JP2017100993A - グルタチオン産生促進剤 - Google Patents
グルタチオン産生促進剤 Download PDFInfo
- Publication number
- JP2017100993A JP2017100993A JP2015235117A JP2015235117A JP2017100993A JP 2017100993 A JP2017100993 A JP 2017100993A JP 2015235117 A JP2015235117 A JP 2015235117A JP 2015235117 A JP2015235117 A JP 2015235117A JP 2017100993 A JP2017100993 A JP 2017100993A
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- Prior art keywords
- group
- glutathione
- ring
- production promoter
- hydrocarbon group
- 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
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- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 title claims abstract description 140
- 229960003180 glutathione Drugs 0.000 title claims abstract description 70
- 108010024636 Glutathione Proteins 0.000 title claims abstract description 69
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 40
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 125000001424 substituent group Chemical group 0.000 claims abstract description 22
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 17
- 125000005843 halogen group Chemical group 0.000 claims abstract description 14
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract description 6
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 21
- 239000002537 cosmetic Substances 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 8
- 230000000694 effects Effects 0.000 abstract description 10
- 210000001339 epidermal cell Anatomy 0.000 abstract description 10
- -1 perhydronaphthalen-1-yl group Chemical group 0.000 description 20
- 210000003491 skin Anatomy 0.000 description 18
- 238000000034 method Methods 0.000 description 12
- 125000000623 heterocyclic group Chemical group 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 235000018417 cysteine Nutrition 0.000 description 6
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
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- 0 *C1C2C1CC*2 Chemical compound *C1C2C1CC*2 0.000 description 5
- 101710107035 Gamma-glutamyltranspeptidase Proteins 0.000 description 5
- 101710173228 Glutathione hydrolase proenzyme Proteins 0.000 description 5
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- 102000006640 gamma-Glutamyltransferase Human genes 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
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- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
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- 125000002723 alicyclic group Chemical group 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 125000004437 phosphorous atom Chemical group 0.000 description 4
- 229910052698 phosphorus Inorganic materials 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010014970 Ephelides Diseases 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
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- 208000003351 Melanosis Diseases 0.000 description 3
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 230000005779 cell damage Effects 0.000 description 3
- 208000037887 cell injury Diseases 0.000 description 3
- 239000013592 cell lysate Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 108010063907 Glutathione Reductase Proteins 0.000 description 2
- 102100036442 Glutathione reductase, mitochondrial Human genes 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108090000992 Transferases Proteins 0.000 description 2
- 102000004357 Transferases Human genes 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 230000003266 anti-allergic effect Effects 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
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- 239000011248 coating agent Substances 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
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- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
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- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 2
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- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
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- VYGUBTIWNBFFMQ-UHFFFAOYSA-N [N+](#[C-])N1C(=O)NC=2NC(=O)NC2C1=O Chemical group [N+](#[C-])N1C(=O)NC=2NC(=O)NC2C1=O VYGUBTIWNBFFMQ-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
本発明の他の目的は、前記グルタチオン産生促進剤を含有する外用組成物を提供することにある。
本発明のグルタチオン産生促進剤は、有効成分として、下記式(1)で表される化合物、及びその塩から選択される1種を単独で、又は2種以上を組み合わせて含むことを特徴とする。
[式(i-2)中、R5〜R7は、同一又は異なって、水素原子、置換基を有していてもよい脂肪族炭化水素基、置換基を有していてもよい芳香族炭化水素基、ハロゲン原子、−COOR8、−CONR8 2、−COR8、−OCOR8、−CF3、−CN、−SR8、−SOR8、−SO2R8、−SO2NR8 2、−PO(OR8)2、及び−NO2からなる群より選択される基を示す。前記R8は、水素原子、アルキル基、又はアルケニル基を示す。R5〜R7から選択される2つの基は互いに結合して、式(i-2)で示される基において、これらの基が結合する炭素原子と共に、環を形成していてもよい]
で表される基を示す]
[式(ii-2)中、Y1は水素原子、アルキル基、アルケニル基、アルコキシ基、アルケニルオキシ基、ハロゲン原子、−COOR8、−CONR8 2、−COR8、−OCOR8、−CF3、−CN、−SR8、−SOR8、−SO2R8、−SO2NR8 2、−PO(OR8)2、及び−NO2からなる群より選択される基を示す。R8は前記に同じ。Y2は水素原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、−COOR3、−CONR3 2、−COR3、−CN、−NO2、−NHCOR3、−OR3、−SR3、−OCOR3、−SO3R3、及び−SO2NR3 2からなる群より選択される基(前記R3は、前記に同じ)を示す。Y1とY2は互いに結合して、式(ii-2)中のベンゼン環を構成する炭素原子と共に、環を形成していてもよい]
[1] カルボキシル基に保護基を導入する
[2] アミノ基に保護基を導入する
[3] リン酸基の2つのヒドロキシル基をハロゲン原子で置換する
[4] R1OHを反応させて、リン原子に結合するハロゲン原子の一方をOR1と置換する
[5] R2OHを反応させて、リン原子に結合するハロゲン原子の他方をOR2と置換する
[6] カルボキシル基とアミノ基を脱保護する
本発明の外用組成物は、上記グルタチオン産生促進剤を含有する。
式(1)で表される化合物(商品名「GGsTop」、和光純薬工業(株)製)をグルタチオン産生促進剤(1)として使用した。
正常ヒト表皮細胞を用いて、下記方法により、前記グルタチオン産生促進剤(1)によるグルタチオン合成促進作用を評価した。
すなわち、正常ヒト表皮細胞を、正常ヒト表皮角化細胞増殖用培地(商品名「HuMedia KG2」、倉敷紡績(株)製)を用いて96穴マイクロプレートに、2.0×104cells/96wellの細胞密度にて播種した。播種24時間後に、下記表に記載の濃度のグルタチオン産生促進剤(1)を含有した正常ヒト表皮角化細胞増殖用培地(商品名「HuMedia KB2」、倉敷紡績(株)製)と交換して培養を続けた。
0、3、6、18、24、48時間の培養後、100μMのフェニルメチルスルフォニルフルオライド含有リン酸バッファーを用い、超音波処理にて細胞を破砕し、後述のグルタチオンレダクターゼリサイクリング法により総グルタチオン量を定量した。
すなわち、細胞破砕液を還元型ニコチンアミドアデニンジヌクレオチドリン酸及びグルタチオンレダクターゼと混合し、37℃にて10分間反応させた。
次に、10mMの5,5’−ジチオビス(2−ニトロ安息香酸)を溶解させた0.1Mリン酸バッファー(0.5mM EDTA含有、pH7.5)を加え、添加直後、及び30分間インキュベート後の吸光度(450nmにおける)を測定し、その差[30分後の吸光度−添加直後の吸光度]をグルタチオン合成量の指標とした
尚、細胞破砕液中の総グルタチオン量は、酸化型グルタチオンを用いて作成した検量線より算出した。また、細胞破砕液のタンパク質含有量は、Pierce Microplate BCA Protein Assay Kit(Thermo SCIENTIFIC)を用いて定量した。各々の培養時間におけるグルタチオン量は、Studentのt検定を用いて有意差検定を行い、グルタチオン産生促進剤(1)による処理を行わなかった細胞(以後、「未処理細胞」と称する場合がある)との差異を評価した。結果を下記表1及び図1に示す。
Claims (4)
- 請求項1に記載のグルタチオン産生促進剤を含有する外用組成物。
- 外皮用薬である請求項2に記載の外用組成物。
- スキンケア用化粧料である請求項2に記載の外用組成物。
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JP7280562B2 (ja) | 2018-08-31 | 2023-05-24 | 株式会社ナールスコーポレーション | 体臭抑制剤 |
JP2020040945A (ja) * | 2018-09-07 | 2020-03-19 | 株式会社メディカルフロント | ホスホン酸ジエステル誘導体類を含有する貼付剤、及びその製造方法 |
JP7078855B2 (ja) | 2018-09-07 | 2022-06-01 | 株式会社メディカルフロント | ホスホン酸ジエステル誘導体類を含有する貼付剤、及びその製造方法 |
CN109608494A (zh) * | 2018-12-19 | 2019-04-12 | 上海辉文生物技术股份有限公司 | 含有膦酰基的羧酸盐、其制备方法和应用 |
CN109608494B (zh) * | 2018-12-19 | 2021-05-14 | 上海辉文生物技术股份有限公司 | 含有膦酰基的羧酸盐、其制备方法和应用 |
WO2020172455A1 (en) * | 2019-02-20 | 2020-08-27 | Rodan & Fields, Llc | Synergistic antioxidant compositions |
US10898423B2 (en) | 2019-02-20 | 2021-01-26 | Rodan & Fields, Llc | Synergistic antioxidant compositions |
JP2022520974A (ja) * | 2019-02-20 | 2022-04-04 | ロダン アンド フィールズ,エルエルシー | 相乗効果のある抗酸化組成物 |
US11400038B2 (en) | 2019-02-20 | 2022-08-02 | Rodan & Fields, Llc | Synergistic antioxidant compositions |
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