JP6254808B2 - Whitening agent and anti-photoaging agent containing benzylidene azolidine derivative or a salt thereof - Google Patents

Description

  The present invention relates to a whitening agent, an anti-photoaging agent, a tyrosinase inhibitor, a melanin production inhibitor, a reactive oxygen species production inhibitor, an SOD-like active agent, and a catalase-like active agent containing a benzylidene azolidine derivative or a salt thereof.

  Non-uniform skin color, wrinkles, sagging, and thinning of skin, such as skin spots such as spots, buckwheat, pigmentation after sunburn, liver spots and sparrow eggs, and solar lentigo (Nikko Kuroko) The rough skin is considered to be a kind of photoaging reaction caused by various stimuli such as ultraviolet rays and inflammation. The main route of action that has been considered in the past is that the activity of tyrosinase is increased by the direct action of ultraviolet rays and reactive oxygen species (singlet oxygen, superoxide anion, hydrogen peroxide, etc.) on melanocytes, Melanin synthesis was promoted to induce pigmentation. In recent years, it has also been reported that skin aging such as wrinkles and sagging is promoted as a result of an inflammatory reaction caused by ultraviolet rays or reactive oxygen species.

  In order to suppress such photoaging reaction, to inhibit tyrosinase activity in the melanin production process, to suppress melanin production, to suppress and eliminate reactive oxygen species generated by UV exposure, and to promote melanin excretion based on accelerated turnover In addition, those intended for activation of cell division of the basal cells of the skin can be considered.

  Moreover, ascorbic acid or a derivative thereof, arbutin, a microbial extract, a fermentation product, and a plant extract are known as a whitening agent and an anti-photoaging agent having the above-described inhibitory action. In recent years, for example, hydridolactone A (see Patent Document 1), hesperidin (see Patent Document 2), cryptomellidiol (see Patent Document 3), chafuroside A (see Patent Document 4), pogozton derivative (see Patent Document 5) ) Etc. have been reported.

JP-A-5-306231 JP 2005-132793 A JP2012-1553639A JP 2012-219076 A JP2013-124249A

  The present invention provides new drugs (whitening agents, anti-photoaging agents, tyrosinase inhibitors, melanin production inhibitors, reactive oxygen species production inhibitors, SOD (superoxide dismutase) -like activators, and catalase-like activators). The purpose is to provide.

  As a result of intensive studies to solve the above problems, the present inventors have found that the above object can be achieved by the following novel benzylidene azolidine derivatives or salts thereof, and have completed the present invention.

  That is, the whitening agent of the present invention is characterized by containing a benzylidene azolidine derivative represented by the general formula (I) or a salt thereof.

(In Structural Formula (I), n is an integer of 1 to 5, A ¹ is O, S, or N—A ⁴ , and A ² , A ^3, and A ⁴ are each independently a hydrogen atom. , An alkyl group having 1 to 8 carbon atoms which may be substituted with a hydroxyl group, a functional group (1) represented by the following structural formula (1), a functional group (2) represented by the following structural formula (2), or It is a functional group (3) represented by the following structural formula (3) (provided that at least one of A ² , A ³ and A ⁴ contains one or more hydroxyl groups), and n is 2 to 5 A plurality of A ³ —O— may be the same or different.)
(In Structural Formula (1), X ¹ is an alkylene group having 2 to 4 carbon atoms, R ¹ is a hydroxyalkyl group having 2 to 4 carbon atoms, and m is an integer of 1 to 4. When m is an integer of 2 to 4, a plurality of X ¹ may be the same or different.)
(In Structural Formula (2), X ² is an alkylene group having 2 to 4 carbon atoms, R ² is a hydroxyalkyl group having 2 to 4 carbon atoms, p is 1 or 2, and q is 0. And when q is an integer of 2 to 4, a plurality of X ² may be the same or different.)
(In Structural Formula (3), X ^3a and X ^3b are each independently an alkylene group having 2 to 4 carbon atoms, and R ^3a and R ^3b are each independently a hydroxyalkyl group having 2 to 4 carbon atoms. And r is 1 or 2, and s and t are each independently an integer of 0 to 4. When s is an integer of 2 to 4, a plurality of X ^3a may be the same or different. (If t is an integer of 2 to 4, the plurality of X ^3b may be the same or different.)

  The whitening agent in the present invention is an agent that improves, suppresses / reduces / prevents, prevents or delays skin pigmentation due to melanin pigments particularly related to dullness and itching of the skin and liver spots. Say. The whitening agent has a whitening effect that keeps the skin white.

  The anti-photoaging agent of the present invention is characterized by containing a benzylidene azolidine derivative represented by the above general formula (I) or a salt thereof.

  In addition, the anti-photoaging agent in the present invention is an agent that improves, suppresses, reduces, prevents, prevents or delays aging phenomena such as wrinkles, sagging, dullness, blotches, and bears caused by ultraviolet rays and reactive oxygen species. Say. The anti-photoaging agent has an action of suppressing damage to the skin by ultraviolet rays, such as skin elasticity reduction, skin blackening, yellowing increase, skin glycation, keratin water content reduction, etc. It is excellent in suppressing photoaging.

  In addition, the tyrosinase inhibitor of the present invention is characterized by containing a benzylidene azolidine derivative represented by the above general formula (I) or a salt thereof.

  The tyrosinase inhibitor in the present invention refers to an agent that inhibits or reduces the activity of tyrosinase involved in melanin synthesis.

  Moreover, the melanin production inhibitor of this invention is characterized by including the benzylidene azolidine derivative represented by the said general formula (I), or its salt.

  In addition, the melanin production inhibitor in this invention means what inhibits or reduces melanin production.

  Moreover, the reactive oxygen species production inhibitor of the present invention is characterized by containing a benzylidene azolidine derivative represented by the above general formula (I) or a salt thereof.

  In addition, the reactive oxygen species production inhibitor in the present invention refers to an agent that inhibits or reduces the production of reactive oxygen species caused by exposure to ultraviolet rays or the like. It also has a function to erase active oxygen species generated by UV exposure.

  The SOD-like activator of the present invention is characterized by containing a benzylidene azolidine derivative represented by the above general formula (I) or a salt thereof.

  The SOD-like active agent in the present invention refers to an agent that inhibits or reduces the production of superoxide anion caused by exposure to ultraviolet rays.

  The catalase-like active agent of the present invention is characterized by containing a benzylidene azolidine derivative represented by the above general formula (I) or a salt thereof.

  The catalase-like active agent in the present invention refers to an agent that inhibits or reduces the production of hydrogen peroxide generated by exposure to ultraviolet rays.

In the whitening agent, anti-photoaging agent, tyrosinase inhibitor, melanin production inhibitor, reactive oxygen species production inhibitor, SOD-like activator, and catalase-like activator of the present invention, A ^{2 in the} structural formula (I) , A ³ and A ⁴ may be the functional group (1), the functional group (2), or the functional group (3).

In the whitening agent, anti-photoaging agent, tyrosinase inhibitor, melanin production inhibitor, reactive oxygen species production inhibitor, SOD-like activator, and catalase-like activator of the present invention, A ^{2 in the} structural formula (I) And / or A ³ may be a hydrogen atom, an alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, the functional group (1), the functional group (2), or the functional group (3). it can.

In the whitening agent, anti-photoaging agent, tyrosinase inhibitor, melanin production inhibitor, reactive oxygen species production inhibitor, SOD-like activator, and catalase-like activator of the present invention, the structural formula (I) has the following structure: A benzylidene azolidine derivative represented by the formula (II) or a salt thereof can be used.
(In the structural formula (II), n ′ is an integer of 0 to 4, and when n ′ is an integer of 1 to 4, a plurality of A ³ —O— may be the same or different. .)

In the whitening agent, anti-photoaging agent, tyrosinase inhibitor, melanin production inhibitor, reactive oxygen species production inhibitor, SOD-like activator, and catalase-like activator of the present invention, the structural formula (I) has the following structure: A benzylidenehydantoin derivative represented by the formula (III) or a salt thereof can be used.

  According to the present invention, a novel drug (whitening agent, anti-photoaging agent, tyrosinase inhibitor, melanin production inhibitor, reactive oxygen species production inhibitor, SOD-like activator, comprising the benzylidene azolidine derivative or a salt thereof as an active ingredient. And catalase-like activators). The benzylidene azolidine derivative or a salt thereof is excellent in solubility (particularly hydrophilic) in the base and easy to formulate (water-soluble agent).

  Further, a whitening agent, an anti-photoaging agent, a tyrosinase inhibitor, a melanin production inhibitor, a reactive oxygen species production inhibitor, an SOD-like active agent, comprising the benzylidene azolidine derivative of the present invention or a salt thereof as an active ingredient, The catalase-like active agent can take various dosage forms and forms such as external compositions (external preparations for skin, cosmetics, etc.), internal preparations and foods and drinks as described later. In particular, it is useful as an external composition, particularly a skin external preparation, and a cosmetic, which can be directly applied to a site damaged by ultraviolet rays.

The graph which shows the measurement result of tyrosinase inhibitory activity evaluation in an Example The graph which shows the measurement result of tyrosinase inhibitory activity evaluation in an Example The graph which shows the measurement result of the melanin production suppression evaluation in an Example The graph which shows the measurement result of SOD like activity evaluation in an Example The graph which shows the measurement result of catalase-like activity evaluation in an Example The graph which shows the measurement result of catalase-like activity evaluation in an Example

  Hereinafter, embodiments of the present invention will be described in detail.

[Benzylidene azolidine derivatives and salts thereof]
The benzylidene azolidine derivative in the present invention is represented by the following structural formula (I).

In the structural formula (I), the moiety represented by the following structural formula (i) and the moiety represented by the following structural formula (ii) are respectively represented by “benzene ring part (i)” and “azolidine moiety (ii)”. ".

As shown in the above structural formula (I), the azolidine moiety (ii) includes “NA ² ”, and when A ¹ is “NA ⁴ ”, “NA ⁴ ” is include. The nitrogen atom of “NA ² ” or “NA ⁴ ” is a basic nitrogen atom, and an inorganic acid or an organic acid can be added to the N atom to form an acid addition salt. Here, examples of the inorganic acid include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and the like. Examples of organic acids include acetic acid, citric acid, gluconic acid, tartaric acid, fumaric acid, maleic acid, lactic acid, methanesulfonic acid, and paratoluenesulfonic acid.

  Further, the salt of the benzylidene azolidine derivative in the present invention is preferable in that the hydrophilicity is improved and the handling becomes easy because it tends to be solid, compared to the benzylidene azolidine derivative in the present invention.

In the structural formulas in the present specification excluding the structural formula (I) and the structural formula (I), “n”, “A ¹ ”, “A ² ”, and “A ³ ” are defined as follows: Is done.

(1) “n”
n is an integer of 1 to 5, and can be an integer of 1 to 3.

(2) “A ¹ ”
A ¹ is O, S, or N—A ⁴ , and preferably N—A ⁴ .

(3) “A ² ”, “A ³ ” and “A ⁴ ”
A ² , A ³ and A ⁴ are each independently a hydrogen atom, an alkyl group having 1 to 8 carbon atoms which may be substituted with a hydroxyl group, or a functional group represented by the following structural formula (1) (functional group ( 1)), a functional group represented by the following structural formula (2) (functional group (2)), or a functional group represented by the following structural formula (3) (functional group (3)). However, at least one of A ² , A ^3, and A ⁴ includes one or more hydroxyl groups.

In addition, at least one of A ² , A ^3, and A ⁴ is preferably the functional group (1), the functional group (2), or the functional group (3), and A ² , A ³ And at least two of A ⁴ are preferably the functional group (1), the functional group (2), or the functional group (3).
(In Structural Formula (1), X ¹ is an alkylene group having 2 to 4 carbon atoms, R ¹ is a hydroxyalkyl group having 2 to 4 carbon atoms, and m is an integer of 1 to 4. When m is an integer of 2 to 4, a plurality of X ¹ may be the same or different.)
(In Structural Formula (2), X ² is an alkylene group having 2 to 4 carbon atoms, R ² is a hydroxyalkyl group having 2 to 4 carbon atoms, p is 1 or 2, and q is 0. And when q is an integer of 2 to 4, a plurality of X ² may be the same or different.)
(In Structural Formula (3), X ^3a and X ^3b are each independently an alkylene group having 2 to 4 carbon atoms, and R ^3a and R ^3b are each independently a hydroxyalkyl group having 2 to 4 carbon atoms. And r is 1 or 2, and s and t are each independently an integer of 0 to 4. When s is an integer of 2 to 4, a plurality of X ^3a may be the same or different. (If t is an integer of 2 to 4, the plurality of X ^3b may be the same or different.)

In addition, when n is an integer of 2 to 5, a plurality of A ³ —O— may be the same or different.

Further, from the viewpoint of exhibiting high water solubility, at least one of A ¹ , A ² and “A ³ —O—” is preferably a functional group having a hydroxyl group.

(3-1) "C1-C8 alkyl group optionally substituted with a hydroxyl group"
The “alkyl group having 1 to 8 carbon atoms which may be substituted with a hydroxyl group” may be linear or branched as long as it is an alkyl group having 1 to 8 carbon atoms. Even if it is substituted with (hydroxyalkyl group), it may be an alkyl group not substituted with a hydroxyl group. Among these, from the viewpoint of improving water-solubility, a linear or branched hydroxyalkyl group having 1 to 8 carbon atoms is preferable.

  Moreover, carbon number of the said alkyl group can be set to 1-8, and can be set to 1-4.

(3-2) "Functional group (1)"
The functional group (1) is a functional group represented by the structural formula (1). Here, X ¹ is an alkylene group having 2 to 4 carbon atoms, and the alkylene group may be linear or branched. In X ¹ , the alkylene group preferably has 1 to 2 carbon atoms (for example, the alkylene group is a methylene group (—CH ₂ —) or an ethylene group (—CH ₂ CH ₂ —)).

R ¹ is a hydroxyalkyl group having 2 to 4 carbon atoms (an alkyl group substituted with at least one hydroxyl group), can be a hydroxyalkyl group having 2 carbon atoms, and is a hydroxyethyl group (—CH ₂ CH ₂ OH).

  m is an integer of 1-4, and can be an integer of 1-2.

In addition, when m is an integer of 2 to 4, a plurality of X ¹ may be the same or different. In this case, it is preferable that a plurality of X ¹ are a methylene group (—CH ₂ —) or an ethylene group (—CH ₂ CH ₂ —).

(3-3) "Functional group (2)"
The functional group (2) is a functional group represented by the structural formula (2). Here, X ² is an alkylene group having 2 to 4 carbon atoms, and the alkylene group may be linear or branched. In X ² , the alkylene group preferably has 1 to 2 carbon atoms (for example, the alkylene group is a methylene group (—CH ₂ —) or an ethylene group (—CH ₂ CH ₂ —)).

R ² is a hydroxyalkyl group having 2 to 4 carbon atoms (an alkyl group substituted with at least one hydroxyl group), can be a hydroxyalkyl group having 2 carbon atoms, and can be a hydroxyethyl group (—CH ₂ CH ₂ OH).

  p is 1 or 2.

  q is an integer of 0 to 4, and can be an integer of 1 to 2.

In addition, when q is an integer of 2 to 4, a plurality of X ¹ may be the same or different. In this case, from the viewpoint that it can be produced from a general-purpose reagent raw material, a plurality of X ¹ are preferably a methylene group (—CH ₂ —) or an ethylene group (—CH ₂ CH ₂ —).

(3-4) "Functional group (3)"
The functional group (3) is a functional group represented by the structural formula (3). Here, X ^3a and X ^3b are each independently 2 to 4 alkylene groups, and the alkylene groups may be linear or branched. X ^3a and X ^3b are each independently preferably an alkylene group having 2 to 4 carbon atoms (for example, the alkylene group is a methylene group (—CH ₂ —) or an ethylene group (—CH ₂ CH ₂ —).

R ^3a and R ^3b are each independently a hydroxyalkyl group having 2 to 4 carbon atoms (an alkyl group substituted with at least a hydroxyl group), and from the viewpoint that it can be produced from a general-purpose reagent raw material, the number of carbon atoms is 2 The hydroxyalkyl group is preferably a hydroxyethyl group (—CH ₂ CH ₂ OH).

  r is 1 or 2;

  s and t are each independently an integer of 0 to 4, and are preferably an integer of 1 to 2 from the viewpoint that they can be produced from general-purpose reagent raw materials.

In addition, when s is an integer of 2 to 4, a plurality of X ^3a may be the same or different, and when t is an integer of 2 to 4, a plurality of X ^3b is the same or different. It may be. In this case, from the viewpoint of being able to produce from general-purpose reagent raw materials, it is preferable that a plurality of X ^3a and X ^3b are methylene groups (—CH ₂ —) or ethylene groups (—CH ₂ CH ₂ —). .

(3-5) “A ² ”
From the viewpoint of further improving hydrophilicity, A ² is a hydrogen atom, a hydroxyl alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, a functional group (1), a functional group (2) or a functional group (3 It is preferably a hydroxylalkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, more preferably a functional group (1), a functional group (2) or a functional group (3). More preferably, it is 1) or functional group (3).

(3-6) “A ³ ”
As described above, A ³ is any one of a hydrogen atom, an alkyl group having 1 to 8 carbon atoms which may be substituted with a hydroxyl group, and functional groups (1) to (3). “A ³ —O—” bonded to (i) is an electron donating group.

A ³ is preferably a hydrogen atom, a hydroxyalkyl group having 1 to 8 carbon atoms, a functional group (1), a functional group (2) or a functional group (3). The functional group (1) or the functional group (3 ) Is more preferable.

Furthermore, “A ³ —O—” is preferably bonded to the para-position of the benzene ring moiety (i) with respect to the “azolidine moiety (ii)”. Such a benzylidene azolidine derivative is represented by the following structural formula (II).
(In the structural formula (II), n ′ is an integer of 0 to 4, and when n ′ is an integer of 1 to 4, a plurality of A ³ —O— may be the same or different. A ³ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms and substituted with a hydroxyl group, a functional group (1), a functional group (2), or a functional group (3).

Here, from the viewpoint that the hydrophilicity can be further improved, n ′ in the structural formula (II) is 0 and A ¹ is NA ⁴ , that is, the benzylidene azolidine derivative in the present invention. It is preferably represented by the following chemical structural formula (III).

In consideration of ease of synthesis (shortening of the synthesis process), A ² and A ³ are more preferably the same functional group.

(3-7) “A ⁴ ”
A ⁴ is preferably a hydrogen atom or a functional group (3), more preferably a hydrogen atom, from the viewpoint that the hydrophilicity can be further improved.

(4) Molecular weight The molecular weight of the benzylidenehydantoin derivative in the present invention is usually 250 to 1000, preferably 300 to 500. The molecular weight is preferably 300 or more in order to reduce the risk of adverse effects such as irritation and toxicity through the skin and absorbed into the body.

[Method for producing benzylidene azolidine derivative and salt thereof]
For example, as shown in the chemical reaction formula (1), the compound (a) represented by the following formula (a) and the compound (b) represented by the following formula (b) are reacted in the presence of a base. To synthesize a compound (c) represented by the following formula (c). Next, as shown in the chemical reaction formula (2), the compound represented by the following formula (c) is reacted with the compound (d) represented by the following formula (d) in the presence of a base. The benzylidene azolidine derivative in the present invention can be synthesized.

Here, as the compound (b), a commercially available product can be used as it is. A compound (b) having a functional group excluding a hydrogen atom as A ³ is represented by the following structural formula (b ′), and a compound (b ′) having a hydrogen atom as A ³ and the following structural formula (e) A compound obtained by reacting with the compound (e) represented by formula (3) in the presence of a base as shown in the reaction formula (3) can be used.

  Moreover, a commercial item can also be used as it is as the said compound (a).

Moreover, as shown by the following formula (4-1), the compound (a) and the compound (d) are reacted in the presence of a base to give a compound represented by the following structural formula (f) ( f) can be synthesized. Alternatively, as shown in the following reaction formula (4-2), the following compound (g) and the following compound (h) are used in the presence or absence of a base with a condensing agent (at this time, The compound (f) represented by the following structural formula (f) can also be synthesized by cyclization in the presence of an acid. Here, when A ¹ of the compound (a) is “NH”, as shown in the reaction formula (5), the compound (f) and the following structural formula (e ′) are combined in the presence of a base. By reacting, compound (f) in which A ¹ is “NA ⁴ ” can be synthesized. Next, as shown in the following reaction formula (6), the benzylidene azolidine derivative in the present invention can be synthesized by reacting the compound (f) with the compound (b) in the presence of a base. .

^{(A 1} of formula (g) is the same as ^{A 1} of formula (I).
Z is a hydroxyl group or an alkoxyl group. )
^{(A 2} of the formula (h) are the same and ^{A 2} in formula (I).)

When the benzylidene azolidine derivative in the present invention has a functional group (2) or a functional group (3) as A ² , A ³ and A ^{4 in} the structural formula (I), the compound (d), Instead of the compound (e) and the compound (e ′), the compound (i) represented by the following structural formula (i), and the following structural formula (j) instead of the compound (h) In the same manner as in the reaction formulas (1) to (6) except that the compound (j) is used, A ² , A ³ or A ^{4 in} the structural formula (I) is represented by the following structural formula (k The compound (k) having a functional group (k) represented by) can be synthesized. Next, the compound (k) may be led to the benzylidene azolidine derivative in the present invention by a general functional group conversion reaction (esterification of carboxylic acid, amidation of carboxylic acid, transesterification, amidation of ester, etc.). it can.
(Y in formula (i) is the same as Y in formula (d), u is 1 or 2, and Z is a hydroxyl group or an alkoxyl group.)
(U in the formula (j) is 1 or 2, and Z is a hydroxyl group or an alkoxyl group.)
(U in the formula (k) is 1 or 2, and Z is a hydroxyl group or an alkoxyl group.)

  Examples of the base used in the method for producing the benzylidene azolidine derivative in the present invention as described above include sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, sodium t-butoxide, potassium t-butoxide, pyridine, and triethylamine. , Triisopropylamine, diisopropylethylamine, pyrrolidine, piperidine, sodium acetate, aqueous ammonia, diazabicycloundecene and diazabicyclononene.

  Examples of the condensing agent used in the method for producing a benzylidene azolidine derivative in the present invention include phosgene, triphosgene, carbonyldiimidazole, trichloromethyl chloroformate, paranitrophenyl chloroformate, and paracyanophenyl chloroformate. .

  Examples of the acid used in the method for producing a benzylidene azolidine derivative in the present invention include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, or acetic acid, citric acid, gluconic acid, tartaric acid, fumaric acid. Examples thereof include organic acids such as acid, maleic acid, lactic acid, methanesulfonic acid, and paratoluenesulfonic acid.

  Further, the benzylidene azolidine derivative obtained as described above can be treated with an adsorbent such as silica gel, alumina, zeolite, activated carbon, ion exchange resin, porous synthetic resin, evaporation of the solvent, and / or recrystallization. A highly purified product can be obtained by purifying by the above.

  The salt of the benzylidene azolidine derivative in the present invention is an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, acetic acid, citric acid, benzylidene azolidine derivative obtained as described above. It can be derived by adding an organic acid such as gluconic acid, tartaric acid, fumaric acid, maleic acid, lactic acid, methanesulfonic acid or paratoluenesulfonic acid, neutralizing, distilling, and purifying.

[Drugs containing benzylidene azolidine derivatives or salts thereof]
(Drug)
The agent of the present invention (whitening agent, anti-photoaging agent, tyrosinase inhibitor, melanin production inhibitor, reactive oxygen species production inhibitor, SOD-like activator, and catalase-like activator) is the benzylidene azolidine derivative or its It contains a salt.

  The whitening agent of the present invention has an excellent whitening action by using the benzylidene azolidine derivative or a salt thereof as an active ingredient.

  The above-mentioned whitening effect is presumed to be manifested by preventing or delaying the skin coloring phenomenon caused by melanin pigments particularly related to dullness and itching of the skin, but is not limited to this. Absent.

  The anti-photoaging agent of the present invention has an excellent anti-photoaging effect by using the benzylidene azolidine derivative or a salt thereof as an active ingredient.

  The above-mentioned anti-photoaging action prevents, prevents or delays skin aging such as wrinkles, sagging, dullness, pigmentation (stains, etc.), bears and thinning caused by the increase of reactive oxygen species due to UV exposure. However, the present invention is not limited to this.

  The tyrosinase inhibitor of the present invention has an excellent inhibitory effect on tyrosinase activity by using the benzylidene azolidine derivative or a salt thereof as an active ingredient.

  The inhibitory effect on the tyrosinase activity is presumed to be expressed by inhibiting or reducing the activity of tyrosinase involved in melanin synthesis.

  Moreover, the melanin production inhibitor of this invention has the outstanding melanin production inhibitory effect by using the said benzylidene azolidine derivative or its salt as an active ingredient.

  The melanin production-suppressing effect is presumed to be expressed by inhibiting or reducing melanin production.

  In addition, the reactive oxygen species inhibitor of the present invention is characterized by containing a benzylidene azolidine derivative represented by the above general formula (I) or a salt thereof.

  The active oxygen species production inhibitor refers to an agent that inhibits or reduces the production of active oxygen species caused by exposure to ultraviolet rays or the like. It also has a function to erase active oxygen species generated by UV exposure.

  The SOD-like activator of the present invention is characterized by containing a benzylidene azolidine derivative represented by the above general formula (I) or a salt thereof.

  The SOD-like active agent refers to an agent that inhibits or reduces the production of superoxide anion generated by ultraviolet exposure or the like.

  The catalase-like active agent of the present invention is characterized by containing a benzylidene azolidine derivative represented by the above general formula (I) or a salt thereof.

  The catalase-like active agent refers to an agent that inhibits or reduces the production of hydrogen peroxide generated by exposure to ultraviolet rays.

  By applying the whitening agent, anti-photoaging agent, tyrosinase inhibitor, melanin production inhibitor, reactive oxygen species production inhibitor, SOD-like activator, and catalase-like activator in the present invention, Prevent skin coloration such as freckles, liver spots, wrinkles, sagging, dullness, skin aging such as thinning of skin, glycation of skin, prevent, prevent, delay progress, for example, skin transparency It can increase skin, firmness and luster, and can also be expected to keep youthful. The effect on the skin is particularly excellent when applied as an outer skin composition, and is also known as a whitening component (tyrosinase inhibiting component, melanin production inhibiting component), anti-photoaging component (reactive oxygen species production inhibiting component, SOD). Like active ingredient, catalase-like active ingredient), anti-glycation component, anti-inflammatory component, anti-wrinkle component, cell activation component, etc. Can do.

  More specifically, for example, arbutin, ascorbic acid or a derivative thereof, vitamin E or a derivative thereof (δ-tocopherols, etc.), hydroquinone, kojic acid, lucinol, glycyrrhizic acid or a derivative thereof, glycyrrhetinic acid or a derivative thereof, hydrolysis Composition for external use in combination with soy protein, retinoids (retinol and its derivatives, retinoic acid, retinal, etc.), kinetin, pyrroloquinoline quinone (PQQ) and their salts, hyaluronic acid and its derivatives and their salts, etc. Agents, cosmetics, etc.).

(Base or carrier)
In the present invention, drugs (whitening agents, anti-photoaging agents, tyrosinase inhibitors, melanin production inhibitors, reactive oxygen species production inhibitors, SOD-like activators, and catalase-like activators) impair the effects of the present invention. In other words, other known bases or carriers used in cosmetics and quasi drugs can be included. A base or a carrier can be used singly or in combination of two or more.

  Bases or carriers include paraffin, liquid paraffin, squalane, white wax, gelled hydrocarbons (plastibase, etc.), ozokerite, ceresin, petrolatum, hard fat, microcrystalline wax, α-olefin oligomer, light liquid paraffin, etc. Hydrocarbons; fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, isostearic acid; such as glyceryl tri-2-ethylhexanoate (trioctanoin), tri (caprylic acid / capric acid) glyceryl Tri-fatty acid glycerides; higher alcohols such as cetanol, stearyl alcohol, behenyl alcohol; methyl polysiloxanes, highly polymerized methyl polysiloxanes, dimethyl siloxane methyl (polyoxyethylene) siloxane methyl (Polyoxypropylene) siloxane copolymer, dimethylsiloxane methyl (polyoxyethylene) siloxane copolymer, dimethylsiloxane methyl (polyoxypropylene) siloxane copolymer, polyoxyethylene methyl polysiloxane copolymer, poly (Oxyethylene / oxypropylene) / methylpolysiloxane copolymer, dimethylsiloxane / methylcetyloxysiloxane copolymer, dimethylsiloxane / methylstearoxysiloxane copolymer, alkyl acrylate copolymer methylpolysiloxane ester, cross-linked type Methylpolysiloxane, crosslinked methylphenylpolysiloxane, crosslinked polyether-modified silicone, crosslinked alkylpolyether-modified silicone, crosslinked alkyl-modified silicone, decamethylcyclopen Such as polysiloxane, ethyltrisiloxane, methyltrimethicone, methylsiloxane network polymer, polyoxyethylene-methylpolysiloxane copolymer, methylhydrogenpolysiloxane, triethoxysilylethylpolydimethylsiloxyethylhexyldimethicone, dimethylpolysiloxane Silicone oils; glycols such as ethylene glycol monoacetate, ethylene glycol diacetate, triethylene glycol diacetate, hexylene glycol diacetate, and 2-methyl-2-propene-1,1-diol diacetate Acetate; triethylene glycol divalerate, 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate, 2,2,4-trimethyl-1,3-pentanediol dii Glycol esters such as butyrate; such as ethylene glycol diacrylate, diethylene glycol diacrylate, propylene glycol monoacrylate, 2,2-dimethyl-trimethylene glycol diacrylate, and 1,3-butylene glycol diacrylate Glycol acrylates; glycol dinitrates such as ethylene glycol dinitrate, diethylene glycol dinitrate, triethylene glycol dinitrate, and propylene glycol dinitrate; 2,2 '-[1,4-phenylenedioxy] diethanol; ethylcellulose, hydroxy Cellulose derivatives such as propylcellulose, hydroxypropylmethylcellulose; polyvinylpyrrolidone; carrageenan; polyvinylbuty Polyethylene glycol; dioxane; butylene glycol adipic acid polyester; esters such as isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, pentaerythrite tetra-2-ethylhexanoate; Polysaccharides such as dextrin and maltodextrin; lower alcohols such as ethanol and isopropanol; ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, Diethylene glycol monobutyl ether, propylene glycol Examples thereof include glycol ethers such as recall monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether and dipropylene glycol monopropyl ether; aqueous bases such as water.

  Among them, hydrocarbons (especially α-olefin oligomers, squalane, light liquid paraffin, liquid paraffin), trifatty acid glycerides (particularly glyceryl tri-2-ethylhexanoate, tri (caprylic acid / capric acid) glyceryl), higher alcohols (Especially cetanol, stearyl alcohol, behenyl alcohol), silicone oil (especially methylpolysiloxane, alkyl acrylate copolymer methylpolysiloxane ester, cross-linked methylpolysiloxane, decamethylcyclopentasiloxane, ethyltrisiloxane, methyltrimethicone , Methylsiloxane network polymer, polyoxyethylene / methylpolysiloxane copolymer, methylhydrogenpolysiloxane, triethoxysilylethylpolydimethylsiloxyethylhexyl dimethyl ester Con, dimethylpolysiloxane), esters (especially isononyl isononanoate, pentaerythritol tetra-2-ethylhexanoate), polysaccharides (especially dextrin, maltodextrin), glycol ethers (especially diethylene glycol monoethyl ether), water Is preferred.

(Additive)
In the present invention, the composition for external use for skin is a known additive added to cosmetics and quasi-drugs, for example, thickeners, surfactants, preservatives, pH, within the range not impairing the effects of the present invention. A regulator, a chelating agent, a stabilizer, an irritation reducing agent, an antiseptic, a colorant, a dispersant, a fragrance, a pearl luster imparting agent, and the like can be added. An additive can be used individually by 1 type or in combination of 2 or more types.

  Examples of the thickener include cellulose-based thickeners such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, guar gum, locust bean gum, carrageenan, and xanthan gum. Such as polysaccharide thickener, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, carboxyvinyl polymer, alkyl methacrylate copolymer, dextrin fatty acid ester, pectin, (hydroxyethyl acrylate / acryloyldimethyltaurine Na) copolymer , Dimethyl distearyl ammonium hectorite, (acrylic Yldimethyltaurate ammonium / vinyl pyrrolidone) copolymer, polyethylene glycol distearate, ethylene glycol triisostearate, polyoxyethylene (20) methyl glucoside triisostearate, polyethylene glycol, bentonite, alginic acid, sodium alginate, propylene glycol alginate, macrogol And water-soluble polymers such as sodium chondroitin sulfate, hyaluronic acid and salts thereof, hyaluronic acid derivatives and salts thereof.

  Among these, in terms of particularly good usability, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, cellulose thickeners such as carboxyethyl cellulose, guar gum, locust bean gum, Carrageenan, thickening polysaccharides such as xanthan gum, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, carboxyvinyl polymer, alkyl methacrylate copolymer, dextrin fatty acid ester, pectin, (hydroxyethyl acrylate / acryloyldimethyl) Taurine Na) copolymer, dimethyl distearyl ammonium hectorite (Acryloyldimethyltauronium ammonium / vinylpyrrolidone) copolymer is preferred, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, xanthan gum, alkyl methacrylate methacrylate (acrylic) An acid hydroxyethyl / acryloyldimethyltaurine Na) copolymer and an (acryloyldimethyltaurine ammonium / vinylpyrrolidone) copolymer are more preferred.

  Examples of the surfactant include sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexylate, and diglycerol sorbitan tetra-2-ethylhexylate. Sorbitan fatty acid esters; glyceryl fatty acids such as glyceryl monostearate and glyceryl monostearate; polyglyceryl fatty acids such as polyglyceryl monostearate, polyglyceryl monoisostearate and polyglyceryl diisostearate; propylene glycol monostearate Propylene glycol fatty acid esters such as: polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil Cured castor oil derivatives such as deca oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), polyoxyethylene hydrogenated castor oil 80; polyoxyethylene (20) sorbitan monolaurate (polysorbate 20) , Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene monooxylate (20) sorbitan (polysorbate 80), polyoxyethylene (20) sorbitan isostearate Polyoxyethylene mono coconut oil fatty acid glyceryl; glycerin alkyl ether; alkyl glucoside; polyoxyalkylene alkyl ether such as polyoxyethylene cetyl ether; stearylamine, olei Examples include amines such as amines; polyoxyethylene / methylpolysiloxane copolymers, silicone surfactants such as lauryl PEG-9 polydimethylsiloxyethyl dimethicone, and PEG-9 polydimethylsiloxyethyl dimethicone. .

  Among them, glycerin fatty acids (particularly glyceryl monostearate), polyglycerin fatty acids (particularly polyglyceryl monostearate), hydrogenated castor oil derivative (particularly polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxy) Ethylene hydrogenated castor oil 60 (HCO-60)), polyoxyethylene sorbitan fatty acid esters (particularly polyoxyethylene (20) sorbitan isostearate, polyoxyethylene (20) sorbitan monostearate (polysorbate 60)), polyoxy Alkylene alkyl ether (especially polyoxyethylene cetyl ether), silicone surfactant (especially polyoxyethylene methylpolysiloxane copolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, PE -9 polydimethylsiloxyethyl dimethicone) is preferred.

  Preservatives and preservatives include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, paraoxybenzoic acid Examples thereof include benzyl, methyl paraoxybenzoate, and phenoxyethanol. Of these, methyl paraoxybenzoate, propyl paraoxybenzoate, and phenoxyethanol are preferable.

  Examples of pH adjusters include inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.), organic acids (lactic acid, acetic acid, citric acid, sodium citrate, tartaric acid, malic acid, succinic acid, sodium succinate, Oxalic acid, gluconic acid, fumaric acid, propionic acid, acetic acid, aspartic acid, ε-aminocaproic acid, glutamic acid, aminoethylsulfonic acid, etc.), gluconolactone, ammonium acetate, inorganic base (sodium bicarbonate, sodium carbonate, hydroxylation) And potassium (sodium hydroxide, calcium hydroxide, magnesium hydroxide, etc.), organic bases (monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, lysine, etc.). Of these, succinic acid, sodium succinate, citric acid, sodium citrate, triethanolamine, potassium hydroxide, and sodium hydroxide are preferable.

  Chelating agents include ethylenediaminetetraacetic acid (edetic acid), ethylenediaminetetraacetic acid salt (sodium salt (sodium edetate: Japanese Pharmacopoeia, EDTA-2Na, etc.), potassium salt, etc.), phytic acid, gluconic acid, polyphosphoric acid, metalin Acids can be raised. Of these, sodium edetate is preferred.

  Examples of the stabilizer include sodium polyacrylate, dibutylhydroxytoluene, butylhydroxyanisole and the like.

  Examples of the irritation reducing agent include licorice extract, sodium alginate, 2-methacryloyloxyethyl phosphorylcholine and the like.

  Examples of the colorant include inorganic pigments and natural pigments.

  Examples of the pearl luster imparting agent include ethylene glycol distearate, ethylene glycol monostearate, and triethylene glycol distearate. Of these, ethylene glycol distearate is preferred.

(Other active ingredients)
In the present invention, the drug includes an antioxidant component, an anti-aging component, an anti-inflammatory component, other whitening component, a keratin soft component, a cell activation component, vitamins, and a blood circulation promoting component, as long as the effects of the present invention are not hindered. Other activities that can be added to cosmetics and quasi-drugs, such as moisturizing ingredients, ingredients that prevent and / or repair DNA damage, UV-absorbing ingredients, UV-scattering ingredients, cleaning ingredients, antibacterial ingredients, and astringent ingredients Ingredients can be blended. Other active ingredients can be used singly or in combination of two or more.

  Antioxidant components include components derived from plants (eg, grapes, ginseng, comfrey, etc.); proanthocyanidins, tocopherols and derivatives thereof, ascorbic acid and derivatives thereof, hesperidin, glucosyl hesperidin, ergothioneine, sodium bisulfite, erythorbine Examples thereof include acids and salts thereof, flavonoids, glutathione, glutathione peroxidase, glutathione-S-transferase, catalase, superoxide dismutase, thioredoxin, taurine, thiotaurine, and hypotaurine. Among them, grape seed extract, grape leaf extract, ginseng extract, comfrey leaf extract, proanthocyanidins, tocopherol and its derivatives (particularly δ-tocopherol, α-tocopherol), ascorbic acid and its derivatives (particularly ascorbic acid, ascorbine) Sodium acid phosphate sodium, magnesium ascorbate phosphate, ascorbyl tetraisopalmitate (ascorbyl tetra-2-hexyldecanoate), hesperidin, glucosyl hesperidin and ergothioneine are preferred.

  Anti-wrinkle and anti-aging components include hydrolyzed soy protein, retinoids (retinol and its derivatives, retinoic acid, retinal, etc.), pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivatives, silicon, silicic acid, N-methyl -L-serine, mevalonolactone and the like can be mentioned. Of these, artemia extract, hydrolyzed soy protein, retinol, retinol acetate, and retinol palmitate are preferred.

  Anti-inflammatory components include components derived from plants (eg Comfrey); allantoin, calamine, glycyrrhizic acid or derivatives thereof, glycyrrhetinic acid or derivatives thereof, zinc oxide, guaiazulene, pyridoxine hydrochloride, menthol, camphor, turpentine oil, indomethacin And salicylic acid or a derivative thereof. Of these, Comfrey leaf extract, allantoin, dipotassium glycyrrhizinate, and stearyl glycyrrhetinate are preferable.

  Other whitening components include, for example, arbutin; hydroquinone; kojic acid; ellagic acid; phytic acid; lucinol; chamomile ET; ascorbic acid or a derivative thereof; vitamin E or a derivative thereof; pantothenic acid or a derivative thereof; The plant component (for example, a plant extract and essential oil) which has a whitening effect | action can be mention | raise | lifted. Among them, arbutin, hydroquinone, kojic acid, ascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, ascorbyl tetraisopalmitate (ascorbyl tetra-2-hexyldecanoate), 2-O-ethylascorbic acid, 3 -O-ethylascorbic acid and tranexamic acid are preferable.

  Examples of the keratin soft component include lanolin, urea, α-hydroxy acid (phytic acid, lactic acid, lactate, glycolic acid, salicylic acid, malic acid, etc.), citric acid, and the like. Of these, lactic acid, sodium lactate, glycolic acid, salicylic acid, and phytic acid are preferable.

  Cell activation components include components derived from plants (eg, bilberry); amino acids such as γ-aminobutyric acid and ε-aminoproic acid; vitamins such as retinol and its derivatives, thiamine, riboflavin, pyridoxine hydrochloride, and pantothenic acids And α-hydroxy acids such as glycolic acid and lactic acid; tannins, flavonoids, saponins, allantoins, and photosensitizer 301. Of these, bilberry leaf extract, retinol, retinol acetate, and retinol palmitate are preferred.

  Vitamins include retinol, retinol acetate, retinol palmitate, etc., retinal, retinoic acid, methyl retinoic acid, ethyl retinoic acid, retinol retinoic acid, d-δ-tocopheryl retinoate, α-tocopheryl retinoate Vitamins such as β-tocopheryl retinoate; provitamins A such as β-carotene, α-carotene, γ-carotene, δ-carotene, lycopene, zeaxanthin, cryptoxanthine, echinone; δ-tocopherol, α- Vitamin Es such as tocopherol, β-tocopherol, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, δ-tocopherol, tocopherol nicotinate; riboflavin, flavin mononucleotide, flavin Vitamin B2 such as denine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate; nicotinic acids such as methyl nicotinate, nicotinic acid, nicotinamide; stearic acid Ascorbyl, L-ascorbyl dipalmitate, ascorbyl tetraisopalmitate (ascorbyl tetra-2-hexyldecanoate), ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, ascorbic acid Vitamin Cs such as glucoside, 2-O-ethylascorbic acid, 3-O-ethylascorbic acid; methyl hesperidin, ergocalci Vitamin Ds such as ferrol and cholecalciferol; vitamin Ks such as phylloquinone and farnoquinone; dibenzoyl thiamine, dibenzoyl thiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine Nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, thiamine triphosphate Vitamin B1 such as monophosphate; Vitamin B6 such as pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5'-pyridoxal phosphate, pyridoxamine hydrochloride, cyanocobalamin, hydro Vitamin B12 such as socobalamin and deoxyadenosylcobalamin; folic acid such as folic acid and pteroylglutamic acid; pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-pantethein, D-panthetin, coenzyme A, pant Examples thereof include pantothenic acids such as tenenyl ethyl ether; biotins such as biotin and biocytin; and vitamin-like agents such as carnitine, ferulic acid, α-lipoic acid, orotic acid, and γ-oryzanol.

  Among them, vitamin A such as retinol, retinol acetate, retinol palmitate, etc .; ascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, ascorbyl tetraisopalmitate (ascorbyl tetra-2-hexyldecanoate), 2- Vitamin Cs such as O-ethylascorbic acid and 3-O-ethylascorbic acid; Vitamin Es such as δ-tocopherol and tocopherol nicotinate; and nicotinic acids such as nicotinamide are preferable.

  Examples of the blood circulation promoting component include plants (for example, ginseng, ashitaba, arnica, ginkgo, fennel, enmelio, dutch oak, chamomile, roman chamomile, carrot, gentian, burdock, rice, hawthorn, shiitake, hawthorn, sorghum, nematode, Assembly, thyme, clove, chimney, spruce, spruce, spruce, carrot, garlic, butcher bloom, grape, button, maronier, melissa, yuzu, yokuinin, rosemary, rosehip, chimpy, touki, spruce, peach, apricot, walnut Ingredients derived from corn); tocopherol nicotinate, glucosyl hesperidin, hesperidin. Of these, ginseng extract, tocopherol nicotinate, glucosyl hesperidin, and hesperidin are preferable.

  Moisturizing ingredients include ingredients derived from plants (eg, Tigaya); amino acids such as alanine, serine, leucine, isoleucine, threonine, glycine, proline, hydroxyproline, glucosamine, theanine and derivatives thereof; collagen, gelatin, elastin Such proteins and peptides, hydrolysates thereof; polyhydric alcohols such as glycerin, 1,3-butylene glycol, propylene glycol, polyethylene glycol, dipropylene glycol, diglycerin; sugar alcohols such as sorbitol; lecithin, hydrogenated lecithin Phospholipids such as: hyaluronic acid, sodium hyaluronate, acetyl hyaluronic acid, sodium acetyl hyaluronate, heparin, chondroitin mucopolysaccharides; lactic acid, pyrrolidone carvone NMF-derived components such as sodium and urea; polyglutamic acid; polymers having a phospholipid polar group such as MPC polymer (for example, LIPIDURE ™); polyoxypropylene methylglucoside; trimethylglycine (betaine); hydroxyethylurea Acrylic acid / acrylamide / dimethyldiallylammonium chloride copolymer; sorbitol and the like. Among them, chigaya root extract, hydrolyzed collagen, hydrolyzed elastin, MPC polymer glycerin, 1,3-butylene glycol, polyethylene glycol, dipropylene glycol, diglycerin, polyoxypropylene methylglucoside, trimethylglycine (betaine), hydroxyethyl Urea, acrylic acid / acrylamide / dimethyldiallylammonium chloride copolymer, hydrogenated lecithin, hyaluronic acid, sodium hyaluronate, acetyl hyaluronic acid, sodium acetyl hyaluronate and sorbitol are preferred.

  Examples of the component having an action of preventing and / or repairing DNA damage include components derived from animals (eg, Artemia); components derived from plants (eg, cat's claw); DNA, DNA salts, RNA, RNA salts, etc. Nucleic acid components can be mentioned. Of these, artemia extract and DNA-Na are preferable.

  Examples of ultraviolet ray absorbing components include 2-methoxyhexyl paramethoxycinnamate, 2- [4- (diethylamino) -2-hydroxybenzoyl] benzoic acid hexyl ester, 2,4,6-tris [4- (2-ethylhexyloxycarbonyl) ) Anilino] -1,3,5-triazine, dimethoxybenzylideneoxoimidazolidinepropionate 2-ethylhexyl, 2,4-bis-[{4- (2-ethylhexyloxy) -2-hydroxy} -phenyl] -6 (4-methoxyphenyl) -1,3,5-triazine and the like can be mentioned. Among them, 2-methoxyhexyl paramethoxycinnamate, 2- [4- (diethylamino) -2-hydroxybenzoyl] benzoic acid hexyl ester, 2,4,6-tris [4- (2-ethylhexyloxycarbonyl) anilino] -1,3,5-triazine is preferred.

  Ultraviolet scattering components include inorganic compounds such as zinc oxide, titanium oxide, iron oxide, cerium oxide, zirconium oxide, titanium silicate, zinc silicate, anhydrous silicic acid, cerium silicate, hydrous silicic acid, and those inorganic compounds Coated with water-containing silicic acid, aluminum hydroxide, coated with inorganic powder such as mica and talc, compounded with resin powder such as polyamide, polyethylene, polyester, polystyrene, nylon, etc. The thing processed with fatty acid aluminum salt etc. can be mention | raise | lifted. Of these, inorganic compounds such as zinc oxide, titanium oxide and iron oxide, and those inorganic compounds coated with inorganic powder such as aluminum hydroxide, hydrous silicic acid, mica and talc, and silicon oil are preferable.

  Cleaning components include polyoxyalkylene alkyl (or alkenyl) ether sulfates, alkyl (or alkenyl) sulfates, higher fatty acid salts, ether carboxylates, amide ether carboxylates, alkyl phosphate esters, N-acyl amino acids Anionic surfactants such as salts, polyoxyalkylene fatty acid amide ether sulfates, acylated isethionates, acylated taurates; amine oxides, glycerin fatty acid esters, sorbitan fatty acid esters, alkyl saccharides, polyoxyalkylene alkyl ethers, fatty acid alkanolamides , Nonionic surfactants such as polyoxyalkylene hydrogenated castor oil; mono- or di-long-chain alkyl having a linear or branched long-chain alkyl group, to which alkylene oxide may be added Cationic surfactants such as ammonium salts; carboxymethyl betaine, sulfobetaine, imidazolinium betaine, may be mentioned amphoteric surfactants such as betaines.

  Of these, anionic surfactants, nonionic surfactants, and amphoteric surfactants are preferred. Anionic surfactants include higher fatty acid salts (particularly salts of higher fatty acids such as palmitic acid, lauric acid, myristic acid and stearic acid), N-acyl amino acid salts (particularly sodium N-lauroyl aspartate, potassium hydroxide / N-coconut oil fatty acid potassium acylglutamate, coconut oil fatty acid acylglycine sodium, myristoyl glutamic acid) are preferred. Among the nonionic surfactants, fatty acid alkanolamides (especially coconut oil fatty acid diethanolamide, coconut oil fatty acid monoethanolamide) and amine oxides (especially coconut oil alkyldimethylamine oxide, lauryldimethylamine oxide) are preferable. Amphoteric surfactants include imidazolinium betaines (especially 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolium betaine, N-coconut oil fatty acid acyl-N-carboxymethoxyethyl-N-carboxymethylethylenediamine disodium. ) Is preferred.

  Antibacterial components include chlorhexidine, salicylic acid, benzalkonium chloride, acrinol, ethanol, benzethonium chloride, cresol, gluconic acid and its derivatives, popidone iodine, potassium iodide, iodine, isopropylmethylphenol, triclocarban, triclosan, photosensitizer 101 Photosensitive element 201, paraben, phenoxyethanol, 1,2-pentanediol, alkyldiaminoglycine hydrochloride, and the like. Among them, benzalkonium chloride, benzethonium chloride, gluconic acid and derivatives thereof, isopropylmethylphenol, triclocarban, triclosan, photosensitizer 101, photosensitizer 201, paraben, phenoxyethanol, 1,2-pentanediol, alkyldiamino hydrochloride Glycine is preferred, and benzalkonium chloride, gluconic acid and its derivatives, benzethonium chloride, and isopropylmethylphenol are more preferred.

  Examples of the astringent component include metal salts such as alum, chlorohydroxyaluminum, aluminum chloride, allantoin aluminum salt, zinc sulfate, and potassium aluminum sulfate; organic acids such as tannic acid, citric acid, lactic acid, and succinic acid. Of these, alum, chlorohydroxyaluminum, aluminum chloride, allantoin aluminum salt, potassium aluminum sulfate, and tannic acid are preferable.

(Formulation)
Moreover, the chemical | medical agent in this invention can be prepared by mixing and stirring each component in accordance with a conventional method, for example.

  In this invention, the form of a chemical | medical agent is not specifically limited, A well-known form can be taken as a form of cosmetics or a quasi-drug. As such known forms, for example, liquids, suspensions, emulsions, creams, ointments, gels, liniments, lotions, aerosols, powders, poultices, non-woven fabrics and the like are impregnated with chemicals. And a stick agent such as a lipstick. Of these, liquids, suspensions, emulsions, creams, ointments, gels, and lotions are preferred, and liquids, emulsions, creams, gels, and lotions are more preferred in terms of good usability. In particular, the benzylidene azolidine derivative or salt thereof is excellent in solubility in the base (particularly hydrophilic) and easy to formulate (water-soluble agent). Formulation forms of emulsions, aqueous gels and aqueous lotions are preferred. Further, depending on the formulation, an oil-in-water type (O / W), a water-in-oil type (W / O) or the like can be appropriately selected according to the purpose of use and the desired feeling of use.

  In addition, the specific use of the cosmetic composition is not particularly limited, and basic cosmetics such as lotion, milky lotion, cream, cosmetic liquid, sunscreen cosmetics, packs, hand creams, body lotions, body creams; Cosmetics for cleaning such as makeup removers, body shampoos, shampoos and rinses; makeup cosmetics such as foundations, concealers, makeup bases, lip balms, lipsticks and teak colors; bathing agents and the like.

  Drugs containing benzylidene azolidine derivative or a salt thereof as an active ingredient in the present invention (whitening agent, anti-photoaging agent, tyrosinase inhibitor, melanin production inhibitor, reactive oxygen species production inhibitor, SOD-like activator, and catalase-like agent In the case where the activator) takes any of the above forms, the content of the benzylidene azolidine derivative or a salt thereof can be 0.00001 wt% or more and 50 wt% or less, and 0.00001 wt% 20 wt% or less, 0.0001 wt% or more and 10 wt% or less, 0.001 wt% or more and 5 wt% or less, 0.01 wt% or more 3 % By weight or less, or 0.1% by weight or more and 1% by weight or less may be used.

  Examples and the like specifically showing the configuration and effects of the present invention will be described below. In addition, the evaluation item in an Example etc. measured as follows.

<Measurement of ¹ H-NMR spectrum>
¹ H-NMR spectrum was measured using a nuclear magnetic resonance apparatus (JNM-ECP500, manufactured by JEOL Ltd.). More specifically, the ¹ H-NMR spectrum was measured using DMSO-d ₆ as a solvent and tetramethylsilane as an internal standard.

<Measurement of UV spectrum>
The UV spectrum was measured using a spectrophotometer (manufactured by Shimadzu Corporation, UV-4250). More specifically, the UV spectrum was measured using a quartz cell with ethanol as a solvent, a sample solution concentration of 5 ppm, and an optical path length of 1 cm. The absorbance was calculated according to Lambert-Beer's law, where Io was the transmitted light intensity of the empty cell and I was the transmitted light intensity of the sample cell, with absorbance = −log ₁₀ (I / I ₀ ). Further, the wavelength at which the absorbance in the obtained UV spectrum becomes maximum was defined as λmax (nm).

<Hydrophilicity evaluation>
The obtained compound (1) was dissolved in the test solvent shown below, the properties were confirmed, and the solubility (g / 100 g test solvent) at 25 ° C. with respect to 100 g of the test solvent was measured.
Test solvent: Mixed solvent containing dipropylene glycol, ethanol, and purified water in amounts of 10% by mass, 10% by mass, and 80% by mass, respectively (however, the total amount of dipropylene glycol, ethanol, and purified water is 100 (Mass%)

In addition, hydrophilicity evaluation was performed as follows by the difference in solubility.
When 1.0 or more (g / 100 g test solvent): particularly high hydrophilicity When 0.2 or more and less than 1.0 (g / 100 g test solvent): high hydrophilicity 0.1 or more If less than 0.2 (g / 100 g test solvent): poor hydrophilicity. If less than 0.1 (g / 100 g test solvent), if there is a solid suspension: not hydrophilic

[Example 1]
(Synthesis of Compound (1))
In a 300 mL eggplant-shaped flask, 16.4 g (132 mmol) of 2- (2-chloroethoxy) ethanol, 33.2 g (240 mmol) of potassium carbonate, and 150 mL of acetonitrile were added to 14.7 g (120 mmol) of 4-hydroxybenzaldehyde. Heated at 105 ° C. with stirring for 14 hours. Furthermore, 1.49 g (12.0 mmol) of 2- (2-chloroethoxy) ethanol was added and heated at 105 ° C. with stirring for 30 hours. After the reaction mixture cooled to room temperature, the solid was removed by celite filtration. The solvent was distilled off under reduced pressure to obtain 34.6 g of a yellow viscous substance mixed with a white solid.

  80 mL of water was added thereto, transferred to a separately prepared 200 mL eggplant-shaped flask, 15.6 g (156 mmol) of hydantoin and 14.4 g of 28% aqueous ammonia were added, and the mixture was heated at 90 ° C. with stirring for 12 hours. After the reaction mixture had cooled to room temperature, the precipitated crystals were collected by filtration. Thereafter, the crystals were washed twice with water and twice with ethanol. After drying, 29.6 g of 5- [4- [2- (2-hydroxyethoxy) ethoxy] benzylidene] hydantoin was obtained.

Subsequently, 17.5 g (60.0 mmol) of the obtained product was added to 7.47 g (60 mmol) of 2- (2-chloroethoxy) ethanol, 20.0 g (145 mmol) of potassium carbonate in a 200 mL eggplant type flask, N, N-dimethylformamide 80mL was added and it heated at 110 degreeC for 3 hours, stirring. After the reaction mixture cooled to room temperature, the solid was removed by celite filtration. The solvent was distilled off under reduced pressure to obtain 30.5 g of a yellow viscous substance mixed with a white solid. This was purified by silica gel column chromatography (developing solvent; isopropanol: toluene = 1: 3) to obtain 9.21 g of yellow crystals. This was treated with activated carbon with ethanol and recrystallized to obtain 6.56 g of the following compound (1) (yield: 25%).
5- [4- [2- (2-hydroxyethoxy) ethoxy] benzylidene] -3- [2- (2-hydroxyethoxy) ethyl] hydantoin (Compound 1)

(Spectral data of compound (1), etc.)
UV spectrum: [lambda] max; 335 nm, absorbance; 0.43 (ethanol).
¹ H-NMR spectrum: δ [ppm, DMSO-d ₆ ] = 3.41-3.46 (m, 4H), 3.48-3.53 (m, 4H), 3.60 (m, 2H) , 3.64 (m, 2H), 3.75 (t, 2H), 4.15 (t, 2H), 4.61 (t, 1H), 4.67 (t, 1H), 6.52 ( s, 1H), 6.99 (d, 2H), 7.62 (d, 2H), 10.71 (s, 1H).
Solubility: 2.0 (g / 100 g test solvent), especially hydrophilic.

[Example 2]
(Synthesis of Compound (2))
In a 200 mL eggplant type flask, 15.6 g (156 mmol) of hydantoin, 80 mL of water, and 14.4 g of 28% aqueous ammonia are added to 14.7 g (120 mmol) of 4-hydroxybenzaldehyde and heated at 90 ° C. with stirring for 12 hours. did. After the reaction mixture had cooled to room temperature, the precipitated crystals were collected by filtration. Thereafter, the crystals were washed twice with water and twice with ethanol. After drying, 20.3 g of 5- (4-hydroxybenzylidene) hydantoin was obtained.

  Subsequently, 18.8 g (92.2 mmol) of the obtained product was dissolved in 180 mL of N, N-dimethylformamide in a 500 mL eggplant type flask, and then 27.1 g (221 mmol) of ethyl chloroacetate, 30 of potassium carbonate. 0.5 g (221 mmol) was added and heated at 120 ° C. with stirring for 2 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, water was added, and extraction was performed three times with ethyl acetate. The organic layers were combined, washed twice with water and once with saturated brine, and then dried over sodium sulfate. Thereafter, sodium sulfate was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained brown crystals were recrystallized with a mixed solvent of ethyl acetate and hexane, dried, and then 5- [ 9.96 g of 4- (2-ethoxy-2-oxoethoxy) benzylidene] -3- (2-ethoxy-2-oxoethyl) hydantoin was obtained.

Subsequently, 7.57 g (72.0 mmol) of diethanolamine was added to 4.50 g (12.0 mmol) of the obtained product in a 50 mL eggplant type flask, and the mixture was heated at 120 ° C. with stirring for 1 hour. After the reaction mixture was cooled to room temperature, the precipitated yellow crystals were recrystallized with a mixed solvent of ethanol and water and dried to obtain 4.46 g of the following compound (2) (yield: 18%).
5- [4- [2- [Bis (2-hydroxyethyl) amino] -2-oxoethoxy] benzylidene] -3- [2- [bis (2-hydroxyethyl) amino] -2-oxoethyl] hydantoin (compound 2)

(Spectral data of compound (2), etc.)
UV spectrum: [lambda] max; 336 nm, absorbance; 0.30 (ethanol).
¹ H-NMR spectrum: δ [ppm, DMSO-d ₆ ] = 3.33-3.36 (m, 4H), 3.42-3.51 (m, 8H), 3.57-3.60 ( m, 4H), 4.49 (s, 2H), 4.71-4.74 (t, 1H x 2), 4.97 (s, 2H), 5.00 (t, 1H), 5.05 (T, 1H), 6.53 (s, 1H), 6.94 (d, 2H), 7.60 (d, 2H), 10.72 (s, 1H).
Solubility: 1.2 (g / 100 g test solvent), especially hydrophilic.

Example 3
(Synthesis of Compound (3))
In a 200 mL eggplant-shaped flask, ethyl acrylate 2 was added to 5.84 g (20.0 mmol) of 5- [4- [2- (2-hydroxyethoxy) ethoxy] benzylidene] hydantoin obtained in the process of Example 1. .40 g (24.0 mmol), potassium hydroxide 0.112 g (2.00 mmol) and N, N-dimethylformamide 45 mL were added and heated at 110 ° C. with stirring for 6 hours. After the reaction mixture cooled to room temperature, the solid was removed by celite filtration. The solvent was distilled off under reduced pressure to obtain a yellow viscous substance.

In another 100 mL eggplant type flask, 6.31 g (60.0 mmol) of diethanolamine was added and heated at 120 ° C. with stirring for 17 hours. After the reaction mixture was cooled to room temperature, crystals were precipitated by adding acetonitrile and isopropanol to the resulting orange viscous substance, and the crystals precipitated by filtration were collected. Then, activated carbon treatment with isopropanol and water and recrystallization gave 3.52 g of the following compound (3) (yield: 39%).
5- [4- [2- (2-hydroxyethoxy) ethoxy] benzylidene] -3- [3- [bis (2-hydroxyethyl) amino] -3-oxopropyl] hydantoin (Compound 3)

(Spectral data of compound (3), etc.)
UV spectrum: [lambda] max; 338 nm, absorbance; 0.34 (ethanol).
¹ H-NMR spectrum: δ [ppm, DMSO-d ₆ ] = 2.72 (t, 2H), 3.32-3-38 (m, 4H), 3.46-3.52 (m, 8H) , 3.66 (t, 2H), 3.75 (t, 2H), 4.14 (t, 2H), 4.69 (s, 2H), 4.85 (s, 1H), 6.47 ( s, 1H), 6.98 (d, 2H), 7.62 (d, 2H), 10.60 (s, 1H).
Solubility: 1.5 (g / 100 g test solvent), especially hydrophilic.

Example 4
(Tyrosinase inhibitory activity evaluation 1)
The tyrosinase inhibitory activity of the compound (1) was evaluated by measuring the dopaic acid activity of tyrosinase.

Specifically, compound (1) dissolved in DMSO as a test sample or DMSO as a control was first added to each well of a 96-well plate. Next, 20 μl of mushroom-derived tyrosinase solution (prepared with phosphate buffer (pH 6.0)) prepared to 400 U / ml was added thereto, and further the reaction solution (0.5 mg / ml L-tyrosine solution, 63 mM CuSO4). ₄ · _5H 2 O / phosphate buffer (pH 6.0)) was added 100 [mu] l, and 30 minutes incubated at 37 ° C.. Thereafter, the absorbance at 640 nm was measured, and these were taken as measurement values (test sample measurement values, control measurement values), and the tyrosinase activity rate relative to the control value was determined by the following equation (Formula 1).
(Formula 1)
Tyrosinase activity rate = [(absorbance at 640 nm of test substance) / (absorbance at 640 nm of control)] × 100 (%)

  The obtained results are shown in FIG. It was confirmed that tyrosinase activity was suppressed by adding compound (1).

Example 5
(Tyrosinase inhibitory activity evaluation 2)
Using compound (2), the tyrosinase inhibitory activity was evaluated in the same manner as in Example 4.

  The obtained results are shown in FIG. It was confirmed that tyrosinase activity was suppressed by adding compound (2).

Example 6
(Melanin production inhibition evaluation)
Using compound (1), a melanin production inhibition test using mouse-derived melanoma cells was performed.

Specifically, mouse-derived melanoma cells were seeded in a 6-well plate at a density of 1.5 × 10 ⁴ cells / well using 10% FBS-containing DMEM medium, and were incubated at 37 ° C., 5% carbon dioxide and 95%. The cells were cultured for 1 day in an air environment. Thereafter, the medium was changed, and compound (1) dissolved in DMSO or DMSO as a control was added, respectively, and cultured under the same conditions for 3 days. Thereafter, the supernatant was removed and washed once with PBS (−). Thereafter, 300 μl of 1N NaOH was added, the cells were lysed by heating at 60 ° C. for 2 hours, and the melanin production amount was determined by measuring the absorbance at 475 nm. This was taken as the measured value (test sample measured value, control measured value), and the melanin production rate relative to the control value was determined by the following formula (Formula 2).
(Formula 2)
Melanin production rate = [(absorbance at 475 nm of test substance) / (absorbance at 475 nm of control)] × 100 (%)

  The obtained results are shown in FIG. By adding the compound (1), the melanin production rate decreased.

Example 7
(SOD-like activity evaluation test)
Using compound (1), an SOD-like activity evaluation test was conducted.

The active oxygen suppression effect was measured according to standard operating methods using SODA Assay Kit-WST (manufactured by Wako Pure Chemical Industries, Ltd.). Specifically, the sample compound (1) solution dissolved in DMSO or DMSO (20 μL) was added as a control, respectively, and a highly water-soluble tetrazolium salt-containing coloring reagent (180 μL) was added, followed by enzyme suspension (20 μL) at 37 ° C. For 30 minutes in a constant temperature bath. Thereafter, the absorbance at 450 nm was measured, and these were taken as measured values (test sample measured values, control measured values), and the superoxide anion production inhibition rate relative to the control values was determined by the following formula (Formula 3).
(Formula 3)
Superoxide anion production inhibition rate = [(absorbance of test substance at 450 nm) / (absorbance of control at 450 nm)] × 100 (%)

  The obtained results are shown in FIG. By adding the compound (1), it was confirmed that the production of superoxide anion was suppressed and SOD-like activity was exhibited.

Example 8
(Catalase-like activity evaluation test 1)
A catalase-like activity evaluation test was conducted using the compound (1).

The active oxygen inhibitory effect was measured according to a standard operation method using Amplex Red (trademark) Catalase Assay Kit (manufactured by Invitrogen). Specifically, a sample compound (1) solution dissolved in DMSO or DMSO 25 μL was added as a control, and 40 μL hydrogen peroxide solution was further added as a reaction substrate. After performing the first phase reaction at room temperature for 30 minutes, 50 μL of a coloring reagent was added. Then, it was made to react for 30 minutes in a 37 degreeC thermostat. Thereafter, the absorbance at 560 nm was measured, and these were taken as measured values (test sample measured values, control measured values), and the hydrogen peroxide generation inhibition rate relative to the control values was determined by the following formula (Formula 4).
(Formula 4)
Hydrogen peroxide generation inhibition rate = [(absorbance at 560 nm of the test substance) / (absorbance at 560 nm of the control)] × 100 (%)

  The obtained results are shown in FIG. It was confirmed that the addition of compound (1) suppressed the production of hydrogen peroxide and exhibited catalase-like activity.

Example 9
(Catalase-like activity evaluation test 2)
Using the compounds (2) and (3), a catalase-like activity evaluation test was conducted in the same manner as in Example 8.

  The obtained result is shown in FIG. By adding the compounds (2) and (3), it was confirmed that the production of hydrogen peroxide was suppressed and a catalase-like activity was exhibited.

Claims (14)

A whitening agent comprising a benzylidene azolidine derivative represented by the general formula (I) or a salt thereof.
(In the structural formula (I), n is an integer of 1 to 5, ^{A 1} is N -A ^{4, A 2} and A ^3, in their respective independently lower Symbol structural formula (1) in represented by functional group (1), or the Ri functional group (3) der represented by the following structural formula (3), A ⁴ is a hydrogen atom, the number of which may carbons 1 substituted with a hydroxyl group 8 alkyl group, a functional group represented by the following structural formula (1) (1), or a functional group (3) represented by the following structural formula (3) (provided that at least ^a 2, ^{a 3} and ^{a 4} Any one or more hydroxyl groups are included . ) When n is an integer of 2 to 5, a plurality of A ³ —O— may be the same or different.
(In Structural Formula (1), X ¹ is an alkylene group having 2 to 4 carbon atoms, R ¹ is a hydroxyalkyl group having 2 to 4 carbon atoms, and m is an integer of 1 to 4. when m is an integer from 2 to 4, X ¹ existing in plural numbers may be the same or different.)
(In Structural Formula (3), X ^3a and X ^3b are each independently an alkylene group having 2 to 4 carbon atoms, and R ^3a and R ^3b are each independently a hydroxyalkyl group having 2 to 4 carbon atoms. And r is 1 or 2, and s and t are each independently an integer of 0 to 4. When s is an integer of 2 to 4, a plurality of X ^3a may be the same or different. (If t is an integer of 2 to 4, the plurality of X ^3b may be the same or different.) In the structural formula (I), A ⁴ is characterized by a hydrogen atom, whitening agent of claim 1. An antiphotoaging agent comprising a benzylidene azolidine derivative represented by the general formula (I) or a salt thereof.
(In the structural formula (I), n is an integer of 1 to 5, ^{A 1} is N -A ^{4, A 2} and A ^3, in their respective independently lower Symbol structural formula (1) in represented by functional group (1), or the Ri functional group (3) der represented by the following structural formula (3), A ⁴ is a hydrogen atom, the number of which may carbons 1 substituted with a hydroxyl group 8 alkyl group, a functional group represented by the following structural formula (1) (1), or a functional group (3) represented by the following structural formula (3) (provided that at least ^a 2, ^{a 3} and ^{a 4} Any one or more hydroxyl groups are included . ) When n is an integer of 2 to 5, a plurality of A ³ —O— may be the same or different.
(In Structural Formula (1), X ¹ is an alkylene group having 2 to 4 carbon atoms, R ¹ is a hydroxyalkyl group having 2 to 4 carbon atoms, and m is an integer of 1 to 4. when m is an integer from 2 to 4, X ¹ existing in plural numbers may be the same or different.)
(In Structural Formula (3), X ^3a and X ^3b are each independently an alkylene group having 2 to 4 carbon atoms, and R ^3a and R ^3b are each independently a hydroxyalkyl group having 2 to 4 carbon atoms. And r is 1 or 2, and s and t are each independently an integer of 0 to 4. When s is an integer of 2 to 4, a plurality of X ^3a may be the same or different. (If t is an integer of 2 to 4, the plurality of X ^3b may be the same or different.) The structural formula (I), A ⁴ is characterized by a hydrogen atom, an anti-photoaging agent according to claim 3. A tyrosinase inhibitor comprising a benzylidene azolidine derivative represented by the general formula (I) or a salt thereof.
(In the structural formula (I), n is an integer of 1 to 5, ^{A 1} is N -A ^{4, A 2} and A ^3, in their respective independently lower Symbol structural formula (1) in represented by functional group (1), or the Ri functional group (3) der represented by the following structural formula (3), A ⁴ is a hydrogen atom, the number of which may carbons 1 substituted with a hydroxyl group 8 alkyl group, a functional group represented by the following structural formula (1) (1), or a functional group (3) represented by the following structural formula (3) (provided that at least ^a 2, ^{a 3} and ^{a 4} Any one or more hydroxyl groups are included . ) When n is an integer of 2 to 5, a plurality of A ³ —O— may be the same or different.
(In Structural Formula (1), X ¹ is an alkylene group having 2 to 4 carbon atoms, R ¹ is a hydroxyalkyl group having 2 to 4 carbon atoms, and m is an integer of 1 to 4. when m is an integer from 2 to 4, X ¹ existing in plural numbers may be the same or different.)
(In Structural Formula (3), X ^3a and X ^3b are each independently an alkylene group having 2 to 4 carbon atoms, and R ^3a and R ^3b are each independently a hydroxyalkyl group having 2 to 4 carbon atoms. And r is 1 or 2, and s and t are each independently an integer of 0 to 4. When s is an integer of 2 to 4, a plurality of X ^3a may be the same or different. (If t is an integer of 2 to 4, the plurality of X ^3b may be the same or different.) In the structural formula (I), A ⁴ is characterized by a hydrogen atom, tyrosinase inhibitor according to claim 5. A melanin production inhibitor comprising a benzylidene azolidine derivative represented by the general formula (I) or a salt thereof.
(In the structural formula (I), n is an integer of 1 to 5, ^{A 1} is N -A ^{4, A 2} and A ^3, in their respective independently lower Symbol structural formula (1) in represented by functional group (1), or the Ri functional group (3) der represented by the following structural formula (3), A ⁴ is a hydrogen atom, the number of which may carbons 1 substituted with a hydroxyl group 8 alkyl group, a functional group represented by the following structural formula (1) (1), or a functional group (3) represented by the following structural formula (3) (provided that at least ^a 2, ^{a 3} and ^{a 4} Any one or more hydroxyl groups are included . ) When n is an integer of 2 to 5, a plurality of A ³ —O— may be the same or different.
(In Structural Formula (1), X ¹ is an alkylene group having 2 to 4 carbon atoms, R ¹ is a hydroxyalkyl group having 2 to 4 carbon atoms, and m is an integer of 1 to 4. when m is an integer from 2 to 4, X ¹ existing in plural numbers may be the same or different.)
(In Structural Formula (3), X ^3a and X ^3b are each independently an alkylene group having 2 to 4 carbon atoms, and R ^3a and R ^3b are each independently a hydroxyalkyl group having 2 to 4 carbon atoms. And r is 1 or 2, and s and t are each independently an integer of 0 to 4. When s is an integer of 2 to 4, a plurality of X ^3a may be the same or different. (If t is an integer of 2 to 4, the plurality of X ^3b may be the same or different.) In the structural formula (I), A ⁴ is characterized by a hydrogen atom, a melanin production inhibitor according to claim 7. A reactive oxygen species production inhibitor comprising a benzylidene azolidine derivative represented by the general formula (I) or a salt thereof.
(In the structural formula (I), n is an integer of 1 to 5, ^{A 1} is N -A ^{4, A 2} and A ^3, in their respective independently lower Symbol structural formula (1) in represented by functional group (1), or the Ri functional group (3) der represented by the following structural formula (3), A ⁴ is a hydrogen atom, the number of which may carbons 1 substituted with a hydroxyl group 8 alkyl group, a functional group represented by the following structural formula (1) (1), or a functional group (3) represented by the following structural formula (3) (provided that at least ^a 2, ^{a 3} and ^{a 4} Any one or more hydroxyl groups are included . ) When n is an integer of 2 to 5, a plurality of A ³ —O— may be the same or different.
(In Structural Formula (1), X ¹ is an alkylene group having 2 to 4 carbon atoms, R ¹ is a hydroxyalkyl group having 2 to 4 carbon atoms, and m is an integer of 1 to 4. when m is an integer from 2 to 4, X ¹ existing in plural numbers may be the same or different.)
(In Structural Formula (3), X ^3a and X ^3b are each independently an alkylene group having 2 to 4 carbon atoms, and R ^3a and R ^3b are each independently a hydroxyalkyl group having 2 to 4 carbon atoms. And r is 1 or 2, and s and t are each independently an integer of 0 to 4. When s is an integer of 2 to 4, a plurality of X ^3a may be the same or different. (If t is an integer of 2 to 4, the plurality of X ^3b may be the same or different.) In the structural formula (I), A ⁴ is characterized by a hydrogen atom, reactive oxygen species generation inhibitor according to claim 9. A SOD-like activator comprising a benzylidene azolidine derivative represented by the general formula (I) or a salt thereof.
(In the structural formula (I), n is an integer of 1 to 5, ^{A 1} is N -A ^{4, A 2} and A ^3, in their respective independently lower Symbol structural formula (1) in represented by functional group (1), or the Ri functional group (3) der represented by the following structural formula (3), A ⁴ is a hydrogen atom, the number of which may carbons 1 substituted with a hydroxyl group 8 alkyl group, a functional group represented by the following structural formula (1) (1), or a functional group (3) represented by the following structural formula (3) (provided that at least ^a 2, ^{a 3} and ^{a 4} Any one or more hydroxyl groups are included . ) When n is an integer of 2 to 5, a plurality of A ³ —O— may be the same or different.
(In Structural Formula (1), X ¹ is an alkylene group having 2 to 4 carbon atoms, R ¹ is a hydroxyalkyl group having 2 to 4 carbon atoms, and m is an integer of 1 to 4. when m is an integer from 2 to 4, X ¹ existing in plural numbers may be the same or different.)
(In Structural Formula (3), X ^3a and X ^3b are each independently an alkylene group having 2 to 4 carbon atoms, and R ^3a and R ^3b are each independently a hydroxyalkyl group having 2 to 4 carbon atoms. And r is 1 or 2, and s and t are each independently an integer of 0 to 4. When s is an integer of 2 to 4, a plurality of X ^3a may be the same or different. (If t is an integer of 2 to 4, the plurality of X ^3b may be the same or different.) The SOD-like activator according to claim 11, wherein A ⁴ in the structural formula (I) is a hydrogen atom . A catalase-like active agent comprising a benzylidene azolidine derivative represented by the general formula (I) or a salt thereof.
(In the structural formula (I), n is an integer of 1 to 5, ^{A 1} is N -A ^{4, A 2} and A ^3, in their respective independently lower Symbol structural formula (1) in represented by functional group (1), or the Ri functional group (3) der represented by the following structural formula (3), A ⁴ is a hydrogen atom, the number of which may carbons 1 substituted with a hydroxyl group 8 alkyl group, a functional group represented by the following structural formula (1) (1), or a functional group (3) represented by the following structural formula (3) (provided that at least ^a 2, ^{a 3} and ^{a 4} Any one or more hydroxyl groups are included . ) When n is an integer of 2 to 5, a plurality of A ³ —O— may be the same or different.
(In Structural Formula (1), X ¹ is an alkylene group having 2 to 4 carbon atoms, R ¹ is a hydroxyalkyl group having 2 to 4 carbon atoms, and m is an integer of 1 to 4. when m is an integer from 2 to 4, X ¹ existing in plural numbers may be the same or different.)
(In Structural Formula (3), X ^3a and X ^3b are each independently an alkylene group having 2 to 4 carbon atoms, and R ^3a and R ^3b are each independently a hydroxyalkyl group having 2 to 4 carbon atoms. And r is 1 or 2, and s and t are each independently an integer of 0 to 4. When s is an integer of 2 to 4, a plurality of X ^3a may be the same or different. (If t is an integer of 2 to 4, the plurality of X ^3b may be the same or different.) In the structural formula (I), A ⁴ is characterized by a hydrogen atom, catalase-like active agent of claim 13.