JP2014181211A - Novel salicylic acid derivative - Google Patents
Novel salicylic acid derivative Download PDFInfo
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- JP2014181211A JP2014181211A JP2013056275A JP2013056275A JP2014181211A JP 2014181211 A JP2014181211 A JP 2014181211A JP 2013056275 A JP2013056275 A JP 2013056275A JP 2013056275 A JP2013056275 A JP 2013056275A JP 2014181211 A JP2014181211 A JP 2014181211A
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- salicylic acid
- acid derivative
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- salt
- keratinocyte proliferation
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- 150000003872 salicylic acid derivatives Chemical class 0.000 title claims abstract description 30
- 210000005175 epidermal keratinocyte Anatomy 0.000 claims abstract description 29
- 230000035755 proliferation Effects 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 239000000845 maltitol Substances 0.000 claims abstract description 9
- 235000010449 maltitol Nutrition 0.000 claims abstract description 9
- 229940035436 maltitol Drugs 0.000 claims abstract description 9
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims abstract description 8
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims abstract description 8
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims abstract description 8
- 229960002160 maltose Drugs 0.000 claims abstract description 8
- 239000004386 Erythritol Substances 0.000 claims abstract description 7
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims abstract description 7
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims abstract description 7
- 235000019414 erythritol Nutrition 0.000 claims abstract description 7
- 229940009714 erythritol Drugs 0.000 claims abstract description 7
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000000811 xylitol Substances 0.000 claims abstract description 7
- 235000010447 xylitol Nutrition 0.000 claims abstract description 7
- 229960002675 xylitol Drugs 0.000 claims abstract description 7
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims abstract description 6
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims abstract description 6
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims abstract description 4
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 claims description 22
- 229960001047 methyl salicylate Drugs 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000002537 cosmetic Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 4
- 125000003071 maltose group Chemical group 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 230000001737 promoting effect Effects 0.000 abstract description 13
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 206010040880 Skin irritation Diseases 0.000 abstract description 5
- 230000036556 skin irritation Effects 0.000 abstract description 5
- 231100000475 skin irritation Toxicity 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract 2
- 235000002639 sodium chloride Nutrition 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 20
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 12
- 229960004889 salicylic acid Drugs 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 210000003491 skin Anatomy 0.000 description 8
- -1 alkali metal salts Chemical class 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000001569 carbon dioxide Substances 0.000 description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 description 6
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 229910021642 ultra pure water Inorganic materials 0.000 description 6
- 239000012498 ultrapure water Substances 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
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- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
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- 229940058287 salicylic acid derivative anticestodals Drugs 0.000 description 3
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- 239000000126 substance Substances 0.000 description 3
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- 208000002874 Acne Vulgaris Diseases 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
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- 229910052783 alkali metal Inorganic materials 0.000 description 2
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- 150000001720 carbohydrates Chemical class 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
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- 239000007789 gas Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000019612 pigmentation Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000005809 transesterification reaction Methods 0.000 description 2
- HBDJFVFTHLOSDW-DNDLZOGFSA-N (2r,3r,4r,5r)-2,3,5,6-tetrahydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyhexanal;hydrate Chemical compound O.O=C[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HBDJFVFTHLOSDW-DNDLZOGFSA-N 0.000 description 1
- ASJSXUWOFZATJM-UHFFFAOYSA-N 2-(3,5-diphenyl-1h-tetrazol-2-yl)-4,5-dimethyl-1,3-thiazole Chemical compound S1C(C)=C(C)N=C1N1N(C=2C=CC=CC=2)NC(C=2C=CC=CC=2)=N1 ASJSXUWOFZATJM-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 231100000951 LabCyte EPI-MODEL Toxicity 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 235000005811 Viola adunca Nutrition 0.000 description 1
- 240000009038 Viola odorata Species 0.000 description 1
- 235000013487 Viola odorata Nutrition 0.000 description 1
- 235000002254 Viola papilionacea Nutrition 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- PPYIVKOTTQCYIV-UHFFFAOYSA-L beryllium;selenate Chemical compound [Be+2].[O-][Se]([O-])(=O)=O PPYIVKOTTQCYIV-UHFFFAOYSA-L 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
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- 230000006870 function Effects 0.000 description 1
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- 230000004054 inflammatory process Effects 0.000 description 1
- 150000002506 iron compounds Chemical class 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229960003017 maltose monohydrate Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 208000035824 paresthesia Diseases 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
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- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 230000036560 skin regeneration Effects 0.000 description 1
- 230000008417 skin turnover Effects 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 159000000008 strontium salts Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 150000003609 titanium compounds Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 150000003682 vanadium compounds Chemical class 0.000 description 1
- 150000003752 zinc compounds Chemical class 0.000 description 1
- 150000003755 zirconium compounds Chemical class 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
本発明は、新規なサリチル酸誘導体、その製造方法およびその利用に関する。 The present invention relates to a novel salicylic acid derivative, a production method thereof and use thereof.
表皮は、深部から表面に向け、基底層、有棘層、顆粒層、角質層の４層構造から成っている。基底層で生まれた表皮角化細胞は、徐々に分化して上層に移動し、ケラチン繊維で満たされた角質細胞となり角質層を形成し、最終的に、いわゆる垢として剥がれ落ちる。 The epidermis consists of a four-layered structure from the deep to the surface, consisting of a basal layer, a spiny layer, a granular layer, and a stratum corneum. Epidermal keratinocytes born in the basal layer gradually differentiate and move to the upper layer, become keratinocytes filled with keratin fibers to form a stratum corneum, and finally peel off as so-called plaque.
角質層は皮膚の最外殻であり、表皮角化細胞が基底層で生まれ垢となって剥がれ落ちるサイクル（ターンオーバー）を絶えず繰り返すことで、一定の水分量を保持し、保湿機能とともに外界からの刺激に対する保護バリア機能を有している。 The stratum corneum is the outermost shell of the skin, and by constantly repeating the cycle (turnover) in which epidermal keratinocytes are born and peeled off in the basal layer, it maintains a certain amount of moisture, from the outside with moisture retention function. It has a protective barrier function against irritation.
しかしながら、加齢や紫外線による影響を受け、表皮角化細胞の新陳代謝機能が衰えると、ターンオーバーが乱れ、色素沈着、肌荒れ、ニキビ等の肌トラブルが生じる。表皮角化細胞の増殖を促進し、乱れたターンオーバーを回復させることで、色素沈着、肌荒れ、ニキビ等の肌トラブルの予防・改善に繋がると考えられている。 However, when the metabolic function of epidermal keratinocytes declines under the influence of aging or ultraviolet rays, turnover is disturbed, causing skin troubles such as pigmentation, rough skin, and acne. It is believed that promoting proliferation of epidermal keratinocytes and restoring disturbed turnover leads to prevention and improvement of skin troubles such as pigmentation, rough skin, and acne.
サリチル酸は従来より角質化した表皮を軟化、剥離し、皮膚のターンオーバーを正常にし、皮膚の再生を促すケミカルピーリングに用いられている。
一方で、サリチル酸は表皮角化細胞増殖促進に効果を有する物質としても知られている（非特許文献１）。しかしながらサリチル酸は皮膚刺激性が強いことから、表皮角化細胞増殖促進剤として用いる場合、サリチル酸の配合量によって炎症や刺痛感等の問題を引き起こす可能性があった。
Salicylic acid is conventionally used for chemical peeling to soften and peel the keratinized epidermis, normalize skin turnover, and promote skin regeneration.
On the other hand, salicylic acid is also known as a substance having an effect on promoting the proliferation of epidermal keratinocytes (Non-patent Document 1). However, since salicylic acid has a strong skin irritation potential, when used as an epidermal keratinocyte proliferation promoter, problems such as inflammation and tingling sensation may occur depending on the amount of salicylic acid.
本発明の目的は、皮膚刺激性が低い表皮角化細胞増殖促進剤として有用な新規化合物およびその製造方法を提供することにある。また、本発明の目的は新規化合物を含有する表皮角化細胞増殖促進剤を提供することにある。 An object of the present invention is to provide a novel compound useful as an epidermal keratinocyte proliferation promoter with low skin irritation and a method for producing the same. Another object of the present invention is to provide an epidermal keratinocyte proliferation promoter containing a novel compound.
本発明者らは、上記事情を鑑み、表皮角化細胞増殖促進効果を有する化合物について鋭意検討し、サリチル酸に特定の糖類を結合させることよって、表皮角化細胞増殖促進効果を有し、かつ皮膚刺激性が低い物質が得られることを見出し本発明を完成した。 In view of the above circumstances, the present inventors have intensively studied about a compound having an effect of promoting proliferation of epidermal keratinocytes, and having an effect of promoting proliferation of epidermal keratinocytes by binding a specific saccharide to salicylic acid, and the skin. The present invention was completed by finding that a substance having low irritation can be obtained.
すなわち、本発明は、式（１）で表されるサリチル酸誘導体：
式（１）
Formula (1)
また、本発明は、式（１）で表されるサリチル酸誘導体またはその塩を含有する表皮角化細胞増殖促進剤を提供する。 Moreover, this invention provides the epidermal keratinocyte proliferation promoter containing the salicylic acid derivative or its salt represented by Formula (1).
本発明のサリチル酸誘導体は、表皮角化細胞増殖促進効果を有し、皮膚刺激性が低い。本発明のサリチル酸誘導体は、皮膚刺激性が低いため、表皮角化細胞増殖促進剤として化粧品等に添加して幅広く利用することが可能である。 The salicylic acid derivative of the present invention has an effect of promoting keratinocyte proliferation and has low skin irritation. Since the salicylic acid derivative of the present invention has low skin irritation, it can be widely used as an epidermal keratinocyte proliferation promoter added to cosmetics and the like.
本発明の式（１）で表されるサリチル酸誘導体は、マルトース、マルチトール、キシリトールおよびエリスリトールからなる群から選ばれる糖残基を有する、サリチル酸のエステル体である。 The salicylic acid derivative represented by the formula (1) of the present invention is an ester of salicylic acid having a sugar residue selected from the group consisting of maltose, maltitol, xylitol and erythritol.
本願明細書並びに特許請求の範囲において、エステルを形成する糖の部位は特に限定されない。式（１）の化合物としては単一の化合物である場合、２またはそれ以上の構造異性体の混合物である場合のいずれも包含する。 In the present specification and claims, the site of the sugar that forms the ester is not particularly limited. The compound of the formula (1) includes both a single compound and a mixture of two or more structural isomers.
本発明は、上記の式（１）で表されるサリチル酸誘導体に加え、式（１）で表されるサリチル酸誘導体の塩も提供する。塩の種類は特に限定されないが、一般的には、ナトリウム塩、カリウム塩等のアルカリ金属塩、カルシウム塩、ストロンチウム塩等のアルカリ土類金属塩、ベリリウム塩、マグネシウム塩等の金属塩等が挙げられる。 In addition to the salicylic acid derivative represented by the above formula (1), the present invention also provides a salt of the salicylic acid derivative represented by the formula (1). The type of salt is not particularly limited, but in general, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and strontium salt, metal salts such as beryllium salt and magnesium salt, etc. It is done.
本発明の式（１）で表されるサリチル酸誘導体の製造方法としては、特に限定されないが、例えば、サリチル酸メチルと糖を、水および／または有機溶媒中において、触媒存在下で減圧しながらエステル交換させる工程、を含む製造方法が挙げられる。 The method for producing the salicylic acid derivative represented by the formula (1) of the present invention is not particularly limited. For example, transesterification of methyl salicylate and a sugar in water and / or an organic solvent while reducing the pressure in the presence of a catalyst. The manufacturing method including the process to make is mentioned.
以下、本発明の式（１）で表されるサリチル酸誘導体の例示的な製造方法を説明するが、本発明の式（１）で表されるサリチル酸誘導体の製造方法は以下の記載に限定されるものではない。 Hereinafter, although the exemplary manufacturing method of the salicylic acid derivative represented by Formula (1) of this invention is demonstrated, the manufacturing method of the salicylic acid derivative represented by Formula (1) of this invention is limited to the following description. It is not a thing.
サリチル酸メチルと糖をエステル交換させる方法としては、サリチル酸メチルと糖を有機溶媒中、触媒の存在下で、１２５〜１５５ｍｍＨｇに減圧し、反応途中に生成するメタノールを除去しながら、９３〜１１０℃で４〜１６時間反応させる方法が挙げられる。 As a method of transesterifying methyl salicylate and sugar, the pressure of methyl salicylate and sugar is reduced to 125 to 155 mmHg in an organic solvent in the presence of a catalyst, and methanol generated during the reaction is removed at 93 to 110 ° C. The method of making it react for 4 to 16 hours is mentioned.
上記反応における溶媒としては、サリチル酸メチルと糖が溶解し、沸点１００〜２５０℃程度のもので、脱水溶媒を用いるのが好ましく、例えば、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド、Ｎ−メチル−２−ピロリドン等を用いることができる。 As the solvent in the above reaction, methyl salicylate and saccharide are dissolved and have a boiling point of about 100 to 250 ° C., and a dehydrating solvent is preferably used. For example, N, N-dimethylformamide, dimethyl sulfoxide, N-methyl-2 -Pyrrolidone etc. can be used.
溶媒の使用量はサリチル酸メチル１重量部に対して、５〜１００重量部が好ましく、７〜７５重量部がより好ましく、９〜５０重量部がさらに好ましい。 The amount of the solvent used is preferably 5 to 100 parts by weight, more preferably 7 to 75 parts by weight, and still more preferably 9 to 50 parts by weight with respect to 1 part by weight of methyl salicylate.
上記反応における触媒としては、アルカリ金属炭酸塩、アルカリ金属水酸化物、アルカリ金属アルコキシド等のアルカリ触媒、塩酸、硫酸、硫酸水素ナトリウム、パラトルエンスルホン酸、ベンゼンスルホン酸、メタンスルホン酸等の酸触媒、ジルコニウム化合物、鉛化合物、鉄化合物、亜鉛化合物、有機スズ化合物、アルミニウム化合物、チタン化合物、バナジウム化合物等を用いることができる。 Examples of the catalyst in the above reaction include alkali catalysts such as alkali metal carbonates, alkali metal hydroxides, and alkali metal alkoxides, and acid catalysts such as hydrochloric acid, sulfuric acid, sodium hydrogen sulfate, paratoluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid. Zirconium compounds, lead compounds, iron compounds, zinc compounds, organotin compounds, aluminum compounds, titanium compounds, vanadium compounds, and the like can be used.
触媒の使用量はサリチル酸メチル１重量部に対して、０．０５〜４重量部が好ましく、０．０６〜３重量部がより好ましく、０．０７〜２重量部がさらに好ましい。 The amount of the catalyst used is preferably 0.05 to 4 parts by weight, more preferably 0.06 to 3 parts by weight, and still more preferably 0.07 to 2 parts by weight with respect to 1 part by weight of methyl salicylate.
かかるエステル交換反応により得られた反応液を、ろ過、シリカゲルカラムクロマトグラフィー、分取操作等の公知の方法によって分離し、回収することにより、本発明の式（１）で表されるサリチル酸誘導体が得られる。 The salicylic acid derivative represented by the formula (1) of the present invention is obtained by separating and recovering the reaction solution obtained by the transesterification reaction by a known method such as filtration, silica gel column chromatography, and preparative operation. can get.
本発明の式（１）で表されるサリチル酸誘導体は、表皮角化細胞増殖促進効果から、マルトースまたはマルチトールのいずれかの糖残基であることが好ましい。これらのサリチル酸誘導体は、例えば、表皮角化細胞増殖促進剤として、単独で用いてもよく、２種以上のサリチル酸誘導体を混合して用いてもよい。 The salicylic acid derivative represented by the formula (1) of the present invention is preferably a sugar residue of either maltose or maltitol because of the effect of promoting proliferation of keratinocytes. These salicylic acid derivatives may be used alone, for example, as an epidermal keratinocyte proliferation promoter, or two or more salicylic acid derivatives may be mixed and used.
また、本発明は、式（１）で表されるサリチル酸誘導体またはその塩を含む表皮角化細胞増殖促進剤を提供する。 Moreover, this invention provides the epidermal keratinocyte proliferation promoter containing the salicylic acid derivative or its salt represented by Formula (1).
本発明の表皮角化細胞増殖促進剤は、式（１）で表されるサリチル酸誘導体またはその塩のみからなるものでも式（１）で表されるサリチル酸誘導体またはその塩を含むものでもよい。表皮角化細胞増殖促進効果を妨げない限り、化粧品、医薬品、医薬部外品等一般に用いられる賦型剤等を適宜用いて顆粒状、粉末状とすることができる他、適当な溶剤等を用いて液状、エマルション、クリーム、ペースト等としてもよい。これらの賦型剤の種類や配合量は、当業者に周知のものから適宜選択することができる。 The epidermal keratinocyte proliferation promoter of the present invention may be composed only of a salicylic acid derivative represented by formula (1) or a salt thereof, or may contain a salicylic acid derivative represented by formula (1) or a salt thereof. As long as it does not interfere with the effect of promoting epidermal keratinocyte proliferation, it can be granulated or powdered by using generally used excipients such as cosmetics, pharmaceuticals, quasi drugs, etc. It may be liquid, emulsion, cream, paste, or the like. The types and blending amounts of these excipients can be appropriately selected from those well known to those skilled in the art.
本発明の表皮角化細胞増殖促進剤は、例えば、化粧品、医薬品、医薬部外品等に配合することができる。本発明の表皮角化細胞増殖促進剤の、化粧品、医薬品、医薬部外品等への配合量は使用する系により異なり、配合する対象の全重量に対して、式（１）で表されるサリチル酸誘導体が０．０１〜２０重量％であることが好ましく、０．０５〜５重量％であることがより好ましく、０．１〜１重量％であることがさらに好ましい。配合量が０．０１重量％未満の場合、十分な表皮角化細胞の増殖効果が発揮されない傾向があり、配合量が２０重量％を超えると表皮角化細胞増殖の効果が低下する傾向がある。 The epidermal keratinocyte proliferation promoter of the present invention can be blended, for example, in cosmetics, pharmaceuticals, quasi drugs and the like. The blending amount of the epidermal keratinocyte proliferation promoter of the present invention into cosmetics, pharmaceuticals, quasi drugs, etc. varies depending on the system used, and is represented by the formula (1) with respect to the total weight of the blending target. The salicylic acid derivative is preferably 0.01 to 20% by weight, more preferably 0.05 to 5% by weight, and still more preferably 0.1 to 1% by weight. When the blending amount is less than 0.01% by weight, there is a tendency that sufficient proliferation effect of epidermal keratinocytes is not exhibited, and when the blending amount exceeds 20% by weight, the effect of epidermal keratinocyte proliferation tends to be reduced. .
以下、実施例により本発明をさらに説明するが、本発明はこれらに限定されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention further, this invention is not limited to these.
実施例１
加熱乾燥した２００ｍｌ４つ口フラスコにマルトース一水和物２１．０ｇを入れ窒素置換し、脱水ＤＭＦ（Ｎ，Ｎ−ジメチルホルムアミド）１４０ｍｌを加え５５℃に昇温した。この溶液に、サリチル酸メチル３．０ｇ、炭酸カリウム（減圧中ヒートガンであぶって乾燥させたもの）０．５ｇを加えて１００〜１１０℃で減圧下（１３５〜１４５ｍｍＨｇ）、１６時間反応させた。反応終了後、反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール／水＝６／１／０．１）とクロマト分取装置（装置：Ｋｐｒｅｐ（ＹＭＣ社製）、展開溶媒：メタノール／超純水＝５０／５０、流速：１０ｍｌ/ｍｉｎ）にて未反応の原料を除去した。構造異性体をまとめて回収し、赤色粘性液体を３．９ｇ得た。
Example 1
In a heat-dried 200 ml four-necked flask, 21.0 g of maltose monohydrate was placed, and the atmosphere was replaced with nitrogen. To this solution, 3.0 g of methyl salicylate and 0.5 g of potassium carbonate (dried with a heat gun under reduced pressure) were added and reacted at 100 to 110 ° C. under reduced pressure (135 to 145 mmHg) for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / methanol / water = 6/1 / 0.1) and a chromatographic fractionator (apparatus: Kprep (manufactured by YMC), developing solvent: (Methanol / ultra pure water = 50/50, flow rate: 10 ml / min) to remove unreacted raw materials. Structural isomers were collected together to obtain 3.9 g of a red viscous liquid.
得られた生成物のＬＣ／ＭＳ分析によりｍ／ｚ４６１（Ｍ−１）のピークを確認し、得られた生成物が以下の式および／またはその構造異性体の混合物であるサリチル酸マルトースエステルであることを確認した。
実施例２
加熱乾燥した２００ｍｌ４つ口フラスコにマルチトール２０．０ｇを入れ窒素置換し、脱水ＤＭＦ１００ｍｌを加え９０℃に昇温した。この溶液に、サリチル酸メチル３．０ｇ、炭酸カリウム（減圧中ヒートガンであぶって乾燥させたもの）０．３ｇを加えて９６〜１１０℃で減圧下（１２５〜１５５ｍｍＨｇ）、４時間反応させた。反応終了後、反応液を減圧濃縮し、残渣に酢酸エチルを加えて１時間還流させた。室温まで冷却した後、ろ過で析出物を取り除き、減圧濃縮することで褐色液体を３．５ｇ得た。クロマト分取装置（装置：Ｋｐｒｅｐ（ＹＭＣ社製）、展開溶媒：メタノール／超純水＝５０／５０、流速：１０ｍｌ/ｍｉｎ）を用いて未反応の原料を取り除き、構造異性体をまとめて回収し、淡桃色オイルを１．４ｇ得た。
Example 2
In a heat-dried 200 ml four-necked flask, 20.0 g of maltitol was placed, and the atmosphere was replaced with nitrogen. To this solution, 3.0 g of methyl salicylate and 0.3 g of potassium carbonate (dried with a heat gun under reduced pressure) were added and reacted at 96 to 110 ° C. under reduced pressure (125 to 155 mmHg) for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was refluxed for 1 hour. After cooling to room temperature, the precipitate was removed by filtration and concentrated under reduced pressure to obtain 3.5 g of a brown liquid. Unreacted raw materials are removed using a chromatographic fractionation apparatus (apparatus: Kprep (manufactured by YMC), developing solvent: methanol / ultra pure water = 50/50, flow rate: 10 ml / min), and structural isomers are collected together. 1.4 g of pale pink oil was obtained.
得られた生成物のＬＣ／ＭＳ分析によりｍ／ｚ４６３（Ｍ−１）のピークを確認し、得られた生成物が以下の式および／またはその構造異性体の混合物であるサリチル酸マルチトールエステルであることを確認した。
実施例３
加熱乾燥した２００ｍＬ４つ口フラスコにキシリトール９．０ｇを入れ窒素置換し、脱水ＤＭＦ３０ｍＬを加え９０℃に昇温した。この溶液に、サリチル酸メチル３．０ｇ、炭酸カリウム（減圧中ヒートガンであぶって乾燥させたもの）０．３ｇを加えて９３〜１１０℃で減圧下（１３５ｍｍＨｇ）、１１時間反応させた。反応終了後、反応液を減圧濃縮し、残渣に酢酸エチルを１００ｍｌ加えて１時間還流させた。室温まで冷却した後、ろ過で析出物を取り除いた。シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝６／１）とクロマト分取装置（装置：Ｋｐｒｅｐ（ＹＭＣ社製）、展開溶媒：メタノール／超純水＝５０／５０、流速：１０ｍＬ/ｍｉｎ）により単離し、淡黄色固体を１．５ｇ得た。この生成物をさらにメタノールで再結晶し、粉状白色固体を１．２ｇ得た。
Example 3
9.0 g of xylitol was placed in a heat-dried 200 mL four-necked flask, and the atmosphere was purged with nitrogen. To this solution, 3.0 g of methyl salicylate and 0.3 g of potassium carbonate (dried with a heat gun under reduced pressure) were added and reacted at 93 to 110 ° C. under reduced pressure (135 mmHg) for 11 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 100 ml of ethyl acetate was added to the residue, and the mixture was refluxed for 1 hour. After cooling to room temperature, the precipitate was removed by filtration. Isolate by silica gel column chromatography (chloroform / methanol = 6/1) and chromatographic fractionator (equipment: Kprep (manufactured by YMC), developing solvent: methanol / ultra pure water = 50/50, flow rate: 10 mL / min). 1.5 g of a pale yellow solid was obtained. This product was further recrystallized from methanol to obtain 1.2 g of a powdery white solid.
得られた生成物のＮＭＲ１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ‐ｄ６）分析により、３．３７−３．６３（ｍ，４Ｈ），３．９０−３．９５（ｍ，１Ｈ），４．３１−４．４１（ｍ，２Ｈ），４．４９−４．５４（ｍ，３Ｈ），５．０５（ｄ，Ｊ＝５．５Ｈｚ），６．９７（ｍ，２Ｈ），７．５３（ｔ，Ｊ＝７．８Ｈｚ，１Ｈ），７．８５（ｄ，Ｊ＝７．９Ｈｚ，１Ｈ），１０．５５（ｓ，１Ｈ）のシグナルを確認し、以下の式のサリチル酸キシリトールエステルであることを確認した。 NMR 1 H NMR (400 MHz, DMSO-d 6 ) analysis of the product obtained gave 3.37-3.63 (m, 4H), 3.90-3.95 (m, 1H), 4.31. -4.41 (m, 2H), 4.49-4.54 (m, 3H), 5.05 (d, J = 5.5 Hz), 6.97 (m, 2H), 7.53 (t , J = 7.8 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 10.55 (s, 1H), confirming that it is a salicylic acid xylitol ester of the following formula. confirmed.
実施例４
加熱乾燥した２００ｍｌ４つ口フラスコにエリスリトール７．２ｇを入れ窒素置換し、脱水ＤＭＦ３０ｍＬを加え９０℃に昇温した。この溶液に、サリチル酸メチル３．０ｇ、炭酸カリウム（減圧中ヒートガンであぶって乾燥させたもの）０．３ｇを加えて９６〜１１０℃で減圧下（１２５〜１３０ｍｍＨｇ）、１２時間反応させた。反応終了後、反応液を減圧濃縮し、残渣に酢酸エチルを２００ｍｌ加えて１時間還流させた。室温まで冷却した後、ろ過で析出物を取り除き、減圧濃縮することで黄色粘性液体を８．９ｇ得た。シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝６／１）とクロマト分取装置（装置：Ｋｐｒｅｐ（ＹＭＣ社製）、展開溶媒：メタノール／超純水＝５０／５０、流速：１０ｍＬ/ｍｉｎ）により単離し、淡桃色固体を３．７ｇ得た。
Example 4
7.2 g of erythritol was put into a 200 ml four-necked flask that had been dried by heating, and the atmosphere was purged with nitrogen. To this solution, 3.0 g of methyl salicylate and 0.3 g of potassium carbonate (dried with a heat gun under reduced pressure) were added and reacted at 96 to 110 ° C. under reduced pressure (125 to 130 mmHg) for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 200 ml of ethyl acetate was added to the residue and refluxed for 1 hour. After cooling to room temperature, the precipitate was removed by filtration and concentrated under reduced pressure to obtain 8.9 g of a yellow viscous liquid. Isolate by silica gel column chromatography (chloroform / methanol = 6/1) and chromatographic fractionator (equipment: Kprep (manufactured by YMC), developing solvent: methanol / ultra pure water = 50/50, flow rate: 10 mL / min). 3.7 g of a light pink solid was obtained.
得られた生成物の１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ‐ｄ６）分析により、３．４１−３．４９（ｍ，２Ｈ），４．２８−４．３３（ｍ，１Ｈ），４．４５−４．５１（ｍ，２Ｈ），４．８２−４．８３（ｍ，１Ｈ），５．１１−５．１３（ｍ，１Ｈ），６．９４−６．９９（ｍ，２Ｈ），７．５３（ｔ，Ｊ＝７．９Ｈｚ，１Ｈ），７．９０（ｄ，Ｊ＝７．９Ｈｚ，１Ｈ），１０．５６（ｓ，１Ｈ）のシグナルを確認し、以下の式のサリチル酸エリスリトールエステルであることを確認した。
実施例５（角化細胞増殖促進効果試験）
ヒト表皮角化細胞（ＨａＣａＴ細胞）を８０ｃｍ２のフラスコで１０％のＦＢＳ（ウシ胎児血清）（バイオウエスト社製）を含むＤＭＥＭ培地（ダルベッコ・フォークト変法イーグル最小必須培地）（ライフテクノロジーズ社製）を用いて３７℃、５％炭酸ガス濃度のインキュベーター内で培養し、常法に従いヒト表皮角化細胞を回収した。得られたヒト表皮角化細胞を２％のＦＢＳを含むＤＭＥＭ培地にて３×１０４個／ｍｌとなるように調整した。１００μｌずつ９６ウエルプレートに播種し、３７℃、５％炭酸ガス濃度のインキュベーター内で１日培養した。培養後、ＤＭＳＯに実施例１および２のサリチル酸誘導体を溶解させたサンプル液を１μｌずつ添加し、３７℃、５％炭酸ガス濃度のインキュベーター内で３日培養した。培養後、Ｃｅｌｌ−Ｃｏｕｎｔｉｎｇ Ｋｉｔ−８（同仁化学社製）を用い細胞数を測定することで、促進作用を評価した。細胞数は各濃度において４回ずつ測定し、その平均値±SDを結果として示した。ｔ−検定により有意差検定（対０ppm）を行い、有意水準０．０５未満の場合に有意差ありと評価した。結果を表１に示す。
Example 5 (Keratinocyte proliferation promoting effect test)
Human epidermis keratinocytes (HaCaT cells) in a 80 cm 2 flask containing 10% FBS (fetal bovine serum) (manufactured by Biowest) DMEM medium (Dulbecco-Folk modified Eagle's minimum essential medium) (manufactured by Life Technologies) ) In an incubator at 37 ° C. and 5% carbon dioxide concentration, and human epidermal keratinocytes were collected according to a conventional method. The obtained human epidermal keratinocytes were adjusted to 3 × 10 4 cells / ml in a DMEM medium containing 2% FBS. 100 μl each was seeded in a 96-well plate and cultured in an incubator at 37 ° C. and 5% carbon dioxide concentration for 1 day. After culturing, 1 μl of a sample solution in which the salicylic acid derivatives of Examples 1 and 2 were dissolved in DMSO was added and cultured for 3 days in an incubator at 37 ° C. and 5% carbon dioxide concentration. After the cultivation, the promoting effect was evaluated by measuring the number of cells using Cell-Counting Kit-8 (manufactured by Dojindo). The number of cells was measured 4 times at each concentration, and the average value ± SD was shown as a result. Significant difference test (vs. 0 ppm) was performed by t-test, and it was evaluated that there was a significant difference when the significance level was less than 0.05. The results are shown in Table 1.
ヒト表皮角化細胞数が有意に増加していることから、本発明のサリチル酸誘導体は、表皮角化細胞増殖促進効果を有することが分かった。 Since the number of human epidermal keratinocytes was significantly increased, it was found that the salicylic acid derivative of the present invention has an effect of promoting proliferation of epidermal keratinocytes.
実施例６（刺激性確認試験）
トランスウエル内で培養された培養皮膚であるヒト三次元培養皮膚モデル（Ｌａｂｃｙｔｅ ＥＰＩ−ＭＯＤＥＬ ジャパン・ティッシュ・エンジニアリング社製）を用いて実施した。まず、Ｌａｂｃｙｔｅを２４ウエルアッセイプレートに入れた。続いて、この２４ウエルアッセイプレートの各ウエルにアッセイ培地（ジャパン・ティッシュ・エンジニアリング社製）を１ｍｌ加え、３７℃、５％炭酸ガス濃度のインキュベーター内で２０時間前培養を行った。
Example 6 (Irritation confirmation test)
This was carried out using a human three-dimensional cultured skin model (Labcyte EPI-MODEL Japan Tissue Engineering Co., Ltd.) which is a cultured skin cultured in a transwell. First, Labcyte was placed in a 24-well assay plate. Subsequently, 1 ml of assay medium (manufactured by Japan Tissue Engineering) was added to each well of this 24-well assay plate, and pre-cultured for 20 hours in an incubator at 37 ° C. and 5% carbon dioxide gas concentration.
次に、Ｌａｂｃｙｔｅの表面に５％に調製した滅菌した実施例１および２のサリチル酸誘導体水溶液を５０μｌ添加した。比較例として、滅菌した超純水５０μｌを添加し、その上からサリチル酸を５０ｍｇ添加した。陰性対照として、滅菌した超純水５０μｌのみを添加した。１５分間放置後、滅菌したＰＢＳ水溶液（タカラバイオ社製）で、Ｌａｂｃｙｔｅを十分に洗浄した。Ｌａｂｃｙｔｅを３７℃、５％炭酸ガス濃度のインキュベーター内で４２時間培養を行った後、０．５ｍｇ／ｍｌのＭＴＴ（３−（４,５−ジメチル−２−チアゾリル）−２,５−ジフェニルテトラゾリウムブロミド）試薬を含むアッセイ培地に交換し、更に３７℃、５％炭酸ガス濃度のインキュベーター内で３時間培養を行った。 Next, 50 μl of the sterilized salicylic acid derivative aqueous solution of Examples 1 and 2 prepared to 5% was added to the surface of Labcyte. As a comparative example, 50 μl of sterilized ultrapure water was added, and 50 mg of salicylic acid was added from above. As a negative control, only 50 μl of sterilized ultrapure water was added. After leaving for 15 minutes, Labcyte was sufficiently washed with a sterilized PBS aqueous solution (Takara Bio Inc.). Labcyte was cultured in an incubator at 37 ° C. and 5% carbon dioxide gas for 42 hours, and then 0.5 mg / ml of MTT (3- (4,5-dimethyl-2-thiazolyl) -2,5-diphenyltetrazolium. The assay medium was changed to an assay medium containing a bromide reagent, and further cultured in an incubator at 37 ° C. and 5% carbon dioxide concentration for 3 hours.
その後、Ｌａｂｃｙｔｅを０．３ｍｌのイソプロパノール液に浸し、生成した青紫色のホルマザンの抽出を２日間行った。抽出終了後、９６ウエルマイクロプレートリーダーを用いて抽出液の５７０ｎｍと６５０ｎｍの吸光度を測定した。細胞生存率は下記計算式により算出した。結果を表２に示す。
測定値＝［サンプルの吸光度（５７０ｎｍ）−ブランクの吸光度（５７０ｎｍ）］−［サンプルの吸光度（６５０ｎｍ）−ブランクの吸光度（６５０ｎｍ）］
細胞生存率＝サンプルの測定値／陰性対照の測定値×１００
Then, Labcyte was immersed in 0.3 ml of isopropanol solution, and the blue-violet formazan produced was extracted for 2 days. After completion of the extraction, the absorbance at 570 nm and 650 nm of the extract was measured using a 96-well microplate reader. The cell viability was calculated by the following formula. The results are shown in Table 2.
Measurement value = [absorbance of sample (570 nm) −absorbance of blank (570 nm)] − [absorbance of sample (650 nm) −absorbance of blank (650 nm)]
Cell viability = measured value of sample / measured value of negative control × 100
本発明の新規サリチル酸誘導体は、サリチル酸と比較して、細胞生存率が高く刺激性が低いことが分かった。 It has been found that the novel salicylic acid derivative of the present invention has a higher cell survival rate and lower irritation than salicylic acid.
実施例７
本発明の化粧品用途として表３に化粧水の処方例を示す。
Table 3 shows an example of formulating lotion for use as a cosmetic product of the present invention.
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| JP2020029428A (en) * | 2018-08-23 | 2020-02-27 | 株式会社岩出菌学研究所 | Yamabushitake-derived novel compound |
| JP7090261B2 (en) | 2018-08-23 | 2022-06-24 | 株式会社岩出菌学研究所 | New compound derived from Lion's mane |
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