JP2021504470A - N−アセチル又はn−アシルアミノ酸を含むアトピー又は痒み症治療用組成物 - Google Patents
N−アセチル又はn−アシルアミノ酸を含むアトピー又は痒み症治療用組成物 Download PDFInfo
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- JP2021504470A JP2021504470A JP2020546261A JP2020546261A JP2021504470A JP 2021504470 A JP2021504470 A JP 2021504470A JP 2020546261 A JP2020546261 A JP 2020546261A JP 2020546261 A JP2020546261 A JP 2020546261A JP 2021504470 A JP2021504470 A JP 2021504470A
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- Prior art keywords
- acetyl
- pruritus
- amino acid
- acyl
- tryptophan
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Abstract
Description
7週齢balb/c雄マウスと7週齢NC/Nga雄マウスをオリエントバイオ社(京畿道城南、韓国)から購入し、特定病原菌のない状態で維持した。マウスを25±1℃の温度及び40±5%の相対湿度に冷暖房装置をした動物部屋に収容し、蒸留水及び実験食餌を供給した。動物処置及び維持は実験動物管理原則(the Principles of Laboratory Animal Care(NIH公開番号第85−23号、1985年改正))及び全北大学校動物福祉に対する倫理委員会が発行したガイドライン(KHUASP(SE)−15−021)を遵守した。全ての手続きは米国国立保健院(NIH)ガイドラインに従って行った。
balb/cマウスにアトピー様皮膚炎を誘発させるために、アセトン/オリーブオイル(3:1)中の0.35%2,4−ジニトロフルオロベンゼン(DNFB)(Sigma,USA)100μLを、剃毛したマウスの背中皮膚に塗布してDNFB感作を誘導し、6日目、9日目、12日目、15日目、18日目、21日目、24日目、27日目に0.25%DNFB 100μLを剃毛した背中皮膚に塗布して皮膚炎を誘発した。対照マウスを同一体積のビークルで処理した(図1A)。
N−アセチル又はN−アシルアミノ酸を0.1%になるようにそれぞれリン酸緩衝等張液(phosphate buffered saline)に溶解させ、これらの溶液200μLを、Balb/cを用いたアトピー皮膚炎モデルでは22日から28日まで、NC/Ngaマウスを用いたアトピー皮膚炎モデルでは15日から21日まで毎日マウス皮膚などに塗布した。N−アセチル又はN−アシルアミノ酸とDNFBを同時に処理するときは、DNFBとN−アセチル又はN−アシルアミノ酸との直接反応を避けるために12時間の間隔をおいてそれぞれ処理した。非処理グループ及び2,4−ジニトロフルオロベンゼン(DNFB)グループは、同一体積のリン酸緩衝等張液で処理した(図1)。本実施例に使用されたN−アセチルアミノ酸はSigma−Aldrich(USA)、MP scientific(USA)、TCI tokyo chemical industry(Japan)、Santacruz(USA)社などの製品を購入し、精製無しで使用した。
皮膚鎮静の程度及びアトピー皮膚炎の程度は、定立された既存のSCORAD(SCORing Atopic Dermatitis)(Oranje et al.,2007)を用いて巨視的に評価した。浮腫、紅斑、痂皮、乾燥、擦過傷及び苔蘚化などの各症状の程度を0から3までに等級化した(0は症状無し;1は軽症;2は中等度;3は重症)。合計皮膚炎点数は、全ての個別点数の和と決定した(表1)。一方、評価は、前記マウスのグループ配分を目撃しなかった研究者によって行われた。表1によれば、20種類のN−アセチル−L−アミノ酸のうち、N−アセチルシステイン、N−アセチルL−アラニン、N−アセチルL−アルギニン、N−アセチルL−トレオニン及びN−アセチルL−トリプトファンなどが有意に皮膚鎮静及びアトピー皮膚炎の治療効果を示した。
試験物質処理終了後、マウスを犠牲させ、心臓から血液を採取した。この血液から血清を分離してIgEを測定した。具体的に、IgE ELISAキット(BD Biosciences,San Diego,CA)を用いて、抗体を緩衝溶液に希釈して96ウェルプレートに付着して4℃で一晩静置し、マニュアルに従って実験を進行した。IgEのタンパク質量はマイクロプレートリーダー(microplate reader)により450nmで吸光度を測定した。図4によれば、N−アセチルシステイン、N−アセチルL−アラニン、N−アセチルL−アルギニン、N−アセチルL−トレオニン及びN−アセチルL−トリプトファンなどをBalb/cマウス種におけるアトピー誘発マウスに処理した場合、有意に血清IgEの減少を誘導し(図4A)、N−アセチルL−アラニン及びN−アセチルL−トリプトファンなどをNC/Ngaマウス種におけるアトピー誘発マウスに処理した場合、有意に血清IgEの減少を誘導した(図4B)。血清IgEの濃度はアトピー皮膚炎の重症度を示す指標であるので、図4の結果は、N−アセチルL−アラニン、N−アセチルL−アルギニン、N−アセチルL−トレオニン及びN−アセチルL−トリプトファンなどがアトピー皮膚炎に治療効果があることを示している。
アトピー誘発皮膚組織から500μLのTrizol(Life Technologies,USA)を用いて製造者のプロトコルに従って全RNAを分離した後、Superscript III逆転写酵素(Life Technologies,USA)を用いてcDNAを合成した後、分析しようとするIL4とインターフェロンγのプライマーと反応させてリアルタイムPCRを行った。リアルタイムPCRはStepOne Plus PCRサイクラー(Applied Biosystems)上でSybrグリーン(Applied Biosystems,Foster City,CA)を用いて行った。mRNA発現データは△△CT方法を用いて分析したが、遺伝子検出のためにβ−アクチンに正規化した。リアルタイムPCRに必要な検証されたプライマーはQuagen(USA)から購入した。図5によれば、N−アセチルシステイン、N−アセチルL−アラニン、N−アセチルL−アルギニン、N−アセチルL−トレオニン及びN−アセチルL−トリプトファンなどをBalb/cアトピー誘発マウスに処理した場合、皮膚組織内のIL4及びインターフェロンγを有意に減少させ(図5A)、N−アセチルL−アラニン及びN−アセチルL−トリプトファンなどをNC/Ngaアトピー誘発マウスに処理した場合、皮膚組織内のIL4及びインターフェロンγを有意に減少させた。IL4はTh2反応を誘導し、インターフェロンγはTh1反応を誘導するものと知られている。したがって、図4の結果は、N−アセチルL−アラニン、N−アセチルL−アルギニン、N−アセチルL−トレオニン及びN−アセチルL−トリプトファンなどがアトピー皮膚炎に活性化されたTh2及びTh1反応を抑制して治療効果があることを示している。
L型、LD型及びD型のN−アセチルアラニン及びN−アセチルトリプトファンなどのアトピー性皮膚炎による効果を調べるために、NC/Ngaアトピー皮膚炎モデルから皮膚炎治療効果を測定した結果、LD型及びD型のN−アセチルアラニン及びN−アセチルトリプトファンの効果は見られず、L型だけが顕著な効果を示した(図6)。これらの物質に対する痒み症抑制作用は立体特異的であることを示している。
L型、LD型及びD型のN−アセチルアラニン、N−アセチルアルギニン、N−アセチルトレオニン及びN−アセチルトリプトファンなどがアトピー性接触性皮膚炎による痒み症を抑制するかどうかを調べるために、生理食塩水に溶解させた0.1%2,4−ジニトロフルオロベンゼン(DNFB)溶液と0.1%N−アセチルアミノ酸液20μLを、2,4−ジニトロフルオロベンゼン(DNFB)の最終処理(27日目)の10分後に1回にわたって右耳に塗り(陰性対照群は生理食塩水を塗った。)、その後、1時間痒み症を測定した。図7は、DNFBによる痒み症誘導時に、それぞれ0.1%濃度でL型のN−アセチルアラニン、N−アセチルトレオニン、N−アセチルアルギニン、N−アセチルトリプトファン及びDL型とD型のN−アセチルアラニン、N−アセチルトリプトファンの痒み症緩和効果を比較したものである。L型のN−アセチルアラニン、N−アセチルトレオニン、N−アセチルアルギニン、N−アセチルトリプトファンは痒み症を顕著に抑制したが、DL型及びD型のN−アセチルアラニン、N−アセチルトリプトファンは効果がほとんどなかった。これらの物質に対する痒み症抑制作用は立体特異的であることを示している。
N−アセチル基以外のN−アシルトリプトファン化合物の効果を測定するために下記の反応式を用いてN−プロピオニルトリプトファン、N−プチリルトリプトファン、N−ペンタノイルトリプトファン、N−ウンデカノイルトリプトファン、N−パルミトイルトリプトファン、N−(Z)−ドコス−13−エノイルトリプトファン、N−ステアロイルトリプトファン、N−オレオイルトリプトファンを合成した。本実施例に使用された試薬はSigma−Aldrich(USA)、TCI(Japan)、Alfa Aesar(USA)、Acros(USA)、Hanawa(Japan)社などの製品を購入し、精製無しで使用した。合成した化合物の純度と反応の進行過程はTLC(Thin layer chromatography)で確認し、PLCシリカゲル60 F254、0.5mm(Merck)を使用した。TLC上で分離された物質の確認のためにUVランプ(254nm、365nm)を使用した。分離は、シリカゲルカラムカートリッジ(4g〜120g、RediSep(登録商標)Rf)を使用してPLC2020(Gilson)としてMPLC(Medium Pressure Liquid Chromatography)用いるか、或いはAgilent 5 Prep−C18 100x21.2mmカラムを使用してYL9100 Semi−prep HPLCシステム(YL9101S Vacuum Degasser、YL9111S Binary Pump、YL9120S UV/Vis Detector;ヨンリン機器)としてHPLC(High Performance Liquid Chromatography)用いた。生成物の質量分析は、Agilent 6130 Quadrupole LC/MSで糾明した。生成物の構造分析のためのNMRスペクトルは、Bruker ultra−shield 300MHz NMR分光計とBruker ultra−shield 500MHz NMR分光計で測定した。NMR溶媒はCambridge Isotope Laboratories社のchloroform−dとdimethylsulfoxide−d6を使用し、TMS(tetramethylsilane)を内部標準物質としてppm単位で表示した。
(反応式)
まず、メチルプロピオニル−L−トリプトファネートを製造するために、プロピオン酸(propionic acid)(2.36mmol)、L−トリプトファンメチルエステルヒドロクロリド(2.60mmol)、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド(EDCI)(2.60mmol)、ヒドロキシベンゾトリアゾール(HOBt)(2.60mmol)、トリエチルアミン(11.8mmol)をジクロロメタンに溶かした混合物を室温で12時間撹拌した。反応物を濃縮し、飽和NaHCO3溶液で希釈した後、エチルアセテートで3回抽出した。抽出された有機溶媒層を集めてブライン(brine)で洗浄し、1N HClで洗浄後に再びブラインで洗浄した。有機溶媒層を無水MgSO4上で乾燥させ、濃縮後にMPLC(Medium pressure liquid chromatography)上でn−ヘキサン及びエチルアセテートを用いて精製した。収得率は74%で、メチルプロピオニル−L−トリプトファネートの性質は次の通りであった。。1HNMR (500 MHz, Chloroform-d) δ 8.19 (s, 1H), 7.61 - 7.53 (m, 1H), 7.39 (dt, J = 8.2, 0.9 Hz, 1H), 7.22 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.16 - 7.07 (m, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.04 - 5.88 (m, 1H), 5.00 (dt, J = 7.9, 5.3 Hz, 1H), 3.73 (s, 3H), 3.44 - 3.29 (m, 2H), 2.21 (qd, J = 7.6, 1.2 Hz, 2H), 1.14 (t, J = 7.6 Hz, 3H). LC-MS (ESI), calcd for C15H18N2O3 274.1, found m/z 275.1 (M + H+)。
まず、メチルブチリル−L−トリプトファネートを製造するために、ブチル酸(butyric acid)(2.36mmol)、L−トリプトファンメチルエステルヒドロクロリド(2.60mmol)、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド(EDCI)(2.60mmol)、ヒドロキシベンゾトリアゾール(HOBt)(2.60mmol)、トリエチルアミン(11.8mmol)をジクロロメタンに溶かした混合物を室温で12時間撹拌した。反応物を濃縮し、飽和NaHCO3溶液で希釈した後、エチルアセテートで3回抽出した。抽出された有機溶媒層を集めてブラインで洗浄し、1N HClで洗浄後に再びブラインで洗浄した。有機溶媒層を無水MgSO4上で乾燥させ、濃縮後にMPLC(Medium pressure liquid chromatography)上でn−ヘキサン及びエチルアセテートを用いて精製した。収得率は83%で、メチルブチリル−L−トリプトファネートの性質は次の通りであった。1H NMR (500 MHz, Chloroform-d) δ 8.15 (s, 1H), 7.61 - 7.51 (m, 1H), 7.39 (dt, J = 8.1, 0.9 Hz, 1H), 7.22 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 7.15 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 5.98 (d, J = 7.9 Hz, 1H), 5.01 (dt, J = 7.9, 5.3 Hz, 1H), 3.73 (s, 3H), 3.39 - 3.29 (m, 2H), 2.16 (t, J = 7.5 Hz, 2H), 1.70 - 1.58 (m, 3H), 0.93 (t, J = 7.4 Hz, 3H). LC-MS (ESI), calcd for C16H20N2O3288.2, found m/z 289.2 (M + H+)。
まず、メチルペンタノイル−L−トリプトファネートを製造するために、ペンタノン酸(pentanoic acid)(2.36mmol)、L−トリプトファンメチルエステルヒドロクロリド(2.60mmol)、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド(EDCI)(2.60mmol)、ヒドロキシベンゾトリアゾール(HOBt)(2.60mmol)、トリエチルアミン(11.8mmol)をジクロロメタンに溶かした混合物を室温で12時間撹拌した。反応物を濃縮し、飽和NaHCO3溶液で希釈した後、エチルアセテートで3回抽出した。抽出された有機溶媒層を集めてブラインで洗浄し、1N HClで洗浄後に再びブラインで洗浄した。有機溶媒層を無水MgSO4上で乾燥させ、濃縮後にMPLC(Medium pressure liquid chromatography)上でn−ヘキサン及びエチルアセテートを用いて精製した。収得率は85%で、メチルペンタノイル−L−トリプトファネートの性質は次の通りであった。1H NMR (500 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.56 (dt, J = 8.0, 1.0 Hz, 1H), 7.39 (dd, J = 8.1, 0.9 Hz, 1H), 7.22 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.15 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 5.97 (d, J = 8.0 Hz, 1H), 5.00 (dt, J = 7.9, 5.4 Hz, 1H), 3.46 - 3.23 (m, 2H), 2.32 - 2.09 (m, 2H), 1.61 - 1.54 (m, 2H), 1.51 - 1.19 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). LC-MS (ESI), calcd for C17H22N2O3302.2, found m/z 303.2 (M + H+)。
まず、メチルウンデカノイル−L−トリプトファネートを製造するために、ウンデカノン酸(2.36mmol)、L−トリプトファンメチルエステルヒドロクロリド(2.60mmol)、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド(EDCI)(2.60mmol)、ヒドロキシベンゾトリアゾール(HOBt)(2.60mmol)、トリエチルアミン(11.8mmol)をジクロロメタンに溶かした混合物を室温で12時間撹拌した。反応物を濃縮し、飽和NaHCO3溶液で希釈した後、エチルアセテートで3回抽出した。抽出された有機溶媒層を集めてブラインで洗浄し、1N HClで洗浄後に再びブラインで洗浄した。有機溶媒層を無水MgSO4上で乾燥させ、濃縮後にMPLC(Medium pressure liquid chromatography)上でn−ヘキサン及びエチルアセテートを用いて精製した。収得率は91%で、メチルウンデカノイル−L−トリプトファネートの性質は次の通りであった。1H NMR (500 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.61 - 7.52 (m, 1H), 7.39 (dt, J = 8.1, 0.9 Hz, 1H), 7.25 - 7.21 (m, 1H), 7.22 - 7.12 (m, 1H), 7.01 (d, J = 2.4 Hz, 1H), 5.97 (d, J = 7.9 Hz, 1H), 5.88 - 5.78 (m, 1H), 3.73 (s, 3H), 3.43 - 3.27 (m, 2H), 2.23 - 2.14 (m, 3H), 2.11 - 2.01 (m, 2H), 1.60 (s, 5H), 1.38 (q, J = 7.0 Hz, 2H), 1.28 (d, J = 2.1 Hz, 9H). LC-MS (ESI), calcd for C23H34N2O3386.2, found m/z 387.2(M + H+)。
まず、メチルパルミトイル−L−トリプトファネートを製造するために、パルミトイン酸(palmitoic acid)(2.36mmol)、L−トリプトファンメチルエステルヒドロクロリド(2.60mmol)、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド(EDCI)(2.60mmol)、ヒドロキシベンゾトリアゾール(HOBt)(2.60mmol)、トリエチルアミン(11.8mmol)をジクロロメタンに溶かした混合物を室温で12時間撹拌した。反応物を濃縮し、飽和NaHCO3溶液で希釈した後、エチルアセテートで3回抽出した。抽出された有機溶媒層を集めてブラインで洗浄し、1N HClで洗浄後に再びブラインで洗浄した。有機溶媒層を無水MgSO4上で乾燥させ、濃縮後にMPLC(Medium pressure liquid chromatography)上でn−ヘキサン及びエチルアセテートを用いて精製した。収得率は84%で、メチルパルミトイル−L−トリプトファネートの性質は次の通りであった。1H NMR (500 MHz, Chloroform-d) δ 8.11 (s, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.51 - 7.33 (m, 1H), 7.19 - 7.06 (m, 1H), 7.01 (d, J = 2.4 Hz, 1H), 5.99 (d, J = 8.0 Hz, 1H), 5.00 (dt, J = 8.0, 5.3 Hz, 1H), 3.73 (s, 3H), 3.39 - 3.29 (m, 2H), 2.38 (d, J = 7.5 Hz, 2H), 2.19 - 2.15 (m, 2H), 1.67 (d, J = 7.3 Hz, 2H), 0.91 (s, 3H). LC-MS (ESI), calcd for C28H44N2O3456.2, found m/z 457.2 (M + H+)。
まず、メチル(Z)−ドコス−13−エノイル−L−トリプトファネートを製造するために、(Z)−ドコス−13−エン酸((Z)−docos−13−enoic acid)(2.36mmol)、L−トリプトファンメチルエステルヒドロクロリド(2.60mmol)、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド(EDCI)(2.60mmol)、ヒドロキシベンゾトリアゾール(HOBt)(2.60mmol)、トリエチルアミン(11.8mmol)をジクロロメタンに溶かした混合物を室温で12時間撹拌した。反応物を濃縮し、飽和NaHCO3溶液で希釈した後、エチルアセテートで3回抽出した。抽出された有機溶媒層を集めてブラインで洗浄し、1N HClで洗浄後に再びブラインで洗浄した。有機溶媒層を無水MgSO4上で乾燥させ、濃縮後にMPLC(Medium pressure liquid chromatography)上でn−ヘキサン及びエチルアセテートを用いて精製した。収得率は74%で、メチル(Z)−ドコス−13−エノイル−L−トリプトファネートの性質は次の通りであった。1H NMR (500 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.56 (dd, J = 8.0, 1.1 Hz, 1H), 7.39 (dt, J = 8.2, 0.9 Hz, 1H), 7.22 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H), 7.14 (ddd, J = 7.9, 7.0, 1.0 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 5.98 (d, J = 7.9 Hz, 1H), 5.43 - 5.31 (m, 2H), 5.00 (dt, J = 7.9, 5.3 Hz, 1H),3.72 (s,3H) ,3.39 - 3.29 (m, 2H), 2.20 - 2.13 (m, 2H), 2.04 (q, J = 6.7 Hz, 4H), 1.61 (q, J = 10.0, 7.5 Hz, 2H), 1.35 - 1.24 (m, 28H), 0.91 (t, J = 6.9 Hz, 3H). LC-MS (ESI), calcd for C34H54N2O353/.4, found m/z 539.4 (M + H+)。
まず、メチルステアロイル−L−トリプトファネートを製造するために、ステアロン酸(stearoic acid)(2.36mmol)、L−トリプトファンメチルエステルヒドロクロリド(2.60mmol)、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド(EDCI)(2.60mmol)、ヒドロキシベンゾトリアゾール(HOBt)(2.60mmol)、トリエチルアミン(11.8mmol)をジクロロメタンに溶かした混合物を室温で12時間撹拌した。反応物を濃縮し、飽和NaHCO3溶液で希釈した後、エチルアセテートで3回抽出した。抽出された有機溶媒層を集めてブラインで洗浄し、1N HClで洗浄後に再びブラインで洗浄した。有機溶媒層を無水MgSO4上で乾燥させ、濃縮後にMPLC(Medium pressure liquid chromatography)上でn−ヘキサン及びエチルアセテートを用いて精製した。収得率は80%で、メチルステアロイル−L−トリプトファネートの性質は次の通りであった。1H NMR (500 MHz, Chloroform-d) δ 8.09 (d, J = 15.2 Hz, 1H), 7.56 (dd, J = 7.9, 1.0 Hz, 1H), 7.39 (dt, J = 8.2, 0.9 Hz, 1H), 7.22 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.14 (ddd, J = 7.9, 7.0, 1.0 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 5.00 (dt, J = 7.9, 5.3 Hz, 1H), 3.73 (s, 3H), 3.39 - 3.28 (m, 2H), 2.37 (t, J = 7.5 Hz, 2H), 2.19 - 2.11 (m, 2H), 1.66 (t, J = 7.4 Hz, 2H), 1.59 (t, J = 7.4 Hz, 2H), 0.91 (s, 3H). LC-MS (ESI), calcd for C30H48N2O3484.4, found m/z 485.4 (M + H+)。
まず、メチルオレオイル−L−トリプトファネートを製造するために、オレオン酸(oleoic acid)(2.36mmol)、L−トリプトファンメチルエステルヒドロクロリド(2.60mmol)、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド(EDCI)(2.60mmol)、ヒドロキシベンゾトリアゾール(HOBt)(2.60mmol)、トリエチルアミン(11.8mmol)をジクロロメタンに溶かした混合物を室温で12時間撹拌した。反応物を濃縮し、飽和NaHCO3溶液で希釈した後、エチルアセテートで3回抽出した。抽出された有機溶媒層を集めてブラインで洗浄し、1N HClで洗浄後に再びブラインで洗浄した。有機溶媒層を無水MgSO4上で乾燥させ、濃縮後にMPLC(Medium pressure liquid chromatography)上でn−ヘキサン及びエチルアセテートを用いて精製した。収得率は73%で、メチルオレオイル−L−トリプトファネートの性質は次の通りであった。1H NMR (500 MHz, Chloroform-d) δ 8.18 (s, 1H), 7.56 (dd, J = 7.9, 1.0 Hz, 1H), 7.39 (dt, J = 8.1, 0.9 Hz, 1H), 7.29 (s, 1H), 7.22 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 7.14 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 5.99 (d, J = 7.9 Hz, 1H), 5.37 (qd, J = 4.1, 2.1 Hz, 2H), 5.00 (dt, J = 8.0, 5.3 Hz, 1H), 3.72 (s, 3H), 3.39 - 3.28 (m, 2H), 2.20 - 2.13 (m, 2H), 2.08 - 1.99 (m, 5H), 1.60 (t, J = 7.4 Hz, 2H), 1.34 - 1.28 (m, 24H), 0.92 - 0.89 (m, 3H). LC-MS (ESI), calcd for C30H46N2O3482.4, found m/z 483.4 (M + H+)。
N−アセチルγ−グルタミルアラニンはGenescript社(USA)に依頼して合成した。この化合物のMSデータは、図9の通りてある。
実施例9で合成したトリプトファンアシル誘導体と実施例10で合成したアラニンアシル誘導体及びN−パルミトイルアラニン(Santacruz(米国)から購入)を対象に実施例4の方法で皮膚鎮静効果及び皮膚炎程度を評価した(表2)
(部処名)科学技術情報通信部
(研究管理専門機関)韓国研究財団
(研究事業名)跳躍研究支援事業後続研究支援
(研究課題名)Leukotriene誘導体基盤アトピー皮膚炎治療候補物質開発
(寄与率)1/2
(主管機関)全北大学校
(研究期間)2017.09.01〜2019.02.28
(課題固有番号)2017R1A5A2015061
(部処名)科学技術情報通信部
(研究管理専門機関)韓国研究財団
(研究事業名)先導研究センター支援事業
(研究課題名)代謝炎症研究センター
(寄与率)1/2
(主管機関)全北大学校
(研究期間)2017.09.01〜2019.02.28
Claims (23)
- N−アセチルアミノ酸、N−アシルアミノ酸又はその薬剤学的に許容可能な塩を有効成分として含むアトピーの予防又は治療用の薬剤学的組成物。
- N−アセチルアミノ酸、N−アシルアミノ酸又はその薬剤学的に許容可能な塩を有効成分として含む痒み症の予防又は治療用の薬剤学的組成物。
- N−アセチルアミノ酸、N−アシルアミノ酸又はその薬剤学的に許容可能な塩を有効成分として含むアトピー及び痒み症の予防又は治療用の薬剤学的組成物。
- 前記N−アセチルアミノ酸は、N−アセチルアラニン(N−acetyl alanine)、N−アセチルトレオニン(N−acetyl threonine)、N−アセチルアルギニン(N−acetyl arginine)及びN−アセチルトリプトファン(N−acetyl tryptophan)から構成された群から選ばれる1つ又は2つ以上のアミノ酸であることを特徴とする、請求項1〜3のいずれかに記載の薬剤学的組成物。
- 前記N−アセチルアミノ酸は、N−アセチルL−アラニン(N−acetyl L−alanine)、N−アセチルL−トレオニン(N−acetyl L−threonine)、N−アセチルL−アルギニン(N−acetyl L−arginine)及びN−アセチルL−トリプトファン(N−acetyl L−tryptophan)から構成された群から選ばれる1つ又は2つ以上のアミノ酸であることを特徴とする、請求項4に記載の薬剤学的組成物。
- 前記N−アシルアミノ酸は、N−アシルトリプトファン(N−acyl tryptophan)又はN−アシルアラニン(N−acyl alanine)であることを特徴とする、請求項1〜3のいずれかに記載の薬剤学的組成物。
- 前記N−アシルアミノ酸は、N−アシルL−トリプトファン(N−acyl L−tryptophan)又はN−アシルL−アラニン(N−acyl L−alanine)であることを特徴とする、請求項6に記載の薬剤学的組成物。
- 前記痒み症は、外陰部掻痒症、膣掻痒症、発作性掻痒症、冬季掻痒症、肛門掻痒症、陰嚢掻痒症、水因性掻痒症、頭皮掻痒症、鼻腔内痒み症、口腔内痒み症及び眼球内痒み症から構成された群から選ばれることを特徴とする、請求項2又は3に記載の薬剤学的組成物。
- 前記組成物の剤形は、皮膚外用剤、エアゾール、スプレー、点眼剤、経口剤及び注射剤から構成された群から選ばれることを特徴とする、請求項1〜3のいずれかに記載の薬剤学的組成物。
- N−アセチルアミノ酸、N−アシルアミノ酸又はその食品学的に許容可能な塩を有効成分として含む、アトピーの予防又は改善用の食品組成物。
- N−アセチルアミノ酸、N−アシルアミノ酸又はその食品学的に許容可能な塩を有効成分として含む、痒み症の予防又は改善用の食品組成物。
- N−アセチルアミノ酸、N−アシルアミノ酸又はその食品学的に許容可能な塩を有効成分として含む、アトピー及び痒み症の予防又は改善用の食品組成物。
- N−アセチルアミノ酸、N−アシルアミノ酸又はその化粧品学的に許容可能な塩を有効成分として含む、皮膚保湿用又は皮膚鎮静用の化粧料組成物。
- 前記化粧料組成物は、皮膚乾燥、浮腫、紅斑、炎症、痂皮、擦過傷及び苔蘚化から構成された群から選ばれる1つ又はそれ以上の皮膚状態を改善することを特徴とする、請求項13に記載の化粧料組成物。
- N−アセチルアミノ酸、N−アシルアミノ酸又はその化粧品学的に許容可能な塩を有効成分として含む、アトピーの予防又は改善用の化粧料組成物。
- N−アセチルアミノ酸、N−アシルアミノ酸又はその化粧品学的に許容可能な塩を有効成分として含む、痒み症の予防又は改善用の化粧料組成物。
- N−アセチルアミノ酸、N−アシルアミノ酸又はその化粧品学的に許容可能な塩を有効成分として含む、アトピー及び痒み症の予防又は改善用の化粧料組成物。
- 前記N−アセチルアミノ酸は、N−アセチルアラニン(N−acetyl alanine)、N−アセチルトレオニン(N−acetyl threonine)、N−アセチルアルギニン(N−acetyl arginine)及びN−アセチルトリプトファン(N−acetyl tryptophan)から構成された群から選ばれる1つ又は2つ以上のアミノ酸であることを特徴とする、請求項13及び15〜17のいずれかに記載の化粧料組成物。
- 前記N−アセチルアミノ酸は、N−アセチルL−アラニン(N−acetyl L−alanine)、N−アセチルL−トレオニン(N−acetyl L−threonine)、N−アセチルL−アルギニン(N−acetyl L−arginine)及びN−アセチルL−トリプトファン(N−acetyl L−tryptophan)から構成された群から選ばれる1つ又は2つ以上のアミノ酸であることを特徴とする、請求項18に記載の化粧料組成物。
- 前記N−アシルアミノ酸は、N−アシルトリプトファン(N−acyl tryptophan)又はN−アシルアラニン(N−acyl alanine)であることを特徴とする、請求項13及び15〜17のいずれかに記載の化粧料組成物。
- 前記N−アシルアミノ酸は、N−アシルL−トリプトファン(N−acyl L−tryptophan)又はN−アシルL−アラニン(N−acyl L−alanine)であることを特徴とする、請求項20に記載の化粧料組成物。
- 前記化粧料組成物の剤形は、クリーム、ローション、スキン、エッセンス又はミストであることを特徴とする、請求項13及び15〜17のいずれかに記載の化粧料組成物。
- 請求項13及び15〜17のいずれか一項の化粧料組成物を含むマスクパック。
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JP7321435B2 (ja) | 2023-08-07 |
CN111971037A (zh) | 2020-11-20 |
EP3714880A4 (en) | 2021-07-21 |
KR20190060694A (ko) | 2019-06-03 |
US20220233485A1 (en) | 2022-07-28 |
US20230248682A1 (en) | 2023-08-10 |
US20200316001A1 (en) | 2020-10-08 |
EP3714880A2 (en) | 2020-09-30 |
BR112020010286A2 (pt) | 2020-11-17 |
JP2023089077A (ja) | 2023-06-27 |
AU2018371606A1 (en) | 2020-07-09 |
AU2018371606B2 (en) | 2022-02-03 |
CA3083412A1 (en) | 2019-05-31 |
KR102139678B1 (ko) | 2020-07-31 |
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