JP2013001658A - Agent for preventing or ameliorating chapped skin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new agent for preventing or ameliorating chapped skin and a skin care preparation that comprises a component and prevents or ameliorates chapped skin.SOLUTION: The agent for preventing or ameliorating chapped skin comprises a compound represented by general formula (1) [wherein Ris an unsubstituted or substituent-containing aromatic group; Ris a hydrogen atom, 1-4C straight-chain or branched alkyl, 1-4C straight-chain or branched alkyl chain-containing acyl; Ris a hydrogen atom, 1-4C straight-chain or branched alkyl], its optical isomer and/or their pharmacologically acceptable salts. The skin care preparation for preventing or ameliorating chapped skin comprises the component.

Description

  The present invention relates to a rough skin prevention or improvement agent suitable for cosmetics (however, including quasi-drugs), and a skin external preparation for preventing or improving rough skin containing the rough skin prevention or improvement agent. 1) Preventing or improving rough skin comprising a compound represented by the following general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof, and preventing or improving rough skin containing the components The present invention relates to an external preparation for skin.

（１）
[式中、Ｒ１は、無置換又は置換基を有する芳香族基を表し、Ｒ２は、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基、炭素数１〜４の直鎖又は分岐のアルキル鎖を有するアシル基を表し、Ｒ３は、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表す。]

(1)
[Wherein, R1 represents an unsubstituted or substituted aromatic group, R2 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched group having 1 to 4 carbon atoms. R3 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. ]

  Skin is important for maintaining the body by providing a barrier function that protects the body from external stimuli such as physical impact, temperature, UV light, or chemical exposure, as well as a moisturizing function that prevents the evaporation of moisture inside the body. Playing a role. Decreased skin barrier functions such as barrier and moisturizing functions become normal due to accumulation of physical stimuli over many years such as UV exposure, genetic factors, aging, etc., rough skin symptoms such as dry skin, exfoliation of keratinocytes As it manifests. In addition, such rough skin symptoms may appear with allergic symptoms such as hay fever, and there is a theory that it is an expression form of autoimmune diseases. Thus, it is difficult to say that a rough skin symptom having a multifaceted aspect has a sufficient therapeutic effect so far due to factors such as the onset factor and the complexity of the onset process. For this reason, the rough skin symptom is not necessarily an intractable disease.

  It is known that rough skin symptoms are closely related to a decrease in skin barrier function (for example, see Non-Patent Document 1). Therefore, paying attention to the relationship between rough skin symptoms and skin barrier function, a method for quantitative analysis and evaluation of rough skin symptoms using the skin barrier function index, as well as the development of rough skin symptoms based on the skin barrier function Research on the mechanism is also actively conducted. Actually, rough skin symptoms include transepidermal water loss (TEWL) (see, for example, Patent Document 1), transepitherial electrical resistance (TER value) (for example, patent) Quantitative evaluation is possible by measuring and evaluating physical property values related to the skin barrier function such as Reference 2). Such a method for quantitatively evaluating rough skin symptoms is a useful evaluation method for developing rough skin prevention or improvement agents, and is widely used.

Amino acids are a general term for organic compounds that have amino and carboxyl groups in their molecular structure. In particular, α-amino acids are proteins that make up living organisms, and are actively studied because they have a variety of physiological activities. Has been done. Such α-amino acids and derivatives thereof have an anti-aging action (see, for example, Patent Document 3), a moisturizing action (for example, see Patent Document 4), and a whitening action (for example, Patent Document 5) even in the cosmetic field alone. Have been reported, and the application to cosmetics and the like has been attempted with the expectation of such pharmacological action. Among the above-mentioned α-amino acids, in particular, regarding serine and its derivatives, serine has a whitening effect (see, for example, Patent Document 6), and N-methylserine has a moisturizing effect (see, for example, Patent Document 7). -It has been reported that benzoylserine has an effect of preventing or improving wrinkles (see, for example, Patent Document 8). However, the inventors have shown that the compounds represented by the general formula (1) of the present invention, isomers thereof and / or pharmacologically acceptable salts thereof have an effect of preventing or improving rough skin pigmentation. As far as I know, it was not reported. The present inventor has found that the compound represented by the general formula (1), isomers thereof and / or pharmacologically acceptable salts thereof have an excellent effect of preventing or improving rough skin pigmentation. .

JP 2007-161612 A JP 2007-174931 A JP 2010-241734 A JP 2000-178118 A JP 2004-315384 A JP 11-049630 A JP-A-11-310510 Table 2007-013662

Development technology for anti-aging, whitening and moisturizing cosmetics, supervised by CMC Technical Library, Masato Suzuki

  The present invention has been made under such circumstances, and an object thereof is to provide a novel rough skin prevention or improvement agent, and a skin external preparation for preventing or improving rough skin containing the component.

In view of such a situation, as a result of diligent efforts and research seeking a novel rough skin prevention or improvement agent, the present inventors have found that the compound represented by the following general formula (1), its optical isomer and / or Alternatively, the present inventors have found that these pharmacologically acceptable salts have an excellent effect of preventing or improving rough skin, and have completed the present invention. The present invention is as follows.
<1> 1) A rough skin preventing or improving agent comprising a compound represented by the following general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof.

（１）
[式中、Ｒ１は、無置換又は置換基を有する芳香族基を表し、Ｒ２は、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基、炭素数１〜４の直鎖又は分岐のアルキル鎖を有するアシル基を表し、Ｒ３は、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表す。]

(1)
[Wherein, R1 represents an unsubstituted or substituted aromatic group, R2 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched group having 1 to 4 carbon atoms. R3 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. ]

<2> The compound represented by the general formula (1) is a compound represented by the following general formula (2), an optical isomer thereof and / or a pharmacologically acceptable salt thereof. The rough skin preventing or improving agent according to <1>.

（２）
[式中、Ｒ４は、無置換又は置換基を有する芳香族基を表し、Ｒ５は、炭素数１〜４の直鎖又は分岐のアルキル基、炭素数１〜４の直鎖又は分岐のアルキル鎖を有するアシル基を表す。]

(2)
[Wherein R4 represents an unsubstituted or substituted aromatic group, R5 represents a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkyl chain having 1 to 4 carbon atoms. Represents an acyl group having ]

<3> The compound represented by the general formula (1) is a compound represented by the following general formula (3), an optical isomer thereof and / or a pharmacologically acceptable salt thereof. The rough skin preventing or improving agent according to <1>.

（３）
[式中、Ｒ６は、無置換又は置換基を有する芳香族基を表し、Ｒ７は、炭素数１〜４の直鎖又は分岐のアルキル基を表す。]

(3)
[Wherein, R6 represents an unsubstituted or substituted aromatic group, and R7 represents a linear or branched alkyl group having 1 to 4 carbon atoms. ]

<4> The compound represented by the general formula (1) is a compound represented by the following general formula (4), an optical isomer thereof and / or a pharmacologically acceptable salt thereof. The rough skin preventing or improving agent according to <1>.

（４）
[式中、Ｒ８は、無置換又は置換基を有する芳香族基を表す。]

(4)
[Wherein R8 represents an unsubstituted or substituted aromatic group. ]

<5> The compound represented by the general formula (1) is N- (p-methylbenzoyl) serine (compound 1), N- (p-ethylbenzoyl) serine (compound 2), N- (p-methoxy). Benzoyl) serine (compound 3), N- (p-fluorobenzoyl) serine (compound 4), N- (p-trifluoromethylbenzoyl) serine (compound 5), N- (2-naphthoyl) serine (compound 6) N- (4-phenylbenzoyl) serine (compound 7), N- (p-methylbenzoyl) serine methyl ester (compound 8), N- (2-naphthoyl) serine methyl ester (compound 9), N-benzoyl- O-methylserine (compound 10), N- (p-methylbenzoyl) -O-methylserine (compound 11), N- (p-methylbenzoyl) -O-acetylserine (compound 12), N- (2- [Futoyl) -O-methylserine (compound 13), optical isomers thereof and / or pharmacologically acceptable salts thereof, rough skin according to any one of <1> to <4> Preventive or ameliorating agent.

N−（p−メチルベンゾイル）セリン（化合物１）

N- (p-methylbenzoyl) serine (Compound 1)

N−（p−エチルベンゾイル）セリン（化合物２）

N- (p-ethylbenzoyl) serine (compound 2)

N−（p−メトキシベンゾイル）セリン（化合物３）

N- (p-methoxybenzoyl) serine (compound 3)

N−（p−フルオロベンゾイル）セリン（化合物４）

N- (p-fluorobenzoyl) serine (compound 4)

N−（p−トリフルオロメチルベンゾイル）セリン（化合物５）

N- (p-trifluoromethylbenzoyl) serine (compound 5)

N−（２−ナフトイル）セリン（化合物６）

N- (2-naphthoyl) serine (Compound 6)

N−（４−フェニルベンゾイル）セリン（化合物７）

N- (4-Phenylbenzoyl) serine (Compound 7)

N−（p−メチルベンゾイル）セリン メチルエステル（化合物８）

N- (p-methylbenzoyl) serine methyl ester (compound 8)

N−（２−ナフトイル）セリン メチルエステル（化合物９）

N- (2-naphthoyl) serine methyl ester (compound 9)

N−ベンゾイル−O−メチルセリン（化合物１０）

N-benzoyl-O-methylserine (compound 10)

N−（p−メチルベンゾイル）−O−メチルセリン（化合物１１）

N- (p-methylbenzoyl) -O-methylserine (Compound 11)

N−（p−メチルベンゾイル）−O−アセチルセリン（化合物１２）

N- (p-methylbenzoyl) -O-acetylserine (compound 12)

N−（２−ナフトイル）−O−メチルセリン（化合物１３）

N- (2-naphthoyl) -O-methylserine (Compound 13)

<6> The rough skin prevention according to any one of <1> to <5>, wherein the rough skin prevention or improvement action is an inhibitory action against an increase in transepidermal water loss (TEWL). Or an improving agent.
<7> A skin external preparation for preventing or improving rough skin, comprising the rough skin preventing or improving agent according to any one of <1> to <6>.
<8> The rough skin preventing or improving agent according to any one of <1> to <6> is contained in an amount of 0.0001% by mass to 20% by mass with respect to the total amount of the external preparation for skin. The skin external preparation for prevention or improvement of the rough skin of description.
<9> A skin external preparation for preventing or improving rough skin according to <7> or <8>, which is a cosmetic (including quasi-drugs).
<10> Prevention or improvement of rough skin containing one or more selected from compounds represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof. Topical skin preparation.
<11> The skin external preparation for preventing or improving rough skin according to any one of <7> to <10>, further comprising an anti-inflammatory component.

ADVANTAGE OF THE INVENTION According to this invention, the skin roughening prevention agent for skin rough prevention or improvement containing the novel rough skin prevention or improvement agent and the said component can be provided.

<The rough skin prevention or improvement agent of the present invention>
The rough skin preventing or improving agent of the present invention comprises the compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof. The rough skin prevention or improvement action of the rough skin prevention or improvement agent of the present invention includes a moisturizing action in addition to the normal rough skin prevention or improvement action. The rough skin prevention or amelioration agent of the present invention is a compound represented by the general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, and may be a rough skin prevention or improvement action. It can be applied without any particular limitation. As the rough skin prevention or improvement action exhibited by the rough skin prevention or improvement agent of the present invention, the rough skin prevention or improvement action for rough skin symptoms caused by an increase in transepidermal water loss (TEWL) due to a decrease in skin barrier function is preferable. It can be exemplified, and more preferably, the rough skin prevention or improvement action against rough skin caused by abnormal skin surface shape resulting from the increase in the transdermal moisture transpiration rate can be suitably exemplified. Suitable examples of the rough skin caused by abnormal skin surface shapes include rough skin formation, desquamation and the like. In such rough skin, it is difficult to maintain the skin surface form due to failure of the skin microcirculation, etc., and there are cases where inflammatory factors such as interleukin are released and secondary inflammation occurs. Since such inflammation is difficult to cure without improving abnormal changes in the skin surface shape, it is important to prevent or improve rough skin also in terms of preventing or improving rough skin with such inflammatory symptoms. is there. In addition, since the rough skin can be defined as rough skin caused by an increase in transepidermal water loss (TEWL), the rough skin improving agent of the present invention is rough skin caused by an increased amount of transdermal water transpiration. It is preferable to target. The rough skin caused by the increased amount of transdermal moisture transpiration in the present invention is 15% or more, more preferably 25% or more of the amount of transdermal moisture transpiration of the normal TEWL value. It is defined as a rough skin caused by increased transpiration.
Specifically, among the agents for preventing or improving rough skin according to the present invention, particularly preferable ones are exemplified by the treatment with a 5% by mass sodium lauryl sulfate (SDS) aqueous solution in the “skin roughening test” described in Example 1 described later. Components where the increase in skin moisture transpiration is suppressed compared to the control group, that is, the TEWL measurement value of the test sample administration group on the fifth day is compared with the TEWL measurement value of the control group on the fifth day A component exhibiting a low value can be suitably exemplified, and more preferably, the difference between the TEWL value of the control group on the first day and the test sample administration group before treatment with the 5 mass% SDS aqueous solution and the TEWL value on the fifth day When the ΔTEWL value corresponding to is calculated, a component in which the ΔTEWL value of the test substance administration group is suppressed to 90% or less compared to the ΔTEWL value of the control group can be suitably exemplified. In addition, if the suppression effect of transdermal moisture transpiration due to natural healing does not affect the evaluation of the rough skin prevention or improvement action, the test period and the TEWL measurement date for the evaluation of the rough skin prevention or improvement action will be special. There is no limitation. In addition, a component having an action of reducing the ΔTEWL value regardless of whether the skin is rough is defined as a rough skin improving action.

The compound represented by the general formula (1) of the present invention, its optical isomer and / or pharmacologically acceptable salt thereof is a novel rough skin prevention or amelioration agent, and is contained in a skin external preparation. It exhibits an excellent effect of preventing or improving rough skin. Among the compounds represented by the general formula (1) of the present invention, more preferred are compounds represented by the general formula (2), optical isomers thereof and / or pharmacologically acceptable compounds thereof. And the compounds represented by the general formula (3), optical isomers thereof and / or pharmacologically acceptable salts thereof can be suitably exemplified. Preferred examples include the compounds represented by 4), optical isomers thereof and / or pharmacologically acceptable salts thereof. Of these compounds, specific examples of particularly preferred compounds are N- (p-methylbenzoyl) serine (compound 1), N- (p-ethylbenzoyl) serine (compound 2), N- (p -Methoxybenzoyl) serine (compound 3), N- (p-fluorobenzoyl) serine (compound 4), N- (p-trifluoromethylbenzoyl) serine (compound 5), N- (2-naphthoyl) serine (compound 6), N- (4-phenylbenzoyl) serine (compound 7), N- (p-methylbenzoyl) serine methyl ester (compound 8), N- (2-naphthoyl) serine methyl ester (compound 9), N- Benzoyl-O-methylserine (compound 10), N- (p-methylbenzoyl) -O-methylserine (compound 11), N- (p-methylbenzoyl) -O-acetylserine (compound) 12) N-(2-naphthoyl) -O- methylserine (Compound 13), its optical isomers and / or their pharmacologically acceptable salts are suitably be exemplified.
In addition, the compound represented by the general formula (1) has an asymmetric carbon in its chemical structure, so that it is an (L) isomer, a (D) isomer or a racemic isomer, and further an (L) isomer. And (D) various forms of existence such as a racemic mixture in which the isomer has an arbitrary mixing ratio can be considered. The compound represented by the general formula (1) of the present invention includes all possible forms such as (D) isomer, (L) isomer, racemate, racemic mixture and the like. Further, among the compounds represented by the general formula (1) and optical isomers thereof, the (L) isomer can be suitably exemplified as a particularly preferable one. This is because it is excellent in properties such as a medicinal effect and safety in preventing or improving rough skin. In addition, one or more of the compounds represented by the general formula (1) of the present invention, optical isomers thereof and / or pharmacologically acceptable salts thereof are selected, and the skin external application of the present invention. It can be contained in the agent.

Here, the compound represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof will be described. In the formula, R1 is unsubstituted or has a substituent. R2 represents an aromatic group, R2 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, an acyl group having a linear or branched alkyl chain having 1 to 4 carbon atoms, and R3 represents a hydrogen atom Represents an atom or a linear or branched alkyl group having 1 to 4 carbon atoms. R1 represents an unsubstituted or substituted aromatic group, and specific examples include methylphenyl group, ethylphenyl group, propylphenyl group, butylphenyl group, methoxyphenyl group, ethoxyphenyl group, propyloxyphenyl. Group, butyloxyphenyl group, N-methylaminophenyl group, N-ethylaminophenyl group, N-propylaminophenyl group, N-butylaminophenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl Group, N, N-dipropylaminophenyl group, N, N-dibutylaminophenyl group, acetylphenyl group, propionylphenyl group, butyrylphenyl group, methoxycarbonylphenyl group, ethoxycarbonylphenyl group, propyloxycarbonylphenyl group, Butyloxycarbonylphenyl group Orophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, hydroxyphenyl, aminophenyl, pyridyl, methylpyridyl, ethylpyridyl, propylpyridyl, butylpyridyl, methoxypyridyl, ethoxypyridyl , Propyloxypyridyl group, butyloxypyridyl group, N-methylaminopyridyl group, N-ethylaminopyridyl group, N-propylaminopyridyl group, N-butylaminopyridyl group, N, N-dimethylaminopyridyl group, N, N-diethylaminopyridyl group, N, N-dipropylaminopyridyl group, N, N-dibutylaminopyridyl group, acetylpyridyl group, propionylpyridyl group, butyrylpyridyl group, methoxycarbonylpyridyl group, ethoxycarbonylpyridyl group, propiyl group Oxycarbonylpyridyl group, butyloxycarbonylpyridyl group, fluoropyridyl group, chloropyridyl group, bromopyridyl group, trifluoromethylpyridyl group, hydroxypyridyl group, aminopyridyl group, naphthyl group, methylnaphthyl group, ethylnaphthyl group, propylnaphthyl group Group, butylnaphthyl group, methoxynaphthyl group, ethoxynaphthyl group, propyloxynaphthyl group, butyloxynaphthyl group, N-methylaminonaphthyl group, N-ethylaminonaphthyl group, N-propylaminonaphthyl group, N-butylaminonaphthyl group Group, N, N-dimethylaminonaphthyl group, N, N-diethylaminonaphthyl group, N, N-dipropylaminonaphthyl group, N, N-dibutylaminonaphthyl group, acetylnaphthyl group, propionylnaphthyl group, butyrylnaphthyl group , Toxylcarbonylnaphthyl group, ethoxycarbonylnaphthyl group, propyloxycarbonylnaphthyl group, butyloxycarbonylnaphthyl group, fluoronaphthyl group, chloronaphthyl group, bromonaphthyl group, trifluoromethylnaphthyl group, hydroxynaphthyl group, aminonaphthyl group, biphenyl group , Methylbiphenyl group, ethylbiphenyl group, propylbiphenyl group, butylbiphenyl group, methoxybiphenyl group, ethoxybiphenyl group, propyloxybiphenyl group, butyloxybiphenyl group, N-methylaminobiphenyl group, N-ethylaminobiphenyl group, N -Propylaminobiphenyl group, N-butylaminobiphenyl group, N, N-dimethylaminobiphenyl group, N, N-diethylaminobiphenyl group, N, N-dipropylaminobiphenyl group, N , N-dibutylaminobiphenyl group, acetylbiphenyl group, propionylbiphenyl group, butyrylbiphenyl group, methoxycarbonylbiphenyl group, ethoxycarbonylbiphenyl group, propyloxycarbonylbiphenyl group, butyloxycarbonylbiphenyl group, fluorobiphenyl group, chlorobiphenyl group , Bromobiphenyl group, trifluoromethylbiphenyl group, hydroxybiphenyl group, aminobiphenyl group and the like can be suitably exemplified, and among these, methylphenyl group, ethylphenyl group, methoxyphenyl group, ethoxyphenyl group, Preferred examples include a fluorophenyl group, a trifluoromethylphenyl group, a naphthyl group, and a biphenyl group. Among the compounds represented by the general formula (1), the compound in which R1 is a methylphenyl group, an ethylphenyl group, a methoxyphenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a naphthyl group, or a biphenyl group, Excellent in preventing or improving rough skin. The number of substituents on the aromatic ring of R1 can be suitably exemplified as 0 to 3, more preferably 0 or 1, and the substituents on the aromatic ring can be present independently. . Moreover, the substitution position of the substituent on the aromatic ring of R1 is not particularly limited, but more preferably, the para position is preferred with respect to the amide bond to which the serine structure of the aromatic ring is bonded. R2 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or an acyl group having a linear or branched alkyl chain having 1 to 4 carbon atoms. Methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, acetyl group, propionyl group, butyryl group and the like can be suitably exemplified, more preferably , A hydrogen atom, a methyl group, an ethyl group, and an acetyl group. Among the compounds represented by the general formula (1), the compound in which R2 is a hydrogen atom, a methyl group, an ethyl group or an acetyl group is particularly excellent in preventing or improving rough skin. R3 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isobutyl group, and an n-butyl group. , Isobutyl group, sec-butyl group, tert-butyl group and the like can be preferably exemplified, and more preferably, a hydrogen atom and a methyl group can be suitably exemplified. Among the compounds represented by the general formula (1), the compound in which R3 is a hydrogen atom or a methyl group is particularly excellent in preventing or improving rough skin.
Of the compounds represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof, specific examples thereof include N- (p-methylbenzoyl). Serine (compound 1), N- (p-ethylbenzoyl) serine (compound 2), N- (p-methoxybenzoyl) serine (compound 3), N- (p-fluorobenzoyl) serine (compound 4), N- (P-trifluoromethylbenzoyl) serine (compound 5), N- (2-naphthoyl) serine (compound 6), N- (4-phenylbenzoyl) serine (compound 7), N- (p-methylbenzoyl) serine Methyl ester (compound 8), N- (2-naphthoyl) serine Methyl ester (compound 9), N-benzoyl-O-methylserine (compound 10), N- (p-methylbenzoyl) -O-methylserine Compound 11), N- (p-methylbenzoyl) -O-acetylserine (compound 12), N- (2-naphthoyl) -O-methylserine (compound 13), optical isomers thereof and / or pharmacological thereof Suitable examples of the salts are acceptable. The compounds represented by the general formulas (1) to (4), optical isomers thereof, and / or pharmacologically acceptable salts thereof are excellent for preventing rough skin by measuring transdermal water transpiration (TEWL value). Or an improvement effect and a moisturizing effect are recognized. Further, such a compound is excellent in solubility in a hydrophilic or lipophilic medium, and it is easy to formulate a skin external preparation. Furthermore, when it mix | blends with the stability and skin retention in a formulation, and it mix | blends with a skin external preparation, a high rough skin prevention or improvement effect and a moisturizing effect are exhibited. In addition, the compounds represented by the general formulas (1) to (4) have excellent safety, and when they are contained in an external preparation for skin, sensitization, skin irritation, etc. Skin safety is extremely high. In addition, by blending in an external preparation for skin together with an anti-inflammatory component to be described later, it exhibits an excellent effect for preventing or improving rough skin due to rough skin caused by abnormal skin surface shape.

  Here, the compound represented by the general formula (2), optical isomers thereof and / or pharmacologically acceptable salts thereof will be described. In the formula, R4 is unsubstituted or has a substituent. Represents an aromatic group, and R5 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or an acyl group having a linear or branched alkyl chain having 1 to 4 carbon atoms. R4 represents an unsubstituted or substituted aromatic group, and preferred examples thereof are preferably the same substituents as the substituent R1 of the compound represented by the general formula (1), and more preferred. Specific examples of the substituent include a methylphenyl group, an ethylphenyl group, a methoxyphenyl group, an ethoxyphenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a naphthyl group, and a biphenyl group. The number of substituents on the aromatic ring of R4 can be suitably exemplified as 0 to 3, more preferably 0 or 1, and the substituents on the aromatic ring can be present independently. . Further, the substitution position of the substituent on the aromatic ring of R4 is not particularly limited, but the para position is more preferred. R5 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or an acyl group having a linear or branched alkyl chain having 1 to 4 carbon atoms. Atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, acetyl group, propionyl group, butyryl group and the like can be suitably exemplified, and more Preferably, a hydrogen atom, a methyl group, and an acetyl group can be illustrated suitably. Specific examples of the compound represented by the general formula (2) and optical isomers thereof among the compound represented by the general formula (4) and compounds not included in the optical isomers are given below. N-benzoyl-O-methylserine, N- (methylbenzoyl) -O-methylserine, N- (ethylbenzoyl) -O-methylserine, N- (propylbenzoyl) -O-methylserine, N- (methoxybenzoyl) -O- Methylserine, N- (ethoxybenzoyl) -O-methylserine, N- (propyloxybenzoyl) -O-methylserine, N- (hydroxybenzoyl) -O-methylserine, N- (aminobenzoyl) -O-methylserine, N- ( Bromobenzoyl) -O-methylserine, N- (chlorobenzoyl) -O-methylserine, N- (fluorobenzoyl) -O-methylserine, N- (tri Fluoromethylbenzoyl) -O-methylserine, N- (pyridinecarbonyl) -O-methylserine, N- (methylpyridinecarbonyl) -O-methylserine, N- (ethylpyridinecarbonyl) -O-methylserine, N- (methoxypyridinecarbonyl) ) -O-methylserine, N- (ethoxypyridinecarbonyl) -O-methylserine, N- (naphthoyl) -O-methylserine, N- (methylnaphthoyl) -O-methylserine, N- (ethylnaphthoyl) -O- Methylserine, N- (methoxynaphthoyl) -O-methylserine, N- (ethoxynaphthoyl) -O-methylserine, N- (biphenylcarbonyl) -O-methylserine, N- (methylbiphenylcarbonyl) -O-methylserine, N -(Ethylbiphenylcarbonyl) -O-methylserine, N- (methoxybiphenyl carbonate) Rubonyl) -O-methylserine, N- (ethoxybiphenylcarbonyl) -O-methylserine, N-benzoyl-O-ethylserine, N- (methylbenzoyl) -O-ethylserine, N- (ethylbenzoyl) -O-ethylserine, N -(Propylbenzoyl) -O-ethylserine, N- (methoxybenzoyl) -O-ethylserine, N- (ethoxybenzoyl) -O-ethylserine, N- (propyloxybenzoyl) -O-ethylserine, N- (hydroxybenzoyl) -O-ethylserine, N- (aminobenzoyl) -O-ethylserine, N- (bromobenzoyl) -O-ethylserine, N- (chlorobenzoyl) -O-ethylserine, N- (fluorobenzoyl) -O-ethylserine, N -(Trifluoromethylbenzoyl) -O-ethylserine, N- (pyridinecarbonyl) O-ethylserine, N- (methylpyridinecarbonyl) -O-ethylserine, N- (ethylpyridinecarbonyl) -O-ethylserine, N- (methoxypyridinecarbonyl) -O-ethylserine, N- (ethoxypyridinecarbonyl) -O- Ethylserine, N- (naphthoyl) -O-ethylserine, N- (methylnaphthoyl) -O-ethylserine, N- (ethylnaphthoyl) -O-ethylserine, N- (methoxynaphthoyl) -O-ethylserine, N- (Ethoxynaphthoyl) -O-ethylserine, N- (biphenylcarbonyl) -O-ethylserine, N- (methylbiphenylcarbonyl) -O-ethylserine, N- (ethylbiphenylcarbonyl) -O-ethylserine, N- (methoxybiphenyl) Carbonyl) -O-ethylserine, N- (ethoxybiphenylcarbonyl) -O-e Tylserine, N-benzoyl-O-acetylserine, N- (methylbenzoyl) -O-acetylserine, N- (ethylbenzoyl) -O-acetylserine, N- (propylbenzoyl) -O-acetylserine, N- ( Methoxybenzoyl) -O-acetylserine, N- (ethoxybenzoyl) -O-acetylserine, N- (propyloxybenzoyl) -O-acetylserine, N- (hydroxybenzoyl) -O-acetylserine, N- (amino Benzoyl) -O-acetylserine, N- (bromobenzoyl) -O-acetylserine, N- (chlorobenzoyl) -O-acetylserine, N- (fluorobenzoyl) -O-acetylserine, N- (trifluoromethyl) Benzoyl) -O-acetylserine, N- (pyridinecarbonyl) -O-acetylserine, N- (methylpyridine cal Nyl) -O-acetylserine, N- (ethylpyridinecarbonyl) -O-acetylserine, N- (methoxypyridinecarbonyl) -O-acetylserine, N- (ethoxypyridinecarbonyl) -O-acetylserine, N- ( Naphthoyl) -O-acetylserine, N- (methylnaphthoyl) -O-acetylserine, N- (ethylnaphthoyl) -O-acetylserine, N- (methoxynaphthoyl) -O-acetylserine, N- ( Ethoxynaphthoyl) -O-acetylserine, N- (biphenylcarbonyl) -O-acetylserine, N- (methylbiphenylcarbonyl) -O-acetylserine, N- (ethylbiphenylcarbonyl) -O-acetylserine, N- (Methoxybiphenylcarbonyl) -O-acetylserine, N- (ethoxybiphenylcarbonyl) -O-acetylserine, N Benzoyl-O-propionylserine, N- (methylbenzoyl) -O-propionylserine, N- (ethylbenzoyl) -O-propionylserine, N- (propylbenzoyl) -O-propionylserine, N- (methoxybenzoyl)- O-propionylserine, N- (ethoxybenzoyl) -O-propionylserine, N- (propyloxybenzoyl) -O-propionylserine, N- (hydroxybenzoyl) -O-propionylserine, N- (aminobenzoyl) -O -Propionylserine, N- (bromobenzoyl) -O-propionylserine, N- (chlorobenzoyl) -O-propionylserine, N- (fluorobenzoyl) -O-propionylserine, N- (trifluoromethylbenzoyl) -O -Propionylserine, N- (pyridinecarbonyl) -O-propyl Lopionylserine, N- (methylpyridinecarbonyl) -O-propionylserine, N- (ethylpyridinecarbonyl) -O-propionylserine, N- (methoxypyridinecarbonyl) -O-propionylserine, N- (ethoxypyridinecarbonyl) -O -Propionylserine, N- (naphthoyl) -O-propionylserine, N- (methylnaphthoyl) -O-propionylserine, N- (ethylnaphthoyl) -O-propionylserine, N- (methoxynaphthoyl) -O -Propionylserine, N- (ethoxynaphthoyl) -O-propionylserine, N- (biphenylcarbonyl) -O-propionylserine, N- (methylbiphenylcarbonyl) -O-propionylserine, N- (ethylbiphenylcarbonyl)- O-propionylserine, N- (methoxybiphenyl Preferred examples include carbonyl) -O-propionylserine, N- (ethoxybiphenylcarbonyl) -O-propionylserine, optical isomers thereof and / or pharmacologically acceptable salts thereof. Among the compounds represented by the general formula (2) and optical isomers thereof, N- (methylbenzoyl) serine, N- (ethylbenzoyl) serine, N- (methoxybenzoyl) serine, N- (fluorobenzoyl) serine, N- (trifluoromethylbenzoyl) serine, N- (naphthoyl) serine, N- (phenylbenzoyl) serine, N-benzoyl-O-methylserine, N- (methylbenzoyl) -O- Methylserine, N- (naphthoyl) -O-methylserine, N- (methylbenzoyl) -O-acetylserine, its optical isomers and / or pharmacologically acceptable salts thereof can be suitably exemplified, and more preferably N- (p-methylbenzoyl) serine (compound 1), N- (p-ethylbenzoyl) serine (compound 2), N- (p-methoxybenzoy ) Serine (compound 3), N- (p-fluorobenzoyl) serine (compound 4), N- (p-trifluoromethylbenzoyl) serine (compound 5), N- (2-naphthoyl) serine (compound 6), N- (4-phenylbenzoyl) serine (compound 7), N-benzoyl-O-methylserine (compound 10), N- (p-methylbenzoyl) -O-methylserine (compound 11), N- (p-methylbenzoyl) ) -O-acetylserine (compound 12), N- (2-naphthoyl) -O-methylserine (compound 13), optical isomers thereof and / or pharmacologically acceptable salts thereof can be preferably exemplified.

  Here, the compound represented by the general formula (3), optical isomers thereof and / or pharmacologically acceptable salts thereof will be described. In the formula, R6 is unsubstituted or has a substituent. Represents an aromatic group, and R7 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. R6 represents an unsubstituted or substituted aromatic group, and preferable examples thereof are preferably the same substituents as the substituent R1 of the compound represented by the general formula (1), and more preferable. Specific examples of the substituent include a methylphenyl group, an ethylphenyl group, a methoxyphenyl group, an ethoxyphenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a naphthyl group, and a biphenyl group. The number of substituents on the aromatic ring of R6 can be suitably exemplified as 0 to 3, more preferably 0 or 1, and the substituents on the aromatic ring can be present independently. . Further, the substitution position of the substituent on the aromatic ring of R6 is not particularly limited, but the para position is more preferred. R7 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and specific examples include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n- A butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group and the like can be preferably exemplified, and a hydrogen atom, a methyl group, an ethyl group and an acetyl group can be suitably exemplified.

  Of the compounds represented by the general formula (3) and optical isomers thereof, the compounds represented by the general formula (4) and compounds not included in the optical isomers are specifically exemplified as follows: (Benzoyl) serine methyl ester, N- (methylbenzoyl) serine methyl ester, N- (ethylbenzoyl) serine methyl ester, N- (propylbenzoyl) serine methyl ester, N- (methoxybenzoyl) serine methyl ester, N- ( Ethoxybenzoyl) serine methyl ester, N- (propyloxybenzoyl) serine methyl ester, N- (hydroxybenzoyl) serine methyl ester, N- (aminobenzoyl) serine methyl ester, N- (chlorobenzoyl) serine methyl ester, N- (Fluorobenzoyl) serine methyl ester, N -(Trifluoromethylbenzoyl) serine methyl ester, N- (pyridinecarbonyl) serine methyl ester, N- (methylpyridinecarbonyl) serine methyl ester, N- (ethylpyridinecarbonyl) serine methyl ester, N- (methoxypyridinecarbonyl) Serine methyl ester, N- (ethoxypyridinecarbonyl) serine methyl ester, N- (naphthoyl) serine methyl ester, N- (methylnaphthoyl) serine methyl ester, N- (ethylnaphthoyl) serine methyl ester, N- (methoxy Naphthoyl) serine methyl ester, N- (ethoxynaphthoyl) serine methyl ester, N- (phenylbenzoyl) serine methyl ester, N- (methylphenylbenzoyl) serine methyl ester, N- (ethylphenol) Phenylbenzoyl) serine methyl ester, N- (methoxyphenylbenzoyl) serine methyl ester, N- (ethoxyphenylbenzoyl) serine methyl ester, N- (benzoyl) serine ethyl ester, N- (methylbenzoyl) serine ethyl ester, N- (Ethylbenzoyl) serine ethyl ester, N- (propylbenzoyl) serine ethyl ester, N- (methoxybenzoyl) serine ethyl ester, N- (ethoxybenzoyl) serine ethyl ester, N- (propyloxybenzoyl) serine ethyl ester, N -(Hydroxybenzoyl) serine ethyl ester, N- (aminobenzoyl) serine ethyl ester, N- (chlorobenzoyl) serine ethyl ester, N- (fluorobenzoyl) serine ethyl ester Ter, N- (trifluoromethylbenzoyl) serine ethyl ester, N- (pyridinecarbonyl) serine ethyl ester, N- (methylpyridinecarbonyl) serine ethyl ester, N- (ethylpyridinecarbonyl) serine ethyl ester, N- (methoxy Pyridinecarbonyl) serine ethyl ester, N- (ethoxypyridinecarbonyl) serine ethyl ester, N- (naphthoyl) serine ethyl ester, N- (methylnaphthoyl) serine ethyl ester, N- (ethylnaphthoyl) serine ethyl ester, N -(Methoxynaphthoyl) serine ethyl ester, N- (ethoxynaphthoyl) serine ethyl ester, N- (phenylbenzoyl) serine ethyl ester, N- (methylphenylbenzoyl) serine ethyl ester, N- ( Tylphenylbenzoyl) serine ethyl ester, N- (methoxyphenylbenzoyl) serine ethyl ester, N- (ethoxyphenylbenzoyl) serine ethyl ester, N- (benzoyl) serine propyl ester, N- (methylbenzoyl) serine propyl ester, N -(Ethylbenzoyl) serine propyl ester, N- (propylbenzoyl) serine propyl ester, N- (methoxybenzoyl) serine propyl ester, N- (ethoxybenzoyl) serine propyl ester, N- (propyloxybenzoyl) serine propyl ester, N- (hydroxybenzoyl) serine propyl ester, N- (aminobenzoyl) serine propyl ester, N- (chlorobenzoyl) serine propyl ester, N- (fluoro Nzoyl) serine propyl ester, N- (trifluoromethylbenzoyl) serine propyl ester, N- (pyridinecarbonyl) serine propyl ester, N- (methylpyridinecarbonyl) serine propyl ester, N- (ethylpyridinecarbonyl) serine propyl ester, N- (methoxypyridinecarbonyl) serine propyl ester, N- (ethoxypyridinecarbonyl) serine propyl ester, N- (naphthoyl) serine propyl ester, N- (methylnaphthoyl) serine propyl ester, N- (ethylnaphthoyl) serine Propyl ester, N- (methoxynaphthoyl) serine propyl ester, N- (ethoxynaphthoyl) serine propyl ester, N- (phenylbenzoyl) serine propyl ester, N- ( Tilphenylbenzoyl) serine propyl ester, N- (ethylphenylbenzoyl) serine propyl ester, N- (methoxyphenylbenzoyl) serine propyl ester, N- (ethoxyphenylbenzoyl) serine propyl ester, its optical isomers and / or their Preferred examples include pharmacologically acceptable salts. Among the compounds represented by the general formula (3) and optical isomers thereof, N- (methylbenzoyl) serine, N- (ethylbenzoyl) serine, N- (methoxybenzoyl) serine N- (fluorobenzoyl) serine, N- (trifluoromethylbenzoyl) serine, N- (naphthoyl) serine, N- (methylbenzoyl) serine methyl ester, N- (naphthoyl) serine methyl ester, optical isomers thereof, and / Or a pharmacologically acceptable salt thereof can be preferably exemplified, and more preferable examples include N- (p-methylbenzoyl) serine (compound 1), N- (p-ethylbenzoyl) serine (compound 2). ), N- (p-methoxybenzoyl) serine (compound 3), N- (p-fluorobenzoyl) serine (compound 4), N- (p-trifluoro) Romethylbenzoyl) serine (compound 5), N- (2-naphthoyl) serine (compound 6), N- (4-phenylbenzoyl) serine (compound 7), N- (p-methylbenzoyl) serine methyl ester (compound) 8), N- (2-naphthoyl) serine methyl ester (compound 9), optical isomers thereof and / or pharmacologically acceptable salts thereof can be preferably exemplified.

  Here, the compound represented by the general formula (4), optical isomers thereof and / or pharmacologically acceptable salts thereof will be described. In the formula, R8 is unsubstituted or has a substituent. Represents an aromatic group. R8 represents an unsubstituted or substituted aromatic group, and preferred examples thereof are preferably the same substituents as the substituent R1 of the compound represented by the general formula (1), and more preferably. Specific examples of the substituent include a methylphenyl group, an ethylphenyl group, a methoxyphenyl group, an ethoxyphenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a naphthyl group, and a biphenyl group. The number of substituents on the aromatic ring of R8 can be suitably exemplified as 0 to 3, more preferably 0 or 1, and the substituents on the aromatic ring can be present independently. . Further, the substitution position of the substituent on the aromatic ring of R8 is not particularly limited, but more preferably, the para position is preferred with respect to the amide bond to which the serine structure on the aromatic ring is bonded.

  Among the compounds represented by the general formula (4) and optical isomers thereof, specific examples of preferred compounds include N- (methylbenzoyl) serine, N- (ethylbenzoyl) serine, N- (propylbenzoyl). ) Serine, N- (butylbenzoyl) serine, N- (methoxybenzoyl) serine, N- (ethoxybenzoyl) serine, N- (propyloxybenzoyl) serine, N- (butyloxybenzoyl) serine, N- (hydroxybenzoyl) ) Serine, N- (aminobenzoyl) serine, N- (N′-methylaminobenzoyl) serine, N- (N′-ethylaminobenzoyl) serine, N- (N ′, N′-dimethylaminobenzoyl) serine, N- (N ′, N′-diethylaminobenzoyl) serine, N- (chlorobenzoyl) serine, N- (fluorobenzoyl) serine, N (Trifluoromethylbenzoyl) serine, N- (pyridinecarbonyl) serine, N- (methylpyridinecarbonyl) serine, N- (ethylpyridinecarbonyl) serine, N- (propylpyridinecarbonyl) serine, N- (methoxypyridinecarbonyl) Serine, N- (ethoxypyridinecarbonyl) serine, N- (propyloxypyridinecarbonyl) serine, N- (hydroxypyridinecarbonyl) serine, N- (aminopyridinecarbonyl) serine, N- (chloropyridinecarbonyl) serine, N- (Fluoropyridinecarbonyl) serine, N- (trifluoromethylpyridinecarbonyl) serine, N- (naphthoyl) serine, N- (methylnaphthoyl) serine, N- (ethylnaphthoyl) serine, N- (propylnaphthoyl) Serine, N- (methoxynaphth Yl) serine, N- (ethoxynaphthoyl) serine, N- (propyloxynaphthoyl) serine, N- (hydroxynaphthoyl) serine, N- (aminonaphthoyl) serine, N- (chloronaphthoyl) serine, N- (fluoronaphthoyl) serine, N- (trifluoromethylnaphthoyl) serine, N- (phenylbenzoyl) serine, N- (methylphenylbenzoyl) serine, N- (ethylphenylbenzoyl) serine, N- (propyl Phenylbenzoyl) serine, N- (methoxyphenylbenzoyl) serine, N- (ethoxyphenylbenzoyl) serine, N- (propyloxyphenylbenzoyl) serine, N- (hydroxyphenylbenzoyl) serine, N- (aminophenylbenzoyl) serine N- (chlorophenylbenzoyl) serine, N- (full (Rophenylbenzoyl) serine, N- (trifluoromethylphenylbenzoyl) serine, optical isomers thereof and / or pharmacologically acceptable salts thereof can be suitably exemplified, and more preferably N- (methylbenzoyl) Serine, N- (ethylbenzoyl) serine, N- (methoxybenzoyl) serine, N- (fluorobenzoyl) serine, N- (trifluoromethylbenzoyl) serine, N- (naphthoyl) serine, N- (phenylbenzoyl) serine , Its optical isomers and / or pharmacologically acceptable salts thereof can be preferably exemplified, and more preferably, N- (p-methylbenzoyl) serine (Compound 1), N- (p-ethylbenzoyl) Serine (compound 2), N- (p-methoxybenzoyl) serine (compound 3), N- (p-fluorobenzoyl) serine (compound ), N- (p-trifluoromethylbenzoyl) serine (compound 5), N- (2-naphthoyl) serine (compound 6), N- (4-phenylbenzoyl) serine (compound 7), its optical isomers and Preferred examples thereof include pharmacologically acceptable salts thereof.

  The compounds represented by the general formulas (1) to (4), optical isomers thereof and / or pharmacologically acceptable salts thereof are obtained by using commercially available serine or serine derivatives as starting materials, and The peptide can be synthesized according to a production method, or can be produced according to the method described in “Basics and Experiments of Peptide Synthesis (Maruzen)”. Such a compound can be used as it is by adding it to the external preparation for skin of the present invention, but it can also be treated with a pharmacologically acceptable acid or base, converted into a salt form, and used as a salt. . For example, mineral salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, para Organic acid salts such as toluene sulfonate and benzene sulfonate, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, triethylamine salt, triethanolamine salt, ammonium salt, Preferred examples include organic amine salts such as monoethanolamine salts and piperidine salts, and basic amino acid salts such as lysine salts and alginates.

  The compounds represented by the general formulas (1) to (4) thus obtained, their optical isomers and / or pharmacologically acceptable salts thereof suppress the increase in transpiration of transdermal water content. It exhibits excellent skin roughness prevention or improvement action and moisturizing action. In order to exert such pharmacological action, 1 selected from the compounds represented by the general formulas (1) to (4), optical isomers thereof and / or pharmacologically acceptable salts thereof. The total amount of the seeds or two or more types is 0.0001% by mass to 20% by mass, more preferably 0.001% by mass to 10% by mass, and still more preferably 0.005% by mass, based on the total amount of the external preparation for skin. It is preferable to contain 5 mass%. This is because the content of the compound represented by the general formulas (1) to (4), its optical isomer and / or pharmacologically acceptable salt thereof is 0.0001% by mass with respect to the total amount of the external preparation for skin. If the amount is less, the effect of preventing or improving pigmentation tends to decrease, and even if an amount exceeding 20% by mass is added, the effect tends to reach its peak, so the degree of freedom of prescription may decrease, The content is preferably based on the total amount of the external preparation for skin.

N−（p−メチルベンゾイル）−Ｌ−セリン （化合物１のＬ体）

N- (p-methylbenzoyl) -L-serine (L-form of Compound 1)

<Production Example 1: Method for producing N- (p-methylbenzoyl) -L-serine (L-form of Compound 1)>
[Step 1] Synthesis of p-methylbenzoyl chloride p-toluic acid (100 g, 0.734 mol) (Tokyo Kasei Kogyo Co., Ltd.) and toluene (500 mL) (Wako Pure Chemical Industries, Ltd.) in a well-dried eggplant flask And p-toluic acid was dissolved. To this solution, thionyl chloride (132.4 mL, 1.84 mol) (Wako Pure Chemical Industries, Ltd.) was added dropwise over 1 hour. After dropping, the mixture was heated under reflux for 2 hours. After the reaction, the reaction mixture was cooled to room temperature, and then remaining thionyl chloride and toluene were distilled off with a rotary evaporator. Toluene (200 mL) was added to the concentrate, and concentration was repeated twice. The residue finally obtained was dissolved in tetrahydrofuran (200 mL) (Wako Pure Chemical Industries, Ltd.) and subjected to the next step.
[Step 2] Synthesis of N- (p-methylbenzoyl) -L-serine L-serine (100 g, 0.952 mol) (Wako Pure Chemical Industries, Ltd.), potassium carbonate (131.5 g, 0.952 mol) in an eggplant flask ) (Wako Pure Chemical Industries, Ltd.) and water (1 L) were added and stirred vigorously. To this solution, p-methylbenzoyl chloride prepared in Step 1 was dissolved in tetrahydrofuran (Wako Pure Chemical Industries, Ltd.) and added dropwise over 30 minutes. In the middle of the process, pH 8 was maintained while adding potassium carbonate. It stirred for 1 hour after completion | finish of dripping. The reaction solution was added to water (1 L) prepared in a separate container, adjusted to pH 3 or less with hydrochloric acid, and cooled to 4 ° C. The precipitated crystals were filtered and recrystallized with a mixed solvent of ethanol (Wako Pure Chemical Industries, Ltd.) / Water = 6/4 to obtain 106.0 g (yield 64.7%) of the desired product. It was.

<Physical constant of L-form of Compound 1>
¹ H-NMR (d ₆ -DMSO): δ 2.36 (3H, s), 3.80 (2H, d), 4.47 (1H, q), 7.29 (2H, d), 7. 80 (2H, d), 8.29 (1H, d).

N−（p−メチルベンゾイル）−ＤＬ−セリン （化合物１のラセミ体）

N- (p-methylbenzoyl) -DL-serine (racemic compound 1)

<Production Example 2: Method for producing N- (p-methylbenzoyl) -DL-serine (racemic compound 1)>
The racemate of Compound 1 was synthesized according to the same method as the L-form of Compound 1 above using p-toluic acid (Tokyo Chemical Industry Co., Ltd.) and DL-serine (Peptide Institute Inc.).

<Physical constant of racemic compound 1>
¹ H-NMR (d ₆ -DMSO): δ 2.36 (3H, s), 3.68 (2H, m), 4.19 (1H, m), 7.26 (2H, d), 7. 76 (2H, d), 8.07 (1H, d).

N−（p−メチルベンゾイル）−Ｄ−セリン （化合物１のＤ体）

N- (p-methylbenzoyl) -D-serine (D-form of Compound 1)

<Production Example 3: Method for producing N- (p-methylbenzoyl) -D-serine (D-form of Compound 1)>
Using D-toluic acid (Tokyo Kasei Kogyo Co., Ltd.) and D-serine (Peptide Institute Inc.), the D-form of Compound 1 was synthesized in the same manner as the L-form of Compound 1 above.

<Physical constant of D-form of Compound 1>
¹ H-NMR (d ₆ -DMSO): δ 2.36 (3H, s), 3.80 (2H, d), 4.47 (1H, q), 7.29 (2H, d), 7. 80 (2H, d), 8.29 (1H, d).

N−（４−エチルベンゾイル）−Ｌ−セリン（化合物２のＬ体）

N- (4-ethylbenzoyl) -L-serine (L-form of Compound 2)

<Production Example 4: Method for producing L-form of Compound 2>
The L-form of Compound 2 was synthesized in the same manner as the L-form of Compound 1 above using p-ethylbenzoyl chloride (Wako Pure Chemical Industries, Ltd.) and L-serine (Peptide Laboratories).

<Physical constant of L-form of Compound 2>
¹ H-NMR (CD ₃ OD): δ 1.27 (3H, t), 2.73 (3H, q), 4.02 (2H, m), 4.72 (1H, m), 7.34 (2H, d), 7.82 (2H, d).

N−（４−メトキシベンゾイル）−Ｌ−セリン（化合物３のＬ体）

N- (4-methoxybenzoyl) -L-serine (L-form of Compound 3)

<Production Example 5: Method for producing L-form of Compound 3>
The p-methoxybenzoyl chloride (Tokyo Kasei Kogyo Co., Ltd.) and L-serine (Peptide Institute, Inc.) were used to synthesize the L-form of Compound 3 according to the same method as the L-form of Compound 1 described above.

<Physical constant of L-form of compound 3>
¹ H-NMR (CD ₃ OD): δ 3.87 (3H, s), 4.00 (2H, m), 4.71 (1H, m), 7.02 (2H, d), 7.88 (2H, d).

N−（４−フルオロベンゾイル）−Ｌ−セリン（化合物４のＬ体）

N- (4-Fluorobenzoyl) -L-serine (L-form of Compound 4)

<Production Example 6: Method for producing L-form of Compound 4>
The L-form of Compound 4 was synthesized in the same manner as the L-form of Compound 1 using p-fluorobenzoyl chloride (Wako Kiwaka Kogyo Co., Ltd.) and L-serine (Peptide Laboratories).

<Physical constant of L-form of Compound 4>
¹ H-NMR (CD ₃ OD): δ 4.01 (2H, m), 4.71 (1H, m), 7.22 (2H, m), 7.96 (2H, m).

N−（４−トリフルオロメチルベンゾイル）−Ｌ−セリン（化合物５のＬ体）

N- (4-trifluoromethylbenzoyl) -L-serine (L-form of Compound 5)

<Production Example 7: Method for producing L-form of Compound 5>
Using L-serine (Peptide Laboratories) and p- (trifluoromethyl) benzoyl chloride (Wako Pure Chemical Industries, Ltd.) did.

<Physical constant of L-form of compound 5>
¹ H-NMR (CD ₃ OD): δ 4.02 (2H, m), 4.74 (1H, m), 7.81 (2H, d), 8.07 (2H, d).

N−（２−ナフトイル）−Ｌ−セリン（化合物６のＬ体）

N- (2-naphthoyl) -L-serine (L-form of Compound 6)

<Production Example 8: Method for producing L-form of Compound 6>
L-serine (2.00 g, 19.0 mmol) (Peptide Institute, Inc.) was dispersed in tetrahydrofuran (19 mL) (Wako Pure Chemical Industries, Ltd.) and stirred under ice-cooling with 2N aqueous sodium hydroxide solution ( 19 mL) was added. Subsequently, 2-naphthoyl chloride (3.64 g, 19.1 mmol) (Tokyo Chemical Industry Co., Ltd.) was added. The water bath was removed, the temperature was returned to room temperature, and the mixture was stirred for 16 hours. Tetrahydrofuran was distilled off under reduced pressure. While stirring under ice cooling, hydrochloric acid (4 mL) (Wako Pure Chemical Industries, Ltd.) was added to adjust the pH to 2 or less. The solid was collected by filtration and washed thoroughly with water. tert-Butyl methyl ether (30 mL) (Tokyo Chemical Industry Co., Ltd.) was added, and insoluble matters were collected by filtration. This was thoroughly washed with tert-butyl methyl ether. Further, the mixture was washed successively with tert-butylmethyl ether: ethyl acetate (= 4: 1) and n-hexane to obtain 2.92 g (yield 59.2%) of Compound L.

<Physical constant of L-form of compound 6>
¹ H-NMR (CD ₃ OD): δ 4.04 (2H, m), 4.77 (1H, m), 7.59 (2H, m), 7.94 (4H, m), 8.46 (1H, s).

N−（４−フェニルベンゾイル）−Ｌ−セリン（化合物７のＬ体）

N- (4-Phenylbenzoyl) -L-serine (L-form of Compound 7)

<Production Example 9: Method for producing L-form of Compound 7>
Using L-serine (Peptide Institute Inc.) and 4-phenylbenzoyl chloride (Wako Pure Chemical Industries, Ltd.) and L-serine (Peptide Institute, Inc.), the L-form of Compound 7 was synthesized in the same manner as the L-form of Compound 1.

<Physical constant of L-form of compound 7>
¹ H-NMR (CD ₃ OD): δ 4.03 (2H, m), 4.75 (1H, m), 7.45 (3H, m), 7.73 (4H, m), 7.9 (2H, s), 8.37 (1H, d).

N−（４−メチルベンゾイル）−Ｌ−セリン メチルエステル（化合物８のＬ体）

N- (4-methylbenzoyl) -L-serine methyl ester (L-form of Compound 8)

<Production Example 10: Method for producing L-form of Compound 8>
L-serine methyl ester hydrochloride (1.55 g, 9.96 mmol) (Tokyo Chemical Industry Co., Ltd.) was dispersed in dichloromethane (30 mL) (Wako Pure Chemical Industries, Ltd.) and triethylamine (2.25 g, 22.2 mmol) (Wako Pure Chemical Industries, Ltd.) was added, and a solution of p-methoxybenzoyl chloride (1.78 g, 11.5 mmol) (Tokyo Chemical Industry Co., Ltd.) / Dichloromethane (5 mL) was added over 3 minutes with stirring under ice cooling. And dripped. After removing the water bath and returning to room temperature and stirring for 6 hours, the reaction solution was diluted with ethyl acetate (100 mL) (Wako Pure Chemical Industries, Ltd.), saturated sodium hydrogen carbonate solution (30 mL), 1N hydrochloric acid (50 mL) and Washed sequentially with saturated saline (30 mL, 60 mL × 2). The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.) and then filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1: 2), and fractions containing the desired product were collected and concentrated under reduced pressure to obtain 1.88 g of compound 8 in L form (yield 79). .5%).

<Physical constant of L-form of compound 8>
¹ H-NMR (CDCl ₃ ): δ 2.41 (3H, s), 2.58 (1H, brs), 3.83 (3H, s), 4.07 (2H, m), 4.88 ( 1H, m), 7.06 (1H, d), 7.25 (2H, d), 7.73 (2H, d).

N−（２−ナフトイル）−L−セリン メチルエステル（化合物９のＬ体）

N- (2-naphthoyl) -L-serine methyl ester (L-form of Compound 9)

<Production Example 11: Method for producing L-form of Compound 9>
Using L-naphthoyl chloride (Tokyo Chemical Industry Co., Ltd.) and L-serine methyl ester hydrochloride (Tokyo Chemical Industry Co., Ltd.), the L-form of Compound 9 was synthesized in the same manner as the L-form of Compound 8 above. .

<Physical constant of L-form of compound 9>
¹ H-NMR (d ₆ -DMSO): δ 3.67 (3H, s), 3.84 (2H, m), 4.61 (1H, m), 5.12 (1H, t), 7. 62 (2H, m), 8.02 (4H, m), 8.53 (1H, s), 8.75 (1H, d).

N−ベンゾイル−ＤＬ−O−メチルセリン（化合物１０のラセミ体）

N-benzoyl-DL-O-methylserine (racemic compound 10)

<Production Example 12: Method for producing racemic compound 10>
A racemic isomer of Compound 10 was synthesized according to the same method as the L isomer of Compound 1 using benzoyl chloride (Wako Pure Chemical Industries, Ltd.) and DL-O-methylserine (Tokyo Chemical Industry Co., Ltd.).

<Physical constant of racemic compound 10>
¹ H-NMR (d ₆ -DMSO): δ 3.28 (3H, s), 3.72 (2H, m), 4.63 (1H, m), 7.62 (2H, m), 7. 51 (3H, m), 7.88 (2H, s), 8.58 (1H, d).

N−（４−メチルベンゾイル）−ＤＬ−O−メチルセリン（化合物１１）

N- (4-Methylbenzoyl) -DL-O-methylserine (Compound 11)

<Production Example 13: Method for producing racemic compound 11>
A racemate of compound 11 was synthesized in the same manner as the L form of compound 1 using p-methylbenzoyl chloride (Sigma Aldrich) and DL-O-methylserine (Tokyo Chemical Industry Co., Ltd.).

<Physical constant of racemic body of compound 11>
¹ H-NMR (d ₆ -DMSO): δ 2.36 (3H, s), 3.28 (3H, s), 3.71 (2H, m), 4.63 (1H, m), 7. 28 (2H, d), 7.80 (2H, d), 8.49 (1H, d).

N−（ｐ−メチルベンゾイル）−０−アセチル−Ｌ−セリン （化合物１２のＬ体）

N- (p-methylbenzoyl) -0-acetyl-L-serine (L-form of Compound 12)

<Production Example 14: Method for producing L-form of Compound 12>
The L form of Compound 12 was synthesized in the same manner as the L form of Compound 1 using p-methylbenzoyl chloride (Sigma Aldrich) and O-acetyl-L-serine hydrochloride (Sigma Aldrich).

<Physical constant of L-form of compound 12>
¹ H-NMR (d ₆ -DMSO): δ 1.91 (3H, s), 2.36 (3H, s), 4.28 (1H, dd), 4.46 (1H, dd), 4. 71 (1H, m), 7.29 (2H, q), 7.78 (2H, q), 8.68 (1H, d).

N−（２−ナフトイル）−DL−O−メチルセリン （化合物１３のラセミ体）

N- (2-naphthoyl) -DL-O-methylserine (racemic compound 13)

<Production Example 15: Method for producing racemic compound 13>
A racemic isomer of Compound 13 was synthesized according to the same method as the L isomer of Compound 1 using 2-naphthoyl chloride (Tokyo Chemical Industry Co., Ltd.) and DL-O-methylserine (Tokyo Chemical Industry Co., Ltd.).

<Physical constant of racemic body of compound 13>
¹ H-NMR (d ₆ -DMSO): δ 3.31 (3H, s), 3.78 (2H, m), 4.72 (1H, m), 7.62 (2H, m), 8. 01 (4H, m), 8.53 (1H, s), 8.78 (1H, d).

<Anti-inflammatory component of the present invention>
The rough skin prevention or improvement agent of the present invention is a rough skin prevention or improvement agent comprising the compound represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof. Moreover, the rough skin prevention or improvement agent which consists of a compound represented by the said General formula (1) of this invention, its isomer, and / or those pharmacologically acceptable salt is contained in skin external preparation. Exhibits excellent rough skin prevention or improvement effect. In addition, the compound represented by the general formula (1), optical isomers thereof, and / or pharmacologically acceptable salts thereof are prevented from rough skin by being contained in a skin external preparation together with an anti-inflammatory component described later. Or the improvement effect, especially, the prevention or improvement effect with respect to the rough skin by abnormality of the skin surface shape by the fall of a skin barrier function improves. Suitable examples of rough skin with abnormal skin surface shape include rough skin that may be accompanied by scab formation, desquamation, and the like. In addition to being difficult to maintain, inflammatory factors such as interleukins may be released, resulting in secondary inflammation. Since such inflammation is difficult to cure without improving abnormal changes in the skin surface shape, it is important to prevent or improve rough skin also in terms of preventing or improving rough skin with such inflammatory symptoms. is there. Moreover, as a component which has the anti-inflammatory action of this invention, forms, such as a pure chemical substance and the extract derived from animals and plants, can be illustrated suitably. Here, the extracts derived from animals and plants are extracts themselves extracted from animals or plants, fractions obtained by fractionating and purifying animal or plant extracts, animals or plant extracts or fractions, solvents for purified products. It means the generic name of the removed material. When such a component having anti-inflammatory activity is contained in the external preparation for skin of the present invention, only one component having the following anti-inflammatory activity can be contained, or two or more components can be contained in combination. You can also.

  The anti-inflammatory component contained in the external preparation for skin together with the compound represented by the general formula (1) of the present invention can be applied without particular limitation as long as it has an anti-inflammatory action. Among the components having such an anti-inflammatory action, preferable examples include an extract of Camellia chamomile chamomile (chamomile), an extract of Osteraceae burdock burdock, an extract of leguminous clara cucumber, and birch birch. Anti-inflammatory plant extracts such as Clarinon, Glabrizine, Glycyrrhizic acid, Glycyrrhetinic acid and its derivatives, etc. Antibacterial plant extracts such as extracts of the genus birch, walnut extract, licorice extract The main components of the product can be exemplified, and more preferably, the extract of the asteraceae burdock burdock, the extract of the leguminous clara kudin, the extract of the birch family birch genus, the extract of the walnut family brunch, glycyrrhizin Preferred examples include those selected from acids, glycyrrhetinic acid derivatives and derivatives thereof, and more preferred. Suitable examples include glycyrrhizic acid and / or a pharmacologically acceptable salt thereof, glycyrrhetinic acid and / or a pharmacologically acceptable salt thereof, alkyl glycyrrhetinate and a pharmacologically acceptable salt thereof. .

  In addition, among the components having anti-inflammatory activity of the present invention, the plant extract is added to the plant body or processed product thereof in an amount of 1 to 20 times by using a lower alcohol such as water or ethanol as a solvent. Stir appropriately, and after several days at room temperature, for several hours at temperatures near the boiling point, after removing insolubles by filtration, etc., if necessary, the solvent is removed by distillation under reduced pressure, etc. Can be used after being purified and fractionated by column chromatography or the like using "Diaion HP20" or the like as a carrier. Preferred sites for preparing the plant extract include: Asteraceae chamomile chamomile, flower buds, Asteraceae burdock roots, leguminous clara genus radix, birch stems, birch family birch genus In the case of birch, the bark, in the case of walnuts, in the leaves, and in the case of legumes, the rhizome is preferably exemplified. Among the components having anti-inflammatory activity of the present invention, the anti-inflammatory component which is a plant extract is a compound represented by the general formula (1), its optical isomer and / or pharmacologically acceptable thereof. By including it in a skin external preparation together with salt, it exhibits an excellent effect of preventing or improving rough skin. In order for the anti-inflammatory component comprising the plant extract of the present invention to exhibit the above effects, the total amount is 0.00001% by mass to 15% by mass, more preferably 0.0001% by mass to the total amount of the external preparation for skin. The content is preferably 10% by mass, more preferably 0.01% by mass to 5% by mass. If the amount is too small, the pharmacological effect tends to decrease. If the amount is too large, the effect tends to reach its peak, and the degree of freedom of prescription may decrease.

  Among the components having anti-inflammatory activity of the present invention, glycyrrhizic acid and its pharmacologically acceptable salt, glycyrrhetinic acid and / or its pharmacologically acceptable salt, alkyl glycyrrhetinate and its pharmacological In addition to the anti-inflammatory effect, the salt acceptable for melanin has a melanin production inhibitory effect and the like. The external preparation for skin of the present invention relates to an external preparation for skin that exhibits an excellent effect on prevention or improvement of rough skin. When using an external preparation for skin for such applications, inflammation due to exposure to ultraviolet rays or the like is caused. Melanogenesis is increased by the inflammatory response and the various skin reactions that accompany it. Therefore, by containing a component having such an anti-inflammatory action, the inflammation subsides or further inflammation is suppressed, and an increase in the amount of transdermal water transpiration is suppressed. That is, the appearance of rough skin after inflammation is also suppressed. In addition, the pigmentation can be prevented from becoming serious.

  The glycyrrhetinic acid and derivatives thereof of the present invention are known as active ingredients of quasi-drugs. Examples of alkyl glycyrrhetinate and salts thereof include stearyl glycyrrhetinate, lauryl glycyrrhetinate and / or their pharmacological properties. Examples of glycyrrhizic acid and its salts include glycyrrhizic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate and the like. Among such glycyrrhetinic acid and its derivatives, stearyl glycyrrhetinate and glycyrrhizin Dipotassium acid is preferred. This is because it is already known that the use record is abundant and the safety is high. 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 above-described effect 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 ingredients are excellent in preventing or improving rough skin by being blended in a skin external preparation together with the compound represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof. Is expressed. In particular, it exerts an effect of preventing or improving rough skin due to abnormal skin surface shape due to a decrease in skin barrier function.

  The anti-inflammatory component of the present invention is excellent in rough skin by containing in a skin external preparation together with the compound represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof. Demonstrates preventive or ameliorating action. The external preparation for skin of the present invention is preferably a component having an effect of preventing or improving rough skin against symptoms of rough skin resulting from increased transepidermal water loss (TEWL) due to a decrease in skin barrier function, more preferably More preferably, it is a component having an effect of preventing or improving rough skin against rough skin due to abnormal skin surface shape resulting from an increase in transdermal moisture transpiration. Suitable examples of rough skin caused by abnormal skin surface shapes resulting from a decrease in skin barrier function include rough skin that may be accompanied by crust formation, desquamation, and the like. In such rough skin, it is difficult to maintain the skin surface morphology due to skin microcirculation insufficiency, etc., and inflammatory factors such as interleukins are released, resulting in secondary inflammation. Since such inflammation is difficult to cure without improving abnormal changes in the skin surface shape, it is important to prevent or improve rough skin also in terms of preventing or improving rough skin with such inflammatory symptoms. is there. For this reason, the skin external preparation of this invention may contain an anti-inflammatory component with the compound represented by the said General formula (1), its optical isomer, and / or those pharmacologically acceptable salts. preferable.

<Skin external preparation of the present invention>
The skin external preparation of the present invention contains an agent for preventing or improving rough skin comprising the compounds represented by the general formulas (1) to (4), optical isomers thereof and / or pharmacologically acceptable salts thereof. It is characterized by doing. In the skin external preparation of the present invention, in addition to the essential components, optional components usually used in cosmetics can be contained. Such optional ingredients include hydrocarbons such as squalane, petrolatum, microcrystalline wax, esters such as jojoba oil, carnauba wax, octyldodecyl oleate, triglycerides such as olive oil, beef tallow, coconut oil, etc. , Fatty acids such as stearic acid, oleic acid, retinoic acid, higher alcohols such as oleyl alcohol, stearyl alcohol, octyldodecanol, anionic surface activity such as sulfosuccinic acid ester and sodium polyoxyethylene alkyl sulfate Agents, amphoteric surfactants such as alkylbetaine salts, cationic surfactants such as dialkylammonium salts, sorbitan fatty acid esters, fatty acid monoglycerides, polyoxyethylene adducts thereof, polyoxyethylene alkyl ethers, polyoxyethylenes Nonionic surfactants such as fatty acid esters, polyhydric alcohols such as polyethylene glycol, glycerin, 1,3-butanediol, thickening / gelling agents, antioxidants, UV absorbers, Coloring agents, preservatives, powders and the like can be contained. Manufacture can be done without difficulty by treating these components according to conventional methods.

  Among the optional components described above, as a particularly preferable component, moisturizing such as hyaluronic acid and / or a pharmacologically acceptable salt thereof (meth) acryloyloxyethyl phosphorylcholine, which has been used for preventing or improving rough skin, has been used. Preferred examples include functional polymers, trehalose, sulfated trehalose, pullulan, maltose, saccharide derivatives such as carboxymethyldextran. The (meth) acryloyloxyethyl phosphorylcholine is a term that integrates methacryloyloxyethyl phosphorylcholine and acryloyloxyethyl phosphorylcholine. Such an amino acid or amine derivative of (meth) acrylic acid is a constituent monomer and Examples of the homopolymer or copolymer include (meth) acryloyloxyethyl phosphorylcholine homopolymer, (meth) acryloyloxyethyl phosphorylcholine, (meth) acrylic acid butyl copolymer, (meth) acryloyloxyethyl phosphorylcholine ( Suitable examples include (meth) acrylic acid stearyl copolymer, poly (meth) acryloyl lysine, poly (meth) acryloyl glycine and the like. Such a thing already exists in the market, and such a commercial item can be purchased and utilized. Preferred commercially available products include, for example, lipid HM (methacryloyloxyethyl phosphorylcholine homopolymer (molecular weight 100000); manufactured by Nippon Oil & Fats Co., Ltd.), lipid PMB (methacryloyloxyethyl phosphorylcholine / (meth) butyl acrylate copolymer (molecular weight). 600,000); manufactured by NOF Corporation, PM lysine (polymethacryloyl lysine; manufactured by Gifu Shellac Co., Ltd.), and the like. Such components are each preferably 0.001% to 3% by mass, more preferably 0.05% to 1% by mass, and still more preferably 0.01 to 0.1% by mass. Furthermore, it is also preferable to contain a moisturizing oil, such as N-acyl glutamate. The content of such components is preferably 0.01% by mass to 10% by mass, more preferably 0.1% by mass to 5% by mass.

  The external preparation for skin of the present invention contains the above-mentioned essential components. The external preparation for skin of the present invention is not particularly limited as long as it is known in the cosmetics field, and it is an agent for lotion preparations, oil-in-water emulsion preparations, water-in-oil emulsion preparations, composite emulsion emulsion preparations and the like. The form can be illustrated preferably, and the form of the emulsifier may be 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 this invention can be manufactured by processing these essential components and arbitrary components according to a conventional method and processing them into lotions, emulsions, essences, creams, pack cosmetics, cleansing agents and the like. As long as the dosage form can be adapted to the skin, any dosage form is possible, but since the active ingredient penetrates the skin and exerts its effect, the lotion and emulsion that are well-familiar with the skin , Cream, essence and the like are more preferable.

In the following, the present invention will be described in more detail with reference to examples, but it goes without saying that the present invention is not limited to such examples.

<Test example 1: rough skin improvement test 1>
Using three male employees (age 25-45 years old) with a rough skin model induced with a 5% by mass sodium lauryl sulfate (SLS) aqueous solution, the test samples (samples 1-2) and control shown in Table 1 -Rule (40% PEG400 aqueous solution) was administered according to the schedule shown in Table 2, and the rough skin prevention or improvement agent of the present invention was evaluated. In other words, two 1.5cmφ parts were provided on the inner side of the forearm, and after measuring the transdermally dissipated moisture (TEWL) with Integral's “Tevameter”, 5% SLS aqueous solution was soaked in the adhesive bandage. It was affixed for 30 minutes on the first, second, third and fourth days. The test sample (1st to 4th times) was applied 3 times a day to the same site as the SLS aqueous solution after applying the 5 mass% SLS aqueous solution from the 1st day to the 4th day. On the fifth day, TEWL was measured. A value obtained by subtracting the TEWL value on the test start date from the TEWL value on the fifth day was defined as “ΔTEWL”, and this value was used as an evaluation target. Table 2 shows the work procedure, and Table 3 shows the test results. From the results of Table 3, it can be seen that the rough skin prevention or improvement agent comprising the compound represented by the general formula (1) of the present invention has a remarkable rough skin prevention or improvement effect. The ΔTEWL ratio (%) in Table 3 represents the degree of improvement in rough skin. Specifically, the TEWL measurement value before treatment with the 5 mass% SLS aqueous solution on the first day of the control group and the test sample administration group. Then, the ΔTEWL value corresponding to the difference in TEWL value after the treatment with the 5 mass% SDS aqueous solution on the fifth day is calculated and calculated as the ΔTEWL value of the test sample administration group with respect to the ΔTEWL value of the control group.

  From the results shown in Table 3, the cosmetics 1 and 2 were found to have a remarkable rough skin prevention or improvement effect as compared with the control (40% PEG400 aqueous solution). From the results of Table 3, the rough skin prevention or amelioration agent comprising the compound represented by the general formula (1) of the present invention, optical isomers thereof and / or pharmacologically acceptable salts thereof, prevents rough skin. Or it was confirmed that there exists an improving action.

<Production Example 16: Method 1 for producing skin external preparation of the present invention>
According to the formulations shown in Table 4 and Table 5 below, the external preparation for skin of the present invention (a cream preparation type, cosmetics 1-2) was prepared. That is, the component B was heated to 80 ° C., stirred and dissolved, and then an appropriate amount of 10% (mass%) potassium hydroxide aqueous solution was added to adjust the pH to 6.5. Finally, water was added so that the total weight was 524.5 g (referred to as mixture A). In addition, component (a) was heated to 80 ° C., stirred, and dissolved (referred to as mixture B). Mixing mixture A heated to 80 ° C. is gradually added to mixture B with emulsification, emulsified, and the particles are homogenized with a homogenizer, followed by stirring and cooling to external preparation for skin (cream formulation, cosmetics 1-2) Was made. By the same operation, Comparative Example 1 in which “water roughening prevention or amelioration agent of the present invention” in Table 6 was replaced with “water” was produced.

<Test Example 2: Rough skin improvement test 2>
A rough skin improvement test was carried out according to the method described in Example 1 for cosmetics 1-2 and Comparative Example 1 prepared according to the method described in Example 2. The results are shown in Table 6. The external preparation for skin according to the present invention (cosmetics 1 and 2) showed an excellent effect of preventing or improving rough skin. This action is due to the effect of containing “a rough skin preventing or improving agent comprising the compound represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof”.

<Production Example 17: Method 2 for producing skin external preparation of the present invention>
The external preparation for skin of the present invention (cream formulation, cosmetic 3) having the formulation components described in Table 7 below was prepared, and a skin roughness improvement test was performed according to the method described in Example 3. When ΔTEWL value was measured for cosmetic 3, the measured value was 15.6, indicating excellent skin roughness prevention or improvement. This action is due to the effect of containing the “compound represented by the general formula (1) (compound 1)” and “anti-inflammatory component (stearyl glycyrrhetinate)”.

  The present invention can be applied to cosmetics for preventing or improving rough skin.

Claims (11)

1) A rough skin preventing or improving agent comprising a compound represented by the following general formula (1), an optical isomer thereof and / or a pharmacologically acceptable salt thereof.

(1)
[Wherein, R1 represents an unsubstituted or substituted aromatic group, R2 represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched group having 1 to 4 carbon atoms. R3 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. ] The compound represented by the general formula (1) is a compound represented by the following general formula (2), an optical isomer thereof and / or a pharmacologically acceptable salt thereof, The rough skin preventing or improving agent according to claim 1.

(2)
[Wherein R4 represents an unsubstituted or substituted aromatic group, R5 represents a linear or branched alkyl group having 1 to 4 carbon atoms, or a linear or branched alkyl chain having 1 to 4 carbon atoms. Represents an acyl group having ] The compound represented by the general formula (1) is a compound represented by the following general formula (3), an optical isomer thereof and / or a pharmaceutically acceptable salt thereof. The rough skin preventing or improving agent according to claim 1.

(3)
[Wherein, R6 represents an unsubstituted or substituted aromatic group, and R7 represents a linear or branched alkyl group having 1 to 4 carbon atoms. ] The compound represented by the general formula (1) is a compound represented by the following general formula (4), an optical isomer thereof and / or a pharmaceutically acceptable salt thereof. The rough skin preventing or improving agent according to claim 1.

(4)
[Wherein R8 represents an unsubstituted or substituted aromatic group. ] The compound represented by the general formula (1) is N- (p-methylbenzoyl) serine (compound 1), N- (p-ethylbenzoyl) serine (compound 2), N- (p-methoxybenzoyl) serine. (Compound 3), N- (p-fluorobenzoyl) serine (Compound 4), N- (p-trifluoromethylbenzoyl) serine (Compound 5), N- (2-naphthoyl) serine (Compound 6), N- (4-phenylbenzoyl) serine (compound 7), N- (p-methylbenzoyl) serine methyl ester (compound 8), N- (2-naphthoyl) serine methyl ester (compound 9), N-benzoyl-O-methylserine (Compound 10), N- (p-methylbenzoyl) -O-methylserine (Compound 11), N- (p-methylbenzoyl) -O-acetylserine (Compound 12), N- (2-naphthoyl) ) -O-methylserine (compound 13), optical isomers thereof and / or pharmacologically acceptable salts thereof, prevention of rough skin according to any one of claims 1 to 4, Or an improving agent.

N- (p-methylbenzoyl) serine (Compound 1)

N- (p-ethylbenzoyl) serine (compound 2)

N- (p-methoxybenzoyl) serine (compound 3)

N- (p-fluorobenzoyl) serine (compound 4)

N- (p-trifluoromethylbenzoyl) serine (compound 5)

N- (2-naphthoyl) serine (Compound 6)

N- (4-Phenylbenzoyl) serine (Compound 7)

N- (p-methylbenzoyl) serine methyl ester (compound 8)

N- (2-naphthoyl) serine methyl ester (compound 9)

N-benzoyl-O-methylserine (compound 10)

N- (p-methylbenzoyl) -O-methylserine (Compound 11)

N- (p-methylbenzoyl) -O-acetylserine (compound 12)

N- (2-naphthoyl) -O-methylserine (Compound 13) 6. The rough skin prevention or improvement agent according to any one of claims 1 to 5, wherein the rough skin prevention or improvement action is an inhibitory action against an increase in transepidermal water loss (TEWL). . A skin external preparation for preventing or improving rough skin, comprising the rough skin preventing or improving agent according to any one of claims 1 to 6. 8. The rough skin according to claim 7, wherein the rough skin preventing or improving agent according to any one of claims 1 to 6 is contained in an amount of 0.0001% by mass to 20% by mass with respect to the total amount of the external preparation for skin. An external preparation for skin prevention or improvement. The skin external preparation for preventing or improving rough skin according to claim 7 or 8, which is a cosmetic (including quasi-drugs). Skin for preventing or improving rough skin, comprising one or more selected from the compounds represented by the general formula (1), optical isomers thereof and / or pharmacologically acceptable salts thereof. Topical agent. The skin external preparation for preventing or improving rough skin according to any one of claims 7 to 10, further comprising an anti-inflammatory component.