant belonging to the genus Clara, the plant belonging to the genus Birch, the plant belonging to the walnut family, and the plant belonging to the genus Leguminosae, respectively. Asteraceae chamomile genus chamomile (chamomile), characterized in that it is a Asteraceae burdock genus burdock, leguminous Clara genus Sophora root, Betulaceae Betula birch, walnut family Koki, and Leguminosae Glycyrrhiza licorice, claims 1-11 The external preparation for skin according to any one of the above. The skin external preparation according to any one of claims 1 to 12, wherein the glycyrrhetinic acid derivative is selected from glycyrrhetinic acid, alkyl glycyrrhetinic acid, and glycyrrhizic acid. The skin external preparation according to any one of claims 1 to 13 , wherein the anti-inflammatory component is contained in an amount of 0.00001% by mass to 15% by mass with respect to the total amount of the external preparation for skin. The external preparation for skin according to any one of claims 1 to 14 , which is a cosmetic (however, including quasi-drugs). The external preparation for skin according to any one of claims 1 to 15 , wherein the preparation is for whitening.