CN105111198B - 硝基异噁唑拼接2-吡咯烷酮类化合物及其制备方法及应用 - Google Patents

硝基异噁唑拼接2-吡咯烷酮类化合物及其制备方法及应用 Download PDF

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CN105111198B
CN105111198B CN201510473644.7A CN201510473644A CN105111198B CN 105111198 B CN105111198 B CN 105111198B CN 201510473644 A CN201510473644 A CN 201510473644A CN 105111198 B CN105111198 B CN 105111198B
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isoxazole
nitro
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pyrrolidone
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刘雄利
景德红
钱余欣
陆毅
黄俊飞
姚震
陈智勇
杨超
周英
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Guizhou University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract

本发明公开了一种硝基异噁唑拼接2‑吡咯烷酮类化合物，本发明以不同取代的3‑(2‑丙烯酸酯)‑3ˊ‑硝基异噁唑氧化吲哚化合物和烷基胺类化合物按摩尔比为3:4的比例在有机溶剂中进行Michael加成‑缩合‑开环反应，获得硝基异噁唑拼接吡咯烷酮化合物，该类骨架包含潜在的生物活性含异噁唑类基团和2‑吡咯烷酮类基团，是一类重要的医药中间体类似物和药物分子类似物，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值，本发明针对这些衍生物对对革兰氏阴性菌大肠杆菌（ATCC25835）和革兰氏阳性细菌金黄色葡萄球菌（MTCC96）体外抗菌活性筛选，证明这些衍生物发现具有一定的抗菌活性，可预期作为抗菌药物用途。

Description

硝基异噁唑拼接2-吡咯烷酮类化合物及其制备方法及应用
技术领域
本发明涉及化学技术领域，尤其是一种异噁唑拼接2-吡咯烷酮类化合物及其制备方法及应用。
背景技术
把具有生物活性的天然产物骨架拼接到一个分子中在有机化学和医药化学中是极其重要的研究领域。（1）2-吡咯烷酮是一类重要的杂环化合物，很多天然产物含有2-吡咯烷酮骨架。由于其在农药及医药等各方面的应用，引起来了人们的普遍关注，例如: 天然产物Methyl pyroglutamate, Clausenamide, Chimonamidine, Donaxaridine等具有抗肿瘤和抗菌等生物活性。（2）异噁唑基团也普遍存在天然产物和药物分子中。例如: 治疗全身感染的磺胺异噁唑以及低毒除草剂异噁唑草酮等属于异噁唑类药物，这些化合物在解除病痛、经济发展中起着重大作用。鉴于2-吡咯烷酮骨架化合物具有潜在的生物活性，异噁唑基团属于潜在的生物活性官能团。因此，把异噁唑基团拼接到2-吡咯烷酮骨架上，合成一系列新的潜在多活性官能团的异噁唑拼接2-吡咯烷酮化合物，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值。
发明内容
本发明的目的是：提供一种硝基异噁唑拼接2-吡咯烷酮类化合物及其制备方法与应用，它是一类重要的医药中间体类似物和药物分子类似物，对药物筛选和制药行业具有重要的应用价值，且其合成方法非常经济简便。
本发明是这样实现的：硝基异噁唑拼接2-吡咯烷酮类化合物，该化合物具有如下通式（Ⅰ）的结构：
式中，R1为烷基；R2为烷基；R3，R4为烷基或卤素；R5为烷基。
硝基异噁唑拼接2-吡咯烷酮类化合物的制备方法，由相应的3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物和烷基胺类化合物按摩尔比为2: 3的比例在有机溶剂中进行Michael加成-缩合-开环反应，获得硝基异噁唑拼接2-吡咯烷酮化合物。
所述的有机溶剂为乙腈、甲醇、乙醇、丙醇、异丙醇、乙醚、四氢呋喃、苯、甲苯、二甲苯、三甲苯、二氧六环、乙二醇二甲醚、异丙醚、氯仿、二氯甲烷或硝基苯。
3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物和烷基胺类化合物反应温度为25-100℃，反应时间为1-48小时。
硝基异噁唑拼接2-吡咯烷酮类化合物在制备抗菌药物中的应用。
本发明的反应原理如下：
其中R1,R2, R3, R4, R5如上所述。
通过采用上述技术方案，以不同取代的3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物和烷基胺类化合物，在有机溶剂中进行Michael加成-缩合-开环反应，获得硝基异噁唑拼接2-吡咯烷酮类化合物，该类骨架包含潜在的生物活性异噁唑基团和2-吡咯烷酮骨架，可以为生物活性筛选提供化合物源，对药物的筛选和制药行业具有重要的应用价值。本发明操作简单易行，原料合成便宜易得（注明：其中原料3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物的合成采用申请人在线申请的专利，申请号为201510049705.7），可以在各种有机溶剂中进行，也具有较好的空气稳定性，适用性广，对于各种取代基都有很好的兼容性。
附图说明
附图1及附图2为本发明的实施例1的化合物1的核磁谱图数据；
附图3及附图4为本发明的实施例1的化合物2的核磁谱图数据；
附图5及附图6为本发明的实施例1的化合物3的核磁谱图数据;
附图7为本发明的反应原理图。
具体实施方式
本发明的实施例1：硝基异噁唑拼接2-吡咯烷酮类化合物的制备，在圆底烧瓶中，先加入10毫升有机溶剂乙醇，再依次加入3-(2-丙烯酸乙酯)-3-硝基异噁唑-N-甲基氧化吲哚1.0 mmol (385 mg）和苄胺1.5 mmol（161 mg），室温搅拌反应24小时，TLC检测反应完全后，反应液直接硅胶柱层析（300-400目）分离（石油醚：乙酸乙酯=10：1），得到黄色固体403毫克, 即化合物1。产率82%, 核磁共振和高分辨质谱测试等结果如下：Yellow oil, dr:20:1, yield 82%; 1H NMR (CDCl3, 400 MHz) δ: 1.29 (t, J = 11.4 Hz, 3H), 2.38(s, 3H), 2.60-2.64 (m, 1H), 2.84-2.88 (m, 1H), 3.11 (s, 3H), 3.37-3.40 (m,1H), 3.58 (s, 2H), 3.72 (d, J = 11.7 Hz, 1H), 4.08 (d, J = 11.7 Hz, 1H),4.18-4.24 (m, 1H), 4.25-4.32 (m, 1H), 6.73 (d, J = 2.6 Hz, 1H), 6.98 (t, J =12.1 Hz, 1H), 7.13 (d, J = 5.9 Hz, 2H), 7.18-7.27 (m, 4H), 7.49 (d, J = 6 Hz,1H); 13C NMR (CDCl3, 100 MHz) δ: 11.6, 14.1, 26.5, 32.5, 47.4, 51.0, 51.8,53.2, 61.2, 108.1, 122.6, 125.3, 126.9, 127.1, 128.0, 128.2, 129.1, 139.6,143.6, 155.1, 169.7, 172.0, 176.0; HRMS (ESI-TOF) m/z: Calcd. forC26H28N4NaO6 [M+Na]+: 515.1907; Found: 515.1913.
化合物2-16的制备方法同化合物1，投料比与化合物1相同，可得到化合物2-16，反应产率和反应非对映选择性见表1，但需强调的是本发明的化合物不限于表1所表示的内容。
本实施例制备化合物2: Yellow oil, dr: 25:1, yield 84%; 1H NMR (CDCl3,400 MHz) δ: 1.31 (t, J = 14.4 Hz, 3H), 2.28 (s, 3H), 2.38 (s, 3H), 2.57-2.61(m, 1H), 2.81-2.86 (m, 1H), 3.09 (s, 3H), 3.33-3.37 (m, 1H), 3.58 (s, 2H),3.71 (d, J = 14.8Hz, 1H), 4.02 (d, J = 14.8 Hz, 1H), 4.20-4.32 (m, 2H), 6.61(d, J = 8Hz, 1H), 7.03-7.05 (m, 1H), 7.12 (d, J = 6.8 Hz, 2H), 7.17-7.26 (m,3H), 7.31 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 11.4, 14.1, 21.1, 26.5, 32.6,47.5, 51.0, 51.8, 53.3, 61.1, 107.9, 126.1, 126.8, 127.2, 127.9, 128.2,129.3, 132.1, 139.9, 141.2, 155.0, 169.8, 172.2, 176.5; HRMS (ESI-TOF) m/z:Calcd. for C27H30N4NaO6 [M+Na]+: 529.2063; Found: 529.2060.
本实施例制备化合物3: Yellow oil, dr: 19:1, yield 88%; 1H NMR (CDCl3,400 MHz) δ: 1.33 (t, J = 14.8 Hz, 3H), 2.42 (s, 3H), 2.50-2.58 (m, 1H), 2.81-2.86 (m, 1H), 3.05 (s, 3H), 3.38 (t, J = 14.8 Hz, 1H), 3.49-3.58 (m, 2H),3.76 (t, J = 17.6 Hz, 1H), 3.97 (d, J = 14.4 Hz, 1H), 4.22-4.35 (m, 2H),6.66-6.69 (m, 1H), 6.95-7.00 (m, 1H), 7.10 (t, J = 8.4 Hz, 2H), 7.20-7.27 (m,3H), 7.40-7.42 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ: 11.5, 14.2, 26.6, 32.5,47.7, 50.6, 52.1, 53.3, 61.4, 108.6 (d, J CF = 8.0 Hz), 108.6 (d, J CF = 8.0Hz), 114.0 (d, J CF = 26.0 Hz), 115.4 (d, J CF = 24.0 Hz), 126.9, 128.0, 128.2,128.90, 129.0, 139.5, 139.8, 155.2, 158.8 (d, J CF = 240.0 Hz), 169.3, 172.0,176.4; HRMS (ESI-TOF) m/z: Calcd. for C26H27FN4NaO6 [M+Na]+: 533.1812; Found:533.1815.
本实施例制备化合物4: Yellow oil, dr: 25:1, yield 80%; 1H NMR (CDCl3,400 MHz) δ: 1.33 (t, J = 11.6 Hz, 3H), 2.44 (s, 3H), 2.56-2.60 (m, 1H), 2.84-2.88 (m, 1H), 3.06 (s, 3H), 3.38 (t, J = 11.6 Hz, 1H), 3.46-3.58 (m, 2H),3.76 (d, J = 12 Hz, 1H), 3.92 (d, J = 12 Hz, 1H), 4.21-4.27 (m, 1H), 4.30-4.35 (m, 1H), 6.68 (d, J = 6.8 Hz, 1H), 7.09 (d, J = 5.2 Hz, 2H), 7.19-7.21(m, 1H), 7.24-7.27 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ: 11.5, 14.2, 26.6,32.5, 47.6, 50.5, 51.9, 53.2, 61.4, 109.1, 126.2, 127.0, 127.9, 128.0, 128.3,129.1, 129.2, 142.5, 155.3, 169.2, 172.0, 176.3; HRMS (ESI-TOF) m/z: Calcd.for C26H27ClN4NaO6 [M+Na]+: 549.1517; Found: 549.1519.
本实施例制备化合物5: Yellow solid, dr: 16:1, yield 80%; mp: 117.1-117.6oC; 1H NMR (CDCl3, 400 MHz) δ: 1.30 (t, J = 11.2 Hz, 3H), 2.43 (s, 3H),2.58-2.62 (m, 1H), 3.36 (t, J = 11.6 Hz, 1H), 3.46 (s, 3H), 3.49-3.60 (m,3H), 3.75 (d, J = 12 Hz, 1H), 3.98 (d, J = 11.6 Hz, 1H), 4.18-4.32 (m, 2H),6.90 (t, J = 12.8 Hz, 1H), 7.11 (d, J = 5.6 Hz, 2H), 7.18-7.22 (m, 2H), 7.25-7.28 (m, 2H), 7.47 (d, J = 6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 11.5, 14.2,30.0, 32.6, 47.6, 51.1, 51.4, 53.4, 61.3, 115.5, 123.2, 123.9, 126.9, 127.6,128.0, 128.3, 128.8, 130.2, 131.4, 139.6, 155.2, 169.3, 171.9, 177.1; HRMS(ESI-TOF) m/z: Calcd. for C26H27ClN4NaO6 [M+Na]+: 549.1517; Found: 549.1517.
本实施例制备化合物6: Yellow oil, dr: >25:1, yield 84%; 1H NMR (CDCl3,400 MHz) δ: 2.38 (s, 3H), 2.60-2.63 (m, 1H), 2.83-2.87 (m, 1H), 3.11 (s, 3H),3.41 (t, J = 11.2 Hz, 1H), 3.59 (s, 2H), 3.70 (d, J = 11.6 Hz, 1H), 3.96 (s,3H), 4.06 (d, J = 11.6 Hz, 1H), 6.74 (d, J = 6.4 Hz, 1H), 6.99 (t, J = 12 Hz,1H), 7.14 (d, J = 5.6 Hz , 2H), 7.21-7.27 (m, 4H), 7.48 (d, J = 6 Hz ,1H); 13CNMR (CDCl3, 100 MHz) δ: 11.5, 26.5, 32.5, 47.3, 50.7, 51.9, 52.3, 53.2,108.3, 122.7, 125.3, 127.0, 127.1, 128.1, 128.3, 129.3, 143.6, 155.1, 169.6,172.5, 176.6; HRMS (ESI-TOF) m/z: Calcd. for C25H26N4NaO6 [M+Na]+: 501.1750;Found: 501.1753.
本实施例制备化合物7: Yellow oil, dr: 16:1, yield 79%; 1H NMR (CDCl3,400 MHz) δ: 2.43 (s, 3H), 2.53-2.57 (m, 1H), 2.80-2.84 (m, 1H), 3. 07 (s,3H), 3.40-3.44 (m, 1H), 3.49-3.57 (m, 2H), 3.74 (d, J = 11.6 Hz, 1H), 3.83(s, 3H), 3.94 (d, J = 11.6 Hz, 1H), 6.67-6.69 (m, 1H), 6.96-6.70 (m, 1H),7.09 (d, J = 5.6 Hz, 2H), 7.18-7.27 (m, 3H), 7.40-7.42 (m, 1H); 13C NMR(CDCl3, 100 MHz) δ: 11.5, 26.6, 32.4, 47.6, 50.4, 52.1, 52.3, 53.2, 108.7 (d,J CF = 6.5 Hz), 114.0 (d, J CF = 20.4 Hz), 115.5 (d, J CF = 18.7 Hz), 127.0,127.9, 128.0, 128.3, 128.9, 139.3, 139.8, 155.2, 158.8 (d, J CF = 192.1 Hz),169.2, 172.6, 176.3; HRMS (ESI-TOF) m/z: Calcd. for C25H25FN4NaO6 [M+Na]+:519.1656; Found: 519.1656.
本实施例制备化合物8: Yellow solid, dr: >25:1, yield 83%; mp: 75.6-76.0oC; 1H NMR (CDCl3, 400 MHz) δ: 2.28 (s, 3H), 2.39 (s, 3H), 2.56-2.60 (m,1H), 2.80-2.84 (m, 1H), 3.08 (s, 3H), 3.37-3.40 (m, 1H), 3.57 (s, 2H), 3.70(d, J = 11.6 Hz, 1H), 3.81 (s, 3H), 4.00 (d, J = 11.6 Hz, 1H), 6.62 (d, J =6.4 Hz, 1H),7.04-7.05 (m, 1H), 7.12 (t, J = 6.8 Hz, 2H), 7.20-7.26 (m, 3H),7.31 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ: 11.5, 21.1, 26.5, 32.9, 47.6, 50.6,51.9, 52.1, 53.2, 108.0, 126.1, 126.9, 127.1, 127.8, 128.0, 128.2, 129.4,132.2, 139.6, 141.2, 155.0, 169.7, 172.7, 176.4; HRMS (ESI-TOF) m/z: Calcd.for C26H28N4NaO6 [M+Na]+: 515.1907; Found: 515.1908.
本实施例制备化合物9: Yellow oil, dr: 20:1, yield 82%; 1H NMR (CDCl3,400 MHz) δ: 1.27 (t, J = 14.4 Hz, 3H), 2.38 (s, 3H), 2.60-2.65 (m, 1H), 2.82-2.87 (m, 1H), 3.39-3.42 (m, 1H), 3.52-3.60 (m, 2H), 3.82 (d, J = 14.8 Hz,1H), 4.12 (d, J = 14.8 Hz, 1H), 4.18-4.30 (m, 2H), 4.80 (d, J = 3.2 Hz, 2H),6.62 (d, J = 7.6 Hz, 1H), 6.93-6.97 (m, 1H), 7.12-7.15 (m, 3H), 7.20-7.29 (m,8H), 7.47-7.49 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ: 11.5, 14.1, 32.4, 44.5,47.2, 51.4, 51.8, 53.2, 61.2, 109.3, 122.6, 125.4, 126.9, 127.1, 127.4,127.6, 127.9, 128.3, 128.7, 129.1, 135.4, 139.7, 143.0, 155.1, 169.6, 172.0,176.7; HRMS (ESI-TOF) m/z: Calcd. for C32H32N4NaO6 [M+Na]+: 591.2220; Found:591.2224.
本实施例制备化合物10: Yellow oil, dr: >25:1, yield 79%; 1H NMR (CDCl3,400 MHz) δ: 1.28 (t, J = 14.4Hz, 3H), 2.34 (s, 3H), 2.38 (s, 3H), 2.59-2.64(m, 1H), 2.80-2.86 (m, 1H), 3.37-3.41 (m, 1H), 3.53-3.61 (m, 2H), 3.81 (d, J = 14.4 Hz, 1H), 4.07 (d, J = 14.8 Hz, 1H), 4.19-4.32 (m, 2H), 4.72-4.83 (m,2H), 6.50 (d, J = 8 Hz, 1H), 6.91-6.93 (m, 1H), 7.11-7.13 (m, 2H), 7.19-7.30(m, 9H); 13C NMR (CDCl3, 100 MHz) δ: 11.4, 14.1, 21.0, 32.5, 44.4, 47.3, 51.351.9, 53.2, 61.2, 109.1, 126.2, 126.8, 127.2, 127.4, 127.5, 127.9, 128.2,128.7, 129.3, 132.2, 135.5, 139.8, 140.5, 155.1, 169.6, 172.1, 176.5; HRMS(ESI-TOF) m/z: Calcd. for C33H34N4NaO6[M+Na]+: 605.2376; Found: 605.2378.
本实施例制备化合物11: Yellow oil, dr: 20:1, yield 82%; 1H NMR (CDCl3,400 MHz) δ: 1.31 (t, J = 14 Hz, 3H), 2.43 (s, 3H), 2.56-2.60 (m, 1H), 2.80-2.85 (m, 1H), 3.42 (t, J = 14.8 Hz, 1H), 3.53 (s, 2H), 3.85 (d, J = 11.2 Hz,1H), 4.10 (d, J = 14.8 Hz, 1H), 4.20-4.34 (m, 2H), 4.69-4.81 (m, 2H), 6.51-6.56 (m, 1H), 6.83-6.88 (m, 1H), 7.01-7.10 (m, 2H), 7.20-7.30 (m, 8H), 7.38-7.41 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ: 11.5, 14.1, 32.4, 44.6, 47.5, 51.0,52.1, 53.1, 61.4, 109.9 (d, J CF = 8.0 Hz), 114.0 (d, J CF = 25.5 Hz), 115.4 (d,J CF = 23.4 Hz), 127.9, 128.3, 128.8, 135.1, 139.1, 139.5, 155.2, 158.8 (d, J CF = 240.2 Hz), 169.1, 172.0, 176.5; HRMS (ESI-TOF) m/z: Calcd. for C32H31FN4NaO6 [M+Na]+: 609.2125; Found: 609.2128.
本实施例制备化合物12: Yellow oil, dr: >25:1, yield 87%; 1H NMR (CDCl3,400 MHz) δ: 1.32 (t, J = 14 Hz, 3H), 2.44 (s, 3H), 2.54-2.59 (m, 1H), 2.80-2.85 (m, 1H), 3.40 (t, J = 14.8 Hz, 1H), 3.51 (s, 2H), 3.85-3.97 (m, 2H),4.23-4.33 (m, 2H), 4.67-4.81 (m, 2H), 6.55 (d, J = 8.4 Hz, 1H), 7.06-7.08 (m,2H), 7.11-7.14 (m, 1H), 7.19-7.31 (m, 8H), 7.62 (d, J = 2 Hz, 1H); 13C NMR(CDCl3, 100 MHz) δ: 11.5, 14.2, 32.4, 44.6, 47.6, 51.0, 51.9, 53.1, 61.4,110.3, 126.2, 126.9, 127.4, 127.7, 127.9, 128.0, 128.3, 128.8, 129.0, 129.2,135.0, 139.6, 141.7, 155.3, 169.1, 172.0, 176.4; HRMS (ESI-TOF) m/z: Calcd.for C32H31ClN4NaO6 [M+Na]+: 625.1830; Found: 625.1833.
本实施例制备化合物13: Yellow oil, dr: 14:1, yield 83%; 1H NMR (CDCl3,400 MHz) δ: 2.38 (s, 3H), 2.61-2.65 (m, 1H), 2.81-2.85 (m, 1H), 3.42-3.45 (m,1H), 3.52-3.60 (m, 2H), 3.77 (s, 3H), 3.81 (d, J = 12.0 Hz, 1H), 4.10 (d, J =12.0 Hz, 1H), 4.76-4.83(m, 2H), 6.63 (d, J = 6.4 Hz, 1H), 6.94-6.97 (m, 1H),7.11-7.13 (m, 3H), 7.24-7.29 (m, 8H), 7.47 (d, J = 6.0 Hz , 1H); 13C NMR(CDCl3, 100 MHz) δ: 11.5, 32.4, 44.4, 47.1, 51.1, 51.8, 52.2, 53.1, 109.4,122.7, 125.4, 127.0, 127.4, 127.5, 127.6, 127.8, 128.0, 128.3, 128.7, 129.1,135.4, 139.4, 142.9, 155.1, 169.5, 172.4, 176.6; HRMS (ESI-TOF) m/z: Calcd.for C31H30N4NaO6 [M+Na]+: 577.2063; Found: 577.2065.
本实施例制备化合物14: Yellow oil, dr: >25:1, yield 72%; 1H NMR (CDCl3,500 MHz) δ: 1.24 (t, J = 14.4 Hz, 3H), 1.51-1.56 (m, 2H), 2.30 (t, J = 14.1Hz, 2H), 2.38 (s, 7H), 2.43-2.50 (m, 1H), 2.54-2.57 (m, 1H), 2.61-2.64 (m,1H), 2.85-2.89 (m, 1H), 3.37-3.40 (m, 1H), 3.68-3.73 (m, 4H), 3.83 (d, J =14.7 Hz, 1H), 4.16-4.20 (m, 2H), 4.24-4.27 (m, 1H), 4.81 (d, J = 15.6 Hz,1H), 4.93 (d, J = 15.7 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 6.96 (t, J = 15.1Hz, 1H), 7.12-7.15 (m, 1H), 7.27 (s, 1H), 7.31 (m, 4H), 7.43 (d, J = 7.4 Hz,1H); 13C NMR (CDCl3, 125.7 MHz) δ: 11.5, 14.1, 28.4, 32.4, 44.5, 47.5, 48.1,51.3, 51.8, 53.6, 57.2, 61.3, 66.7, 109.3, 122.7, 125.3, 126.9, 127.5, 127.7,128.8, 129.2, 135.4, 142.9, 155.1, 169.5, 171.8, 176.5; HRMS (ESI-TOF) m/z:Calcd. for C32H39N5NaO7 [M+Na]+: 628.2747; Found: 628.2747.
本实施例制备化合物15: Yellow oil, dr: >25:1, yield 77%; 1H NMR (CDCl3,400 MHz) δ: 0.89 (t, J = 11.6 Hz, 3H), 1.21 (t, J = 11.2 Hz, 3H), 1.26-1.33(m, 2H), 1.50-1.56 (m, 2H), 2.38 (s, 3H), 2.64-2.67 (m, 2H), 2.83-2.85 (m,1H), 3.10-3.12 (m, 1H), 3.19 (s, 3H), 3.53-3.55 (m, 1H), 3.75 (d, J = 11.6Hz, 1H), 4.15-4.29 (m, 3H), 6.75 (d, J = 6.0 Hz, 1H), 6.98 (t, J = 12 Hz,1H), 7.23-7.28 (m, 1H), 7.40 (d, J = 6 Hz ,1H); 13C NMR (CDCl3, 100 MHz) δ:11.4, 13.7, 13.9, 20.1, 26.6, 29.9, 32.5, 46.4, 48.4, 49.3, 51.7, 61.9,108.3, 122.8, 125.0, 126.5, 129.5 130.9, 143.4, 155.1, 169.3, 171.0, 176.1;HRMS (ESI-TOF) m/z: Calcd. for C23H30N4NaO6 [M+Na]+: 481.2063; Found: 481.2067.
本实施例制备化合物16: Yellow solid, dr: >25:1, yield 76%; mp: 56.7-57.0oC; 1H NMR (CDCl3, 400 MHz) δ: 0.83 (t, J = 11.6 Hz, 3H), 1.19-1.25 (m,6H), 2.35-2.38 (m, 3H), 2.48-2.56 (m, 1H), 2.76-2.80 (m, 1H), 3.18 (s, 3H),3.32-3.35 (m 1H), 3.72 (d, J = 11.6 Hz, 1H), 3.80 (s, 3H), 4.08 (d, J = 11.6Hz, 1H), 6.75 (d, J = 6.0 Hz, 1H), 6.99 (t, J = 12 Hz, 1H), 7.14 (d, J = 5.6Hz , 2H), 7.24-7.28 (m, 1H), 7.48 (d, J = 6 Hz ,1H); 13C NMR (CDCl3, 100 MHz)δ: 11.5, 13.9, 20.2, 26.5, 31.9, 32.4, 48.0, 49.1, 51.1, 51.8, 52.1, 108.2,122.6, 125.3, 127.0, 129.1 130.9, 143.6, 155.1, 169.7, 172.7, 176.6; HRMS(ESI-TOF) m/z: Calcd. for C22H28N4NaO6 [M+Na]+: 467.1907; Found: 467.1907.
本发明的式（1）化合物具有重要的生物活性，体外对革兰氏阳性细菌金黄色葡萄球菌（MTCC96）以及革兰氏阴性菌大肠杆菌（ATCC25835）的抗菌试验表明：此类式（1）所示的结构的硝基异噁唑拼接2-吡咯烷酮类化合物对细菌具有抑制作用，有可能发展成为新的抗菌药物。
药理实施例1：化合物1-16对革兰氏阳性细菌金黄色葡萄球菌（MTCC96）的抗菌活性
体外抗菌活性实验方法：根据Dhar及其他研究者的报道，将供试样品溶解于DMSO中，得到1mg / mL的储备溶液。接种肉汤（含微生物孢子肉汤），在37±1℃下培养24h。根据麦氏标准104-105cfu/mL的范围进行调整，用平板计数法接种菌落得到个/ml微生物孢子（cfu/mL）。本实验最终确定抗菌实验的接种量为105 cfu/mL。细菌金黄色葡萄球菌实验的pH范围为 6.5±0.2。将0.2mL供试样品的溶液加入到1.8mL的接种培养液中得到第一次稀释液。取1mL第一次稀释液这与另外1毫升接种培养液混合，得到第二稀释液，以此类推，直到获得六个这样的稀释液。另外需要同时运行一组只含有接种培养液，保持相同的溶剂的对照实验。该组在孵化器BOD中，37±1℃，对B细菌金黄色葡萄球菌进行孵育。孵育24h后（细菌金黄色葡萄球菌）通过观察记录最小抑菌浓度（MIC）。青霉素被用作革兰氏阳性细菌金黄色葡萄球菌（MTCC96）的标准。
化合物1对金黄色葡萄球菌（MTCC96）的MIC为5.13 μmol/L；化合物2对金黄色葡萄球菌（MTCC96）的MIC为3.21 μmol/L；化合物3对金黄色葡萄球菌（MTCC96）的MIC为7.18 μmol/L；化合物4对金黄色葡萄球菌（MTCC96）的MIC为6.99 μmol/L；化合物5对金黄色葡萄球菌（MTCC96）的MIC为7.86 μmol/L；化合物6对金黄色葡萄球菌（MTCC96）的MIC为3.59 μmol/L；化合物7对金黄色葡萄球菌（MTCC96）的MIC为4.63 μmol/L；化合物8对金黄色葡萄球菌（MTCC96）的MIC为5.34 μmol/L；化合物9对金黄色葡萄球菌（MTCC96）的MIC为5.24 μmol/L；化合物10对金黄色葡萄球菌（MTCC96）的MIC为4.52 μmol/L；化合物13对金黄色葡萄球菌（MTCC96）的MIC为2.82 μmol/L；化合物14对金黄色葡萄球菌（MTCC96）的MIC为5.77 μmol/L; 化合物15对金黄色葡萄球菌（MTCC96）的MIC为5.39 μmol/L; 化合物16对金黄色葡萄球菌（MTCC96）的MIC为4.15 μmol/L；而阳性照青霉素对金黄色葡萄球菌（MTCC96）的MIC为1.56 μmol/L。
实验结论：革兰氏阳性细菌金黄色葡萄球菌（MTCC96）是测试化合物体外抗菌活性的有效工具和评价指标。本实验表明此类式（1）所示的硝基异噁唑拼接2-吡咯烷酮类化合物对革兰氏阳性细菌金黄色葡萄球菌（MTCC96）具有较强的抗菌活性，其中化合物2, 6, 7,10, 13和16抗菌活性MIC小于5μmol/L，已经接近阳性对照药青霉素，有可能发展成新的具有抗菌作用的药物。
药理实施例2：化合物1-16对革兰氏阴性菌大肠杆菌（ATCC25835）的抗菌活性
具体方法如药理实施例1。化合物1对大肠杆菌（ATCC25835）的MIC为25.45 μmol/L；化合物2对大肠杆菌（ATCC25835）的MIC为19.90 μmol/L；化合物5对大肠杆菌（ATCC25835）的MIC为14.57μmol/L；化合物7对大肠杆菌（ATCC25835）的MIC为21.90 μmol/L；化合物9对大肠杆菌（ATCC25835）的MIC为29.45 μmol/L；化合物14对大肠杆菌（ATCC25835）的MIC为24.52 μmol/L；而阳性照链霉素对大肠杆菌（ATCC25835）的MIC为12.10 μmol/L。
实验结论：革兰氏阴性菌大肠杆菌（ATCC25835）是测试化合物体外抗菌活性的有效工具和评价指标。本实验表明此类式（1）所示的硝基异噁唑拼接2-吡咯烷酮类化合物对革兰氏阴性菌大肠杆菌（ATCC25835）具有一定的抗菌活性。
从以上药理实施例中我们可以看出这些化合物对革兰氏阴性菌大肠杆菌（ATCC25835）和革兰氏阳性细菌金黄色葡萄球菌（MTCC96）都显示有一定的抗菌活性。其中对革兰氏阳性细菌金黄色葡萄球菌（MTCC96）的抗菌活性明显好于革兰氏阴性菌大肠杆菌（ATCC25835），其中化合物2, 6, 7, 10, 13和16对革兰氏阳性细菌金黄色葡萄球菌（MTCC96）的抗菌活性MIC小于5μmol/L，已经接近阳性对照药青霉素，有可能发展成新的具有抗菌作用的药物。可见这些化合物具有开发成为抗菌药物的潜力，值得继续深入研究下去。

Claims (5)

1.一种硝基异噁唑拼接2-吡咯烷酮类化合物，其特征在于：选自如下化合物：
2.一种如权利要求1所述的硝基异噁唑拼接2-吡咯烷酮类化合物的制备方法，其特征在于：将3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物和烷基胺类化合物按摩尔比为2:3的比例在有机溶剂中进行Michael加成-缩合-开环反应，获得硝基异噁唑拼接2-吡咯烷酮类化合物。
3.根据权利要求2所述的硝基异噁唑拼接2-吡咯烷酮类化合物的制备方法，其特征在于：所述的有机溶剂为乙腈、甲醇、乙醇、丙醇、异丙醇、乙醚、四氢呋喃、苯、甲苯、二甲苯、三甲苯、二氧六环、乙二醇二甲醚、异丙醚、氯仿、二氯甲烷或硝基苯。
4.根据权利要求2所述的硝基异噁唑拼接2-吡咯烷酮类化合物的制备方法，其特征在于：3-(2-丙烯酸酯)-3ˊ-硝基异噁唑氧化吲哚化合物和烷基胺类化合物反应温度为25-100℃，反应时间为1-48小时。
5.一种如权利要求1所述的硝基异噁唑拼接2-吡咯烷酮类化合物在制备抗菌药物中的应用。
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Inventor after: Huang Junfei

Inventor after: Yao Zhen

Inventor after: Chen Zhiyong

Inventor after: Yang Chao

Inventor after: Zhou Ying

Inventor before: Liu Xiongli

Inventor before: Jing Dehong

Inventor before: Lu Yi

Inventor before: Huang Junfei

Inventor before: Yao Zhen

Inventor before: Chen Zhiyong

Inventor before: Yang Chao

Inventor before: Zhou Ying

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