WO2007037295A1

WO2007037295A1 - Wrinkling prevention or mitigation with adam inhibitor

Info

Publication number: WO2007037295A1
Application number: PCT/JP2006/319236
Authority: WO
Inventors: Takuya Hiruma; Hirotada Fukunishi; Masaru Suetsugu; Yukiko Matsunaga; Michio Shibata; Satoshi Amano
Original assignee: Shiseido Company, Ltd.
Priority date: 2005-09-29
Filing date: 2006-09-28
Publication date: 2007-04-05
Also published as: JP2007119444A; TW200744657A

Abstract

Wrinkles are more effectively prevented or mitigated. An ADAM inhibitor comprising a benzohydroxamic acid represented by the following general formula (I) or a salt thereof is applied to the skin. [Chemical formula 1] (I) (In the formula, R1's each independently is C1-18 alkyl, C3-8 cycloalkyl, halogeno, hydroxy, C1-18 alkoxy, benzyloxy, amino, or acylamino; R2 is hydrogen, methyl, or phenyl; and n is an integer of 0-3.)

Description

Specification

Prevention or improvement of wrinkles with AD AM inhibitors

Technical field

[0001] The present invention relates to a novel ADAM inhibitor and the prevention or improvement of wrinkles using the same.

Background art

[0002] In recent years, with the growing interest in beauty among middle-aged and older women, fine lines appearing in the corners of the eyes and mouth that are manifested by a decrease in the water retention capacity of the epidermal stratum corneum with age and a decrease in sebum due to a decrease in the secretion of epidermal lipids. There is a growing interest in Wrinkles are thought to be caused by skin dryness, and are thought to be significantly different from the large wrinkles caused by photoaging in the generation mechanism, morphological, histological, or biochemical changes. The For example, it has been verified in humans that there is a correlation between the stratum corneum moisture content and the level of fine lines (Non-patent Document 1). In addition, it has been reported that continuous destruction of the barrier function with unsaturated fatty acids causes epidermal wrinkles (Non-patent Document 2). Until now, the prevention and improvement of such wrinkles had to be relied upon by protecting the dryness of the skin with cosmetics containing moisturizers such as glycerin, sorbitol, and plant juice extract. However, it was not possible to sufficiently prevent or improve fine wrinkles by only protecting the skin with a moisturizer or the like, but it was strongly desired to prevent and improve fine lines more effectively.

[0003] A group of membrane-type meta-proteases called ADAM (a disintegrin and metalloprotease), along with matrix metalloprotease (MMP), is heparin-binding EGF¾ neprin-binding epidermal growth factor. -like growth factor (HB-EGF) and tumor necrosis factor (TNF), and many other membrane proteins are cleaved by the cell surface and released outside the cell. It has been known that it contributes to cell proliferation and sorting by growth factors. For example, it has been reported that HB-EGF expressed on the cell surface is cleaved by ADAM-9, 10, 12, and 17 and released to the outside of the cell. (For example, see Non-Patent Documents 3-7). [0004] Furthermore, various stimuli such as ultraviolet rays, oxidation, and osmotic pressure promote the expression of growth factors such as HB-EGF and TNF-α in skin cells' release from the cell membrane, and the mechanism of autocrine and paracrine. It has been known that ADAM activity that occurs in skin cells occurs when a signal such as proliferation and separation is transmitted to cells to cause proliferation and thickening of the skin.

Non-Patent Document 1: Ninagawa et al., Fragrance Journal; 1992 (11) 29-42

Non-Patent Document 2: Jin Masaki Perfume Journal; 2001 Vol.25, No. 1, 34-38

Non-patent literature 3: Asakura, M., et al. 2002.Cardiac hypertrophy is inhioited by antagon ismof ADAM 12 processing of HB-EGF: metalloproteinase inhibitors as a new thera py. Nat. Med. 8: 35-40

Patent Document 4: Izumi, Y., et al. 1998. A metalloprotease- disintegrin, MDC9 / meltrin -— / ADAM9 and PKC_ are involved in TPA- induced ectodomain shedding of membra ne— anchored heparin— binding EGF— like growth factor. EMBO J. 17: 7260—7272. Non-Patent Document 5: Lemjabbar, H., and C. Basbaum. 2002. Platelet-activating factor rece ptorand ADAM 10 mediate responses to Staphylococcus aureus in epithelial cells. Nat. Med. 8: 41-46

Patent Document 6: Sunnarborg, S.W., et al. 2002.Tumor necrosis factor-alpha convertin g enzyme (TACE) regulates epidermal growth factor receptor ligand availability.J. B iol. Chem. 277: 12838-12845

Non-Patent Document 7: Yan, Y., K. Shirakabe, and Z. Werb. 2002. The metalloprotease Kuzb anian (ADAM 10) mediates the trans activation of EGF receptor by G protein-coupled receptors. J. Cell Biol. 158 : 221-226.

Disclosure of the invention

Problems to be solved by the invention

In view of the circumstances as described above, the present invention aims to find a novel compound capable of effectively preventing or improving wrinkles, particularly fine wrinkles, and to use it to more effectively prevent or improve wrinkles. It is what.

Means for solving the problem [0006] The present inventor has found that the continuous barrier destruction of the skin by repeatedly applying tape stripping to hairless mice causes changes in the epidermis and dermis similar to fine lines in human skin to occur in the mouse skin. Succeeded in creating a fine mouse model. Furthermore, in such a fine wrinkle mouse model, proteins belonging to the ADAM (a disintegrin and metalloprotease) family such as ADAM-9 and ADAM-17 (hereinafter referred to as ADAM), and their release from the cell membrane and activity are caused by ADAM. It was found that gene expression in the epidermis of HB-EG F and Amphiregulin was enhanced, and Sarako could suppress wrinkle formation by inhibiting epidermal and dermal thickening by inhibiting ADAM in the skin.

[0007] Therefore, in searching for novel compounds that can inhibit ADAM, certain benzohydroxamic acids and salts thereof have high ADAM inhibitory activity, and also remarkably inhibit wrinkle formation. It has been found that the present invention has been achieved.

[0008] ADAMs such as ADAM-9, ADAM-10, and ADAM-17 are present on the skin cell surface, and growth factors such as HB—EGF, Amphiregulin, TNF—a, and TGF—a are released from the cell membrane in the skin. It is an enzyme that is released and activated. Due to skin noria destruction, ADAM is activated or up-regulated in the skin and promotes the release and activation of growth factors such as HB-EGF, resulting in thickening of the epidermis and dermis. This is considered to be one important mechanism of fine wrinkle formation. Therefore, by suppressing the activity of ADAM in the skin, it is considered that the increased activity of HB-EGF and the like can be suppressed, and the thickening of the epidermis and dermis can be suppressed to prevent or improve wrinkles, particularly fine lines. Fig. 1 shows a schematic diagram illustrating the mechanism for preventing or improving wrinkles by inhibiting AD AM activity in the skin.

[0009] The ADAM inhibitor of the present invention is characterized by comprising benzohydroxamic acid represented by the following general formula (I) or a salt power thereof.

[Chemical 1]

(I)

[In the formula, each R is independently an alkyl group having 1 to 18 carbon atoms or a cycloamino group having 3 to 8 carbon atoms.

1

An alkyl group, a halogen atom, a hydroxyl group, an alkoxy group having 1 to 18 carbon atoms, a benzyloxy group, an amino group or an acylamino group, and R is a hydrogen atom, a methyl group or a phenyl group.

2

N is an integer of 0-3. )

In the benzohydroxamic acid or a salt thereof, R is preferably a hydrogen atom.

2

It is. Furthermore, R is an alkyl group having 1 to 18 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms,

1

It is preferably a hydroxyl group or an alkoxy group having 1 to 18 carbon atoms, and n is preferably 1 to 2. In addition, it is preferable that R is substituted at the 4-position, and in this case, R is a carbon number of 1 to

1 1

It is preferably an 18 alkyl group, a cycloalkyl group having 3 to 8 carbon atoms, or an alkoxy group having 1 to 18 carbon atoms, and R is preferably a hydrogen atom.

2

Here, the alkyl group has 1 to 18 carbon atoms, preferably linear or branched, and preferably 1 to 6 carbon atoms.

[0012] The cycloalkyl group has 3 to 8 carbon atoms, and is preferably a cyclopentyl group, a cyclohexyl group, or a cycloheptyl group.

[0013] The rhogen atom and the rogen atom are preferably a fluorine atom or a chlorine atom.

[0014] The alkoxy group is a hydroxyl group substituted with an alkyl having 1 to 18 carbon atoms, preferably a hydroxyl group substituted with an alkyl having 1 to 6 carbon atoms, more preferably

, A methoxy group.

The benzyloxy group may have a substituent on the benzene ring, and may be an alkyl group, a cycloalkyl group, a halogen atom, a hydroxyl group, an alkoxy group, a benzyloxy group, an aryloxy group, an amino group, an acylamino group, an aryl group. Etc. may be substituted. [0016] The acylamino group is an amino group substituted with an acyl group, and the acyl group is an alkyl group, a cycloalkyl group, a halogen atom, a hydroxyl group, an alkoxy group, a benzyloxy group, an aryloxy group, an amino group, an acylamino group, It may be substituted with a substituent such as aryl group.

[0017] Among the ADAM inhibitors of the present invention, 4-methoxybenzohydroxamic acid is a tyrosinase inhibitor and has been reported to have a whitening effect by preventing or inhibiting pigment formation (for example, international 1S 4_Methoxybenzohydroxamic acid S SADAM activity can be inhibited, and wrinkles can be prevented or ameliorated! / Was never known.

[0018] The wrinkle prevention or improvement agent of the present invention is characterized in that it also has the above-mentioned benzohydroxamic acid, which is an ADAM inhibitor, or a salt power thereof.

[0019] The method for preventing or improving wrinkles of the present invention is characterized by applying the above-mentioned benzohydroxamic acid or a salt thereof, which is an ADAM inhibitor, to the skin.

[0020] As described above, the benzohydroxamic acid of the present invention can suppress an increase in the activity of HB-EGF or the like by inhibiting or suppressing the activity of ADAM in the skin, thereby reducing the thickness of the epidermis and dermis. Suppress to prevent wrinkle formation or improve formed wrinkles. The invention's effect

[0021] By applying the ADAM inhibitor of the present invention to the skin, the activity of ADAM present in the skin such as ADAM-9, ADAM-10, or ADAM-17 is inhibited to reduce sebum, wash the face, etc. Suppresses the growth of growth factors such as HB-EGF in the epidermis and dermis induced by the destruction of the skin barrier caused by various factors, and suppresses thickening of the epidermis and dermis. It is possible to effectively prevent or improve the formation of wrinkles, especially fine lines.

Brief Description of Drawings

[0022] [FIG. 1] FIG. 1 is a schematic diagram illustrating a mechanism for preventing or improving wrinkles by inhibiting ADAM activity in the epidermis.

[FIG. 2] FIG. 2 is a graph showing the wrinkle improving effect of 4-methoxybenzohydroxamic acid in visual judgment. [Fig. 3] Fig. 3 is a graph showing the wrinkle improvement effect of 4-methoxybenzohydroxamic acid in wrinkle area (%).

FIG. 4 is a graph showing the inhibitory effect of 4-methoxybenzohydroxamic acid on TEWL elevation. BEST MODE FOR CARRYING OUT THE INVENTION

[0023] The benzohydroxamic acid or a salt thereof used in the present invention is represented by the following general formula (I):

[In the formula, each R independently represents an alkyl group having 1 to 18 carbon atoms or a cycloamino group having 3 to 8 carbon atoms.

1

2

N is an integer of 0-3. )

Examples of the benzohydroxamic acid of the present invention include 4-methoxybenzohydroxamic acid, 4-butylbenzohydroxamic acid, benzohydroxamic acid, 2-hydroxy-3-methylbenzohydroxamic acid, 3- (phenoxycetylamino) Benzohydroxamic acid, 4-cyclohexyl benzohydroxamic acid, 2-chloro-orchid benzohydroxamic acid, 3-methoxybenzohydroxamic acid, 2-methoxybenzohydroxamic acid, 4- clo-benzobenzoxamic acid, 4- (4-Fluorobenzyloxy) -3-isobutylbenzohydroxamic acid, 2-hydroxy-5-methylbenzohydroxamic acid and the like.

[0025] The benzohydroxamic acid used in the present invention includes a medically acceptable salt form in addition to the free acid. Examples of these salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, methylamine salts, dimethylamine salts, trimethylamine salts, methylbiperidine salts, and ethanolamine salts. The Powers including, but not limited to, amine salts such as ethanolamine salt, triethanolamine salt, lysine salt, ammonium salt, basic amino acid salt and the like.

[0026] Benzohydroxamic acid and salts thereof can be produced according to known production methods, and commercially available products can also be used.

[0027] Although not limited, the benzohydroxamic acid of the present invention or a salt wrinkle preventing or improving agent thereof, preferably used in a skin external preparation. The blending amount of benzohydroxamic acid or a salt thereof in the external preparation for skin varies depending on the use mode, product form, etc., and is not particularly limited. For example, it is preferably 0.001% by mass to 10% based on the total amount of the external preparation for skin. % By mass, more preferably 0.005% by mass to 5% by mass, and still more preferably 0.01% by mass to 1% by mass.

In the present specification, “skin external preparation” includes cosmetics, pharmaceuticals, quasi drugs and the like. In addition, the dosage form can be any agent such as aqueous solution, solubilization system, emulsification system, oil liquid system, gel system, paste system, ointment system, aerosol system, water oil 2 layer system, water oil powder 3 layer, etc. Includes type. Moreover, what was carry | supported by the sheet-like base material is also included.

[0029] In addition, the product form and use of the external preparation for skin are also arbitrary, and for example, it can be used as an external preparation for facial, body, or scalp such as lotion, milky lotion, cream, knock.

[0030] In addition to the above-mentioned benzohydroxamic acid or a salt thereof, the external preparation for skin is appropriately formulated with other optional components that are usually used in external preparations for skin such as cosmetics and pharmaceuticals as needed. According to the dosage form to be manufactured, it can manufacture by a conventional method. For example, a skin external preparation can be prepared by blending benzohydroxamic acid or a salt thereof and one or more of the following components.

Examples of ultraviolet absorbers include aminobenzoic acid (hereinafter abbreviated as PABA), PABA monoglycerin ester, Ν, Ν-dipropoxy PABA ethyl ester, Ν, Ν-diethoxy PABA ethyl ester, Ν, Ν-dimethyl PABA Benzoic acid UV absorbers such as ethyl ester, Ν, Ν-dimethyl PABA butyl ester, Ν, Ν-dimethyl PABA methyl ester, anthracic acid UV absorbers such as homomenthyl-N-acetylethyl anthracate, Rate, menthyl salicylate, homomenthyl salicylate, octyl salicylate, feni Salicylic acid UV absorbers such as rusalicylate, benzyl salicylate, p-isopropanol phenol salicylate, octylcinnamate, ethyl-4-isopropylcinnamate, methyl-2,5-diisopropylcinnamate, ethyl-2 4-diisopropyl cinnamate, methyl-2,4-diisopropyl cinnamate, propyl-p-methoxycinnamate, isopropyl-P-methoxycinnamate, isoamyl-P-methoxycinnamate, octyl-p-methoxycinnamate (2 -Ethylhexyl-p-methoxycinnamate), 2-Ethoxyethyl-p-methoxycinnamate, Cyclohexyl-p-methoxycinnamate, Ethyl-α-Channo j8-Phenol-cinnamate, 2-Ethylhexyl-α- Ciano-j8-felucinnamate, glyceryl mono-2-ethylhexanoyl Cinnamic acid UV absorbers such as -diparamethoxycinnamate, methylbis (trimethylsiloxane) silylisopentyl trimethoxycinnamate, 3- (4'-methylbenzylidene) -d, l-camphor, 3-benzylidene-d, l -Camphor, urocanic acid, urocanic acid ethyl ester, 2_phenyl _5_methylbenzoxazole, 2,2'-hydroxy-5-methylphenylbenzotriazole, 2- (2 and hydroxy-5 and t -Octylphenyl) benzotriazole, 2- (2'-hydroxy-5'-methylphenol penzotriazole, dibenzalazine, dianisylmethane, 4-methoxy-4'-t-butyldibenzoylmethane, 5- (3,3-dimethyl-2-norbornylidene) -3-pentan-2-one, dimorpholinopyridazinone and the like can be mentioned, and any one or two or more can be used.

[0032] Examples of the ultraviolet light scattering agent include powders of titanium oxide, fine particle titanium oxide, zinc oxide, fine particle zinc oxide, iron oxide, fine particle iron oxide, cerium oxide and the like.

[0033] As these ultraviolet scattering agents, needle-like, spindle-like, spherical and granular powders are usually used. Further, a fine particle powder having a particle size of 0.1 m or less is preferable.

[0034] Silicone treatment such as methylhydrogen polysiloxane silane coupling agent; metal calcite treatment; perfluoroalkyl phosphate diethanolamine salt hydrofluorination by perfluoroalkyl silane, dextrin fatty acid ester treatment, etc. A treated UV scattering agent is also preferred.

[0035] Examples of liquid fats include apogado oil, camellia oil, turtle oil, macadamia nut oil, corn oil, mink oil, olive oil, rapeseed oil, egg yolk oil, sesame oil, persic oil, barley germ oil, southern power oil , Castor oil, linseed oil, safflower oil, cottonseed oil, eno oil, soybean oil Peanut oil, tea seed oil, oyster oil, rice bran oil, cinnagiri oil, Japanese kiri oil, jojoba oil, germ oil, triglycerin and the like.

[0036] Examples of the solid fat include cacao butter, coconut oil, horse fat, hydrogenated coconut oil, palm oil, beef tallow, sheep fat, hardened beef tallow, palm kernel oil, pork tallow, beef bone fat, mollusc kernel oil, hardened And oil, beef leg fat, beeswax and hydrogenated castor oil.

[0037] Examples of waxes include beeswax, candelilla wax, cotton wax, carnauba wax, beveri wax, ibota wax, straw wax, montan wax, nuka wax, lanolin, kapok wax, lanolin acetate, liquid lanolin, sugar cane wax, lanolin fatty acid isopropyl, Examples include hexyl laurate, reduced lanolin, jojoba wax, hard lanolin, shellac wax, POE lanolin alcohol ether, POE lanolin alcohol acetate, POE cholesterol ether, lanolin fatty acid polyethylene glycol, and POE hydrogenated lanolin alcohol ether.

[0038] Examples of the hydrocarbon oil include liquid paraffin, ozokerite, squalene, pristane, paraffin, ceresin, squalene, petrolatum, microcrystalline wax, polyethylene tuss, and Fischer-Tropsch wax.

[0039] Examples of higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, undecylenic acid, toluic acid, linoleic acid, linolenic acid, eicosapentaenoic acid (EPA), docosa Hexaenoic acid (DHA) and the like can be mentioned.

[0040] Examples of higher alcohols include linear alcohols (for example, lauryl alcohol, cetino-leanolecanole, stearino-leanoleconore, behenino-leanolecanol, myristino-leanolol, oleyl alcohol, ceto alcohol. Stearyl alcohol, etc.); branched chain alcohols (eg, monostearyl glycerin ether (batyl alcohol), 2-decyltetradecinol, lanolin alcohol, cholesterol, phytosterol, hexyldodecanol, octyl dodecanol, etc.).

[0041] Synthetic ester oils include isopropyl myristate, cetyl octanoate, octyldodecyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, decyl oleate, hexyldecyl dimethyloctanoate , Cetyl lactate, myristyl lactate, lanolin acetate, isocetyl stearate, isocetyl isostearate, cholesteryl 12-hydroxystearate, ethylene di-2-ethylhexanoate Glycol, dipentaerythritol fatty acid ester, N-alkyl glycol monoisostearate, neopentyl glycol dicaprate, diisostearyl malate, glycerin di-2-heptyl decanoate, tri-2-ethylhexyl trimethylolpropane, triethyl Trimethylolpropane sostearate, pentaerythritol tetra-2-ethylhexanoate, glycerin tri-2-ethylhexanoate, glyceryl trioctanoate, glycerin triisopalmitate, glycerin, trimethylolpropane triisostearate, cetyl 2- Ethylhexanoate, 2-ethylhexyl palmitate, glyceryl trimyristate, glyceride tri-2-heptylundecanoate, castor oil fatty acid methyl ester, oleate oleate, acetate glyceride , 2-heptylundecyl palmitate, diisobutyl adipate, N-lauroyl- L-glutamic acid-2-octyldodecyl ester, di-2-heptyldecyl adipate, ethyl laurate, di-2-ethylhexyl sebacate, myristic acid 2 -Hexyldecyl, 2-hexyldecyl palmitate, 2-hexyldecyl adipate, 2-ethylhexyl succinate, triethyl taenoate, polyoxyethylene / polyoxypropylene random polymer methyl ether, and the like.

[0042] Examples of the silicone oil include linear polysiloxanes (for example, dimethylpolysiloxane, methylphenol polysiloxane, diphenylpolysiloxane, etc.); cyclic polysiloxanes (for example, otatamethylcyclotetrasiloxane, decamethyl). Cyclopentasiloxane, dodecamethylcyclohexasiloxane, etc.), silicone resin, silicone rubber, various modified polysiloxanes that form a three-dimensional network structure (amino-modified polysiloxane, polyether-modified polysiloxane, alkyl-modified polysiloxane) , Fluorine-modified polysiloxane, etc.).

[0043] In addition, for example, moisturizing agents such as polyethylene glycol, glycerin, 1,3-butylene glycol, erythritol, sorbitol, xylitol, maltitol; cellulose, hydroxychetinoresenorelose, hydroxypropinoresenorelose, Methinorehydroxypropinore senorelose, methinorescenorelose, canoleboxy methinorescenellose, quince seed, carrageenan, pectin, mannan, curdlan, chondroitin sulfate, starch, galactan, dermatan sulfate, glycogen, gum arabic, to Paran sulfate, hyaluronic acid, sodium hyaluronate, tragacanth gum, keratan sulfate, chondroitin, xanthan gum, mucoy Thin sulfate, hydroxyethyl dagam, carboxymethyl dagam, guagam, dextran, keratosulfate, locust bean gum, succinoglucan, caronate, chitin, chitosan, carboxymethylchitin, thickener such as agar, ethanol Lower alcohols such as butyl hydroxytoluene, tocopherol, phytin, etc .; antibacterial agents such as benzoic acid, salicylic acid, sorbic acid, paraoxybenzoic acid alkyl ester, hexaclofen phen; Organic acids such as acids (eg, lauroyl sarcosine sodium), dartathione, citrate, malic acid, tartaric acid, lactic acid; vitamin A and its derivatives, vitamin B6 hydrochloride, vitamin B6 tripalmitate, vitamin B6 dioctanoate, vitamin B2 and Its derivative, vitamin B12, bi Vitamin B such as Min B15 and its derivatives, ascorbic acid, ascorbic acid sulfate (salt), ascorbic acid phosphate (salt), vitamin C such as ascorbic acid dipalmitate, α-tocopherol, j8-tocopherol, δ —Tocopherol, vitamin Ε Vitamin such as Acetate, Vitamin D, Vitamin Η, Nonthenoic acid, Panthetin and other vitamins; Nicotinamide, benzyl nicotinate, γ-oryzanol, allantoin, glycyrrhizic acid (salt), glycyrrhetin Acids and derivatives thereof, hinokitiol, bisabolol, eucanoleptone, timonore, inositol, psychosaponin, carrot saponin, hechisaponin, muclodisaponin, saponins, pantyruethyl ether, ethur estra Various drugs such as oar, tranexamic acid, arbutin, cephalanthin, and placenta extract, borage, clara, kohone, orange, sage, sawtooth, zeaoi, assembly, thyme, toki, spruce, perch, sugina, hechima, maronier, Yukinoshita, Anoleni, Lily, Mugwort, Peonies, Aloe, Gardenia, Sawara, Seiha Hawthorn Extract, Seiyo Hypericum Extract, Iris' In Extract, Acacia Extract, Ichiyou Leaf Extract, Ibuki Jiyako Extract, Ukiyocha Extract, Oolong Tea Extract , Water lily extract, age extract, enmiso extract, ogonex, obata extract, odrichos soup extract, licorice extract, gardenia extract, tea extract, cedar curry extract, tonormentilla extract Extracts of plants such as rose extract, hechima extract, peppermint kiss, rosemary extract, royal jelly extract, pigment, sorbitan monolaurate, sorbitan monopalmitate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene sorbitan monolaurate, Monostearic acid polio Xylene sorbitan, polyethylene glycol monooleate, polyoxyethylene alkyl ether, polyglycol gel ether, lauroyl jetanol amide, fatty acid isopropanol amide, maltitol hydroxy fatty acid ether, alkylated polysaccharide, alkyl dalcoside, sugar ester Nonionic surfactants such as stearyltrimethyl ammonium chloride, salt surfactants such as benzalcoum, laurylamine oxide, sodium palmitate, sodium laurate, sodium laurate, potassium lauryl sulfate, Key-on interfaces such as alkyl sulfate triethanolamine ether, funnel oil, linear dodecyl benzene sulfate, polyoxyethylene hydrogenated castor oil maleic acid, and acyl methyl taurine Sex, amphoteric surfactants, neutralizing agents, [delta] tocopherol Fellow Honoré, Sani spoon inhibitors such as Petit Le hydroxytoluene, phenoxyethanol, preservatives such as paraben and the like.

[0044] In the method for preventing or improving wrinkles of the present invention, benzohydroxamic acid or a salt thereof is applied to the skin in any form as long as it can be applied to the skin and the object of the present invention can be achieved. It can be applied alone or in combination with other optional ingredients. Moreover, the place of the skin to apply is not limited, and includes any skin on the body surface including the scalp. The method of the present invention is usually used as a cosmetic method.

[0045] The use of the ADAM inhibitor comprising the benzohydroxamic acid of the present invention or a salt thereof is not limited to the prevention or improvement of wrinkles described above, but can be any use that can exert an effect by inhibiting the activity of ADAM. For example, it can also be used for the treatment or prevention of various diseases that are adversely affected by the proliferation or differentiation of skin cells due to the activity of ADAM. Example

Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention is not limited to the following examples. In addition, the compounding quantity of a compound is the mass% unless there is particular notice.

[0047] 1. Search for new ADAM inhibitors

First, various compounds were screened for ADAM activity inhibitory effects by the following method to search for novel ADAM inhibitors.

[0048] HB-EGF-AP / HT-1080 (Heat-alkaline phosphatase (Α Using human fibrosarcoma-derived cultured cells (HT-1080) modified so as to forcefully express the fusion protein added with P), a compound having ADAM enzyme inhibitory activity was screened. The full-length HB-EGF molecule is expressed on the cell surface of the cell line HB-EGF-AP / HT-1080 used in the form fused with alkaline phosphatase! When these cells are stimulated with phorbol ester, the ADAM enzyme on the cell membrane surface is activated and cleaves the HB-EGF molecule. Cleaved free HB-EGF binds alkaline phosphatase, so the alkaline phosphatase activity in the culture supernatant is measured to indirectly increase the ADA M enzyme inhibitory activity of the compound. It can be measured.

Specifically, HB-EGF-AP / HT-080 with the number of cells adjusted to 2.0 × 10 ⁵ cells / ml was seeded on a 96-well culture microplate at 0.2 ml / well at 37 ° C. It was cultivated. After removing the medium and washing with PBS (−), 0.1 ml / well of the medium containing the test substance was added and incubated at 37 ° C. for 30 minutes for pretreatment. Thereafter, the culture supernatant is removed, and a medium containing the test substance and 60 nM TPA (honorebonole estenole: 12-0—Tetradecanoylphorbo 卜 acetate; Sigma P8139) is added again at 0.2 ml / well. Treated by incubating for minutes. After completion of the treatment, 0.1 ml of the culture supernatant of each well was transferred to a well of a microplate for alkaline phosphatase activity measurement, and incubated at 65 ° C. for 10 minutes to inactivate the endogenous alfa phosphatase. 1 mg / ml AP substrate (p-nitrophenylphosphate, Wako; 141-02341) was added to each well at 0.1 ml / well, and the absorbance of each well was measured immediately at 405 nm. After incubation for 2 hours at room temperature in the dark, the absorbance of each well was measured again. The absorbance of each well was obtained by subtracting the absorbance immediately after addition of AP substrate from the absorbance after incubation for 2 hours. The inhibition rate (%) was calculated using the following formula, where the absorbance of 0% inhibition control (medium containing only TPA) was A0, the absorbance of 100% inhibition control (medium only) was A100, and the absorbance of the sample was AS:

Inhibition rate (%) = (A0-AS) / (A0-A100) * 100

As a result, the benzohydroxamic acid of the present invention showed a high inhibitory effect on HB-EGF release, suggesting that it inhibits ADAM activity. Table 1 shows the release inhibition rate of each benzohydroxamic acid.

[table 1] Inhibition s

Test substance

5jLig / m 30 zg / mL

0

4-Methoxybenzohydroxamic acid H ₃ C, Q a 14.8 55.8

0,

4-Putylpenzohydroxamic acid

6.9 18.8

0

A «z ^0H

Benzohydroxamic acid `` I 3.2 14.7

2-hydroxy-1-3-methylbenzo

Hydroxamic acid 1.1 10.3

3- (phenoxyacetylamino)

Benzohydroxamic acid

0.9 19.3

0

4 hexyl f S- ^Q to Shikuro

Benzohydroxamic acid ΓΥ ^ ^Η 3.8 25.8

2—Black mouth Benzo

Hydroxamic acid -6.2 10.6

3-methoxybenzo (

Droxamic acid Υ ¹ ν.

Η Η ^Η 0.1 13.2

1.3 11.4

1.3 9.1

-4.5 3.3

Evaluation of wrinkle improving effect of methoxybenzohydroxamic acid. Next, we investigated the wrinkle-improving effect of 4-methoxybenzohydroxamic acid, which has a high inhibition rate (%) among the novel ADAM inhibitor compounds, using a mouse model for destroying wrinkles.

[0051] Transdermal water transpiration (T EWL) (measured using MEECO; Meeco, USA) force on the left back of hairless mice (HR-1, male 6-week-old, Hoshino experimental animal) Tape stripping was continued 3 times a week for 4 weeks to 4-8 mg / cm ² / h. Immediately after tape stripping treatment, 100% each of 4-methoxybenzohydroxamic acid dissolved in 50% aqueous ethanol solution to 1% each was applied to the left back of the mouse. As a target, 50% ethanol aqueous solution (Vehicle) was applied in the same manner. The n number was 6 to 7 in each group.

[0052] The occurrence of wrinkles after 4 weeks was scored by visual evaluation. The evaluation criteria for wrinkle occurrence were “no wrinkles; 0”, “light wrinkles; 1”, “obvious wrinkles; 2”, “deep wrinkles; 3” and scored in 0.5 increments. The larger the score, the deeper the wrinkle. Average values and standard deviations for each group were calculated, and the results are shown in Figure 2.

[0053] As is clear from FIG. 2, the average score of the vehicle was 1.17, whereas 4-methoxybenzohydroxamic acid showed a significant wrinkle suppression effect that was significantly low at 0.91.

Next, the replica of the back of the mouse was analyzed using a wrinkle analyzer (Hamano Engineering), and the wrinkle area (%) was calculated. A lower percentage of the wrinkle area indicates that wrinkle formation is suppressed. The results are shown in Figure 3.

[0055] As is clear from FIG. 3, the average value of the wrinkle area (%) of 4-methoxybenzohydroxamic acid showed a significantly higher wrinkle suppressing effect than that of the vehicle.

[0056] Further, the transepidermal water transpiration (TE WL) in the back of the mouse before and 4 weeks after the start of the test was also examined. TEWL values for the left back with tape stripping treatment and 4-methoxybenzohydroxamic acid or 50% aqueous ethanol (Vehicle) and the right back without any treatment were measured using Vapometer (Technologies Ltd, Kuopio , Finland) was measured twice. The ratio (relative TEWL (%)) of the left TEWL value when the TEWL value on the right side of each individual was taken as 100 was determined, and the average value for each group was calculated. The higher the percentage value, the higher the roughness of the skin. The results are shown in Figure 4. [0057] As is apparent from Fig. 4, TEWL increased to 216% in the vehicle application group, while it remained only 126% increase in the 4-methoxybenzohydroxamic acid application group. Benzohydroxamic acid significantly inhibited the increase in TEWL due to tape stripping.

[0058] From these results, 4-methoxybenzohydroxamic acid inhibits the release of HB-EGF, an epidermal growth factor, by inhibiting activated ADAM, and suppresses the growth and thickening of the skin. It has been suggested that formation can be prevented or improved. Furthermore, it was suggested that 4-methoxybenzohydroxamic acid significantly suppresses the increase in transepidermal water transpiration (TEWL) due to skin destruction, and also has an effect of preventing rough skin.

[0059] Examples of the preparation of the external preparation for skin containing the benzohydroxamic acid or a salt thereof of the present invention are shown below, but the present invention is not limited thereto. In addition, all compounding quantities are represented by the mass% with respect to the external preparation whole quantity.

[0060] Formulation Example 1: Emulsion

(Prescription) Mass%

Stearic acid 2.5

Cecino Reano Reconore 1.5

Vaseline 5.0

Liquid paraffin 5.0

Polyoxyethylene (10 mol) monooleate 2.0

Positive ethylene gudge INORE 1500 3. 0

卜 Diethanolamine 1.0

Canoleboxyvininole polymer 0.05

4-Methoxybenzohydroxamic acid 2. 0

Sodium bisulfite 0. 01

Ethylparaben 0.2

Perfume

(Production method) Dissolve carboxybulu polymer in a small amount of purified water (phase A). Remaining purified water Add polyethylene glycol 1500, triethanololamine, and 4-methoxybenzohydroxamic acid to heat and dissolve at 70 ° C (aqueous phase). Mix other ingredients, heat and melt and keep at 70 ° C (oil phase). The oil phase was added to the aqueous phase and pre-emulsified, and the A phase was uniformly emulsified with a cake homomixer. After emulsification, the mixture was cooled to 30 ° C. while stirring well to obtain an emulsion.

[0061] Formulation Example 2: Lotion

(Prescription) Mass%

Ethanol 5.0

Canoleboxyvininole polymer 0.3

Polyoxyethylene (15 mol) oleyl ether 0.8

1, 3 Butylene glyconore 5.0

4-Methoxybenzohydroxamic acid 2. 0

Quenic acid 0.03

Sodium quenate 0.07

Methylparaben 0.1

Purified water residue

(Manufacturing method) Quenchic acid, sodium kennate and 4-methoxybenzohydroxamic acid were dissolved in purified water to obtain an aqueous phase. On the other hand, the other ingredients were dissolved by stirring and added to the aqueous phase to homogenize to obtain a lotion.

[0062] Formulation Example 3: Cream

(Prescription) Mass%

Stearic acid 2.0

Stearyl alcohol 7.0

Hydrogenated lanolin 2. 0

2-Otachidodecyl alcohol 6.0

Polyoxyethylene (25 mol) cetyl alcohol ether 3.0

Glycerin monostearate ester 2.0

4-Methoxybenzohydroxamic acid 2. 0

2-Hydroxy-5-methylbenzohydroxamic acid 2.0 1, 3 Butylene glyconore 5.0

Edetic acid trisodium 0.1

Sodium glycyrrhetinate 0.1

Vitamin E acetate 0.3

Ethylparaben 0.3

Purified water residue

(Manufacturing method) 4-Methoxybenzohydroxamic acid, 2-hydroxy-5-methylbenzohydroxamic acid, 1,3 butylene glycol, trisodium edetate, and sodium glycyrrhetinate are added to purified water and kept at 70 ° C to make an aqueous phase. . On the other hand, the other ingredients were mixed, heated and melted and kept at 70 ° C to make an oil phase. The oil phase was added to the aqueous phase for pre-emulsification, and the mixture was uniformly emulsified with a homomixer and then cooled to 30 ° C to obtain a cream.

Formulation Example 4 Emulsion

(Prescription) Mass%

Dimethylol polysiloxane 3.0

Decamethylcyclopentasiloxane 4.0

Ethanol 5.0

Glycerin 6.0

1, 3 Butylene glyconore 5.0

4-Methoxybenzohydroxamic acid 0.5

2-hydroxy-3-methylbenzohydroxamic acid 0.5

Polyoxyethylene methyl darcoside 3.0

Castor oil 1. 0

Skullan 2.0

Potassium hydroxide 0.1

Sodium hexametaphosphate 0. 05

Hydroxypropyl mono-β-cyclodextrin 0.1

4-methoxysalicylate potassium 1.0

Dipotassium glycyrrhizinate 0. 05 Bi Bamboo Leaf Extract 0.1

L Sodium glutamate 0.05 Alcohol extract 0.1 0.1 Yeast extract 0.1 Lavender oil 0.1 Diol extract 0.1 Dimonoreforinopyridazinone 0.1 Xanthan gum 0.1 Canoleboxibininore polymer 0.1 Acryl Acid 'alkyl methacrylate copolymer (Pemulene TR— 1) 0.1 Bengala appropriate amount Yellow iron oxide appropriate amount Noraben appropriate amount Purified water Residue Example formulation 5 Emulsion

(Formulation) Mass% Dimethylol polysiloxane 3.0 Decamethylcyclopentasiloxane 4.0 Ethanol 5. 0 Glycerin 6.0

1, 3 Butylene glyconore 5.0

2 Hydroxy 3 Methylbenzohydroxamic acid 1. 0 Polyoxyethylene methyl darcoside 3. 0 Castor oil 1. 0 Scranane 2. 0 Potassium hydroxide 0.1 Sodium hexametaphosphate 0.05 Hydroxypropyl β-cyclodextrin 0. 1 Potassium 4-methoxysalicylate 1.0 Dipotassium glycyrrhizinate 0. 05 Bi-leaf extract 0. 1

L-Sodium Glutamate 0.05 Alcohol Extract 0.1 0.1 Yeast Extract 0.1 Lavender Oil 0.1 Diol Extract 0.1 Dimonoreforinopyridazinone 0.1 Xanthan Gum 0.1 Canoleboxyvininole Polymer 0.1 Acrylic acid 'alkyl methacrylate copolymer (Pemulene TR— 1) 0.1 Bengala appropriate amount Yellow iron oxide appropriate amount Noraben appropriate amount Purified water Residue Example formulation 6 Emulsion

(Formulation) Mass% Dimethinorepolysiloxane 2.0 Benorenoreconore 1. 0 No Reinoreconole 0.5 Glycerin 5.0

1,3-Butyleneglycolanol 7.0

4-Methoxybenzohydroxamic acid 0.5

4-cyclohexylbenzohydroxamic acid 1.0 tranexamic acid methylamide hydrochloride 0.7 erythritol 2. 0 hydrogenated oil 3.0 Squalane 6. 0 Pentaerythritol tetra-2-ethylhexanoate 2.0 Polyoxyethylene glyceryl isostearate 1.0 Polyoxyethylene glyceryl monostearate 1. 0 Potassium hydroxide Appropriate sodium hexametaphosphate 0. 05 Phenoxy Ethanol Appropriate amount Canoleboxyvininole polymer 0.1 Purified water Residue Formulation Example 7 Emulsion

1,3-Butyleneglycolanol 7.0

4-Cyclohexylbenzohydroxamic acid 1. 0 Tranexamic acid methylamide hydrochloride 0. 7 Erythritol 2. 0 Hardened oil 3. 0 Sculane 6. 0 Tetra-2-ethylhexanoic acid pentaerythritol 2. 0 Polyoxyethylene glyceryl isostearate 1.0 Polyoxyethylene glyceryl monostearate1.0 Potassium hydroxide appropriate amount Sodium hexametaphosphate 0.05 0.05 Phenooxyethanol appropriate amount Canoleboxyvininole polymer 0.1 Purified water Residue Formulation Example 8 Emulsion

(Formulation) Mass% Liquid paraffin 7.0 Petrolatum 3. 0 Decamethylcyclopentasiloxane 2. 0 Beno-Renore Cornole 0.5 Glycerin 5. 0 Dipropylene glycol 7.0

4-Methoxybenzohydroxamic acid 1.0

2-Hydroxy-5-methylbenzohydroxamic acid 1.0

2 Hydroxy 3 Methylbenzohydroxamic acid 1.0 0 Posiethylene gutinole 1500 2. 0 Jojoba oil 1. 0 Isostearic acid 0.5 Stearic acid 0.5 Behenic acid 0.5 Tetra-2-ethylhexyl acid pentaerythrit 3. 0

2 Cetyl hexylhexanoate 3.0 Glycerol monostearate 1.0 Polyoxyethylene glyceryl monostearate 1.0 Potassium hydroxide 0.1 Sodium hexametaphosphate 0. 05 Stearyl glycyrrhetinate 0. 05

L Arginine hydrochloride 0.1 Royanore jelly extract 0.1 yeast extract 0.1 turmeric extract 0.1 Tocopherol acetate 0.1 Acetylated sodium hyaluronate 0. 1 Trisodium edetate 0. 05

4-tert-Butyl- 4'-methoxydibenzoylmethane 0.1 Ethyl 2-methoxy cinnamate 2-0.1 Ethyl canoloxy vininopolymer 0.15 Noraben appropriate amount Purified water Residue fragrance Appropriate amount Formulation example 9 Emulsion

(Prescription) Mass% Petrolatum 5.0 Behe-Noranoreconoret 0.5 Notinorenoreconoret 0.5 Glycerin 7.0

1, 3 Butylene Gliconole 7.0

2-Hydroxy-5-methylbenzohydroxamic acid 1.0

2 Hydroxy 3 methylbenzohydroxamic acid 1.0

1, 2—Pentangi-Nore 1. 0 Xylit 3.0 0 Posiethylene Gujinore 20000 2. 0 Hardened oil 2. 0 Jojoba oil 2. 0 Scullane 5. 0 Isostearic acid 0.5 Tetra-2-ethylhexyl acid pentaerythlit 2. 0 polyoxyethylene hydrogenated castor oil 0.5 lauryl dimethylamino acetate betaine 0.4 Potassium hydroxide appropriate amount Sodium pyrosulfite 0. 01 Sodium hexametaphosphate 0. 05 Dipotassium glycyrrhizinate 0. 05 Trimethylglycine 3. 0 Anolebutin 3. 0 Ichaxou extract 0. 1 Oyster extract 0. 1 Lumpuyan extract 0. 1 Yeast Extract 0.1 Tocopherol acetate 0.1 Thiotaurine 0.1 Clara extract 0.1 Bengala quince seed extract 0.1 0.1 Canoleboxyvininore polymer 0.2 Phenoethanol ethanol Purified water Residual formulation Example 10 Emulsion

(Prescription) Mass% Petrolatum 5.0 Dimethinorepolysiloxane 2.0 Benorenoreconole 0.6 Notinorenoreconole 0.5 Dipropylene glycol 2.0

1, 3 Butylene Gliconole 4.0

4-Methoxybenzohydroxamic acid 10.0

2-Hydroxy-5-methylbenzohydroxamic acid 3.0 2 Hydroxy 3 Methylbenzohydroxamic acid 3.0 Xylit 1.0

Posiethylene gudge INORE 1500 1. 0

School 5.

Glyceryl tri-2-ethylhexylate 2.0 Retinol acetate 0.03 Retinol (1.5 million units) 0.01 Polyoxyethylene hydrogenated castor oil 0.5 Tranexamic acid methylamide hydrochloride 0.7 Dipotassium glycyrrhizate 0.1

2—0—Ethylu L-ascorbic acid 0.1 yeast extract 0.1

Azajak extract 0.1

Peonies extract 0.1

Hougi extract 0.1

HEDTA 3 sodium 0.05

Xanthan gum 0.1

Canoleboxyvininole polymer 0.15 Purified water Remaining

Perfume

Formulation Example 11 Lotion

(Prescription) Mass%

Ethino Reno Conorre 5.0

Glycerin 1.0

1, 3 Butylene glyconore 5.0

4-Methoxybenzohydroxamic acid 3.0

2 Hydroxy 3 methylbenzohydroxamic acid 10.0 Polyoxyethylene polyoxypropylene decyl tetradecyl ether 0.2 Sodium hexametaphosphate 0.03 Trimethylglycine 1.0

Sodium polyaspartate 0.1 α Tocopherol 2-L potassium ascorbate diester potassium 0.1

2—0—Ethyru L-ascorbic acid 0.1 Green tea extract 0.1

Beech extract 0.1

Tonin extract 0.1

Western Heart Force Extract 0. 1 Iris Root Extract 0. 1

HEDTA3 sodium 0.1

Canoleboxyvininole polymer 0.05 Alkaline hydroxide 0.02 Suitable amount of phenoxyethanol Purified water Residual

Perfume

Formulation Example 12 Lotion

(Prescription) Mass%

Glycerin 2.0

1, 3 Butylene Gliconole 4.0

4-Methoxybenzohydroxamic acid 1.0

2 Hydroxy 3 methylbenzohydroxamic acid 1.0

2-Hydroxy-5-methylbenzohydroxamic acid 1.0

4-Cyclohexylbenzohydroxamic acid 1.0 Erythritol 1.0

Polyoxyethylene methyl darcoside 1.0 Polyoxyethylene hydrogenated castor oil 0.5

L Ascorbic acid 2-Dalcoside 2.0 Xylitol Nole 0.1 Quenic acid 0.02 Sodium citrate 0.08 Phenooxyethanol Appropriate amount N Palm oil fatty acid Asil L Arginine ethyl

• DL Pyrrolidonecarboxylic acid 0.1 Purified water Residual

[0072] Formulation Example 13 Lotion

(Prescription) Mass% Glycerin 2.0

1, 3 Butylene Gliconole 4.0

2-Hydroxy-5-methylbenzohydroxamic acid 1.0

4-Cyclohexylbenzohydroxamic acid 1. 0 Erythritol 1. 0 Polyoxyethylene methyl darcoside 1. 0 Polyoxyethylene hydrogenated castor oil 0.5

L-Ascorbic acid 2-Dalcoside 2.0 Xylitolole 0.1 Cenic acid 0.02 Sodium quenate 0.08 Phenoxyethanol Appropriate amount N Palm oil fatty acid Asil L Arginine ethyl

• DL Pyrrolidonecarboxylic acid 0.1 Purified water Residual

[0073] Formulation Example 14 Lotion

(Formulation) Mass% Ethanol 10. 0 Dipropylene glycol 1.0 4-Methoxybenzohydroxamic acid 1.0

2-Hydroxy-5-methylbenzohydroxamic acid 1.0

2 Hydroxy 3 methylbenzohydroxamic acid 1.0

4-Cyclohexylbenzohydroxamic acid 1. 0 Posiethylene gutyl monole 1000 1. 0 Polyoxyethylene methyl darcoside 1. 0 Jojoba oil 0.11 Glyceryl tri-2-ethylhexanoate 0.1 Polyoxyethylene hydrogenated castor oil 0. 2 Polyglyceryl diisostearate 0.15

N—Stearoyl— L Sodium glutamate 0.1 Cenic acid 0.05 Sodium quenate 0.2 Potassium hydroxide 0.4 Dipotassium glycyrrhizinate 0.1 Arginine hydrochloride 0.1

L Asconolevic acid 2-Gnolecoside 2. 0-year-old Ugon extract 0. 1 Yukinosita extract 0. 1 Oyster extract 0. 1 Thyme extract 0. 1 Majora extract 0. 1 Tranexamic acid 1. 0 Trisodium edetate 0. 05 Paramethoxycinnamic acid 2-Ethylhexyl 0. 01 Dibutylhydroxytoluene Appropriate amount Noraben Appropriate amount Deep seawater 3.0 Purified water Residue Fragrance Appropriate amount

[0074] Formulation Example 15 Lotion

(Prescription) Mass% Dimethylolene polysiloxane 1.0 Ethanol 3.0 Benorerno cornore 0.3 Glycerin 5.0 Dipropylene glycol 5.0

4-Methoxybenzohydroxamic acid 0.1

2 Hydroxy 5 Methylbenzohydroxamic acid 0.1 Erythritol 1. 0 Posiethylene IJn—Nole 4000 1. 0 Squalane 0.4

2-Ethylhexanoic acid cetyl 0.1

N—Stearoyl— L Sodium glutamate 0.2 Magnesium chloride 0.1 Arginine chloride 0.1 Hypotaurine 0.1 Trisodium edetate 0.1 Noraben appropriate amount Purified water Residue perfume Appropriate amount

[0075] Formulation Example 16 Lotion

(Formulation) Mass% Ethanol 40. 0 Dipropylene glycol 1.0

4-Methoxybenzohydroxamic acid 0.1 2 Hydroxy 3 Methylbenzohydroxamic acid 0.1 Polyoxyethylene polyoxypropylene decyl tetradecyl ether 0. Caic anhydride 1.0

Salicylic acid 0.1

Sodium quenate 0.2

Zinc parafenolic sulfonate 0.2 Dipotassium glycyrrhizinate 0.1 Pyridoxine hydrochloride 0.1

L-Serine 0.1

L-Mentore 0. 05

Sodium HEDTA 0.05 0.05 Cellulose powder 1. 0 Bentonite 0.8

Purified water residue

Formulation Example 17 Lotion

(Prescription) Mass%

Ethanol 40. 0

Dipropylene glycol 1.0

2 Hydroxy 3 Methylbenzohydroxamic acid 0.1 Polyoxyethylene polyoxypropylene decyl tetradecyl ether 0. Caic anhydride 1.0

Salicylic acid 0.1

Sodium quenate 0.2

L-Serine 0.1

L-Mentore 0. 05 HEDTA3 Sodium 0.05 Cellulose powder 1.0 Bentonite 0.8 Purified water Residue Formulation Example 18 Gil

(Prescription) Mass% Dimethylol polysiloxane 5.0 Glycerin 2.0

1, 3 Butylene glyconore 5.0

4-Methoxybenzohydroxamic acid 0.1

2 Hydroxy 3 methyl benzohydroxamic acid 0.1

2-Hydroxy-5-methylbenzohydroxamic acid 0.1

4-Cyclohexylbenzohydroxamic acid 0.1 Posiethylene Gudi Monore 1500 3. 0 Posiethylene Gudi Monore 20000 3.0 0 Cetyl Octanoate 3.0 Cenoic acid 0.01 Sodium oxalate 0.1 Sodium hexametaphosphate 0.1 Glycyrrhizic acid Dipotassium 0.1

L Ascorbic acid 2-Dalcoside 2.0

L-ascorbic acid phosphate magnesium 0.1 tocopherol acetate 0.1 0.1 year old gonon extract 0.1 time extract 0.1 cypress extract 0.1 edetate trisodium 0.1 xanthan gum 0.3 Acrylic acid 'alkyl methacrylate copolymer (Pemulen TR-2) 0. 05 Agar powder 1.5

Phenoxyethanol Appropriate amount Dibutylhydroxytoluene Appropriate amount Purified water Residue

Formulation example 19 packs

(Prescription) Mass%

Ethanol 10.0

1, 3 Butylene glyconore 6.0

4-Methoxybenzohydroxamic acid 1.0

2 Hydroxy 3 methylbenzohydroxamic acid 1.0

2-Hydroxy-5-methylbenzohydroxamic acid 1. 0 Posiethylene guji Monore 4000 2. 0 Olive oil 1.0

Macadamia nut oil 1. 0 Phytosteryl hydroxystearate 0. 05 Lactic acid 0. 05

Sodium lactate 0.1

L-ascorbic acid sulfate disodium 0.1 α α tocopherol 2- L potassium ascorbic acid phosphate diester 0.1 Vitamin Εacetate 0.1 Fish collagen 0.1

Sodium chondroitin sulfate 0.1 Sodium carboxymethylcellulose 0.2

Noroxybenzoic acid ester Suitable amount Purified water Residual

Perfume Formulation example 20 pack

(Prescription) Mass% Ethanol 3.0 Glycerol 5.0

1, 3 Butylene glyconore 6.0

4-Methoxybenzohydroxamic acid 1.0

2 Hydroxy 3 methylbenzohydroxamic acid 1.0

2-Hydroxy-5-methylbenzohydroxamic acid 1.0

4-Cyclohexylbenzohydroxamic acid 1. 0 Posiethylene guji monole 1500 5. 0 Polyoxyethylene methyl darcoside 2. 0 Glyceryl tri-2-ethylhexanoate 1. 0 Sodium hexametaphosphate 0. 05 Hydroxypropyl mono β-cyclo Dextrin 0.1 Dipotassium glycyrrhizinate 0.1 Bi birch leaf extract 0.1

L Sodium glutamate 0.1 0.1 Wikipedia extract 0.1

Nomadamerisu extract 0.1 Ova Bata extract 0.1 Dior extract 0.1 Eucalyptus oil 0. 05 Dimonoreforinopyridazinone 0. 1 Xanthan gum 0. 05 Canoleboxyvininole polymer 0.5 Acrylic acid 'alkyl methacrylate copolymer (Pemulene TR— 1) 0. 05 Potassium hydroxide 0. 05 Phenoxyethanol Purified water residue

[0080] Formulation Example 21 pack

(Prescription) Mass% Ethanol 3.0 Glycerol 5.0

1,3-Butyleneglycolanol 6.0

L-Sodium Glutamate 0.1 0.1 Wikiweed Extract 0.1 0.1 Wild Bean Meris Extract 0.1 0.1 Pepper Extract 0. 1 Zio Extract 0. 1 Eucalyptus Oil 0. 05 Dimonoreforinopyridazinone 0. 1 Xanthan Gum 0.5. Polymer 0.5 Acrylic acid 'alkyl methacrylate copolymer (Pemulene TR— 1) 0. 05 Potassium hydroxide 0.5.5 Phenoxyethanol Suitable amount Purified water Residue

[0081] Formulation Example 22 Cream (Prescription) Mass%

Liquid paraffin 3.0 Vaseline 1.0

Dimethinorepolysiloxane 1. 0 Stearyl alcohol 1. 8 Behe-Noleanolecanol 1. 6 Glycerin 8.0

Dipropylene glycol 5.0

4-Methoxybenzohydroxamic acid 5.0

2 Hydroxy 3 methyl benzohydroxamic acid 5.0

2-Hydroxy-5-methylbenzohydroxamic acid 5.0

4-Cyclohexylbenzohydroxamic acid 5.0 Macadamia nut oil 2. 0 Hardened oil 3.0

Skullan 6.0

Stearic acid 2.0

Cholesteryl hydroxystearate 0.5

2 Cetyl ethylhexanoate 4.0 Polyoxyethylene hydrogenated castor oil 0.5 Self-emulsifying glyceryl monostearate 3.0 Potassium hydroxide 0.15 Sodium hexametaphosphate 2.0 0.05 Trimethylglycine 2.0

α Tocopherol 2-L potassium ascorbic acid phosphate diester 1.0 Tocopherol acetate 0.1 甜 Tea extract 0.1

Noraben appropriate amount

Edetic acid trisodium 0. 05 4-tert-Butyl- 4'-Methoxydibenzoylmethane 0.05 0.05 Mono-diparamethoxycinnamic acid 2-Ethylhexyl glyceryl 0. Coloring agent Suitable amount

Canoleboxyvininole polymer 0.05 0.05 Purified water Residue Formulation Example 23 Cream

(Formulation) Mass% Liquid paraffin 8.0 Petrolatum 3.0

Dimethylolene polysiloxane 2. 0 Stearyl alcohol 3. 0 Behe-noreno-reconole 2. 0 Glycerin 5.0

Dipropylene glycol 4.0

4-Methoxybenzohydroxamic acid 3.0

2 Hydroxy 3 methyl benzohydroxamic acid 3.0

2-Hydroxy-5-methylbenzohydroxamic acid 3.0

4-Cyclohexylbenzohydroxamic acid 3.0 Trenosulose 1.0 Pentaerythritol tetratetraethylhexanoate 4.0 Polyoxyethylene glyceryl monoisostearate 2. 0 Polyoxyethylene glyceryl monostearate 1.0 Lipophilic Type Glycerol Monostearate 2.0 Cenoic Acid 0.05 Sodium Quenate 0.05 Sodium Potassium Hydroxide 0.105 Oil Soluble Licorice Extract 0.1 Retinol Palmitate (1 Million Units) 0.25 Tocopherol acetate 0.1 Noroxybenzoate Suitable amount Phenoxyethanol Suitable amount Dibutylhydroxytoluene Suitable amount edetate trisodium 0. 05

4-tert-Butyl- 4'-Methoxydibenzoylmethane 0.1 01 Paramethoxycinnamic acid 2-Ethylhexyl 0.1 β-Strength rotin 0.1 01 Polybure alcohol 0.5 Hydroxyenosenorerose 0.5 Canolevo Xivininore polymer 0.05 Purified water Residue Fragrance Appropriate amount Formulation example 24 Cream

(Formulation) Mass% Liquid paraffin 8. 0 Vaseline 3.0 Dimethinole polysiloxane 2. 0 Stearyl alcohol 3.0 Behe-Norenoreconole 2. 0 Glycerin 5. 0 Dipropylene glycol 4.0

4-Cyclohexylbenzohydroxamic acid 3.0 Trenosylose 1.0 Tetra-2-Ethylhexanoic acid pentaerythritol 4.0 Polyoxyethylene glyceryl monoisostearate 2. 0 Polyoxyethylene glyceryl monostearate 1.0 Parent Oil type glyceryl monostearate2.0 Quenic acid 0.05 Sodium citrate 0.05 Alkaline hydroxide 0.1 015 Oil-soluble licorice extract 0.1 Retinol palmitate (1 million units _) 0.25 Tocopherol acetate 0.1 Noroxybenzoate Suitable amount Phenooxy Ethanol appropriate amount Dibutylhydroxytoluene appropriate amount edetate trisodium 0. 05

4-tert-Butyl- 4'-Methoxydibenzoylmethane 0.1 01 Paramethoxycinnamic acid 2-Ethylhexyl 0.1 β-Strength rotin 0.1 01 Polybure alcohol 0.5 Hydroxyenosenorerose 0.5 Canolevo Xivininore polymer 0.05 Purified water Residue Fragrance Appropriate amount Formulation example 25 Cream

(Formulation) Mass% Petrolatum 2.0 Dimethinorepolysiloxane 2. 0 Ethanol 5. 0 Beno-Renore Cornole 0.5 Notinorenore Cornole 0.2 0.2 Glycerin 7.0

1, 3-Butyleneglycolanol 5.0

4-Methoxybenzohydroxamic acid 1.0 2 Hydroxy 3 methylbenzohydroxamic acid 1.0

2-Hydroxy-5-methylbenzohydroxamic acid 1.0

4-Cyclohexylbenzohydroxamic acid 1. 0 Posiethylene guji mononole 20000 0.5 Jojoba oil 3.0

Skullan 2.0

Phytosteryl hydroxystearate 0.5 Pentaerythritol tetra-2-ethylhexanoate 1. 0 Polyoxyethylene hydrogenated castor oil 1. 0 Potassium hydroxide 0.1 Sodium pyrosulfite 0. 01 Sodium hexametaphosphate 0. 05 Glycyrrhetinic acid Stearyl 0.1 Nonethylenyl ether 0.1 Anolebutin 7. 0 Tranexamic acid 1. 0 Tocopherol acetate 0. 1 Sodium hyanorenoate 0.05 Alkaline benzoate Trisodium edetate 0. 05

4-tert-Butyl- 4'-Methoxydibenzoylmethane 0.1 Diparamethoxycinnamic acid mono-2-Ethylhexanoate glyceryl 0.1 Yellow iron oxide

Xanthan gum 0.1 Canoleboxini vinylol polymer 0.2 Purified water Residual

Formulation Example 26 Cream

(Prescription) Mass% Liquid paraffin 10.0 Dimethylol polysiloxane 2.0 Glycerin 10.0

1, 3 Butylene glyconole 2. 0

4-Methoxybenzohydroxamic acid 1.0

2 Hydroxy 3 methylbenzohydroxamic acid 1.0

2-Hydroxy-5-methylbenzohydroxamic acid 1.0

4-Cyclohexylbenzohydroxamic acid 1. 0 Erythritol 1. 0 Posiethylene guji mononole 1500 5. 0 Scran 15.0 Tetra-2-ethylhexanoic acid pentaerythritol 5. 0 Potassium hydroxide 0.1 Hexametaphosphate 0. 05 Tocophorol acetate 0.05 Aloxybenzoate appropriate amount Hydroxypropyl methylcellulose 0.3 Polybutyl alcohol 0.1 Canoloxivininole polymer 0.2 Acrylic acid 'alkyl methacrylate copolymer (Pemulene TR-2) 0. 1 Purified water Residue Formulation Example 27 Cream

(Formulation) Mass% Liquid paraffin 10. 0 Dimethylol polysiloxane 2. 0 Glycerin 10.0

1, 3 Butylene glyconole 2. 0

2-Hydroxy-5-methylbenzohydroxamic acid 1.0 Erythritol 1. 0 Posiethylene IJn—Nole 1500 5. 0 Scran 15. 0 Tetra-2-ethyl hexanoate pentaerythritol 5. 0 Potassium hydroxide 0. 1 Sodium hexametaphosphate 0. 05 Tocophorol acetate 0. 05 Noroxybenzoic acid Ester Appropriate amount Hydroxypropylmethylcellulose 0.3 Polybulal alcohol 0.1 Canoleboxyvininole polymer 0.2 Acrylic acid 'alkyl methacrylate copolymer (Pemulene TR— 2) 0.1 Purified water Residue Example formulation 28 Two layers Type cream

(Formulation) Mass% Dimethylolene polysiloxane 5.0 Decamethylcyclopentasiloxane 25. 0 Trimethylsiloxyketic acid 5.0 Polyoxyethylene 'methylpolysiloxane copolymer 2.0 Dipropylene glycol 5.0

4-Methoxybenzohydroxamic acid 0.01

2-hydroxy-3-methylbenzohydroxamic acid 0. 01

2-hydroxy-5-methylbenzohydroxamic acid 0. 01

4-Cyclohexylbenzohydroxamic acid 0. 01 Palmitic acid dextrin-coated microparticles of acid and zinc (60 nm) 15. 0 Dipotassium glycyrrhizinate 0.02 Glutathione 1.0 Thiotaurine 0. 05 Clara extract 1. 0

Noraben appropriate amount

Suitable amount of phenoxyethanol

Edetate trisodium

2-Methoxyhexyl paramethoxycinnamate 7.5

Dimethyl distearyl ammonium hectorite 0.5

Spherical polyalkyl acrylate powder 5.0

Butinole Etinore Propane Gonole 0.5

Purified water residue

Perfume

Any of the above-mentioned preparations for external preparation of skin has high wrinkle prevention or improvement effect.

Claims

Claims [1] ADAM (^ disint egnn and consisting of benzohydroxamic acid represented by the following general formula (I) or a salt thereof

[Chemical 1]

(In the formula, each R is independently an alkyl group having 1 to 18 carbon atoms or a cycloaryl having 3 to 8 carbon atoms.

1

2

N is an integer of 0-3. )

[2] The ADAM inhibitor according to claim 1, wherein R is a hydrogen atom.

2

[3] R force C1-C18 alkyl group, C3-C8 cycloalkyl group, hydroxyl group,

1

Alternatively, the ADAM inhibitor according to claim 1 or 2, which is an alkoxy group having 1 to 18 carbon atoms and n is an integer of 1 to 2.

[4] A according to any one of claims 1 to 3, wherein n = l and R is substituted at the 4-position

1

DAM inhibitor.

[5] R force C1-C18 alkyl group, C3-C8 cycloalkyl group, or C1

1

The AD according to claim 4, wherein R is a hydrogen atom.

2

AM inhibitor.

[6] The ADAM inhibitory power according to any one of claims 1 to 5 and any one of claims 1, wherein the wrinkle prevention or amelioration agent.

[7] A method for preventing or improving wrinkles, comprising applying the ADAM inhibitor according to any one of claims 1 to 5 to the skin.