JP5974083B2 - 酸化窒素放出及びバイオフィルム発達の調節 - Google Patents
酸化窒素放出及びバイオフィルム発達の調節 Download PDFInfo
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- JP5974083B2 JP5974083B2 JP2014510613A JP2014510613A JP5974083B2 JP 5974083 B2 JP5974083 B2 JP 5974083B2 JP 2014510613 A JP2014510613 A JP 2014510613A JP 2014510613 A JP2014510613 A JP 2014510613A JP 5974083 B2 JP5974083 B2 JP 5974083B2
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- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
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Description
からなる群から選択される]を提供する。
を有する。
からなる群から選択される]を提供する。
を有し得る。
化合物9から13は、この同じ方法を使用して、適切に官能化されたPMBで保護されたセファロスポリン及びジアゼニウムジオレートを選択することにより、調製した。化合物9から13についての分光分析データを以下に提示する。
1H NMR(500MHz, CDCl3): δ 7.36-7.24(m, 7H), 6.88(d, 2H, J=9Hz), 6.08(d, 1H, J=10Hz), 5.81(dd, 1H, J=10, 4.5Hz), 5.33及び4.98(ABq, 2H, J=14Hz), 5.17(s, 2H), 4.88(d, 1H, J=5Hz), 3.79(s, 3H), 3.67及び3.62(ABq, 2H, J=9Hz), 3.44及び3.42(ABq, 2H, J=18Hz), 3.10(q, 4H, J=7Hz), 1.05(m, 6H, J=7Hz). 13C NMR(500MHz, CDCl3): 171.1, 164.6, 161.2, 159.9, 133.6, 130.7, 129.4, 129.2, 127.8, 126.7, 126.4, 125.5, 114.0, 72.0, 68.1, 59.2, 57.5, 55.2, 48.4, 43.3, 26.0, 11.5. FTIR(cm-1, neat): 3284, 1778, 1726, 1660, 1519, 1352, 1228, 1187, 1030, 982, 818, 716, 699, 679. M.P 126-128℃, [α]D(c=1.0, CH2Cl2)=+76.9, ESI-HRMS(m/z) 計算値: 584.2179 [M+H]+ C28H34N5O7S, 実測値: 584.2205.
化合物10
1H NMR(500MHz, CD3OCD3): δ 8.90(s, 1H), 8.26(d, 1H, J=6Hz), 7.30(d, 2H, J=8.5Hz), 6.86(d, 2H, J=8.5Hz), 5.78(q, 1H, J=5Hz), 5.32及び5.27(ABq, 2H, J=16.5Hz), 5.18(s, 2H), 5.17及び5.02(ABq, 2H, J=13Hz), 4.95(d, 1H, J=5Hz), 3.78(s, 3H), 3.56及び3.51(ABq, 2H, J=19Hz), 3.14(q, 4H, J=7Hz), 1.05(t, 6H, J=7Hz). 13C NMR(125MHz, CD3OD): δ 166.3, 164.4, 161.5, 160.2, 144.5, 130.0, 126.8, 126.6, 126.3, 114.2, 72.1, 68.5, 59.7, 57.5, 55.5, 50.1, 48.4, 26.5, 11.7. FTIR(cm-1, neat): 3290, 3137, 2973, 2902, 1771, 1702, 1662, 1556, 1378, 1233, 1170, 1094, 1049, 801. M.P 171℃, [α]D(c=1.0, アセトン)=-51.9, ESI-HRMS(m/z) 計算値: 574.1838 [M-H]- C23H28N9O7S-, 実測値: 574.1830.
化合物11
1H NMR(500MHz, CDCl3): δ 7.36(m, 2H), 7.32(d, 2H, J=8.5Hz), 7.26(m, 3H), 6.88(d, 1H, J=8.5Hz), 6.05(d, 1H, J=9Hz), 5.82及び5.80(dd, 1H, J=4.5, 5Hz), 5.21-5.15(m, 3H), 4.91(d, 1H, J=4.4Hz), 4.87(d, 1H, J=13.5Hz), 3.80(s, 3H), 3.68及び3.62(ABq, 2H, J=16Hz), 3.52及び3.43(ABq, 2H, J=18.5Hz), 3.46(t, 4H, J=7Hz), 1.91(t, 4H, J=7Hz). 13C NMR(125MHz, CDCl3): 171.0, 164.7, 161.3, 159.9, 133.5, 130.6, 129.4, 129.2, 127.8, 126.8, 126.7, 125.3, 114.0, 71.4, 68.0, 59.1, 57.4, 55.2, 50.7, 43.3, 26.1, 22.8. FTIR(cm-1, neat): 3265, 2965, 2162, 2030, 1756, 1714, 1652, 1612, 1536, 1486, 1446, 1392, 1266, 1244, 1217, 1180, 1013, 986. M.P 157℃. [α]D(c=1.0, MeOH)=+20.6. ESI-HRMS(m/z) 計算値: 580.1871 [M-H]- C28H30N5O7S-, 実測値: 580.1895.
化合物12
1H NMR(500MHz, CDCl3): δ 8.33(d, 2H, J=4.5Hz), 7.39-7.26(m, 5H), 7.32(d, 2H, J=7.5Hz), 6.88(d, 2H, J=7.5Hz), 6.56(t, 1H, J=2Hz), 6.18(d, 1H, J=9Hz), 5.82(q, 1H, J=5Hz), 5.24及び4.95(ABq, 2H, J=13.5Hz), 5.18(d, 2H, J=2.5Hz), 4.91(d, 1H, J=4.5Hz), 3.98(t, 4H, J=4.5Hz), 3.78(s, 3H), 3.66及び3.61(ABq, 2H, J=16Hz), 3.53及び3.40(ABq, 2H, J=18.5Hz), 3.41(t, 4H, J=4.5Hz). 13C NMR(500MHz, CDCl3): δ 171.0, 164.7, 161.3, 159.9, 157.8, 133.6, 130.7, 129.4, 129.2, 127.7, 126.6, 125.8, 125.7, 113.9, 110.7, 71.8, 68.1, 59.2, 57.4, 55.2, 50.9, 43.3, 42.3, 26.1. FTIR(cm-1, neat): 3286, 3137, 2976, 2908, 2904, 1772, 1702, 1662, 1557, 1411, 1377, 1232, 1049. [α]D(c=1.0, MeOH)=+39.5. ESI-HRMS(m/z) 計算値: 675.2344 [M+H]+ C32H35N8O7S+, 実測値: 675.2373. M.P 136℃.
化合物13
1H NMR(500MHz, CDCl3): δ 7.36-7.24(m, 6H), 6.93-6.91(m, 2H), 6.88(d, 2H, J=9Hz), 6.16(m, 1H), 5.81(q, 1H, J=5Hz), 5.24(d, 1H, J=2.5Hz), 5.21(s, 2H), 5.17及び4.96(ABq, 2H, J=12Hz), 4.91(d, 2H, J=2.5Hz), 3.78(s, 3H), 3.67及び3.58(ABq, 2H, J=16Hz), 3.53及び3.40(ABq, 2H, J=18.5Hz), 3.51(m, 4H), 3.29(m, 4H). 13C NMR(125MHz, CDCl3): δ 171.3, 164.9, 161.5, 160.2, 150.4, 133.8, 130.9, 129.6, 129.5, 129.4, 127.9, 126.9, 126.0, 121.0, 116.8, 114.2, 72.0, 68.4, 59.4, 57.7, 55.4, 51.1, 48.4, 43.5, 26.1. FTIR(cm-1, neat): 3389, 3286, 3197, 3030, 2897, 1756, 1647, 1607, 1546, 1492, 1448, 1384, 1351, 1224, 1004. [α]D(c=1.0, MeOH)=+54.3, ESI-HRMS(m/z) 計算値: 673.2439 [M+H]+ C34H37N6O7S+, 実測値: 673.2409. M.P 106℃.
次いで、未希釈のトリフルオロ酢酸を使用して、PMBで保護されたセファロスポリン-3'-ジアゼニウムジオレート(3及び9から13)を脱保護して、遊離カルボン酸を得た。
化合物15から19は、この同じ方法を使用して調製した。化合物15から19についての分光分析データを以下に提示する。
1H NMR(500MHz, CD3OD): δ 7.35-7.26(m, 5H), 5.75(d, 1H, J=4.8,Hz), 5.36及び5.07(ABq, 2H, J=12.9Hz), 5.05(d, 1H, J=4.8Hz), 5.03(m, 1H), 3.68-3.45(m, 4H), 3.19(q, 4H, J=7.0Hz), 1.07(t, 6H, J=7.0Hz). 13C NMR(500MHz, CD3OD): δ 175.4, 167.3, 166.6, 137.2, 132.1, 131.0, 130.4, 128.8, 123.0, 74.6, 61.5, 59.8, 50.1, 44.0, 27.7, 12.6. FTIR(cm-1, neat): 3287, 1780, 1663, 1505, 1337, 1223, 998, 618. M.P 84-86℃, [α]D(c=1.0, CH2Cl2)=+19.4, ESI-HRMS(m/z) 計算値: 462.1453(C20H24N5O6S) [M-H]-, 実測値: 462.1465.
化合物16
1H NMR(300MHz, CD3OCD3): δ 9.40(d, 1H, J=6Hz), 9.11(s, 1H), 5.72(d, 2H, J=8Hz), 5.29(s, 2H), 5.22及び4.99(ABq, 2H, J=22Hz), 5.01(s, 1H), 3.52及び3.49(ABq, 2H, J=19Hz), 3.10(q, 4H, J=7Hz), 0.95(t, 6H, J=7Hz). 13C NMR(125MHz, CD3OD): δ 167.4, 165.8, 164.4, 146.0, 128.1, 127.5, 72.9, 60.6, 58.7, 50.3, 49.3, 27.1, 11.7. FTIR(cm-1, neat): 3282, 3136, 2975, 2875, 1773, 1703, 1662, 1559, 1414, 1227, 1170, 1026, 800. M.P 156℃. [α]D(c=1.0, MeOH)=+117.3, ESI-HRMS(m/z) 計算値: 454.1263 [M-H]- C15H20N9O6S-, 実測値: 454.1266.
化合物17
1H NMR(500MHz, CD3OD): δ 7.30-7.22(m, 5H), 5.72(d, 1H, J=7.5Hz), 5.23及び4.97(ABq, 2H, J=22.5Hz), 5.07(d, 1H, J=8Hz), 3.64-3.50(m, 4H), 3.50(t, 4H, J=7Hz), 1.93(t, 4H, J=7Hz). 13C NMR(125MHz, CDCl3): 174.5, 166.2, 164.5, 136.4, 130.4, 129.5, 127.9, 127.6, 72.5, 60.7, 59.1, 51.5, 43.1, 27.2, 23.7. FTIR(cm-1, neat): 3296, 1756, 1729, 1642, 1530, 1469, 1429, 1388, 1318, 1141, 1028, 944. [α]D(c=1.0, MeOH)=122.8, ESI-HRMS(m/z) 計算値: 484.1261 [M+Na]+ C20H23N5NaO6S+, 実測値: 484.1281. M.P 146℃.
化合物18
1H NMR(300MHz, CD3OCD3): δ 8.37(s, 2H), 7.34-7.23(m, 5H), 6.65(s, 1H), 5.84(s, 1H), 5.24及び4.97(ABq, 2H, J=7.8Hz), 5.14(s, 1H), 3.97(s, 4H), 3.69-3.41(m, 4H), 3.46(s, 4H). 13C NMR(75MHz, CDCl3): 172.1, 166.4, 164.0, 163.0, 159.5, 137.5, 130.9, 129.9, 128.0, 126.7, 111.9, 72.8, 61.5, 58.2, 52.0, 43.3, 42.3, 26.1. FTIR(cm-1, neat): 3286, 3137, 2976, 2908, 2904, 1772, 1702, 1662, 1557, 1411, 1232, 1049. [α]D(c=1.0, MeOH)=+36.6, ESI-HRMS(m/z) 計算値: 555.1769 [M+H]+ C24H27N8O6S+, 実測値: 555.1799. M.P 116℃.
化合物19
1H NMR(500MHz, CD3COCD3): δ 8.05(d, 1H, J=8.5Hz), 7.36-7.23(m, 8H), 7.02(d, 2H, J=7.5Hz), 6.84(t, 1H, J=7.5), 5.85(q, 1H, J=5Hz), 5.25及び5.01(ABq, 2H, J=13.5Hz), 5.14(d, 1H, J=4.5Hz), 3.70及び3.58(m, 4H), 3.55(m, 4H), 3.35(m, 4H). 13C NMR(500MHz, CD3COCD3): 171.6, 165.8, 163.1, 151.5, 136.5, 130.0, 129.8, 129.1, 127.4, 125.9, 120.7, 117.2, 72.2, 60.3, 58.5, 51.6, 48.7, 42.9, 26.7. FTIR(cm-1, neat): 3397, 3286, 3197, 3028, 2897, 1755, 1647, 1607, 1548, 1492, 1448, 1383, 1351, 1225, 1004, 985. [α]D(c=1.0, MeOH)=+57.7 ESI-HRMS(m/z) 計算値: 553.1864 [M+H]+ C26H29N6O6S+, 実測値: 553.1847. M.P 96℃.
次いで、化合物14、15、17及び18をそれらのカリウム塩に変換した。化合物20は、下記の方法を利用して調製した。
化合物21、23及び24は、この同じ方法を使用して調製した。化合物21、23及び24についての分光分析データを以下に提示する。
1H NMR(500MHz, CD3OD): δ 7.30-7.20(m, 5H,), 5.65(d, 1H, J=4.8,Hz), 5.35及び4.85(ABq, 2H, J=12.0Hz), 4.98(d, 1H, J=4.8,Hz), 3.60及び3.55(ABq, 2H, J=14Hz), 3.57及び3.37(ABq, 2H, J=18Hz), 3.15(q, 4H, J=7.0Hz), 1.04(t, 6H, J=7.0Hz). 13C NMR(500MHz, CD3OD): δ 174.6, 168.7, 165.3, 136.5, 134.5, 130.2, 129.6, 128.0, 116.9, 74.7, 60.4, 58.9, 49.4, 43.1, 26.8, 11.8. IR(cm-1, neat): 3395, 1765, 1609, 1495, 1345, 1248, 997, 679. M.P 35-37℃. [α]D(c=1.0, CH2Cl2)=+ 19.0, ESI-HRMS(m/z) 計算値: 502.1157 C20H25KN5O6S [M+H]+, 実測値: 502.1163.
化合物23
1H NMR(500MHz, D2O): δ 7.35-7.2(m, 5H), 5.53(d, 1H, J=4Hz), 5.05及び4.72(ABq, 2H, J=12Hz), 4.99(d, 1H, J=4Hz), 3.62-3.58(m, 2H), 3.50及び3.30(ABq, 2H, J=13Hz), 3.4(m, 4H), 1.82(m, 4H). 13C NMR(125MHz, D2O): δ 175.5, 168.4, 164.9, 135.0, 132.3, 129.3, 129.1, 127.9, 116.5, 72.9, 59.2, 58.0, 51.6, 42.3, 25.8, 22.5. FTIR(cm-1, neat): 3399, 3283, 3194, 2976, 2980, 2897, 1758, 1648, 1609, 1542, 1492, 1451, 1386, 1351, 1224, 1001. [α]D(c=1.0, MeOH)=-390.3. ESI-HRMS(m/z) 計算値: 500.1001 [M+H]+ C20H23KN5O6S+, 実測値: 500.1015.
化合物24
1H NMR(300MHz, CD3OD): δ 8.33(s, 2H), 7.39-7.26(m, 5H), 7.32(d, 1H, J=7.5Hz), 6.56(t, 1H, J=2Hz), 5.63(d, 1H, J=5Hz), 5.24及び4.95(ABq, 2H, J=13.5Hz), 5.18(d, 2H, J=2.5Hz), 4.91(d, 1H, J=4.5Hz), 3.98(m, 4H, J=4.5Hz), 3.66及び3.61(ABq, 2H, J=16Hz), 3.53及び3.40(ABq, 2H, J=18.5Hz), 3.41(t, 4H, J=4.5Hz). 13C NMR(125MHz, CD3OD): 171.0, 164.7, 161.3, 159.9, 157.8, 133.6, 130.7, 129.4, 129.2, 127.7, 126.6, 125.8, 125.7, 113.9, 110.7, 71.8, 68.1, 59.2, 57.4, 55.2, 50.9, 43.3, 42.3, 26.1. FTIR(cm-1, neat): 3394, 3282, 3190, 3034, 2980, 2894, 1756, 1645, 1609, 1543, 1492, 1448, 1352, 1224, 994. [α]D(c=1.0, MeOH)=-190.6, ESI-HRMS(m/z) 計算値: 593.1328 [M+H]+ C24H26KN8O6S+, 実測値: 593.1366.
ジアゼニウムジオレート2及び6から8は、文献の手順に従って調製され得る。例として、化合物2は次の通りに調製した。
[実施例2]
インビトロ及び緑膿菌抽出物による化合物14から19からの酸化窒素放出
化合物14から19からの酸化窒素放出は、Apollo 4000分析機を用いる酸化窒素特異的プローブISO-NOP(World Precision Instruments)を使用して検出した。酸化窒素プローブは、SNAPの溶液を使用し、メーカーの指示に従って新たに較正し、pH 7.0のトリス緩衝液を含有するバイアル中に浸漬し、室温で連続的に撹拌した。酸化窒素レベルをモニターしながら、種々の試薬を首尾よく添加した。
緑膿菌細胞における化合物21からの酸化窒素放出の誘導
緑膿菌の無傷細胞における酸化窒素放出を研究するために、緑膿菌NSGFPレポーター株を使用した(Barraudら、2009)。この株は、酸化窒素誘導的nirS遺伝子が発現されている場合に緑色蛍光タンパク質(GFP)を発現する遺伝子レポーター構築物を有する。緑膿菌NSGFP細胞を、亜阻止濃度のアンピシリン(50μg/ml)を加えて又は加えずに増殖させて、β-ラクタマーゼ活性を誘導した。次いで、3ml細菌培養物のアリコートを、化合物21、公知の酸化窒素供与体ニトロプルシドナトリウム(SNP)、セファロチン(Sigma参照番号C4520)又はペニシリナーゼとともに2時間インキュベートした後、NSGFP細胞のGFP蛍光を測定した。
化合物21からの酸化窒素の放出はバイオフィルム分散を誘導する
緑膿菌PAO1野生型ATCC及びMA67株、緑膿菌FRD1、粘液状、嚢胞性線維症(CF)分離株(Ohman及びChakrabarty、1981)、並びにタスマニア州において慢性的に感染した個体のCF喀痰試料から単離した臨床株緑膿菌18A(Kirovら、2007)を、バイオフィルム分散アッセイに使用した。バイオフィルムを、M9最少培地(48mM Na2HPO4、22mM KH2PO4、9mM NaCl、19mM NH4Cl、pH7.2、2mM MgSO4、20mMグルコース及び100μM CaCl2を含有する)中、24ウェルプレートバッチ培養にて、37℃、200rpmで振とうしながら増殖させた。PAO1野生型バイオフィルムについては6時間のインキュベーション後、又はFRD1及び18Aバイオフィルムについては24時間のインキュベーション後、各ウェルにプレート当たり1分未満で処理物を添加し、プレートを、37℃、200rpmで振とうしながらさらに10分間インキュベートした。浮遊バイオマスを上清のOD600の直接測定によって定量化し、残りのバイオフィルムバイオマスをクリスタルバイオレット染色(O'Toole及びKolter、1998)によって定量化した。
化合物21の最小発育阻止濃度
緑膿菌PAO1野生型細胞を、96ウェルプレート内のM9最少培地中、静止状態で、広範な濃度の化合物21ジエチルアミンジアゼニウムジオレート(DEA;化合物21の合成に使用される酸化窒素供与体)、並びに/又は抗生物質セファロチン、セフタジジム及びテトラサイクリンの存在下、37℃で増殖させた。浮遊増殖を、種々の時点で、上清のOD600の直接測定によって定量化した。抗生物質処理の最小発育阻止濃度(MIC)を、20時間の増殖後に35%以下のOD600nmをもたらす抗生物質の濃度として定義した。バイオフィルム生存能力実験では、緑膿菌(P. aerugionsa)バイオフィルムを、24ウェルマイクロタイタープレート中で上述した通りに(実施例4を参照)7時間増殖させた後、指示されている最終濃度の化合物21及び抗生物質の処理を追加し、通常の培養条件下でもう1時間又は2時間インキュベートした。各時点について、浮遊細菌を収集し、滅菌リン酸緩衝生理食塩水(PBS)中で連続希釈し、LB寒天プレート上に広げた。バイオフィルムをPBSで一回優しくすすぎ、滅菌綿棒を使用して壁及び底部ウェル表面(全表面積=4.4cm2)から再懸濁した。細菌凝集体を音波破砕浴内で10分間さらに粉砕させた。次いで、バイオフィルム細菌を連続希釈し、LB寒天プレート上に広げた。37℃で1日間インキュベーション後、コロニー形成単位(CFU)を決定した。
化合物21及び抗生物質を伴う組合せ処理
バイオフィルム及び分散された細胞の生存能力に対する化合物21及び抗生物質の効果を評価するために、化合物21とセフタジジムとの組合せ処理を、マイクロタイタープレート中で増殖させたバイオフィルムに対して行い(実施例5において上述した通り)、バイオフィルムCFU及び浮遊CFUの両方を決定した。結果は、ウェル当たり1.9×108から1.3×108CFUまでのバイオフィルムCFUにおける同時減少、及び化合物21 100μM単独での1時間の処理後、ウェル当たり4.8×108から11×108CFUまでの浮遊CFUにおける増大を実証しており(図11A及び11Bを参照)、これは以前に取得されたOD及びCV測定値と一致する(実施例4;図4を参照)。さらに、バイオフィルム及び浮遊細菌の両方に対する10μMセフタジジムの効能は、化合物21の存在下で1時間インキュベートした場合に、セフタジジム単独で処理されたバイオフィルム及び浮遊細菌と比較して増大した(図8A及び8B)。バイオフィルム細菌に対するセフタジジムの効能も、化合物21の存在下、2時間の処理後、化合物21なしで処理されたバイオフィルムと比較して2.3倍増大した(図11C)。
Claims (18)
- R1が、セファロスポリン系抗生物質の7-NHC(O)-基に結合した置換基に対応する置換基であるか;又は
R1がY-アリール又はY-ヘテロアリールであり、ここで、Yは、1から4個の間の炭素原子を有する二価の炭化水素である、
請求項1又は2に記載の化合物。 - R2及びR3が、水素、C3〜C7シクロアルキル、C3〜C7シクロアルケニル、(CH2)pOC(O)PhOC(O)C1〜C6アルキル、(CH2)pOC(O)APhC1〜C6アルキル、分枝鎖又は直鎖C1〜C20アルキル、分枝鎖又は直鎖C2〜C20アルケニル、分枝鎖又は直鎖C2〜C20アルキニルから独立に選択され、前記アルキル、アルケニル又はアルキニル鎖は、O、S、NH、NH2 +から選択される1以上の基/ヘテロ原子によって場合により中断されていてよく、前記アルキル、アルケニル又はアルキニル基は、ハロゲン、シアノ、COOH、(CH2)pC(O)OC1〜C6アルキル、C(O)OC1〜C6アルケニル、SO3H、SO2ハロゲン、SO2NH2、NH2、NH3 +、OH、SH、OC1〜C6アルキル、OC2〜C6アルケニル、OC2〜C6アルキニル、アリール及びヘテロアリールからなる群から選択される1以上の置換基によって場合により置換されていてよく、或いはR2及びR3は、それらが結合した窒素と一緒になって、1、2、3、4、5又は6個の追加の窒素原子を場合により含有してよく、飽和、不飽和又は部分不飽和であってよい4、5、6、7又は8員環を形成し、前記4、5、6、7又は8員環は、-C(O)C1〜C3アルキレン-ナフチル-OC1〜C6アルキル、-C(O)C1〜C3アルキレン-Ph-C(O)-Ph、-C(O)CH2O(CH2)pOCH3、-C(O)OPhNO2、-C(O)OPhNH2、-C(O)O(CH2)pCハロゲン3、-C(O)O(CH2O)pCH3、C1〜C6-アルキル、C2〜C6アルケニル、C2〜C6アルキニル、-C(O)C1〜C6アルキレンCOOC1〜C6アルキル、-C(O)C1〜C3アルキレンPhC1〜C6アルキル、-C(O)O-ピロリジニル-2,5-ジオン、-C(O)C1〜C3アルキレンPhC1〜C6アルキル、-C(O)(CH2)pOC1〜C6アルキル、-C(O)O(CH2)pハロゲン、-C(O)O(CH2)pPh、-(CH2)pSH、-SO2ナフチル-NC1〜C6アルキル、-C(O)ONC1〜C6アルキル、-(CH2)pOH、-C(O)PhOAc、-C(O)(CH2)pNHC(O)C1〜C6アルキル、-C(O)NH2、-C(O)M、-C(O)NR4R5、-(CH2)pCH(OH)CHOH、ハロゲン、シアノ、-COOH、-C(O)O(CH2)pPh、-C(O)OC1〜C6アルキル、-C(O)OC2〜C6アルケニル、-C(O)OC2〜C6アルキニル、-C(O)SC1〜C6アルキル、-C(O)SC2〜C6アルケニル、-C(O)SC2〜C6アルキニル、-C(O)C1〜C6アルキル、SO3H、SO2ハロゲン、SO2フェニル、SO2NH2、SO2NR4R5、SO2PhNHCOC1〜C6アルキル、NH2、OH、SH、OC1〜C6アルキル、OC2〜C6アルケニル、OC2〜C6アルキニル、アリール及びヘテロアリールからなる群から選択される1以上の置換基によって場合により置換されていてよく、ここで、Aは、1から4個の間の炭素原子を有する二価の炭化水素基であり、pは、0から4の間の数字であり、R4及びR5は、独立に、C1〜C6アルキルを表し、Mは、ピリジル、ピリミジニル、ピラジニル、フェニル又はトリアジニルであるか;或いは
R2及びR3が、水素、C5〜C7シクロアルキル、(CH2)pOC(O)PhOC(O)C1〜C6アルキル、(CH2)pOC(O)APhC1〜C6アルキル、分枝鎖又は直鎖C1〜C10アルキル、分枝鎖又は直鎖C2〜C10アルケニル及び分枝鎖又は直鎖C2〜C10アルキニルから独立に選択され、前記アルキル、アルケニル又はアルキニル鎖は、O、S、NH及びNH2 +から選択される1から3個の間の基/ヘテロ原子によって場合により中断されていてよく、前記アルキル、アルケニル又はアルキニル鎖は、ハロゲン、フェニル、エトキシ、メトキシ、プロポキシ、COOH、(CH2)pCOOC1〜C4アルキル、NH2、NH3 +、OH及びSHからなる群から選択される1から6個の間の置換基によって場合により置換されていてよく、ここで、Aは、1又は2個の炭素原子を有する二価の炭化水素基であり、pは、0、1又は2であるか;或いは
R2及びR3が、水素、C5〜C7シクロアルキル、分枝鎖又は直鎖C1〜C10アルキル、分枝鎖又は直鎖C2〜C10アルケニル、分枝鎖又は直鎖C2〜C10アルキニルから独立に選択され、前記アルキル、アルケニル又はアルキニル鎖は、O、NH及びNH2 +から選択される1から3個の間の基によって場合により中断されていてよく、前記アルキル、アルケニル又はアルキニル鎖は、ハロゲン、フェニル、メトキシ、COOH、CH2COOC1〜C4アルキル、NH2及びNH3 +からなる群から選択される1から4個の間の置換基によって場合により置換されていてよいか;或いは
R2及びR3が、水素、シクロヘキシル、分枝鎖若しくは直鎖C1〜C10アルキル又は分枝鎖若しくは直鎖C2〜C10アルケニルから独立に選択され、前記アルキル又はアルケニル鎖は、NH及びNH2 +から選択される1又は2個の基によって場合により中断されていてよく、前記アルキル、アルケニル又はアルキニル鎖は、フェニル、メトキシ、COOH、NH2及びNH3 +からなる群から選択される1から3個の間の置換基によって場合により置換されていてよいか;或いは
R2及びR3が、それらが結合した窒素と一緒になって、1、2、3、4又は5個の追加の窒素原子を場合により含有してよく、飽和、不飽和又は部分不飽和であってよい4、5、6又は7員環を形成し、前記4、5、6又は7員環は、SO2NMe2、SO3H、SO2ハロゲン、SO2NH2、-C(O)O(CH2)pPh、-C(O)Me、-C(O)ピリジル、-(CH2)pOH、-C(O)NH2、-COOH、-C(O)NMe2、-C(O)NEt2、フェニル、ナフチル、ピリジニル、ピリミジニル、ピラジニル、トリアジニル、ピロリジニル、イミダゾリル、C1〜C6-アルキル、C2〜C6アルケニル、C2〜C6アルキニル、-C(O)OC1〜C6アルキル、-C(O)OC2〜C6アルケニル、-C(O)OC2〜C6アルキニル、-C(O)O(CH2)pPh、-(CH2)pSH、ハロゲン、SO2PhNHCOC1〜C6アルキル、NH2、SH、OC1〜C6アルキルからなる群から選択される1以上の置換基によって場合により置換されていてよく、ここで、pは0から2の間の数字であるか;或いは
R2及びR3が、それらが結合した窒素と一緒になって、1、2又は3個の追加の窒素原子を場合により含有してよく、飽和、不飽和又は部分不飽和であってよい5、6又は7員環を形成し、前記5、6又は7員環は、SO2NMe2、SO2NH2、-COO(CH2)pPh-C(O)Me、-C(O)ピリジル、-(CH2)pOH、-C(O)NH2、-COOH、-C(O)NMe2、-C(O)NEt2、フェニル、ピリジニル、ピリミジニル、ピラジニル、トリアジニル、ピロリジニル、イミダゾリル、C1〜C6-アルキル、C2〜C6アルケニル、C2〜C6アルキニル、-C(O)OC1〜C6アルキル、-C(O)OC2〜C6アルケニル、-C(O)OC2〜C6アルキニル、-C(O)O(CH2)pPh、-(CH2)pSH、ハロゲン、NH2、SH、OC1〜C6アルキルからなる群から選択される1から4個の間の置換基によって場合により置換されていてよく、pは、0から2の間の数字であるか;或いは
R2及びR3が、それらが結合した窒素と一緒になって、1、2又は3個の追加の窒素原子を場合により含有してよい飽和5、6又は7員環を形成し、前記5、6又は7員環は、SO2NMe2、SO2NH2、-C(O)Me、-C(O)ピリジル、-(CH2)pOH、-C(O)NH2、-COOH、-C(O)NMe2、-C(O)NEt2、フェニル、ピリジニル、ピリミジニル、ピラジニル、トリアジニル、ピロリジニル、イミダゾリル、C1〜C6-アルキル、C2〜C6アルケニル、-C(O)OC1〜C6アルキル、-C(O)OC2〜C6アルケニル、ハロゲン、NH2、SH、OC1〜C6アルキルからなる群から選択される1から3個の間の置換基によって場合により置換されていてよく、pは、0から2の間の数字であるか;或いは
R2及びR3が、それらが結合した窒素と一緒になって、
R2及びR3が、C1〜C10アルキルから独立に選択されるか、或いはR2及びR3が、それらが結合した窒素と一緒になって、1から3個の間の追加の窒素原子を場合により含有してよく、アリール又はヘテロアリール基で場合により置換されていてよい5又は6員環を形成するか;或いは
R2及びR3が、C1〜C6アルキルから独立に選択されるか、或いはR2及びR3が、それらが結合した窒素と一緒になって、1個の追加の窒素原子を場合により含有してよく、ピリミジニル及びフェニルからなる群から選択される置換基で場合により置換されていてよい飽和5又は6員環を形成するか;或いは
R2及びR3が、C1〜C6アルキルから独立に選択されるか、或いはR2及びR3が、それらが結合した窒素と一緒になって、
- 前記R2及び/又はR3置換基を介して結合した抗生物質化合物をさらに含む、請求項1から5のいずれか一項に記載の化合物。
- 前記抗生物質が、シプロフロキサシン又はN-デスメチルレボフロキサシンである、請求項6に記載の化合物。
- バイオフィルムからの微生物の分散を促進するため;又はバイオフィルムの形成及び/若しくは発達を阻害するため;又はバイオフィルムを形成することができる微生物によって感染症が引き起こされている対象において、バイオフィルム関連感染症、疾患又は障害を治療する又は予防するための組成物の製造のための、請求項1から7のいずれか一項に記載の化合物の使用。
- 前記化合物又は組成物が、バイオフィルム形成を受けやすい表面又は界面にコーティングされ、含浸され、又は接触している、請求項8に記載の使用。
- 前記表面が、埋め込み型医療デバイス、装具又は医療若しくは手術用機器の表面である、請求項9に記載の使用。
- 前記バイオフィルム形成微生物がβ-ラクタマーゼ又はトランスペプチダーゼを発現する、請求項8から10のいずれか一項に記載の使用。
- 前記β-ラクタマーゼがペニシリナーゼである、請求項11に記載の使用。
- 前記バイオフィルム又はバイオフィルム形成微生物が、前記化合物又は組成物への暴露の前に又はそれと同時にβ-ラクタム抗生物質に暴露される、請求項8に記載の使用。
- 前記バイオフィルムが、対象の体表面上、前記対象の内部又は外部において形成され、前記バイオフィルム又はバイオフィルム形成微生物の前記化合物又は組成物への暴露が、前記対象への前記化合物又は組成物の投与を介するものである、請求項8から13のいずれか一項に記載の使用。
- バイオフィルムからの微生物の分散を促進するステップ、又はバイオフィルムの形成を防止するステップが、分散につながるバイオフィルム内の微生物における分化事象を誘導するステップを含む、又はバイオフィルム形成につながる微生物における分化事象の誘導を防止するステップを含むか;或いは、バイオフィルムからの微生物の分散を促進するステップ、又はバイオフィルムの形成を防止するステップが、抗菌剤に対する微生物の感受性を増大させるステップを含む、請求項8から14のいずれか一項に記載の使用。
- 前記バイオフィルム又はバイオフィルム形成微生物が、有効量の前記化合物又は組成物に暴露され、それにより、放出され、故に前記バイオフィルム又は微生物に暴露される酸化窒素供与体又は酸化窒素の濃度は、前記バイオフィルム又は微生物が存在する環境又は対象に対して非毒性である、請求項8から15のいずれか一項に記載の使用。
- 前記バイオフィルムが、対象の体表又は体内にあり、前記対象が罹患している疾患又は障害に関連する、請求項8から16のいずれか一項に記載の使用。
- 前記疾患又は障害が、嚢胞性線維症、細菌性心内膜炎、中耳炎、在郷軍人病、結核及び腎臓結石からなる群から選択される、請求項17に記載の使用。
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AU2011901872 | 2011-05-16 | ||
AU2011901872A AU2011901872A0 (en) | 2011-05-16 | Regulation of nitric oxide release and biofilm development | |
PCT/AU2012/000542 WO2012155203A1 (en) | 2011-05-16 | 2012-05-16 | Regulation of nitric oxide release and biofilm development |
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WO2016010988A1 (en) * | 2014-07-14 | 2016-01-21 | Novan, Inc. | Nitric oxide releasing nail coating compositions, nitric oxide releasing nail coatings, and methods of using the same |
US10849864B2 (en) | 2015-07-28 | 2020-12-01 | Novan, Inc. | Combinations and methods for the treatment and/or prevention of fungal infections |
US11541105B2 (en) | 2018-06-01 | 2023-01-03 | The Research Foundation For The State University Of New York | Compositions and methods for disrupting biofilm formation and maintenance |
CN113383019B (zh) * | 2018-12-28 | 2023-11-17 | 北卡罗来纳大学教堂山分校 | 一氧化氮释放型抗菌聚合物和由其制成的支架和其相关方法 |
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WO2006125262A1 (en) * | 2005-05-24 | 2006-11-30 | Environmental Biotechnology Crc Pty Limited | Methods and compositions for regulating biofilm development |
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WO2009124379A1 (en) * | 2008-04-09 | 2009-10-15 | Enox Biopharma, Inc. | Biofilm-inhibiting catheters and tubings |
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BR112013029485B1 (pt) | 2020-11-24 |
EP2710016A4 (en) | 2014-10-15 |
KR20140061318A (ko) | 2014-05-21 |
WO2012155203A1 (en) | 2012-11-22 |
CA2835642C (en) | 2021-01-05 |
KR101980285B1 (ko) | 2019-05-20 |
JP2014513700A (ja) | 2014-06-05 |
CN105820176A (zh) | 2016-08-03 |
BR112013029485A2 (pt) | 2016-08-30 |
AU2012255694B2 (en) | 2015-09-17 |
US9156855B2 (en) | 2015-10-13 |
CN103649098B (zh) | 2017-04-19 |
US20140221331A1 (en) | 2014-08-07 |
AU2012255694A1 (en) | 2013-05-02 |
EP2710016B1 (en) | 2016-04-27 |
CA2835642A1 (en) | 2012-11-22 |
IL229422A0 (en) | 2014-01-30 |
EP2710016A1 (en) | 2014-03-26 |
IL229422A (en) | 2015-05-31 |
CN103649098A (zh) | 2014-03-19 |
US20160009733A1 (en) | 2016-01-14 |
DK2710016T3 (en) | 2016-08-15 |
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