JP2018024610A - ウイルス増殖阻害剤 - Google Patents
ウイルス増殖阻害剤 Download PDFInfo
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- JP2018024610A JP2018024610A JP2016157619A JP2016157619A JP2018024610A JP 2018024610 A JP2018024610 A JP 2018024610A JP 2016157619 A JP2016157619 A JP 2016157619A JP 2016157619 A JP2016157619 A JP 2016157619A JP 2018024610 A JP2018024610 A JP 2018024610A
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- virus
- hydrogen atom
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- fraction
- growth inhibitor
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Abstract
Description
本発明のウイルス増殖阻害剤の有効成分である、式(I)で表わされるプロアントシアニジンガレート類は、プロアントシアニジン類の一種である。
テアシネンシン類は、カテキン類がB環同士で結合した二量体であり、烏龍茶や紅茶に含まれる。良く知られたテアシネンシン類としては以下の式(VII)や(VIII)で表わされるテアシネンシンA、テアシネンシンB、テアシネンシンC、テアシネンシンD、テアシネンシンEが挙げられる。
超純水1.2Lに溶解したポリフェノンG(緑茶抽出物粉末、三井農林株式会社製)100gをDIAION HP20カラム(70mm×310mm、三菱化学株式会社製)に供し、超純水1.8L、20%、40%、60%、80%メタノール(水/メタノール=8/2、6/4、4/6、2/8(体積比))水溶液各3L、アセトン3Lで順次溶出した。各溶出液を減圧濃縮、凍結乾燥を行い、水画分46.02g、20%メタノール画分16.97g、40%メタノール画分20.28g、60%メタノール画分14.25g、80%メタノール画分1.87g、アセトン画分0.50gを得た。
8mgの(-)-EGCg-(4β→8)-(-)-EGCgを超純水1.5mLに溶解し、スミチームTAN(タンナーゼ、新日本化学工業株式会社製)2mgを加え37℃で30分間反応させた。その後、Mightysil RP-18 GP II(20×250mm、粒子径5μm)を用いた分取HPLCにより反応液の精製(移動相:水/メタノール/ギ酸=950/50/1(体積比)、カラム温度:26℃、流速:16mL/min)を行い、(-)-EGC-(4β→8)-(-)-EGCを5mg得た。
1.8gの(-)-EGCg(三井農林株式会社製)を超純水60mLとMcIlvaine緩衝液(pH 5)60mLで溶解した。50mLコニカルビーカー4つそれぞれにこの溶液30mLと10%パラジウム/炭素(50%水湿潤品、SIGMA-ALDRICH社製)170mgを加えて、空気雰囲気下室温で180分間撹拌した。触媒をろ別した後、ろ液にジチオスレイトール463mgを加えて、室温で45分間撹拌した。反応液に1M水酸化ナトリウム水溶液を加えてpH6に調整した。反応液を酢酸エチル50mLで5回抽出し、酢酸エチル層を硫酸ナトリウムで脱水した。硫酸ナトリウムをろ別後、ろ液をロータリーエバポレーターで濃縮乾固した。酢酸エチル画分1.5gをメタノール5mLで溶解後、TOYOPEARL HW-40Sカラムクロマトグラフィー(40mm×450mm、移動相:メタノール、流速:15mL/min)に供し、粗テアシネンシンAを374mg得た。得られた粗テアシネンシンAを5%アセトニトリル(水/アセトニトリル=9.5/5、体積比)15mLに溶解後、MCIGEL-CHP55Yカラムクロマトグラフィー(20mm×300mm、三菱化学株式会社製、移動相:水/アセトニトリル/ギ酸=870/130/1(体積比)、流速:7.5mL/min)により精製し、テアシネンシンAを286mg得た。
0.6gの(-)-EGC(三井農林株式会社製)と、0.9gの(-)-EGCgを超純水60mLとMcIlvaine緩衝液(pH5)60mLを用いて溶解した。50mLコニカルビーカー4つそれぞれにこの溶液30mLと10%パラジウム/炭素(50%水湿潤品)250mgを加えて、空気雰囲気下室温で210分間撹拌した。触媒をろ別した後、ろ液にトリス(2-カルボキシエチル)ホスフィン塩酸塩860mgを加え、室温で10分間撹拌した。反応液を直接DIAION HP-20カラムクロマトグラフィー(30mm×140mm)に供し、超純水350mLで洗浄後、40%メタノール(水/メタノール=6/4、体積比)500mLで溶出した。濃縮乾固した40%メタノール画分1.1gをメタノール5mLで溶解後、TOYOPEARL HW-40Sカラムクロマトグラフィー(40mm×450mm、移動相:メタノール、流速:15mL/min)に供し、粗テアシネンシンBを294mg得た。得られた粗テアシネンシンBを5%アセトニトリル(水/アセトニトリル=9.5/5、体積比)7.5mLに溶解後、MCIGEL-CHP55Yカラムクロマトグラフィー(20mm×300mm、移動相:水/アセトニトリル/ギ酸=900/100/1(体積比)、流速:7.5mL/min)にて精製し、テアシネンシンBを188mg得た。
1.2gの(-)-EGCを、超純水60mLとMcIlvaine緩衝液(pH5)60mLを用いて溶解した。50mLコニカルビーカー4つそれぞれにこの溶液30mLと10%パラジウム/炭素(50%水湿潤品)170mgを加えて、空気雰囲気下室温で240分間撹拌した。触媒をろ別した後、ろ液にトリス(2-カルボキシエチル)ホスフィン塩酸塩860mgを加え、室温で10分間撹拌した。反応液をMCIGEL-CHP55Yカラムクロマトグラフィー(20mm×300mm、移動相:水/メタノール/ギ酸=950/50/1(体積比)、流速:7.5mL/min)にて精製し、テアシネンシンCを369mg得た。
製造例1〜5で得られた画分、プロアントシアニジン類、テアシネンシン類のSARSコロナウイルスに対する増殖阻害活性の測定を行った。また、カテキン類((-)-EC、(-)-EGC、(-)-ECg、(-)-EGCg、全て三井農林株式会社製)についても活性の測定を行った。SARSコロナウイルスはFFM-1株(Dr. H.W. Doerr,Frankfurt University of Medicine,Germanyより分与)を用いた。培養細胞はVero細胞(アフリカミドリザル腎臓由来)を用い、培地には10重量%ウシ胎児血清、ストレプトマイシン(100μg/mL)、ペニシリン(100U/mL)を添加したダルベッコ変法イーグル最小必須培地(SIGMA-ALDRICH社製)を用いて5体積%濃度のCO2存在下、37℃で培養した。
プロアントシアニジンガレート類である(+)-GC-(4α→8)-(-)-EGCgとテアシネンシン類のネコカリシウイルスに対する増殖阻害活性の測定を行った。SARSコロナウイルスに代えてネコカリシウイルスF9株、Vero細胞に変えてCRFK細胞(ネコ腎臓由来)を使用した以外は試験例1と同様の方法で、ネコカリシウイルスに対する被験物質のIC50を算出した。
プロアントシアニジンガレート類である(+)-GC-(4α→8)-(-)-EGCgのインフルエンザウイルスに対する増殖阻害活性の測定を行った。SARSコロナウイルスに代えてA型インフルエンザウイルスPR8株、Vero細胞に代えてMDCK細胞(イヌ腎臓由来)を使用した以外は試験例1と同様の方法で、インフルエンザウイルスに対する被験物質のIC50を算出した。(+)-GC-(4α→8)-(-)-EGCgのIC50は10μg/mLであった。
(+)-GC-(4α→8)-(-)-EGCg0.5重量部、キシリトール33.8重量部、マンニトール30.6重量部、微結晶性セルロース6.1重量部、着香料14.1重量部、ステアリン酸4.3重量部、タルク0.6重量部、ソルビトール10.0重量部を混合した粉体を錠剤プレスによって圧縮し、ウイルス増殖阻害剤を含有する錠剤を得た。
Claims (7)
- 式(I)で表わされるプロアントシアニジンガレート類及び式(II)で表わされるテアシネンシン類から選ばれる1種又は2種以上を有効成分として含有するウイルス増殖阻害剤。
- 式(I)で表わされるプロアントシアニジンガレート類から選ばれる1種又は2種以上を有効成分として含有するウイルス増殖阻害剤。
- 式(II)で表わされるテアシネンシン類から選ばれる1種又は2種以上を有効成分として含有するウイルス増殖阻害剤。
- 前記ウイルスがコロナウイルス、カリシウイルス、及びインフルエンザウイルスからなる群より選択される、請求項1〜3のいずれか一項に記載のウイルス増殖阻害剤。
- 請求項1〜4のいずれか一項に記載のウイルス増殖阻害剤を含む、ウイルスの増殖を阻害するための飲食品。
- 請求項1〜4のいずれか一項に記載のウイルス増殖阻害剤を含む、医薬品又は医薬部外品。
- 式(I)又は(II)で示される化合物の有効量を投与することを特徴とするウイルス増殖抑制のための方法。
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CN116685215A (zh) * | 2020-10-02 | 2023-09-01 | 学校法人北里研究所 | 用于预防或治疗新型冠状病毒感染症的抗病毒剂 |
WO2022102590A1 (ja) * | 2020-11-13 | 2022-05-19 | 株式会社 伊藤園 | 抗ウイルス剤 |
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