WO1998042308A1 - Preventives for skin aging - Google Patents

Preventives for skin aging Download PDF

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Publication number
WO1998042308A1
WO1998042308A1 PCT/JP1998/001143 JP9801143W WO9842308A1 WO 1998042308 A1 WO1998042308 A1 WO 1998042308A1 JP 9801143 W JP9801143 W JP 9801143W WO 9842308 A1 WO9842308 A1 WO 9842308A1
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Prior art keywords
group
agent
skin aging
skin
preventing
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Application number
PCT/JP1998/001143
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French (fr)
Japanese (ja)
Inventor
Naoko Tsuji
Shigeru Moriwaki
Genji Imokawa
Yasuto Suzuki
Yoshinori Nishizawa
Original Assignee
Kao Corporation
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Publication date
Priority claimed from JP07170097A external-priority patent/JP3688846B2/en
Priority claimed from JP7169897A external-priority patent/JPH10265359A/en
Application filed by Kao Corporation filed Critical Kao Corporation
Publication of WO1998042308A1 publication Critical patent/WO1998042308A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • A61Q19/08Anti-ageing preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A61K8/447Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof containing sulfur
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/46Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur

Definitions

  • 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.
  • 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.
  • 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
  • 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
  • n represents a number of 1 to 20
  • 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
  • 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.
  • an alkyl group, a cyclic alkyl group, an aromatic hydrocarbon group or an aralkyl group is preferred.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • phosphonic acid derivatives (1) include the following compounds.
  • 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.
  • mercaptopropionamide derivative (2) examples include the following compounds.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • the suspension was suspended in 100 / 0.2 ⁇ Tris-HCl buffer ( ⁇ 8.0) and sonicated to obtain an enzyme solution.
  • 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.
  • 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
  • Vitamin E 0.5 Ceramic 5 Fragrance trace pigment
  • 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.

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

明 細 書 皮膚老化予防剤 技術分野  Description Skin aging preventive agent Technical field
本発明は皮膚老化予防剤に関し、 さらに詳細には皮膚の老化によって生じるし わ、 たるみの発生やはりの減少などの外観変化を防止又は改善することのできる 皮廣老化予防剤に関する。 背景技術  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
しわ、 たるみの発生、 はりの減少などの皮膚の形態的変化については、 充分に 研究が進んでいるとはいえないのが現状である。 例えばコラーゲンを配合した化 粧料が用いられているが、 充分なしわ発生防止効果やはりの減少防止効果は得ら れていない。  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.
しわなどの発生については、 特に紫外線との関連性が強いとされており、 紫外 線照射により生じた皮膚の老化を光老化と称して、 種々研究されている。 しかし、 未だ紫外線吸収剤又は紫外線防禦剤に代わる化粧料が開発されていないのが現状 である。  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.
従って、 本発明の目的はしわに代表される皮膚の老化によって生じる症状を予 防又は改善することのできる薬剤又は化粧料を提供することにある。 発明の開示  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
本発明者らは、 これまで高血圧治療剤、 心,脳循環疾患治療剤、 腎疾患治療剤 等として知られていた特定のホスホン酸誘導体 (特開平 5— 1 0 5 6 9 8号公報) 及びコラゲナーゼ抑制剤として知られていた特定のメルカプトプロピオンァミ ド 誘導体 (特開昭 5 7 - 2 4 3 5 4号公報) に着目した。 そして意外にもこれらの 化合物及びその塩がしわに代表される皮膚の老化によって生じる症状を予防、 改 善できることを見出した。 また金属依存型エラスチン分解酵素に対する阻害剤が しわ形成の予防に有効であり、 さらに前記メルカプトプロピオンアミ ド誘導体及 びその塩が前記金属依存型エラスチン分解酵素を有効に阻害することを見出し、 本発明を完成させた。 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.
すなわち、 本発明は次の一般式 ( 1 )  That is, the present invention provides the following general formula (1)
(式中、 R 1 、 R 2 及び R 3 は水素原子、 置換基を有していてもよい炭化水素基 又は置換基を有していてもよい糖残基を示す) (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)
で表されるホスホン酸誘導体もしくはその塩、 又は次の一般式 (2 ) A phosphonic acid derivative or a salt thereof represented by the following general formula (2):
R5 R 5
R4-SCH2CHCONH(CH2)n6 ( 2 ) R 4 -SCH 2 CHCONH (CH 2 ) n6 (2)
(式中、 R 4 は水素原子又はァシル基を示し、 R 5 は水素原子又は置換基を有し ていてもよい炭化水素基を示し、 R 6 は水素原子、 カルボキシル基、 アルコキシ カルボニル基、 置換基を有していてもよい炭化水素基、 置換基を有していてもよ い複素環式基又はァシル基を示し、 nは 1〜 2 0の数を示す) (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)
で表されるメルカプトプロピオンァミ ド誘導体もしくはその塩を含有する皮膚老 化予防剤を提供するものである。 And a skin aging preventive agent containing a mercaptopropionamide derivative or a salt thereof represented by the formula:
本発明はまた前記メルカプトプロピオンァミ ド誘導体又はその塩を有効成分と する金属依存型エラスチン分解酵素阻害剤及び金属依存型エラスチン分解酵素阻 害剤を有効成分とするしわ形成予防剤を提供するものである。 発明を実施するための最良の形態 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
上記式 ( 1 ) 及び (2 ) 中、 R 1 、 R 2 、 R 3 、 R 5 及び R 6 で示される置換 基を有していてもよい炭化水素基は、 飽和炭化水素基及び不飽和炭化水素基のい ずれでもよく、 アルキル基、 アルケニル基、 アルキニル基、 環状アルキル基、 環 状アルケニル基、 芳香族炭化水素基、 ァラルキル基等が挙げられる。 これらの炭 化水素基は、 炭素数が 1〜2 4のもの、 特に 1〜 1 8のものが好ましい。 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.
前記炭化水素基のうち、 アルキル基、 環状アルキル基、 芳香族炭化水素基又は ァラルキル基が好ましい。 ここで、 アルキル基は直鎖状又は分技状の炭素数 1 ~ 1 2のアルキル基が好ましく、 例えば、 メチル基、 ェチル基、 n —プロピル基、 イソプロピル基、 n —ブチル基、 イソブチル基、 s e c—ブチル基、 t e r t— ブチル基、 n —ペンチル基、 イソアミル基、 t e r t—アミル基、 n—へキシル 基、 n—ォクチル基、 n —デシル基、 n — ドデシル基などが挙げられる。 環状ァ ルキル基は 5〜7員環の脂環状アルキル基が好ましく、 シクロペンチル基、 シク 口へキシル基、 シクロへプチル基等が挙げられる。 芳香族炭化水素基は、 フエ二 ル基、 ナフチル基等の炭素数 6〜 1 4の芳香族炭化水素基が好ましい。 ァラルキ ル基は炭素数 6〜 1 2の芳香族炭化水素基で置換された炭素数 1〜 5のアルキル 基が好ましく、 例えば、 フヱニルメチル (=ベンジル) 基、 2—フヱニルェチル 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.
( =フヱネチル) 基、 1 一ナフチルメチル基、 2—ナフチルメチル基、 2 — ( 1 一ナフチル) ェチル基、 2— (2—ナフチル) ェチル基、 3—フエニルプロピル 基などが挙げられる。 (= Phenyl) group, 1-naphthylmethyl group, 2-naphthylmethyl group, 2- (1-naphthyl) ethyl group, 2- (2-naphthyl) ethyl group, 3-phenylpropyl group and the like.
また、 これらの炭化水素基に置換し得る基は、 ハロゲン原子、 ヒ ドロキシル基、 アルコキシル基、 ァシル基、 保護されていてもよいアミノ基、 複素環式基等が挙 げられる。 ここでハロゲン原子は塩素原子、 臭素原子、 ヨウ素原子等が挙げられ る。 アルコキシル基は、 炭素数 1〜 1 2のアルコキシル基が好ましく、 例えばメ トキシ基、 エトキシ基、 イソプロポキシ基等が挙げられる。 ァシル基は、 炭素数 1〜 1 2のアルカノィル基が好ましく、 例えばァセチル基、 プロピオニル基、 ブ チリル等が挙げられる。 保護されていてもよいアミノ基は、 アミノ基、 ァシルァ ミノ基、 アルキルアミノ基、 ジアルキルアミノ基等が挙げられる。 複素環式基は、 ヘテロ原子として窒素原子、 酸素原子及び/又は硫黄原子を 1〜 3個有する 5〜 1 4員の単環又は縮合環の基が好ましく、 例えばピリジル基、 ピリダジニル基、 フリル基、 チェニル基、 インドリル基、 チアゾリル基、 ィミダブリル基、 ベンゾ フリル基、 ベンゾチェ二ル基等が挙げられる。 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.
R 1 、 R 2 及び R 3 で示される糖残基は、 単糖残基又はオリゴ糖残基が挙げら れる。 またこれらの糖残基に置換し得る基は、 アルキル基、 ァシル基、 ァラルキ ル基等が挙げられる。 ここでアルキル基、 ァシル基、 ァラルキル基は前記と同様 のものが挙げられる。 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.
R 4 及び R 6 で示されるァシル基は、 アルカノィル基及びァリールカルボニル 基が挙げられる。 当該アルカノィル基は炭素数 1〜 1 2のアルカノィル基が好ま しく、 例えばァセチル基、 プロピオニル基、 プチリル基等が挙げられる。 またァ リールカルボニル基は、 炭素数 7〜 1 5のァリールカルボニル基が好ましく、 例 えばベンゾィル基、 置換ベンゾィル基、 ナフチルカルボニル基、 置換ナフチルカ ルポニル基等が挙げられる。 ここでベンゾィル基やナフチルカルボニル基に置換 する基はアルキル基、 アルコキシ基、 ハロゲン基、 アミノ基、 ヒドロキシ基、 ァ ルカノィルォキシ基等が挙げられる。 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.
R 6 で示される複素環式基は、 ヘテロ原子として窒素原子、 酸素原子及び Z又 は硫黄原子を 1〜 3個有する 5〜 1 4員の単環又は縮合環の基が好ましく、 例え ばピリジル基、 ピリダジニル基、 フリル酸、 チェニル基、 インドリル基、 チアゾ リル基、 ィミダゾリル基、 ベンゾフリル基、 ベンゾチェ二ル基、 ピロリジニル基、 ピペリジニル基、 乇ルホリニル基、 ピペラジニル基が挙げられる。 また、 当該複 素環式基に置換し得る基は、 ハロゲン原子、 ヒドロキシル基、 アルコキシル基、 ァシル基、 保護されていてもよいアミノ基等が挙げられる。 これらの置換基の具 体例は前記 R5 及び R8 の炭化水素基の置換基と同様のものが挙げられる。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 .
R6 で示されるアルコキシカルボニル基は、 炭素数 1〜 1 2のアルコキシカル ボニル基が挙げられ、 その具体例はメ トキシカルボニル基、 エトキシカルボニル 基、 イソプロポキシカルボニル基、 ブトキシカルポニル基等が挙げられる。 nは 1〜2 0の数を示し、 1〜 1 0が好ましく、 2が特に好ましい。 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.
これらのホスホン酸誘導体 ( 1 ) の具体例は、 次の化合物が挙げられる。  Specific examples of these phosphonic acid derivatives (1) include the following compounds.
化合物 1 Compound 1
化合物 2Compound 2
化合物 3Compound 3
化合物 4Compound 4
ホスホン酸誘導体 ( 1 ) の塩としては、 ナトリウム塩、 カリウム塩のアルカリ 金属塩、 カルシウム塩、 マグネシウム塩等のアルカリ土類金属塩、 アンモニゥム 塩、 アルキルアミン塩等が挙げられる。 またホスホン酸誘導体 ( 1 ) は水和物と しても使用できる。 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.
またメルカプトプロピオンアミ ド誘導体 (2) の具体例は、 次の化合物が挙げ られる。  Further, specific examples of the mercaptopropionamide derivative (2) include the following compounds.
化合物 5Compound 5
メルカプトプロピオンアミ ド誘導体 ( 2) の塩は塩酸塩、 硫酸塩等の無機酸塩、 酢酸塩等の有機酸塩が挙げられる。 またメルカプトプロピオンアミ ド誘導体 (2) は、 水和物としても使用できる。 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.
ホスホン酸誘導体 ( 1 ) 又はその塩は、 例えば特開平 5 - 1 0 5 6 9 8号公報 に記載の方法によって製造することができる。  The phosphonic acid derivative (1) or a salt thereof can be produced, for example, by the method described in JP-A-5-105988.
またこれらのメルカプトプロピオンアミ ド誘導体 ( 2) は、 例えば特開昭 5 7 - 2 4 3 5 4号公報に記載の方法によって製造することができる。  These mercaptopropionamide derivatives (2) can be produced, for example, by the method described in JP-A-57-243554.
本発明の皮膚老化防止剤は、 皮膚の老化により生じる形態的変化、 例えばしわ、 たるみの発生やはりの減少に対して予防又は改善作用を有するが、 特にしわの発 生やはりの減少に対する予防又は改善作用が優れている。  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.
本発明のしわ形成予防剤は、 金属依存型エラスチン分解酵素に対する阻害剤を 有効成分とするものである。  The agent for preventing wrinkle formation of the present invention contains an inhibitor for metal-dependent elastin-degrading enzyme as an active ingredient.
本発明のしわ形成予防剤に用いられる金属依存型エラスチン分解酵素阻害剤は、 金属依存型エラスターゼ阻害剤、 特に真皮線維芽細胞由来の金属依存型エラス夕 ーゼ阻害剤が好ましい。 このような阻害剤は、 例えば培養ヒ ト線 維芽細胞から 0. 1 %トリ トン X— 1 0 0Z0. 2M トリス—塩酸緩衝液 (pH 8 · 0 ) で 抽出した酵素液を用い、 N—サクシ二ルー A 1 a - A 1 a - A 1 a— p—二トロ ァニリ ドを基質とした酵素活性測定系において 1 mMで 5 0 %以上の阻害活性を示 す物質が挙げられる。 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.
このような金属依存型エラスチン分解酵素阻害剤の例は、 例えば前記したホス ホン酸誘導体 ( 1 ) 、 メルカプトプロピオンアミ ド誘導体 ( 2 ) 及びそれらの塩 等が挙げられる。 このうちメルカプトアミ ド誘導体及びその塩が特に好ましい。 本発明皮膚老化予防剤又はしわ形成予防剤の投与形態としては皮膚外用剤、 経 口剤などが挙げられるが、 皮膚外用剤とするのが好ましい。 皮膚外用剤とする場 合のホスホン酸誘導体 ( 1 ) 、 メルカプトプロピオンアミ ド誘導体 ( 1 ) 又はそ れらの塩の配合量は、 特に制限されないが、 全組成に対し 0 . 0 0 0 0 1〜 1 0 重量%、 特に 0 . 0 0 0 1〜5重量%とするのが好ましい。  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.
本発明の皮膚老化予防剤及びしわ形成予防剤には、 ホスホン酸誘導体 ( 1 ) 、 メルカプトプロピオンァミ ド誘導体もしくはそれらの塩又は金属依存型エラスチ ン分解酵素阻害剤以外に紫外線吸収剤、 紫外線防禦剤、 コラーゲン、 保湿剤、 抗 炎症剤、 抗酸化剤等の成分を配合することができるが、 特に紫外線吸収剤及びノ 又は紫外線防禦剤を配合するのが好ましい。  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.
ここで、 紫外線吸収剤としては、 p —メ トキシ桂皮酸 2 —ェチルへキシル、 4 - t 一プチルー 4 ' —メ トキシジベンゾィルメタン等が挙げられる。 紫外線防禦 剤としては、 酸化チタン、 酸化亜鉛等が挙げられる。 保湿剤としては、 ヒアルロ ン酸、 セラミ ド類等が挙げられる。 また抗炎症剤としては、 アラン トイン、 グリ チルリチン等が挙げられる。 これらの紫外線吸収剤、 紫外線防禦剤、 コラーゲン、 保湿剤、 抗炎症剤、 抗酸 化剤等は、 本発明の皮膚老化予防剤中に 0 . 0 0 1 〜 9 9重量%、 特に 0 . 0 0 1〜5 0重量%配合するのが好ましい。  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.
本発明の皮膚老化予防剤の具体的な剤型は、 クリーム、 軟膏、 ゲル、 口一ショ ン、 溶液、 ノ、'ック、 ファンデーション等が挙げられ、 これらの剤型とするにあた つて各種油剤、 界面活性剤、 ゲル化剤、 防腐剤、 酸化防止剤、 溶剤、 アルコール、 キレー ト剤、 増粘剤、 色素、 香料、 水等を配合することができる。 実施例 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
次に実施例を示して本発明をさらに詳細に説明するが、 本発明は以下の実施例 に限定されるものではない。  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.
実施例 1 Example 1
ヘアレスマウスによるしわ形成抑制試験  Wrinkle formation inhibition test by hairless mouse
ヘアレスマウス (HRZ I CR, 実験開始時 6週齢) の背部に、 健康線用ラン プ (東芝製、 SE 20) で、 1回の照射量が 1 MED以下となるように調節して UV— B光の照射を行い、 直後に前記した化合物 1、 5又は 2を含む 8 0 %エタ ノール溶液を 1 0 0 ^を塗布した。 この作業を 2 0週間にわたって行った。 比 較例としてエラス夕チナール (化合物 6) を用いた。 照射エネルギー量は UV— R a d i om e t e r (TOKYOO PT I C AL社製、 UVR— 3 0 5 / 3 6 5 D) を用いて測定した。 また、 コントロールとして 8 0 %ェ夕ノールのみ を塗布したものをサンプルと同様に試験した。 試験終了後、 形成されたしわの度 数を肉眼により下記の基準 (しわ指数) で評価した。 結果を表 1に示す。  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.
<しわ指数 > <Wrinkle index>
0 : しわが無形成  0: No wrinkles formed
1 : しわがかすかに形成  1: Wrinkle faintly formed
2 : しわが微量形成  2: Wrinkle trace formation
3 : しわが若干形成  3: Some wrinkles are formed
4 : しわが強固に形成 表 1 4: Wrinkles are firmly formed table 1
表 1 より明らかなように、 ホスホン酸誘導体 ( 1 ) 及びメルカプトプロピオン アミ ド誘導体 ( 2) はしわ形成抑制作用を示したが、 化合物 6はしわ形成抑制作 用を示さなかった。 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.
実施例 2 Example 2
培養ヒト線維芽細胞のエラスターゼ活性抑制試験  Elastase activity inhibition test of cultured human fibroblasts
大日本製薬社より市販されている正常ヒト線維芽細胞は 1 0 %牛胎児血清を含 む DME培地で継代培養し、 本試験に供した。 ラバ一ポリスマンを用いてシヤー レからはがした細胞は、 生理食塩水中に浮遊させ、 低速の遠心分離器を使って細 胞を集め、 生理食塩水で、 3回洗浄した。 細胞は 0. 1 % ト リ トン X— 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—
1 0 0/0. 2Μ トリスー塩酸緩衝液 (ρΗ 8. 0) に浮遊させ、 超音波破砕し、 酵素液とした。 The suspension was suspended in 100 / 0.2Μ Tris-HCl buffer (ρΗ8.0) and sonicated to obtain an enzyme solution.
酵素活性測定の基質には 1 2 5mM N—スクシ二ル A l a— A l a— A l a 一 p—二トロア二リ ドを用い、 酵素液+前記化合物 1、 5又は 2 1 0 0 ^に 1 ^添加し、 3 7でで 1時間反応させ、 5 ^の酢酸を加えて反応を停止させ た。 生成したニト αァニリン量は分光光度計で、 4 0 5 nmにおける吸光度を測定 し、 求めた。 対照として化合物 6を用いた。  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.
サンプル濃度を変えて、 酵素活性抑制率をプロッ ト し、 5 0 %抑制濃度 ( I C 5。) を求めた。 結果を表 2に示す。 表 2 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
表 2から明らかなように好中球由来のセリンプロテア一ゼ型エラスターゼ阻害 剤として知られている化合物 6は、 金属依存型エラスタ一ゼであるヒト線維芽細 胞由来の酵素に対しては抑制作用を示さなかった。 これに対し、 化合物 1、 5及 び 2は金属依存型エラス夕一ゼを強力に抑制した。 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.
実施例 3 Example 3
皮膚老化予防剤のはりに及ぼす効果を検討するために、 以下の方法で皮膚の弾 力性を機械的に測定した。 (方法) 3週令の SD系雄性ラッ トの両足底を 3群に 分け、 5mM化合物 2塗布群、 8 0 %エタノール (溶媒) 塗布群、 無処理群とした。 健康線用ランプ (東芝 S E 2 0) を用いて、 UV - B ( 1 MED以下) 照射を特 定時刻に 1 日おきに週 3回、 6週間行った。 塗布は、 照射直後及び非照射日は照 射日と同時刻に、 毎日 1 0 1ノ片足底行った。  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.
皮膚の弾力性測定はキュートメ一夕一 SES 5 7 5 (クレ一ジュ · カザ力社製) を用い、 5 0 Ombで 3秒間吸引後、 解放し、 その後 3秒間の計 6秒間の変位を測 定した。 測定は 1足底に対して 5回ずつ行い、 U e (瞬間弾性変位) 及び U f (最終変位) 値を求めた。 U e値は弾力性の指標、 U f 値は柔軟性の指標であり、 レ、ずれも紫外線老化により低下する。 結果を表 3に示す。 表 3 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エタノール群) #: pく 0. 05 ( vs無処理群) 表 3から明らかなように、 エラス夕一ゼ阻害活性を有する化合物 2は U V— B による皮膚の弾力性低下を強く予防する効果が認められ、 皮膚のはりを保持する ことが可能である。 *: 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.
次にホスホン酸誘導体 ( 1 ) 又はメルカプトプロピオンァミ ド誘導体 ( 2 ) を 配合した、 皮膚老化防止用の外用剤の処方例を示す。  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.
実施例 4 Example 4
ク リーム  Cream
(成分) (重量  (Ingredients) (Weight
化合物 1 2  Compound 1 2
スクヮラン 5  Squalane 5
ステアリ ン酸 2  Stearate 2
グリセリ ンモノステアレー 1 0  Glycerin monosteary 1 0
エタノール 2  Ethanol 2
パラォキシ安息香酸メチル 0 . 2 セ夕ノール 2  Methyl para-oxybenzoate 0.2 Cenool 2
オリーブ油 4  Olive oil 4
ワセリ ン 5  Vaseline 5
グリチルリチン酸 1  Glycyrrhizic acid 1
ビタミン E 0 . 5 セラ ミ 5 香料 微量 色素 Vitamin E 0.5 Ceramic 5 Fragrance trace pigment
精製水  purified water
計 1 0 0 . 0 実施例 5  Total 100.0 Example 5
スキン口一ション  Skin mouthpiece
(成分) (重量%) 化合物 5 1 グリセリ ンモノステアレー ト 1 エタノール 1 5 プロピレングリ コール 4 ィソプロピルパルミテー ト 3 ラノ リ ン 1 パラォキシ安息香酸メチル 0 . 1 セラ ミ ド 1 香料  (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
色素  Pigment
精製水  purified water
計 1 0 0 . 0 実施例 6  Total 100.0 Example 6
パック剤  Packing agent
(成分) (重量%) 化合物 2 3 ポリ ビニルアルコール 2 0 グリセリ ン 5 エタノール 1 6 (Ingredient) (% by weight) Compound 23 Polyvinyl alcohol 20 Glycerin 5 Ethanol 1 6
香料  Spice
色素 微量  Pigment
精製水  purified water
計 1 0 0 . 0 実施例 7  Total 100.0 Example 7
ファンデーショ ン  Foundation
(成分) (重量  (Ingredients) (Weight
化合物 1 1  Compound 1 1
球伏シリ力ビース 2 0  Sukebushi Power Bead 2 0
シリ力被覆セリサイ ト 4 5  Sericite coated sericite 4 5
超微粒子酸化チタン 1 0  Ultrafine titanium oxide 10
黄酸化鉄 3  Yellow iron oxide 3
タルク 5  Talc 5
マイ力 5  My strength 5
ベンガラ 1  Bengara 1
グンジヨウ 1  Gunjiyo 1
パラベン 0 2 流動パラフィ ン 4 8 スクヮラン 4  Paraben 0 2 Liquid paraffin 4 8 Squalane 4
1 0 0 . 0 産業上の利用可能性  1 0 0 .0 Industrial applicability
本発明の皮膚老化予防剤、 しわ形成予防剤及び金属依存型エラスチン分解酵素 阻害剤はいずれも工業的に量産可能であり、 化粧品業界等において利用可能であ る o 日本国特許出願番号 9 一 7 1 6 9 8号、 9 一 7 1 6 9 9号及び 9 一 7 1 7 0 0 号明細書に記載の内容を本明細書の一部としてここに引用する。 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 . 次の一般式 ( 1 ) 1. The following general formula (1)
 Contract
(式中、 R 1 、 R 2 及び R 3 は水素原子、 置換基を有していてもよい炭化水素基 の (In the formula, R 1 , R 2 and R 3 are a hydrogen atom or a hydrocarbon group which may have a substituent.
又は置換基を有していてもよい糖残基を示す) Or a sugar residue which may have a substituent)
で表されるホスホン酸誘導体又はその塩を含有する皮膚老化予防剤。 A skin aging preventive agent comprising a phosphonic acid derivative represented by the formula or a salt thereof.
2 . 次の一般式 (2 ) 2. The following general formula (2)
R5 R 5
R4— SCH2CHCONH(CH2)n— R6 ( 2 ) R 4 — SCH 2 CHCONH (CH 2 ) n — R 6 (2)
(式中、 R 4 は水素原子又はァシル基を示し、 R 5 は水素原子又は置換基を有し ていてもよい炭化水素基を示し、 R 6 は水素原子、 カルボキシル基、 アルコキシ カルボニル基、 置換基を有していてもよい炭化水素基、 置換基を有していてもよ い複素環式基又はァシル基を示し、 nは 1〜2 0の数を示す) (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)
で表されるメルカプトプロピオンァミ ド誘導体又はその塩を含有する皮膚老化予 防剤。 A skin aging preventive agent comprising a mercaptopropionamide derivative represented by the formula or a salt thereof.
3 . 皮膚のしわ予防 ·改善剤である請求項 1又は 2記載の皮膚老化予防剤。 3. The agent for preventing skin aging according to claim 1 or 2, which is an agent for preventing and improving skin wrinkles.
4 . 投与形態が、 皮膚外用剤である請求項 1〜3のいずれか 1項記載の皮膚老化 予防剤。 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 . さらに、 紫外線吸収剤又は紫外線防禦剤を含有するものである請求項 1〜4 のいずれか 1項記載の皮膚老化予防剤。  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 . 請求項 2記載のメルカプトプロピオンアミ ド誘導体又はその塩を有効成分と する金属依存型ェラスチン分解酵素阻害剤。 6. The mercaptopropionamide derivative or a salt thereof according to claim 2 as an active ingredient. Metal-dependent elastin-degrading enzyme inhibitor.
7 . 金属依存型エラスチン分解酵素に対する阻害剤を有効成分とするしわ形成予 防剤。  7. An anti-wrinkle agent containing an inhibitor of metal-dependent elastin-degrading enzyme as an active ingredient.
8 . 金属依存型エラスチン分解酵素が、 真皮線維芽細胞由来のエラスチン分解酵 素である請求項 7記載のしわ形成予防剤。  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 . 投与形態が、 皮膚外用剤である請求項 7又は 8記載のしわ形成予防剤。 9. The agent for preventing wrinkle formation according to claim 7 or 8, wherein the administration form is an external preparation for skin.
1 0 . さらに、 紫外線吸収剤又は紫外線防禦剤を含有するものである請求項?〜 9のいずれか 1項記載のしわ形成予防剤。 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.
PCT/JP1998/001143 1997-03-25 1998-03-18 Preventives for skin aging WO1998042308A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP9/71700 1997-03-25
JP9/71699 1997-03-25
JP07170097A JP3688846B2 (en) 1997-03-25 1997-03-25 Skin aging preventive
JP9/71698 1997-03-25
JP7169997 1997-03-25
JP7169897A JPH10265359A (en) 1997-03-25 1997-03-25 Preventive for wrinkle formation

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