WO1998042308A1

WO1998042308A1 - Preventives for skin aging

Info

Publication number: WO1998042308A1
Application number: PCT/JP1998/001143
Authority: WO
Inventors: Naoko Tsuji; Shigeru Moriwaki; Genji Imokawa; Yasuto Suzuki; Yoshinori Nishizawa
Original assignee: Kao Corporation
Priority date: 1997-03-25
Filing date: 1998-03-18
Publication date: 1998-10-01

Abstract

Preventives for skin aging, whereby changes in the appearance caused by skin aging, for example, formation of wrinkles and sags and lessened tension can be prevented or ameliorated. Specifically, preventives for skin aging, which contain phosphonic acid derivatives represented by general formula (1), wherein R?1, R2 and R3¿ represent each hydrogen, etc.; or mercaptopropionamide derivatives represented by general formula (2), wherein R?4, R5 and R6¿ represent each hydrogen, etc.; or salts thereof, whereby formation of wrinkles and lessened tension which cannot be sufficiently prevented by the conventional methods can be efficaciously prevented.

Description

Description Skin aging preventive agent Technical field

The present invention relates to a preventive agent for skin aging, and more particularly to a preventive agent for skin aging which can prevent or improve appearance changes such as wrinkles and sagging caused by skin aging. Background art

At present, studies on morphological changes of the skin such as wrinkles, sagging, and reduction of swelling are not sufficiently advanced. For example, cosmetics containing collagen are used, but the effect of preventing the occurrence of wrinkles has not yet been obtained.

The occurrence of wrinkles and the like is particularly considered to be strongly related to ultraviolet rays, and various studies have been made on the aging of skin caused by ultraviolet irradiation, called photoaging. However, at present, no cosmetics have been developed to replace UV absorbers or UV protectors.

Accordingly, an object of the present invention is to provide a drug or cosmetic which can prevent or improve symptoms caused by skin aging represented by wrinkles. Disclosure of the invention

The present inventors have proposed specific phosphonic acid derivatives (Japanese Patent Application Laid-Open No. 5-165898) which have heretofore been known as a therapeutic agent for hypertension, a therapeutic agent for heart and cerebral circulatory diseases, a therapeutic agent for renal diseases and the like. Attention was paid to a specific mercaptopropionamide derivative known as a collagenase inhibitor (Japanese Patent Application Laid-Open No. 57-244354). And surprisingly these It has been found that compounds and salts thereof can prevent and improve symptoms caused by skin aging represented by wrinkles. Further, they have found that an inhibitor of metal-dependent elastin-degrading enzyme is effective in preventing wrinkle formation, and that the mercaptopropionamide derivative and its salt effectively inhibit the metal-dependent elastin-degrading enzyme. Completed.

That is, the present invention provides the following general formula (1)

(Wherein R ¹ , R ² and R ³ represent a hydrogen atom, a hydrocarbon group which may have a substituent or a sugar residue which may have a substituent)

A phosphonic acid derivative or a salt thereof represented by the following general formula (2):

R ⁵

R ⁴ -SCH ₂ CHCONH (CH ₂ ) _n — ⁶ (2)

(Wherein, R ⁴ represents a hydrogen atom or an acyl group, R ⁵ represents a hydrogen atom or a hydrocarbon group which may have a substituent, R ⁶ represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, A hydrocarbon group which may have a group, a heterocyclic group which may have a substituent or an acyl group, and n represents a number of 1 to 20)

And a skin aging preventive agent containing a mercaptopropionamide derivative or a salt thereof represented by the formula:

The present invention also provides a metal-dependent elastin-degrading enzyme inhibitor containing the mercaptopropionamide derivative or a salt thereof as an active ingredient, and a wrinkle-preventing agent containing the metal-dependent elastin-degrading enzyme inhibitor as an active ingredient. It is. BEST MODE FOR CARRYING OUT THE INVENTION

In the above formulas (1) and (2), the hydrocarbon group which may have a substituent represented by R ¹ , R ² , R ³ , R ⁵ and R ⁶ is a saturated hydrocarbon group or an unsaturated hydrocarbon group. Any of a hydrogen group may be used, and examples thereof include an alkyl group, an alkenyl group, an alkynyl group, a cyclic alkyl group, a cyclic alkenyl group, an aromatic hydrocarbon group, and an aralkyl group. These hydrocarbon groups preferably have 1 to 24 carbon atoms, particularly preferably 1 to 18 carbon atoms.

Among the hydrocarbon groups, an alkyl group, a cyclic alkyl group, an aromatic hydrocarbon group or an aralkyl group is preferred. Here, the alkyl group is preferably a linear or branched alkyl group having 1 to 12 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isoamyl group, tert-amyl group, n-hexyl group, n-octyl group, n-decyl group, n-dodecyl group and the like. The cyclic alkyl group is preferably a 5- to 7-membered alicyclic alkyl group, and examples thereof include a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. The aromatic hydrocarbon group is preferably an aromatic hydrocarbon group having 6 to 14 carbon atoms, such as a phenyl group and a naphthyl group. The aralkyl group is preferably an alkyl group having 1 to 5 carbon atoms substituted with an aromatic hydrocarbon group having 6 to 12 carbon atoms. Examples thereof include a phenylmethyl (= benzyl) group and a 2-phenylethyl group.

(= Phenyl) group, 1-naphthylmethyl group, 2-naphthylmethyl group, 2- (1-naphthyl) ethyl group, 2- (2-naphthyl) ethyl group, 3-phenylpropyl group and the like.

Examples of the group which can be substituted for these hydrocarbon groups include a halogen atom, a hydroxyl group, an alkoxyl group, an acyl group, an amino group which may be protected, and a heterocyclic group. Here, the halogen atom includes a chlorine atom, a bromine atom, an iodine atom and the like. The alkoxyl group is preferably an alkoxyl group having 1 to 12 carbon atoms, such as a methoxy group, an ethoxy group, and an isopropoxy group. The sacyl group has the carbon number An alkanol group of 1 to 12 is preferable, and examples thereof include an acetyl group, a propionyl group, and a butyryl group. Examples of the amino group which may be protected include an amino group, an acylamino group, an alkylamino group and a dialkylamino group. The heterocyclic group is preferably a 5- to 14-membered monocyclic or condensed ring group having 1 to 3 nitrogen atoms, oxygen atoms and / or sulfur atoms as hetero atoms, such as a pyridyl group, a pyridazinyl group, and a furyl group. Phenyl, thienyl, indolyl, thiazolyl, imidabryl, benzofuryl, benzochenyl and the like.

The sugar residues represented by R ¹ , R ² and R ³ include a monosaccharide residue or an oligosaccharide residue. Examples of the group that can be substituted for these sugar residues include an alkyl group, an acyl group, and an aralkyl group. Here, the alkyl group, the acyl group, and the aralkyl group are the same as those described above.

The acyl group represented by R ⁴ and R ⁶ includes an alkanoyl group and an arylcarbonyl group. The alkanoyl group is preferably an alkanoyl group having 1 to 12 carbon atoms, and examples thereof include an acetyl group, a propionyl group and a petyryl group. The arylcarbonyl group is preferably an arylcarbonyl group having 7 to 15 carbon atoms, and examples thereof include a benzoyl group, a substituted benzoyl group, a naphthylcarbonyl group, and a substituted naphthylcarbonyl group. Here, the group substituted with a benzoyl group or a naphthylcarbonyl group includes an alkyl group, an alkoxy group, a halogen group, an amino group, a hydroxy group, and a alkanoyloxy group.

The heterocyclic group represented by R ⁶ is preferably a 5- to 14-membered monocyclic or condensed ring group having 1 to 3 nitrogen atoms, oxygen atoms and Z or sulfur atoms as a hetero atom, for example, pyridyl Groups, pyridazinyl group, furylic acid, chenyl group, indolyl group, thiazolyl group, imidazolyl group, benzofuryl group, benzochelyl group, pyrrolidinyl group, piperidinyl group, perforinyl group, and piperazinyl group. Examples of the group that can be substituted for the complex cyclic group include a halogen atom, a hydroxyl group, an alkoxyl group, an acyl group, and an amino group which may be protected. Components of these substituents Examples of the substituent include the same substituents as those described above for the hydrocarbon group for R ⁵ and R ⁸ .

The alkoxycarbonyl group represented by R ⁶ includes an alkoxycarbonyl group having 1 to 12 carbon atoms, and specific examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, and a butoxycarbonyl group. . n represents a number of 1 to 20, preferably 1 to 10, and particularly preferably 2.

Specific examples of these phosphonic acid derivatives (1) include the following compounds.

Compound 1

Compound 2

Compound 3

Compound 4

Examples of the salts of the phosphonic acid derivative (1) include sodium salts and alkali salts of potassium salts. Examples thereof include alkaline earth metal salts such as metal salts, calcium salts, and magnesium salts, ammonium salts, and alkylamine salts. The phosphonic acid derivative (1) can also be used as a hydrate.

Further, specific examples of the mercaptopropionamide derivative (2) include the following compounds.

Compound 5

Examples of the salt of the mercaptopropionamide derivative (2) include inorganic acid salts such as hydrochloride and sulfate, and organic acid salts such as acetate. The mercaptopropionamide derivative (2) can also be used as a hydrate.

The phosphonic acid derivative (1) or a salt thereof can be produced, for example, by the method described in JP-A-5-105988.

These mercaptopropionamide derivatives (2) can be produced, for example, by the method described in JP-A-57-243554.

The agent for preventing skin aging of the present invention has a preventive or ameliorating effect on morphological changes caused by aging of the skin, such as wrinkles and sagging. The action is excellent.

The agent for preventing wrinkle formation of the present invention contains an inhibitor for metal-dependent elastin-degrading enzyme as an active ingredient.

The metal-dependent elastin-degrading enzyme inhibitor used in the wrinkle formation preventive agent of the present invention is preferably a metal-dependent elastase inhibitor, particularly a metal-dependent elastase inhibitor derived from dermal fibroblasts. Such an inhibitor can be prepared, for example, by using an enzyme solution extracted from cultured human fibroblasts with 0.1% Triton X-100Z0.2M Tris-HCl buffer (pH 8.0). Sakushirou A 1 a-A 1 a-A 1 a— p—Nitro Substances that show an inhibitory activity of 50% or more at 1 mM in an enzyme activity measurement system using anilide as a substrate.

Examples of such metal-dependent elastin-degrading enzyme inhibitors include, for example, the above-mentioned phosphonic acid derivative (1), mercaptopropionamide derivative (2), and salts thereof. Among them, mercaptoamide derivatives and salts thereof are particularly preferred. Examples of the dosage form of the preventive agent for preventing skin aging or wrinkle formation of the present invention include an external preparation for the skin and an oral preparation. The external preparation for the skin is preferable. The amount of the phosphonic acid derivative (1), the mercaptopropionamide derivative (1) or a salt thereof when used as an external preparation for skin is not particularly limited, but is 0.0000 to the total composition. It is preferably from 10 to 10% by weight, particularly preferably from 0.001 to 5% by weight.

The skin aging preventive agent and the wrinkle preventive agent of the present invention include, in addition to the phosphonic acid derivative (1), the mercaptopropionamide derivative or a salt thereof, and a metal-dependent elastin-degrading enzyme inhibitor, an ultraviolet absorber, an ultraviolet light protector. Ingredients, collagen, moisturizing agents, anti-inflammatory agents, antioxidants and the like can be blended, but it is particularly preferable to blend a UV absorber and a UV absorber.

Here, examples of the ultraviolet absorbent include 2-ethylhexyl p-methoxycinnamate, 4-t-butyl-4'-methoxydibenzoylmethane, and the like. Examples of the ultraviolet protective agent include titanium oxide and zinc oxide. Examples of the humectant include hyaluronic acid and ceramides. Examples of the anti-inflammatory agent include allantoin, glycyrrhizin and the like. These ultraviolet absorbers, ultraviolet protective agents, collagen, humectants, anti-inflammatory agents, antioxidants and the like are contained in the anti-aging agent for skin of the present invention in an amount of 0.001 to 99% by weight, particularly 0.09% by weight. It is preferable to add 0 to 50% by weight.

Specific dosage forms of the skin aging preventive agent of the present invention include creams, ointments, gels, mouth lotions, solutions, tablets, foundations, and the like. Various oils, surfactants, gelling agents, preservatives, antioxidants, solvents, alcohols, A chelating agent, a thickener, a coloring matter, a fragrance, water and the like can be added. Example

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples.

Example 1

Wrinkle formation inhibition test by hairless mouse

Adjust the irradiation dose to 1 MED or less with a health line lamp (Toshiba, SE 20) on the back of a hairless mouse (HRZ ICR, 6 weeks old at the start of the experiment). Irradiation with B light was performed, and immediately thereafter, 100% of an 80% ethanol solution containing the above-mentioned compound 1, 5 or 2 was applied. This was done for 20 weeks. Eras evening tinal (compound 6) was used as a comparative example. The irradiation energy amount was measured using UV-Radiom e ter (manufactured by TOKYOO PT ICAL, UVR-305 / 365D). As a control, a sample to which only 80% ethanol was applied was tested in the same manner as the sample. After the test was completed, the frequency of the formed wrinkles was visually evaluated according to the following criteria (wrinkle index). Table 1 shows the results.

0: No wrinkles formed

1: Wrinkle faintly formed

2: Wrinkle trace formation

3: Some wrinkles are formed

4: Wrinkles are firmly formed table 1

As is clear from Table 1, the phosphonic acid derivative (1) and the mercaptopropion amide derivative (2) showed an inhibitory effect on wrinkle formation, but the compound 6 did not show an inhibitory effect on wrinkle formation.

Example 2

Elastase activity inhibition test of cultured human fibroblasts

Normal human fibroblasts commercially available from Dainippon Pharmaceutical Co., Ltd. were subcultured in a DME medium containing 10% fetal bovine serum and used for this test. Cells detached from the dish using a mule policeman were suspended in saline, the cells were collected using a low-speed centrifuge, and washed three times with saline. Cells are 0.1% Triton X—

The suspension was suspended in 100 / 0.2Μ Tris-HCl buffer (ρΗ8.0) and sonicated to obtain an enzyme solution.

As the substrate for the enzyme activity measurement, use 125 mM N-succinyl A la-A la-A la-p-nitroalide, and use the enzyme solution + the compound 1, 5 or 2100 ^ ^ Was added and the reaction was carried out at 37 for 1 hour, and the reaction was stopped by adding 5 ^ acetic acid. The amount of nitro-aniline formed was determined by measuring the absorbance at 405 nm with a spectrophotometer. Compound 6 was used as a control.

Changing the sample concentrations, the enzymatic activity inhibition rate was plotted to determine the 50% inhibitory concentration (IC _5.). Table 2 shows the results. Table 2

As is clear from Table 2, compound 6, which is known as a neutrophil-derived serine protease elastase inhibitor, inhibits the enzyme derived from human fibroblasts, a metal-dependent elastase. No effect was shown. In contrast, compounds 1, 5, and 2 strongly inhibited metal-dependent elastase.

Example 3

In order to examine the effect of the skin aging preventive agent on the beam, the elasticity of the skin was measured mechanically by the following method. (Method) The two soles of a 3-week-old male SD rat were divided into three groups, and a 5 mM compound 2 application group, an 80% ethanol (solvent) application group, and an untreated group were used. UV-B (less than 1 MED) irradiation was carried out at a specified time every other day three times a week for 6 weeks using a health line lamp (Toshiba SE20). The application was performed on one sole every day immediately after irradiation and on the non-irradiation day at the same time as the irradiation day.

The skin elasticity was measured using Cuteme Ichiichi SES 575 (manufactured by Kleige Kazarik), aspirated at 50 Omb for 3 seconds, released, and then measured displacement for 3 seconds for a total of 6 seconds. Specified. The measurement was performed five times for each sole, and Ue (instantaneous elastic displacement) and Uf (final displacement) values were obtained. The Ue value is an index of elasticity, and the Uf value is an index of flexibility. Table 3 shows the results. Table 3

*: P <0.05 (vs. ethanol group) #: p <0.05 (vs. untreated group) As is clear from Table 3, compound 2 having elas enzyme inhibition activity was found to inhibit UV-B It has the effect of strongly preventing a decrease in elasticity, and is capable of retaining a skin beam.

Next, a formulation example of an external preparation for preventing skin aging containing a phosphonic acid derivative (1) or a mercaptopropionamide derivative (2) will be described.

Example 4

Cream

(Ingredients) (Weight

Compound 1 2

Squalane 5

Stearate 2

Glycerin monosteary 1 0

Ethanol 2

Methyl para-oxybenzoate 0.2 Cenool 2

Olive oil 4

Vaseline 5

Glycyrrhizic acid 1

Vitamin E 0.5 Ceramic 5 Fragrance trace pigment

purified water

Total 100.0 Example 5

Skin mouthpiece

(Ingredients) (% by weight) Compound 5 1 Glycerin monostearate 1 Ethanol 15 Propylene glycol 4 Isopropyl palmitate 3 Lanolin 1 Methyl paraoxybenzoate 0.1 Ceramide 1 Flavor

Pigment

purified water

Total 100.0 Example 6

Packing agent

(Ingredient) (% by weight) Compound 23 Polyvinyl alcohol 20 Glycerin 5 Ethanol 1 6

Spice

Pigment

purified water

Total 100.0 Example 7

Foundation

(Ingredients) (Weight

Compound 1 1

Sukebushi Power Bead 2 0

Sericite coated sericite 4 5

Ultrafine titanium oxide 10

Yellow iron oxide 3

Talc 5

My strength 5

Bengara 1

Gunjiyo 1

Paraben 0 2 Liquid paraffin 4 8 Squalane 4

1 0 0 .0 Industrial applicability

The skin aging preventive agent, wrinkle preventive agent and metal-dependent elastin degrading enzyme inhibitor of the present invention can be industrially mass-produced and can be used in the cosmetics industry, etc. The contents described in Japanese Patent Application Nos. 9-171698, 917169, and 917700 are incorporated herein by reference.

Claims

1. The following general formula (1)

Contract

(In the formula, R ¹ , R ² and R ³ are a hydrogen atom or a hydrocarbon group which may have a substituent.

Or a sugar residue which may have a substituent)

A skin aging preventive agent comprising a phosphonic acid derivative represented by the formula or a salt thereof.

2. The following general formula (2)

R ⁵

R ⁴ — SCH ₂ CHCONH (CH ₂ ) _n — R ⁶ (2)

(Wherein, R ⁴ represents a hydrogen atom or an acyl group, R ⁵ represents a hydrogen atom or a hydrocarbon group which may have a substituent, R ⁶ represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, Represents a hydrocarbon group which may have a group, a heterocyclic group which may have a substituent or an acyl group, and n represents a number of 1 to 20)

A skin aging preventive agent comprising a mercaptopropionamide derivative represented by the formula or a salt thereof.

3. The agent for preventing skin aging according to claim 1 or 2, which is an agent for preventing and improving skin wrinkles.

4. The preventive agent for skin aging according to any one of claims 1 to 3, wherein the administration form is an external preparation for skin.

5. The skin aging preventive agent according to any one of claims 1 to 4, further comprising an ultraviolet absorbent or an ultraviolet protective agent.

6. The mercaptopropionamide derivative or a salt thereof according to claim 2 as an active ingredient. Metal-dependent elastin-degrading enzyme inhibitor.

7. An anti-wrinkle agent containing an inhibitor of metal-dependent elastin-degrading enzyme as an active ingredient.

8. The agent for preventing wrinkle formation according to claim 7, wherein the metal-dependent elastin-degrading enzyme is an elastin-degrading enzyme derived from dermal fibroblasts.

9. The agent for preventing wrinkle formation according to claim 7 or 8, wherein the administration form is an external preparation for skin.

10. A claim which further contains an ultraviolet absorber or an ultraviolet protective agent? 10. The agent for preventing wrinkle formation according to any one of claims 9 to 9.