JPH02306952A - Amide derivative and external-use drug for skin containing the same compound - Google Patents
Amide derivative and external-use drug for skin containing the same compoundInfo
- Publication number
- JPH02306952A JPH02306952A JP12646289A JP12646289A JPH02306952A JP H02306952 A JPH02306952 A JP H02306952A JP 12646289 A JP12646289 A JP 12646289A JP 12646289 A JP12646289 A JP 12646289A JP H02306952 A JPH02306952 A JP H02306952A
- Authority
- JP
- Japan
- Prior art keywords
- skin
- formula
- hydrocarbon group
- amide derivative
- external
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001408 amides Chemical class 0.000 title claims description 24
- 150000001875 compounds Chemical class 0.000 title abstract description 19
- 239000003814 drug Substances 0.000 title abstract 2
- 229940079593 drug Drugs 0.000 title abstract 2
- 238000002360 preparation method Methods 0.000 claims abstract description 27
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract 9
- 125000002252 acyl group Chemical group 0.000 claims abstract 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 7
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 abstract description 11
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 abstract description 8
- 238000006243 chemical reaction Methods 0.000 abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 3
- 125000005907 alkyl ester group Chemical group 0.000 abstract description 2
- GYZLOYUZLJXAJU-UHFFFAOYSA-N diglycidyl ether Chemical compound C1OC1COCC1CO1 GYZLOYUZLJXAJU-UHFFFAOYSA-N 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 150000002596 lactones Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 210000003491 skin Anatomy 0.000 description 49
- 230000004888 barrier function Effects 0.000 description 22
- 210000000434 stratum corneum Anatomy 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 10
- -1 hydroxy fatty acid Chemical class 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- 235000014113 dietary fatty acids Nutrition 0.000 description 8
- 239000000194 fatty acid Substances 0.000 description 8
- 229930195729 fatty acid Natural products 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000002537 cosmetic Substances 0.000 description 6
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 210000002615 epidermis Anatomy 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 230000001771 impaired effect Effects 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- AOTMRIXFFOGWDT-UHFFFAOYSA-N methyl 16-hydroxyhexadecanoate Chemical compound COC(=O)CCCCCCCCCCCCCCCO AOTMRIXFFOGWDT-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- NQLIIKFWBDSAQK-UHFFFAOYSA-N 1-hexadecoxy-3-(2-hydroxyethylamino)propan-2-ol Chemical compound CCCCCCCCCCCCCCCCOCC(O)CNCCO NQLIIKFWBDSAQK-UHFFFAOYSA-N 0.000 description 3
- 206010013786 Dry skin Diseases 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 235000004626 essential fatty acids Nutrition 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229940032094 squalane Drugs 0.000 description 3
- 235000015961 tonic Nutrition 0.000 description 3
- 230000001256 tonic effect Effects 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010016260 Fatty acid deficiency Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000000284 resting effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- YZUMRMCHAJVDRT-UHFFFAOYSA-N 2-(hexadecoxymethyl)oxirane Chemical compound CCCCCCCCCCCCCCCCOCC1CO1 YZUMRMCHAJVDRT-UHFFFAOYSA-N 0.000 description 1
- YGSDEFSMJLZEOE-RHRFEJLCSA-N 2-hydroxybenzoic acid Chemical compound OC(=O)[14C]1=CC=CC=C1O YGSDEFSMJLZEOE-RHRFEJLCSA-N 0.000 description 1
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 1
- 101150032866 CDC11 gene Proteins 0.000 description 1
- 241000257411 Hygrophila difformis Species 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010039792 Seborrhoea Diseases 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 239000003212 astringent agent Substances 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008271 cosmetic emulsion Substances 0.000 description 1
- 239000008406 cosmetic ingredient Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- RVWOWEQKPMPWMQ-UHFFFAOYSA-N methyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OC RVWOWEQKPMPWMQ-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000037312 oily skin Effects 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003014 reinforcing effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000001732 sebaceous gland Anatomy 0.000 description 1
- 210000002374 sebum Anatomy 0.000 description 1
- 230000037075 skin appearance Effects 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960000716 tonics Drugs 0.000 description 1
- 230000005068 transpiration Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野〕
本発明は、新規なアミド誘導体、及びそれを含有する皮
膚外用剤、特に、角層のバリアー機能を本質的に改善（
正常なバリアー機能の維持、障害を受けたバリアー機能
の回復）し得る皮膚外用剤に関する。Detailed Description of the Invention (Industrial Field of Application) The present invention relates to a novel amide derivative and a skin external preparation containing the same, in particular a novel amide derivative that essentially improves the barrier function of the stratum corneum (
The present invention relates to an external skin preparation that can maintain normal barrier function and restore damaged barrier function.
角層は、皮膚の最表面にあって、体表面全体を覆い、体
外からの刺激や異物の侵入を防ぎ、また体内からの水分
の蒸散を防ぐ等の役割を果たしている。The stratum corneum is located on the outermost surface of the skin, covers the entire body surface, and plays the role of preventing external stimuli and foreign substances from entering the body, as well as preventing water evaporation from within the body.
しかし、何らかの原因によって角層のバリアー機能が弱
まると、皮膚に炎症が起きやすくなったリ、肌あれが生
じ易くなるなどの問題が起こる。However, if the barrier function of the stratum corneum is weakened for some reason, problems such as the skin becoming more prone to inflammation and roughness occur.
また、アラキドン酸やリノール酸などの必須脂肪酸を含
まない食物を摂取し続けるなどして体内で必須脂肪酸が
不足もしくは欠乏し、必須脂肪酸欠乏症になると、角層
のバリアー機能に障害が生じることが知られている。In addition, it is known that when essential fatty acids become insufficient or deficient in the body due to continuous intake of foods that do not contain essential fatty acids such as arachidonic acid and linoleic acid, the barrier function of the stratum corneum becomes impaired. It is being
そして、上記角層のバリアー機能の維持には、角層細胞
間の脂質、特にＯ−アシルセラミドが極めて重要な働き
を示すことが、細胞間の脂質の分析等の結果から明らか
となっている。The results of analyzes of intercellular lipids have shown that lipids between stratum corneum cells, especially O-acylceramide, play an extremely important role in maintaining the barrier function of the stratum corneum. .
また、皮脂腺から分泌される脂質が皮表で皮脂膜を形成
することにより、角層のバリアー機能の一部が補われる
とされており、従来、ワセリン等を配合した皮膚外用剤
等が、皮膚表面に被膜を形成させて角層のバリアー機能
を補充する目的で使用されている。In addition, it is believed that lipids secreted from sebaceous glands form a sebum film on the skin surface, which partially compensates for the barrier function of the stratum corneum. It is used to form a film on the surface and replenish the barrier function of the stratum corneum.
しかしながら、従来の皮膚外用剤等は、あくまでも一時
的に皮膚表面に被膜を形成させてバリアー機能を補充し
ているにすぎず、本質的に角層のバリアー機能を改善さ
せるものではなかった。However, conventional skin preparations only temporarily form a film on the skin surface to replenish the barrier function, but do not essentially improve the barrier function of the stratum corneum.
従って、本発明の目的は、角層の正常なバリアー機能を
維持することができ、また障害を受けたバリアー機能を
回復することのできる皮膚外用剤、即ち、角層のバリア
ー機能を本質的に改善でき、炎症や肌あれ等を起こし難
くする皮膚外用剤を提供することにある。Therefore, an object of the present invention is to provide an external skin preparation that can maintain the normal barrier function of the stratum corneum and restore the impaired barrier function, that is, essentially improve the barrier function of the stratum corneum. To provide an external skin preparation that can improve the skin's appearance and make inflammation, rough skin, etc. less likely to occur.
本発明者らは、上記目的を達成すべく鋭意研究した結果
、下記一般式（１）で表される新規アミド誘導体を含有
する皮１Ｇ外用剤が角層のバリアー機能を本質的に改善
できることを見出し、本発明を完成した。As a result of intensive research to achieve the above object, the present inventors have found that the skin 1G external preparation containing a novel amide derivative represented by the following general formula (1) can essentially improve the barrier function of the stratum corneum. The present invention has been completed.
Ｒ’０ＣＨｚ
Ｒ’Ｏ−Ｒ”−Ｃ−Ｎ−Ｃｉ（□
ＣＦ（２ＣＩ（、ＯＮ
（式中、Ｒ１は炭素数１０〜４０の直鎖若しくは分岐鎖
の飽和若しくは不飽和の炭化水素基を示し、Ｒ２は炭素
数３〜３９の直鎖若しくは分岐鎖の炭化水素基を示し、
Ｒ′は水素原子又は炭素数］Ｏ〜４０の直鎖若しくは分
岐鎖の飽和若しくは不飽和の炭化水素基若しくはアンル
基を示す、）即ち、本発明は、前記一般式Ｎ）で表わさ
れるアミド誘導体及びそれを含有する皮膚外用剤を提供
するものである。R'0CHz R'O-R"-C-N-Ci(□ CF(2CI(,ON and R2 represents a straight or branched hydrocarbon group having 3 to 39 carbon atoms,
R' represents a hydrogen atom or a linear or branched saturated or unsaturated hydrocarbon group having 0 to 40 carbon atoms, or an anlu group; and a skin external preparation containing the same.
以下、まず本発明のアミド誘導体について説明する。Hereinafter, first, the amide derivative of the present invention will be explained.
前記一般式四）で表わされる本発明のアミド誘導体は、
その製造法は特に限定されるものではなく、例えば、次
のｆｉｌ〜（３）の方法により製造することができる。The amide derivative of the present invention represented by the general formula 4) is
The manufacturing method thereof is not particularly limited, and for example, it can be manufactured by the following methods fil to (3).
１１）前記一般式（１）においてＲ３が水素原子である
アミド誘導体（１−Ａ）の製造方法：上記アミド誘導体
（Ｉ−Ａ）は、公知の方法〔例えば、特開昭６３−２１
６８５２号公報に記載の方法〕に準じて製造することが
できる。即ち、次に示される反応式に従ってグリシジル
エーテルとエタノールアミンから得られるアミンｍ１体
（「）に対して、塩基触媒の存在下でヒドロキシ脂肪酸
低級アルキルエステル（Ｉｆｆ−Ａ）又はヒドロキシ脂
肪酸ラクトン（ｒＶ）を作用させ、生成する低級アルコ
ールを留去しつつ反応させることにより製造することが
できる。11) Method for producing an amide derivative (1-A) in which R3 is a hydrogen atom in the general formula (1): The above amide derivative (IA) can be produced by a known method [for example, JP-A-63-21
It can be produced according to the method described in Japanese Patent No. 6852]. That is, in the presence of a base catalyst, hydroxy fatty acid lower alkyl ester (Iff-A) or hydroxy fatty acid lactone (rV) is converted to amine m1 body ('') obtained from glycidyl ether and ethanolamine according to the reaction formula shown below. can be produced by reacting while distilling off the lower alcohol produced.
Ｃ１１ｌＣＩｌｔＯ１＋
又は １１０−Ｒ” Ｃ−Ｎ−ＣＨｚ（式中、
Ｒ１及びＲ２は前記一般式（１）における場合と同じ意
味を表わしＲ４は炭素数１〜５のフルキル基を示す。）
（２）前記一般式（Ｉ）においてＲ３が炭素数１０〜４
０の直鎖若しくは分岐鎖の飽和若しくは不飽和の炭化水
素基であるアミド誘導体（ｆ−８）の製造方法：
上記アミド誘導体（１−Ｂ）は、次に示される反応式に
従って、ヒドロキシ脂肪酸（ＩＩＩ）若しくはヒドロキ
シ脂肪酸エステル（ＩＩＩ−Ａ）とアルキルハライド（
Ｖ）Ｍしくはスルホン酸アルキルエステル（Ｖｌ）とを
塩基の存在下で反応させることによりエーテル化脂肪酸
エステル（ＩＩＩ−Ｂ）を得、こ坑と前記（１）の方法
で得られるアミン誘導体（ｎ）とを塩基触媒存在下で作
用させ、生成するアルコールを留去しつつ反応させるこ
とにより、製造することができる。C111CIltO1+ or 110-R" C-N-CHz (in the formula,
R1 and R2 have the same meanings as in the general formula (1), and R4 represents a furkyl group having 1 to 5 carbon atoms. ) (2) In the general formula (I), R3 has 10 to 4 carbon atoms.
Method for producing amide derivative (f-8) which is a straight chain or branched saturated or unsaturated hydrocarbon group of 0: The above amide derivative (1-B) is prepared by preparing a hydroxy fatty acid ( III) or hydroxy fatty acid ester (III-A) and alkyl halide (
V) Etherified fatty acid ester (III-B) is obtained by reacting M or a sulfonic acid alkyl ester (Vl) in the presence of a base, and the amine derivative (III-B) obtained by the method (1) above is obtained. n) in the presence of a base catalyst, and can be produced by reacting while distilling off the alcohol produced.
■
ＣＨｚＣｔｌｚＯＨ（■）
（式中、Ｒ１，Ｒ２及びＲ４は前記ｆｉｌの反応式にお
ける場合と同じ青味を表わし、Ｒ３は炭素数１０〜４０
の直鎖若しくは分岐鎖の飽和若しくは不飽和の炭化水素
基を示し、Ｒ５はメチル基、フェニル基又はｐ−トルイ
ル基を示す。また、ＸはＣｌ５Ｂｒ又は■を示す、）
（３）前記一般式（１）においてＲ３が炭素数１０〜４
０の直鎮若しくは分岐鎖の飽和若しくは不飽和のアンル
基であるアミド誘導体（１−Ｃ）の製造方法：
上記アミド誘導体（１−Ｃ，）は、次に示される反応式
に従って、ヒドロキシ脂肪酸エステル（■−Ａ）と脂肪
酸（■）とを適当な脱水剤〔例えば、８１０ Ｃ−Ｎ
＝ Ｎ −ＣＯＥＬ及びＰ （Ｃｂ Ｉｔ Ｓ） ３）
の存在下に縮合させてアシル脂肪酸エステル（ｍ −Ｃ
）とし、これと前記（１）の方法で得られるアミンｉＦ
’ｒＲ体（ＩＩ）とを塩基触媒存在下で作用させ、生成
するアルコールを留去しつつ反応させることにより、製
造することができる。■ CHzCtlzOH (■) (In the formula, R1, R2 and R4 represent the same blue tint as in the reaction formula of fil, and R3 has a carbon number of 10 to 40
represents a straight chain or branched chain saturated or unsaturated hydrocarbon group, and R5 represents a methyl group, phenyl group or p-tolyl group. (X represents Cl5Br or ■) (3) In the general formula (1), R3 has 10 to 4 carbon atoms
Method for producing an amide derivative (1-C), which is a straight or branched saturated or unsaturated amyl group of (■-A) and fatty acid (■) using a suitable dehydrating agent [for example, 810 C-N
= N-COEL and P (Cb It S) 3)
was condensed in the presence of acyl fatty acid ester (m-C
), and the amine iF obtained by this and the method (1) above
It can be produced by reacting with 'rR form (II) in the presence of a base catalyst and distilling off the alcohol produced.
（■）
（ＩＩ）
（式中、Ｒ１、Ｒ２及びＲ４は前記＋１１の反応式にお
ける場合と同じ意味を表わし、Ｒ”は炭素数９〜３９の
直鎖若しくは分岐鎖の飽和若しくは不飽和の炭化水素基
を示す。）
次に、上述の本発明のアミＦＰＩＥ体を含有する本発明
の皮膚外用剤について説明する。(■) (II) (In the formula, R1, R2 and R4 represent the same meanings as in the reaction formula of +11 above, and R'' is a linear or branched saturated or unsaturated carbonized carbon having 9 to 39 carbon atoms. (Indicates a hydrogen group.) Next, the skin external preparation of the present invention containing the above-mentioned ami-FPIE compound of the present invention will be described.
本発明のアミド誘導体を本発明の皮膚外用剤として用い
る場合の配合量は、特に制限されないが、通常、乳化型
の皮膚外用剤の場合には全組成の０．００１〜５０重量
％（以下、単に％で示す）が好ましく、スクワラン等の
液状炭化水素を基剤とする油性の皮膚外用剤の場合には
０゜０１〜５０％が好ましい。The amount of the amide derivative of the present invention used as the skin external preparation of the present invention is not particularly limited, but in the case of an emulsion type skin external preparation, it is usually 0.001 to 50% by weight of the total composition (hereinafter referred to as (Simply expressed as %) is preferred, and in the case of oily skin external preparations based on liquid hydrocarbons such as squalane, 0.01 to 50% is preferred.
本発明の皮膚外用剤は、従来の皮膚外用剤の基剤に前記
一般式（Ｉ＞で表されるアミド誘導体を含有させてなる
もので、その使用形態において、薬用皮膚外用剤と化粧
料に大別される。The external skin preparation of the present invention contains the amide derivative represented by the general formula (I>) in the base of a conventional skin external preparation. Broadly classified.
薬用皮膚外用剤としては、例えば、薬効成分を含有する
各種軟膏剤を挙げることができる。軟膏剤としては、油
性基剤をヘースとするもの、油／水、水／油型の乳化系
基剤をヘースとするもののいずれであってもよい。上記
油性基剤としては、特に制限はなく、例えば、植物油、
動物油、合成油、脂肪酸、及び天然又は合成のグリセラ
イド等が挙げられる。また、上記薬効成分としては、特
に制限はなく、例えば、鎮痛消炎剤、鎮序剤、殺菌消毒
剤、収斂剤、皮膚軟化剤、ホルモン剤等を必要に応じて
適宜使用することができる。Examples of medicated skin preparations include various ointments containing medicinal ingredients. The ointment may be one having an oil base as a base, or one having an oil/water or water/oil type emulsion base as a base. The oily base is not particularly limited and includes, for example, vegetable oil,
Examples include animal oils, synthetic oils, fatty acids, natural or synthetic glycerides, and the like. The medicinal ingredients are not particularly limited, and for example, analgesic and anti-inflammatory agents, anti-inflammatory agents, sterilizing agents, astringents, emollients, hormonal agents, etc. can be used as appropriate.
また、化粧料として使用する場合は、必須成分である本
発明のアミド誘導体の他に、化粧料成分として一般に使
用されている油分、保湿剤、紫外線吸収剤、アルコール
類、キレート剤、ｐ）ｌ調整剤、防腐剤、増粘剤、色素
、香料等を任意に組み合わせて配合することができる。When used as a cosmetic, in addition to the amide derivative of the present invention, which is an essential ingredient, oils, humectants, ultraviolet absorbers, alcohols, chelating agents, p)l, etc. commonly used as cosmetic ingredients, etc. Conditioners, preservatives, thickeners, pigments, fragrances, etc. can be blended in any combination.
化粧料としては、種々の形態、例えば、水／油、油／水
型乳化化粧料、クリーム、化粧乳液、化粧水、油性化粧
料、口紅、ファンデーション、皮１洗浄剤、ヘアートニ
ック、整髪剤、養毛剤、育毛剤等の皮膚化粧料とするこ
とができる。Cosmetics can be used in various forms, such as water/oil, oil/water type emulsified cosmetics, creams, cosmetic emulsions, lotions, oil-based cosmetics, lipsticks, foundations, skin cleansers, hair tonics, hair styling products, It can be used as a skin cosmetic such as a hair tonic or a hair tonic.
前記一般式（りで表される本発明のアミド誘導体を含有
する皮膚外用剤の作用機構の詳細は完全には解明されて
いないが、皮ａ外用剤として皮膚に適用されることによ
り、角質細胞間の脂質膜を補強して角層のバリアー機能
を改善するものと推察される。Although the details of the mechanism of action of the skin external preparation containing the amide derivative of the present invention represented by the general formula (R) have not been completely elucidated, when applied to the skin as a skin a external preparation, the keratinocytes It is thought to improve the barrier function of the stratum corneum by reinforcing the lipid membrane between them.
次に、実施例を挙げて本発明を更に詳しく説明する。 Next, the present invention will be explained in more detail with reference to Examples.
実施例Ｉ
Ｎ−−ヒドロキシ−３−ヘキサ−゛シロキシプロピル
−Ｎ−２−ヒ゛ロキシエチル−１２−ヒ′ロキシオ
−′カン ミ １１．二毀弐」ユＨ
■
ＣＨＣＩ（−で るアミドｆシＬ幻−はニノ山ユ辺治迩
し
■ Ｎ−（２−ヒドロキシ−３−ヘキサデシロキシプロ
ビル）エタノールアミン（Ｉｌａ）の合成：
撹拌装置、滴下漏斗、温度計及び還流冷却器を備えた２
００ＩＲ１４ツロフラスコにエタノールアミン６１．
１ ｇ （１，０ｍｏｌ）を入れ、６０〜７０℃に加熱
攪拌しつつ、これにヘキサデシルグリシジルエーテル２
４．３ ｇ （０，０８２ｍｏｌ）を４５分かけて滴下
した。滴下終了後、更に同条件下で２時間加熱攪拌し、
未反応のエタノールアミンを減圧下に留去（７９〜８１
℃／ ２０ Ｔｏｒｒ） した。残渣をシリカゲルフラ
ッシュカラムクロマトグラフィーで精製することにより
、標記化合物（■ａ）１８゜４ｇを得た（収率６３％）
、尚、得られた化合物の’Ｈ−ＮＭＩ？の測定結果は次
の通りであった。Example I N-hydroxy-3-hex-siloxypropyl
-N-2-hydroxyethyl-12-hydroxy
-'Kan Mi 11. Synthesis of N-(2-hydroxy-3-hexadecyloxypropyl)ethanolamine (Ila): 2 equipped with a stirrer, dropping funnel, thermometer and reflux condenser
Ethanolamine 61.00IR14 in Tulo flask.
1 g (1.0 mol) and heated to 60 to 70°C while stirring, add 2 hexadecyl glycidyl ether.
4.3 g (0,082 mol) was added dropwise over 45 minutes. After the dropwise addition was completed, the mixture was further heated and stirred for 2 hours under the same conditions.
Unreacted ethanolamine was distilled off under reduced pressure (79-81
℃/20 Torr). The residue was purified by silica gel flash column chromatography to obtain 18.4 g of the title compound (■a) (yield 63%).
, Furthermore, 'H-NMI?' of the obtained compound? The measurement results were as follows.
’Ｈ−ＮＭＲ（δ、 ＣＤＣ１１） ：０．８５
（ｔ、 ３Ｈ） 、１．２３ （ｂｓ、 ２
８Ｈ） 、 ２．６〜２．８ （ｍ、 ４Ｈ）
、 ３．１〜３．９ （ｍ、 ｌ０Ｈ）
■ アミド誘導体（ｆ−Ａａ）の合成：攪拌装置、滴下
ロート、温度計及び蒸溜装置を備えた１０（ｌｄフラス
コに、上記■で得た化合物（■ａ）１７．３ ｇ（４８
ｍ ｍｏｌ）及びＫＯＨｏ、１４ｇ （２，５ｍ ｍｏ
ｌ）を仕込み、８０℃／ ２０ Ｔｏｒｒで減圧下に加
熱攪拌しつつ、１２−ヒドロキシオクタデカン酸メチル
１５．１ｇ （４８ｍ ｍｏｌ）を１時間かけて滴下し
た０滴下終了後、更に同条件下で１時間攪拌し、得られ
た粗生成物をシリカゲルフラッシュカラムクロマトグラ
フィーで精製することにより、標記化合物（１−Ａａ）
２３．０ ｇを得た（収率７４％）、得られた化合物の
融点、ＩＲ及び’Ｈ−ＮＭＲの測定結果は次の通りであ
った。'H-NMR (δ, CDC11): 0.85
(t, 3H) , 1.23 (bs, 2
8H), 2.6-2.8 (m, 4H)
, 3.1 to 3.9 (m, 10H) ■ Synthesis of amide derivative (f-Aa): Into a 10 (ld) flask equipped with a stirring device, a dropping funnel, a thermometer, and a distillation device, add the compound obtained in step (1) above. (■a) 17.3 g (48
m mol) and KOHo, 14 g (2,5 m mol)
1) was prepared, and 15.1 g (48 mmol) of methyl 12-hydroxyoctadecanoate was added dropwise over 1 hour while heating and stirring under reduced pressure at 80°C/20 Torr. The title compound (1-Aa) was obtained by stirring for hours and purifying the obtained crude product by silica gel flash column chromatography.
23.0 g (yield 74%) was obtained. The melting point, IR and 'H-NMR measurement results of the obtained compound were as follows.
融点ニアｏ、ａ〜７１．３℃
ＩＲ：３３５２．２９２６．２８５４．１６１７゜１４
７３．１１２２．１０７７Ｃ１１−’薯Ｈ−ＮＭＲ（δ
、 ＣＤＣｌ５） ：０．８８（ｔ、 Ｊ＝６．
３Ｈｚ、 ６Ｈ）、１，１２〜１．８２（ｍ、 ５
６ Ｈ）、２．２４〜２．５１（ｍ、２！＋）、３．２
３〜４．３０ （ｍ、 １５Ｈ）
実施例２
実施例１の■で得たアミン（Ｉｌａ）と１６−ヒトロキ
シヘキサデカン酸メチルとを実施例１の■と同様の方法
で反応させ、無色粉末の目的化合物（１−Ａｂ）を得た
（収率７５％）。得られた化合物の融点、ＩＲ及び’Ｈ
−ＮＭＲの測定結果は次の通りであった。Melting point near o, a ~ 71.3°C IR: 3352.2926.2854.1617°14
73.1122.1077C11-' 薯H-NMR(δ
, CDCl5): 0.88 (t, J=6.
3Hz, 6H), 1,12~1.82(m, 5
6 H), 2.24-2.51 (m, 2!+), 3.2
3-4.30 (m, 15H) Example 2 The amine (Ila) obtained in Example 1 (■) and methyl 16-hydroxyhexadecanoate were reacted in the same manner as in Example 1 (■) to form a colorless powder. The target compound (1-Ab) was obtained (yield 75%). Melting point, IR and 'H of the obtained compound
-NMR measurement results were as follows.
融点：ＳＯ，６〜８１．５℃
ｌＲ１３７０，２９２０，２８５４，１６２６゜１５９
６．１４７３．１１３１．１０６２、１２３ｃｍ−’
’Ｈ−ＮＭＲ（δ、ＣＤＣｌ、）：
０．８８（ｔ、Ｊ＝６．６ｔｌｚ、３Ｈ）、０．９６〜
１．８０（ｍ、 ５４旧、２．３０〜２．４８（ｍ、２
旧、３．２４〜４．１７ （ｍ、 ｌ ５Ｈ）
実施例３
■ １６− （９Ｚ、１２２−オクタデカジエニロキシ
）ヘキサデカン酸メチル（Ｉ［Ｉ−Ｂａ）の合成：攪拌
装置、滴下ロート、温度計及び還流冷却器を備えた３
００ｄ４ツロフラスコに、１６−ヒトロキシヘキサテカ
ン酸２．７２８ （ｌ Ｏｍｍｏｌ）、無水テトラヒ
ドロフラン５０−１無水ヘキサメチルホスホリルトリア
ミド５＃＋！及び水素化ナトリウム０．２４ ｇ （１
０ｍ ｍｏｌ）を入れ、Ｎｔ気流下、室温で３０分間攪
拌した０次いで、この混合物を一７０℃まで冷却し、！
、６Ｎブチルリチウムヘキサン溶液６．２５ｍ１（ｌ
Ｏｍ ｍｏｌ）を加えた後、３０分かけて室温まで加温
し、ここで水素化ナトリウム０．２４ ｇ （１０ｍ
ｍｏｌ）を加えてさらに３０分間室温で攪拌した０次に
、ここにｐ−トルエンスルホン１９Ｚ、１２２−オクタ
デカジェニルエステル９．２５ ｇ （２２ｍ ＋ｗｏ
ｌ）を滴下し、６５℃で１８時間加熱攪拌し、次いでこ
の反応混合物に無水メタノール１５０−を加え、更に６
５℃で１時間攪拌した。反応混合物を室温まで冷却後、
塩化アンモニウム水溶液で過剰のアルカリを中和し、ト
ルエンで反応混合物を抽出し、溶媒を減圧留去後、残渣
をフラッシュカラムクロマトグラフィーで精製すること
により、標記化合物（ＩＩＩ−Ｂａ）０、７２ ｇを得
た（収率１３．５％）。Melting point: SO, 6-81.5°C lR1370, 2920, 2854, 1626°159
6.1473.1131.1062, 123 cm-'' H-NMR (δ, CDCl, ): 0.88 (t, J = 6.6 tlz, 3H), 0.96 ~
1.80 (m, 54 old, 2.30-2.48 (m, 2
Old, 3.24-4.17 (m, l 5H) Example 3 ■ Synthesis of methyl 16-(9Z, 122-octadecadienyloxy)hexadecanoate (I[I-Ba): Stirring device, dropping funnel , equipped with a thermometer and a reflux condenser.
00d4 Turow flask, 2.728 (l Ommol) of 16-hydroxyhexatecanoic acid, anhydrous tetrahydrofuran 50-1 anhydrous hexamethylphosphoryltriamide 5#+! and sodium hydride 0.24 g (1
0m mol) and stirred at room temperature for 30 minutes under a Nt stream.Then, this mixture was cooled to -70°C, and!
, 6.25 ml (l) of 6N butyllithium hexane solution
After adding 0.24 g of sodium hydride (10 m
Next, 9.25 g of p-toluenesulfone 19Z, 122-octadecagenyl ester (22 m
1) was added dropwise, and the mixture was heated and stirred at 65°C for 18 hours. Then, 150% of anhydrous methanol was added to the reaction mixture, and further 60% of anhydrous methanol was added to the reaction mixture.
The mixture was stirred at 5°C for 1 hour. After cooling the reaction mixture to room temperature,
The excess alkali was neutralized with an aqueous ammonium chloride solution, the reaction mixture was extracted with toluene, the solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography to obtain 0.72 g of the title compound (III-Ba). was obtained (yield 13.5%).
■ アミド誘導体（１−Ｂａ）の合成：上記■で得た化
合物（［［Ｉ−Ｂａ）と実施例ｉの■で得たアミン（■
ａ）とを実施例１の■と同様の方法で反応させ、無色粉
末の目的化合物（Ｔ−Ｂａ）を得た（収率７１％）。得
られた化合物の融点、ＩＲ及び’Ｈ−ＮＭＲの測定結果
は次の通りであった。■ Synthesis of amide derivative (1-Ba): Compound ([[I-Ba) obtained in step (1) above and amine (1-Ba) obtained in step (■) of Example i]
a) was reacted in the same manner as in Example 1 (2) to obtain the target compound (T-Ba) as a colorless powder (yield 71%). The melting point, IR and 'H-NMR measurement results of the obtained compound were as follows.
融点：６３．０〜６４．３℃
ＩＲ：３３０４．２９２０．２８５４．１６１４．１４
６７．１１１６．１０６２．７２０１−１’Ｈ−ＮＭＲ
（δ、ＣＤＣ１ｄ ：
０．８０〜０．９５ （ｍ、 ６ Ｈ） 、０．９
５〜１．７０ （ｍ、 ７２Ｈ） 、１．９５〜２
．１２（ｍ、４Ｈ） 、２．３９ （ｔ、Ｊ＝１．Ｉ
Ｈｔ、。Melting point: 63.0-64.3°C IR: 3304.2920.2854.1614.14
67.1116.1062.7201-1'H-NMR
(δ, CDC1d: 0.80-0.95 (m, 6H), 0.9
5-1.70 (m, 72H), 1.95-2
．． 12 (m, 4H), 2.39 (t, J=1.I
Ht.
２Ｈ） 、２．７７ （ｂ ｔ、 Ｊ ＝５．７Ｈ
ｚ、 ２Ｈ） 、３．３９ （ｔ、Ｊ＝６．６Ｈｚ
、４Ｈ）、３．２３〜４．２３ （ｍ、 ｌ ３
Ｈ） 、５．２４〜５．４４ （ｍ、４Ｈ）
実施例４
■ １６− （９Ｚ、１２２−オクタデカジェノイルオ
キシ）ヘキサデカン酸メチル（１−Ｃａ）の合成：
攪拌装置、滴下ロート及び温度計を備えた３００−フラ
スコに、１６−ヒトロキシヘキサデカン酸メチル４．３
０ ｇ （１５ｍ ｍｏｌ） 、リノール酸８．４１
ｇ （１３ｍ ５ｏｌ） 、）す７ ｚ 二）Ｌｉホ
スフィン７．８７ ｇ （３０ｍ ｍｏｌ）及びテトラ
ヒドロフラン１００−を仕込み、室温で攪拌下にアゾジ
カルボン酸ジエチル５．２２ ｇ （３０ｎ ５ｏｌ）
を１時間かけて滴下した０滴下終了後、更に室温で４時
間攪（↑した後、溶媒を減圧下に留去し、残渣をシリカ
ゲルフラッシュクロマトグラフィーで精製することにり
、標記化合物（ＩＩＩ−Ｃａ） ６．７６ ｇを得た（
収率８２％）。2H), 2.77 (b t, J = 5.7H
z, 2H), 3.39 (t, J=6.6Hz
, 4H), 3.23-4.23 (m, l 3
H) , 5.24-5.44 (m, 4H) Example 4 ■ Synthesis of methyl 16-(9Z, 122-octadecajenoyloxy)hexadecanoate (1-Ca): Stirring device, dropping funnel, and temperature 4.3 methyl 16-hydroxyhexadecanoate in a 300 flask equipped with a
0 g (15 mmol), linoleic acid 8.41
g (13m 5ol),)su7z 2) Li phosphine 7.87g (30mmol) and tetrahydrofuran 100- are charged, and diethyl azodicarboxylate 5.22g (30n 5ol) is added under stirring at room temperature.
was added dropwise over 1 hour. After stirring for 4 hours at room temperature, the solvent was distilled off under reduced pressure and the residue was purified by silica gel flash chromatography to obtain the title compound (III- 6.76 g of Ca) was obtained (
yield 82%).
■ アミド誘導体（Ｉ−〇ａ）の合成：攪拌装置、滴下
ロート、温度計及び蒸溜装置を備えた５０−フラスコに
、上記■で得た化合物（ＩＩＩ−Ｃａ）２．７４ ｇ
（５ｍ ｍｏり 、実施例１の■で得たアミン（ＩＩ
ａＮ、８０ ｇ（５ｍ ｍｏｌ）及びカリウムｔｅｒ
ｔ−ブトキシド０．０２８ ｇ （０，２５ｍａｎａｌ
）を仕込み、８０ ’ｃ／ ２０Ｔｏｒｒの減圧下で３
０分間加熱攪拌した。得られた粗生成物をシリカゲルカ
ラムクロマトグラフィー及びゲルクロマトグラフィーで
精製することにより、標記化合物（１−Ｃａ）１．６５
ｇを得た（収率３８％）。得られた化合物の融点、＋
Ｒ，’Ｈ−ＮＭＲ及びＭＳの測定結果は次の通りであっ
た。■ Synthesis of amide derivative (I-○a): In a 50-flask equipped with a stirring device, dropping funnel, thermometer, and distillation device, 2.74 g of the compound (III-Ca) obtained in step (1) above was placed.
(5 m mole, amine (II) obtained in Example 1
aN, 80 g (5 mmol) and potassium ter
t-butoxide 0.028 g (0.25 manal
) and heated under reduced pressure of 80'c/20Torr.
The mixture was heated and stirred for 0 minutes. The obtained crude product was purified by silica gel column chromatography and gel chromatography to obtain the title compound (1-Ca) 1.65
g (yield 38%). The melting point of the compound obtained, +
The measurement results of R,'H-NMR and MS were as follows.
融点：５８．２〜５８．９℃
ＩＲ： ３３０４．２９２０．２８５６．１７３４．１
６１２．１４６４．１４４０．１２１６．１ １ Ｇ
６．１ １０８．７５６．７２０ｃｍ−’ＩＨ−ＮＭＲ
（δ、ＣＤＣｌ５） ：０．８０〜１．００ （ｍ
、 ６Ｈ） 、１．００〜１．７３ （ｍ、
６０ ［１） 、１．９５〜２．１６（ｍ、 ４［
（） 、２．２８ （ｔ、 Ｊ＝７．５１１ｚ。Melting point: 58.2-58.9°C IR: 3304.2920.2856.1734.1
612.1464.1440.1216.1 1 G
6.1 108.756.720cm-'IH-NMR
(δ, CDCl5): 0.80 to 1.00 (m
, 6H), 1.00-1.73 (m,
60 [1), 1.95-2.16 (m, 4 [
(), 2.28 (t, J=7.511z.
２Ｈ） 、２．３９ （ｂ ｔ、 Ｊ＝７．７１
１ｚ、 ２ｔ（） 、２．７７（ｂ ｔ、 Ｊ＝５
．９１１ｚ、 ２Ｈ）、３．２３〜４．２５ （ｍ
、 １：ＨＩ） 、４．０５（ｔ、 Ｊ＝６．６
１１ｚ、 ２１ｒ） 、５．２６〜５．４７ （
ｍ、 ４Ｈ）
ＭＳ （ＦＡＢ、 ＰＯ３） ：８７７ （Ｍ
＋１）、８５９．６３４．５９６．３６０
（ＦＡＢ、 ＮＥＣ） ：
８７５ （Ｍ−１）、８７３．８３１．６１３．５３
４．３５９．３０５．２７９実施例５
下記第１表に示す本発明のアミド誘導体１０％及びスク
ワラン９０％からなる本発明の皮膚外用剤をそれぞれ製
造し、これらの皮膚外用剤につぃて、下記の試験方法に
より経表皮水分奈ｎシ量及び経皮吸収量を評価した。ま
た、比較としてスクワランのみからなる皮膚外用剤（比
較品）についても同様の試験を行った。その結果を下記
第１表に示す。2H), 2.39 (b t, J=7.71
1z, 2t(), 2.77(b t, J=5
．． 911z, 2H), 3.23~4.25 (m
, 1:HI), 4.05(t, J=6.6
11z, 21r), 5.26-5.47 (
m, 4H) MS (FAB, PO3): 877 (M
+1), 859.634.596.360 (FAB, NEC): 875 (M-1), 873.831.613.53
4.359.305.279 Example 5 The external skin preparations of the present invention consisting of 10% of the amide derivative of the present invention and 90% of squalane as shown in Table 1 below were manufactured, and for these external skin preparations, Transepidermal moisture content and transdermal absorption were evaluated using the following test methods. For comparison, a similar test was also conducted on a skin external preparation (comparative product) consisting only of squalane. The results are shown in Table 1 below.
（試験方法）
必須脂肪酸を含まない飼料のみでウィスター（縁１ｓＬ
ｅｒ）系別性ラットを飼育し、必須脂肪酸欠乏症の症状
が現れたラットに対し、剃毛した背部皮膚に皮膚外用剤
を１日１回３週間塗布する。３週間の塗布が終了した翌
日に次の項目について試験を行った。(Test method) Wistar (Edge 1sL) using only feed that does not contain essential fatty acids
er) Rats of different sexes are bred, and for rats showing symptoms of essential fatty acid deficiency, a topical skin preparation is applied to the shaved back skin once a day for 3 weeks. The next day after the three-week application was completed, the following tests were conducted.
尚、皮膚外用剤それぞれについてラット３匹ずつを試験
に供した。In addition, three rats were used for the test for each topical skin preparation.
（１）経表皮水分藤１１３！量
３７℃の温水でラットの背部皮膚を洗浄後、温度２０℃
及び湿度４５％の部屋で１時間安静な状態においた後、
表皮からの水分藩敗量をエバポリメーターにて測定した
。この水分渾敗量の値が大きいほど角層のバリアー機能
が低下しており、肌あれが生じていることを示す。(1) Transepidermal water wisteria 113! After washing the rat's back skin with warm water at 37°C, the temperature was 20°C.
And after leaving it in a resting state for 1 hour in a room with a humidity of 45%,
The amount of water absorbed from the epidermis was measured using an Evapolymeter. The larger the value of the water loss amount, the lower the barrier function of the stratum corneum, indicating that rough skin is occurring.
正常なバリアー機能が維持されている場合、この値は１
０以下となるが、バリアー機能が障害を受けた必須脂肪
酸欠乏症のラットでは３５以上となる。測定値は平均値
上標準偏差で示した。If normal barrier function is maintained, this value is 1.
It is less than 0, but it is more than 35 in rats with essential fatty acid deficiency where the barrier function is impaired. Measured values are expressed as the average value and standard deviation.
（２）経皮吸収量
３７℃の温水でラットの背部皮膚を洗浄後、該皮膚を切
り取り、経皮吸収チャンバーに表皮側を上にしてはさみ
込む。下部受器にはリン酸緩衝平衡塩類溶液を満たし、
表皮側容器には３７ＫＢｑの１４Ｃ−サリチル酸を含む
溶剤１１Ｒ１を入れる。２時間後に下部受器中に浸透し
た１４ｃｍサリチル酸量を測定する。正常なバリアー機
能が維持されている場合、２時間ではほとんど浸透せず
、バリアー機能の障害が大きいほどこの値は大きくなる
。(2) Transdermal Absorption Amount After washing the rat's back skin with warm water at 37°C, cut out the skin and place it in a transdermal absorption chamber with the epidermis side up. Fill the lower reservoir with phosphate buffered balanced salt solution,
A solvent 11R1 containing 37 KBq of 14C-salicylic acid is placed in the epidermis side container. After 2 hours, the amount of 14 cm of salicylic acid that has permeated into the lower receiver is measured. When normal barrier function is maintained, there is almost no penetration within 2 hours, and this value increases as the barrier function is impaired.
第１表
実施例６
本発明のアミド誘導体を用いて、下記第２表に示す組成
の本発明の皮膚外用剤（乳化化粧料）をそれぞれ製造し
、その肌あれ改善効果を下記の試験方法により評価した
。また、比較として本発明のアミド誘導体を含まない皮
膚外用剤（比較品）についても同様の試験を行った。そ
の結果を下記第３表に示す。Table 1 Example 6 Using the amide derivatives of the present invention, external skin preparations (emulsified cosmetics) of the present invention having the compositions shown in Table 2 below were manufactured, and their rough skin improving effects were evaluated by the following test method. evaluated. In addition, for comparison, a similar test was conducted on a skin external preparation (comparative product) that does not contain the amide derivative of the present invention. The results are shown in Table 3 below.
（試験方法）
冬期に頬部に肌あれを起こしている２０〜４０才の女性
１０名を被験者とし、左右の頬に異なる皮膚外用剤を１
日１回３週間塗布する。３週間の塗布が終了した翌日に
次の項目について試験を行った。(Test method) Ten women between the ages of 20 and 40 who suffer from rough skin on their cheeks during the winter were used as subjects, and a different topical skin preparation was applied to each cheek.
Apply once a day for 3 weeks. The next day after the three-week application was completed, the following tests were conducted.
（１）経表皮水分蒸散量
３７℃の温水で洗ｆｊＢ後、温度２０℃及び湿度４５％
の部屋で３０分間安静にした後、表皮からの水分蒸散量
をエバポリメーターにて測定した。この水分蒸散量の値
が大きいほど角層のバリアー機能が低下しており、肌あ
れが生していることを示す。この値が４０を超えるとひ
どい肌あれであり、肌あれがほとんど認められない場合
は１０以下となる。測定値は平均埴土標準偏差で示した
。(1) Transepidermal water transpiration After washing fjB with warm water of 37°C, temperature 20°C and humidity 45%
After resting in a room for 30 minutes, the amount of water evaporated from the epidermis was measured using an Evapolymeter. The larger the value of the amount of water evaporation, the lower the barrier function of the stratum corneum, indicating that the skin becomes rough. If this value exceeds 40, the skin is severely rough, and if the skin roughness is hardly observed, the value is 10 or less. Measured values are expressed as average clay standard deviation.
（２）肌あれスコア
肌あれを肉眼で観察し、下記基準により判定した。スコ
アは平均値±４Ｉ準偏差で示した。(2) Skin roughness score Skin roughness was observed with the naked eye and judged according to the following criteria. Scores were expressed as mean ± 4I standard deviation.
スコア 肌あれ判定
Ｏ肌あれを認めない
■ かすかに肌あれを認める
２ 肌あれを認める
３ ややひどい肌あれを認める
４ ひどい肌あれを認める
第３表
〔発明の効果］
本発明のアミド誘導体を含有する皮膚外用剤は、角層の
バリアー機能を本質的に改善できる効果を存するもので
、皮膚に適用することにより、炎症や肌あれ等を起こし
難くすることができる。Score Rough skin: O No rough skin ■ Slightly rough skin 2 Some rough skin 3 Somewhat severe rough skin 4 Severe rough skin Table 3 [Effects of the invention] Contains the amide derivative of the present invention The external skin preparation has the effect of essentially improving the barrier function of the stratum corneum, and by applying it to the skin, it can make it difficult to cause inflammation, rough skin, etc.
Claims (2)
鎖の飽和若しくは不飽和の炭化水素基を示し、Ｒ＾２は
炭素数３〜３９の直鎖若しくは分岐鎖の炭化水素基を示
し、Ｒ＾３は水素原子又は炭素数１０〜４０の直鎖若し
くは分岐鎖の飽和若しくは不飽和の炭化水素基若しくは
アシル基を示す。）(1) An amide derivative represented by the following general formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 represents a straight chain or branched chain saturated or unsaturated hydrocarbon group having 10 to 40 carbon atoms, and R^2 represents the number of carbon atoms. 3 to 39 straight chain or branched hydrocarbon group, R^3 represents a hydrogen atom or a straight chain or branched saturated or unsaturated hydrocarbon group or acyl group having 10 to 40 carbon atoms.)
含有する皮膚外用剤。 ▲数式、化学式、表等があります▼（ I ） （式中、Ｒ＾１は炭素数１０〜４０の直鎖若しくは分岐
鎖の飽和若しくは不飽和の炭化水素基を示し、Ｒ＾２は
炭素数３〜３９の直鎖若しくは分岐鎖の炭化水素基を示
し、Ｒ＾３は水素原子又は炭素数１０〜４０の直鎖若し
くは分岐鎖の飽和若しくは不飽和の炭化水素基若しくは
アシル基を示す。）(2) A skin external preparation containing an amide derivative represented by the following general formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 represents a straight chain or branched chain saturated or unsaturated hydrocarbon group having 10 to 40 carbon atoms, and R^2 represents the number of carbon atoms. 3 to 39 straight chain or branched hydrocarbon group, R^3 represents a hydrogen atom or a straight chain or branched saturated or unsaturated hydrocarbon group or acyl group having 10 to 40 carbon atoms.)
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12646289A JPH072698B2 (en) | 1989-05-19 | 1989-05-19 | Amide derivative and external preparation for skin containing the same |
| ES90109167T ES2058670T3 (en) | 1989-05-19 | 1990-05-15 | AMIDIC DERIVATIVES AND DERMATOLOGICAL PREPARATIONS THAT CONTAIN THEM. |
| AT90109167T ATE109767T1 (en) | 1989-05-19 | 1990-05-15 | AMIDE DERIVATIVES AND SKIN PREPARATIONS CONTAINING THEM. |
| EP90109167A EP0398272B1 (en) | 1989-05-19 | 1990-05-15 | Amide derivatives and dermatologic preparations containing the same |
| DE69011402T DE69011402T2 (en) | 1989-05-19 | 1990-05-15 | Amide derivatives and skin preparations containing them. |
| US07/524,864 US5175321A (en) | 1989-05-19 | 1990-05-18 | Amide derivatives and dermatologic preparations containing the same |
| US07/794,980 US5221757A (en) | 1989-05-19 | 1991-11-20 | Amide derivatives and dermatologic preparations containing the same |
| HK116296A HK116296A (en) | 1989-05-19 | 1996-07-04 | Amide derivatives and dermatologic preparations containing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12646289A JPH072698B2 (en) | 1989-05-19 | 1989-05-19 | Amide derivative and external preparation for skin containing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02306952A true JPH02306952A (en) | 1990-12-20 |
| JPH072698B2 JPH072698B2 (en) | 1995-01-18 |
Family
ID=14935817
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12646289A Expired - Lifetime JPH072698B2 (en) | 1989-05-19 | 1989-05-19 | Amide derivative and external preparation for skin containing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH072698B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0761644A3 (en) * | 1995-09-07 | 1999-04-07 | Kao Corporation | Amide derivatives and their use in cosmetic composition |
-
1989
- 1989-05-19 JP JP12646289A patent/JPH072698B2/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0761644A3 (en) * | 1995-09-07 | 1999-04-07 | Kao Corporation | Amide derivatives and their use in cosmetic composition |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH072698B2 (en) | 1995-01-18 |
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